CN100415735C - Amino Alcohol Derivatives - Google Patents

Abstract

The present invention relates to the following formula (I) compound with excellent immunosuppressive activity, its pharmacologically acceptable salt, its ester or other derivatives; In the formula, R ^{and R} are each a hydrogen atom, a protecting group of amino; R ³ represents a protecting group for a hydrogen atom or a hydroxyl group; R ⁴ represents a lower alkyl group; n represents an integer of 1-6; X represents an ethylene group; Y represents a C ₁ -C ₁₀ alkylene group, substituted by 1-3 selected from A C ₁ -C ₁₀ alkylene group substituted by a group of groups a and b; R ⁵ represents an aryl group; R ⁶ and R ⁷ are each a hydrogen atom, a group selected from substituent group a; the condition is that when R ⁵ When it is a hydrogen atom, Y does not represent a single bond or a linear C ₁ -C ₁₀ alkylene group.

Description

Amino Alcohol Derivatives

This application is a divisional application, the application number of the original application is 01815340.2, the application date is July 10, 2001, and the invention name is "amino alcohol derivatives".

technical field

The present invention relates to an aminoalcohol derivative with excellent immunosuppressive effect, its pharmaceutically acceptable salt, its ester or other derivatives; a pharmaceutical composition containing said compound as an active ingredient; said compound is used for preparing the pharmaceutical composition or the method of preventing or treating autoimmune diseases and the like by administering a pharmacologically effective amount of the compound to warm-blooded animals.

The present invention also relates to novel optically active aminoalcohol compounds, especially optically active 4,4-disubstituted oxazolidin-2-one compounds, which can be used as synthetic intermediates of the aforementioned aminoalcohol derivatives and other drugs.

The present invention further relates to a novel preparation method with excellent selectivity of optically active 2-substituted-2-amino-1,3-propanediol monoester derivatives, which are important synthetic intermediates of the aforementioned optically active aminoalcohol compounds.

technical background

In the treatment of immune-related diseases such as rheumatism or other autoimmune diseases, anti-inflammatory agents such as steroids have been used for inflammatory reactions caused by abnormal immune responses. But this is a symptomatic treatment, not a fundamental treatment.

It is reported that the onset of diabetes and nephritis is also related to the abnormality of the immune system [KidneyInternational, 51, 94 (1997); Journal of Immunology, 157, 4691 (1996)], but it has not yet developed a drug for improving its abnormality.

The development of methods to suppress the immune response is also extremely important to prevent immune rejection in organ and cell transplantation, and to treat and prevent various autoimmune diseases. However, previously known immunosuppressants such as cyclosporine A (CsA) and tacrolimus (TRL) are known to be toxic to the kidneys and liver. The current situation is that there is no side effect and the degree of fully exerting the immunosuppressive effect has not been reached.

From the background described above, various attempts have been made to find compounds with low toxicity and excellent immunosuppressive effect.

Known immunosuppressants include, for example, the compounds shown below.

(1) WO 94/08943 (EP627406)

The publication discloses a compound having the following general formula (a) as an immunosuppressant,

[In the above compound (a),

R is a straight or branched carbon chain that may have substituents {the chain may have double bonds, triple bonds, oxygen, sulfur, -N(R ⁶ )- (where R ⁶ is hydrogen), and may have substituents An arylene group, a heteroarylene group that may have a substituent, and an aryl group that may have a substituent, a cycloalkyl group that may have a substituent, or a heteroaryl group that may have a substituent may have a substituent at the chain end. }, R ² , R ³ , R ⁴ , and R ⁵ are the same or different, each being hydrogen or an alkyl group. ].

The above-mentioned compound (a) of the prior art must have two oxymethyl groups (-CH ₂ OR ⁴ and -CH ₂ OR ⁵ ), and the corresponding groups of the compounds of the present invention are -CH ₂ OR ³ group and lower alkyl group, which is different from the above-mentioned compound (a).

The publication does not specifically disclose compounds similar in structure to the compound (I) of the present invention, and only the compounds shown below are disclosed even if the compound most similar in structure to the compound (I) of the present invention is selected.

Example 29

Example 293

(2) WO 96/06068

This publication discloses a compound having the following general formula (b) as an immunosuppressant,

[In the above compound (b),

R ¹ , R ² and R ³ are hydrogen atoms, etc., W is a hydrogen atom, an alkyl group, etc., Z is a single bond or an alkylene group, X is a hydrogen atom or an alkoxy group, and Y is a hydrogen atom, an alkyl group, or an alkoxy group. group, acyl group, acyloxy group, amino group, amido group, etc. ].

The phenyl group in the basic skeleton of the above-mentioned compound (b) is essential, while the corresponding group of the compound (I) of the present invention is a heterocyclic thienyl group, which is different from the above-mentioned compound (b).

The publication does not specifically disclose compounds similar in structure to the compound (I) of the present invention, and only the compounds shown below are disclosed even if the compound most similar in structure to the compound (I) of the present invention is selected.

Example 26

Example 57

Example 87

(3) WO 98/45249

The publication discloses a compound having the following general formula (c) as an immunosuppressant,

[In the above compound (c),

R ¹ , R ² , R ³ , and R ⁴ are the same or different, and each is hydrogen or acyl. ].

The substituents that the above-mentioned compound (c) must have are two oxymethyl groups (-CH ₂ OR ³ and -CH ₂ OR ⁴ ), and the corresponding groups that the compound of the present invention has are -CH ₂ OR ³ and lower alkyl , which is different from the above compound (c). In addition, the phenyl group between the -(CH ₂ ) ₂ -group and the -CO-(CH ₂ ) ₄ -group in the basic skeleton of the above-mentioned compound (c) is an essential group, while the compound (I) of the present invention has The corresponding group of is a heterocyclic thienyl group, which is different from the above-mentioned compound (c).

The above-mentioned compound (c) has a phenyl group as an essential substituent of -CO-(CH ₂ ) ₄ - at the chain end, and the corresponding group that the compound (I) of the present invention may have is a cycloalkyl group, a heterocyclic group, It is also different on this point.

The publication does not specifically disclose compounds similar in structure to the compound (I) of the present invention, and only the compounds shown below are disclosed even if the compound most similar in structure to the compound (I) of the present invention is selected.

Example 1

Example 3

On the other hand, many optically active substituted amino acids and substituted amino alcohol derivatives (especially α-substituted amino acids and α-substituted amino alcohol derivatives) are physiologically active substances, natural substances, partial constituents of drugs, Synthetic intermediates and other important compounds.

For example, α-methyl-α-vinyl amino acid as an inhibitor of amino acid decarboxylase, and α-ethynyl-α-methyl amino acid as an inhibitor of glutamic acid decarboxylase are all useful compounds. Parts of biologically active natural substances such as ISP-1 (myriocin), which is isolated from the metabolites of Isalia sinclairii with immunosuppressive effects, and Conagenin, which is known to participate in the regulation of immune responses through T cells The constituents, optically active α-substituted amino acids and aminoalcohol derivatives are also very interesting compounds in biochemistry and organic synthetic chemistry.

Since these α-substituted amino acid and amino alcohol derivatives have an asymmetric carbon atom, a method for efficiently synthesizing one enantiomer thereof is desired.

Preparation method of optically active substituted amino acid and amino alcohol derivatives and optically active 4,4-disubstituted oxazolidin-2-one compounds and the like which can be used as synthetic intermediates of drugs such as optically active substituted amino acids and amino alcohol derivatives There are very few synthetic examples of optically active aminoalcohol compounds, such as known C.Cativiela et al. Tetrahedron: Asymmetry, 9,3517 (1998) general remarks, R.M.William "Synthesis of Optically Active α-amino acid" (Pergamon The various methods outlined in Press) can be roughly divided into two categories.

The first type is the diastereoselective alkylation method using an asymmetric auxiliary group. The known representative method is the method reported by Seebach et al. in Helv.Chim.Acta., 71, 224 (1988) or as Nagao, Sano, etc. reported in Tetrahedron Lett., 36, 2097 (1995), Tetrahedron Lett., 36, 4101 (1995), the chiral bis-lactam ether carboxylate and Mg (II) and Sn ( II) is a method for synthesizing a Lewis acid into an α-substituted serine derivative through a highly diastereoselective aldol condensation reaction.

The second type is the enantioselective enzymatic method of α-substituted-α-protected aminomalonate diester reported in Chemistry Lett., 239 (1989), Chemistry Lett., 2381 (1994) by Nagao, Yujing, etc. The hydrolysis method is typically a method of synthesizing α-substituted serine derivatives by enantioselective enzymatic hydrolysis of prochiral σ-symmetric diesters.

The preparation methods belonging to the first category all have many steps and require the use of stoichiometric amounts of asymmetric sources. The second type of method, however, is limited when it has substituents that are unstable under reducing conditions due to the reduction step.

Although there are many examples of such reports, there are very few practical methods. Generally speaking, the method of optically resolving the racemate to obtain an optical isomer is a commonly used method, but it has the problem of unavoidable reduction of the total yield.

disclosure of invention

The present inventors conducted in-depth research on derivatives with immunosuppressive effect, and found that the amino alcohol derivative (I) of the present invention has low toxicity and excellent immunosuppressive effect, and can be used for systemic lupus erythematosus, rheumatoid arthritis Inflammation, polymyositis, dermatomyositis, scleroderma, Behcet's disease, Chron's disease, ulcerative colitis, autoimmune hepatitis, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia , multiple sclerosis, autoimmune bullae, psoriasis, vasculitis syndrome, Wegener's granulomatosis, uveitis, idiopathic interstitial pneumonia, Goodpasture syndrome, sarcoidosis, allergic granulomatosis vasculitis, bronchial asthma, myocarditis, cardiomyopathy, aortitis syndrome, post-myocardial infarction syndrome, primary pulmonary hypertension, minimally variable nephropathy, membranous nephropathy, membranous proliferative nephritis, renal Focal sclerosis, crescentic nephritis, myasthenia gravis, inflammatory neuropathy, atopic dermatitis, chronic actinic dermatitis, acute polyarthritis, Sydenham chorea, systemic sclerosis, adult onset diabetes mellitus, insulin Dependent diabetes, juvenile diabetes, atherosclerosis, glomerulonephritis, tubulointerstitial nephritis, primary biliary cirrhosis, primary sclerosing cholangitis, fulminant hepatitis, viral hepatitis, GVHD, immune rejection caused by various organ transplants, contact dermatitis, septicemia and other autoimmune phlegm diseases or other immune-related diseases, thus completing the present invention.

Therefore, the object of the present invention is to provide aminoalcohol derivatives, their pharmacologically acceptable salts, their esters or other derivatives with low toxicity and excellent immunosuppressive effect.

Another object of the present invention is to provide a pharmaceutical composition containing the above-mentioned amino alcohol derivative, its pharmacologically acceptable salt, its ester or other derivatives as an active ingredient; the application of the compound in the preparation of the above-mentioned pharmaceutical composition or a method for preventing or treating the above-mentioned diseases such as autoimmune diseases of warm-blooded animals by administering a pharmacologically effective amount of the compound.

In addition, the present inventors conducted intensive studies to solve the above-mentioned problems in the production methods of optically active aminoalcohol compounds and their intermediates, and as a result found that a new Optically active aminoalcohol compounds (La) and (Lb), especially optically active 4,4-disubstituted oxazolidin-2-one derivatives, and the derivatives are useful as optically active substituted amino acid and substituted aminoalcohol derivatives Intermediates for the preparation of other drugs.

The present inventors also conducted in-depth research on the selective preparation methods of the above-mentioned optically active aminoalcohol compounds (La) and (Lb), and found that as their synthetic intermediates, optically active 2-substituted-2-amino-1 is preferred, 3-propanediol monoester derivative (XLIVa) or (XLIVb), said compound (XLIVa) and (XLIVb) can be 2-substituted-2-amino-1,3-propanediol derivative (XLII) as raw material, in lipase The present invention has been accomplished easily and simply by selectively acylation of only one hydroxyl group in the presence of carboxylic acid vinyl ester derivative (XLIII) in good yield.

Right now,

(1) The amino alcohol derivative of the present invention has the following general formula (I). A compound of the following formula (I), its pharmacologically acceptable salt, its ester or other derivatives:

[in the formula

R ¹ and R ² are the same or different, and represent a protecting group for a hydrogen atom or an amino group;

R ³ represents a protecting group for a hydrogen atom or a hydroxyl group;

R ⁴ represents lower alkyl;

n represents an integer of 1-6;

X represents an ethylene group, a vinylidene group, an ethynylene group, a group having the formula -D-CH ₂ - (wherein D represents a carbonyl group, a group having the formula -CH(OH)-, an oxygen atom, a sulfur atom or Nitrogen atom), an aryl group or an aryl group substituted by 1-3 groups selected from substituent group a;

Y represents a single bond, a C ₁ -C ₁₀ alkylene group, a C ₁ -C ₁₀ alkylene group substituted by 1-3 groups selected from substituent groups a and b, having oxygen in the carbon chain or at the chain end A C ₁ -C ₁₀ alkylene group of an atom or a sulfur atom, or a C 1 group substituted by 1 to 3 groups selected from substituent groups a and b, having an oxygen atom or a sulfur atom in _the carbon chain or at the chain end -C ₁₀ alkylene;

R ⁵ represents a hydrogen atom, a cycloalkyl group, an aryl group, a heterocyclic group, a cycloalkyl group substituted by 1-3 groups selected from substituent groups a and b, and a cycloalkyl group substituted by 1-3 groups selected from substituent group a An aryl group substituted with a group of b, or a heterocyclic group substituted by 1-3 groups selected from substituent groups a and b;

R ⁶ and R ⁷ are the same or different, representing a hydrogen atom or a group selected from substituent group a,

Provided that when R ⁵ is a hydrogen atom, Y does not represent a single bond and a straight-chain C ₁ -C ₁₀ alkylene].

<Substituent group a>

Halogen atom, lower alkyl, halogenated lower alkyl, lower alkoxy, lower alkylthio, carboxyl, lower alkoxycarbonyl, hydroxyl, lower aliphatic acyl, amino, mono-lower alkylamino, di-lower alkylamino , lower aliphatic amido, cyano and nitro,

<Substituent group b>

Cycloalkyl, aryl, heterocyclyl, cycloalkyl substituted by 1-3 groups selected from substituent group a, aryl substituted by 1-3 groups selected from substituent group a, and a heterocyclic group substituted with 1 to 3 groups selected from Substituent Group a.

Among the above compounds (1), preferred compounds are exemplified as follows.

(2) The compound of formula (Ia) in (1), its pharmacologically acceptable salt, its ester or other derivatives

(3) The compound of formula (Ib) in (1), its pharmacologically acceptable salt, its ester or other derivatives

(4) ^The compound of any one of (1)-(3) or a pharmacologically acceptable salt thereof, wherein R and ^R are the same or different, and each is a hydrogen atom, a lower alkoxycarbonyl group, an aralkyloxy group Carbonyl or aralkyloxycarbonyl substituted by 1-3 groups selected from substituent group a;

(5) The compound of any one of (1)-(3), or a pharmacologically acceptable salt thereof, wherein R ¹ and R ² are hydrogen atoms;

(6) The compound of any one of (1)-(5) or a pharmacologically acceptable salt thereof, wherein R ³ is a hydrogen atom, a lower alkyl group, a lower aliphatic acyl group, an aromatic acyl group or is replaced by 1-3 An aromatic acyl group substituted by a group selected from substituent group a;

(7) The compound of any one of (1)-(5), or a pharmacologically acceptable salt thereof, wherein R ³ is a hydrogen atom;

(8) The compound of any one of (1)-(7), or a pharmacologically acceptable salt thereof, wherein R ⁴ is C ₁ -C ₄ alkyl;

(9) The compound of any one of (1)-(7), or a pharmacologically acceptable salt thereof, wherein R ⁴ is C ₁ -C ₂ alkyl;

(10) The compound of any one of (1)-(7), or a pharmacologically acceptable salt thereof, wherein R ⁴ is methyl;

(11) The compound of any one of (1)-(10), or a pharmacologically acceptable salt thereof, wherein n is 2 or 3;

(12) The compound of any one of (1)-(10), or a pharmacologically acceptable salt thereof, wherein n is 2;

(13) The compound of any one of (1)-(12) or a pharmacologically acceptable salt thereof, wherein X is ethylene, ethynylene, aryl or is replaced by 1-3 substituents selected from group a The aryl group substituted by the group;

(14) The compound of any one of (1)-(12), or a pharmacologically acceptable salt thereof, wherein X is ethylene;

(15) The compound of any one of (1)-(12), or a pharmacologically acceptable salt thereof, wherein X is an ethynylene group;

(16) The compound of any one of (1)-(12), or a pharmacologically acceptable salt thereof, wherein X is a group having the formula -D-CH ₂ -;

(17) The compound of any one of (1)-(12) or a pharmacologically acceptable salt thereof, wherein X is a group having the formula -D-CH ₂ - (wherein D represents a carbonyl group or a group having the formula -CH (OH)-group);

(18) The compound of any one of (1)-(17), or a pharmacologically acceptable salt thereof, wherein Y is a C ₁ -C ₁₀ alkylene group or is replaced by 1-3 substituents selected from substituent groups a and b A C ₁ -C ₁₀ alkylene group substituted by a group;

(19) The compound of any one of (1)-(17) or a pharmacologically acceptable salt thereof, wherein Y is a C ₁ -C ₆ alkylene group or is replaced by 1-3 substituents selected from substituent groups a and b A C ₁ -C ₆ alkylene group substituted by a group;

(20) The compound of any one of (1)-(17), or a pharmacologically acceptable salt thereof, wherein Y is ethylene, 1,3-propylene, 1,4-butylene or replaced by 1- Ethylene, 1,3-propylene or 1,4-butylene substituted by 3 groups selected from substituent groups a and b;

(21) The compound of any one of (1)-(17), or a pharmacologically acceptable salt thereof, wherein Y is ethylene, 1,3-propylene or 1,4-butylene;

(22) The compound of any one of (1)-(17), or a pharmacologically acceptable salt thereof, wherein Y is ethylene or 1,3-propylene;

(23) The compound of any one of (1)-(17), or a pharmacologically acceptable salt thereof, wherein Y is a C ₁ -C ₁₀ alkylene group having an oxygen atom or a sulfur atom in the carbon chain or at the chain end , or a C ₁ -C ₁₀ alkylene group having an oxygen atom or a sulfur atom in the carbon chain or at the chain end, substituted by 1-3 groups selected from substituent groups a and b;

(24) The compound of any one of (1)-(17), or a pharmacologically acceptable salt thereof, wherein Y is a C ₁ -C ₁₀ alkylene group having an oxygen atom or a sulfur atom in the carbon chain or at the chain end ;

(25) The compound of any one of (1)-(17), or a pharmacologically acceptable salt thereof, wherein Y is a C ₁ -C ₁₀ alkylene group having an oxygen atom in the carbon chain or at the chain end;

(26) The compound of any one of (1)-(17), or a pharmacologically acceptable salt thereof, wherein Y is a C ₁ -C ₆ alkylene group having an oxygen atom in the carbon chain or at the chain end;

(27) The compound of any one of (1)-(17), or a pharmacologically acceptable salt thereof, wherein Y is -O-CH ₂ -, -O-(CH ₂ ) ₂ -, -O-( CH ₂ ) ₃ -, -CH ₂ -O-, -(CH ₂ ) ₂ -O- or -(CH ₂ ) ₃ -O-;

(28) The compound of any one of (1)-(17), or a pharmacologically acceptable salt thereof, wherein Y is a group having -CH ₂ -O-;

(29) The compound of any one of (1)-(17), or a pharmacologically acceptable salt thereof, wherein Y is a group having -O-(CH ₂ ) ₂ - or -(CH ₂ ) ₂ -O- group;

(30) The compound of any one of (1)-(29), or a pharmacologically acceptable salt thereof, wherein R ⁵ is a hydrogen atom;

(31) The compound of any one of (1)-(29) or a pharmacologically acceptable salt thereof, wherein R ⁵ is cycloalkyl, heterocyclyl, 1-3 selected from substituent groups a and b A cycloalkyl group substituted by a group or a heterocyclic group substituted by 1-3 groups selected from substituent groups a and b;

(32) The compound of any one of (1)-(29), or a pharmacologically acceptable salt thereof, wherein ^R is cycloalkyl or is substituted by 1-3 groups selected from substituent groups a and b Cycloalkyl;

(33) The compound of any one of (1)-(29), or a pharmacologically acceptable salt thereof, wherein R ⁵ is cycloalkyl;

(34) The compound of any one of (1)-(29), or a pharmacologically acceptable salt thereof, wherein R ⁵ is cyclohexyl;

(35) The compound of any one of (1)-(29), or a pharmacologically acceptable salt thereof, wherein ^R is aryl or is substituted by 1-3 groups selected from substituent groups a and b Aryl;

(36) The compound of any one of (1)-(29) or a pharmacologically acceptable salt thereof, wherein R ⁵ is an aryl group or an aryl group substituted by 1-3 substituents (the substituents are selected from halogen atom, lower alkyl, halogenated lower alkyl, lower alkoxy, lower alkylthio and lower aliphatic acyl);

(37) The compound of any one of (1)-(29) or a pharmacologically acceptable salt thereof, wherein R ⁵ is an aryl group or an aryl group substituted by 1-3 substituents (the substituents are selected from halogen atom, lower alkyl, halogenated lower alkyl, lower alkoxy and lower aliphatic acyl);

(38) The compound of any one of (1)-(29) or a pharmacologically acceptable salt thereof, wherein R ⁵ is phenyl or phenyl substituted by 1-3 substituents (the substituents are selected from halogen atom, lower alkyl, halogenated lower alkyl, lower alkoxy and lower aliphatic acyl);

(39) The compound of any one of (1)-(29), or a pharmacologically acceptable salt thereof, wherein R is ^phenyl or phenyl substituted by 1-3 substituents (the substituents are selected from fluorine atom, chlorine atom, methyl, trifluoromethyl, methoxy and acetyl);

(40) The compound of any one of (1)-(29), or a pharmacologically acceptable salt thereof, wherein R is phenyl, ³ -fluorophenyl, 4-fluorophenyl, 3,4-difluoro Phenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-methylphenyl, 4 -Methylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,4-bis( Trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3 , 5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-acetylphenyl or 4-acetylphenyl;

(41) The compound of any one of (1)-(40), or a pharmacologically acceptable salt thereof, wherein R ⁶ and R ⁷ are the same or different, and each is a hydrogen atom, a halogen atom, a lower alkyl group, a halogenated lower Alkyl, lower alkoxy or lower alkylthio;

(42) The compound of any one of (1)-(40), or a pharmacologically acceptable salt thereof, wherein R ⁶ and R ⁷ are hydrogen atoms;

(43) Any compound selected from the following in (1), its pharmacologically acceptable salt, its ester or other derivatives:

2-Amino-2-methyl-4-[5-(6-cyclohexylhexyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(6-cyclohexylhex-1-ynyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(6-cyclohexylhexanoyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-cyclohexylbutyryl)thiophen-2-yl]butan-1-ol,

2-Amino-2-ethyl-4-[5-(6-cyclohexylhexyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-ethyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-ethyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-ethyl-4-[5-(6-cyclohexylhex-1-ynyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-ethyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-ethyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-ethyl-4-[5-(6-cyclohexylhexanoyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-ethyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-ethyl-4-[5-(4-cyclohexylbutyryl)thiophen-2-yl]butan-1-ol,

2-amino-2-methyl-4-[5-(6-phenylhexyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-phenylbutyl)thiophen-2-yl]butan-1-ol,

2-amino-2-methyl-4-[5-(6-phenylhex-1-ynyl)thiophen-2-yl]butan-1-ol,

2-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

2-amino-2-methyl-4-[5-(4-phenylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(6-phenylhexanoyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-phenylbutyryl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(5-cyclohexyloxypent-1-ynyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(3-cyclohexyloxypropynyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(5-cyclohexyloxypentyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-cyclohexyloxybutyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(3-cyclohexyloxypropyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(5-cyclohexyloxypentanoyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-cyclohexyloxybutyryl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(3-cyclohexyloxypropionyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(5-phenoxypent-1-ynyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-phenoxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(3-phenoxypropynyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(5-phenoxypentyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-phenoxybutyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(3-phenoxypropyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(5-phenoxypentanoyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-phenoxybutyryl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(3-phenoxypropionyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-benzyloxyphenyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-cyclohexylmethoxyphenyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-cyclohexylethoxyphenyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(3-cyclohexylmethoxypropynyl)thiophen-2-yl]butan-1-ol,

2-amino-2-methyl-4-[5-(3-cyclohexylmethoxypropyl)thiophen-2-yl]butan-1-ol and

2-Amino-2-methyl-4-[5-(3-cyclohexylmethoxypropionyl)thiophen-2-yl]butan-1-ol;

(44) Any compound selected from the following in (1), its pharmacologically acceptable salt, its ester or other derivatives:

2-Amino-2-methyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-cyclohexyloxybutyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-{5-[4-(4-fluorophenoxy)butyl]thiophen-2-yl}butan-1-ol,

2-Amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butyl]thiophen-2-yl}butan-1-ol,

2-Amino-2-methyl-4-[5-(4-benzyloxybutyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

2-amino-2-methyl-4-[5-(4-phenylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

2-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-{5-[5-(4-fluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

2-Amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

2-Amino-2-methyl-4-{5-[3-(4-methylcyclohexyloxy)propynyl]thiophen-2-yl}butan-1-ol,

2-Amino-2-methyl-4-{5-[3-(4-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

2-Amino-2-methyl-4-{5-[3-(4-ethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

2-Amino-2-methyl-4-{5-[3-(4-methylthiophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

2-Amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

2-amino-2-methyl-4-{5-[4-(4-methylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

2-Amino-2-methyl-4-[5-(3-cyclohexylmethoxypropynyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-phenylmethoxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-cyclohexylbutyryl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(4-phenylbutyryl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-{5-[5-(4-fluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

2-Amino-2-ethyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-ethyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-ethyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,

2-Amino-2-methyl-4-{5-[3-(4-chlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

2-Amino-2-methyl-4-{5-[3-(3-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

2-amino-2-methyl-4-{5-[3-(3,4-dimethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

2-Amino-2-methyl-4-{5-[3-(3-methoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

2-amino-2-methyl-4-{5-[3-(3,4-dimethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

2-amino-2-methyl-4-{5-[3-(3,5-dimethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

2-Amino-2-methyl-4-{5-[3-(3-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol and

2-amino-2-methyl-4-{5-[3-(4-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol.

In the above compound (I), it is also preferred to be selected from (2) or (3), (4) or (5), (6) or (7), (8)-(10), (11) or (12) ), (13)-(17), (18)-(29), (30)-(40), and any combination of (41) or (42).

(45) The optically active aminoalcohol compound of the present invention has the following general formula (La) or (Lb). Compounds represented by the formula:

[in the formula

R ¹ and R ² are the same or different, and represent a protecting group for a hydrogen atom or an amino group;

R ^3a represents a protecting group for a hydrogen atom or a hydroxyl group; or

R ¹ is a hydrogen atom, and R ² and R ^3a together represent a group of formula (-(C=O)-);

R ^4a represents C ₁ -C ₂₀ alkyl, C ₂ -C ₂₀ alkyl containing heteroatoms, C ₁ -C ₂₀ alkyl substituted by aryl or aromatic heterocyclic group, C ₂ -C ₂₀ alkynyl , C ₃ -C ₂₀ alkynyl containing heteroatoms, C ₂ -C ₂₀ alkynyl substituted by aryl or aromatic heterocyclic group, C ₂ -C ₂₀ alkenyl, C ₃ - C ₂₀ alkenyl, C ₂ -C ₂₀ alkenyl substituted by aryl or aromatic heterocyclic group, C ₂ -C ₂₀ alkyl substituted by aryl or aromatic heterocyclic group with heteroatoms or Cycloalkyl;

m represents an integer of 0-4;

Ar represents an aryl group, an aromatic heterocyclic group, an aryl group substituted by 1-5 groups selected from substituent group a, an aromatic heterocyclic group substituted by 1-5 groups selected from substituent group a base. with the proviso that when Ar is aryl, ^R1 does not represent a hydrogen atom and ^R2 and/or ^R3a do not represent a hydrogen atom. ].

<Substituent group a>

Halogen atom, lower alkyl, halogenated lower alkyl, lower alkoxy, lower alkylthio, carboxyl, lower alkoxycarbonyl, hydroxyl, lower aliphatic acyl, amino, mono-lower alkylamino, di-lower alkylamino , lower aliphatic amido, cyano and nitro.

Among the above compounds (La) or (Lb), preferred compounds are exemplified as follows.

(46) The compound of (45), which has the general formula (La);

(47) The compound of (45) or (46), wherein R ¹ is a hydrogen atom;

(48) The compound of any one of (45)-(47), wherein R ^and R ^together are a group of formula (-(C=O)-);

(49) The compound of any one of (45)-(47), wherein R ^3a is a hydrogen atom;

(50) The compound of any one of (45)-(49), wherein R4 ^a is C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkyl with heteroatoms, aryl or aromatic heterocycle C ₁ -C ₁₀ alkyl substituted by radical, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ alkynyl with heteroatoms in it, C ₂ -C ₁₀ alkynyl substituted by aryl or aromatic heterocyclic group , C ₂ -C ₁₀ alkenyl, C ₃ -C ₁₀ alkenyl with heteroatoms, C ₂ -C ₁₀ alkenyl substituted by aryl or aromatic heterocyclic group, substituted by aryl or aromatic C ₂ -C ₁₀ alkyl or C ₅ -C ₁₀ cycloalkyl with heteroatoms substituted by heterocyclyl;

(51) The compound of any one of (45)-(49), wherein R ^4a is C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkyl with heteroatoms, aryl or aromatic heterocycle C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkynyl, C ₂ -C ₁₀ alkenyl or C ₅ -C ₁₀ cycloalkyl substituted by radical;

(52) The compound of any one of (45)-(49), wherein R ^4a is C ₁ -C ₁₀ alkyl;

(53) The compound of any one of (45)-(49), wherein R ^4a is C ₁ -C ₆ alkyl;

(54) The compound of any one of (45)-(49), wherein R ^4a is methyl or ethyl;

(55) The compound of any one of (45)-(54), wherein Ar is phenyl, furyl, thienyl, benzothienyl, or is substituted by 1-4 groups selected from the above substituent group a phenyl, furyl, thienyl or benzothienyl;

(56) The compound of any one of (45)-(54), wherein Ar is thienyl or thienyl substituted with 1-4 groups selected from the above-mentioned substituent group a;

(57) The compound of any one of (45)-(54), wherein Ar is benzothienyl or benzothienyl substituted with 1 to 4 groups selected from the substituent group a above;

(58) The compound of any one of (45)-(57), wherein m is 0;

(59) The compound of any one of (45)-(57), wherein the substituent group a is a halogen atom, a hydroxyl group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a carboxyl group, a lower aliphatic acyl group, Lower aliphatic amido, amino, cyano and nitro.

(60) In addition, the present invention relates to a preparation method of a compound having the following general formula (XLIVa) or (XLIVb), that is, 2-substituted-2-amino-1,3- Propylene Glycol Monoester Derivatives

[in the formula

R ¹ and R ² are the same or different, and represent a protecting group for a hydrogen atom or an amino group;

R ^4a represents C ₁ -C ₂₀ alkyl, C ₂ -C ₂₀ alkyl containing heteroatoms, C ₁ -C ₂₀ alkyl substituted by aryl or aromatic heterocyclic group, C ₂ -C ₂₀ alkynyl , C ₃ -C ₂₀ alkynyl containing heteroatoms, C ₂ -C ₂₀ alkynyl substituted by aryl or aromatic heterocyclic group, C ₂ -C ₂₀ alkenyl, C ₃ - C ₂₀ alkenyl, C ₂ -C ₂₀ alkenyl substituted by aryl or aromatic heterocyclic group, C ₂ -C ₂₀ alkyl substituted by aryl or aromatic heterocyclic group with heteroatoms or Cycloalkyl;

R ¹¹ represents the same group as in the definition of R ^4a . ]

The preparation method is characterized in that: in the presence of lipase, with formula (XLIII)

R ¹¹ COOCH=CH ₂ (XLIII)

Carboxylic acid vinyl ester derivatives (in the formula R ¹¹ represents the same meaning as above) to the general formula (XLII)

[wherein R ¹ , R ² and R ^4a represent the same meaning as above. ]

One hydroxyl group of the 2-substituted-2-amino-1,3-propanediol derivatives shown is selectively acylated.

Among the above, preferably

(61) The production method of (60), wherein one of R ¹ and R ² is a hydrogen atom, and the other is a protecting group of an amino group;

(62) The production method of (60) or (61), wherein R ^4a is a C ₁ -C ₁₀ alkyl group, a C ₂ -C ₁₀ alkyl group containing a heteroatom, substituted by an aryl group or an aromatic heterocyclic group C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ alkynyl containing heteroatoms, C ₂ -C ₁₀ alkynyl substituted by aryl or aromatic heterocyclic group, C ₂ -C ₁₀ alkenyl, C ₃ -C ₁₀ alkenyl with heteroatoms, C ₂ -C ₁₀ alkenyl substituted by aryl or aromatic heterocyclic group, substituted by aryl or aromatic heterocyclic group Substituted C ₂ -C ₁₀ alkyl or C ₅ -C ₁₀ cycloalkyl with heteroatoms therein;

(63) The production method of (60) or (61), wherein R ^4a is a C ₁ -C ₁₀ alkyl group, a C ₂ -C ₁₀ alkyl group containing a heteroatom, substituted by an aryl group or an aromatic heterocyclic group C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkynyl, C ₂ -C ₁₀ alkenyl or C ₅ -C ₁₀ cycloalkyl;

(64) The production method of (60) or (63), wherein R ¹¹ is C ₁ -C ₂₀ alkyl or C ₁ -C ₂₀ alkyl substituted by aryl or heteroaryl.

In the above formula, in the definitions of X, R ⁵ , Ar and substituent group b, "aryl", "aryl substituted by 1-3 groups selected from substituent group a", "aryl substituted by 1-3 Examples of the aryl moiety in the aryl group substituted by two groups selected from substituent groups a and b" and "aryl group substituted by 1 to 5 groups selected from substituent group a" include phenyl, indenyl , naphthyl and other aromatic hydrocarbon groups with 6-10 carbon atoms, preferably phenyl or naphthyl, most preferably phenyl.

In the above formula, C 1 of "C ₁ -C ₁₀ alkylene" and "C ₁ -C ₁₀ alkylene substituted by 1-3 groups selected from substituent groups _a and b" in the definition of Y -C ₁₀ alkylene moiety is methylene, methylmethylene, ethylene, 1,2-propylene, 1,3-propylene, 1-methylethylene, 1,4- Butylene, 1-methyl-1,3-propylene, 2-methyl-1,3-propylene, 3-methyl-1,3-propylene, 1-methyl-1,2 -Propylene, 1,1-dimethylethylene, 1,5-pentylene, 1-methyl-1,4-butylene, 2-methyl-1,4-butylene, 3- Methyl-1,4-butylene, 4-methyl-1,4-butylene, 1,1-dimethyl-1,3-propylene, 2,2-dimethyl-1,3- Propylene, 3,3-dimethyl-1,3-propylene, 1,6-hexylene, 1-methyl-1,5-pentylene, 2-methyl-1,5-propylene Pentyl, 3-methyl-1,5-pentylene, 4-methyl-1,5-pentylene, 5-methyl-1,5-pentylene, 1,1-dimethyl- 1,4-butylene, 2,2-dimethyl-1,4-butylene, 3,3-dimethyl-1,4-butylene, 4,4-dimethyl-1,4-butylene Base, 1,7-heptylene, 1-methyl-1,6-hexylene, 2-methyl-1,6-hexylene, 5-methyl-1,6-hexylene, 3-ethyl -1,5-pentylene, 1,8-octylene, 2-methyl-1,7-heptylene, 5-methyl-1,7-heptylene, 2-ethyl-1, 6-hexylene, 2-ethyl-3-methyl-1,5-pentylene, 3-ethyl-2-methyl-1,5-pentylene, 1,9-nonylene, 2 -Methyl-1,8-octylene, 7-methyl-1,8-octylene, 4-ethyl-1,7-heptylene, 3-ethyl-2-methyl-1, 6-hexylene, 2-ethyl-1-methyl-1,6-hexylene, 1,10-decylene and other straight-chain or branched alkylene groups with 1-10 carbon atoms, preferably C ₁ -C ₆ alkylene, more preferably C ₁ -C ₅ alkylene, more preferably ethylene, 1,3-propylene or 1,4-butylene, most preferably ethylene or 1,3-ethylene Propyl.

In the above formula, in the definition of Y, "a C ₁ -C ₁₀ alkylene group having an oxygen atom or a sulfur atom in the carbon chain or at the chain end" and "substituted by 1-3 groups selected from substituent groups a and b Substituted, C ₁ -C ₁₀ alkylene having an oxygen atom or a sulfur atom in the carbon chain or at the chain end""C ₁ -C ₁₀ alkylene having an oxygen atom or a sulfur atom in the carbon chain or at the chain end The " part is a group having an oxygen atom or a sulfur atom at the chain end or in the chain of the above-mentioned "C ₁ -C ₁₀ alkylene", for example, -O-CH ₂ -, -O-(CH ₂ ) ₂ -, -O-(CH ₂ ) ₃ -, -O-(CH ₂ ) ₄ -, -O-(CH ₂ ) ₅ -, -O-(CH ₂ ) ₆ -, -O-(CH ₂ ) ₇ -, -O-(CH ₂ ) ₈ -, -O-(CH ₂ ) ₉ -, -O-(CH ₂ ) ₁₀ -, -CH ₂ -O-CH ₂ -, -CH ₂ -O-(CH ₂ ) ₂ -, -CH ₂ -O-(CH ₂ ) ₃ -, -CH ₂ -O-(CH ₂ ) ₄ -, -(CH ₂ ) ₂ -O-CH ₂ -, -(CH ₂ ) ₂ -O -(CH ₂ ) ₂ -, -(CH ₂ ) ₂ -O-(CH ₂ ) ₃ -, -(CH ₂ ) ₂ -O-(CH ₂ ) ₄ -, -(CH ₂ ) ₃ -O-CH ₂ -, -(CH ₂ ) ₃ -O-(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -O-(CH ₃ ) ₃ -, -(CH ₂ ) ₄ -O-CH ₂ -, -( CH ₂ ) ₄ -O-(CH ₂ ) ₂ -, -(CH ₂ ) ₅ -O-CH ₂ -, -CH ₂ -O-, -(CH ₂ ) ₂ -O-, -(CH ₂ ) ₃ -O-, -(CH ₂ ) ₄ -O-, -(CH ₃ ) ₅ -O-, -(CH ₂ ) ₆ -O-, -(CH ₂ ) ₇ -O-, -(CH ₂ ) ₈ -O-, -(CH ₂ ) ₉ -O-, -(CH ₂ ) ₁₀ -O-, -S-CH ₂ -, -S-(CH ₂ ) ₂ -, -S-(CH ₂ ) ₃ - , -S-(CH ₂ ) ₄ -, -S-(CH ₂ ) ₅ -, -S-(CH ₂ ) ₆ -, -S-(CH ₂ ) ₇ -, -S-(CH ₂ ) ₈ - , -S-(CH ₂ ) ₉ -, -S-(CH ₂ ) ₁₀ -, -CH ₂ -S-CH ₂ -, -CH ₂ -S-(CH ₂ ) ₂ -, -CH ₂ -S- (CH ₂ ) ₃ -, -CH ₂ -S-(CH ₂ ) ₄ -, -(CH ₂ ) ₂ -S-CH ₂ -, -(CH ₂ ) ₂ -S-(CH ₂ ) ₂ -, - (CH ₂ ) ₂ -S-(CH ₂ ) ₃ -, -(CH ₂ ) ₂ -S-(CH ₂ ) ₄ -, -(CH ₂ ) ₃ -S-CH ₂ -, -(CH ₂ ) ₃ -S-(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -S-(CH ₂ ) ₃ -, -(CH ₂ ) ₄ -S-CH ₂ -, -(CH ₂ ) ₄ -S-(CH ₂ ) ₂ -, -(CH ₂ ) ₅ -S-CH ₂ -, -CH ₂ -S-, -(CH ₂ ) ₂ -S-, -(CH ₂ ) ₃ -S-, -(CH ₂ ) ₄ -S-, -(CH ₂ ) ₅ -S-, -(CH ₂ ) ₆ -S-, -(CH ₂ ) ₇ -S-, -(CH ₂ ) ₈ -S-, -(CH ₃ ) ₉ -S-, -(CH ₂ ) ₁₀ -S-

, preferably a C ₁ -C ₆ alkylene group with an oxygen atom in the carbon chain or at the end of the chain, more preferably with -O-CH ₂ -, -O-(CH ₂ ) ₂ -, -O-(CH ₂ ) ₃ -, -CH ₂ -O-, -(CH ₂ ) ₂ -O- or -(CH ₂ ) ₃ -O-, most preferably with -CH ₂ -O-, -O-(CH ₂ ) ₂ - or -(CH ₂ ) ₂ -O- group.

In the above formula, in the definition of R ^4a , R ⁵ , R ¹¹ and substituent group b, "cycloalkyl", "cycloalkyl substituted by 1-3 groups selected from substituent group a" and " Examples of the cycloalkyl moiety of "cycloalkyl" substituted by 1 to 3 groups selected from substituent groups a and b include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, nor A saturated carbocyclic group with 3-10 carbon atoms such as norbornyl, adamantyl, and indanyl may also be fused with other cyclic groups such as benzene ring. Cycloalkyl in the definition of R ⁵ and substituent group b is preferably C ₅ -C ₆ cycloalkyl, most preferably cyclohexyl; and cycloalkyl in the definition of R ^4a and R ¹¹ is preferably C ₅ -C ₁₀ cycloalkane base.

基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、1，2，3-噁二唑基、三唑基、四唑基、噻二唑基、吡喃基、吡啶基、哒嗪基、嘧啶基和吡嗪基之类的芳族杂环基。In the above formula, "aromatic heterocyclic group" and "aromatic heterocyclic group substituted by 1-5 groups selected from substituent group a" in the definition of Ar mean that they contain 1-3 sulfur atoms, oxygen atoms and/or 5-7 membered heterocyclic groups of nitrogen atoms, such as furyl, thienyl, pyrrolyl, aza

Base, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyr Aromatic heterocyclic groups such as pyryl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

In addition, the above-mentioned "aromatic heterocyclic group" may be condensed with other cyclic groups, examples of which include benzothienyl, isobenzofuryl, benzopyranyl, xanthenyl, phenothioxyl, and nitrogen Indenyl, isoindolyl, indolyl, indazolyl, purinyl, quinazinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridyl, quinoxalinyl, quinazolinyl, Carbazolyl, carbolinyl, acridinyl, isoindolinyl and the like. Preferred such "aromatic heterocyclic groups" are furyl, thienyl, benzothienyl, most preferably thienyl or benzothienyl.

In the above formula, in the definition of R ⁵ and substituent group b, "heterocyclic group", "heterocyclic group substituted by 1-3 groups selected from substituent group a" and "by 1-3 selected The heterocyclic group part of the "heterocyclic group substituted from the substituent groups a and b" represents a 5-7 membered heterocyclic ring containing 1-3 sulfur atoms, oxygen atoms and/or nitrogen atoms, examples of which include the above-mentioned " Aromatic heterocyclic group" and tetrahydropyranyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxazole Partially or completely reduced saturated heterocyclic groups corresponding to alkyl, isoxazolidinyl, thiazolidinyl and pyrazolidinyl. The heterocyclic group is preferably a 5-6 membered aromatic heterocyclic group, most preferably morpholinyl, thiomorpholinyl or piperidinyl.

In the above formula, "halogen atom" in the definition of substituent group a is fluorine, chlorine, bromine, iodine atom, preferably fluorine atom or chlorine atom, most preferably fluorine atom.

In the above formula, "lower alkyl" in the definition of R and substituent group a is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec ^- butyl, tert-butyl, pentyl Base, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl and other straight-chain or branched-chain alkyl groups with 1-6 carbon atoms, preferably _C1 -C ₄ alkyl, more preferably C ₁ -C ₂ alkyl, most preferably methyl.

In the above formula, "halogenated lower alkyl" in the definition of substituent group a means the aforementioned "lower alkyl" substituted by a halogen atom, such as trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethane base, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl Halogenated C 1 -C 6 alkyl such as radical, 2-iodoethyl, 3 _- chloropropyl, 4-fluorobutyl, 6-iodohexyl, 2,2 _- dibromoethyl, preferably halogenated C ₁ -C ₄ alkyl, more preferably halogenated C ₁ -C ₂ alkyl, most preferably trifluoromethyl.

In the above formula, "lower alkoxy" in the definition of substituent group a means a group formed by combining the aforementioned "lower alkyl" with an oxygen atom, such as methoxy, ethoxy, propoxy, isopropoxy Butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, 1-ethylpropoxy, 2-ethyl Propoxy, neopentyloxy, hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 3,3-dimethylbutoxy, 2, 2-Dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy Linear or branched chain alkoxy with 1-6 carbon atoms such as oxy, preferably C ₁ -C ₄ alkoxy, more preferably C ₁ -C ₂ alkoxy, most preferably methoxy.

In the above formula, "lower alkylthio" in the definition of substituent group a means a group formed by combining the aforementioned "lower alkyl" with a sulfur atom, such as methylthio, ethylthio, propylthio, isopropylthio butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, hexylthio, 4-methyl Amylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethyl Butylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio and other straight or branched chains with 1-6 carbon atoms Alkylthio, preferably C ₁ -C ₄ alkylthio, more preferably C ₁ -C ₂ alkylthio, most preferably methylthio.

In the above formula, "lower alkoxycarbonyl" in the definition of substituent group a means a group formed by combining the aforementioned "lower alkoxy" with a carbonyl group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy Carbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, 2-methylbutoxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, 4-methyl pentyloxycarbonyl, 3-methylpentyloxycarbonyl, 2-methylpentyloxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethyl Butoxycarbonyl, 1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl, 2,3-dimethylbutoxycarbonyl and other straight or branched chains with 1-6 carbon atoms Alkoxycarbonyl, preferably C ₁ -C ₄ alkoxycarbonyl, more preferably C ₁ -C ₂ alkoxycarbonyl, most preferably methoxycarbonyl.

In the above formula, the "lower aliphatic acyl group" in the definition of substituent group a refers to a hydrogen atom or a group formed by combining a saturated or unsaturated chain hydrocarbon group with a carbonyl group, such as formyl, acetyl, propionyl, butyryl, Isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl, crotonoyl and other straight-chain or branched lower aliphatic acyl groups with 1-7 carbon atoms, preferably C ₁ -C ₄ lower aliphatic acyl, more preferably acetyl or propionyl, most preferably acetyl.

In the above formula, "mono-lower alkylamino" in the definition of substituent group a means a group formed by combining the aforementioned "lower alkyl" with one amino group, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino, 1-ethylpropyl Amino, Hexylamino, Isohexylamino, 4-Methylpentylamino, 3-Methylpentylamino, 2-Methylpentylamino, 1-Methylpentylamino, 3,3-Dimethylbutyl Amino, 2,2-dimethylbutylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3- Mono- _C 1 -C 6 alkylamino such as dimethylbutylamino, 2-ethylbutylamino, preferably mono-C ₁ -C ₄ alkylamino, _more preferably mono-C ₁ -C ₂ alkyl Amino, most preferably methylamino.

In the above formula, "di-lower alkylamino" in the definition of substituent group a means a group formed by combining two aforementioned "lower alkyl" and amino groups, such as dimethylamino, diethylamino, N-ethyl -Di-C ₁ -C ₆ alkylamino such as N-methylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, preferably di-C ₁ -C ₄ alkylamino, More preferred is di-C ₁ -C ₂ alkylamino, most preferred is dimethylamino.

In the above formula, "lower aliphatic amido" in the definition of substituent group a means the group formed by combining the aforementioned "lower aliphatic acyl" with an amino group, such as formamido, acetylamino, propionylamino, butyrylamino, Isobutyrylamino, valerylamino, isovalerylamino, pivalylamino, caproylamino, acrylamido, methacrylamido, crotonylamino and other straight or branched chains with 1-7 carbon atoms Chain lower aliphatic amido, preferably acetylamino or propionylamino, most preferably acetylamino.

In the above formula, "the protecting group of amino" in the definition of ^R and ^R refers to the protecting group of amino usually used in the field of organic synthetic chemistry, including for example

The aforementioned "lower alkyl";

The aforementioned "lower aliphatic acyl", halogenated lower aliphatic acyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, tetrafluoroacetyl, etc., substituted by lower alkoxy such as methoxyacetyl "aliphatic acyls" such as aliphatic acyl;

Benzoyl, 1-indancarbonyl, 2-indancarbonyl, 1- or 2-naphthoyl and other aromatic acyl, 4-chlorobenzoyl, 4-fluorobenzoyl, 2,4,6-tri Methylbenzoyl, 4-toluoyl, 4-methoxybenzoyl, 4-nitrobenzoyl, 2-nitrobenzoyl, 2-(methoxycarbonyl)benzoyl, 4-phenyl "Aromatic acyl groups" such as benzoyl groups substituted by 1-3 groups selected from the aforementioned substituent group a, such as aromatic acyl groups;

The aforementioned "lower alkoxycarbonyl", 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl and other lower alkoxycarbonyl substituted by halogen or tri-lower alkylsilyl, etc. "alkoxycarbonyls";

"Alkenyloxycarbonyls" such as vinyloxycarbonyl and allyloxycarbonyl;

Aralkyloxycarbonyl such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl "Aralkyloxycarbonyls" such as "aralkyloxycarbonyls" substituted by 1-3 groups selected from the aforementioned substituent group a;

Trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-tert-butylsilyl Tri-lower alkylsilyl groups such as triisopropylsilyl, diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropyl "Silyl groups" such as trisubstituted silyl groups substituted by aryl groups or aryl groups and lower alkyl groups;

Benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl , 9-anthracenylmethyl and other lower alkyls substituted by 1-3 aryl groups, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethyl Benzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis(2-nitrophenyl)methyl, piperonyl and the like are replaced by 1-3 aromatic rings through lower alkyl, lower alkanes "Aralkyl" such as lower alkyl substituted with aryl substituted by oxy, nitro, halogen or cyano; and

N,N-Dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorosalicylidene, diphenylene Methyl, (5-chloro-2-hydroxyphenyl)phenylmethylene and the like "Schiff base forming substituted methylene". Preferred are lower alkoxycarbonyl, aralkyloxycarbonyl, or aralkyloxycarbonyl substituted with 1 to 3 groups selected from Substituent Group a.

In the definition of R ³ and R ^3a , "protecting group of hydroxyl group" means "general protecting group in reaction" which can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, photolysis, etc. Protecting groups for cleavage by scientific methods".

Examples of said "general protecting groups in reactions" are:

The aforementioned "lower alkyl";

The aforementioned "aliphatic acyls";

The aforementioned "aromatic acyls";

Tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxy tetrahydropyran-2-yl "Tetrahydropyranyl or tetrahydrothiopyranyls" such as hydrothiopyran-4-yl;

Tetrahydrofuran-2-yl, tetrahydrothiophen-2-yl and the like “tetrahydrofuranyl or tetrahydrothiophene-yls”;

The aforementioned "silyl groups";

Methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, tert-butoxy Lower alkoxymethyl groups such as 2-methoxyethoxymethyl, lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl groups , "alkoxymethyl" such as halogenated lower alkoxymethyl such as bis(2-chloroethoxy)methyl;

1-ethoxyethyl, lower alkoxylated ethyl such as 1-(isopropoxy)ethyl, haloethyl such as 2,2,2-trichloroethyl, etc. kind";

The aforementioned "aralkyl group";

The aforementioned "alkoxycarbonyls";

The aforementioned "alkenyloxycarbonyls";

The aforementioned "aralkyloxycarbonyl".

On the other hand, examples of "a protecting group that can be cleaved by a biological method such as hydrolysis in vivo" include ethylcarbonyloxymethyl, pivaloyloxymethyl, dimethylaminoacetoxymethyl, Acyloxyalkyls such as 1-acetoxyethyl;

1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl, ethoxycarbonyloxymethyl, 1-(isopropoxycarbonyloxy)ethyl, 1-(tert-butyl 1-(alkoxycarbonyloxy)alkyl such as oxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)propyl, 1-(cyclohexyloxycarbonyloxy)ethyl;

2-Benzo[c]furanonyl;

4-Methyl-oxodioxolenyl (dioxolenyl)methyl, 4-phenyl-oxodioxolylmethyl, oxodioxolenylmethyl, etc. "Carbonyloxyalkyls" such as oxodioxolylmethyl;

The aforementioned "aliphatic acyls";

The aforementioned "aromatic acyls";

"half-ester salt residue of succinic acid";

"phosphate residue";

"ester-forming residues of amino acids, etc.";

Carbamoyl;

Aralkylene groups such as benzylidene; alkoxyethylene groups such as methoxyethylene and ethoxyethylene; oxymethylene; thiomethylene and the like"2 Hydroxyl protecting group";

and "carbonyloxyalkoxycarbonyl" such as pivaloyloxymethoxycarbonyl. Whether it is such a derivative can be determined by administering intravenous injection to experimental animals such as rats or mice, and then analyzing the body fluids of the animals to determine whether the original compound or its pharmacologically acceptable salt can be detected. The protecting group of such a hydroxyl group is preferably a lower alkyl group, a lower aliphatic acyl group, an aromatic acyl group or an aromatic acyl group substituted with 1 to 3 groups selected from substituent group a.

Among the above, in the definition of R ⁵ , the specific examples of "cycloalkyl substituted by 1-3 groups selected from substituent groups a and b" include 2-fluorocyclopropyl, 2-chlorocyclopropyl, 2 - or 3-fluorocyclopentyl, 2- or 3-chlorocyclopentyl, 2-, 3- or 4-fluorocyclohexyl, 2-, 3- or 4-chlorocyclohexyl, 2-, 3- or 4 -Bromocyclohexyl, 2-, 3- or 4-iodocyclohexyl, 2-methylcyclopropyl, 2-ethylcyclopropyl, 2- or 3-methylcyclopentyl, 2- or 3-ethyl Cyclopentyl, 2-, 3- or 4-methylcyclohexyl, 2-, 3- or 4-ethylcyclohexyl, 2-trifluoromethylcyclopropyl, 2- or 3-trifluoromethyl Cyclobutyl, 2- or 3-trifluoromethylcyclopentyl, 2-, 3- or 4-trifluoromethylcyclohexyl, 2-methoxycyclopropyl, 2- or 3-methoxycyclo Butyl, 2- or 3-methoxycyclopentyl, 2-, 3- or 4-methoxycyclohexyl, 2-, 3- or 4-ethoxycyclohexyl, 2-, 3- or 4 -propoxycyclohexyl, 2-, 3- or 4-isopropoxycyclohexyl, 2-, 3- or 4-(1-ethylpropoxy)cyclohexyl, 2-, 3- or 4- (2-Ethylpropoxy)cyclohexyl, 2-carboxycyclopropyl, 2- or 3-carboxycyclopentyl, 2-, 3- or 4-carboxycyclohexyl, 2-methoxycarbonylcyclopropyl, 2- or 3-methoxycarbonylcyclopentyl, 2-, 3- or 4-methoxycarbonylcyclohexyl, 2-hydroxycyclopropyl, 2- or 3-hydroxycyclopentyl, 2-, 3- or 4 -Hydroxycyclohexyl, 2-formylcyclopropyl, 2- or 3-formylcyclopentyl, 2-, 3- or 4-formylcyclohexyl, 2-acetylcyclopropyl, 2- or 3- Acetylcyclopentyl, 2-, 3- or 4-acetylcyclohexyl, 2-aminocyclopropyl, 2- or 3-aminocyclopentyl, 2-, 3- or 4-aminocyclohexyl, 2- Methylaminocyclopropyl, 2- or 3-methylaminocyclobutyl, 2- or 3-methylaminocyclopentyl, 2-, 3- or 4-methylaminocyclohexyl, 2-dimethyl Aminocyclopropyl, 2- or 3-dimethylaminocyclobutyl, 2- or 3-dimethylaminocyclopentyl, 2-, 3- or 4-dimethylaminocyclohexyl, 2-cyano Cyclopropyl, 2- or 3-cyanocyclopentyl, 2-, 3- or 4-cyanocyclohexyl, 2- or 3-cyclohexylcyclopentyl, 2-, 3- or 4-cyclohexyl Hexyl, 2-phenylcyclopropyl, 2- or 3-phenylcyclopentyl, 2-, 3- or 4-phenylcyclohexyl, 3,4-difluorocyclohexyl, 3,4-dichlorocyclo Hexyl, 2,3-dimethoxycyclohexyl, 3,4-dimethoxycyclohexyl, 3,5-dimethoxycyclohexyl, 3,4,5-trimethoxycyclohexyl, preferably 1 -cycloalkyl substituted by 3 substituents (the substituents are selected from halogen atoms, lower alkyl, halogenated lower alkyl, lower alkoxy, lower alkylthio and lower aliphatic acyl), more preferably 1 -Cycloalkyl substituted by 3 substituents (the substituents are selected from halogen atoms, lower alkyl groups, halogenated lower alkyl groups, lower alkoxy groups and lower aliphatic acyl groups), more preferably 1-3 substituents Substituted cyclohexyl (the substituent is selected from halogen atom, lower alkyl, halogenated lower alkyl, lower alkoxy and lower aliphatic acyl), most preferably cyclohexyl substituted by 1-3 substituents (the The substituents are selected from the group consisting of fluorine atom, chlorine atom, methyl group, trifluoromethyl group, methoxy group and acetyl group).

In the above, in the definition of R ⁵ , the specific examples of "aryl group substituted by 1-3 groups selected from substituent groups a and b" include 2-, 3- or 4-fluorophenyl, 2-, 3 - or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-iodophenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4-ethylphenyl, 2-, 3-, or 4-propylphenyl, 2-, 3-, or 4-butylphenyl, 2-, 3-, or 4-pentylphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 2-, 3- or 4-propoxy phenyl, 2-, 3-, or 4-isopropoxyphenyl, 2-, 3-, or 4-butoxyphenyl, 2-, 3-, or 4-(1-ethylpropoxy) Phenyl, 2-, 3- or 4-(2-ethylpropoxy)phenyl, 2-, 3- or 4-methylphenylthio, 2-, 3- or 4-ethylphenylthio , 2-, 3- or 4-carboxyphenyl, 2-, 3- or 4-methoxycarbonylphenyl, 2-, 3- or 4-ethoxycarbonylphenyl, 2-, 3- or 4-hydroxy Phenyl, 2-, 3-, or 4-formylphenyl, 2-, 3-, or 4-acetylphenyl, 2-, 3-, or 4-aminophenyl, 2-, 3-, or 4-methyl Aminophenyl, 2-, 3- or 4-dimethylaminophenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-cyclopentylphenyl, 2-, 3- or 4-cyclohexylphenyl, 2-, 3- or 4-biphenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2 , 4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dibromophenyl, 2,3-dimethylphenyl, 3,4-di Methylphenyl, 3,5-dimethylphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3, 4,5-trimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-methyl-2-methoxyphenyl, 6-fluoro-4-methyl-2-methoxyphenyl Base, 5-fluoroinden-3-yl, 5-fluoroinden-3-yl, 5-methylinden-3-yl, 5-methoxyinden-3-yl, 5-fluoroinden-2-yl, 5-chloroinden-2-yl, 5-methylinden-2-yl, 5-methoxyinden-2-yl, 5-hydroxyinden-3-yl, 5-nitroinden-3-yl, 5 -Cyclohexylinden-3-yl, 5-phenylinden-3-yl, 5-phenoxyinden-3-yl, 5-benzyloxyinden-3-yl, 5-phenylthianden-3- Base, 5-hydroxyinden-2-yl, 5-nitroinden-2-yl, 5-cyclohexylinden-2-yl, 5-phenylinden-2-yl, 5-fluoronaphthalen-2-yl, 5-methylnaphthalene-2-yl, 5-methoxynaphthalene-2-yl, 5-fluoronaphthalene-1-yl, 5-methylnaphthalene-1-yl, 5-methoxynaphthalene-1-yl , 5-hydroxynaphthalene-2-yl, 5-nitronaphthalene-2-yl, 5-cyclohexylnaphthalene-2-yl, 5-phenylnaphthalene-2-yl, 5-phenoxynaphthalene-2-yl , 5-benzyloxynaphthalene-2-yl, 5-phenylthionaphthalene-2-yl, 5-hydroxynaphthalene-1-yl, 5-nitronaphthalene-1-yl, 5-cyclohexylnaphthalene-1-yl Base, 5-phenylnaphthalen-1-yl, preferably aryl substituted by 1-3 substituents (the substituents are selected from halogen atom, lower alkyl, halogenated lower alkyl, lower alkoxy, lower alkylthio and lower aliphatic acyl), more preferably aryl substituted by 1-3 substituents (the substituents are selected from halogen atoms, lower alkyl, halogenated lower alkyl, lower alkoxy and lower aliphatic family acyl), more preferably phenyl substituted by 1-3 substituents (the substituents are selected from halogen atom, lower alkyl, halogenated lower alkyl, lower alkoxy and lower aliphatic acyl), still more Preferably phenyl substituted by 1-3 substituents (the substituents are selected from fluorine atom, chlorine atom, methyl, trifluoromethyl, methoxy and acetyl), most preferably 3-fluorophenyl, 4 -Fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichloro Phenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3-trifluoromethylphenyl, 4-trifluoro Methylphenyl, 3,4-bis(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3 , 4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-acetylphenyl or 4-acetylphenyl.

In the above, in the definition of R ⁵ , the specific examples of "heterocyclic group substituted by 1-3 groups selected from substituent groups a and b" include 3-, 4- or 5-methylfuran-2-yl , 2-, 4- or 5-methylfuran-3-yl, 3-, 4- or 5-fluorothiophen-2-yl, 2-, 4- or 5-fluorofuran-3-yl, 3-, 4- or 5-bromothiophen-2-yl, 2-, 4- or 5-bromofuran-3-yl, 3-, 4- or 5-methylthiophen-2-yl, 2-, 4- or 5 -Methylthiophen-3-yl, 3-, 4- or 5-ethylthiophen-2-yl, 2-, 4- or 5-ethylthiophen-3-yl, 3-, 4- or 5-methyl Oxythiophen-2-yl, 2-, 4- or 5-methoxythiophen-3-yl, 3- or 4-methylthiazol-5-yl, 3-, 4- or 5-fluorobenzothiophene -2-yl, 3-, 4- or 5-bromobenzothiophen-2-yl, 3-, 4- or 5-methylbenzothiophen-2-yl, 3-, 4- or 5-methoxy phenylbenzothiophen-2-yl, 2-, 4- or 5-fluorobenzothiophen-3-yl, 2-, 4- or 5-bromobenzothiophen-3-yl, 2-, 4- or 5 -Methylbenzothiophen-3-yl, 2-, 4-, or 5-methoxybenzothiophen-3-yl, 4-, 5-, 6-, or 7-methylbenzothiophen-2-yl , 3-, 4- or 5-hydroxyfuran-2-yl, 2-, 4- or 5-hydroxyfuran-3-yl, 3-, 4- or 5-hydroxythiophen-2-yl, 3-, 4 - or 5-nitrothiophen-2-yl, 3-, 4- or 5-phenylthiophen-2-yl, 2-, 4- or 5-hydroxythiophen-3-yl, 2-, 4- or 5 -cyanothiophen-3-yl, 1-, 2-, or 3-hydroxypyridin-4-yl, 1-, 2-, or 3-cyanopyridin-4-yl, 1-, 2-, or 3-phenyl Pyridin-4-yl, preferably 3-, 4- or 5-fluorothien-2-yl or 2-, 4-, or 5-fluorofuran-3-yl.

In the above, examples of "C ₁ -C ₂₀ alkyl" in the definitions of R ^4a and R ¹¹ include the aforementioned "lower alkyl", heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl , 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methyl Heptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl , Decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl, 7,7-dimethyloctyl base, undecyl, 4,8-dimethylnonyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl , hexadecyl, 4,8,12-trimethyltridecyl, 1-methylpentadecyl, 14-methylpentadecyl, 13,13-dimethyltetradecyl, Heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl, eicosyl and 3,7,11,15-tetramethyldecyl Straight chain or branched C1-20 alkyl such as hexaalkyl, preferably C ₁ -C ₁₀ alkyl, more preferably C ₁ -C ₆ alkyl, most preferably methyl or ethyl.

In the above, in the definition of R ^4a and R ¹¹ , "the C ₂ -C ₂₀ alkyl group with heteroatoms" refers to the "alkyl group with 2-20 carbon atoms" in the aforementioned "C ₁ -C ₂₀ alkyl group". Groups having 1 or 2 identical or different sulfur, oxygen or nitrogen atoms, examples of which are methylthiomethyl, 1-methylthioethyl, 2-methylthioethyl, ethylthiomethyl Base, 1-methylthiopropyl, 2-methylthiopropyl, 3-methylthiopropyl, 2-ethylthioethyl, 2-methyl-2-methylthioethyl, 1-methyl Thiobutyl, 2-methylthiobutyl, 3-methylthiobutyl, 2-ethylthiopropyl, 3-methyl-3-methylthiopropyl, 4-methylthiopentyl, 3-methylthiopentyl, 2-methylthiopentyl, 1-methylthiopentyl, 3,3-dimethylthiobutyl, 2,2-dimethylthiobutyl, 1,1- Dimethylthiobutyl, 1-methyl-2-methylthiobutyl, 1,3-dimethylthiobutyl, 2,3-dimethylthiobutyl, 2-ethylthiobutyl, 1-methylthiohexyl, 2-methylthiohexyl, 3-methylthiohexyl, 4-methylthiohexyl, 5-methylthiohexyl, 1-propylthiobutyl, 4-methyl-4- Methylthiopentyl, 1-methylthioheptyl, 2-methylthioheptyl, 3-methylthioheptyl, 4-methylthioheptyl, 5-methylthioheptyl, 6-methylthioheptyl Heptyl, 1-propylthiopentyl, 2-ethylthiohexyl, 5-methyl-5-methylthiohexyl, 3-methylthiooctyl, 4-methylthiooctyl, 5-methylthiooctyl Thiooctyl, 6-methylthiooctyl, 1-propylthiohexyl, 2-ethylthioheptyl, 6-methyl-6-methylthioheptyl, 1-methylthiononyl, 3 -Methylthiononyl, 8-methylthiononyl, 3-ethylthiooctyl, 3-methyl-7-methylthiooctyl, 7,7-dimethylthiooctyl, 4-methylthiooctyl Base-8-methylthiononyl, 3,7-dimethyl-11-methylthiododecyl, 4,8-dimethyl-12-methylthiotridecyl, 1-methylthio Pentadecyl, 14-methylthiopentadecyl, 13-methyl-13-methylthiotetradecyl, 15-methylthiohexadecyl, 1-methylthioheptadecyl And 3,7,11-trimethyl-15-methylthiohexadecyl and other alkyl groups with 2-20 carbon atoms having 1 or 2 sulfur atoms; methyloxymethyl, 1- Methyloxyethyl, 2-methyloxyethyl, ethyloxymethyl, 1-methyloxypropyl, 2-methyloxypropyl, 3-methyloxypropyl, 2-ethyloxyethyl, 2-methyl-2-methyloxyethyl, 1-methyloxybutyl, 2-methyloxybutyl, 3-methyloxybutyl, 2-ethyloxypropyl, 3-methyl-3-methyloxypropyl, 4-methyloxypentyl, 3-methyloxypentyl, 2-methyloxypentyl, 1-methyloxypentyl, 3,3-dimethyloxybutyl, 2,2-dimethyloxybutyl, 1,1-dimethyloxybutyl, 1-methyl- 2-methyloxybutyl, 1,3-dimethyloxybutyl, 2,3-dimethyloxybutyl, 2-ethyloxybutyl, 1-methyloxyhexyl, 2-methyloxyhexyl, 3-methyloxyhexyl, 4-methyloxyhexyl, 5-methyloxyhexyl, 1-propyloxybutyl, 4-methyl-4-methyl Oxypentyl, 1-methyloxyheptyl, 2-methyloxyheptyl, 3-methyloxyheptyl, 4-methyloxyheptyl, 5-methyloxyheptyl, 6-methyloxyheptyl, 1-propyloxypentyl, 2-ethyloxyhexyl, 5-methyl-5-methyloxyhexyl, 3-methyloxyoctyl, 4- Methyloxyoctyl, 5-methyloxyoctyl, 6-methyloxyoctyl, 1-propyloxyhexyl, 2-ethyloxyheptyl, 6-methyl-6-methyl oxyheptyl, 1-methyloxynonyl, 3-methyloxynonyl, 8-methyloxynonyl, 3-ethyloxyoctyl, 3-methyl-7-methyl Oxyloxyoctyl, 7,7-dimethyloxyoctyl, 4-methyl-8-methyloxynonyl, 3,7-dimethyl-11-methyloxydodecyl , 4,8-dimethyl-12-methyloxytridecyl, 1-methyloxypentadecyl, 14-methyloxypentadecyl, 13-methyl-13-methyl Oxytetradecyl, 15-methyloxyhexadecyl, 1-methyloxyheptadecyl and 3,7,11-trimethyl-15-methyloxyhexadecyl Alkyl groups with 2-20 carbon atoms in which there are 1 or 2 oxygen atoms; N-methylaminomethyl, 1-(N-methylamino)ethyl, 2-(N-methylamino) Ethyl, N-ethylaminomethyl, 1-(N-methylamino)propyl, 2-(N-methylamino)propyl, 3-(N-methylamino)propyl, 2-( N-ethylamino) ethyl, 2-(N,N-dimethylamino) ethyl, 1-(N-methylamino) butyl, 2-(N-methylamino) butyl, 3- (N-methylamino)butyl, 2-(N-ethylamino)propyl, 3-(N,N-dimethylamino)propyl, 4-(N-methylamino)pentyl, 3 -(N-methylamino)pentyl, 2-(N-methylamino)pentyl, 1-(N-methylamino)pentyl, 3-(N,N-dimethylamino)butyl, 2-(N,N-dimethylamino)butyl, 1-(N,N-dimethylamino)butyl, 1-methyl-2-(N-methylamino)butyl, 1,3 - bis(N-methylamino)butyl, 2,3-bis(N-methylamino)butyl, 2-(N-ethylamino)butyl, 1-(N-methylamino)hexyl, 2-(N-methylamino)hexyl, 3-(N-methylamino)hexyl, 4-(N-methylamino)hexyl, 5-(N-methylamino)hexyl, 1-(N-propane Amino)butyl, 4-methyl-4-(N-methylamino)pentyl, 1-(-N-methylamino)heptyl, 2-(N-methylamino)heptyl, 3- (-N-methylamino)heptyl, 4-(N-methylamino)heptyl, 5-(N-methylamino)heptyl, 6-(N-methylamino)heptyl, 1-( N-propylamino) pentyl, 2-(N-ethylamino) hexyl, 5-methyl-5-(N-methylamino) hexyl, 3-(N-methylamino) octyl, 4- (N-methylamino)octyl, 5-(N-methylamino)octyl, 6-(N-methylamino)octyl, 1-(N-propylamino)hexyl, 2-(N- Ethylamino) heptyl, 6-methyl-6-(N-methylamino) heptyl, 1-(N-methylamino) nonyl, 3-(N-methylamino) nonyl, 8- (N-methylamino)nonyl, 3-(N-ethylamino)octyl, 3-methyl-7-(N-methylamino)octyl, 7,7-di(N-methylamino) ) octyl, 4-methyl-8-(N-methylamino)nonyl, 3,7-dimethyl-11-(N-methylamino)dodecyl, 4,8-dimethyl -12-(N-methylamino)tridecyl, 1-(N-methylamino)pentadecyl, 14-(N-methylamino)pentadecyl, 13-methyl-13- (N-methylamino)tetradecyl, 15-(N-methylamino)hexadecyl, 1-(N-methylamino)heptadecyl and 3,7,11-trimethyl- 15-(N-methylamino)hexadecyl and the like, an alkyl group having 2 to 20 carbon atoms in which there are 1 or 2 nitrogen atoms; preferably a C ₂ -C ₁₀ alkyl group in which a heteroatom is present.

In the above, "C ₁ -C ₂₀ alkyl substituted by aryl or aromatic heterocyclic group" in the definition of R ^4a and R ¹¹ means that the aforementioned "C ₁ -C ₂₀ alkyl" is replaced by 1 or 3 same or different A group substituted with the aforementioned "aryl" or the aforementioned "aromatic heterocyclic group".

In the above, examples of "C ₂ -C ₂₀ alkynyl" in the definitions of R ^4a and R ¹¹ include ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1 -Methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1 -Ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3 -pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl , 5-hexynyl, heptynyl, 1-methylhexynyl, 2-methylhexynyl, 3-methylhexynyl, 4-methylhexynyl, 5-methylhexynyl , 1-propylbutynyl, 4,4-dimethylpentynyl, octynyl, 1-methylheptynyl, 2-methylheptynyl, 3-methylheptynyl, 4- Methylheptynyl, 5-methylheptynyl, 6-methylheptynyl, 1-propylpentynyl, 2-ethylhexynyl, 5,5-dimethylhexynyl, nonyl Alkynyl, 3-methyloctynyl, 4-methyloctynyl, 5-methyloctynyl, 6-methyloctynyl, 1-propylhexynyl, 2-ethylheptynyl , 6,6-dimethylheptynyl, decynyl, 1-methylnonynyl, 3-methylnonynyl, 8-methylnonynyl, 3-ethyloctynyl, 3, 7-Dimethyloctynyl, 7,7-Dimethyloctynyl, Undecynyl, 4,8-Dimethylnonynyl, Dodecynyl, Tridecynyl, Tetradecynyl , Pentadecynyl, 3,7,11-trimethyldodecynyl, hexadecanyl, 4,8,12-trimethyltridecynyl, 1-methylpentadedecynyl, 14- Methylpentadeynyl, 13,13-dimethyltetradecynyl, heptadecanyl, 15-methylhexadeynyl, octadecynyl, 1-methylheptadeynyl, nonadecanyl straight chain or branched chain alkynyl with 2-20 carbon atoms such as eicosynyl and 3,7,11,15-tetramethylhexadeynyl; preferably C ₂ -C ₁₀ alkynyl.

In the above, "C ₃ -C ₂₀ alkynyl with heteroatoms" in the definitions of R ^4a and R ¹¹ means that in the aforementioned "C ₂ -C ₂₀ alkynyl" in the "alkynyl with 3-20 carbon atoms" there is 1 or 2 groups of the same or different sulfur atoms, oxygen atoms or nitrogen atoms, examples of which are 1-methylthioethynyl, 2-methylthioethynyl, 1-methylthiopropynyl, 2- Methylthiopropynyl, 3-methylthiopropynyl, 2-ethylthioethynyl, 2-methyl-2-methylthioethynyl, 1-methylthiobutynyl, 2-methylthio Butynyl, 3-methylthiobutynyl, 2-ethylthiopropynyl, 3-methyl-3-methylthiopropynyl, 4-methylthiopentynyl, 3-methylthio 2-methylthiopentynyl, 2-methylthiopentynyl, 1-methylthiopentynyl, 3,3-dimethylthiobutynyl, 2,2-dimethylthiobutynyl, 1,1 -Dimethylthiobutynyl, 1-methyl-2-methylthiobutynyl, 1,3-dimethylthiobutynyl, 2,3-dimethylthiobutynyl, 2-eth Thiobutynyl, 1-methylthiohexynyl, 2-methylthiohexynyl, 3-methylthiohexynyl, 4-methylthiohexynyl, 5-methylthiohexynyl , 1-propylthiobutynyl, 4-methyl-4-methylthiopentynyl, 1-methylthioheptynyl, 2-methylthioheptynyl, 3-methylthioheptynyl , 4-methylthioheptynyl, 5-methylthioheptynyl, 6-methylthioheptynyl, 1-propylthiopentynyl, 2-ethylthiohexynyl, 5-methyl -5-methylthiohexynyl, 3-methylthiooctynyl, 4-methylthiooctynyl, 5-methylthiooctynyl, 6-methylthiooctynyl, 1-propylthio Hexynyl, 2-ethylthioheptynyl, 6-methyl-6-methylthioheptynyl, 1-methylthiononynyl, 3-methylthiononynyl, 8-methylthio Nonynyl, 3-ethylthiooctynyl, 3-methyl-7-methylthiooctynyl, 7,7-dimethylthiooctynyl, 4-methyl-8-methylthio Nonynyl, 3,7-dimethyl-11-methylthiododedecynyl, 4,8-dimethyl-12-methylthiotridecynyl, 1-methylthiopentadedecynyl, 14-methylthiopentadetynyl, 13-methyl-13-methylthiotetradecynyl, 15-methylthiohexadeynyl, 1-methylthioheptadeynyl and 3,7,11 - Trimethyl-15-methylthiohexadecanyl and other alkynyl groups with 3-20 carbon atoms containing 1 or 2 sulfur atoms; 1-methyloxyethynyl, 2-methyloxy Ethynyl, 1-methyloxypropynyl, 2-methyloxypropynyl, 3-methyloxypropynyl, 2-ethyloxyethynyl, 2-methyl-2-methyl Oxyethynyl, 1-methyloxybutynyl, 2-methyloxybutynyl, 3-methyloxybutynyl, 2-ethyloxypropynyl, 3-methyl -3-methyloxypropynyl, 4-methyloxypentynyl, 3-methyloxypentynyl, 2-methyloxypentynyl, 1-methyloxypentynyl , 3,3-dimethyloxybutynyl, 2,2-dimethyloxybutynyl, 1,1-dimethyloxybutynyl, 1-methyl-2-methyloxy 1,3-dimethyloxybutynyl, 2,3-dimethyloxybutynyl, 2-ethyloxybutynyl, 1-methyloxyhexynyl , 2-methyloxyhexynyl, 3-methyloxyhexynyl, 4-methyloxyhexynyl, 5-methyloxyhexynyl, 1-propyloxybutynyl , 4-methyl-4-methyloxypentynyl, 1-methyloxyheptynyl, 2-methyloxyheptynyl, 3-methyloxyheptynyl, 4-methyl Oxyheptynyl, 5-methyloxyheptynyl, 6-methyloxyheptynyl, 1-propyloxypentynyl, 2-ethyloxyhexynyl, 5-methyl -5-methyloxyhexynyl, 3-methyloxyoctynyl, 4-methyloxyoctynyl, 5-methyloxyoctynyl, 6-methyloxyoctynyl , 1-propyloxyhexynyl, 2-ethyloxyheptynyl, 6-methyl-6-methyloxyheptynyl, 1-methyloxynonynyl, 3-methyl Oxynonynyl, 8-methyloxynonynyl, 3-ethyloxyoctynyl, 3-methyl-7-methyloxyoctynyl, 7,7-dimethyloxy Octynyl, 4-methyl-8-methyloxynonynyl, 3,7-dimethyl-11-methyloxydodedecynyl, 4,8-dimethyl-12-methyl Oxytridecynyl, 1-methyloxypentadecynyl, 14-methyloxypentadeynyl, 13-methyl-13-methyloxytetradecynyl, 15-methyloxy 1-hexadeynyl, 1-methyloxyheptadetynyl, and 3,7,11-trimethyl-15-methyloxyhexadeynyl, which have 1 or 2 carbon atoms such as oxygen atoms Alkynyl of number 3-20; 1-(N-methylamino)ethynyl, 2-(N-methylamino)ethynyl, 1-(N-methylamino)propynyl, 2-(N-methyl Baseamino)propynyl, 3-(N-methylamino)propynyl, 2-(N-ethylamino)ethynyl, 2-(N,N-dimethylamino)ethynyl, 1-( N-methylamino)butynyl, 2-(N-methylamino)butynyl, 3-(N-methylamino)butynyl, 2-(N-ethylamino)propynyl, 3 -(N,N-dimethylamino)propynyl, 4-(N-methylamino)pentynyl, 3-(N-methylamino)pentynyl, 2-(N-methylamino) Pentynyl, 1-(N-methylamino)pentynyl, 3-(N,N-dimethylamino)butynyl, 2-(N,N-dimethylamino)butynyl, 1 -(N,N-dimethylamino)butynyl, 1-methyl-2-(N-methylamino)butynyl, 1,3-bis(N-methylamino)butynyl, 2 , 3-bis(N-methylamino)butynyl, 2-(N-ethylamino)butynyl, 1-(N-methylamino)hexynyl, 2-(N-methylamino) Hexynyl, 3-(N-methylamino)hexynyl, 4-(N-methylamino)hexynyl, 5-(N-methylamino)hexynyl, 1-(N-propyl Amino)butynyl, 4-methyl-4-(N-methylamino)pentynyl, 1-(N-methylamino)heptynyl, 2-(N-methylamino)heptynyl, 3-(N-methylamino)heptynyl, 4-(N-methylamino)heptynyl, 5-(N-methylamino)heptynyl, 6-(N-methylamino)heptynyl Base, 1-(N-propylamino)pentynyl, 2-(N-ethylamino)hexynyl, 5-methyl-5-(N-methylamino)hexynyl, 3-(N Methylamino) octynyl, 4-(N-methylamino) octynyl, 5-(N-methylamino) octynyl, 6-(N-methylamino) octynyl, 1-( N-propylamino)hexynyl, 2-(N-ethylamino)heptynyl, 6-methyl-6-(N-methylamino)heptynyl, 1-(N-methylamino) Nonynyl, 3-(N-methylamino)nonynyl, 8-(N-methylamino)nonynyl, 3-(N-ethylamino)octynyl, 3-methyl-7- (N-methylamino)octynyl, 7,7-bis(N-methylamino)octynyl, 4-methyl-8-(N-methylamino)nonynyl, 3,7-bis Methyl-11-(N-methylamino)dodecynyl, 4,8-dimethyl-12-(N-methylamino)tridecynyl, 1-(N-methylamino)pentadeynyl Base, 14-(N-methylamino)pentadeynyl, 13-methyl-13-(N-methylamino)tetradecynyl, 15-(N-methylamino)hexadeynyl, 1 -(N-methylamino)heptadecanyl and 3,7,11-trimethyl-15-(N-methylamino)hexadeynyl and the like, the number of carbon atoms in which there are 1 or 2 nitrogen atoms 3-20 alkynyl; preferably C ₃ -C ₁₀ alkynyl containing heteroatoms.

In the above, "C ₂ -C ₂₀ alkynyl substituted by aryl or aromatic heterocyclic group" in the definition of R ^4a and R ¹¹ means that the aforementioned "C ₂ -C ₂₀ alkynyl" is replaced by 1 or 3 same or different A group substituted with the aforementioned "aryl" or the aforementioned "aromatic heterocyclic group".

In the above, examples of "C ₂ -C ₂₀ alkenyl" in the definitions of R ^4a and R ¹¹ include vinyl, 2-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl Base, 2-ethyl-2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-ethyl-2-butenyl , 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 2-pentenyl, 1-methyl -2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl Base, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, heptene Base, 1-methylhexenyl, 2-methylhexenyl, 3-methylhexenyl, 4-methylhexenyl, 5-methylhexenyl, 1-propylbutenyl, 4,4-dimethylpentenyl, octenyl, 1-methylheptenyl, 2-methylheptenyl, 3-methylheptenyl, 4-methylheptenyl, 5-methylheptenyl Heptenyl, 6-methylheptenyl, 1-propylpentenyl, 2-ethylhexenyl, 5,5-dimethylhexenyl, nonenyl, 3-methyloctene Base, 4-methyloctenyl, 5-methyloctenyl, 6-methyloctenyl, 1-propylhexenyl, 2-ethylheptenyl, 6,6-dimethylheptenyl Alkenyl, Decenyl, 1-Methylnonenyl, 3-Methylnonenyl, 8-Methylnonenyl, 3-Ethyloctenyl, 3,7-Dimethyloctenyl, 7,7-Dimethyloctenyl, Undecenyl, 4,8-Dimethylnonenyl, Dodecenyl, Tridecenyl, Tetradecenyl, Pentadecenyl Base, 3,7,11-trimethyldodecenyl, hexadecenyl, 4,8,12-trimethyltridecenyl, 1-methylpentadecenyl, 14- Methylpentadecenyl, 13,13-dimethyltetradecenyl, heptadecenyl, 15-methylhexadecenyl, octadecenyl, 1-methylheptadecenyl Alkenyl, nonadecenyl, eicosenyl, and 3,7,11,15-tetramethylhexadecenyl and other straight-chain or branched alkenyl groups with 2-20 carbon atoms, preferably C ₂ -C ₁₀ alkenyl.

In the above, "C ₃ -C ₂₀ alkenyl with heteroatoms" in the definition of R ^4a and R ¹¹ means "alkenyl with 3-20 carbon atoms" in the aforementioned "C ₂ -C ₂₀ alkenyl". "There are 1 or 2 identical or different sulfur atoms, oxygen atoms or nitrogen atoms, examples of which are 1-methylthiovinyl, 2-methylthiovinyl, 1-methylthiopropenyl, 2-methylthiopropenyl, 3-methylthiopropenyl, 2-ethylthiovinyl, 2-methyl-2-methylthiovinyl, 1-methylthiobutenyl, 2-methylthio 3-methylthiobutenyl, 3-methylthiobutenyl, 2-ethylthiopropenyl, 3-methyl-3-methylthiopropenyl, 4-methylthiopentenyl, 3-methylthiopentenyl Alkenyl, 2-methylthiopentenyl, 1-methylthiopentenyl, 3,3-dimethylthiobutenyl, 2,2-dimethylthiobutenyl, 1,1-di Methylthiobutenyl, 1-methyl-2-methylthiobutenyl, 1,3-dimethylthiobutenyl, 2,3-dimethylthiobutenyl, 2-ethylthiobutenyl Butenyl, 1-methylthiohexenyl, 2-methylthiohexenyl, 3-methylthiohexenyl, 4-methylthiohexenyl, 5-methylthiohexenyl, 1 -Propylthiobutenyl, 4-methyl-4-methylthiopentenyl, 1-methylthioheptenyl, 2-methylthioheptenyl, 3-methylthioheptenyl, 4 -Methylthioheptenyl, 5-methylthioheptenyl, 6-methylthioheptenyl, 1-propylthiopentenyl, 2-ethylthiohexenyl, 5-methyl-5 -Methylthiohexenyl, 3-methylthiooctenyl, 4-methylthiooctenyl, 5-methylthiooctenyl, 6-methylthiooctenyl, 1-propylthiohexyl Alkenyl, 2-ethylthioheptenyl, 6-methyl-6-methylthioheptenyl, 1-methylthiononenyl, 3-methylthiononenyl, 8-methylthiononenyl Alkenyl, 3-ethylthiooctenyl, 3-methyl-7-methylthiooctenyl, 7,7-dimethylthiooctenyl, 4-methyl-8-methylthiononene Base, 3,7-dimethyl-11-methylthiododecenyl, 4,8-dimethyl-12-methylthiotridecenyl, 1-methylthiopentadecenyl , 14-methylthiopentadecenyl, 13-methyl-13-methylthiotetradecenyl, 15-methylthiohexadecenyl, 1-methylthioheptadecenyl and 3,7,11-trimethyl-15-methylthiohexadecenyl and other alkenyl groups with 3 to 20 carbon atoms containing 1 or 2 sulfur atoms; 1-methyloxyvinyl , 2-methyloxyethenyl, 1-methoxypropenyl, 2-methoxypropenyl, 3-methoxypropenyl, 2-ethyloxyethenyl, 2-methyl -2-methyloxyvinyl, 1-methyloxybutenyl, 2-methyloxybutenyl, 3-methyloxybutenyl, 2-ethyloxypropenyl, 3 -Methyl-3-methyloxypropenyl, 4-methyloxypentenyl, 3-methyloxypentenyl, 2-methyloxypentenyl, 1-methyloxypentenyl Alkenyl, 3,3-dimethyloxybutenyl, 2,2-dimethyloxybutenyl, 1,1-dimethyloxybutenyl, 1-methyl-2-methyl oxybutenyl, 1,3-dimethyloxybutenyl, 2,3-dimethyloxybutenyl, 2-ethyloxybutenyl, 1-methyloxybutenyl Alkenyl, 2-methyloxyhexenyl, 3-methyloxyhexenyl, 4-methyloxyhexenyl, 5-methyloxyhexenyl, 1-propyloxybutanyl Alkenyl, 4-methyl-4-methyloxypentenyl, 1-methyloxyheptenyl, 2-methyloxyheptenyl, 3-methyloxyheptenyl, 4- Methyloxyheptenyl, 5-methyloxyheptenyl, 6-methyloxyheptenyl, 1-propyloxypentenyl, 2-ethyloxyhexenyl, 5- Methyl-5-methyloxyhexenyl, 3-methyloxyoctenyl, 4-methyloxyoctenyl, 5-methyloxyoctenyl, 6-methyloxyoctene Alkenyl, 1-propyloxyhexenyl, 2-ethyloxyheptenyl, 6-methyl-6-methyloxyheptenyl, 1-methyloxynonenyl, 3- Methyloxynonenyl, 8-methyloxynonenyl, 3-ethyloxyoctenyl, 3-methyl-7-methyloxyoctenyl, 7,7-dimethyl Oxyoctenyl, 4-methyl-8-methyloxynonenyl, 3,7-dimethyl-11-methyloxydodecenyl, 4,8-dimethyl-12 -Methyloxytridecenyl, 1-methyloxypentadecenyl, 14-methyloxypentadecenyl, 13-methyl-13-methyloxytetradecenyl 15-methyloxyhexenyl, 1-methyloxyheptadecenyl, and 3,7,11-trimethyl-15-methyloxyhexadecenyl, among which 1 Or alkenyl group with 3-20 carbon atoms and 2 oxygen atoms; 1-(N-methylamino)vinyl, 2-(N-methylamino)vinyl, 1-(N-methylamino) Propyl, 2-(N-methylamino)propenyl, 3-(N-methylamino)propenyl, 2-(N-ethylamino)vinyl, 2-(N,N-dimethylamino ) vinyl, 1-(N-methylamino)butenyl, 2-(N-methylamino)butenyl, 3-(N-methylamino)butenyl, 2-(N-ethyl Amino)propenyl, 3-(N,N-dimethylamino)propenyl, 4-(N-methylamino)pentenyl, 3-(N-methylamino)pentenyl, 2-(N -Methylamino)pentenyl, 1-(N-methylamino)pentenyl, 3-(N,N-dimethylamino)butenyl, 2-(N,N-dimethylamino) Butenyl, 1-(N,N-dimethylamino)butenyl, 1-methyl-2-(N-methylamino)butenyl, 1,3-di(N-methylamino) Butenyl, 2,3-bis(N-methylamino)butenyl, 2-(N-ethylamino)butenyl, 1-(N-methylamino)hexenyl, 2-(N -Methylamino)hexenyl, 3-(N-methylamino)hexenyl, 4-(N-methylamino)hexenyl, 5-(N-methylamino)hexenyl, 1- (N-propylamino)butenyl, 4-methyl-4-(N-methylamino)pentenyl, 1-(N-methylamino)heptenyl, 2-(N-methylamino ) heptenyl, 3-(N-methylamino)heptenyl, 4-(N-methylamino)heptenyl, 5-(N-methylamino)heptenyl, 6-(N-methyl ylamino)heptenyl, 1-(N-propylamino)pentenyl, 2-(N-ethylamino)hexenyl, 5-methyl-5-(N-methylamino)hexenyl , 3-(N-methylamino)octenyl, 4-(N-methylamino)octenyl, 5-(N-methylamino)octenyl, 6-(N-methylamino)octyl Alkenyl, 1-(N-propylamino)heptenyl, 2-(N-ethylamino)heptenyl, 6-methyl-6-(N-methylamino)heptenyl, 1-( N-methylamino)nonenyl, 3-(N-methylamino)nonenyl, 8-(N-methylamino)nonenyl, 3-(N-ethylamino)octenyl, 3 -Methyl-7-(N-methylamino)octenyl, 7,7-bis(N-methylamino)octenyl, 4-methyl-8-(N-methylamino)nonenyl , 3,7-dimethyl-11-(N-methylamino) dodecenyl, 4,8-dimethyl-12-(N-methylamino) tridecenyl, 1-( N-methylamino)pentadecenyl, 14-(N-methylamino)pentadecenyl, 1 3-methyl-13-(N-methylamino)tetradecenyl, l5- (N-methylamino)hexadecenyl, 1-(N-methylamino)heptadecenyl and 3,7,11-trimethyl-15-(N-methylamino)hexadecanyl Alkenyl having 3 to 20 carbon atoms such as alkenyl having 1 or 2 nitrogen atoms therein; preferably C ₃ -C ₁₀ alkenyl having heteroatoms therein.

In the above, "C ₂ -C ₂₀ alkenyl substituted by aryl or aromatic heterocyclic group" in the definition of R ^4a and R ¹¹ means that the aforementioned "C ₂ -C ₂₀ alkenyl" is replaced by 1 or 3 identical Or a different group substituted with the aforementioned "aryl" or the aforementioned "aromatic heterocyclic group".

In the above, in the definition of R ^4a and R ¹¹ , "a C ₂ -C 20 alkyl group with a heteroatom substituted by an aryl group or an aromatic heterocyclic group" means the aforementioned "C ₂ -C ₂₀ alkyl group with a heteroatom in _it ". "group" is substituted by 1 or 3 identical or different aforementioned "aryl groups" or aforementioned "aromatic heterocyclic groups".

"Lipase" used in the present invention is not particularly limited, and the most suitable lipase is different with the kind of raw material compound, preferably by Pseudomonas sp (Pseudomonas sp), Pseudomonas fluorescens (Pseudomonas fluorescens), Pseudomonas cepacia Pseudomonas cepacia, Chromobacterium viscosum, Aspergillus niger, Aspergillus oryzae, Candida antarctica, Candidacylindracea, Candida lipolytica, Candida wrinkled ( Candidarugosa), Candida utilis, Penicillium roqueforti, Rhizopus arrhizus, Rhizopus delemar, Rhizopus javanicus, Rhizomucor miehei, Rhizopus niveus, Humicola lanuginosa, Mucor javanicus, Mucor miehei, Thermus aquaticus, Thermus flavus, Thermus thermophilus Bacteria (Thermus thermophilus) etc. or lipase obtained from human pancreas, porcine (hog) pancreas, porcine (porcine) pancreas, wheat germ. Not only can the enzyme be partially or completely purified, but it can also be used in an immobilized form. An enzyme obtained by immobilizing Pseudomonas (for example, immobilized lipase from Pseudomonas (TOYOBA Corporation)) is most preferable.

The most preferred vinyl carboxylate derivatives (R ¹¹ COOCH-CH ₂ ) of the formula (XLIII) used in the present invention vary with the type of raw material compound, and vinyl n-hexanoate, vinyl n-heptanoate, n-pentyl vinyl linear aliphatic carboxylic acid vinyl esters such as vinyl acetate and vinyl acetate, most preferably vinyl n-hexanoate.

"Pharmacologically acceptable salt thereof" means that the compound of the general formula (I) of the present invention reacts with an acid in the case of having a basic group such as an amino group, or reacts with an acid in the case of having an acidic group such as a carboxyl group. A salt formed by reacting with a base.

Salts based on basic groups are preferably hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide, and inorganic acid salts such as nitrates, perchlorates, sulfates, and phosphates ;Methanesulfonate, trifluoromethanesulfonate, ethanesulfonate and other lower alkanesulfonates, benzenesulfonate, arylsulfonate such as p-toluenesulfonate, acetate, malic acid Salt, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate and other organic acid salts; and glycinate, lysine salt, arginine salt, ornithine Amino acid salts such as acid salts, glutamic acid salts, and aspartic acid salts. Organic acid salts are most preferred.

On the other hand, salts based on acidic groups are preferably alkali metal salts such as sodium salts, potassium salts, and lithium salts, alkaline earth metal salts such as calcium salts and magnesium salts, metal salts such as aluminum salts and iron salts; Class of inorganic salts, tert-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, Diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl Amine salts such as organic salts such as phenethylamine salts, piperazine salts, tetramethylammonium salts, and tris(hydroxymethyl)aminomethane salts; and glycinate, lysine salts, arginine salts, ornithine salts Amino acid salts such as salt, glutamate, and aspartate.

The compound with general formula (I) of the present invention, its pharmacologically acceptable salt, its ester or other derivatives are placed in the atmosphere or due to recrystallization will absorb water, bring adsorption water, and form hydrates, such hydration are also included within the scope of the salts of the present invention.

The compounds with general formula (I), their pharmacologically acceptable salts, their esters or other derivatives of the present invention have asymmetric carbon atoms in their molecules, so there are optical isomers. The optical isomers and the mixture of optical isomers of the compound of the present invention are represented by a single formula, ie general formula (I). Therefore, the present invention includes all optical isomers and mixtures of optical isomers in arbitrary ratios. For example, the compound of the present invention with general formula (I), its pharmacologically acceptable salt, its ester or other derivatives have the following formula:

In the above formula, the -NR ¹ R ² group is connected to an asymmetric carbon atom, and compounds with R absolute configuration are particularly preferred.

The above-mentioned "ester" refers to the ester formed by the compound (I) of the present invention. Examples of such ester include "ester of hydroxyl group" and "ester of carboxyl group", and various ester residues refer to "general protective group in the reaction" Or "a protecting group that can be cleaved by biological methods such as hydrolysis in vivo".

"General protective group in the reaction" refers to a protective group that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, and photolysis.

"General protective group during reaction" and "protective group cleavable by biological methods such as in vivo hydrolysis" in "ester of hydroxy" have the same meaning as the aforementioned "protective group of hydroxy".

The "general protective group in the reaction" in "carboxyl ester" is preferably the aforementioned "lower alkyl"; vinyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl- 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3 -Methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1 -Ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, Lower alkenyl such as 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl; ethynyl, 2-propynyl, 1-methyl -2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl Base, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 3-pentynyl, 1-methyl Base-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hex Lower alkynyl such as alkynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl; the aforementioned "halogenated lower alkyl"; 2-hydroxyethyl, 2,3-dihydroxypropyl Hydroxyl "lower alkyl" such as , 3-hydroxypropyl, 3,4-dihydroxybutyl, 4-hydroxybutyl; "lower aliphatic acyl"-"lower alkyl" such as acetylmethyl ; the aforementioned "aralkyl group"; the aforementioned "silyl group".

"Protecting group that can be cleaved by biological methods such as hydrolysis in vivo" refers to a protecting group that can be cleaved by biological methods such as hydrolysis in the human body to generate free acid or its salt. Whether it is such a derivative, it can be administered intravenously Injection is administered to experimental animals such as rats or mice, and then the body fluids of the animals are analyzed to determine whether the original compound or its pharmacologically acceptable salt can be detected. The "protecting group that can be cleaved by biological methods such as hydrolysis in vivo" in "ester of carboxyl group" is preferably methoxyethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl , 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxyethyl, ethoxymethyl, Lower alkoxy lower alkyl such as n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, tert-butoxymethyl; 2-methoxyethoxymethyl and the like lower alkoxylated lower alkoxy lower alkyl; "aryl" oxy "lower alkyl" such as phenoxymethyl; 2,2,2-trichloroethoxymethyl, di( "Alkoxyalkyl" such as halogenated lower alkoxy lower alkyl such as 2-chloroethoxy)methyl; "lower alkoxy"carbonyl"lower alkyl such as methoxycarbonylmethyl ""; "cyano"lower alkyl"" such as cyanomethyl, 2-cyanoethyl; ""lower alkyl"thiomethyl" such as methylthiomethyl, ethylthiomethyl "aryl" thiomethyl" such as phenylthiomethyl and naphthylthiomethyl; "maybe" such as 2-methylsulfonylethyl and 2-trifluoromethylsulfonylethyl "Lower alkyl" sulfonyl "lower alkyl"" substituted by halogen; ""aryl"sulfonyl "lower alkyl"" such as 2-benzenesulfonylethyl, 2-toluenesulfonylethyl; the foregoing "1-(acyloxy)"lower alkyl""; the aforementioned "2-benzo[c]furanonyl"; the aforementioned "aryl"; the aforementioned "lower alkyl"; alkyl”; and “amide-forming residues of amino acids” such as phenylalanine.

"Other derivatives" refer to derivatives other than the above-mentioned "pharmacologically acceptable salts" and the above-mentioned "esters" formed by the compounds of the general formula (I) of the present invention having amino and/or carboxyl groups . Examples of such derivatives are amide derivatives such as acyl groups.

The specific example of the compound with general formula (I) of the present invention has the compound listed in the following table 1 and table 2, the specific example of the compound with general formula (La) and (La-1) of the present invention has the following table 3 and the compounds listed in Table 4, but the present invention is not limited to these compounds.

The abbreviations in the table are as follows:

Ac ： Acetyl

Boc : tert-butoxycarbonyl

Bpyrr: benzopyrrolyl

Bu : Butyl

iBu : Isobutyl

Bz : Benzyl

Bzt : Benzothienyl

Et : ethyl

Fur ： furyl

cHx : cyclohexyl

Me : methyl

Np(1): Naphthalene-1-yl

Np(2): Naphthalene-2-yl

Ph ： phenyl

cPn : cyclopentyl

Pr : Propyl

iPr : Isopropyl

Pyr : pyridyl

TBDMS: tert-butyldimethylsilyl

The ： Thienyl

[Table 1]

[Table 2]

In Tables 1 and 2 above,

Preferred compounds of the present invention (I) are the following numbered exemplified compounds:

1-19, 1-23～1-32, 1-36～1-45, 1-49～1-58, 1-62～1-71, 1-75～1-84, 1-88～1- 102, 1-106～1-156, 1-160～1-214, 1-218～1-268, 1-272～1-322, 1-325～1-334, 1-338～1-347, 1-351～1-360, 1-364～1-373, 1-377～1-386, 1-390～1-404, 1-408～1-458, 1-462～1-513, 1- 517～1-526, 1-530～1-544, 1-548～1-598, 1-602～1-657, 1-670, 1-674～1-683, 1-696, 1-700～ 1-717, 1-721～1-730, 1-734～1-743, 1-747～1-756, 1-760～1-774, 1-778～1-828, 1-832～1- 886, 1-890～1-940, 1-944～1-993, 1-997～1-1006, 1-1010～1-1019, 1-1045, 1-1049～1-1058, 1-1062～ 1-1076, 1-1080～1-1130, 1-1134～1-1185, 1-1189～1-1198, 1-1202～1-1208, 1-1212～1-1216, 1-1220～1- 1270, 1-1274～1-1331, 1-1335～1-1344, 1-1348～1-1357, 1-1361～1-1370, 1-1374～1-1387, 1-1391～1-1400, 1-1404～1-1418, 1-1422～1-1472, 1-1476～1-1527, 1-1531～1-1540, 1-1544～1-1558, 1-1562～1-1612, 1- 1616～1-1673, 1-1677～1-1686, 1-1690～1-1699, 1-1703～1-1712, 1-1716～1-1729, 1-1733～1-1744, 1-1748～ 1-1767, 1-1772～1-1793, 1-1797～1-1818, 1-1824～1-1846, 1-1850～1-1869, 1-1872, 1-1876, 1-1880, 1- 1884, 1-1888～1-1892, 1-1896, 1-1900, 1-1908～1-1913, 1-1917～1-1939, 1-1943～1-1966, 1-1970～1-1991, 1-1995～1-2013, 1-2017, 1-2021, 1-2025, 1-2029, 1-2033, 1-2037～1-2042, 1-2045～1-2068, 1-2072～1- 2089, 1-2093, 1-2097, 1-2101, 1-2105, 1-2109, 1-2113, 1-2117, 1-2121, 1-2125, 1-2129, 1-2133, 1-2135, 1-2139～1-2158, 1-2161～1-2164, 1-2184～1-2346,

2-9～2-18, 2-22～2-43, 2-47～2-70, 2-74～2-96, 2-100～2-119, 2-142, 2-146, 2- 150, 2-154, 2-158～2-163, 2-167～2-183, 2-185～2-189, 2-193～2-216, 2-220～2-241, 2-245～ 2-263, 2-267, 2-271, 2-275, 2-279, 2-283, 2-287～2-292, 2-296～2-318, 2-322～2-338, 2- 343, 2-347, 2-351, 2-371, 2-375～2-377, 2-381～2-407

,

More preferred are the compounds numbered below:

1-19, 1-32, 1-36～1-45, 1-57, 1-62～1-71, 1-84, 1-88, 1-97～1-100, 1-152～1- 154, 1-160～1-214, 1-218～1-227, 1-264～1-268, 1-272～1-322, 1-334, 1-347, 1-360, 1-373, 1-386, 1-390～1-402, 1-454～1-458, 1-462～1-513, 1-526, 1-530～1-542, 1-594～1-598, 1- 602～1-653, 1-743, 1-756, 1-760～1-768, 1-770～1-774, 1-778～1828, 1-832～1-886, 1-890～1- 940, 1-944～1-993, 1-1045, 1-1058, 1-1062～1-1074, 1-1126～1-1130, 1-1134～1-1185, 1-1198, 1-1202～ 1-1208, 1-1212, 1-1213, 1-1214, 1-1266～1-1270, 1-1274～1-1331, 1-1344, 1-1348～1-1357, 1-1370, 1- 1374～1-1387, 1-1400, 1-1404～1-1416, 1-1468～1-1472, 1-1476～1-1527, 1-1540, 1-1544～1-1556, 1-1608～ 1-1612, 1-1616～1-1666, 1-1729, 1-1742, 1-1744, 1-1759～1-1767, 1-1789～1-1793, 1-1797～1-1818, 1- 1842～1-1846, 1-1900, 1-1908～1-1913, 1-1935～1-1939, 1-1943～1-1966, 1-1987～1-1991, 1-2013, 1-2017, 1-2029, 1-2033, 1-2037～1-2042, 1-2064～1-2068, 1-2072～1-2089, 1-2093, 1-2097, 1-2101, 1-2105, 1- 2109, 1-2129, 1-2133, 1-2135, 1-2184～1-2346,

2-11～2-18, 2-39～2-43, 2-47～2-70, 2-185～2-189, 2-193～2-216, 2-287～2-292, 2- 338, 2-343, 2-347, 2-351,

Even more preferred are the compounds numbered below:

1-45, 1-71, 1-84, 1-88, 1-97～1-100, 1-152～1-154, 1-160～1-206, 1-209～1-212, 1- 264～1-266, 1-334, 1-373, 1-386, 1-390～1-402, 1-454～1-458, 1462～1-485, 1-509, 1-510, 1- 513, 1-526, 1-530～1-542, 1-594～1-598, 1-602～1-613, 1-649, 1-650, 1-743, 1-756, 1-760～ 1-768, 1-770～1-772, 1-824～1-828, 1-832～1-884, 1-936, 1-1045, 1-1058, 1-1062～1-1074, 1- 1126～1-1130, 1-1134～1-1145, 1-1148～1-1151, 1-1162, 1-1163, 1-1179～1-1182, 1-1185, 1-1198, 1-1202～ 1-1208, 1-1212, 1-1213, 1-1214, 1-1266～1-1270, 1-1274～1-1285, 1-1288～1-1291, 1-1319～1-1322, 1- 1329～1-1331, 1-1344, 1-1348～1-1357, 1-1370, 1-1387, 1-1400, 1-1404～1-1416, 1-1468～1-1472, 1-1476～ 1-1487, 1-1490～1-1493, 1-1504, 1-1505, 1-1521～1-1524, 1-1527, 1-1540, 1-1544～1-1556, 1-1608～1- 1612, 1-1616～1-1627, 1-1663, 1-1664, 1-1729, 1-1742, 1-1744, 1-1761～1-1766, 1-1789～1-1791, 1-1815～ 1-1818, 1-1900, 1-1909, 1-1962, 1-2064～1-2066, 1-2089, 1-2093, 1-2097, 1-2105, 1-2133, 1-2216～1- 2288, 1-2290～1-2346,

Further more preferred exemplary compounds are as follows:

1-71: 2-Amino-2-methyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol,

1-84: 2-Amino-2-methyl-4-[5-(4-phenylbutyl)thiophen-2-yl]butan-1-ol,

1-98: 2-Amino-2-methyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,

1-152: 2-Amino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butan-1-ol,

1-210: 2-Amino-2-methyl-4-[5-(6-cyclohexylhexyl)thiophen-2-yl]butan-1-ol,

1-264: 2-Amino-2-methyl-4-[5-(6-phenylhexyl)thiophen-2-yl]butan-1-ol,

1-373: 2-Amino-2-methyl-4-[5-(3-cyclohexyloxypropyl)thiophen-2-yl]butan-1-ol,

1-386: 2-Amino-2-methyl-4-[5-(3-phenoxypropyl)thiophen-2-yl]butan-1-ol,

1-400: 2-amino-2-methyl-4-[5-(4-cyclohexyloxybutyl)thiophen-2-yl]butan-1-ol,

1-454: 2-Amino-2-methyl-4-[5-(4-phenoxybutyl)thiophen-2-yl]butan-1-ol,

1-509: 2-Amino-2-methyl-4-[5-(5-cyclohexyloxypentyl)thiophen-2-yl]butan-1-ol,

1-510: 2-Amino-2-methyl-4-[5-(5-phenoxypentyl)thiophen-2-yl]butan-1-ol,

1-513: 2-Amino-2-methyl-4-[5-(3-cyclohexylmethoxypropyl)thiophen-2-yl]butan-1-ol,

1-743: 2-Amino-2-methyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

1-756: 2-Amino-2-methyl-4-[5-(4-phenylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

1-770: 2-Amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

1-824: 2-Amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

1-882: 2-Amino-2-methyl-4-[5-(6-cyclohexylhex-1-ynyl)thiophen-2-yl]butan-1-ol,

1-936: 2-Amino-2-methyl-4-[5-(6-phenylhex-1-ynyl)thiophen-2-yl]butan-1-ol,

1-1045: 2-Amino-2-methyl-4-[5-(3-cyclohexyloxypropynyl)thiophen-2-yl]butan-1-ol,

1-1058: 2-Amino-2-methyl-4-[5-(3-phenoxypropynyl)thiophen-2-yl]butan-1-ol,

1-1072: 2-Amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

1-1126: 2-Amino-2-methyl-4-[5-(4-phenoxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

1-1181: 2-Amino-2-methyl-4-[5-(5-cyclohexyloxypent-1-ynyl)thiophen-2-yl]butan-1-ol,

1-1182: 2-Amino-2-methyl-4-[5-(5-phenoxypent-1-ynyl)thiophen-2-yl]butan-1-ol,

1-1185: 2-Amino-2-methyl-4-[5-(3-cyclohexylmethoxypropynyl)thiophen-2-yl]butan-1-ol,

1-1329: 2-Amino-2-methyl-4-[5-(4-cyclohexylbutyryl)thiophen-2-yl]butan-1-ol,

1-1330: 2-Amino-2-methyl-4-[5-(4-phenylbutyryl)thiophen-2-yl]butan-1-ol,

1-1331: 2-Amino-2-methyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,

1-1344: 2-Amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol,

1-1357: 2-Amino-2-methyl-4-[5-(6-cyclohexylhexanoyl)thiophen-2-yl]butan-1-ol,

1-1370: 2-Amino-2-methyl-4-[5-(6-phenylhexanoyl)thiophen-2-yl]butan-1-ol,

1-1387: 2-Amino-2-methyl-4-[5-(3-cyclohexyloxypropionyl)thiophen-2-yl]butan-1-ol,

1-1400: 2-Amino-2-methyl-4-[5-(3-phenoxypropionyl)thiophen-2-yl]butan-1-ol,

1-1414: 2-Amino-2-methyl-4-[5-(4-cyclohexylbutyryl)thiophen-2-yl]butan-1-ol,

1-1468: 2-Amino-2-methyl-4-[5-(4-phenoxybutyryl)thiophen-2-yl]butan-1-ol,

1-1523: 2-Amino-2-methyl-4-[5-(5-cyclohexyloxypentanoyl)thiophen-2-yl]butan-1-ol,

1-1524: 2-Amino-2-methyl-4-[5-(5-phenoxypentanoyl)thiophen-2-yl]butan-1-ol,

1-1527: 2-Amino-2-methyl-4-[5-(3-cyclohexylmethoxypropionyl)thiophen-2-yl]butan-1-ol,

1-1729: 2-Amino-2-methyl-4-[5-(4-cyclohexylmethoxyphenyl)thiophen-2-yl]butan-1-ol,

1-1742: 2-Amino-2-methyl-4-[5(4-cyclohexylethoxyphenyl)thiophen-2-yl]butan-1-ol,

1-1744: 2-Amino-2-methyl-4-[5-(4-benzyloxyphenyl)thiophen-2-yl]butan-1-ol,

1-1761: 2-Amino-2-ethyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol,

1-1764: 2-Amino-2-ethyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,

1-1816: 2-Amino-2-ethyl-4-[5-(6-cyclohexylhexyl)thiophen-2-yl]butan-1-ol,

1-1900: 2-Amino-2-ethyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

1-1909: 2-Amino-2-ethyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

1-1962: 2-Amino-2-ethyl-4-[5-(6-cyclohexylhex-1-ynyl)thiophen-2-yl]butan-1-ol,

1-2089: 2-Amino-2-ethyl-4-[5-(4-cyclohexylbutyryl)thiophen-2-yl]butan-1-ol,

1-2097: 2-Amino-2-ethyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol and

1-2105: 2-Amino-2-ethyl-4-[5-(6-cyclohexylhexanoyl)thiophen-2-yl]butan-1-ol and

1-463: 2-Amino-2-methyl-4-{5-[4-(4-fluorophenoxy)butyl]thiophen-2-yl}butan-1-ol,

1-479: 2-Amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butyl]thiophen-2-yl}butan-1-ol,

1-594: 2-Amino-2-methyl-4-[5-(4-benzyloxybutyl)thiophen-2-yl]butan-1-ol,

1-760: 2-Amino-2-methyl-4-{5-[4-(4-fluorophenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-761: 2-Amino-2-methyl-4-{5-[4-(4-methylphenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-762: 2-Amino-2-methyl-4-{5-[4-(4-ethylphenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-763: 2-Amino-2-methyl-4-{5-[4-(4-trifluoromethylphenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-764: 2-Amino-2-methyl-4-{5-[4-(4-methoxyphenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-765: 2-Amino-2-methyl-4-{5-[4-(4-ethoxyphenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-766: 2-Amino-2-methyl-4-{5-[4-(4-methylthiophenyl)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-832: 2-Amino-2-methyl-4-{5-[5-(3-fluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-833: 2-Amino-2-methyl-4-{5-[5-(4-fluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-834: 2-Amino-2-methyl-4-{5-[5-(4-chlorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-836: 2-Amino-2-methyl-4-{5-[5-(3-methylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-837: 2-Amino-2-methyl-4-{5-[5-(4-methylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-846: 2-Amino-2-methyl-4-{5-[5-(3-trifluoromethylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-847: 2-Amino-2-methyl-4-{5-[5-(4-trifluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-848: 2-Amino-2-methyl-4-{5-[5-(3-methoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-849: 2-Amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-860: 2-Amino-2-methyl-4-{5-[5-(3-methylthiophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-861: 2-Amino-2-methyl-4-{5-[5-(4-methylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-877: 2-Amino-2-methyl-4-{5-[5-(3,4-dimethylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol ,

1-878: 2-Amino-2-methyl-4-{5-[5-(3,5-dimethylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol ,

1-1050: 2-Amino-2-methyl-4-{5-[3-(4-methylcyclohexyloxy)propynyl]thiophen-2-yl}butan-1-ol,

1-1062: 2-Amino-2-methyl-4-{5-[3-(4-fluorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-1063: 2-Amino-2-methyl-4-{5-[3-(4-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-1064: 2-Amino-2-methyl-4-{5-[3-(4-ethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-1065: 2-Amino-2-methyl-4-{5-[3-(4-trifluoromethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-1066: 2-Amino-2-methyl-4-{5-[3-(4-methoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-1067: 2-Amino-2-methyl-4-{5-[3-(4-ethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-1068: 2-Amino-2-methyl-4-{5-[3-(4-methylthiophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-1134: 2-Amino-2-methyl-4-{5-[4-(3-fluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-1135: 2-Amino-2-methyl-4-{5-[4-(4-fluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-1136: 2-Amino-2-methyl-4-{5-[4-(4-chlorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-1138: 2-Amino-2-methyl-4-{5-[4-(3-methylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-1139: 2-Amino-2-methyl-4-{5-[4-(4-methylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-1148: 2-Amino-2-methyl-4-{5-[4-(3-trifluoromethylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol ,

1-1149: 2-Amino-2-methyl-4-{5-[4-(4-trifluoromethylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol ,

1-1150: 2-Amino-2-methyl-4-{5-[4-(3-methoxyphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-1151: 2-Amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-1162: 2-Amino-2-methyl-4-{5-[4-(3-methylthiophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-1163: 2-Amino-2-methyl-4-{5-[4-(4-methylthiophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-1179: 2-Amino-2-methyl-4-{5-[4-(3,4-dimethylphenoxy)but-1-ynyl]thiophen-2-yl}but-1- alcohol,

1-1180: 2-Amino-2-methyl-4-{5-[4-(3,5-dimethylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1- alcohol,

1-1198: 2-Amino-2-methyl-4-[5-(3-phenylmethoxypropynyl)thiophen-2-yl]butan-1-ol,

1-1202: 2-Amino-2-methyl-4-{5-[3-(4-fluorophenyl)methoxypropynyl]thiophen-2-yl}butan-1-ol,

1-1203: 2-Amino-2-methyl-4-{5-[3-(4-methylphenyl)methoxypropynyl]thiophen-2-yl}butan-1-ol,

1-1204: 2-Amino-2-methyl-4-{5-[3-(4-ethylphenyl)methoxypropynyl]thiophen-2-yl}butan-1-ol,

1-1205: 2-Amino-2-methyl-4-{5-[3-(4-trifluoromethylphenyl)methoxypropynyl]thiophen-2-yl}butan-1-ol,

1-1206: 2-Amino-2-methyl-4-{5-[3-(4-methoxyphenyl)methoxypropynyl]thiophen-2-yl}butan-1-ol,

1-1207: 2-Amino-2-methyl-4-{5-[3-(4-ethoxyphenyl)methoxypropynyl]thiophen-2-yl}butan-1-ol,

1-1208: 2-Amino-2-methyl-4-{5-[3-(4-methylthiophenyl)methoxypropynyl]thiophen-2-yl}butan-1-ol,

1-1212: 2-Amino-2-methyl-4-[5-(4-cyclohexylmethoxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

1-1266: 2-Amino-2-methyl-4-[5-(4-phenylmethoxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

1-1274: 2-Amino-2-methyl-4-{5-[4-(3-fluorophenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,

1-1275: 2-Amino-2-methyl-4-{5-[4-(4-fluorophenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,

1-1276: 2-Amino-2-methyl-4-{5-[4-(4-chlorophenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol,

1-1278: 2-Amino-2-methyl-4-{5-[4-(3-methylphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol ,

1-1279: 2-Amino-2-methyl-4-{5-[4-(4-methylphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1-ol ,

1-1288: 2-Amino-2-methyl-4-{5-[4-(3-trifluoromethylphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1 -alcohol,

1-1289: 2-Amino-2-methyl-4-{5-[4-(4-trifluoromethylphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1 -alcohol,

1-1290: 2-Amino-2-methyl-4-{5-[4-(3-methoxyphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1- alcohol,

1-1291: 2-Amino-2-methyl-4-{5-[4-(4-methoxyphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan-1- alcohol,

1-1319: 2-Amino-2-methyl-4-{5-[4-(3,4-dimethylphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan- 1-alcohol,

1-1320: 2-Amino-2-methyl-4-{5-[4-(3,5-dimethylphenyl)methoxybut-1-ynyl]thiophen-2-yl}butan- 1-alcohol,

1-1348: 2-Amino-2-methyl 4-{5-[5-(4-fluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-1349: 2-Amino-2-methyl-4-{5-[5-(4-methylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-1350: 2-Amino-2-methyl-4-{5-[5-(4-ethylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-1351: 2-Amino-2-methyl-4-{5-[5-(4-trifluoromethylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-1352: 2-Amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-1353: 2-Amino-2-methyl-4-{5-[5-(4-ethoxyphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-1354: 2-Amino-2-methyl-4-{5-[5-(4-methylthiophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-1476: 2-Amino-2-methyl-4-{5-[4-(3-fluorophenoxy)butyryl]thiophen-2-yl}butan-1-ol,

1-1477: 2-Amino-2-methyl-4-{5-[4-(4-fluorophenoxy)butyryl]thiophen-2-yl}butan-1-ol,

1-1478: 2-Amino-2-methyl-4-{5-[4-(4-chlorophenoxy)butyryl]thiophen-2-yl}butan-1-ol,

1-1480: 2-Amino-2-methyl-4-{5-[4-(3-methylphenoxy)butyryl]thiophen-2-yl}butan-1-ol,

1-1481: 2-Amino-2-methyl-4-{5-[4-(4-methylphenoxy)butyryl]thiophen-2-yl}butan-1-ol,

1-1490: 2-Amino-2-methyl-4-{5-[4-(3-trifluoromethylphenoxy)butyryl]thiophen-2-yl}butan-1-ol,

1-1491: 2-Amino-2-methyl-4-{5-[4-(4-trifluoromethylphenoxy)butyryl]thiophen-2-yl}butan-1-ol,

1-1492: 2-Amino-2-methyl-4-{5-[4-(3-methoxyphenoxy)butyryl]thiophen-2-yl}butan-1-ol,

1-1493: 2-Amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butyryl]thiophen-2-yl}butan-1-ol,

1-1504: 2-Amino-2-methyl-4-{5-[4-(3-methylthiophenoxy)butyryl]thiophen-2-yl}butan-1-ol,

1-1505: 2-Amino-2-methyl-4-{5-[4-(4-methylthiophenoxy)butyryl]thiophen-2-yl}butan-1-ol,

1-1521: 2-Amino-2-methyl-4-{5-[4-(3,4-dimethylphenoxy)butyryl]thiophen-2-yl}butan-1-ol,

1-1522: 2-Amino-2-methyl-4-{5-[4-(3,5-dimethylphenoxy)butyryl]thiophen-2-yl}butan-1-ol,

1-2093: 2-Amino-ethyl-4-[5-(4-phenylbutyryl)thiophen-2-yl]butan-1-ol,

1-2101: 2-Amino-ethyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol,

1-2109: 2-Amino-ethyl-4-[5-(6-phenylhexanoyl)thiophen-2-yl]butan-1-ol,

1-2257: 2-Amino-2-methyl-4-{5-[5-(3,4-difluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-2258: 2-Amino-2-methyl-4-{5-[5-(3,5-difluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-2259: 2-Amino-2-methyl-4-{5-[5-(3-chlorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-2260: 2-Amino-2-methyl-4-{5-[5-(3,4-dichlorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-2261: 2-Amino-2-methyl-4-{5-[5-(3,5-dichlorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-2262: 2-Amino-2-methyl 4-{5-[5-(3,4-bis(trifluoromethyl)phenyl)pent-1-ynyl]thiophen-2-yl}butan- 1-alcohol,

1-2263: 2-Amino-2-methyl-4-{5-[5-(3,5-bis(trifluoromethyl)phenyl)pent-1-ynyl]thiophen-2-yl}butyl -1-ol,

1-2264: 2-Amino-2-methyl-4-{5-[5-(3,4-dimethoxyphenyl)pent-1ynyl]thiophen-2-yl}butan-1-ol ,

1-2265: 2-Amino-2-methyl-4-{5-[5-(3,5-dimethoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1- alcohol,

1-2266: 2-Amino-2-methyl-4-{5-[5-(3,4,5-trimethoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1 -alcohol,

1-2267: 2-Amino-2-methyl-4-{5-[5-(3-acetylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-2268: 2-Amino-2-methyl-4-{5-[5-(4-acetylphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-2269: 2-Amino-2-methyl-4-{5-[3-(3-fluorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2270: 2-Amino-2-methyl-4-{5-[3-(3,4-difluorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2271: 2-Amino-2-methyl-4-{5-[3-(3,5-difluorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2272: 2-Amino-2-methyl-4-{5-[3-(3-chlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2273: 2-Amino-2-methyl-4-{5-[3-(4-chlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2274: 2-Amino-2-methyl-4-{5-[3-(3,4-dichlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2275: 2-Amino-2-methyl-4-{5-[3-(3,5-dichlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2276: 2-Amino-2-methyl-4-{5-[3-(3-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2278: 2-amino-2-methyl-4-{5-[3-(3,4 dimethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2279: 2-Amino-2-methyl-4-{5-[3-(3,5-dimethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2280: 2-Amino-2-methyl-4-{5-[3-(3-trifluoromethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2281: 2-Amino-2-methyl-4-{5-[3-(3,4-bis(trifluoromethyl)phenoxy)propynyl]thiophen-2-yl}butan-1 -alcohol,

1-2282: 2-Amino-2-methyl-4-{5-[3-(3,5-bis(trifluoromethyl)phenoxy)propynyl]thiophen-2-yl}butan-1 -alcohol,

1-2283: 2-Amino-2-methyl-4-{5-[3-(3-methoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2284: 2-Amino-2-methyl-4-{5-[3-(3,4-dimethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2285: 2-Amino-2-methyl-4-{5-[3-(3,5-dimethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2286: 2-Amino-2-methyl-4-{5-[3-(3,4,5-trimethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol ,

1-2287: 2-Amino-2-methyl-4-{5-[3-(3-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2288: 2-Amino-2-methyl-4-{5-[3-(4-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2290: 2-Amino-2-methyl-4-{5-[4-(3,4-difluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol ,

1-2291: 2-Amino-2-methyl-4-{5-[4-(3,5-difluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol ,

1-2292: 2-Amino-2-methyl-4-{5-[4-(3-chlorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-2293: 2-Amino-2-methyl-4-{5-[4-(3,4-dichlorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol ,

1-2294: 2-Amino-2-methyl-4-{5-[4-(3,5-dichlorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol ,

1-2295: 2-Amino-2-methyl-4-{5-[4-(3,4-bis(trifluoromethyl)phenoxy)but-1-ynyl]thiophen-2-yl} Butan-1-ol,

1-2296: 2-Amino-2-methyl-4-{5-[4-(3,5-bis(trifluoromethyl)phenoxy)but-1-ynyl]thiophen-2-yl} Butan-1-ol,

1-2297: 2-Amino-2-methyl-4-{5-[4-(3,4-dimethoxyphenoxy)but-1-ynyl]thiophen-2-yl}butan-1 -alcohol,

1-2298: 2-Amino-2-methyl-4-{5-[4-(3,5-dimethoxyphenoxy)but-1-ynyl]thiophen-2-yl}butan-1 -alcohol,

1-2299: 2-Amino-2-methyl-4-{5-[4-(3,4,5-trimethoxyphenoxy)but-1-ynyl]thiophen-2-yl}butan- 1-alcohol,

1-2300: 2-amino-2-methyl-4-{5-[4-(3-acetylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-2301: 2-Amino-2-methyl-4-{5-[4-(4-acetylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-2328: 2-Amino-2-methyl-4-{5-[5-(3-fluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-2329: 2-Amino-2-methyl-4-{5-[5-(3,4-difluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-2330: 2-Amino-2-methyl-4-{5-[5-(3,5-difluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-2331: 2-Amino-2-methyl-4-{5-[5-(3-chlorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-2332: 2-Amino-2-methyl-4-{5-[5-(4-chlorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-2333: 2-Amino-2-methyl-4-{5-[5-(3,4-dichlorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-2334: 2-Amino-2-methyl-4-{5-[5-(3,5-dichlorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-2335: 2-Amino-2-methyl-4-{5-[5-(3-methylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-2336: 2-Amino-2-methyl-4-{5-[5-(3,4-dimethylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-2337: 2-Amino-2-methyl-4-{5-[5-(3,5-dimethylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-2338: 2-Amino-2-methyl-4-{5-[5-(3-trifluoromethylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-2339: 2-Amino-2-methyl-4-{5-[5-(3,4-bis(trifluoromethyl)phenyl)pentanoyl]thiophen-2-yl}butan-1-ol ,

1-2340: 2-Amino-2-methyl-4-{5-[5-(3,5-bis(trifluoromethyl)phenyl)pentanoyl]thiophen-2-yl}butan-1-ol ,

1-2341: 2-Amino-2-methyl-4-{5-[5-(3-methoxyphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-2342: 2-Amino-2-methyl-4-{5-[5-(3,4-dimethoxyphenyl)pentanoyl]thiophene 2-yl}butan-1-ol,

1-2343: 2-Amino-2-methyl-4-{5-[5-(3,5-dimethoxyphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-2344: 2-Amino-2-methyl-4-{5-[5-(3,4,5-trimethoxyphenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-2345: 2-Amino-2-methyl-4-{5-[5-(3-acetylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol and

1-2346: 2-Amino-2-methyl-4-{5-[5-(4-acetylphenyl)pentanoyl]thiophen-2-yl}butan-1-ol.

The most preferred compounds are as follows:

1-71: 2-Amino-2-methyl-4-[5-(4-cyclohexylbutyl)thiophen-2-yl]butan-1-ol,

1-98: 2-Amino-2-methyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,

1-152: 2-Amino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butan-1-ol,

1-400: 2-amino-2-methyl-4-[5-(4-cyclohexyloxybutyl)thiophen-2-yl]butan-1-ol,

1-463: 2-Amino-2-methyl-4-{5-[4-(4-fluorophenoxy)butyl]thiophen-2-yl}butan-1-ol,

1-479: 2-Amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butyl]thiophen-2-yl}butan-1-ol,

1-594: 2-Amino-2-methyl-4-[5-(4-benzyloxybutyl)thiophen-2-yl]butan-1-ol,

1-743: 2-Amino-2-methyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

1-756: 2-Amino-2-methyl-4-[5-(4-phenylbut-1-ynyl)thiophen-2-yl]butan-1-ol,

1-770: 2-Amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

1-824: 2-Amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

1-833: 2-Amino-2-methyl-4-{5-[5-(4-fluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-849: 2-Amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol,

1-1050: 2-Amino-2-methyl-4-{5-[3-(4-methylcyclohexyloxy)propynyl]thiophen-2-yl}butan-1-ol,

1-1063: 2-Amino-2-methyl-4-{5-[3-(4-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-1064: 2-Amino-2-methyl-4-{5-[3-(4-ethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-1068: 2-Amino-2-methyl-4-{5-[3-(4-methylthiophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-1072: 2-Amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

1-1135: 2-Amino-2-methyl-4-{5-[4-(4-fluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-1139: 2-Amino-2-methyl-4-{5-[4-(4-methylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol,

1-1185: 2-Amino-2-methyl-4-[5-(3-cyclohexylmethoxypropynyl)thiophen-2-yl]butan-1-ol,

1-1266: 2-Amino-2-methyl-4-[5-(4-phenylmethoxybut-1-ynyl)thiophen-2-yl]butan-1-ol,

1-1329: 2-Amino-2-methyl-4-[5-(4-cyclohexylbutyryl)thiophen-2-yl]butan-1-ol,

1-1330: 2-Amino-2-methyl-4-[5-(4-phenylbutyryl)thiophen-2-yl]butan-1-ol,

1-1331: 2-Amino-2-methyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,

1-1344: 2-Amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol,

1-1348: 2-Amino-2-methyl-4-{5-[5-(4-fluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol,

1-1764: 2-Amino-2-ethyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol,

1-1909: 2-Amino-2-ethyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol,

1-2097: 2-Amino-2-ethyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol,

1-2273: 2-Amino-2-methyl-4-{5-[3-(4-chlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2276: 2-Amino-2-methyl-4-{5-[3-(3-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2278: 2-Amino-2-methyl-4-{5-[3-(3,4-dimethylphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2283: 2-Amino-2-methyl-4-{5-[3-(3-methoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2284: 2-Amino-2-methyl-4-{5-[3-(3,4-dimethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2285: 2-Amino-2-methyl-4-{5-[3-(3,5-dimethoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol,

1-2287: 2-Amino-2-methyl-4-{5-[3-(3-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol and

1-2288: 2-Amino-2-methyl-4-{5-[3-(4-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol.

[table 3]

[Table 4]

In the above tables 3 and 4, preferably 3-5, 3-6, 3-7, 3-8, 3-11, 3-12, 4-4, 4-5, 4-6, 4-7, 4- 8, 4-9, 4-10, 4-11, 4-12, 4-13, 4-17, 4-23, 4-24, 4-27, 4-28, 4-31 and 4-32 compound.

The most preferred compounds are those numbered as follows:

4-4: 4-methyl-4-[(thiophen-3-yl)ethyl]oxazolidin-one,

4-5: 4-methyl-4-[(thiophen-3-yl)ethyl]oxazolidin-one,

4-8: 4-Methyl-4-[(5-bromothien-3-yl)ethyl]oxazolidin-one and

4-9: 4-Methyl-4-[(5-bromothien-3-yl)ethyl]oxazolidin-one.

Compounds (I), (XLIVa), (XLIVb), (La) and (Lb) of the present invention can be produced as follows.

Method A is the method for preparing compound (I) and compound (Ic), compound (Ic) is that in compound (I) R ¹ is a hydrogen atom; R ² is lower alkoxycarbonyl, aralkyloxycarbonyl or replaced by 1- A compound of aralkyloxycarbonyl substituted by three substituents selected from substituent group a.

Method A

In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X, Y and n represent the same meanings as above; R ⁸ represents formyl, carboxyl or lower alkoxycarbonyl; R ⁹ and R ^9a are the same or different, representing a hydrogen atom or a lower alkyl group; R ¹⁰ represents a lower alkyl group, an aralkyl group, or an aralkyl group substituted by 1-3 groups selected from substituent group a; R ^5a , R ^6a and R ^7a represent each R ⁵ , R ⁶ and R ⁷ substituents contained in the group amino, hydroxyl and/or carboxyl can be protected amino, hydroxyl and/or carboxyl group, and with R ^5. A group that is the same as the group defined in ^R6 and ^R7 .

The "protecting group" of the "amino group that can be protected" in the definition of R ^5a , R ^6a and R ^7a above is not particularly limited as long as it is a protecting group for an amino group used in the field of organic synthetic chemistry, and it means the same as above meaning, preferably lower alkoxycarbonyl, most preferably tert-butoxycarbonyl.

The "protecting group" of the "hydroxyl group that can be protected" in the definition of R ^5a , R ^6a and R ^7a above is not particularly limited as long as it is a protecting group for a hydroxyl group used in the field of organic synthesis chemistry, for example, it means the same as the aforementioned " The same meaning as the general protecting group in the reaction described in the ester of hydroxy, preferably lower aliphatic acyl, aromatic acyl, lower alkoxycarbonyl or (lower alkoxy) methyl, more preferably lower aliphatic acyl or (lower alkoxy)methyl, most preferably acetyl or methoxymethyl.

The "protecting group" of the "carboxyl group that can be protected" in the definition of R ^5a , R ^6a and R ^7a above is not particularly limited as long as it is a protecting group for a carboxyl group used in the field of organic synthetic chemistry, for example, it means the same as the aforementioned " The ester of carboxyl group has the same meaning as the general protecting group in the reaction described above, preferably lower alkyl, most preferably methyl.

Step A1 is the step of preparing a compound of general formula (III) by reacting a compound of general formula (II) with a reducing agent in an inert solvent in the presence or absence (preferably in the presence) of a base .

As long as the inert solvent used in the above-mentioned reaction is inert to this reaction, it is not particularly limited, and can be aliphatic hydrocarbons such as hexane, heptane, naphtha, sherwood oil and the like; Aromatic hydrocarbons like chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride and other halogenated hydrocarbons; acetic acid, methyl acetate, ethyl acetate, propyl acetate, butyl acetate esters, such as diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diglyme; methanol, ethanol, n- Alcohols such as propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; formamide, Amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoryl triamide; water; or water or a mixed solvent of the above solvents. Ethers are preferred (most preferably tetrahydrofuran).

The reducing agent used in the above reaction is, for example, alkali metal borohydrides such as sodium borohydride, lithium borohydride, sodium cyanoborohydride; diisobutylaluminum hydride, lithium aluminum hydride, lithium triethoxyaluminum hydride such as aluminum hydride compounds. Alkali metal borohydrides are preferred (most preferably sodium borohydride).

The reaction temperature varies depending on the starting compound, the reducing agent used, the type of solvent, etc., but is usually -50°C to 100°C (preferably 0°C to 50°C).

The reaction time varies depending on the starting compound, the reducing agent used, the solvent, the reaction temperature, etc., and is usually 15 minutes to 150 hours (preferably 1 hour to 100 hours).

After the reaction, the target compound (III) of this reaction can be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by the following operations: neutralize the reaction mixture properly, or filter it out when there is insoluble matter, and then add water and ethyl acetate and other immiscible organic solvents to separate the organic compound containing the target compound. The layer was washed with water and the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate and the like, and then the solvent was distilled off. If necessary, conventional methods, such as recrystallization, reprecipitation, etc., which are commonly used in the separation and purification of organic compounds, can be properly combined, chromatographed, and eluted with an appropriate eluent to separate and purify the obtained target compound .

Step A2 is the step of preparing a compound of general formula (IV), by converting the hydroxyl group of compound (III) into a leaving group in the presence of a base in an inert solvent, and then reacting it with an iodinating agent This is done by iodination of the leaving group.

Reagents that form leaving groups include: sulfonyl halides such as methanesulfonyl chloride and p-toluenesulfonyl chloride, thionyl halides such as thionyl chloride, thionyl bromide, and thionyl iodide, sulfonyl chloride, sulfonyl Sulfonyl halides such as acid bromide and sulfonyl iodide, phosphorus trihalides such as phosphorus trichloride, phosphorus tribromide and phosphorus triiodide, phosphorus pentachloride, phosphorus pentabromide, phosphorus pentaiodide Such as phosphorus pentahalides, halogenating agents such as phosphorus oxychloride, phosphorus oxybromide, phosphorus oxyiodide and other phosphorus oxyhalides; and rhenium reagents such as methyltrioxorhenium (VII). Sulfonyl halides are preferred.

Examples of bases used when converting a hydroxyl group into a leaving group are alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate; Salts; alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; lithium methoxide, sodium methoxide, sodium ethoxide, Alkali metal alkoxides such as potassium tert-butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino) Pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2. 2] Organic amines such as octane (DABCO) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Organic amines are preferred (most preferably triethylamine).

The inert solvent used when converting the hydroxyl group into a leaving group is not particularly limited as long as it is inert to the reaction, and can be aliphatic hydrocarbons such as hexane, heptane, naphtha, sherwood oil and the like; , toluene, xylene and other aromatic hydrocarbons; chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride and other halogenated hydrocarbons; diethyl ether, diisopropyl ether, tetrahydrofuran, Ethers such as dioxane, dimethoxyethane, and diglyme; ketones such as acetone and 2-butanone; formamide, dimethylformamide, dimethylacetamide, Amides such as hexamethylphosphamide; sulfoxides such as dimethyl sulfoxide; sulfolane. Halogenated hydrocarbons are preferred (most preferably dichloromethane).

The reaction temperature for converting a hydroxyl group into a leaving group varies depending on the starting compound, the reagent used, the type of solvent, etc., and is usually -50°C to 200°C (preferably -10°C to 150°C).

The reaction time for converting a hydroxyl group into a leaving group varies depending on the starting compound, reagent used, solvent, reaction temperature, etc., and is usually 15 minutes to 24 hours (preferably 30 minutes to 12 hours).

The iodide used in the above reaction is, for example, phosphorus pentaiodide, phosphorus oxyiodide, sodium iodide, potassium iodide, preferably sodium iodide.

The reaction temperature for iodination of the leaving group varies depending on the starting compound, the reagent used, the type of solvent, etc., and is usually 0°C to 200°C (preferably 10°C to 150°C).

The reaction time for iodination of the leaving group varies depending on the starting compound, reagent used, solvent, reaction temperature, etc., and is usually 15 minutes to 24 hours (preferably 30 minutes to 12 hours).

After the reaction, the target compound (IV) of this reaction can be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by the following operations: neutralize the reaction mixture properly, or filter it out when there is insoluble matter, and then add water and ethyl acetate and other immiscible organic solvents to separate the organic compound containing the target compound. The layer was washed with water and the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate and the like, and then the solvent was distilled off. If necessary, conventional methods, such as recrystallization, reprecipitation, etc., which are commonly used in the separation and purification of organic compounds, can be properly combined, chromatographed, and eluted with an appropriate eluent to separate and purify the obtained target compound .

Step A3 is a step of preparing a compound of general formula (VI) by reacting compound (IV) with a compound of general formula (V) in an inert solvent in the presence of a base.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the reaction, and can be, for example, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diglyme Ethers such as ethers; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl Alcohols such as cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoryl triamide; water; or water or a mixed solvent of the above solvents. Alcohols or amides are preferred (most preferably dimethylformamide).

The base used in the above reaction is, for example, the same base as that used for converting a hydroxyl group into a leaving group in step A2 of the aforementioned method A, preferably alkali metal hydrides or alkali metal alkoxides (most preferably sodium hydride).

The reaction temperature varies depending on the type of starting compound, base, solvent, etc., but is usually -78°C to 100°C (preferably 0°C to 50°C).

The reaction time varies depending on the starting compound, base, solvent, reaction temperature, etc., but is usually 15 minutes to 48 hours (preferably 30 minutes to 12 hours).

After the reaction, the target compound (VI) of this reaction can be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by the following operations: neutralize the reaction mixture properly, or filter it out when there is insoluble matter, and then add water and ethyl acetate and other immiscible organic solvents to separate the organic compound containing the target compound. The layer was washed with water and the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate and the like, and then the solvent was distilled off. If necessary, conventional methods, such as recrystallization, reprecipitation, etc., which are commonly used in the separation and purification of organic compounds, can be properly combined, chromatographed, and eluted with an appropriate eluent to separate and purify the obtained target compound .

Step A4 is a step for preparing a compound of general formula (VII), which is carried out by reacting compound (VI) with a base in an inert solvent to hydrolyze an ester group into a carboxyl group.

As long as the inert solvent used in the above-mentioned reaction is inert to this reaction, it is not particularly limited, and can be aliphatic hydrocarbons such as hexane, heptane, naphtha, sherwood oil and the like; aromatic hydrocarbons; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diglyme; methanol, ethanol, n-propanol, isopropanol Alcohols such as alcohol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve, or water or a mixed solvent of the above solvents . Alcohols are preferred (most preferably ethanol).

The base used in the above reaction is, for example, the same base as that used for converting the hydroxyl group into a leaving group in step A2 of the aforementioned method A, preferably alkali metal hydroxides (most preferably potassium hydroxide).

The reaction temperature varies depending on the type of starting compound, base, solvent, etc., but is usually -20°C to 200°C (preferably 0°C to 50°C).

The reaction time varies depending on the starting compound, base, solvent, reaction temperature, etc., and is usually 30 minutes to 120 hours (preferably 1 hour to 80 hours).

After the reaction, the target compound (VII) of this reaction can be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by the following operations: neutralize the reaction mixture properly, or filter it out when there is insoluble matter, and then add water and ethyl acetate and other immiscible organic solvents to separate the organic compound containing the target compound. The layer was washed with water and the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate and the like, and then the solvent was distilled off. If necessary, conventional methods, such as recrystallization, reprecipitation, etc., which are commonly used in the separation and purification of organic compounds, can be properly combined, layered, and eluted with an appropriate eluent to separate and purify the resulting target compound .

Step A5 is a step for preparing a compound of general formula (IX), which converts the carboxyl group of compound (VII) into a carbamate through Curtis rearrangement, which is carried out in an inert solvent under the presence of a base It is carried out by reacting compound (VII) with a diaryl phosphoryl azide derivative such as diphenyl phosphoryl azide in the presence of the compound, and then reacting it with a compound having the general formula (VIII) under heating.

As long as the inert solvent used in the above-mentioned reaction is inert to this reaction, it is not particularly limited, and can be aliphatic hydrocarbons such as hexane, heptane, naphtha, sherwood oil and the like; aromatic hydrocarbons; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyl Ethers such as oxyethane and diglyme; or water or a mixed solvent of the above solvents. Aromatic hydrocarbons are preferred (most preferably benzene).

The base used in the above reaction is, for example, the same base as that used for converting the hydroxyl group into a leaving group in step A2 of the aforementioned method A, preferably organic amines (most preferably triethylamine).

The reaction temperature when reacting the compound (VII) with the diaryl phosphoryl azide derivative and the reaction temperature when reacting with the compound (VIII) are different depending on the type of raw material compound, base, solvent, etc., usually 0 ° C to 200°C (preferably 20°C to 150°C).

The reaction time when making compound (VII) react with diaryl phosphoryl azide derivatives and the reaction time when reacting with compound (VIII) are all different with raw material compound, base, solvent, reaction temperature etc., are usually 15 minutes to 24 hours (preferably 30 minutes to 12 hours).

When compound (VII) is reacted with diaryl phosphoryl azide derivatives, the carboxyl group can be converted into carbamate.

After the reaction, the target compound (IX) of this reaction can be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by the following operations: neutralize the reaction mixture properly, or filter it out when there is insoluble matter, and then add water and ethyl acetate and other immiscible organic solvents to separate the organic compound containing the target compound. The layer was washed with water and the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate and the like, and then the solvent was distilled off. If necessary, conventional methods, such as recrystallization, reprecipitation, etc., which are commonly used in the separation and purification of organic compounds, can be properly combined, chromatographed, and eluted with an appropriate eluent to separate and purify the obtained target compound .

Step A6 is a step of preparing a compound having the general formula (X) by reducing an ester of compound (IX) by reacting compound (IX) with a reducing agent in an inert solvent.

As long as the inert solvent used in the above-mentioned reaction is inert to this reaction, it is not particularly limited, and can be aliphatic hydrocarbons such as hexane, heptane, naphtha, sherwood oil and the like; aromatic hydrocarbons; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyl Ethers such as oxyethane, diglyme; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin Alcohols such as , octanol, cyclohexanol, methyl cellosolve, or a mixed solvent of the above solvents. A mixed solvent of alcohols and ethers is preferred (a mixed solvent of ethanol and tetrahydrofuran is most preferred).

The reducing agent used in the above reaction is, for example, the same reducing agent used in step A1 of the aforementioned method A, preferably alkali metal borohydrides (most preferably sodium borohydride or lithium borohydride).

The reaction temperature varies depending on the starting compound, the type of solvent, etc., but is usually -78°C to 150°C (preferably -20°C to 50°C).

The reaction time varies depending on the starting compound, solvent, reaction temperature, etc., but is usually 5 minutes to 48 hours (preferably 30 minutes to 24 hours).

After the reaction, the target compound (X) of this reaction can be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by the following operations: neutralize the reaction mixture properly, or filter it out when there is insoluble matter, and then add water and ethyl acetate and other immiscible organic solvents to separate the organic compound containing the target compound. The layer was washed with water and the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate and the like, and then the solvent was distilled off. If necessary, conventional methods, such as recrystallization, reprecipitation, etc., which are commonly used in the separation and purification of organic compounds, can be properly combined, chromatographed, and eluted with an appropriate eluent to separate and purify the obtained target compound .

Step A7 is a step of preparing a compound of general formula (XI), which is carried out by reacting compound (X) with a base to form an oxazolidine ring by ring closure.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the reaction, and can be, for example, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diglyme Ethers such as ethers; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl Alcohols such as cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoryl triamide; water; or water or a mixed solvent of the above solvents. Alcohols or amides are preferred (most preferably dimethylformamide).

The base used in the above reaction is, for example, the same base as that used for converting the hydroxyl group into a leaving group in step A2 of the aforementioned method A, preferably alkali metal alkoxides (most preferably potassium tert-butoxide).

The reaction temperature varies depending on the type of starting compound, base, solvent, etc., but is usually -78°C to 100°C (preferably -50°C to 50°C).

The reaction time varies depending on the starting compound, base, solvent, reaction temperature, etc., but is usually 15 minutes to 48 hours (preferably 30 minutes to 12 hours).

After the reaction, the target compound (XI) of this reaction can be collected from the reaction mixture according to a conventional method. For example, the target compound can be obtained by the following operations: neutralize the reaction mixture properly, or filter it out when there is insoluble matter, and then add water and ethyl acetate and other immiscible organic solvents to separate the organic compound containing the target compound. The layer was washed with water and the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate and the like, and then the solvent was distilled off. If necessary, conventional methods, such as recrystallization, reprecipitation, etc., which are commonly used in the separation and purification of organic compounds, can be properly combined, chromatographed, and eluted with an appropriate eluent to separate and purify the obtained target compound .

Step A8 is a step for preparing a compound having the general formula (I). After hydrolysis occurs by reacting compound (XI) with a base in an inert solvent, R ¹ , R ² , R ³ , R ^5a , R ^6a and the protecting group of amino, hydroxyl and/or carboxyl in R ^7a , protect the amino group in R ¹ and/or R ² , and/or protect the hydroxyl group in R ³ to carry out.

The inert solvent used when making the compound (XI) react with the base is not particularly limited as long as it is inert to the reaction, and can be aliphatic hydrocarbons such as hexane, heptane, naphtha, sherwood oil and the like; benzene, Aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; diethyl ether, diisopropyl ether, tetrahydrofuran, di Ethers such as oxane, dimethoxyethane, diglyme: methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, Alcohols such as diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; water; or a mixed solvent of the above solvents. A mixed solvent of alcohols and ethers is preferred (a mixed solvent of methanol and tetrahydrofuran is most preferred).

The base used when compound (XI) is reacted with a base includes, for example, the same base as the base used when the hydroxyl group is converted into a leaving group in Step A2 of the aforementioned method A, preferably alkali metal hydroxides (most preferably potassium hydroxide ).

The reaction temperature varies depending on the type of starting compound, base, solvent, etc., but is usually -20°C to 200°C (preferably 0°C to 100°C).

The reaction time varies depending on the starting compound, base, solvent, reaction temperature, etc., but is usually 30 minutes to 48 hours (preferably 1 hour to 24 hours).

The removal of the protecting groups of the amino, hydroxyl and carboxyl groups varies with the species, and can generally be carried out by methods well known in the art of organic synthetic chemistry, such as T.W.Green, (Protective Groups in Organic Synthesis), John Wiley & Sons: J.F.W.McOmis, ( Protective Groups in Organic Chemistry), the method described in Plenum Press is carried out as follows.

When the protecting group of the amino group is a silyl group, it is usually removed by treating with a compound that generates a fluoride anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine, or potassium fluoride.

The solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction, for example, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diglyme and the like are preferred. of ethers.

The reaction temperature and reaction time are not particularly limited, but usually at 0°C to 50°C for 10 minutes to 18 hours.

When the protecting group of the amino group is an aliphatic acyl group, an aromatic acyl group, an alkoxycarbonyl group or a substituted methylene group forming a Schiff base group, it can be removed by treatment with an acid or base in the presence of an aqueous solvent .

As long as the acid used in the above-mentioned reaction is a commonly used acid that does not hinder the reaction, it is not particularly limited, for example, it can be inorganic acids such as hydrobromic acid, hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid, nitric acid, and the like, preferably hydrochloric acid.

As long as the base used in the above-mentioned reaction does not affect other parts of the compound, it is not particularly limited, preferably alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate; Lithium hydroxide, sodium hydroxide, Alkali metal hydroxides such as potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, and potassium tert-butoxide; ammonia such as ammonia water and concentrated ammonia-methanol.

The solvent used in the above reaction is not particularly limited as long as it is a solvent used in a common hydrolysis reaction, and it can be, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butyl Alcohols such as alcohol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane , Diethylene glycol dimethyl ether and other ethers; water; a mixed solvent of water and the above-mentioned organic solvents. Ethers are preferred (most preferably dioxane).

The reaction temperature and reaction time vary depending on the raw material compound, solvent, acid or base used, etc., and are not particularly limited. In order to suppress side reactions, the reaction is usually carried out at 0°C to 150°C for 1 hour to 10 hours.

When the protecting group of the amino group is an aralkyl group or an aralkyloxycarbonyl group, it is generally preferred to remove it by contacting with a reducing agent (preferably in the presence of a catalyst, at room temperature, by catalytic reduction) in an inert solvent or A method of removal with an oxidizing agent.

The solvent used during removal by catalytic reduction is not particularly limited as long as it is inert to the reaction, and can be aliphatic hydrocarbons such as hexane, heptane, naphtha, petroleum ether; toluene, benzene, xylene Aromatic hydrocarbons such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate and other esters; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyl Ethers such as oxyethane, diglyme; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin Alcohols such as , octanol, cyclohexanol, and methyl cellosolve; organic acids such as acetic acid; water; mixed solvents of the above solvents and water. Alcohols, ethers, organic acids or water are preferred (alcohols or organic acids are most preferred).

The catalyst used for removal by catalytic reduction is not particularly limited as long as it is a catalyst commonly used in catalytic reduction reactions, and palladium carbon, Raney nickel, platinum oxide, platinum black, rhodium-alumina, and triphenylphosphine are preferably used. - rhodium chloride, palladium - barium sulfate.

The pressure is not particularly limited, and it is usually carried out at 1-10 atmospheres.

The reaction temperature and reaction time vary with raw material compounds, catalysts, solvents, etc., and are usually carried out at 0°C to 100°C for 5 minutes to 24 hours.

The solvent used for removal by oxidation is not particularly limited as long as it does not participate in this reaction, and a water-containing organic solvent is preferable.

Examples of such organic solvents include halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; nitriles such as acetonitrile; diethyl ether, diisopropyl ether, tetrahydrofuran , dioxane, dimethoxyethane, diglyme and other ethers; acetone and other ketones; formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoryl amides such as triamines; and sulfoxides such as dimethylsulfoxide; sulfolane. Halogenated hydrocarbons, ethers or sulfoxides are preferred (halogenated hydrocarbons or sulfoxides are most preferred).

The oxidant used is not particularly limited as long as it is a compound that can be used for oxidation. Potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3-dichloro-5,6-dicyano- p-Benzoquinone (DDQ).

The reaction temperature and reaction time vary with raw material compounds, catalysts, solvents, etc., and are usually carried out at 0°C to 150°C for 10 minutes to 24 hours.

When the protecting group of the amino group is an aralkyl group, the protecting group can also be removed with an acid.

The acid used in the above reaction is not particularly limited as long as it is an acid that can be used as an acid catalyst in a common reaction, and it may be an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, or phosphoric acid. Bronsted acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and other organic acids; zinc chloride, tin tetrachloride, Lewis acids such as boron trichloride, boron trifluoride, boron tribromide; acidic ion exchange resins. Inorganic or organic acids are preferred (most preferably hydrochloric acid, acetic acid or trifluoroacetic acid).

As long as the inert solvent used in the above-mentioned front section reaction is inert to this reaction, it is not particularly limited, and can be aliphatic hydrocarbons such as hexane, heptane, naphtha, sherwood oil and the like; Benzene, toluene, xylene Aromatic hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride and other halogenated hydrocarbons; methyl acetate, ethyl acetate, propyl acetate, butyl acetate , diethyl carbonate and other esters; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diglyme and other ethers; methanol, ethanol, n-propyl Alcohols such as alcohol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; formamide, di Amides such as methylformamide, dimethylacetamide, and hexamethylphosphoryl triamide; water; or water or a mixed solvent of the above solvents. Preference is given to ethers, alcohols or water (most preferably dioxane, tetrahydrofuran, ethanol or water).

The reaction temperature varies depending on the starting compound, the acid used, the solvent, etc., and is usually -20°C to boiling point temperature (preferably 0°C to 100°C).

The reaction time varies depending on the starting compound, the acid used, the solvent, the reaction temperature, etc., and is usually 15 minutes to 48 hours (preferably 30 minutes to 20 hours).

When the protecting group of the amino group is an alkenyloxycarbonyl group, usually when the protecting group of the aforementioned amino group is the aforementioned aliphatic acyl group, aromatic acyl group, alkoxycarbonyl group or a substituted methylene group forming a Schiff base The removal reaction is removed by treatment with base under the same conditions.

In addition, when the protecting group is an allyloxycarbonyl group, it can be easily removed using palladium and triphenylphosphine or nickel tetracarbonyl especially with less occurrence of side reactions.

When silyl groups are used as protecting groups for hydroxyl groups, they can usually be treated with compounds that generate fluoride anions such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine, potassium fluoride, or hydrochloric acid , hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid and other inorganic acids or acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and other organic acids The acid is treated to remove it.

In addition, when removing by fluoride anion, the reaction can be accelerated by adding an organic acid such as formic acid, acetic acid, or propionic acid.

As long as the inert solvent used in the above-mentioned reaction is inert to this reaction, it is not particularly limited, preferably diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diglyme ethers; nitriles such as acetonitrile and isobutyronitrile; organic acids such as acetic acid; water; mixed solvents of the above solvents.

The reaction temperature and reaction time vary with raw material compounds, catalysts, solvents, etc., and are usually carried out at 0°C to 100°C (preferably 10°C to 50°C) for 1 hour to 24 hours.

When the protecting group of the hydroxyl group is an aralkyl group or an aralkyloxycarbonyl group, it is generally preferred to remove it by contacting with a reducing agent in an inert solvent (preferably in the presence of a catalyst, catalytic reduction at room temperature) or by using an oxidant method of removal.

The solvent used for removal by catalytic reduction is not particularly limited as long as it does not participate in the reaction, and can be aliphatic hydrocarbons such as hexane, heptane, naphtha, petroleum ether; toluene, benzene, xylene Aromatic hydrocarbons such as ethyl acetate and propyl acetate; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diglyme, etc. ethers; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve Alcohols such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, amides such as hexamethylphosphoryl triamide; fatty acids such as formic acid and acetic acid ; Water; Mixed solvent of the above solvents. Alcohols are preferred (most preferably methanol).

The catalyst used for removal by catalytic reduction is not particularly limited as long as it is a catalyst commonly used in catalytic reduction reactions, and may be, for example, palladium carbon, palladium black, Raney nickel, platinum oxide, platinum black, rhodium-alumina , Triphenylphosphine-rhodium chloride, palladium-barium sulfate, preferably palladium carbon.

The pressure is not particularly limited, and it is usually carried out at 1-10 atmospheres.

The reaction temperature and reaction time vary with raw material compounds, catalysts, solvents, etc., and are usually carried out at 0°C to 100°C (preferably 20°C to 70°C) for 5 minutes to 48 hours (preferably 1 hour to 24 hours).

The solvent used for removal by chlorination is not particularly limited as long as it does not participate in this reaction, and an aqueous organic solvent is preferable.

Examples of such organic solvents are ketones such as acetone; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride; nitriles such as acetonitrile; diethyl ether, tetrahydrofuran, dioxane and the like ethers; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoryl triamide; and sulfoxides such as dimethylsulfoxide.

The oxidant used is not particularly limited as long as it is a compound that can be used for oxidation. Potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3-dichloro-5,6-dicyano- p-Benzoquinone (DDQ).

The reaction temperature and reaction time vary with raw material compounds, catalysts, solvents, etc., and are usually carried out at 0°C to 150°C for 10 minutes to 24 hours.

In addition, it can also be used in liquid ammonia or methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol Alcohols such as methyl cellosolve and the like are removed by treating them with alkali metals such as metal lithium and metal sodium at -78°C to 0°C.

It can also be removed in a solvent with ammonium chloride-sodium iodide or haloalkylsilanes such as trimethylsilyl iodide.

The solvent used is not particularly limited as long as it does not participate in the reaction, preferably halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; nitriles such as acetonitrile; and mixed solvents of the above solvents.

The reaction temperature and reaction time vary depending on the starting compound, solvent, etc., but are usually carried out at 0°C to 50°C for 5 minutes to 72 hours.

In addition, when the reactant has a sulfur atom, ammonium chloride-sodium iodide is preferably used.

When the protecting group of the hydroxyl group is an aliphatic acyl group, an aliphatic acyl group or an alkoxycarbonyl group, it can be removed by treating with a base in a solvent.

As long as the base used in the above-mentioned reaction does not affect other parts of the compound, it is not particularly limited, and can be alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate; lithium bicarbonate, sodium bicarbonate , potassium bicarbonate and other alkali metal bicarbonates; lithium hydroxide, sodium hydroxide, potassium hydroxide and other alkali metal hydroxides; lithium methoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like metal alkoxides; ammonia water, concentrated ammonia-methanol and other ammonia. Preference is given to alkali metal hydroxides, metal alkoxides or ammonia (most preferably alkali metal hydroxides or metal alkoxides).

The solvent used is not particularly limited as long as it is a solvent used in a common hydrolysis reaction, and is preferably, for example, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, di-methoxyethane, diglyme Ethers such as ethers; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl Alcohols such as cellosolve; water; mixed solvents of the above solvents.

The reaction temperature and reaction time vary depending on the raw material compound, the base used, the solvent, etc., and are not particularly limited. In order to suppress side reactions, it is usually carried out at -20°C to 150°C for 1 hour to 10 hours.

When the protecting group of hydroxy is alkoxymethyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuryl, tetrahydrothiophenyl or substituted ethyl, it is usually passed in a solvent Remove by acid treatment.

The acid used is not particularly limited as long as it is an acid commonly used as a Bronsted acid or a Lewis acid, and hydrogen chloride, inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, or acetic acid, trifluoroacetic acid, and methanesulfonic acid are preferably used. acid, organic acids such as p-toluenesulfonic acid such as Bronsted acid; Lewis acid such as boron trifluoride. Strongly acidic cation exchange resins such as Dowex 50W can also be used.

As long as the solvent used in the above-mentioned reaction is inert to this reaction, it is not particularly limited, and can be aliphatic hydrocarbons such as hexane, heptane, naphtha, sherwood oil and the like; Benzene, toluene, xylene and the like aromatic hydrocarbons; dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene and other halogenated hydrocarbons; ethyl formate, ethyl acetate, propyl acetate, butyl acetate esters, such as diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diglyme; methanol, ethanol, n- Alcohols such as propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; acetone, methyl Ketones such as methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; water; mixed solvents of the above solvents. Ethers (most preferably tetrahydrofuran) or alcohols (most preferably methanol) are preferred.

The reaction temperature and reaction time vary depending on the starting compound, the acid used, the solvent, etc., and are usually carried out at -10°C to 200°C (preferably 0°C to 150°C) for 5 minutes to 48 hours (preferably 30 minutes to 10 hours).

When the protecting group of the hydroxy group is an alkenyloxycarbonyl group, it can usually be obtained by using Alkaline treatment to remove.

In addition, when the protecting group is allyloxycarbonyl, especially palladium and triphenylphosphine or bis(methyldiphenylphosphine)(1,5-cyclooctadiene) can be conveniently used with less side reactions. ) Iridium (I) hexafluorophosphate to remove.

When _the carboxyl protecting group _{is C 1 -C 6 alkyl or C 6 -} C ₁₀ aryl substituted C ₁ -C ₆ alkyl, usually under the same conditions as the removal reaction when the protective group of the aforementioned hydroxyl group is the aforementioned aliphatic acyl, aromatic acyl or alkoxycarbonyl, Removed by treatment with base.

In addition, the removal of the protecting groups of the amino group, the hydroxyl group and/or the carboxyl group can be carried out sequentially in different orders to carry out the desired removal reactions.

The method of protecting an amino group and a hydroxyl group differs depending on the type of the protecting group, but it can generally be carried out by a well-known method in the art of organic synthetic chemistry as follows.

The method for protecting the amino group can be carried out as follows: in an inert solvent (preferably ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diglyme; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve and other alcohols), In the presence or absence of a base (organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine), R in compound ( ^I ) and Compounds wherein R ² is a hydrogen atom and compounds of the following formula

R ^1a -Z (XII)

[In the above formula, R ^1a represents an amino protecting group (represents the same meaning as above), and Z represents a halogen atom. ]

The reaction is carried out at 0°C to 50°C (preferably around room temperature) for 30 minutes to 10 hours (preferably 1 hour to 5 hours).

The method for protecting a hydroxyl group can be carried out as follows: in an inert solvent (preferably chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride and the like halogenated hydrocarbons; formamide, dimethylformamide, di Amides such as methylacetamide and hexamethylphosphoryl triamide; sulfoxides such as dimethyl sulfoxide), in alkali (preferably alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride) class; in the presence of organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine), make ^R in compound (I) the compound of hydrogen atom with the following compound

R ^3a -Z (XIII)

[In the above formula, R ^3a represents a protecting group of a hydroxyl group (representing the same meaning as above), and Z represents the same meaning as above. ]

The reaction is carried out at 0°C to 50°C (preferably around room temperature) for 30 minutes to 24 hours (preferably 1 hour to 24 hours).

In addition, the removal of the protecting group of the amino group, hydroxyl group and/or carboxyl group and the reaction of protecting the amino group and/or hydroxyl group can be carried out sequentially in different orders.

After the reaction, the target compound (I) of this reaction can be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by the following operations: neutralize the reaction mixture properly, or filter it out when there is insoluble matter, and then add water and ethyl acetate and other immiscible organic solvents to separate the organic compound containing the target compound. The layer was washed with water and the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate and the like, and then the solvent was distilled off. If necessary, conventional methods, such as recrystallization, reprecipitation, etc., which are commonly used in the separation and purification of organic compounds, can be properly combined, chromatographed, and eluted with an appropriate eluent to separate and purify the obtained target compound .

Step A9 is a step of preparing a compound having a compound (I) from compound (X). After hydrolysis occurs by reacting compound (X) with a base in an inert solvent, R ¹ , R ² , and R ³ are removed as required , R ^5a , R ^6a and R ^7a in the amino, hydroxyl and/or carboxyl protecting group, protect the amino in R ¹ and/or R ² , and/or protect the hydroxyl in R ³ to carry out, this step is the same as the previous method A step A8 is similarly carried out.

Step A10 is the step of preparing compound (Ic), by removing the amino, hydroxyl and/or carboxyl groups in R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a as required after reducing the ester of compound (IX) The protecting group of ^R1 and/or ^R2 is protected, and/or the hydroxyl group in ^R3 is protected, and the method of reducing the ester of compound (IX) can be carried out in the same way as the aforementioned method A step A6.

Method B is to prepare the compound (Id) in which X is an ethynylene group, the compound (Ie) in which X is an ethenylene group, the compound (If) in which X is an ethylene group, and X is a compound (Id) with -CO-CH ₂ - the compound (Ig) of the group, X is a group having -CO-CH ₂ - and R ¹ is a compound (Ig-1) of -CO ₂ R ¹⁰ , X is a compound (Ig-1) having -CH(OH)-CH ₂ The compound (Ih) in which X is an aryl group or an aryl group substituted by 1-3 groups selected from substituent group a (Ii) and the compound (Ij) in which X is an oxygen atom or a sulfur atom )Methods.

Method B

In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5a , R ⁶ , R ^6a , R ⁷ , R ^7a , R ¹⁰ , Y and n represent the same meanings as above; X _a represents An oxygen atom or a sulfur atom; Ya is a C ₁ -C ₁₀ alkylene group or a C ₁ -C ₁₀ alkylene group substituted by 1-3 groups selected from substituent groups a and b; Ring A represents an aryl group or An aryl group substituted by 1-3 groups selected from substituent group a; W represents a group with the following general formula:

[In the above formula, R ⁴ and R ¹⁰ represent the same meaning as above; R' and R" are the same or different, representing lower alkyl, aryl or substituted by 1-3 groups selected from substituent group a Aryl].

Step B1 is a step of preparing a compound of general formula (XVI) by Sonogashira reaction between a compound of general formula (XIV) and a compound of general formula (XV) in the presence of a base and a palladium catalyst in an inert solvent for coupling reactions.

As long as the solvent used in the above-mentioned reaction is inert to this reaction, it is not particularly limited, and can be aliphatic hydrocarbons such as hexane, heptane, naphtha, sherwood oil and the like; Benzene, toluene, xylene and the like aromatic hydrocarbons; dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene and other halogenated hydrocarbons; ethyl formate, ethyl acetate, propyl acetate, butyl acetate esters, such as diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diglyme; acetone, methyl ethyl ether, etc. Ketones such as base ketone, methyl isobutyl ketone, isophorone, and cyclohexanone; nitriles such as acetonitrile and isobutyronitrile; formamide, dimethylformamide, dimethylacetamide, Amides such as hexamethylphosphoryl triamide; sulfoxides such as dimethyl sulfoxide and sulfolane. Ethers, amides or sulfoxides are preferred (amides or ethers are most preferred). In addition, adding a small amount of water to the reaction solvent can promote the reaction.

The base used in the above reaction can be, for example, the same base as that used for converting the hydroxyl group into a leaving group in step A2 of the aforementioned method A, preferably organic amines (most preferably triethylamine).

As long as the palladium catalyst used in the above-mentioned reaction is a catalyst for the usual Sonogashira coupling reaction, it is not particularly limited, and can be palladium salts such as palladium acetate, palladium chloride, palladium carbonate; Palladium complexes such as dichlorobis(triphenylphosphine)palladium that form complexes.

The yield can be improved by using the additives cuprous iodide and benzyltriethylammonium chloride.

The reaction temperature varies depending on the starting compound, base, solvent, etc., but is usually -20°C to 200°C (preferably 0°C to 120°C).

The reaction time varies depending on the starting compound, base, solvent, reaction temperature, etc., but is usually 5 minutes to 48 hours (preferably 15 minutes to 24 hours).

After the reaction, the target compound (XVI) of this reaction can be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by the following operations: neutralize the reaction mixture properly, or filter it out when there is insoluble matter, and then add water and ethyl acetate and other immiscible organic solvents to separate the organic compound containing the target compound. The layer was washed with water and the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate and the like, and then the solvent was distilled off. If necessary, conventional methods, such as recrystallization, reprecipitation, etc., which are commonly used in the separation and purification of organic compounds, can be properly combined, chromatographed, and eluted with an appropriate eluent to separate and purify the obtained target compound .

Step B2 is the step of preparing a compound with the general formula (Id). When the W of compound (XVI) is a (W-1) group, it can be obtained by making it with the aforementioned method A step A7 and step A8, or the aforementioned method A step Prepared by the same reaction as A9. Alternatively, when W in compound (XVI) is (W-2) or (W-3), it can be reacted in the same way as in step A8 of the aforementioned method A to prepare a compound of general formula (Id).

Step B3 is a step of preparing a compound having the general formula (XVII) by reacting compound (XV) with catecholborane, followed by Suzuki coupling reaction with compound (XIV).

The reaction temperature for reacting compound (XV) with catecholborane varies depending on the type of starting compound, base, solvent, etc., but is usually 0°C to 150°C (preferably 10°C to 100°C).

The reaction time for reacting compound (XV) with catecholborane varies depending on the starting compound, base, solvent, reaction temperature, etc., and is usually 15 minutes to 24 hours (preferably 30 minutes to 12 hours).

Thereafter, the method of performing the Suzuki coupling reaction can be performed in the same manner as the Sonogashira coupling reaction of the aforementioned method B step B1.

The solvent used in the above reaction is, for example, the same solvent as that used in step B1 of the aforementioned method B, preferably aromatic hydrocarbons (most preferably toluene).

The base used in the above reaction is, for example, the same base as that used to convert the hydroxyl group into a leaving group in step A2 of the aforementioned method A, preferably alkali metal alkoxides (most preferably sodium ethoxide).

The palladium catalyst used in the above reaction includes, for example, the same catalyst as that used in the step B1 of the aforementioned method B, preferably palladium complexes (most preferably dichlorobis(triphenylphosphine)palladium).

Step B4 is a step for preparing a compound with general formula (Ie). When W of compound (XVII) is a (W-1) group, it can be obtained by making it with the aforementioned method A step A7 and step A8, or the aforementioned method A step Prepared by the same reaction as A9. Alternatively, when W of compound (XVII) is (W-2) or (W-3), it can be reacted in the same way as in step A8 of the aforementioned method A to prepare a compound of general formula (Ie).

Step B5 is a step of preparing a compound of general formula (XVIII), which is carried out by reducing compound (XVI) in an inert solvent (preferably in the presence of a catalyst at normal temperature).

The solvent used during removal by catalytic reduction is not particularly limited as long as it is inert to the reaction, and can be aliphatic hydrocarbons such as hexane, heptane, naphtha, petroleum ether; toluene, benzene, xylene Aromatic hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene and other halogenated hydrocarbons; methyl acetate, ethyl acetate, propyl acetate, Esters such as butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diglyme; methanol, ethanol , n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve and other alcohols; acetic acid , organic acids such as hydrochloric acid; water; a mixed solvent of the above solvents and water. Alcohols or ethers are preferred (most preferably methanol).

The catalyst used for removal by catalytic reduction is not particularly limited as long as it is a catalyst commonly used in catalytic reduction reactions, and palladium-on-carbon, Raney nickel, platinum oxide, platinum black, rhodium-alumina, and triphenylene oxide are preferably used. Phosphine-rhodium chloride, palladium-barium sulfate.

The reaction temperature varies depending on the type of starting compound, base, solvent, etc., but is usually -20°C to 200°C (preferably 0°C to 100°C).

The reaction time varies depending on the starting compound, base, solvent, reaction temperature, etc., but is usually 5 minutes to 96 hours (preferably 15 minutes to 72 hours).

After the reaction, the target compound (XVIII) of this reaction can be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by the following operations: neutralize the reaction mixture properly, or filter it out when there is insoluble matter, and then add water and ethyl acetate and other immiscible organic solvents to separate the organic compound containing the target compound. The layer was washed with water and the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate and the like, and then the solvent was distilled off. If necessary, conventional methods, such as recrystallization, reprecipitation, etc., which are commonly used in the separation and purification of organic compounds, can be properly combined, chromatographed, and eluted with an appropriate eluent to separate and purify the obtained target compound .

Step B6 is a step for preparing a compound of the general formula (If). When the W of compound (XVIII) is a (W-1) group, it can be obtained by making it with the aforementioned method A step A7 and step A8, or the aforementioned method A step Prepared by the same reaction as A9. Alternatively, when W of compound (XVIII) is (W-2) or (W-3), it can be reacted in the same way as in step A8 of the aforementioned method A to prepare a compound of general formula (If).

Step B7 is a step for preparing a compound with the general formula (XIX). When W of compound (XVI) is a (W-1) group, it can be obtained by making it with the aforementioned method A step A7 and step A8, or the aforementioned method A step Prepared by the same reaction as A9. Alternatively, when W of compound (XVI) is (W-2) or (W-3), it can be reacted in the same way as in step A8 of the aforementioned method A to prepare a compound of general formula (XIX).

Step B8 is a step of preparing a compound having the general formula (Ig), which can be carried out in an inert solvent by subjecting the compound (XIX) to a water addition reaction using an acid catalyst or a hydroxymercuration reaction using mercuric oxide, as required Remove the protecting group of amino, hydroxyl and/or carboxyl in R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a , protect R ¹ and/or R ² in amino group, and/or protect R ³ in hydroxyl to proceed.

As long as the solvent used in the above-mentioned reaction is inert to this reaction, it is not particularly limited, and can be aliphatic hydrocarbons such as hexane, heptane, naphtha, sherwood oil and the like; Benzene, toluene, xylene and the like aromatic hydrocarbons; dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene and other halogenated hydrocarbons; ethyl formate, ethyl acetate, propyl acetate, butyl acetate esters, such as diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diglyme; methanol, ethanol, n- Alcohols such as propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; acetone, methyl Ketones such as methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; water; mixed solvents of the above solvents. Alcohols are preferred (most preferably methanol).

The acid catalyst used in the above-mentioned reaction is not particularly limited as long as it is an acid catalyst used as an acid catalyst in a common reaction, and it can be, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, or phosphoric acid. acid, or Bronsted acid such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and other organic acids; or zinc chloride, tetrachloro Lewis acids such as tin chloride, boron trichloride, boron trifluoride, boron tribromide; or acidic ion exchange resins. Mineral acids are preferred (most preferably sulfuric acid).

The reaction temperature varies depending on the type of starting compound, base, solvent, etc., but is usually -20°C to 200°C (preferably 0°C to 100°C).

The reaction time varies depending on the starting compound, base, solvent, reaction temperature, etc., but is usually 5 minutes to 96 hours (preferably 15 minutes to 72 hours).

According to the method of removing the protecting group of amino group, hydroxyl group and/or carboxyl group in R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a , protect the amino group in R ¹ and/or R ² and/or protect R The method for the hydroxyl group in ³ can be carried out in the same manner as in step A8 of the aforementioned method A.

Step B9 is a step of preparing a compound having the general formula (Ig-1) by subjecting the compound (XVIa) to a water addition reaction using an acid catalyst or a hydroxymercuration reaction using mercuric oxide in an inert solvent , as needed to remove the protecting group of amino, hydroxyl and/or carboxyl in R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a , and/or protect the hydroxyl group in R ³ , this step is the same as the previous method B step B8 is similarly carried out.

Step B10 is a step of preparing a compound having the general formula (XX) by subjecting compound (XIX) to a water addition reaction using an acid catalyst or a hydroxymercuration reaction using mercuric oxide in an inert solvent, removing R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a are amino, hydroxyl and/or carboxyl protecting groups, protecting the amino group in R ¹ and/or R ² , and/or protecting the hydroxyl group in R ³ To carry out, this step is carried out in the same manner as step B8 of the aforementioned method B.

Step B11 is a step for preparing a compound of general formula (Ih), by reducing compound (XX) in an inert solvent, and then removing the amino group in R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a as required , the protecting group of hydroxyl and/or carboxyl, the amino group in R ¹ and/or R ² is protected, and/or the hydroxyl group in R ³ is protected.

As long as the inert solvent used in the above-mentioned reaction is inert to this reaction, it is not particularly limited, and can be aliphatic hydrocarbons such as hexane, heptane, naphtha, sherwood oil and the like; Benzene, xylene and the like aromatic hydrocarbons; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy Ethers such as ethyl ethane and diglyme; Methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, Alcohols such as octanol, cyclohexanol, and methyl cellosolve; or a mixed solvent of the above solvents. Ethers or alcohols are preferred (most preferably methanol or ethanol).

The reducing agent used in the above reaction can be, for example, alkali metal borohydrides such as sodium borohydride, lithium borohydride, sodium cyanoborohydride; diisobutylaluminum hydride, lithium aluminum hydride, triethoxyaluminum hydride Aluminum hydride compounds such as lithium. Preference is given to alkali metal borohydrides (sodium cyanoborohydride).

The reaction temperature varies depending on the type of starting compound, base, solvent, etc., but is usually -10°C to 100°C (preferably -20°C to 20°C).

The reaction time varies depending on the starting compound, base, solvent, reaction temperature, etc., but is usually 10 minutes to 48 hours (preferably 30 minutes to 12 hours).

According to the method of removing the protecting group of amino group, hydroxyl group and/or carboxyl group in R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a , protect the amino group in R ¹ and/or R ² and/or protect R The method for the hydroxyl group in ³ can be carried out in the same manner as in step A8 of the aforementioned method A.

After the reaction, the target compound (Ih) of this reaction can be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by the following operations: neutralize the reaction mixture properly, or filter it out when there is insoluble matter, and then add water and ethyl acetate and other immiscible organic solvents to separate the organic compound containing the target compound. The layer was washed with water and the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate and the like, and then the solvent was distilled off. If necessary, conventional methods, such as recrystallization, reprecipitation, etc., which are commonly used in the separation and purification of organic compounds, can be properly combined, chromatographed, and eluted with an appropriate eluent to separate and purify the obtained target compound .

Step B12 is a step for preparing a compound of general formula (XXII), which is carried out by making compound (XXI) and compound (XIV) undergo a Suzuki coupling reaction, and this step is carried out in the same manner as the Sonogashira coupling reaction part of the aforementioned method B step B3 .

Step B13 is a step for preparing a compound of general formula (Ii). When the W of compound (XXII) is a (W-1) group, it can be obtained by making it with the aforementioned method A step A7 and step A8, or the aforementioned method A step Prepared by the same reaction as A9. Alternatively, when W of compound (XXII) is (W-2) or (W-3), it can be reacted in the same way as in step A8 of the aforementioned method A to prepare a compound of general formula (Ii).

Step B14 is a step for preparing a compound of general formula (XXIV), by making a compound of general formula (XIV) and a compound of general formula (XXII) in the absence of solvent or in an inert solvent in the presence of a copper catalyst The alkali metal salt reaction of the compound is carried out. In this step, for example, the method described in JHeterocyclic. Chem., 20, 1557 (1983) can be used.

The solvent used in the above reaction is not particularly limited as long as it is inert to the reaction, and can be ethers such as diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane, diglyme, etc. ; Pyridines such as pyridine, picoline, lutidine, and collidine. Preferably no solvent is used. The copper catalyst used in the above reaction may be, for example, cuprous iodide, cuprous bromide, cuprous oxide, cupric oxide, preferably cuprous oxide.

The alkali metal salt of the compound (XXIII) used in the above reaction can be prepared from the general formula (XXIII) and an alkali metal or an alkali metal compound. Examples of alkali metals include lithium, sodium, and potassium, and examples of alkali metal compounds include alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride. Preference is given to preparation with metallic sodium. In addition, the yield can be increased by using the additive potassium iodide.

The reaction temperature varies with the types of raw material compounds, catalysts, and solvents, but is usually room temperature to 150°C (preferably 60°C to 120°C).

The reaction time varies with the types of raw material compounds, catalysts, and solvents, but is usually 1 hour to 7 days (preferably 3 hours to 72 hours).

After the reaction, the target compound (XXIV) of this reaction can be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by the following operations: neutralize the reaction mixture properly, or filter it out when there is insoluble matter, and then add water and ethyl acetate and other immiscible organic solvents to separate the organic compound containing the target compound. The layer was washed with water and the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate and the like, and then the solvent was distilled off. If necessary, conventional methods, such as recrystallization, reprecipitation, etc., which are commonly used in the separation and purification of organic compounds, can be properly combined, chromatographed, and eluted with an appropriate eluent to separate and purify the obtained target compound .

Step B15 is a step for preparing a compound with general formula (Ij). When W of compound (XXIV) is a (W-1) group, it can be obtained by making it with the aforementioned method A step A7 and step A8, or the aforementioned method A step Prepared by the same reaction as A9. Alternatively, when W of compound (XXIV) is (W-2) or (W-3), it can be reacted in the same way as in step A8 of the aforementioned method A to prepare a compound of general formula (Ij).

Step B16 is a step for preparing a compound of general formula (XXVI) by reacting a compound of general formula (XIV) with a compound of general formula (XXV). This step is performed in the same manner as step B1 of the aforementioned method B.

Step B17 is a step for preparing compound (XVIb) in which Y is a group of formula -Ya-O- in compound (XVI), by subjecting compound (XXVI) to a compound of general formula (XXVII) in an inert solvent Mitsunobu reaction (Mitsunobu reaction) condensation to carry out.

The reagent used in the Mitsunobu reaction is not particularly limited as long as it is a reagent commonly used in the Mitsunobu reaction, and azodicarboxylic acids such as diethyl azodicarboxylate and diisopropyl azodicarboxylate are preferred. Azo compounds such as di-lower alkyl esters or azodicarbonyl such as 1,1'-(azobiscarbonyl)dipiperidine and triarylphosphine such as triphenylphosphine or tri-n-butylphosphine Combinations of phosphines such as tri-lower alkyl phosphines, such as tri-lower alkyl phosphines, and combinations of di-lower alkyl azodicarboxylates and triaryl phosphines are more preferred.

As long as the used solvent does not hinder the reaction and can dissolve the raw material to a certain extent, it is not particularly limited, preferably aromatic hydrocarbons such as benzene, toluene, xylene; dichloromethane, chloroform, carbon tetrachloride, dichloromethane, Halogenated hydrocarbons such as ethyl chloride, chlorobenzene, and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and diethyl carbonate; diethyl ether, diisopropyl Ether, tetrahydrofuran, dioxane, dimethoxyethane, ethers such as diglyme; nitriles such as acetonitrile and isobutyronitrile; formamide, N,N-dimethylformamide , N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidone, amides such as hexamethylphosphoryl triamide; sulfoxides such as dimethyl sulfoxide and sulfolane kind. Aromatic hydrocarbons and ethers are preferred.

The reaction temperature is -20°C to 100°C, preferably 0°C to 50°C.

The reaction time mainly varies with the reaction temperature, the raw material compound, the reaction reagent or the solvent used, and is usually 10 minutes to 3 days, preferably 30 minutes to 12 hours.

After the reaction, the target compound (XVIb) of this reaction can be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by the following operations: neutralize the reaction mixture properly, or filter it out when there is insoluble matter, and then add water and ethyl acetate and other immiscible organic solvents to separate the organic compound containing the target compound. The layer was washed with water and the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate and the like, and then the solvent was distilled off. If necessary, conventional methods, such as recrystallization, reprecipitation, etc., which are commonly used in the separation and purification of organic compounds, can be properly combined, chromatographed, and eluted with an appropriate eluent to separate and purify the obtained target compound .

It is also possible to use other methods different from this method to prepare compound (Id)- (Ij).

The starting compounds (II), (V), (VIII), (XII), (XIII), (XIV), (XV), (XXI), (XXIII), (XXV) and (XXVII) are known or It can be easily produced according to a known method or a method analogous thereto.

The starting compounds (II) and (XIV) can also be produced by the following methods.

Method C is the method for preparing compound (XIV) and compound (XIVa), and compound (XIVa) is that there is a bromine atom as a substituent on the 2-position of thienyl in compound (XIV), and -(CH ₂ ) Compounds of _n -W groups.

Method C

In the above formula, R ⁴ , R ^6a , R ^7a , R ⁸ , R ⁹ , R ^9a , R ¹⁰ , n and W have the same meanings as above.

Step C1 is a step of preparing a compound of general formula (XXIX) by reacting a compound of general formula (XXVIII) with a reducing agent in an inert solvent in the presence or absence (preferably in the presence) of a base , this step is carried out in the same manner as the aforementioned method A step A1.

Step C2 is a step for preparing a compound of general formula (XXX), which is carried out by iodination after converting the hydroxyl group of compound (XXIX) into a leaving group in the presence of a base in an inert solvent. The steps are carried out in the same manner as step A2 of the aforementioned method A.

Step C3 is a step for preparing a compound of general formula (XXXI), which is carried out by reacting compound (XXX) with compound (V) in an inert solvent in the presence of a base. This step is the same as step A3 of the aforementioned method A conduct.

Step C4 is a step for preparing a compound of general formula (XXXII), which is carried out by reacting compound (XXXI) with a base in an inert solvent to undergo hydrolysis, and this step is carried out in the same manner as step A4 of the aforementioned method A.

Step C5 is a step for preparing a compound of general formula (XXXIII), which step converts the carboxyl group of compound (XXXII) into a carbamate through a Curtis rearrangement reaction in the presence of a base in an inert solvent Next, compound (XXXII) is reacted with diaryl phosphoryl azide derivatives such as diphenyl phosphoryl azide, and then reacted with compound (VIII). This step is the same as step A5 of the aforementioned method A conduct.

Step C6 is a step for preparing compound (XIV), which is carried out by reducing the ester of compound (XXXIII), and this step is carried out in the same manner as step A6 of the aforementioned method A.

After the reaction, the target compound (XIV) of this reaction can be collected from the reaction mixture according to a conventional method. For example, the target compound can be obtained by the following operations: neutralize the reaction mixture properly, or filter it out when there is insoluble matter, and then add water and ethyl acetate and other immiscible organic solvents to separate the organic compound containing the target compound. The layer was washed with water and the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate and the like, and then the solvent was distilled off. If necessary, conventional methods, such as recrystallization, reprecipitation, etc., which are commonly used in the separation and purification of organic compounds, can be properly combined, chromatographed, and eluted with an appropriate eluent to separate and purify the obtained target compound .

Step C7 is a step of preparing a compound of general formula (XXXV) by reacting a compound of general formula (XXXIV) with a reducing agent in an inert solvent in the presence or absence (preferably in the presence) of a base , this step is carried out in the same manner as the aforementioned method A step A1.

Step C8 is a step for preparing a compound of general formula (XXXVI), which is carried out by iodination after converting the hydroxyl group of compound (XXXV) into a leaving group in the presence of a base in an inert solvent. The steps are carried out in the same manner as step A2 of the aforementioned method A.

Step C9 is a step for preparing a compound of general formula (XXXVII), which is carried out by reacting compound (XXXVI) with compound (V) in an inert solvent in the presence of a base. This step is the same as step A3 of the aforementioned method A conduct.

Step C10 is a step for preparing a compound of general formula (XXXVIII), which is carried out by reacting compound (XXXVII) with a base in an inert solvent to undergo hydrolysis, and this step is performed in the same manner as step A4 of the aforementioned method A.

Step C11 is a step for preparing a compound of general formula (XXXIX), which step converts the carboxyl group of compound (XXXVIII) into a carbamate through a Curtis rearrangement reaction in the presence of a base in an inert solvent , making compound (XXXVIII) react with diaryl phosphoryl azide derivatives such as diphenyl phosphoryl azide, and then reacting it with compound (VIII), this step is carried out in the same manner as step A5 of the aforementioned method A .

Step C12 is a step for preparing a compound of general formula (XL), which is carried out by reducing the ester of compound (XXXIX), and this step is carried out in the same manner as step A6 of the aforementioned method A.

Step C13 is a step of preparing compound (XIVa) by reacting compound (XL) with a brominating agent in an inert solvent.

The solvent used in the above reaction is not particularly limited as long as it is inert to the reaction, and can be halogenated compounds such as methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride, chlorobenzene, dichlorobenzene, etc. Hydrocarbons; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diglyme; formamide, dimethylformamide, dimethylacetamide , Amides such as hexamethylphosphoryl triamide. Amides are preferred (most preferably dimethylformamide).

The brominating agent used in the above reaction is not particularly limited, and may be, for example, those described in "Comprehensive Organic Transformations" (Larock, VCH, pages 316-317). N-bromosuccinimide or bromine is preferred.

The reaction temperature varies depending on the type of starting compound, brominating agent, solvent, etc., but is usually -78°C to 150°C (preferably -20°C to 100°C).

The reaction time varies depending on the starting compound, brominating agent, solvent, reaction temperature, etc., and is usually 5 minutes to 48 hours (preferably 30 minutes to 24 hours).

After the reaction, the target compound (XIVa) of this reaction can be collected from the reaction mixture according to a conventional method. For example, the target compound can be obtained by the following operations: neutralize the reaction mixture properly, or filter it out when there is insoluble matter, and then add water and ethyl acetate and other immiscible organic solvents to separate the organic compound containing the target compound. The layer was washed with water and the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate and the like, and then the solvent was distilled off. If necessary, conventional methods, such as recrystallization, reprecipitation, etc., which are commonly used in the separation and purification of organic compounds, can be properly combined, chromatographed, and eluted with an appropriate eluent to separate and purify the obtained target compound .

Method D is to prepare compound (IIa) in which X is ethynylene, compound (IIb) in which X is ethylene, compound (IIc) in which X is vinylidene, and X is compound (IIc) with -CO-CH ₂ in compound (II). - Compound (IId), X is a compound (IIe) having a -CH(OH)-CH ₂ - group, X is an aryl group or is replaced by 1-3 groups selected from substituent group a A method for a compound (IIf) having a substituted aryl group and a compound (IIg) wherein X is an oxygen atom or a sulfur atom.

Method D

In the above formula, R ^5a , R ^6a , R ^7a , R ⁸ , n, X _a , Y, Y _a and ring A have the same meanings as above.

Step D1 is the step of preparing compound (IIa), which is carried out by making compound (XXVIII) and a compound of general formula (XV) undergo Sonogashira coupling reaction in the presence of a base and a palladium catalyst in an inert solvent. This step Carry out in the same manner as step B1 of the aforementioned method B.

Step D2 is the step of preparing compound (IIb), which is carried out by reducing compound (IIa) in an inert solvent (preferably in the presence of a catalyst, catalytic reduction at room temperature), this step is carried out in the same way as step B5 of the aforementioned method B.

Step D3 is the step of preparing compound (IIc), which is carried out by reacting compound (XV) with catechol borane, followed by Suzuki coupling reaction with compound (XXVIII). This step is performed in the same way as step B3 of the aforementioned method B.

Step D4 is the step of preparing compound (IId), which is carried out by subjecting compound (IIa) to water addition reaction using an acid catalyst or hydroxymercuration reaction using mercuric oxide in an inert solvent. This step is the same as the aforementioned method B step B8 is similarly performed.

Step D5 is a step for preparing compound (IIe) by reducing compound (IId) in an inert solvent, and this step is performed in the same manner as step B11 of the aforementioned method B.

Step D6 is the step of preparing compound (IIf), which is carried out by Suzuki coupling reaction between compound (XXI) and compound (XXVIII). This step is carried out in the same way as step B3 of the aforementioned method B.

Step D7 is a step for preparing compound (IIg), which is carried out by reacting compound (XXVIII) with an alkali metal salt of compound (XXIII) in the presence of a copper catalyst in the absence of a solvent or in an inert solvent. This step is the same as Step B14 of the aforementioned method B is also carried out.

Step D8 is a step for preparing a compound of general formula (XLI), which is carried out by reacting compound (XXVIII) with compound (XXV). This step is carried out in the same manner as step B1 of the aforementioned method B.

Step D9 is the step of preparing compound (IIa-1) in which Y is a group having -Ya-O- in compound (IIa), by reacting compound (XLI) with compound (XXVII), this step is the same as the aforementioned method B step B17 is similarly carried out.

Method E is a method for preparing intermediate compounds (XLIVa), (XLIVb), (La) and (Lb) of compound (I) of the present invention.

Method E

In the above formula, R ¹ , R ² , R ³ , R ^4a , R ¹¹ , Ar, m and Z have the same meanings as above.

Step E1 is the step of preparing general formula (XLIVa) or (XLIVb), by using the compound of general formula (XLIII) in the presence or absence of a solvent, in the presence of lipase, only having the general formula Acylation of one side of the compound of (XLII) is carried out.

The solvent used in the present invention is not particularly limited, it can only be compound (XLIII), the most suitable solvent varies with the type of raw material compound, various organic solvents, aqueous organic solvents can be used, preferably diisopropyl ether, tert-butyl methyl ethers such as base ether, diethyl ether and tetrahydrofuran; aliphatic hydrocarbons such as n-hexane and n-pentane; aromatic hydrocarbons such as benzene and toluene; and methylene chloride, 1,2-dichloroethane Halogenated hydrocarbons such as alkanes. Ethers are more preferred, most preferably diisopropyl ether.

The reaction temperature varies depending on the starting compound, the solvent used, the lipase used and the type of compound (XLIII), etc., and is usually -50°C to 50°C, preferably 0°C to 40°C.

The reaction time also varies depending on the starting compound, the solvent used, the lipase used and the type of compound (XLIII), etc., and is usually 15 minutes to 150 hours, preferably 30 minutes to 24 hours.

After the reaction, the target compound (XLIVa) or (XLIVb) of this reaction can be collected from the reaction mixture according to conventional methods. For example, the target compound can be obtained by the following operation: when there is an insoluble matter, it is removed by filtration, then concentrated as it is or an immiscible organic solvent such as water and ethyl acetate is added, the organic layer containing the target compound is separated, and the After drying with sodium sulfate, anhydrous magnesium sulfate, etc., the solvent was distilled off.

If necessary, the obtained target compound can also be isolated and purified by conventional methods such as recrystallization, reprecipitation, etc., or by performing chromatography and eluting with an appropriate eluent.

Step E2 is a step of preparing a compound having the general formula (XLV) by oxidizing the alcohol portion of the compound (XLIVa) to an aldehyde in an inert solvent in the presence of an oxidizing agent.

The oxidation reaction used in this step is not particularly limited as long as it can generate an aldehyde from a primary alcohol, and its examples are: Collins oxidation in dichloromethane with pyridine and chromic acid; in dichloromethane with chlorochromic acid PCC oxidation with pyridinium (PCC); PDC oxidation with pyridinium dichromate (PDC) in dichloromethane; Acyl chloride, sulfonyl chloride, oxalyl chloride, dicyclohexyl carbodiimide, stilbene-p-tolyl imine, N, N-diethylaminoacetylene, sulfur trioxide pyridine complex, etc.) and di DMSO oxidations such as Swern oxidation with methyl sulfoxide (DMSO); and manganese dioxide oxidation with manganese dioxide in dichloromethane or benzene, etc.

Preference is given to PCC oxidation or Swern oxidation in dichloromethane.

The reaction temperature varies depending on the type of starting compound, solvent, oxidizing agent, etc., but is usually -50°C to 50°C, preferably -10°C to 30°C.

The reaction time varies depending on the type of starting compound, solvent, oxidizing agent, reaction temperature, etc., and is usually 10 minutes to 2 days, preferably 30 minutes to 24 hours.

For example, the target compound can be obtained by neutralizing the oxidizing agent with sodium bisulfite water, etc., filtering it off when there is an insoluble matter, and then concentrating as it is or adding an immiscible organic solvent such as water and ethyl acetate, The organic layer containing the target compound was separated, dried over anhydrous sodium sulfate, anhydrous magnesium sulfate, etc., and the solvent was distilled off.

If necessary, the obtained target compound can also be isolated and purified by conventional methods such as recrystallization, reprecipitation, etc., or by performing chromatography and eluting with an appropriate eluent.

Step E3 is a step of preparing a compound of general formula (XLVII) by reacting an aldehyde of compound (XLV) with a compound of general formula (XLVI) in an inert solvent in the presence of a base.

As long as the solvent used does not hinder the reaction and can dissolve the raw material to a certain extent, it is not particularly limited, preferably aromatic hydrocarbons such as benzene, toluene, xylene; dichloromethane, chloroform, carbon tetrachloride, 1 , Halogenated hydrocarbons such as 2-dichloroethane, chlorobenzene, and dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, and tetrahydrofuran; acetonitrile, isobutyronitrile, etc. Nitriles; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoryl triamide; sulfones such as dimethyl sulfoxide and sulfolane . Ethers are more preferred.

As long as the base used is the base used in the usual reaction, it is not particularly limited, preferably alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate; sodium bicarbonate, potassium bicarbonate, lithium bicarbonate alkali metal bicarbonates; alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, and lithium hydroxide ; Inorganic bases such as sodium fluoride and potassium fluoride and other alkali metal fluorides; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, and lithium methoxide; N -Methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, 4-pyrrolidinylpyridine, picoline, 4-( N,N-dimethylamino)pyridine, 2,6-di-tert-butyl-4-picoline, N,N-dimethylaniline, N,N-diethylaniline, 1,4-diazo Heterobicyclo[4.3.0]octane (DABCO), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 1,5-diazabicyclo[4.3.0] -Organic amines such as 5-nonene (DBN); or organometallic bases such as butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide. More preferred are alkali metal alkoxides, alkali metal hydrides and organometallic bases.

The reaction temperature varies depending on the raw material compound, solvent, type of phosphonium salt, type of base, etc., and is usually -80°C to 100°C, preferably -20°C to 50°C.

The reaction time varies depending on the raw material compound, solvent, type of phosphonium salt, type of base, etc., and is usually 10 minutes to 2 days, preferably 30 minutes to 12 hours.

For example, the target compound can be obtained by neutralizing the reaction liquid with dilute hydrochloric acid, etc., and removing it by filtration when there is an insoluble matter, then concentrating as it is or adding an immiscible organic solvent such as water and ethyl acetate, and separating the compound containing The organic layer of the target compound was dried over anhydrous sodium sulfate, anhydrous magnesium sulfate, etc., and then the solvent was distilled off.

If necessary, the obtained target compound can also be isolated and purified by conventional methods such as recrystallization, reprecipitation, etc., or by performing chromatography and eluting with an appropriate eluent.

Step E4 is a step of preparing a compound of general formula (XLVIII), which is carried out by hydrolyzing compound (XLVII) in an inert solvent in the presence of a base.

As long as the solvent used does not hinder the reaction and can dissolve the raw material to a certain extent, it is not particularly limited, preferably alcohols such as methanol and ethanol; aromatic hydrocarbons such as benzene, toluene and xylene; dichloromethane , chloroform, carbon tetrachloride, dichloroethane and other halogenated hydrocarbons; diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diglyme and other ethers; or these A mixed solvent of solvents or a mixed solvent of these solvents and water. Alcohols and ethers are more preferred.

The base to be used is not particularly limited as long as it is a base commonly used in the reaction, and alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and barium hydroxide are preferred.

The reaction temperature varies depending on the type of starting compound, solvent, base, etc., but is usually -20°C to 200°C, preferably 0°C to 20°C.

The reaction time varies depending on the starting compound, reaction temperature, solvent, type of base, etc., but is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

For example, the target compound can be obtained by neutralizing the reaction liquid with dilute hydrochloric acid, etc., and removing it by filtration when there is an insoluble matter, then concentrating as it is or adding an immiscible organic solvent such as water and ethyl acetate, and separating the compound containing The organic layer of the target compound was dried over anhydrous sodium sulfate, anhydrous magnesium sulfate, etc., and then the solvent was distilled off.

If necessary, the obtained target compound can also be isolated and purified by conventional methods such as recrystallization, reprecipitation, etc., or by performing chromatography and eluting with an appropriate eluent.

Step E5 is a step of preparing a compound having the general formula (IL), which step converts compound (XLVIII) into compound (IL) in the presence of a base in an inert solvent.

The solvent used is not particularly limited as long as it does not hinder the reaction and can dissolve the raw materials to a certain extent, preferably ethers such as diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane, and diglyme Amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidone, hexamethylphosphoryl triamide; benzene , Toluene, xylene and other aromatic hydrocarbons. More preferred are ethers and amides.

The base used is not particularly limited as long as it is a base commonly used in the reaction, and alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride are preferred; alkali metal fluorides such as sodium fluoride and potassium fluoride are preferred. Inorganic bases such as compounds; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, and lithium methoxide; or butyllithium, lithium diisopropylamide, di( Organometallic bases such as lithium trimethylsilyl)amide. More preferred are alkali metal alkoxides and alkali metal hydrides.

The reaction temperature varies depending on the type of starting compound, solvent, base, etc., but is usually -80°C to 100°C, preferably 0°C to 50°C.

The reaction time varies depending on the types of raw material compounds, reaction temperature, solvent, and base, and is usually 5 minutes to 48 hours.

For example, the target compound can be obtained by neutralizing the reaction liquid with dilute hydrochloric acid, etc., and removing it by filtration when there is an insoluble matter, then concentrating as it is or adding an immiscible organic solvent such as water and ethyl acetate, and separating the compound containing The organic layer of the target compound was dried over anhydrous sodium sulfate, anhydrous magnesium sulfate, etc., and then the solvent was distilled off.

If necessary, the obtained target compound can also be isolated and purified by conventional methods such as recrystallization, reprecipitation, etc., or by performing chromatography and eluting with an appropriate eluent.

Step E6 is the step of preparing compound (La-1) in which R ¹ is a hydrogen atom and R ² and R ^3a together are a group of formula (-(C=O)-) in compound (La), and this step is carried out in an inert solvent In , the compound (IL) is converted into the target compound (La-1) in the presence of a reducing agent.

As long as the solvent used does not hinder the reaction and can dissolve the raw material to a certain extent, there is no special limitation to it, preferably alcohols such as methanol, ethanol, isopropanol; diethyl ether, diisopropyl ether, tert-butyl methyl ether Ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and cyclohexane; ethyl acetate and propyl acetate and the like esters. Alcohols are more preferred.

As long as the reductant used is a reductant commonly used in catalytic reduction reactions, it is not particularly limited, preferably palladium carbon, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride (Will Jinsen complex), palladium-barium sulfate, Raney nickel. Palladium on carbon is more preferred.

The pressure is not particularly limited, and it is usually carried out at 1-10 atmospheres.

The reaction temperature varies depending on the type of starting compound, solvent, base, etc., but is usually 0°C to 100°C.

The reaction time varies depending on the types of raw material compounds, reaction temperature, solvent, and base, and is usually 5 minutes to 48 hours.

For example, the target compound can be obtained by the following operations: after removing the catalyst by filtration, concentrate as it is or add an immiscible organic solvent such as water and ethyl acetate, separate the organic layer containing the target compound, and wash it through anhydrous sodium sulfate, anhydrous sulfuric acid, etc. After drying with magnesium etc., the solvent was distilled off.

If necessary, the obtained target compound can also be isolated and purified by conventional methods such as recrystallization, reprecipitation, etc., or by performing chromatography and eluting with an appropriate eluent.

Step E7 is a step for preparing a compound of general formula (LI). This step converts compound (XLVII) into compound (LI) in the presence of a reducing agent in an inert solvent, which can be carried out according to the aforementioned method E, step E6.

Step E8 is the step of preparing the compound (La-2) in which R in the compound (La) is a hydrogen atom, and this step is in an inert solvent, in the presence of ^a base, hydrolyzing the compound (LI) to prepare the compound (La-2) , can be carried out according to step E4 of the aforementioned method E.

Step E9 is a step for preparing compound (La-1). This step is to prepare target compound (La-1) from compound (La-2) in the presence of a base in an inert solvent, which can be carried out according to the aforementioned method E step E5 .

Step E10 is the step of preparing compound (La-3) in which R ² and R ^3a together do not represent a group of formula (-(C=O)-) in compound (La), by protecting compound (La-2) as required Hydroxyl is carried out, and this step is different according to the protective group of hydroxyl, and can be carried out by a commonly used method such as the method described in Protective Groups in Organic Synthesis (third edition, 1999, issued by John Wiley & Sons, Inc.).

Compound (Lb) can be prepared by carrying out steps E2-E10 of the above-mentioned Method E, substituting compound (XLIVb) for compound (XLIVa).

Method F

In the above formula, Ar and Z have the same meaning as above.

Step F1 is a step of preparing compound (XLVI) by reacting a compound having general formula (LII) with triphenylphosphine in an inert solvent.

As long as the inert solvent used in the above-mentioned reaction is inert to this reaction, it is not particularly limited, and can be aliphatic hydrocarbons such as hexane, heptane, naphtha, sherwood oil and the like; aromatic hydrocarbons; dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene and other halogenated hydrocarbons; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane , Dimethoxyethane, diglyme and other ethers. Aromatic hydrocarbons are preferred (most preferably benzene).

The reaction temperature varies depending on the starting compound, the type of solvent, etc., and is usually carried out at room temperature to 200°C, preferably 0°C to 150°C (most preferably 110°C).

The reaction time mainly varies with the reaction temperature, the starting compound, the type of solvent used, etc., and is usually 5 minutes to 96 hours, preferably 15 minutes to 48 hours (most preferably 24 hours).

The target compound in each step of this method F can be obtained by conventional methods, such as recrystallization, reprecipitation, or methods commonly used in the separation and purification of organic compounds, such as using silica gel, aluminum oxide, magnesium-silica gel Florisil, etc. Carrier adsorption column chromatography; partition column chromatography using a carrier such as Sephadex LH-20 (manufactured by Pharmacia), Amberlite XAD-11 (manufactured by Rohm & Haas), Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation) method using a synthetic adsorbent, ion-exchange chromatography, or normal-phase and reverse-phase column chromatography (preferably high performance liquid chromatography) using silica gel or alkylated silica gel in an appropriate combination, with appropriate elution Reagent elution for separation and purification.

In addition, when it is necessary to separate the isomers, it can be carried out by the above-mentioned separation and purification method after the completion of the reaction of the above-mentioned steps, or at an appropriate period after the completion of the required steps.

Starting compounds (XXVIII), (XXXIV), (XLII), (XLIII) and (LII) are known or can be easily prepared by known methods or similar methods.

The effect of the invention

The aminoalcohol derivative with general formula (I) of the present invention, its pharmacologically acceptable salt, its ester or other derivatives have low toxicity and have excellent immunosuppressive effect, containing the aminoalcohol derivative with general formula (I) of the present invention Compounds, their pharmacologically acceptable salts or their esters or other derivatives as active ingredients in pharmaceutical compositions are particularly useful as systemic lupus erythematosus, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma syndrome, Behcet's disease, Chron's disease, ulcerative colitis, autoimmune hepatitis, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, multiple sclerosis, autoimmune bullae, Psoriasis, vasculitis syndrome, Wegener's granulomatosis, uveitis, idiopathic interstitial pneumonia, Goodpasture syndrome, sarcoidosis, allergic granulomatous vasculitis, bronchial asthma, myocarditis, cardiomyopathy, Aortitis syndrome, post-myocardial infarction syndrome, primary pulmonary hypertension, minimally variable nephropathy, membranous nephropathy, membranous proliferative nephritis, glomerular focal sclerosis, crescentic nephritis, severe Myasthenia, inflammatory neuropathy, atopic dermatitis, chronic actinic dermatitis, acute polyarthritis, Sydenham chorea, systemic sclerosis, adult-onset diabetes, insulin-dependent diabetes, juvenile diabetes, atherosclerosis, renal Glomerulonephritis, tubulointerstitial nephritis, primary biliary cirrhosis, primary sclerosing cholangitis, fulminant hepatitis, viral hepatitis, GVHD, immune rejection caused by various organ transplants, contact A preventive or therapeutic agent for autoimmune diseases such as dermatitis and sepsis or other immune-related diseases.

The novel optically active aminoalcohol compounds (La) and (Lb) of the present invention are useful as intermediates for the preparation of medicines.

As the synthetic intermediates of the above-mentioned optically active aminoalcohol compounds (La) and (Lb), optically active 2-substituted-2-amino-1,3-propanediol monoester derivatives (XLIVa) or (XLIVb) are preferred. The 2-substituted-2-amino-1,3-propanediol monoester derivatives (XLIVa) and (XLIVb) can be obtained by using 2-substituted-2-amino-1,3-propanediol derivatives (XLII) as raw materials in In the presence of lipase, only one hydroxyl group is selectively acylated using a vinyl carboxylate derivative (XLIII), and it is easily and simply prepared in good yield.

Industrial availability

When the compound with general formula (I) of the present invention, its pharmacologically acceptable salt or its ester is used as the above-mentioned therapeutic agent or preventive agent, it can be used by itself or with an appropriate pharmacologically acceptable excipient , diluents, etc., and administered orally in the form of tablets, capsules, granules, powders, syrups, etc., or parenterally in the form of injections, suppositories, etc.

These preparations can be prepared by well-known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, diluents, such as lactose, sucrose, glucose, etc. , mannitol, sorbitol and other sugar derivatives, corn starch, potato starch, α-starch, dextrin and other starch derivatives, crystalline cellulose and other cellulose derivatives, gum arabic, dextran, pullulan ) and other organic excipients; and silicate derivatives such as light silicic anhydride, synthetic aluminum silicate, calcium silicate, magnesium aluminosilicate, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, calcium sulfate, etc. Inorganic excipients such as sulfates. The lubricants include metal stearate such as stearic acid, calcium stearate, and magnesium stearate; talc; colloidal silicon oxide; propolis; waxes such as spermaceti; boric acid; adipic acid; sodium sulfate, etc. Sulfates; glycols; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salts; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; and The aforementioned starch derivatives. The binder includes, for example, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, polyethylene glycol, and the same compounds as the above-mentioned excipients. The disintegrants include cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, internal cross-linked carboxymethyl cellulose sodium; carboxymethyl starch, carboxymethyl Chemically modified starch and cellulose such as sodium starch glycolate and cross-linked polyvinylpyrrolidone. The stabilizers include, for example, paraben esters such as methyl p-hydroxybenzoate and propyl p-hydroxybenzoate; alcohols such as chlorobutanol, benzyl alcohol, and phenethyl alcohol; benzalkonium chloride; phenol, cresol, etc. Phenols; Thimerosal; Dehydroacetic Acid and Sorbic Acid. The flavoring and flavoring agents include, for example, commonly used sweeteners, sour agents, spices, and the like.

Its dosage varies with symptoms, age, etc. For adults, a daily lower limit of 0.05 mg (preferably 5 mg) and an upper limit of 200 mg (preferably 40 mg) are given each time during oral administration; The daily lower limit is 0.01 mg (preferably 1 mg), the upper limit is 100 mg (preferably 10 mg), and the administration is divided into 1-6 times a day according to the symptoms.

[Best way to practice the invention]

The following examples and test examples are given to illustrate the present invention in more detail, but the scope of the present invention is not limited thereto.

Example 1

(2R)-Amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol

(Exemplary compound 1-770)

Example 1(a)

Diethyl 2-methyl-2-(2-thienyl)ethylmalonate

Suspend 18.8g (0.43mol) of sodium hydride (55%) in dimethylformamide (200ml), and slowly add 50.0g (0.29mol) of diethyl methylmalonate over 30 minutes under ice cooling , and stirred for another 30 minutes. Then, under a nitrogen atmosphere, a solution of 75.2 g (0.32 mol) of 2-(2-iodoethyl)thiophene in dimethylformamide (200 ml) was added over 15 minutes, followed by stirring at room temperature for 4 hours. The reaction mixture was poured into ice-cooled 10% hydrochloric acid (500ml), and extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent; hexane:ethyl acetate=10:1-5:1) to obtain 53.1 g (65%) of title compound.

Infrared absorption spectrum v _max cm ^-1 (CHCl ₃ ): 2986, 1726, 1271, 1252

Mass spectrum (FAB) m/z: 285 ((M+H) ⁺ ).

Example 1(b)

Monoethyl 2-methyl-2-(2-thienyl)ethylmalonate

52.7 g (0.19 mol) of 2-methyl-2-(2-thienyl) ethyl malonate diethyl ester obtained in Example 1 (a) was dissolved in ethanol (240 ml) and water (80 ml), Under ice cooling, 11.4 g (0.20 mol) of potassium hydroxide was added and stirred for 2 hours. Then, 5.7 g (0.1 mol) of potassium hydroxide was added three times at intervals of one hour, and the mixture was stirred for 6 hours. Water (300ml) and ice-cooled 10% hydrochloric acid (500ml) were added, and extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent; hexane:ethyl acetate=2:1-0:1) to obtain 28.6 g (60%) of title compound.

Infrared absorption spectrum v _max cm ^-1 (CHCl ₃ ): 2987, 1732, 1712, 1251, 1109

Mass spectrum (FAB) m/z: 257 ((M+H) ⁺ ).

Example 1(c)

2-Methylhydrocarbonylamino-2-methyl-4-(2-thienyl)butanoic acid ethyl ester

The 2-methyl-2-(2-thienyl) ethyl malonate monoethyl ester obtained in 19.0g (74.3mmol) embodiment 1 (b) is dissolved in benzene (450ml), adds 11.4ml (81.7 mmol) triethylamine and 17.6 ml (81.7 mmol) of diphenylphosphoryl azide were stirred at room temperature for 10 minutes, and then stirred at 80° C. for 1.5 hours. Then, at the same temperature, 60.3 ml (1.49 mol) of methanol was slowly added dropwise over 30 minutes, followed by further stirring for 8 hours. The reaction mixture was poured into water (500ml), and extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent; hexane:ethyl acetate=8:1-4:1) to obtain 14.7 g (69%) of title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.11 (1H, d, J=5.1Hz), 6.90 (1H, dd, J=5.1, 3.5Hz), 6.77 (1H, d, J=3.5Hz), 5.69 (1H, brs), 4.19 (2H, qJ = 7.3Hz), 3.66 (3H, s), 2.84 (2H, dd, J = 10.5, 10.5Hz), 2.64 (2H, m), 2.20 (2H, dd, J=10.5, 8.4Hz), 1.61(3H, s), 1.28(3H, t, J=7.3Hz)

Infrared absorption spectrum v _max cm ^-1 (CHCl ₃ ); 3417, 2987, 1719, 1503, 1453, 1081

Mass spectrum (FAB) m/z: 286 ((M+H) ⁺ ).

Example 1(d)

2-Methoxycarbonylamino-2-methyl-4-(2-thienyl)butan-1-ol

14.7 g (51.6 mmol) of ethyl 2-methoxycarbonylamino-2-methyl-4-(2-thienyl) butyrate obtained in Example 1 (c) were dissolved in ethanol (150 ml) and tetrahydrofuran (100 ml ), add 5.07g (0.13mol) of sodium borohydride and 5.68g (0.13mol) of lithium chloride, and stir overnight under a nitrogen atmosphere at room temperature. The next morning, 5.07 g (0.13 mol) of sodium borohydride and 5.68 g (0.13 mol) of lithium chloride were also added, and stirred overnight under a nitrogen atmosphere at room temperature. The same operation as this was carried out for another 2 days. The reaction mixture was poured into ice-cooled 10% hydrochloric acid (500ml), and extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent; hexane:ethyl acetate=2:1-1:5) to obtain 11.7 g (93%) of the title compound as white crystals .

Infrared absorption spectrum v _max cm ^-1 (KBr): 3406, 3244, 1687, 1562, 1264, 1089

Mass Spectrum (FAB) m/z: 244 ((M+H) ⁺ )

Elemental analysis value; (% relative to C ₁₁ H ₁₇ NO ₃ S)

Calculated: C: 54.30, H: 7.04, N: 5.76, S: 13.18

Found: C: 54.18, H: 6.98, N: 5.78, S: 13.34.

Example 1(e)

2-Methoxycarbonylamino-2-methyl-4-(5-bromothien-2-yl)butan-1-ol

11.7g (48.0mmol) of 2-methoxycarbonylamino-2-methyl-4-(2-thienyl)butan-1-ol obtained in Example 1 (d) was dissolved in dimethylformamide (120ml ), under ice-cooling, 10.8 g (60.8 mmol) of N-bromosuccinimide was added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 4 hours. The reaction mixture was poured into ice-cooled 10% hydrochloric acid (300ml), and extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent; hexane:ethyl acetate=4:1-1:3) to obtain 12.4 g (80%) of title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 6.84 (1H, d, J = 3.7Hz), 6.57 (1H, d, J = 3.7Hz), 4.80 (1H, brs), 3.68 (2H, m), 3.64 (3H, s), 2.80 (2H, m), 1.9-2.2 (2H, m), 1.24 (3H, s)

Infrared absorption spectrum v _max cm ^-1 (CHCl ₃ ): 3627, 3436, 2956, 1722, 1711, 1513, 1259, 1087, 1048

Mass spectrum (FAB) m/z: 322 ((M+H) ⁺ ).

Example 1(f)

4-[2-(5-Bromothien-2-yl)]ethyl-4-methyloxazolidin-2-one

12.4 g (38.6 mmol) of 2-methoxycarbonylamino-2-methyl-4-(5-bromothiophen-2-yl) butan-1-ol obtained in Example 1 (e) was dissolved in dimethyl To formamide (125 ml), 6.50 g (57.9 mmol) of potassium tert-butoxide was added under ice-cooling under a nitrogen atmosphere, followed by stirring at the same temperature for 3 hours. The reaction mixture was poured into ice-cooled 10% hydrochloric acid (300ml), and extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent; hexane:ethyl acetate=4:1-1:2) to obtain 10.7 g (95%) of the title compound as white crystals .

NMR spectrum (400MHz, CDCl ₃ ) δppm: 6.86 (1H, d, J = 3.7Hz), 6.58 (1H, d, J = 3.7Hz), 5.73 (1H, brs), 4.18 (1H, d, J = 8.6Hz), 4.08(1H, d, J=8.6Hz), 2.84(2H, m), 1.94(2H, m), 1.41(3h, s)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3211, 1749, 1399, 1037, 798

Mass spectrum (FAB) m/z: 290 ((M+H) ⁺ )

Elemental analysis value; (% relative to C ₁₀ H ₁₂ NO ₂ SBr)

Calculated: C: 41.39, H: 4.17, N: 4.83, S: 11.05, Br: 27.54

Found values: C: 41.36, H: 4.04, N: 4.82, S: 11.08, Br: 27.29.

Example 1(g)

(4R)-[2-(5-bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one and (4S)-[2-(5-bromothiophene- 2-yl)]ethyl-4-methyloxazolidin-2-one

The 4-[2-(5-bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one obtained in Example 1 (f) was passed through the preparative optical HPLC column (ChiralCel OD, Daicel ) for optical resolution (column, ChiralCel OD (2cmφ×25cm); elution solvent, hexane:2-propanol=70:30; flow rate, 5ml/min). The first elution (55 minutes) is the 4S body, and the last elution (77 minutes) is the 4R body. In addition, the absolute configuration was determined by X-ray crystal structure analysis.

(4S) body; [α] _D ²⁴ -4.2 (c1.03, methanol)

(4R) body; [α] _D ²⁴ +4.2 (c1.00, methanol).

Example 1(h)

(4R)-{2-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]}ethyl-4-methyloxazolidin-2-one

(4R)-[2-(5-bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one obtained in 450 mg (1.55 mmol) of Example 1 (g) was dissolved in 4.5 In ml dimethylformamide, add 1.40g (4.65mmol) 5-cyclohexylpent-1-yne (50% xylene solution), 2.16ml (15.5mmol) triethylamine, 30mg (0.16mmol) copper iodide (I) and 109 mg (0.16 mmol) of dichlorobis(triphenylphosphine)palladium were stirred under a nitrogen atmosphere at 80°C for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1-3:2) to obtain 456 mg (82%) of the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 6.92 (1H, d, J = 3.6Hz), 6.63 (1H, d, J = 3.6Hz), 5.45 (1H, brs), 4.18 (1H, d, J = 8.6Hz), 4.07(1H, d, J=8.6Hz), 2.78-2.90(2H, m), 2.38(2H, t, J=7.2Hz), 1.92-2.00(2H, m), 1.55-1.75( 7H, m), 1.40 (3H, s), 1.10-1.35 (6H, m), 0.83-0.95 (2H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr: 3450, 2925, 2852, 1758, 1382, 1046.

Example 1(i)

(2R)-Amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol

(4R)-(2-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]}ethyl-4-methanol obtained in 456 mg (1.27 mmol) of Example 1 (h) Base oxazolidin-2-one is dissolved in 1ml tetrahydrofuran, 2ml methyl alcohol, under ice-cooling, adds 2ml 5N potassium hydroxide aqueous solution, heats and refluxes for 18 hours.Add water in the reaction solution, extract with dichloromethane. Dichloromethane The methane layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluting solvent; dichloromethane:methanol=20:1-dichloromethane:methanol:ammonia water=10:1: 0.1) Purification afforded 353 mg (83%) of the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 6.92 (1H, d, J=3.5Hz), 6.62 (1H, d, J=3.5Hz), 3.37 (1H, d, J=10.5Hz), 3.32 (1H , d, J=10.5Hz), 2.75-2.90 (2H, m), 2.38 (2H, t, J=7.1Hz), 1.52-1.79 (9H, m), 1.12-1.33 (6H, m), 1.11 ( 3H, s), 0.81-0.96 (2H, m)

Infrared absorption spectrum v _max cm ^-1 (CHCl ₃ ): 2925, 2852, 1449, 1041

Mass spectrum (FAB) m/z: 334 ((M+H) ⁺ )

Elemental analysis value; (% relative to C ₂₀ H ₃₁ NOS·0.3H ₂ O)

Calculated: C: 70.87, H: 9.40, N: 4.13, S: 9.46

Measured values: C: 70.83, H: 9.21, N: 4.22, S: 9.64

[α] _D ²⁴ -2.0 (c0.60, methanol).

Example 2

(2R)-Amino-2-methyl-4-[5-(6-cyclohexylhex-1-ynyl)thiophen-2-yl]butan-1-ol

(Exemplary compound 1-882)

The same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 6.91 (1H, d, J=3.6Hz), 6.62 (1H, d, J=3.6Hz), 3.39 (1H, d, J=10.7Hz), 3.34 (1H , d, J=10.7Hz), 2.82(2H, t, J=8.5Hz), 2.40(2H, t, J=6.9Hz), 2.18-1.92(4H, m), 1.88-1.51(8H, m) , 1.47-1.38 (2H, m), 1.28-1.07 (9H, m), 0.93-0.78 (2H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3327, 3275, 2922, 2850, 1611, 1563, 1539, 1447, 1065, 1040, 803, 521

Example 3

2-Amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol

(Exemplary compound 1-824)

Using racemic 4-[2-(5-bromothien-2-yl)]ethyl-4-methyloxazolidin-2-one as the starting material, the same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.32-7.26 (2H, m), 7.25-7.16 (3H, m), 6.94 (1H, d, J=3.6Hz), 6.93 (1H, d, J=3.6 Hz), 3.37(1H, d, J=10.8Hz), 3.31(1H, d, J=10.4Hz), 2.83(2H, t, J=8.4Hz), 2.77(2H, t, J=7.6Hz) , 2.42(2H, t, J=7.2Hz), 1.96-1.85(2H, m), 1.84-164(2H, m), 1.50(3H, brs), 1.11(3H, s)

Infrared absorption spectrum v _max cm ^-1 (liquid film): 2931, 2859, 1748, 1602, 1584, 1538, 1496, 1455, 1191, 1053, 908, 804, 747, 700, 573.

Example 4

2-Amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1-olate salt

(Exemplary compound 1-849)

Using racemic 4-[2-(5-bromothien-2-yl)]ethyl-4-methyloxazolidin-2-one as the starting material, the same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.07 (3H, brs), 7.10 (2H, d, J = 8.6Hz), 6.89 (1H, d, J = 3.5Hz), 6.81 (2H, d, J = 8.6Hz), 6.65(1H, d, J=3.5Hz), 4.72(1H, brs), 3.77(3H, s), 3.65(2H, s), 2.78-2.97(2H, m), 2.66(2H, t, J=7.5Hz), 2.36(2H, t, J=7.1Hz), 1.77-2.20(4H, m), 1.36(3H, s)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3370, 3009, 2932, 1589, 1511, 1245, 1070, 1036.

Example 5

2-Amino-2-methyl-4-{5-[5-(4-fluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol maleic acid Salt

(Exemplary compound 1-833)

Using racemic 4-[2-(5-bromothien-2-yl)]ethyl-4-methyloxazolidin-2-one as the starting material, the same operation as in Example 1 was used to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 7.18-7.25 (2H, m), 6.95-7.03 (2H, m), 6.94 (1H, d, J = 3.6Hz), 6.73 (1H, d, J = 3.6Hz), 6.26(2H, s), 3.61(1H, d, J=11.6Hz), 3.52(1H, d, J=11.6Hz), 2.80-2.95(2H, m), 2.74(2H, t, J =7.8Hz), 2.40(2H, t, J=7.0Hz), 1.80-2.10(4H, m), 1.31(3H, s)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3352, 2940, 1578, 1509, 1385, 1367, 1221, 1194.

Example 6

2-Amino-2-methyl-4-[5-(biphenyl-4-yl)ethynylthiophen-2-yl]butan-1-ol

(Exemplary compound 1-742)

Using racemic 4-[2-(5-bromothien-2-yl)]ethyl-4-methyloxazolidin-2-one as the starting material, the same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.55-7.65 (6H, m), 7.43-7.50 (2H, m), 7.33-7.40 (1H, m), 7.11 (1H, d, J=3.6Hz), 6.72(1H, d, J=3.6Hz), 3.39(1H, d, J=10.4Hz), 3.34(1H, d, J=10.4Hz), 2.80-2.95(2H, m), 1.70-1.90(2H , m), 1.13(3H, s)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3335, 3075, 2924, 1485, 1463, 1051, 837, 809, 764, 698.

Example 7

2-Amino-2-methyl-4-[5-(4-butylphenyl)ethynylthiophen-2-yl]butan-1-ol

(Exemplary compound 1-737)

Using racemic 4-[2-(5-bromothien-2-yl)]ethyl-4-methyloxazolidin-2-one as the starting material, the same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.42 (2H, d, J = 8.1Hz), 7.36-7.15 (5H, m), 7.16 (2H, d, J = 8.1Hz), 7.07 (1H, d, J=3.3Hz), 6.70(1H, d, J=3.3Hz), 3.99(2H, s), 3.36-3.24(2H, m), 2.92-2.81(2H, m), 201-1.95(2H, m ), 2.65-2.26 (3H, m), 1.11 (3H, s)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3326, 3264, 2926, 2904, 1603, 1541, 1468, 1454, 1211, 1063, 1033, 803, 701.

Example 8

2-Amino-2-methyl-4-[5-(4-cyclohexylphenyl)ethynylthiophen-2-yl]butan-1-ol

(Exemplary compound 1-741)

Using racemic 4-[2-(5-bromothien-2-yl)]ethyl-4-methyloxazolidin-2-one as the starting material, the same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, DMSO-d ₆ ) δppm: 7.42 (2H, d, J=8.2Hz), 7.26 (2H, d, J=8.2Hz), 7.20 (1H, d, J=3.6Hz), 6.83 (1H, d, J=3.6Hz), 3.66-3.24 (5H, m), 2.88-2.70 (2H, m), 1.89-1.52 (7H, m), 1.43-1.21 (6H, m), 0.97 (3H , s)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3326, 3279, 2924, 2850, 1645, 1567, 1539, 1448, 1385, 1055, 826, 547.

Example 9

2-Amino-2-methyl-4-[5-(4-propylphenyl)ethynylthiophen-2-yl]butan-1-ol

(Exemplary compound 1-736)

Using racemic 4-[2-(5-bromothien-2-yl)]ethyl-4-methyloxazolidin-2-one as the starting material, the same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 7.36 (2H, d, J = 8.2Hz), 7.18 (2H, d, J = 8.2Hz), 7.06 (1H, d, J = 3.5Hz), 6.76 ( 1H, d, J = 3.5Hz), 3.39 (1H, d, J = 10.7Hz), 3.38 (1H, d, J = 10.7Hz), 2.93-2.80 (2H, m), 2.69-2.58 (2H, m ), 1.83-1.59 (4H, m), 1.10 (3H, s), 0.94 (3H, t, J=7.3Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3323, 3267, 2959, 2929, 2869, 1611, 1540, 1510, 1468, 1213, 1066, 1035, 816, 804, 510.

Example 10

2-Amino-2-methyl-4-[5-(4-propoxyphenyl)ethynylthiophen-2-yl]butan-1-ol

(Exemplary compound 1-740)

Using racemic 4-[2-(5-bromothien-2-yl)]ethyl-4-methyloxazolidin-2-one as the starting material, the same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 7.37 (2H, d, J = 8.9Hz), 7.03 (1H, d, J = 3.6Hz), 6.89 (2H, d, J = 8.9Hz), 6.75 ( 1H, d, J=3.6Hz), 3.95(2H, t, J=6.3Hz), 3.39(1H, d, J=10.7Hz), 3.35(1H, d, J=107Hz), 2.92-2.78(2H , m), 1.86-1.72 (4H, m), 1.09 (3H, s), 1.04 (3H, t, J=7.6Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3329, 3275, 2964, 2936, 1604, 1509, 1466, 1249, 1065, 975, 832, 807.

Example 11

(2R)-Amino-2-methyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol

(Exemplary compound 1-98)

175 mg (0.53 mmol) of (2R)-amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1- obtained in Example 1 The alcohol was dissolved in 9ml of ethanol, 90mg of 10% palladium on carbon was added, and stirred for 2 days under a hydrogen atmosphere. Palladium carbon was filtered through celite, and the filtrate was distilled off under reduced pressure to obtain 150 mg (85%) of the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 6.58 (1H, d, J=3.2Hz), 6.55 (1H, d, J=3.2Hz), 3.36 (1H, d, J=10.5Hz), 3.31 (1H , d, J=10.5Hz), 2.75-2.90 (2H, m), 2.73 (2H, t, J=7.6Hz), 1.59-1.83 (9H, m), 1.12-1.32 (10H, m), 1.11 ( 3H, s), 0.81-0.89 (2H, m)

Infrared absorption spectrum v _max cm ^-1 (CHCl ₃ ): 2926, 2853, 1440, 1042

Mass Spectrum (FAB) m/z: 338 ((M+H) ⁺ )

Elemental analysis value; (% relative to C ₂₀ H ₃₅ NOS·H ₂ O)

Calculated: C: 67.56, H: 10.49, N: 3.94, S: 9.01

Measured values: C: 67.11, H: 10.03, N: 3.93, S: 8.88

[α] _D ²⁴ -0.7 (c3.03, methanol).

Example 12

(2R)-Amino-2-methyl-4-[5-(6-cyclohexylhexyl)thiophen-2-yl]butan-1-ol

(Exemplary compound 1-210)

Using (2R)-amino-2-methyl-4-[5-(6-cyclohexylhex-1-ynyl)thiophen-2-yl]butan-1-ol obtained in Example 2, and Example 11, the title compound was obtained by the same operation.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 6.58 (1H, d, J = 3.3Hz), 6.55 (1H, d, J = 3.3Hz), 3.37 (1H, d, J = 10.4Hz), 3.32 (1H , d, J=10.4Hz), 2.68-2.93 (4H, m), 1.05-1.85 (24H, m), 0.77-0.93 (2H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3334, 3269, 3159, 2922, 2850, 1465, 1448, 1060

Mass Spectrum (EI) m/z: 351 (M ⁺ )

Elemental analysis value; (% relative to C ₂₁ H ₃₇ NOS)

Calculated: C: 71.74, H: 10.61, N: 3.98, S: 9.12

Measured values: C: 71.47, H: 10.48, N: 3.98, S: 9.37

[α] _D ²⁴ -1.3 (c1.15, methanol).

Example 13

2-Amino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butan-1-ol

(Exemplary compound 1-152)

Using the 2-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol obtained in Example 3, the same as in Example 11 The operation afforded the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.31-7.24 (2H, m), 7.20-7.14 (3H, m), 6.68 (1H, d, J=2.8Hz), 6.54 (1H, d, J=3.6 Hz), 3.36(1H, d, J=10.8Hz), 3.31(1H, d, J=10.4Hz), 2.81(2H, t, J=8.4Hz), 2.74(2H, t, J=7.6Hz) , 2.61(2H, t, J=7.6Hz), 1.84-1.56(6H, m), 1.52(3H, brs), 1.46-1.37(2H, m), 1.11(3H, s)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3333, 3263, 2927, 2852, 1496, 1453, 1059, 969, 928, 798, 747, 699, 569.

Example 14

2-Amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pentyl]thiophen-2-yl}butan-1-ol

(Exemplary compound 1-177)

Using the 2-amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pent-1-ynyl]thiophen-2-yl}butan-1- obtained in Example 4 Alcohol, the same operation as in Example 11 to obtain the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.08 (2H, d, J=8.5Hz), 6.82 (2H, d, J=8.5Hz), 6.58 (1H, d, J=3.3Hz), 6.54 (1H , d, J=3.3Hz), 3.79(3H, s), 3.36(1H, d, J=10.5Hz), 3.31(1H, d, J=10.5Hz), 2.70-2.85(4H, m), 2.55 (2H, t, J=7.7Hz), 1.55-1.85(6H, m), 1.35-1.45(2H, m), 1.11(3H, s)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3333, 3263, 3103, 2926, 2852, 1514, 1247, 1061, 1029.

Example 15

2-Amino-2-methyl-4-{5-[5-(4-fluorophenyl)pentyl]thiophen-2-yl}butan-1-ol

(Exemplary compound 1-161)

Using the 2-amino-2-methyl-4-{5-[5-(4-fluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol obtained in Example 5, The title compound was obtained by the same operation as in Example 11.

NMR spectrum (400MHz, CD ₃ OD) δppm: 7.12-7.18 (2H, m), 6.92-6.98 (2H, m), 6.63 (1H, d, J = 3.5Hz), 6.56 (1H, d, J = 3.5Hz), 6.25(2H, s), 3.61(1H, d, J=11.6Hz), 3.51(1H, d, J=11.6Hz), 2.70-2.90(4H, m), 2.58(2H, t, J=7, 6Hz), 1.88-2.03 (2H, m), 1.57-1.70 (4H, m), 1.28-1.42 (5H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 2929, 2854, 1578, 1509, 1464, 1387, 1356, 1223.

Example 16

2-Amino-2-methyl-4-{5-[2-(biphenyl-4-yl)ethyl]thiophen-2-yl}butan-1-ol

(Exemplary compound 1-44)

Using the 2-amino-2-methyl-4-[5-(biphenyl-4-yl)ethynylthiophen-2-yl]butan-1-ol obtained in Example 6, the same operation as in Example 11 was obtained title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.25-7.65 (9H, m), 6.60 (1H, d, J=3.5Hz), 6.59 (1H, d, J=3.5Hz), 3.37 (1H, d, J=10.5Hz), 3.32(1H, d, J=10.5Hz), 3.06-3.15(2H, m), 2.95-3.04(2H, m), 2.75-2.90(2H, m), 1.65-1.85(2H , m), 1.12(3H, s)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3333, 3265, 2924, 2852, 1598, 1486, 1448, 1059, 798, 695.

Example 17

(2R)-Amino-2-methyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol

(Exemplary compound 1-1331)

126 mg (0.41 mmol) of (2R)-amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1- obtained in Example 1 Dissolve the alcohol in 2ml of methanol, add 2ml of 6N sulfuric acid, and heat to reflux for 4 hours. The reaction solution was made alkaline with 1N aqueous sodium hydroxide solution, and then extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 130 mg (91%) of the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δ99m: 7.54 (1H, d, J = 3.7Hz), 6.84 (1H, d, J = 3.7Hz), 3.39 (1H, d, J = 10.4Hz), 3.34 (1H , d, J=10.4Hz), 2.78-2.98 (4H, m), 1.13 (3H, brs), 0.8-1.9 (19H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3332, 3267, 3134, 2922, 2851, 1647, 1457, 1057

Mass Spectrum (EI) m/z: 351 (M ⁺ )

Elemental analysis value; (% relative to C ₂₀ H ₃₃ NO ₂ S)

Calculated: C: 68.33, H: 9.46, N: 3.98, S: 9.12

Measured values: C: 67.99, H: 9.48, N: 3.92, S: 9.11

[α] _D ²⁴ -2.1 (c1.03, methanol).

Example 18

(2R)-Amino-2-methyl-4-[5-(6-cyclohexylhexanoyl)thiophen-2-yl]butan-1-ol

(Exemplary compound 1-1357)

Using (2R)-amino-2-methyl-4-[5-(6-cyclohexylhex-1-ynyl)thiophen-2-yl]butan-1-ol obtained in Example 2, and Example 17 was similarly operated to obtain the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.53 (1H, d, J = 3.9Hz), 6.63 (1H, d, J = 3.9Hz), 3.39 (1H, d, J = 10.5Hz), 3.34 (1H , d, J=10.5Hz), 2.80-2.95 (4H, m), 1.33 (3H, brs), 0.8-1.9 (21H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3149, 2922, 2851, 1654, 1460, 1059, 922

Mass Spectrum (BI) m/z: 365 (M ⁺ )

Elemental analysis value; (% relative to C ₂₁ H ₃₅ NO ₂ S)

Calculated values: C: 69.00, H: 9.65, N: 3.83, S: 8.77

Measured values: C: 68.74, H: 9.50, N: 3.83, S: 8.85

[α] _D ²⁴ -1.3 (c1.15, methanol).

Example 19

2-Amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol hydrochloride

(Exemplary compound 1-1344)

Using the 2-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol obtained in Example 3, the same as in Example 17 The operation afforded the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 7.71 (1H, d, J = 4.0Hz), 7.28-7.20 (2H, m), 7.20-7.10 (3H, m), 6.98 (1H, d, J = 3.6Hz), 3.62(1H, d, J=7.6Hz), 3.53(1H, d, J=12.0Hz), 3.04-2.88(4H, m), 2.64(2H, t, J=7.2Hz), 2.15 -2.04(1H, m), 2.04-1.92(1H, m), 1.78-1362(4H, m), 1.32(3H, s)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3378, 2927, 1648, 1588, 1562, 1504, 1456, 1230, 1067, 827, 748, 698, 578.

Example 20

2-Amino-2-methyl-4-{5-[5-(4-fluorophenyl)pentanoyl]thiophen-2-yl}butan-1-ol

(Exemplary compound 1-1348)

Using the 2-amino-2-methyl-4-{5-[5-(4-fluorophenyl)pent-1-ynyl]thiophen-2-yl}butan-1-ol obtained in Example 6, The same operation as in Example 17 was performed to obtain the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm; 7.51 (1H, d, J = 3.7Hz), 7.08-7.17 (2H, m), 6.90-7.00 (2H, m), 6.83 (1H, d, J = 3.7 Hz), 3.39(1H, d, J=10.4Hz), 3.33(1H, d, J=10.4Hz), 2.80-2.98(4H, m), 2.62(2H, t, J=7.5Hz), 1.60- 1.90(6H, m), 1.12(3H, s)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3178, 2935, 2858, 1645, 1455, 1218, 1058.

Example 21

2-Amino-2-methyl-4-[5-(biphenyl-4-yl)acetylthiophen-2-yl]butan-1-ol

(Exemplary compound 1-1326)

Using the 2-amino-2-methyl-4-[5-(biphenyl-4-yl)ethynylthiophen-2-yl]butan-1-ol obtained in Example 6, the same operation as in Example 17 was obtained title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.64 (1H, d, J = 3.7Hz), 7.52-7.60 (4H, m), 7.30-7.47 (5H, m), 6.86 (1H, d, J = 3.7 Hz), 4.18(2H, s), 3.38(1H, d, J=10.3Hz), 3.33(1H, d, J=10.3Hz), 2.84-2.98(2H, m)1.70-1.87(2H, m) , 1.12(3H,s)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3420, 2927, 1654, 1488, 1455, 1234, 1058, 751.

Example 22

2-Amino-2-methyl-4-[5-(5-phenylpent-1-enyl)thiophen-2-yl]butan-1-ol maleate

(Exemplary compound 1-670)

Example 22(a)

4-Methyl-4-{2-[5-(5-phenylpent-1-enyl)thiophen-2-yl]}ethyloxazolidin-2-one

After adding 500 mg (1.72 mmol) of catecholborane to 0.38 ml (2.58 mmol) of 5-phenylpent-1-yne at room temperature, the mixture was stirred at 60° C. for 3 hours. After the reaction solution was cooled to room temperature, 5.0ml of toluene, 500mg (1.72mmol) of 4-[2-(5-bromothiophen-2-yl) synthesized in Example 1(f) were added to the reaction solution at room temperature. ] Ethyl-4-methyloxazolidin-2-one, 119 mg (0.17 mmol) dichlorobis(triphenylphosphine) palladium, 0.83 ml (20% ethanol solution) sodium ethoxide. It was stirred at 60°C for 2 hours. After cooling the reaction solution to room temperature, 1N sodium hydroxide was added. It was extracted with ethyl acetate, washed with water and saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography (elution solvent; hexane:ethyl acetate=1:1) to obtain 378 mg (68%) of the title compound.

Example 22(b)

2-Amino-2-methyl-4-[5-(5-phenylpent-1-enyl)thiophen-2-yl]butan-1-ol maleate

By adding 370 mg (1.15 mmol) of 4-methyl-4-{2-[5-(5-phenylpent-1-enyl)thiophen-2-yl]}ethyl obtained in Example 22 (a) Oxazolidin-2-one was hydrolyzed in the same manner as in Example 1 (i), to obtain 205 mg (0.69 mmol) of 2-amino-2-methyl-4-[5-(5-phenylpent-1-enyl) Thiophen-2-yl]butan-1-ol. This was followed by the usual preparation method of maleic acid salt to obtain 160 mg (34%) of the title compound as maleic acid salt.

NMR spectrum (400MHz, DMSO-d ₆ ) δppm; 7.83-7.70 (2H, m), 7.38-7.12 (5H, m), 6.78 (1H, d, J=3.5Hz), 6.71 (1H, d, J =3.5Hz), 6.50(1H, d, J=15.6Hz), 6.02(2H, s), 5.96-5.83(1H, m), 5.52(2H, brs), 5.36-5.10(1H, m), 3.51 -3.38(2H,m), 2.83-2.58(4H,m), 2.28-2.15(2H,m), 1.88-1.63(4H,m), 1.18(3H,s)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3026, 2932, 1579, 1497, 1386, 1357, 1194, 1075, 1012, 865, 699, 570.

Example 23

2-Amino-2-methyl-4-[5-(5-cyclohexylpent-1-enyl)thiophen-2-yl]butan-1-ol

(Exemplary compound 1-657)

The same operation as in Example 22 was performed to obtain the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 6.64 (1H, d, J=3.5Hz), 6.61 (1H, d, J=3.5Hz), 6.41 (1H, d, J=15.7Hz), 5.95-5.88 (1H, m), 3.36 (1H, d, J = 10.5Hz), 3.31 (1H, d, J = 10.5Hz), 2.86-2.73 (2H, m), 2.29-2.08 (2H, m), 1.83- 1.55(8H, m), 1.52-1.33(4H, m), 1.30-1.12(6H, m), 1.11(3H, s), 0.92-0.79(2H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3328, 3275, 2921, 2850, 1610, 1447, 1225, 1066, 1038, 957, 804, 504.

Example 24

2-Amino-2-methyl-4-[5-(6-cyclohexylhex-1-enyl)thiophen-2-yl]butan-1-ol maleate

(Exemplary compound 1-683)

The same operation as in Example 22 was performed to obtain the title compound.

NMR spectrum (400MHz, DMSO-d ₆ ) δppm: 7.90-7.69 (2H, m), 6.77 (1H, d, J=3.4Hz), 6.70 (1H, d, J=3.4Hz), 6.47 (1H, d, J=15.8Hz), 6.04(2H, s), 5.92-5.84(1H, m), 5.55(1H, brs), 3.49-3.32(2H, m), 2.85-2.71(2H, m), 2.18 -2.06(2H, m), 1.96-1.53(8H, m), 1.42-1.03(14H, m), 0.93-0.78(2H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3042, 2924, 2851, 1695, 1577, 1533, 1493, 1477, 1387, 1362, 1351, 1210, 1074, 866.

Example 25

2-Amino-2-methyl-4-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol hydrochloride

(Exemplary compound 2-185)

Example 25(a)

4-(5-Phenylpent-1-ynyl)thiophene-2-carbaldehyde

18.1g (126mmol) of 5-phenylpent-1-yne was dissolved in 100ml of tetrahydrofuran, and 18.7g (98mmol) of 4-bromothiophene-2-carbaldehyde, 150ml (1.07mol) of tri Ethylamine, 962 mg (5.05 mmol) of copper(I) iodide, and 3.54 g (5.04 mmol) of dichlorobis(triphenylphosphine)palladium were stirred under a nitrogen atmosphere at 50° C. for 4 hours. The reaction solution was filtered, and the filtrate was distilled off under reduced pressure. Ether was added to the residue, followed by washing with water and saturated brine. The ether layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=100:1-10:1) to obtain 19.4 g (78%) of the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 9.88 (1H, s), 7.72 (1H, s), 7.71 (1H, s), 7.35-7.27 (2H, m), 7.24-7.16 (3H, m), 2.78(2H, t, J=7.2Hz), 2.41(2H, t, J=7.2Hz), 1.98-1.88(2H, m)

Infrared absorption spectrum v _max cm ^-1 (liquid film): 2238, 1679, 1440, 1234, 1157, 858, 748, 700, 665, 620

Mass spectrum (FAB) m/z: 255 ((M+H) ⁺ ).

Example 25(b)

[4-(5-Phenylpent-1-ynyl)thiophen-2-yl]methanol

15.0 g (59.0 mmol) of 4-(5-phenylpent-1-ynyl) thiophene-2-carbaldehyde obtained in Example 25 (a) was dissolved in 150 ml of methanol, and 2.29 g of (60.5 mmol) sodium borohydride. After stirring for 25 minutes under ice-cooling, the solvent was distilled off under reduced pressure. Water was added to the residue, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 15.2 g (99%) of the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.34-7.27 (3H, m), 7.24-7.17 (3H, m), 6.98 (1H, s), 4.78 (2H, d, J=5.6Hz), 2.77 ( 2H, t, J=7.6Hz), 2.39(2H, t, J=7.2Hz), 1.96-1.85(2H, m), 1.77(1H, t, J=5.6Hz)

Infrared absorption spectrum v _max cm ^-1 (liquid film): 3346, 3026, 2940, 2861, 2235, 1602, 1496, 1455, 1355, 1182, 1141, 1013, 844, 748, 700, 626

Mass spectrum (FAB) m/z: 256 (M ⁺ ).

Example 25(c)

[4-(5-Phenylpent-1-ynyl)thiophen-2-yl]acetonitrile

[4-(5-phenylpent-1-ynyl) thiophen-2-yl]methanol synthesized in 4.68g (18.3mmol) embodiment 25 (b) was dissolved in 70ml tetrahydrofuran, under ice-cooling condition, 20 ml of tetrahydrofuran in which 0.69 ml (7.30 mmol) of phosphorus tribromide was dissolved was added dropwise. After completion of the dropwise addition, the mixture was stirred for 10 minutes under ice-cooling and a nitrogen atmosphere. Ice water was added to the reaction liquid, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium bicarbonate and saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 120 ml of acetonitrile, and 2.85 g (18.3 mmol) of tetraethylammonium cyanide was added under ice-cooling, and stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction solution was poured into 5% aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=20:1-15:1) to obtain 3.21 g (66%) of the title compound.

NMR spectrum (270MHz, CDCl ₃ ) δppm: 7.15-7.35 (6H, m), 7.03 (1H, s), 3.86 (2H, s), 2.77 (2H, t, J=7.5Hz), 2.39 (2H, t, J=7.0Hz), 1.83-1.98 (2H, m)

Infrared absorption spectrum v _max cm ^-1 (CHCl ₃ ): 3691, 2946, 2236, 1603, 1497, 1454, 1416, 1361.

Example 25(d)

2-[4-(5-Phenylpent-1-ynyl)thiophen-2-yl]ethanol

[4-(5-phenylpent-1-ynyl) thiophen-2-yl] acetonitrile obtained in 3.21g (12.1mmol) embodiment 25 (c) was dissolved in 15ml ethanol, under ice-cooling condition, Add 1.70 g (30.2 mmol) of potassium hydroxide dissolved in 15 ml of water, and heat to reflux for 2 hours. The reaction solution was acidified with 1N hydrochloric acid, followed by extraction with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 15 ml of tetrahydrofuran, and 1.69 ml (12.1 mmol) of triethylamine was added. Thereafter, under ice-cooling, 15 ml of tetrahydrofuran in which 1.21 ml (12.7 mmol) of ethyl chloroformate was dissolved was added dropwise to the reaction solution, followed by stirring for 30 minutes under ice-cooling and a nitrogen atmosphere. The reaction solution was filtered, and the obtained filtrate was slowly added to an aqueous solution (10 ml) of 2.29 g (60.5 mmol) of sodium borohydride under ice-cooling, and stirred at room temperature for 3 days. After cooling the reaction liquid, it was acidified with 1N hydrochloric acid, and then extracted with ethyl acetate, and the ethyl acetate layer was washed with 1N aqueous sodium hydroxide solution and saturated brine. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1-4:1) to obtain 2.74 g (84%) of the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.15-7.30 (6H, m), 6.86 (1H, s), 3.85 (2H, t, J=6.2Hz), 3.02 (2H, t, J=6.2Hz) , 2.77(2H, t, J=7.6Hz), 2.39(2H, t, J=7.1Hz), 1.85-1.95(2H, m)

Infrared absorption spectrum v _max cm ^-1 (CHCl ₃ ): 3620, 2947, 1732, 1603, 1497, 1454, 1359, 1250, 1046.

Example 25(e)

2-(2-iodoethyl)-4-(5-phenylpent-1-ynyl)thiophene

Use the 2-[4-(5-phenylpent-1-ynyl) thiophen-2-yl] ethanol that obtains in 2.69g (9.95mmol) embodiment 25 (d), operate similarly with embodiment 1 (g) , yielding 3.45 g (91%) of the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.15-7.30 (6H, m), 6.84 (1H, s), 3.30-3.35 (4H, m), 2.77 (2H, t, J=7.6Hz), 2.39 ( 2H, t, J=7.0Hz), 1.85-1.95 (2H, m)

Infrared absorption spectrum v _max cm ^-1 (CHCl ₃ ): 2946, 2863, 1603, 1497, 1454, 1429, 1360, 1172.

Example 25(f)

Monoethyl 2-methyl-2-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]ethylmalonate

1.57g (9.02mmol) of diethyl methylmalonate was dissolved in 30ml of dimethylformamide, and under ice-cooling, 0.38g (9.47mmol) of sodium hydride was added, followed by stirring at room temperature under a nitrogen atmosphere for 1 Hour. Then, under ice-cooling, 30 ml of 2-(2-iodoethyl)-4-(5-phenylpent-1-ynyl)thiophene obtained in Example 25 (e) was dissolved dropwise into the reaction solution. Dimethylformamide, stirred at room temperature under nitrogen atmosphere for 4 hours. After cooling the reaction liquid, it was acidified with 1N hydrochloric acid, and then extracted with ethyl acetate, and the ethyl acetate layer was washed with 1N aqueous sodium hydroxide solution and saturated brine. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was partially purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=50:1-20:1). The resulting mixture was dissolved in 9 ml of ethanol and 1 ml of water, and 0.80 g (14.3 mmol) of potassium hydroxide was added under ice-cooling, followed by stirring at room temperature for 3 days. The reaction solution was made acidic with 1N hydrochloric acid, followed by extraction with ethyl acetate. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; dichloromethane:methanol=50:1) to obtain 1.02 g (28%) of the title compound.

NMR spectrum (500MHz, CDCl ₃ ) δppm: 7.15-7.30 (6H, m), 6.79 (1H, s), 4.23 (2H, q, J=7.1Hz), 2.60-2.85 (4H, m), 2.38 ( 2H, t, J=7.0Hz) 2.20-2.32(2H, m), 1.86-1.94(2H, m), 1.53(3H, s), 1.29(3H, t, J=7.1Hz)

Infrared absorption spectrum v _max cm ^-1 (CHCl ₃ ): 3509, 2944, 1732, 1713, 1455, 1377, 1254, 1181, 1113.

Example 25(g)

2-Methoxycarbonylamino-2-methyl-4-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]butanoic acid ethyl ester

Using 0.99 g (2.48 mmol) of 2-methyl-2-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]ethylmalonate obtained in Example 25 (f) Ethyl ester, the same operation as in Example 1(j), yielded 0.85 g (80%) of the title compound.

NMR spectrum (500MHz, CDCl ₃ ) δppm: 7.15-7.30 (5H, m), 7.13 (1H, s), 6.75 (1H, s), 5.69 (1H, brs), 4.15-4.33 (2H, m), 3.66(3H, s), 2.50-2.80(5H, m), 2.38(2H, t, J=7.0Hz), 2.15-2.23(1H, m), 1.87-1.93(2H, m), 1.60(3H, s), 1.25-1.30 (3H, m)

Infrared absorption spectrum v _max cm ^-1 (CHCl ₃ ): 3417, 2987, 2945, 1719, 1504, 1453, 1323, 1077.

Example 25(h)

4-Methyl-4-{2-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]}ethyloxazolidin-2-one

0.82g (1.92mmol) of 2-methoxycarbonylamino-2-methyl-4-[4-(5-phenylpent-1-ynyl)thiophen-2-yl obtained in Example 25(g) ] Ethyl butyrate was dissolved in 15ml ethanol, 10ml tetrahydrofuran, under ice-cooling, 0.24g (5.75mmol) lithium chloride, 0.22g (5.75mmol) sodium borohydride were added, stirred at 70°C for 2 Hour. After cooling the reaction liquid, it was made acidic with 1N hydrochloric acid, and extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1-1:1) to obtain 0.65 g (96%) of the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.15-7.35 (6H, m), 6.79 (1H, s), 5.38 (1H, brs), 4.18 (1H, d, J=8.6Hz), 4.08 (1H, d, J=8.6Hz), 2.80-2.90(2H, m), 2.77(2H, t, J=7.6Hz), 2.38(2H, t, J=7.0Hz), 1.85-2.00(4H, m), 1.41(3H,s)

Infrared absorption spectrum v _max cm ^-1 (CHCl ₃ ): 3450, 2978, 2945, 1757, 1497, 1401, 1382, 1249, 1046.

Example 25(i)

2-Amino-2-methyl-4-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol hydrochloride

200 mg (0.57 mmol) of 4-methyl-4-{2-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]}ethyloxamon obtained in Example 25 (h) Oxazolidin-2-one was dissolved in 1ml of tetrahydrofuran and 2ml of methanol, under ice cooling, 2ml of 5N potassium hydroxide aqueous solution was added, and heated to reflux for 18 hours. Water was added to the reaction liquid, followed by extraction with dichloromethane. After the dichloromethane layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in 2ml 1,4-dioxane, under ice-cooling conditions, 4N hydrochloric acid dioxane solution was added, the solvent was distilled off, and then the white solid obtained was washed with ether and dried to obtain 165mg (80%) title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 7.15-7.30 (6H, m), 6.84 (1H, s), 3.61 (1H, d, J=11.5Hz), 3.52 (1H, d, J=11.5Hz ), 2.80-2.95(2H, m), 2.75(2H, t, J=7.5Hz), 2.35(2H, t, J=7.0Hz), 1.82-2.10(4H, m), 1.32(3H, s)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3351, 3027, 2928, 1594, 1509, 1455, 1389, 1062.

Example 26

2-Amino-2-methyl-4-[4-(5-phenylpentyl)thiophen-2-yl]butan-1-ol hydrochloride

(Exemplary compound 2-39)

Example 26(a)

4-Methyl-4-{2-[4-(5-phenylpentyl)thiophen-2-yl]}ethyloxazolidin-2-one

174 mg (0.49 mmol) of 4-methyl-4-{2-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]}ethyloxamon obtained in Example 25(h) Oxazolidin-2-one was dissolved in 9ml of ethanol, 90mg of 5% palladium on carbon was added, and stirred for 4 hours under a hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to obtain 164 mg (93%) of the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.25-7.30 (2H, m), 7.15-7.20 (3H, m), 6.70 (1H, s), 6.63 (1H, s), 5.33 (1H, brs), 4.18(1H, d, J=8.6Hz), 4.07(1H, d, J=8.6Hz), 2.80-2.90(2H, m), 2.61(2H, t, J=7.8.Hz), 2.53(2H, t, J=7, 7Hz), 1.93-2.02 (2H, m), 1.55-1.70 (4H, m), 1.35-1.45 (5H, m)

Infrared absorption spectrum v _max cm ^-1 (CHCl ₃ ): 3451, 2977, 2934, 2858, 1757, 1400, 1382, 1045.

Example 26(b)

2-Amino-2-methyl-4-[4-(5-phenylpentyl)thiophen-2-yl]butan-1-ol hydrochloride

Use 136 mg (0.38 mmol) of 4-methyl-4-{2-[4-(5-phenylpentyl)thiophen-2-yl]}ethyloxazolidine-2 obtained in Example 26 (a) - Ketone, the same procedure as in Example 25(i) was used to obtain 107 mg (76%) of the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.10-7.30 (5H, m), 6.63 (1H, s), 6.61 (1H, s), 3.66 (2H, s), 2.80-2.95 (2H, m), 2.58(2H, t, J=7.7Hz), 2.47(2H, t, J=7.7Hz), 2.00-2.18(2H, m), 1.52-1.67(4H, m), 1.25-1.45(5H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3223, 2929, 2887, 1606, 1525, 1455, 1400, 1054.

Example 27

2-Amino-2-methyl-4-[4-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol hydrochloride

(Exemplary compound 2-343)

178 mg (0.49 mmol) of 2-amino-2-methyl-4-[4-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1 obtained in Example 26(i) -Alcohol hydrochloride was dissolved in 2ml of methanol, 2ml of 6N sulfuric acid was added, and heated to reflux for 4 hours. The reaction solution was made alkaline with 1N aqueous sodium hydroxide solution, and then extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 2ml 1,4-dioxane, under ice cooling, 4N hydrochloric acid dioxane solution was added, the solvent was distilled off, and then the white solid obtained was washed with ether and dried to obtain 100 mg (53%) of the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 8.14 (1H, s), 7.29 (1H, s), 7.10-7.27 (5H, m), 3.63 (1H, d, J=11.6Hz), 3.53 (1H , d, J=11.6Hz), 2.85-3.00 (4H, m), 2.64 (2H, t, J=7.0Hz), 1.92-2.13 (2H, m), 1.67-1.75 (4H, m), 1.33 ( 3H, s)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3361, 3026, 2939, 1666, 1591, 1456, 1154, 1072.

Example 28

2-Amino-2-ethyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol maleate

(Exemplary compound 1-1909)

Using racemic 4-[2-(5-bromothien-2-yl)]ethyl-4-ethyloxazolidin-2-one as the starting material, the same operation as in Example 1 was used to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 6.90 (1H, d, J = 3.6Hz), 6.72 (1H, d, J = 3.6Hz), 6.25 (2H, s), 3.61 (1H, d, J =11.7Hz), 3.57(1Hd, J=11.7Hz), 2.75-2.90(2H, m), 2.38(2H, t, J=7.0Hz), 1.88-2.06(2H, m), 1.52-1.82(9H , m), 1.12-1.37 (6H, m), 0.85-1.04 (5H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3191, 2922, 2851, 1576, 1521, 1386, 1362, 1193, 1068

Example 29

2-Amino-2-ethyl-4-[5-(5-cyclohexylpentyl)thiophen-2-yl]butan-1-ol maleate

(Exemplary compound 1-1764)

Using the 2-amino-2-ethyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol obtained in Example 28, the same as in Example 11 The operation afforded the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 6.64 (1H, d, J = 3.7Hz), 6.57 (1H, d, J = 3.7Hz), 6.25 (2H, s), 3.61 (1H, d, J =11.8Hz), 3.57(1H, d, J=11.8Hz), 2.70-2.87(4H, m), 1.88-2.05(2H, m), 1.56-1.82(9H, m), 1.10-1.38(10H, m), 0.99 (3H, t, J=7.5Hz), 0.81-0.93 (2H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3196, 2923, 2852, 1581, 1523, 1385, 1368, 1193, 1067, 1016

Example 30

2-Amino-2-ethyl-4-[5-(5-cyclohexylpentanoyl)thiophen-2-yl]butan-1-ol maleate

(Exemplary compound 1-2097)

Using the 2-amino-2-ethyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol obtained in Example 28, the same as in Example 17 The operation afforded the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 7.72 (1H, d, J = 3.7Hz), 6.99 (1H, d, J = 3.7Hz), 6.25 (2H, s), 3.63 (1H, d, J =11.6Hz), 3.59(1H, d, J=11.6Hz), 2.85-3.02(4H, m), 1.94-2.12(2H, m), 1.60-1.83(9H, m), 1.10-1.42(8H, m), 1.01(3H, t, J=7.5Hz), 0.82-0.96(2H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3395, 2922, 2851, 1654, 1582, 1520, 1458, 1385, 1370, 1203, 1067

Example 31

(2R)-Amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)thiophen-2-yl]butan-1-olmaleic salt

(Exemplary compound 1-1072)

Using 4-[2-(5-bromothien-2-yl)]ethyl-4-methyloxazolidin-2-one as a starting material, the same operation as in Example 1 was used to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 6.93 (1H, d, J = 3.6Hz), 6.73 (1H, d, J = 3.6Hz), 6.25 (2H, s), 3.57-3.67 (3H, m ), 3.51(1H, d, J=11.6Hz), 3.32-3.42(1H, m), 2.78-2.95(2H, m), 2.63(2H, t, J=6.7Hz), 1.50-2.10(7H, m), 1.17-1.37 (8H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3394, 2932, 2858, 1583, 1506, 1386, 1367, 1194, 1104

Example 32

2-Amino-2-methyl-4-[5-(4-cyclohexylmethoxyphenyl)thiophen-2-yl]butan-1-ol

(Exemplary compound 1-1729)

Using 4-[2-(5-bromothien-2-yl)]ethyl-4-methyloxazolidin-2-one as a starting material, the same operation as in Example 1 was used to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 7.45 (2H, d, J = 8.7Hz), 7.02 (1H, d, J = 3.6Hz), 6.88 (2H, d, J = 8.7Hz), 6.76 ( 1H, d, J = 3.6Hz), 3.77 (2H, d, J = 6.3Hz), 3.40 (1H, d, J = 10.9Hz), 3.36 (1H, d, J = 10.9Hz), 2.91-2.79 ( 2H, m), 1.90-1.68 (8H, m), 1.41-1.08 (5H, m), 1.11 (3H, s)

Example 33

2-Amino-2-methyl-4-[5-(4-benzyloxyphenyl)thiophen-2-yl]butan-1-ol

(Exemplary compound 1-1744)

Using 4-[2-(5-bromothien-2-yl)]ethyl-4-methyloxazolidin-2-one as a starting material, the same operation as in Example 1 was used to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 7.51-7.27 (7H, m), 7.07 (1H, d, J = 3.6Hz), 6.98 (2H, d, J = 8.7Hz), 6.76 (1H, d , J=3.6Hz) 5.06(2H, s), 3.44-3.38(2H, m), 2.91-2.80(2H, m), 1.86-1.74(2H, m), 1.11(3H, s)

Example 34

(2R)-Amino-2-methyl-4-{5-[3-(4-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol maleate

(Exemplary compound 1-1063)

The same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 1.31 (3Hs), 1.88-2.10 (2H, m), 2.27 (3H, s), 2.80-2.95 (2H, m), 3.51 (1H, d, J= 11.6Hz), 3.60(1H, d, J=11.6Hz), 4.89(2H, s), 6.25(2H, s), 6.77(1H, d, J=3.6Hz), 6.88(2H, d, J= 8.6Hz), 7.05(1H, d, J=3.6Hz), 7.09(2H, d, J=8.6Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr: 3338, 3211, 3006, 2923, 2229, 1583, 1511, 1372, 1228, 1018

Example 35

(2R)-Amino-2-methyl-4-{5-[3-(4-methylphenoxy)propyl]thiophen-2-yl}butan-1-ol Torate

(Exemplary compound 1-391)

Using (2R)-amino-2-methyl-4-{5-[3-(4-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol obtained in Example 34 For the maleate salt, the same operation as in Example 11 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 1.31 (3H, s), 1.88-2.10 (4H, m), 2.25 (3H, s), 2.77-2.92 (2H, m), 2.94 (2H, t, J=7.5Hz), 3.51(1H, d, J=11.6Hz), 3.60(1H, d, J=11.6Hz), 3.93(2H, t, J=6.2Hz), 6.25(2H, s), 6.62 (1H, d, J = 3.3Hz), 6.65 (1H, d, J = 3.3Hz), 6.77 (2H, d, J = 8.5Hz), 7.04 (2H, d, J = 8.5Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3412, 3028, 2947, 2926, 1577, 1513, 1387, 1357, 1239, 1055

Example 36

(2R)-Amino-2-methyl-4-{5-[3-(3-methylphenoxy)propynyl]thiophen-2-yl}butan-1-ol Oxalate

(Exemplary compound 1-2276)

The same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 1.31 (3H, s), 1.90-2.10 (2H, m), 2.31 (3H, s), 2.82-2.96 (2H, m), 3.52 (1H, d, J=11.7Hz), 3.60(1H, d, J=11.7Hz), 4.90(2H, s), 6.73-6.85(4H, m), 7.05(1H, d, J=3.6Hz), 7.16(1H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 2923, 2575, 2226, 1621, 1583, 1559, 1489, 1290, 1255, 1154, 1045

Example 37

(2R)-Amino-2-methyl-4-{5-[3-(4-ethylphenylhydrogen)propynyl]thiophen-2-yl}butan-1-ol maleate

(Exemplary compound 1-1064)

The same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 1.20 (3H, t, J = 7.6Hz), 1.31 (3H, s), 1.88-2.10 (2H, m), 2.68 (2H, q, J = 7.6Hz ), 2.80-2.95 (2H, m), 3.51 (1H, d, J = 11.5Hz), 3.60 (1H, d, J = 11.5Hz), 4.89 (2H, s), 6.25 (2H, s), 6.77 (1H, d, J = 3.6Hz), 6.90 (2H, d, J = 8.6Hz), 7.05 (1H, d, J = 3.6Hz), 7.12 (2H, d, J = 8.6Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3385, 2959, 2928, 2226, 1581, 1510, 1384, 1232, 1020

Example 38

(2R)-Amino-2-methyl-4-{5-[3-(4-methylthiophenoxy)propynyl]thiophen-2-yl}butan-1-ol maleate

(Exemplary compound 1-1068)

The same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 1.31 (3H, s), 1.88-2.10 (2H, m), 2.42 (3H, s), 2.81-2.96 (2H, m), 3.51 (1H, d, J=11.5Hz), 3.60(1H, d, J=11.5Hz), 4.92(2H, s), 6.25(2H, s), 6.78(1H, d, J=3.6Hz), 6.96(2H, d, J=8.9Hz), 7.06(1H, d, J=3.6Hz), 7.27(2H, d, J=8.9Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3401, 2984, 2918, 2227, 1575, 1492, 1376, 1237, 1011

Example 39

(2R)-amino-2-methyl-4-{5-[3-(3,5-dimethoxyphenoxy)propynyl]thiophen-2-yl}butan- 1-alcohol fumarate

(Exemplary compound 1-2285)

The same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 1.31 (3H, s), 1.90-2.10 (2H, m), 2.82-2.96 (2H, m), 3.51 (1H, d, J=11.6Hz), 3.61 (1H, d, J = 11.6Hz), 3.75 (6H, s), 4.89 (2H, s), 6.13 (1H, dd, J = 2.2, 2.2Hz), 6.43 (2H, d, J = 2.2Hz) , 6.69(2H, s), 6.78(1H, d, J=3.6Hz), 7.07(1H, d, J=3.6Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3382, 2936, 2222, 1682, 1601, 1476, 1205, 1152, 1066

Example 40

(2R)-amino-2-methyl-4-{5-[3-(3,4-dimethoxyphenoxy)propynyl]thiophen-2-yl}butan- 1-alcohol maleate

(Exemplary compound 1-2284)

The same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 1.31 (3H, s), 1.88-2.10 (2H, m), 2.81-2.95 (2H, m), 3.51 (1H, d, J=11.4Hz), 3.61 (1H, d, J=11.4Hz), 3.78(3H, s), 3.81(3H, s), 4.88(2H, s), 6.25(2H, s), 6.54(1H, dd, J=8.7, 2.7 Hz), 6.66 (1H, d, J = 2.7Hz), 6.78 (1H, d, J = 3.6Hz), 6.87 (1H, d, J = 8.7Hz), 7.05 (1H, d, J = 3.6Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3361, 2934, 2221, 1581, 1512, 1385, 1369, 1228, 1196, 1023

Example 41

(2R)-Amino-2-methyl-4-{5-[3-(4-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol

(Exemplary compound 1-2288)

The same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 1.07 (3H, s), 1.68-1.82 (2H, m), 2.56 (3H, s), 2.77-2.91 (2H, m), 3.33 (1H, d, J = 11.0Hz), 3.36 (1H, d, J = 11.0Hz), 5.05 (2H, s), 6.73 (1H, d, J = 3.6Hz), 7.04 (1H, d, J = 3.6Hz), 7.10 (2H, d, J=9.0Hz), 8.00 (2H, d, J=9.0Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3351, 3315, 3287, 2916, 2878, 2734, 2229, 1673, 1599, 1376, 1364, 12553, 1174

Example 42

(2R)-Amino-2-methyl-4-{5-[3-(4-carboxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol Hydrochloride

(Exemplary compound 1-2289)

The same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 1.31 (3H, s), 1.90-2.10 (2H, m), 2.82-2.96 (2H, m), 3.51 (1H, d, J=11.5Hz), 3.61 (1H, d, J = 11.5Hz), 5.04 (2H, s), 6.79 (1H, d, J = 3.7Hz), 7.05-7.11 (3H, m), 7.99 (2H, d, J = 8.8Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3383, 3064, 2226, 1699, 1604, 1508, 1379, 1233, 1170, 1002

Example 43

(2R)-Amino-2-methyl-4-{5-[3-(3-methoxyphenoxy)propynyl]thiophen-2-yl}butan-1-ol maleate

(Exemplary compound 1-2283)

The same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₂ OD) δppm: 1.31 (3H, s), 1.88-2.10 (2H, m), 2.80-2.96 (2H, m), 3.51 (1H, d, J=11.6Hz), 3.60 (1H, d, J=11.6Hz), 3.77(3H, s), 4.91(2H, s), 6.25(2H, s), 6.52-6.61(3H, m), 6.78(1H, d, J=3.6 Hz), 7.06(1H, d, J=3.6Hz), 7.18(1H, t, J=8.4Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3005, 2940, 2223, 1583, 1493, 1387, 1362, 1284, 1191, 1153, 1080, 1045, 1020, 866, 813, 758, 687, 565

Example 44

(2R)-Amino-2-methyl-4-{5-[4-(4-methylphenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol maleate

(Exemplary compound 1-1139)

The same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 1.31 (3H, s), 1.87-2.10 (2H, m), 2.26 (3H, s), 2.85 (2H, t, J=6.8Hz), 2.78-2.95 (2H, m), 3.51 (1H, d, J = 11.6Hz), 3.61 (1H, d, J = 11.6Hz), 4.09 (2H, t, J = 6.8Hz), 6.25 (2H, s), 6.73 (1H, d, J = 3.6Hz), 6.82 (2H, d, J = 8.4Hz), 6.96 (1H, d, J = 3.6Hz), 7.07 (2H, d, J = 8.4Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3032, 2925, 2596, 1578, 1513, 1388, 1359, 1293, 1244, 1205, 1176, 1079, 1039, 867, 812, 509

Example 45

(2R)-Amino-2-methyl-4-{5-[4-(4-fluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1-ol

(Exemplary compound 1-1135)

The same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 1.15 (3H, s), 1.72-1.89 (2H, m), 2.22 (3H, brs), 2.88 (2H, t, J=6.8Hz), 2.76-2.93 (2H, m), 3.37 (1H, d, J = 10.8Hz), 3.42 (1H, d, J = 10.8Hz), 4.11 (2H, t, J = 6.8Hz), 6.64 (1H, d, J = 3.6Hz), 6.84-6.90(2H, m), 6.93-7.03(3H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3356, 3296, 3090, 2971, 2950, 2916, 2896, 2877, 2812, 2735, 1589, 1506, 1465, 1389, 1289, 1245, 1219, 1203, 1154, 1065, 1039, 974, 923, 831, 819, 742, 568, 523, 509

Example 46

(2R)-amino-2-methyl-4-{5-[3-(3,4-dimethylphenoxy)propynyl]thiophen-2-yl}butan-1- alcohol maleate

(Exemplary compound 1-2278)

The same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD) δppm: 1.31 (3H, s), 1.90-2.09 (2H, m), 2.19 (3H, s), 2.23 (3H, s), 2.81-2.94 (2H, m) , 3.31(1H, s), 3.51(1H, d, J=11.6Hz), 3.61(1H, d, J=11.6Hz), 4.87(2H, s), 6.25(2H, s), 6.70-6.78( 3H, m), 7.01-7.04 (2H, m)

Infrared absorption spectrum v _max cm ^-1 (liquid film): 3353, 3022, 2971, 2923, 2226, 1579, 1500, 1385, 1368, 1287, 1249, 1205, 1165, 1120, 1077, 1039, 930, 865, 806 , 713, 573, 446

Example 47

(2R)-2-Amino-2-methyl-4-[2-(3-phenylpropoxy)thiophen-5-yl]butan-1-ol tartrate

(Exemplary compound 1-2395)

Example 47(a)

(2R)-Amino-2-methyl-4-thiophen-2-ylbutan-1-ol 1/2D-(-)-tartrate

7.30 g (34.6 mmol) of (4R)-methyl-4-[2-(thiophen-2-yl)]ethyl oxazolidin-2-one of 85% ee obtained in Example 56 was dissolved in 35 ml of tetrahydrofuran and 70ml of methanol, under ice-cooling, add 70ml of 5N aqueous potassium hydroxide solution, and stir at 80°C for 2 days. Dichloromethane was added to the reaction solution, followed by washing with water. The dichloromethane layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 6.20 g of the obtained residue was dissolved in 60 ml of ethanol, a solution of 5.19 g (34.6 mmol) D-(-)-tartaric acid in 50 ml of ethanol was added, and the precipitate was filtered to obtain 7.56 g of the crude title compound. 7.54 g of the resulting crude title compound was recrystallized from 75 ml of ethanol and 50 ml of water to obtain 5.89 g (98% ee) of the title compound. 5.88 g of the obtained target compound were recrystallized again from 60 ml of ethanol and 54 ml of water to obtain 5.11 g (57%, 99.7% ee) of the title compound.

Infrared absorption spectrum v _max cm ^-1 (KHr): 3400, 3218, 3126, 2937, 2596, 1599, 1530, 1400, 1124, 1077, 715

Elemental analysis value; (% relative to C ₉ H ₁₅ NOS·0.5C ₄ H ₄ O ₆ )

Calculated: C, 50.95; H, 6.61; N, 5.40; S, 12.36

Found values: C, 50.68; H, 6.91; N, 5.38; S, 12.48

[α] _D ²⁴ -14 (c1.00, H ₂ O)

Example 47(b)

(2R)-Acetylamino-2-methyl-4-(thiophen-2-yl)butyl acetate

Under ice cooling, to (2R)-amino-2-methyl-4-thiophene-2-ylbutan-1-alcohol 1/2D-(-) obtained in 5.11g (19.6mmol) embodiment 47 (a) - After adding 30ml of 1N aqueous sodium hydroxide solution to the tartrate to make it into a free form, extract it with dichloromethane. After the dichloromethane layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 3.55 g (98%) of (2R)-amino-2-methyl-4-thiophen-2-ylbutan-1-ol. Add 30ml of pyridine to 1.51g (8.15mmol) of the obtained (2R)-amino-2-methyl-4-(thiophen-2-yl)butan-1-alcohol, and add 1.95ml (20.7mmol ) acetic anhydride, 200mg (1.64mmol) 4-(dimethylamino)pyridine. Stir at room temperature under nitrogen atmosphere for 2.5 hours. The reaction solution was poured into 150ml of 1N hydrochloric acid under ice cooling, extracted with ethyl acetate, and the ethyl acetate layer was washed successively with 1N hydrochloric acid and saturated brine. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1-1:2) to obtain 2.15 g (98%) of the title compound.

NMR spectrum (400MHz, CDCl ₃ ): δ1.37(3H, s), 1.93(3H, s), 1.94-2.10(1H, m), 2.10(3H, s), 2.24-2.38(1H, m) , 2.85(2H, t, J=8.0Hz), 4.18(1H, d, J=11.6Hz), 4.32(1H, d, J=11.6Hz), 5.39(1H, brs), 6.81(1H, dd, J=1.2, 3.6Hz), 6.92 (1H, dd, J=3.6, 5.2Hz), 7.12 (1H, dd, J=1.2, 5.2Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3265, 3079, 2933, 2862, 1735, 1638, 1559, 1472, 1441, 1374, 1318, 1241, 1179, 1039, 701, 616

Example 47(c)

(2R)-Acetylamino-2-methyl-4-(5-bromothien-2-yl)butyl acetate

(2R)-acetylamino-2-methyl-4-(thiophen-2-yl)butyl ester obtained in 1.81 g (6.70 mmol) of Example 47 (b) was dissolved in 20 ml of dimethylformamide , under ice cooling, 1.27 g (7.11 mmol) of N-bromosuccinimide was added, stirred under nitrogen atmosphere for 10 minutes under ice cooling, and stirred at room temperature for a whole day and night. The reaction solution was poured into water, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1-1:2) to obtain 2.32 g (99%) of the title compound.

NMR spectrum (400MHz, CDCl ₃ ): δ1.35(3H, s), 1.95(3H, s), 1.95-2.08(1H, m), 2.10(3H, s), 2.24-2.37(1H, m) , 2.76 (2H, t, J = 8.4Hz), 4.15 (1H, d, J = 11.2Hz), 4.30 (1H, d, J = 11.2Hz), 5.39 (1H, brs), 6.57 (1H, d, J=3.6Hz), 6.84 (1H, d, J=3.6Hz)

Infrared absorption spectrum v _max cm ^-1 (liquid film): 3300, 3076, 2980, 2937, 1740, 1657, 1544, 1466, 1446, 1373, 1242, 1045, 794, 604

Example 47(d)

(2R)-2-Amino-2-methyl-4-[2-(3-phenylpropoxy)thiophen-5-yl]butan-1-ol tartrate

Sodium (0.06 g, 2.6 mmol) was added to 3-phenyl-1-propanol (1 ml), the temperature was raised slowly, and the mixture was stirred at 80°C to 90°C for 3 hours. Let it cool, and add (2R)-acetate acetylamino-2-methyl-4-(5-bromothiophen-2-yl)butyl ester (0.177g, 0.51mmol) obtained in Example 47(c) , potassium iodide (0.8mg, 0.005mmol) and copper(II) oxide (21.0mg, 0.26mmol), stirred at 90°C for 19 hours. After cooling, the reaction solution was subjected to silica gel column chromatography (elution solvent; methylene chloride: methanol: triethylamine, 10:1:0-100:10:1, V/V/V) and basic silica gel column chromatography (elution solvent; dichloromethane:methanol, 100:1, V/V) to obtain (2R)-2-amino-2-methyl-4-[2-(3-phenylpropoxy ) Thiophen-5-yl]butan-1-ol (9.1 mg, yield 6%).

The obtained (2R)-2-amino-2-methyl-4-[2-(3-phenylpropoxy)thiophen-5-yl]butan-1-ol (15.2 mg, 0.048 mmol) was dissolved in methanol (1ml), tartaric acid (4.5mg, 0.049mmol) was added, and stirred at room temperature for 1.5 hours. After concentration under reduced pressure, ethyl acetate was added thereto, and the precipitated crystals were filtered, washed with ethyl acetate and dried to obtain the target compound (18.5 mg, 95%).

NMR spectrum (400MHz, CD ₃ OD) δppm: 1.30 (3H, s), 1.86-2.07 (4H, m), 2.68-2.79 (4H, m), 3.51 (1H, d, J=11.6Hz), 3.59 (1H, d, J = 11.6Hz), 3.97 (2H, t, J = 6.5Hz), 6.00 (1H, d, J = 3.7Hz), 6.44 (1H, d, J = 3.7Hz), 7.14-7.28 (5H, m)

Mass spectrum (ESI) m/z: 342. (M+Na) ⁺ , 320 (M+H) ⁺ .

Example 48

(2R)-Amino-2-methyl-4-{5-[3-(3-acetylphenoxy)propynyl]thiophen-2-yl}butan-1-ol Oxalate

(Exemplary compound 1-2287)

The same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD): δ1.31(3H, s), 1.88-2.10(2H, m), 2.60(3H, s), 2.82-2.95(2H, m), 3.51(1H, d , J=11.6Hz), 3.60(1H, d, J=11.6Hz), 5.02(2H, s), 6.78(1H, d, J=3.6Hz), 7.06(1H, d, J=3.6Hz), 7.26(1H, m), 7.44(1H, m), 7.61-7.67(2H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3346, 3213, 2929, 2224, 1679, 1596, 1582, 1277, 1205, 721

Example 49

(2R)-Amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol oxalate

(Exemplary compound 1-824)

Example 49(a)

(2R)-Acetylamino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butyl acetate

(2R)-acetylamino-2-methyl-4-(5-bromothiophen-2-yl) butyl ester synthesized in 1.60 g (4.59 mmol) of Example 47 (c) was dissolved in 16 ml of dimethyl In formamide, add 1.99g (13.8mmol) 5-phenylpent-1-yne, 6.40ml (45.9mmol) triethylamine, 175mg (0.92mmol) copper(I) iodide and 322mg (0.46mmol) dichloro · Bis(triphenylphosphine)palladium was stirred at 80° C. for 2 hours in a nitrogen atmosphere. The reaction solution was poured into water, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1-2:3) to obtain 1.41 g (75%) of the title compound.

NMR spectrum (400MHz, CDCl ₃ ): δ1.36(3H, s), 1.85-2.05(3H, m), 1.94(3H, s), 2.10(3H, s), 2.25-2.35(1H, m) , 2.43(2H, t, J=7.0Hz), 3.70-3.80(4H, m), 4.17(1H, d, J=11.2Hz), 4.31(1H, d, J=11.2Hz), 5.38(1H, brs), 6.64(1H, d, J=3.6H2), 6.94(1H, d, J=3.6Hz), 7.15-7.42(5H, m)

Infrared absorption spectrum v _max cm ^-1 (CHCl ₃ ): 3443, 2946, 2862, 1737, 1681, 1511, 1374, 1251, 1042

Example 49(b)

(2R)-Amino-2-methyl 4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol oxalate

(2R)-Acetylamino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophene-2 obtained in 1.40 g (3.40 mmol) of Example 49 (a) -Byl]butyl ester was dissolved in 14ml of tetrahydrofuran:methanol:water=1:1:1 solution, added 1.43g (34.0mmol) lithium hydroxide monohydrate, stirred at 50°C for 4 hours. The reaction solution was poured into water and extracted with dichloromethane. After the dichloromethane layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; dichloromethane:methanol:ammonia=20:1:0-10:1:0.1) to obtain 1.11 g (100%) of (2R)-amino-2-methanol yl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol. 360 mg (1.10 mmol) of the resulting (2R)-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol were dissolved in methanol , 99 mg (1.10 mmol) of oxalic acid was added, and the precipitated crystals were recrystallized from methanol to obtain 394 mg (86%) of the title compound as white crystals.

NMR spectrum (400MHz, CD ₃ OD): δ1.31(3H, s), 1.82-2.10(4H, m), 2.40(2H, t, J=7.0Hz), 2.75(2H, t, J=7.5 Hz), 2.80-2.95(2H, m), 3.62(1H, d, J=11.5Hz), 3.61(1H, d, J=11.5Hz), 6.73(1H, d, J=3.6Hz), 6.94( 1H, d, J=3.6Hz), 7.13-7.30 (5H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3383, 3106, 3026, 2980, 2942, 2622, 2514, 1721, 1609, 1639, 1198, 699

Mass Spectrum (FAB) m/z: 328(M+H) ⁺ (free form)

Elemental analysis value; (% relative to C ₂₀ H ₂₅ NOS · C ₂ H ₂ O ₄ · 0.2H ₂ O)

Calculated: C, 62.75; H, 6.65; N, 3.32; S, 7.61

Found: C, 62.50; H, 6.29; N, 3.39; S, 7.70

[α] _D ²⁵ -0.9 (c1.00, methanol)

Example 50

(2R)-Amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol oxalate

(Exemplary compound 1-1344)

With 387 mg (1.18 mmol) of (2R)-amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]but-1- Dissolve alcohol in 4ml methanol, add 4ml 6N sulfuric acid, and heat to reflux for 4 hours. After cooling the reaction liquid to 0° C., it was adjusted to basicity (pH 14) with 1N aqueous sodium hydroxide solution, and extracted with dichloromethane. After the dichloromethane layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (Chromatorex NH (100-200 mesh)) (elution solvent; dichloromethane:methanol=1:0-50 :1) Purification afforded 336 mg (82%) of (2R)-amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol. This was dissolved in methanol, 88 mg (0.97 mmol) of oxalic acid was added, and the obtained crystals were recrystallized from methanol to obtain 332 mg (78%) of the title compound as white crystals.

NMR spectrum (400MHz, DMSO-d ₆ ): δ1.19(3H, s), 1.55-1.67(4H, m), 1.80-1.98(2H, m), 2.60(2H, t, J=6.7Hz) , 2.83-2.96 (4H, m), 3.40 (1H, d, J = 11.3Hz), 3.47 (1H, d, J = 11.3Hz), 7.00 (1H, d, J = 3.7Hz), 7.13-7.22 ( 3H, m), 7.23-7.31 (2H, m), 7.80 (1H, d, J=3.7Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3126, 2942, 2657, 1915, 1718, 1649, 1609, 1547, 1445, 1205, 700

Mass spectrum (FAB) m/z: 346 (M+H) ⁺ (free form)

Elemental analysis value; (% relative to C ₂₀ H ₂₇ NO ₂ S · C ₂ H ₂ O ₄ · 0.5H ₂ O)

Calculated: C, 59.44; H, 6.80; N, 3.15; S, 7.21

Found values: C, 59.62; H, 6.53; N, 3.31; S, 7.43

Example 51

(2R)-Amino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butan-1-ol oxalate

(Exemplary compound 1-152)

With 337 mg (0.82 mmol) of (2R)-acetic acid acetylamino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophene-2- obtained in Example 49 (a), Base] butyl ester was dissolved in 17ml of methanol, 170mg of 10% palladium on carbon was added, and stirred for 16 hours under a hydrogen atmosphere. After filtering off the catalyst with celite, the filtrate was distilled off under reduced pressure to obtain 318 mg (93%) of (2R)-acetylamino-2-methyl-4-[5-(5-phenylpentyl)thiophene- 2-yl] butyl ester. 298 mg (0.72 mmol) of the obtained (2R)-acetate acetylamino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butyl ester was dissolved in 6 ml THF:methanol:water = To a solution of 1:1:1, 301 mg (7.17 mmol) of lithium hydroxide monohydrate was added, and stirred at 50° C. for 6 hours. The reaction solution was poured into water and extracted with dichloromethane. After the dichloromethane layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. 243 mg of the residue was dissolved in methanol, 65 mg (0.72 mmol) of oxalic acid was added, and the precipitated crystals were filtered to obtain 251 mg (83%) of the title compound as white crystals.

NMR spectrum (400MHz, CD ₃ OD): δ1.31 (3H, s), 1.32-1.42 (2H, m), 1.58-1.70 (4H, m), 1.88-2.08 (2H, m), 2.59 (2H , t, J=7.6Hz), 2.74(2H, t, J=7.4Hz), 2.75-2.91(2H, m), 3.52(1H, d, J=11.6Hz), 3.61(1H, d, J= 11.6Hz), 6.56(1H, d, J=3.3Hz), 6.63(1H, d, J=3.3Hz), 7.09-7.17(3H, m), 7.19-7.27(2H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3458, 3134, 2929, 2855, 2595, 1724, 1642, 1543, 1219, ^{710cm -1}

Example 52

(2R)-amino-2-methyl-4-{5-[3-(4-chlorophenoxy)propynyl]thiophen-2-yl}butan-1-ol oxalate (exemplary compound 1- 2273)

Example 52(a)

(2R)-Acetylamino-2-methyl-4-[5-(3-hydroxypropynyl)thiophen-2-yl]butyl acetate

(2R)-acetylamino-2-methyl-4-(5-bromothiophen-2-yl)butyl ester synthesized in 1.38g (3.95mmol) of Example 47 (c) was dissolved in 20ml of dimethyl In formamide, add 0.69ml (11.9mmol) propargyl alcohol, 5.60ml (40.1mmol) triethylamine, 76mg (0.40mmol) copper iodide (I) and 276mg (0.39mmol) dichlorobis(triphenylphosphine ) and palladium, stirred for 1 hour under nitrogen atmosphere at 80°C. The reaction solution was poured into water, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1-1:3) to obtain 685 mg (54%) of the title compound as white crystals.

NMR spectrum (500MHz, CDCl ₃ ): δ1.35(3H, s), 1.91(1H, brs), 1.94(3H, s), 1.97-2.05(1H, m), 2.10(3H, s), 2.27 -2.35(1H, m), 2.75-2.82(2H, m), 4.16(1H, d, J=11.2Hz), 4.31(1H, d, J=11.2Hz), 4.49(2H, s), 5.43( 1H, brs), 6.66 (1H, d, J=3.6Hz), 7.02 (1H, d, J=3.6Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3295, 3077, 2981, 2217, 1740, 1644, 1556, 1373, 1251, 1028

Example 52(b)

(2R)-Amino-2-methyl-4-{5-[3-(4-chlorophenoxy)propynyl]thiophen-2-yl}butan-1-alpha salt

(2R)-acetylamino-2-methyl-4-[5-(3-hydroxypropynyl)thiophen-2-yl]butyl ester synthesized in 285mg (0.88mmol) of Example 52(a) and 136mg (1.06mmol) of 4-chlorophenol were dissolved in 5ml of anhydrous tetrahydrofuran, and 230mg (1.32mmol) of diethyl azodicarboxylate and 346mg (1.32mmol) of triphenylphosphine were added under ice cooling, and stirred at room temperature for 4 hours . The reaction mixture was poured into water, and extracted with ethyl acetate. After the ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1-1:3) to obtain 195 mg ( 51%) (2R)-Acetylamino-2-methyl-4-{5-[3-(4-chlorophenoxy)propynyl]thiophen-2-yl}butyl as pale yellow oil ester. This was dissolved in 6 ml of a solution of tetrahydrofuran:methanol:water=1:1:1, 370 mg (8.82 mmol) of lithium hydroxide monohydrate was added, and the mixture was stirred at 50° C. for 6 hours. The reaction solution was poured into water and extracted with dichloromethane. After the dichloromethane layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. 175 mg (0.50 mmol) of the residue was dissolved in 5 ml of ethyl acetate, 45 mg (0.50 mmol) of oxalic acid was added, and the precipitated crystals were filtered to obtain 198 mg (86%) of the title compound as white crystals.

NMR spectrum (400MHz, DMSO-d ₆ ): δ1.18 (3H, s), 1.7-2.0 (2H, m), 2.84 (2H, t, J=8.7Hz), 3.43 (2H, m), 5.07 (2H, s), 6.83 (1H, d, J = 3.6Hz), 7.05 (2H, d, J = 9.0Hz), 7.19 (1H, d, J = 3.6Hz), 7.37 (2H, d, J = 9.0Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3416, 1719, 1597, 1490, 1375, 1241, 1201, 1092, 1006, 830

Mass spectrum (FAB) m/z: 350 (M+H) ⁺ (free form)

Elemental analysis value; (% relative to C ₂₀ H ₂₇ NO ₂ S·C ₂ H ₂ O ₄ )

Calculated: C, 54.61; H, 5.04; N, 3.18; S, 7.29; Cl, 8.06

Found: C, 54.61; H, 5.04; N, 3.01; S, 7.16; Cl, 7.77

Example 53

(2R)-Amino-2-methyl-4-[5-(1-hydroxy-5-phenylpentyl)thiophen-2-yl]butan-1-ol oxalate

(Exemplary compound 1-1686)

Dissolve 130mg (0.38mmol) of (2R)-amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol obtained in Example 50 in 3ml To methanol, 17 mg (0.45 mmol) of sodium borohydride was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Under ice-cooling, water was added to the reaction liquid, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol, 34 mg (0.38 mmol) of oxalic acid was added, and the solvent was distilled off under reduced pressure. 3 ml of ethanol was added thereto, and the precipitate was obtained by filtration to obtain 95 mg (58%) of the title compound as white crystals.

NMR spectrum (400MHz, CD ₃ OD): δ1.25-1.50 (2H, m), 1.30 (3H, s), 1.58-1.68 (2H, m), 1.70-2.08 (4H, m), 2.52-2.64 (2H, m), 2.80-2.94 (2H, m), 3.53 (1H, d, J=11.7Hz), 3.59 (1H, d, J=11.7Hz), 4.74 (1H, t, J=6.8Hz) , 6.69 (1H, d, J = 3.6Hz), 6.74 (1H, d, J = 3.6Hz), 7.08-7.27 (5H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3357, 2933, 2857, 1579, 1496, 1454, 1310, 1070, 699

Example 54

(2R)-Amino-2-methyl-4-[5-(4-phenylbut-1-ynyl)thiophen-2-yl]butan-1-ol oxalate

(Exemplary compound 1-756)

The title compound was prepared as in Example 49 using (2R)-acetylamino-2-methyl-4-(5-bromothien-2-yl)butyl ester and 4-phenylbut-1-yne .

NMR spectrum (400MHz, CD ₃ OD): δ1.31 (3H, s), 1.88-2.09 (2H, m), 2.68 (2H, t, J=7.3Hz), 2.78-2.93 (4H, m), 3.52 (1H, d, J = 11.6Hz), 3.61 (1H, d, H = 11.6Hz), 6.72 (1H, d, J = 3.6Hz), 6.88 (1H, d, J = 3.6Hz), 7.16- 7.31 (5H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3204, 3110, 3026, 2981, 2929, 2887, 1719, 1608, 1541, 1202, 699

Example 55

(2R)-Amino-2-methyl-4-[5-(4-phenylbutyryl)thiophen-2-yl]butan-1-ol oxalate

(Exemplary compound 1-1330)

As in Example 50, using (2R)-amino-2-methyl-4-[5-(4-phenylbut-1-ynyl)thiophen-2-yl]butan-1 obtained in Example 54 -alcohol to give the title compound.

NMR spectrum (400MHz, DMSO-d ₃ ): δ1.19 (3H, s), 1.82-1.98 (4H, m), 2.62 (2H, t, J=7.7Hz), 2.85-2.97 (4H, m) , 3.39(1H, d, J=11.7Hz), 3.45(1H, d, J=11.7Hz), 7.00(1H, d, J=3.8Hz), 7.15-7.33(5H, m), 7.76(1H, d, J=3.8Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3410, 3210, 2941, 2653, 2576, 1665, 1641, 1530, 1452, 1325

Example 56

(2R)-Amino-2-methyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol

(Exemplary compound 1-743)

The same operation as in Example 1 was carried out to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD): δ0.87-0.99 (2H, m), 1.08 (3H, s), 1.11-1.50 (6H, m), 1.62-1.81 (7H, m), 2.41 (2H , t, J=7.2Hz), 2.74-2.88(2H, m), 3.34(1H, d, J=11.0Hz), 3.37(1H, d, J=11.0Hz), 6.66(1H, d, J=11.0Hz), 6.66(1H, d, J= 3.6Hz), 6.87 (1H, d, J = 3.6Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3334, 3269, 3153, 2922, 2851, 1618, 1449, 1060, 804

Example 57

(2R)-Amino-2-methyl-4-[5-(4cyclohexylbutyl)thiophen-2-yl]butan-1-ol

(Exemplary compound 1-71)

Using (2R)-amino-2-methyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol obtained in Example 56, and Example 11, the title compound was obtained by the same operation.

NMR spectrum (400MHz, CD ₃ OD): δ0.80-0.95 (2H, m), 1.08 (3H, s), 1.10-1.40 (8H, m), 1.54-1.81 (9H, m), 2.68-2.87 (4H, m), 3.34 (1H, d, J = 10.9Hz), 3.37 (1H, d, J = 10.9Hz), 6.53 (1H, d, J = 3.2Hz), 6.58 (1H, d, J = 3.2Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3333, 3269, 3170, 2923, 2850, 1619, 1461, 1447, 1059, 801

Example 58

(2R)-Amino-2-methyl-4-[5-(4-cyclohexylbutyryl)thiophen-2-yl]butan-1-ol

(Exemplary compound 1-1329)

Using (2R)-amino-2-methyl-4-[5-(4-cyclohexylbut-1-ynyl)thiophen-2-yl]butan-1-ol obtained in Example 56, and Example 17 was similarly operated to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD): δ0.83-0.97 (2H, m), 1.09 (3H, s), 1.10-1.33 (6H, m), 1.61-1.86 (9H, m), 2.82-3.00 (4H, m), 3.35 (1H, d, J = 10.9Hz), 3.39 (1H, d, J = 0.9Hz), 6.94 (1H, d, J = 3.7Hz), 7.69 (1H, d, J = 3.7Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3333, 3268, 3142, 2921, 2849, 1648, 1457, 1208, 1057, 923, 816

Example 59

2-Amino-2-methyl-4-[5-(3-cyclohexylmethoxypropynyl)thiophen-2-yl]butan-1-olmaleic salt

(Exemplary compound 1-1185)

The same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD): δ0.92-1.04 (2H, m), 1.13-1.37 (3H, m), 1.31 (3H, s), 1.53-1.82 (6H, m), 1.89-2.11 (2H, m), 2.82-2.96 (2H, m), 3.35 (2H, d, J = 6.4Hz), 3.51 (1H, d, J = 11.5Hz), 3.61 (1H, d, J = 11.5Hz) , 4.87(2H, s), 6.25(2H, s), 6.78(1H, d, J=3.6Hz), 7.05(1H, d, J=3.6Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 2924, 2852, 2218, 1577, 1496, 1386, 1366, 1195, 1089, 866

Example 60

(2R)-Amino-2-methyl-4-[5-(4-cyclohexyloxybutyl)thiophen-2-yl]butan-1-ol maleate

(Exemplary compound 1-400)

Using (2R)-amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-yl)thiophen-2-yl]butan-1-ol obtained in Example 31, and implementing Example 11 was performed in the same manner to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD): δ1.15-1.35 (5H, m), 1.31 (3H, s), 1.50-1.80 (7H, m), 1.85-2.08 (4H, m), 2.73-2.92 (4H, m), 3.20-3.30 (1H, m), 3.45-3.55 (3H, m), 3.60 (1H, d, J=11.6Hz), 6.25 (2H, s), 6.59 (1H, d, J =3.3Hz), 6.64 (1H, d, J = 3.3Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 2931, 2856, 1577, 1490, 1471, 1459, 1388, 1357, 1108, 1081, 868

Example 61

(2R)-Amino-2-methyl-4-{5-[4-(4-fluorophenoxy)butyl]thiophen-2-yl}butan-1-ol

(Exemplary compound 1-463)

Using (2R)-amino-2-methyl-4-{5-[4-(4-fluorophenoxy)but-1-ynyl]thiophen-2-yl}butan-1 obtained in Example 45 -Alcohol, the same operation as in Example 11 to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD): δ1.08 (3H, s), 1.70-1.85 (6H, m), 2.73-2.88 (4H, m), 3.34 (1H, d, J=10.9Hz), 3.38 (1H, d, J = 10.9Hz), 3.94 (2H, t, J = 5.9Hz), 6.58 (1H, d, J = 3.7Hz), 6.60 (1H, d, J = 3.7Hz), 6.83- 6.90(2H, m), 6.93-7.00(2H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3333, 3268, 3162, 2940, 2865, 1509, 1474, 1244, 1220, 1060, 830, 763

Example 62

(2R)-Amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butyl]thiophen-2-yl}butan-1-ol

(Exemplary compound 1-479)

Using (4R)-methyl-4-{2-[4-(4-methoxyphenoxy)but-1-ynyl]}ethyl oxazolidine obtained by the same operation as in Example 1h, according to Example 26 produced the title compound.

NMR spectrum (400MHz, CD ₃ OD): δ1.08 (3H, s), 1.68-1.84 (6H, m), 2.73-2.87 (4H, m), 3.34 (1H, d, J=10.8Hz), 3.38(1H,d,J=10.8Hz), 3.72(3H,s), 3.91(2H,t,J=6.0Hz), 6.58(1H,d,J=3.1Hz), 6.60(1H,d,J =3.1Hz), 6.81(4H,s)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3335, 3273, 3183, 2945, 2868, 1514, 1473, 1233, 1045, 825, 735

Example 63

(2R)-Amino-2-methyl-4-[5-(4-benzyloxybut-1-ynyl)thiophen-2-yl]butan-1-ol oxalate

(Exemplary compound 1-1266)

The same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD): δ1.31 (3H, s), 1.89-2.10 (2H, m), 2.70 (2H, t, J=6.8Hz), 2.80-2.94 (2H, m), 3.52 (1H, d, J = 11.6Hz), 3.61 (1H, d, J = 11.6Hz), 3.64 (2H, t, J = 6.8Hz), 4.57 (2H, s), 6.74 (1H, d, J =3.6Hz), 6.94(1H, d, J=3.6Hz), 7.23-7.39(5H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 3358, 3028, 2926, 2544, 1719, 1702, 1605, 1496, 1468, 1454, 1402, 1279, 1204, 1105, 806, 739, 720, 699, 500

Mass Spectrum (FAB) m/z: 344 (M+H) ⁺ (free form)

Example 64

(2R)-Amino-2-methyl-4-[5-(4-benzyloxybutyl)thiophen-2-yl]butan-1-ol maleate

(Exemplary compound 1-594)

Using (2R)-amino-2-methyl-4-[5-(4-benzyloxybut-1-ynyl)thiophen-2-yl]butan-1-ol obtained in Example 63, and implementing The title compound was obtained by the same operation as in Example 11.

NMR spectrum (400MHz, CD ₃ OD): δ1.31 (3H, s), 1.59-1.76 (4H, m), 1.88-2.08 (2H, m), 2.76 (2H, t, J=7.2Hz), 2.79-2.91(2H, m), 3.49(2H, t, J=6.4Hz), 3.51(1H, d, J=11.6Hz), 3.60(1H, d, J=11.6Hz), 4.48(2H, s ), 6.25(2H, s), 6.58(1H, d, J=3.6Hz), 6.64(1H, d, J=3.6Hz), 7.23-7.38(5H, m)

Infrared absorption spectrum v _max cm ^-1 (KBr): 2935, 2862, 1579, 1496, 1386, 1363, 1195, 1104, 1077, 1012, 875, 866, 804, 737, 698, 569

Mass spectrum (FAB) m/z: 348 (M+H) ⁺ (free form)

Example 65

(2R)-Amino-2-methyl-4-{5-[3-(4-methylcyclohexylchloro)propynyl]thiophen-2-yl}butan-1-ol maleate

(Exemplary compound 1-1050)

The same operation as in Example 1 was performed to obtain the title compound.

NMR spectrum (400MHz, CD ₃ OD): δ0.89, 0.90 (3H, d, J=6.4Hz), 1.31 (3H, s), 0.92-1.56, 1.70-2.12 (11H, m), 2.81-2.96 (2H, m), 3.40-3.49, 3.73-3.79 (1H, m), 3.52 (1H, d, J=11.2Hz), 3.61 (1H, d, J=11.2Hz), 4.36, 4.39 (2H, s ), 6.25 (2H, s), 6.78 (1H, d, J=3.6Hz), 7.04 (1H, d, J=3.6Hz)

Infrared absorption spectrum v _max cm ^-1 (KBr): 2927, 2864, 2219, 1579, 1508, 1386, 1366, 1193, 1093, 1077, 876, 865, 807, 717, 568

Mass spectrum (FAB) m/z: 336 (M+H) ⁺ (free form)

Example 66

(4R)-methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one (exemplary compound 4-4

Example 66(a)

(2R)-tert-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol

Suspend 20.0g (97.4mmol) of 2-tert-butoxycarbonylamino-2-methyl-1,3-propanediol in 200ml of diisopropyl ether, add 16.3ml (0.10mol) of vinyl n-hexanoate and 0.8g of lipase [Immobilized lipase from Pseudomonas (TOYOBO; 0.67 U/mg)], stirred vigorously at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=10:1-2:1) to obtain 25.0 g (85%) of the title compound as a colorless oil.

Determine the obtained (2R)-tert. Optical purity of butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol.

The 2S form was eluted first (8.2 minutes), and the 2R form was eluted later (10.5 minutes). It was confirmed that the optical purity in this reaction was 85% ee.

[α] _D ²⁵ -8.5 (c1.86, CHCl ₃ )

NMR spectrum (400MHz, CDCl ₃ ) δppm: 4.86(s, 1H), 4.25(d, 1H, J=11.2Hz), 4.19(d, 1H, J=11.2Hz), 3.86(brs, 1H), 3.70 -3.55(m, 2H), 2.36(t, 2H, J=7.4Hz), 1.68-1.58(m, 2H), 1.44(s, 9H), 1.40-1.30(m, 4H), 1.25(s, 3H ), 0.90(t, 3H, J=7.0Hz)

Infrared absorption spectrum vmax cm ^-1 (liquid film): 3415, 3380, 2961, 2935, 2874, 1721, 1505, 1458, 1392, 1368, 1293, 1248, 1168, 1076

Mass spectrum (FAB) m/z: 304 ((M+H) ⁺ )

Example 66(b)

(2S)-tert-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanal

分子筛和43.6g(0.20mol)氯铬酸吡啶鎓，之后在室温下搅拌2小时。将反应液用乙醚稀释，然后过滤。减压馏去滤液，将残余物通过硅胶柱层析(洗脱溶剂；正己烷∶乙酸乙酯＝10∶1-5∶1)纯化，得到28.8g(95％)为无色油状物的标题化合物。30.7 g (0.10 mol) of (2R)-tert-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol obtained in Example 66 (a) was dissolved in 600 ml of dichloromethane, Add 220g4 under ice cooling

Molecular sieves and 43.6 g (0.20 mol) of pyridinium chlorochromate were then stirred at room temperature for 2 hours. The reaction solution was diluted with ether and filtered. The filtrate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent; n-hexane:ethyl acetate=10:1-5:1) to obtain 28.8 g (95%) of the title compound as a colorless oil. compound.

NMR spectrum (400MHz, CDCl ₃ ) δ ppm: 9.45(s, 1H), 5.26(brs, 1H), 4.44(d, 1H, J=11.2Hz), 4.32(d, 1H, J=11.2Hz), 2.32(t, 2H, J=7.6Hz), 1.70-1.55(m, 2H), 1.45(s, 9H), 1.38(s, 3H), 1.40-1.25(m, 4H), 0.90(t, 3H, J=7.0Hz)

Infrared absorption spectrum vmax cm ^-1 (liquid film): 3367, 2961, 2935, 2874, 1742, 1707, 1509, 1458, 1392, 1369, 1290, 1274, 1254, 1166, 11100, 1078

Mass spectrum (FAB) m/z: 302 ((M+H) ⁺ )

Example 66(c)

(2R)-tert-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(thiophen-2-yl)-3-butene

Suspend 67.1 g (0.15 mol) of 2-thienylmethyltriphenylphosphonium bromide in 750 ml of tetrahydrofuran, add 17.2 g (0.15 mol) of potassium tert-butoxide, and stir at room temperature for 20 minutes under a nitrogen atmosphere. Under ice-cooling conditions, 23.0 g (76.4 mmol) of (2S)-tert-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1 obtained in Example 66 (b) dissolved in 250 ml of tetrahydrofuran - Propionaldehyde was added dropwise to the reaction solution, and after the dropwise addition was completed, it was stirred for 30 minutes under ice cooling. Water was then added to the reaction liquid, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent; n-hexane:ethyl acetate=20:1) to obtain 27.8 g (96 %) the title compound as a colorless oil.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.32-7.26, 7.16-7.14 (m, 1H), 7.04-7.01, 7.01-6.93 (m, 2H), 6.63 (d, 0.5H, J=16.0Hz), 6.60(d, 0.5H, J=13.6Hz), 6.10(d, 0.5H, J=16.0Hz), 5.58(d, 0.5H, J=13.6Hz), 4.94, 4.93(brs, 1H), 4.40- 4.10(m, 2H), 2.34(t, 2H, J=7.4Hz), 1.70-1.55(m, 2H), 1.57, 1.50, 1.44(s, 9H), 1.40-1.25(m, 7H), 0.88( t, 3H, J=7.0Hz)

Infrared absorption spectrum v max cm ^-1 (liquid film): 3370, 2961, 2933, 1725, 1495, 1456, 1391, 1367, 1247, 1167, 1109, 1100, 1072, 697

Mass Spectrum (FAB) m/z: 381 (M ⁺ )

Example 66(d)

(4R)-Methyl-4-[2-(thiophen-2-yl)vinyl]oxazolidin-2-one

40.5 g (0.11 mol) of (2R)-tert-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(thiophen-2-yl)-3- Butene was dissolved in 150 ml of tetrahydrofuran and 150 ml of methanol, 530 ml of 1N aqueous sodium hydroxide solution was added thereto under ice cooling, stirred for 30 minutes under ice cooling, and stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, water was added, extracted with dichloromethane, and the dichloromethane layer was washed with saturated brine. After the dichloromethane layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 35.0 g of a crude product. This crude product was dissolved in 300 ml of tetrahydrofuran, and 17.8 g (0.16 mol) of potassium tert-butoxide was added under ice cooling, followed by stirring under ice cooling for 10 minutes and at room temperature for 40 minutes. Water was added to the reaction liquid, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=3:1-1:1) to obtain 18.0 g (81%) of the title compound as a white solid.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.34(d, 0.5H, J=5.1Hz), 7.19(d, 0.5H, J=5.0Hz), 7.07-6.91(m, 2H), 6.74(d, 0.5H, J=16.0Hz), 6.59(d, 0.5H, J=12.5), 6.17(brs, 1H), 6.06(d, 0.5H, J=16.0Hz), 5.65(d, 0.5H, J= 12.5Hz), 4.41(d, 0.5H, J=8.6Hz), 4.31-4.16(m, 1.5H), 1.60(s, 1.5H), 1.55(s, 1.5H)

Infrared absorption spectrum vmax cm ^-1 (KBr): 3275, 3110, 2974, 1752, 1391, 1376, 1281, 1169, 1039, 960, 704

Mass Spectrum (FAB) m/z: 209 (M ⁺ )

Example 66(e)

(4R)-Methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one

(4R)-methyl-4-[2-(thiophen-2-yl)vinyl]oxazolidin-2-one obtained in 18.0 g (86.0 mmol) of Example 66 (d) was dissolved in 150 ml of methanol , add 4.5g 10% palladium on carbon, and stir at room temperature for 10 hours in a hydrogen atmosphere. The palladium carbon in the reaction liquid was filtered with a Kiriyama funnel covered with a thin layer of silica gel, and the filtrate was distilled off under reduced pressure. The resulting solid was washed with diethyl ether and dried to afford 16.5 g (91%) of the title compound as a white solid.

Determine the obtained (4R) by analyzing an optically active HPLC column (ChiralCel OD-H (Daicel), (0.46cm × 25cm), elution solvent; n-hexane: 2-propanol=60:40, flow rate: 0.5ml/min) - Optical purity of methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one.

The 2S form eluted first (16.8 minutes) and the 2R form eluted later (17.6 minutes), and the optical purity in this reaction was confirmed to be 85% ee.

[α] ^D ₂₅ +5.1 (c2.4, CHCl ₃ )

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.15 (d, 1H, J=5.2Hz), 6.93 (dd, 1H, J=5.2, 3.6Hz), 6.81 (d, 1H, J=3.6Hz), 5.39 (brs, 1H), 4.19(d, 1H, J=8.4Hz), 4.08(d, 1H, J=8.4Hz), 3.00-2.84(m, 2H), 2.08-1.92(m, 2H), 1.42( s, 3H)

Infrared absorption spectrum vmax cm ^-1 (KBr): 3283, 1770, 1399, 1244, 1043, 941, 846, 775, 706, 691

Mass spectrum (EI) m/z: 211 (M ⁺ )

To 11 g of (4R)-methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one with an optical purity of 85% ee, 25 ml of ethyl acetate and 5.0 ml of n-hexane were added , heated to dissolve, and then left at room temperature for 2 hours. The precipitated white crystals were filtered and dried to obtain 4.0 g of the title compound with an optical purity of 99%ee.

[α] ^D ₂₅ +7.8 (c2.0, CHCl ₃ )

Example 67

(4R)-Methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one (exemplary compound 4-4)

Example 67(a)

(2R)-tert-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(thiophen-2-yl)butane

(2R)-tert-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(thiophen-2-yl)-3- Butene was dissolved in 450ml of ethanol, 14.0g of 10% palladium on carbon was added, and stirred at room temperature for 4 days in a hydrogen atmosphere. Palladium carbon in the reaction solution was filtered through celite, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=20:1-10:1) to obtain 22.1 g (80%) of the title compound as a colorless oil.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.02 (d, 1H, J=5.2Hz), 6.91 (dd, 1H, J=5.2, 3.6Hz), 6.80 (d, 1H, J=3.6Hz), 4.53 (brs, 1H), 4.26-4.12(m, 2H), 2.85(t, 2H, J=8.4Hz), 2.34(t, 2H, J=7.6Hz), 2.26-2.16(m, 1H), 2.01- 1.90(m, 1H), 1.68-1.56(m, 2H), 1.44(s, 9H), 1.31(s, 3H), 1.40-1.26(m, 4H), 0.89(t, 3H, J=7.6Hz)

Infrared absorption spectrum vmax cm ^-1 (liquid film): 3371, 2961, 2933, 2872, 2864, 1721, 1502, 1466, 1455, 1392, 1367, 1246, 1168, 1074, 694,

Mass Spectrum (FAB) m/z: 384 ((M+H) ⁺ )

Example 67(b)

(2R)-tert-butoxycarbonylamino-2-methyl-4-(thiophen-2-yl)-1-butanol

Dissolve 22.0 g (57.4 mmol) of (2R)-tert-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(thiophen-2-yl)butane obtained in Example 67(a) In the mixed solution of 140ml tetrahydrofuran and 280ml methanol, 280ml 1N aqueous sodium hydroxide solution was added thereto under ice cooling, stirred under ice cooling for 30 minutes, and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, then water was added, extracted with dichloromethane, and the dichloromethane layer was washed with saturated brine. After the dichloromethane layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 15.5 g (95%) of the title compound as a white solid.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.11 (d, 1H, J=5.2Hz), 6.92 (dd, 1H, J=5.2, 3.6Hz), 6.81 (d, 1H, J=3.6Hz), 4.64 (brs, 1H), 4.08 (brs, 1H), 3.74-3.60 (m, 2H), 2.98-2.76 (m, 2H), 2.20-2.10 (m, 1H), 2.03-1.90 (m, 1H), 1.44 (s, 9H), 1.22 (s, 3H)

Infrared absorption spectrum vmax cm ^-1 (KBr): 3279, 3250, 3067, 2973, 2929, 2908, 2857, 1679, 1552, 1367, 1291, 1245, 1167, 1076, 1064, 1009, 861, 851, 701

Mass Spectrum (FAB) m/z: 286 ((M+H) ⁺ )

Example 67(c)

(4R)-Methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one

(2R)-tert-butoxycarbonylamino-2-methyl-4-(thiophen-2-yl)-1-butanol obtained in 15.4 g (53.9 mmol) of Example 67 (b) was dissolved in 200 ml of N, To N-dimethylformamide, 9.07 g (80.8 mmol) of potassium tert-butoxide was added under ice cooling, followed by stirring under ice cooling for 10 minutes and then at room temperature for 40 minutes. Water was added to the reaction liquid, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; hexane ethyl acetate = 3:1-1:1) to obtain 11.5 g (100%) of the title compound as a white solid. Various instrument data are consistent with the substance obtained in Example 66.

Example 68

(4R)-[2-(Benzo[b]thiophen-6-yl)ethyl]-4-methyloxazolidin-2-one

(Exemplary compound 4-17)

Example 68(a)

(2R)-tert-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(benzo[b]thiophen-6-yl)-3-butane ene

(2R)-tert-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanal synthesized in 28.2g (93.6mmol) embodiment 66 (b) and 45.8g (93.6mmol) 6 - Triphenylphosphonium benzo[b]thiophene bromide was suspended in 700 ml of tetrahydrofuran, 11.6 g (0.10 mol) of potassium tert-butoxide was added thereto, and stirred at room temperature for 30 minutes. Thereafter, water was added to the reaction liquid, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=10:1) to obtain 28.0 g (69%) of the title compound as a colorless oil.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.82(d, 1H, J=9.7Hz), 7.75(d, 1H, J=8.2Hz), 7.44-7.39(m, 1H), 7.32-7.26(m, 2H), 6.74, 5.73(d, 1H, J=12.6Hz), 6.61, 6.34(d, 1H, J=16.2Hz), 4.87, 4.69(br s, 1H), 4.34-4.16, (m, 2H) , 2.37-2.32 (m, 2H), 1.67-1.15 (m, 20H), 0.91-0.84 (m, 3H).

Infrared absorption spectrum v _max cm ^-1 (liquid film): 3440, 3373, 2961, 2932, 2872, 1724, 1597, 1498, 1457, 1390, 1367, 1247, 1167, 1099, 1073.

Mass Spectrum (FAB) m/z: 431 (M ⁺ )

Example 68(b)

(2R)-tert-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(benzo[b]thiophen-6-yl)butane

With 28.0 g (64.9 mmol) of (2R)-tert-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(benzo[b]thiophene-6- Base) butene was dissolved in 700ml of methanol, 14.0g of 10% palladium on carbon was added, and stirred at room temperature for 6 days in a hydrogen atmosphere. Palladium carbon in the reaction solution was filtered through celite, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=15:1-10:1) to obtain 24.30 g (87%) of the title compound as a colorless oil.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.73(d, 1H, J=8.2Hz), 7.69(s, 1H), 7.36(d, 1H, J=5.2Hz), 7.28(d, 1H, J= 5.6Hz), 7.19(d, 1H, J=8.1Hz), 4.56(br s, 1H), 4.28(d, 1H, J=11.0Hz), 4.14(d, 1H, J=11.0Hz), 2.73( t, 2H, J=8.7Hz), 2.34(t, 2H, J=7.5Hz), 1.68-1.61(m, 2H), 1.45(s, 9H), 1.41-1.38(m, 8H), 0.89(t , 3H, J=6.7Hz).

Infrared absorption spectrum vmax cm ^-1 (liquid film): 3371, 2960, 2933, 2870, 1720, 1604, 1501, 1466, 1392, 1367, 1248, 1167, 1074.

Mass Spectrum (FAB) m/z: 456 ((M+Na) ⁺ )

Example 68(c)

(4R)-[2-(Benzo[b]thiophen-6-yl)ethyl]-4-methyloxazolidin-2-one

24.3 g (56.0 mmol) of (2R)-tert-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(benzo[b]thiophene-6- Base) butane was dissolved in 220ml of tetrahydrofuran and 110ml of methanol, 110ml of 1N aqueous sodium hydroxide solution was added thereto under ice-cooling, stirred for 15 minutes under ice-cooling, and stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, water was added, extracted with dichloromethane, and the dichloromethane layer was washed with saturated brine. After the dichloromethane layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 18.8 g (100%) of a crude product. The resulting crude product was dissolved in 380 ml of dimethylformamide, 9.43 g (84.1 mmol) of potassium tert-butoxide was added under ice cooling, stirred for 5 minutes under ice cooling, and then stirred at room temperature for 1 hour. Water was added to the reaction liquid, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=3:2-2:1) to obtain 13.8 g (94%) of the title compound as a white solid.

Determine the obtained (4R)-[ Optical purity of 2-(benzo[b]thiophen-6-yl)ethyl]-4-methyloxazolidin-2-one.

The 4S form eluted first (15.9 minutes) and the 4R form eluted later (17.6 minutes), and it was confirmed that the optical purity in this reaction was 80% ee.

[α] _D ²⁴ +2.3 (c0.6, CHCl ₃ )

NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.73(d, 1H, J=8.2Hz), 7.68(s, 1H), 7.38(d, 1H, J=5.7Hz), 7.29(d, 1H, J=5.7Hz), 7.29(d, 1H, J= 13.0Hz), 7.18(d, 1H, J=13.6Hz), 5.91(br s, 1H), 4.21(d, 1H, J=8.7Hz), 4.09(d, 1H, J=8.7Hz), 2.84- 2.76(m, 2H), 1.97(t, J=8.5Hz, 3H).

Infrared absorption spectrum vmax cm ^-1 (KBr): 3292, 2970, 2930, 1749, 1722, 1601, 1479, 1461, 1397, 1277, 1045.

Mass Spectrum (EI) m/z: 261 (M ⁺ )

Example 69

(2R)-tert-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol

Dissolve 200 mg (0.97 mmol) of 2-tert-butoxycarbonylamino-2-methyl-1,3-propanediol in 2 ml of diisopropyl ether, add 0.16 ml (1.02 mmol) of vinyl n-hexanoate and 20 mg of lipase [from Immobilized lipase from Pseudomonas (TOYOBO, 0.67 U/mg)], stirred at room temperature for 4 hours.

After filtering off the insoluble matter in the reaction mixture, the residue was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent; n-hexane:ethyl acetate=10:1-7:3) to obtain 258 mg (87%) of the title compound as a colorless oil.

Determine the obtained (2R)-tert-butoxycarbonyl group by analyzing an optically active HPLC column (ChiralCel OF, Daicel, 0.46cmφ×25cm, elution solvent; hexane: 2-propanol=70:30, flow rate: 0.5ml/min) Optical purity of amino-3-n-hexanoyloxy-2-methyl-1-propanol.

The 2S form eluted first (8.2 minutes) and the 2R form eluted later (10.5 minutes), and it was confirmed that the optical purity in this reaction was 89% ee.

In addition, a compound known in literature (TetrahedronAsymmetry 10 (1999) 4653-4661) which can be easily synthesized from this compound by comparative study, that is, (2R)-tert-butoxycarbonylamino prepared in Reference Example 1(a) -Specific optical rotation of 2-methyl-3-buten-1-ol to determine its absolute configuration.

NMR spectrum (400MHz, CD ₃ CL ₃ ) δppm: 4.89 (1H, br.s), 4.24 (1H, d, J=11.2H), 4.19 (1H, d, J=11.2Hz), 3.66-3.54 ( 2H, m), 2.36 (2H, t, J=7.4Hz), 1.69-1.57 (2H, m), 1.44 (9H, s), 1.39-1.22 (4H, m), 1.25 (3H, s), 0.90 (3H,t,J=6.6Hz)

Infrared absorption spectrum v _max cm ^-1 (CHCL ₃ ): 3411, 3380, 2961, 2934, 1722, 1504, 1459, 1392, 1368, 1292, 1248, 1168, 1077, 1015

Optical rotation [α] ²⁴ _D : -1.1° (c=0.81, methanol)

Example 70

(2R)-tert-butoxycarbonylamino-3-n-hexanoyloxy-2-ethyl-1-propanol

Using 200 mg (0.91 mmol) of 2-tert-butoxycarbonylamino-2-ethyl-1,3-propanediol, the same procedure as in Example 69 was carried out to obtain 252 mg (87%) of the title compound as a colorless oil.

Determine the obtained (2R)-tert-butoxycarbonyl group by analyzing an optically active HPLC column (ChiralCel OF, Daicel, 0.46cmφ×25cm, elution solvent; hexane: 2-propanol=70:30, flow rate: 0.5ml/min) Optical purity of amino-3-n-hexanoyloxy-2-ethyl-1-propanol.

The 2S form eluted first (8.5 minutes) and the 2R form eluted later (10.7 minutes), and it was confirmed that the optical purity in this reaction was 95% ee.

In addition, a compound known in literature (Helvetica Chimica Acta 69 (1986) 1365-1377) which can be easily synthesized from this compound by comparative study, that is, (+)-(R)- prepared in Reference Example 5(f) Specific optical rotation of α-ethyl-α-vinylglycine to determine its absolute configuration.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 4.78 (1H, br.s), 4.28 (1H, d, J=11.1Hz), 4.13 (1H, d, J=11.1Hz), 3.72-3.57 (2H, m), 2.35(2H, t, J=7.6Hz), 1.83-1.54(4H, m), 1.44(9H, s), 1.38-1.24(4H, m), 0.95-0.86(6H, m)

Infrared absorption spectrum v _max (CHCl ₃ ) cm ^-1 : 3371, 2966, 2935, 1722, 1503, 1450, 1368, 1249, 1168, 1086, 1028, 866, 781

Optical rotation [α] ²⁴ _D : -2.4° (c=0.72, methanol)

Use the compound synthesized in Example 69 or Example 70 to prepare known useful compounds (-)-(R)-α-methyl-α-vinylglycine (Reference Example 1), (+)-(S) - α-methyl-α-ethynylglycine (Reference Example 2) and (+)-(R)-α-ethyl-α-vinylglycine (Reference Example 3).

Reference example 1

(-)-(R)-α-Methyl-α-vinylglycine

Reference example 1(a)

(2R)-tert-butoxycarbonylamino-2-methyl-3-buten-1-ol

To 1.5 g (4.9 mmol) of (2R)-tert-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol prepared in Example 69 in dichloromethane (18 ml) was added 4A molecular sieves (10.5 g), stirred at room temperature for 10 minutes, then added 2.1 g (9.8 mmol) of pyridinium chlorochromate, and stirred for 1 hour.

Diethyl ether was added to the reaction solution, and insoluble matter was filtered off with a short silica gel column (eluent: diethyl ether). The organic solvent was distilled off under reduced pressure to obtain 1.5 g of a residue, which was used in the subsequent reaction.

At 0°C, 1.3 g (11.5 mmol) of potassium t-butoxide was added to a suspension (10 ml) of 4.5 g (12.5 mmol) of methyltriphenylphosphonium bromide in tetrahydrofuran, followed by stirring for 1 hour.

To this reaction solution, a tetrahydrofuran solution (10 ml) of the residue obtained in the previous reaction was added dropwise.

The reaction solution was stirred at 0°C for 30 minutes, distilled water was added, and extracted with ethyl acetate. It was washed successively with distilled water and saturated brine, and dried over magnesium sulfate. After distilling off the solvent, the insoluble matter was removed by passing through a short column of silica gel (eluent; hexane:ethyl acetate=10:1).

After concentrating the solvent, 1.2 g of the obtained residue was made into a methanol solution (20 ml), to which was added 1N aqueous sodium hydroxide solution (20 ml), followed by stirring at room temperature for 30 minutes. Diethyl ether was added to the reaction solution, followed by successive washing with distilled water and saturated brine, and drying over magnesium sulfate.

The solvent was distilled off, followed by purification by preparative thin-layer chromatography (eluent; hexane:ethyl acetate=1:1) to obtain 180 mg (0.894 mmol, yield 18%) of the title compound.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 5.89 (1H, ddd, J=11.0, 6.6, 1.5Hz), 5.21 (1H, d, J=1.5Hz), 5.17 (1H, d, J=6.6Hz) , 4.84(1H, br.s), 3.76(1H, br.s), 3.62(2H, m), 1.44(9H, s), 1.32(3H, s)

Infrared absorption spectrum v _max (CHCl ₃ ) cm ^-1 : 3418, 3348, 2979, 1692, 1499, 1455, 1393, 1368, 1283, 1253, 1170, 1074, 918

Optical rotation [α] ²⁴ _D : +10.4° (c=0.51, methanol)

Reference example 1(b)

(2R)-tert-butoxycarbonylamino-2-methyl-3-butenal

(2R)-tert-butoxycarbonylamino-2-methyl-3-butene-1-alcohol obtained in 180mg (0.894mmol) of Reference Example 1 (a) was dissolved in 5.0ml of dichloromethane, under ice cooling , add 2.0g 4A molecular sieves, 386mg (1.79mmol) pyridinium chlorochromate, stir at room temperature for 1 hour. Diethyl ether was added to the reaction solution, and the insoluble matter in the reaction mixture was filtered off, and the residue was concentrated under reduced pressure.

The residue was purified by flash silica gel column chromatography (elution solvent; n-hexane:ethyl acetate=10:1) to obtain 160 mg (90%) of the title compound as a colorless oil.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 9.26 (1H, s), 5.83 (1H, dd, J=17.5, 10.6Hz), 5.35 (1H, d, J=10.6Hz), 5.32 (1H, d, J=17.5Hz), 5.22(1H, br.s), 1.48(3H, s), 1.45(9H, s)

Infrared absorption spectrum v _max (CHCl ₃ ) cm ^-1 : 3350, 2980, 1737, 1707, 1505, 1455, 1369, 1279, 1256, 1168, 1069, 925, 867

Reference example 1(c)

(2R)-tert-butoxycarbonylamino-2-methyl-3-butenoic acid

(2R)-tert-butoxycarbonylamino-2-methyl-3-butenal obtained in 160 mg (0.803 mmol) of Reference Example 1 (b) was dissolved in 8.0 ml of tert-butanol and 2.0 ml of water, and 0.38 ml ( 3.61 mmol) of 2-methyl-2-butene, 96 mg (0.803 mmol) of sodium dihydrogen phosphate dihydrate, and 254 mg (2.81 mmol) of sodium chlorite were stirred at room temperature for 1 hour.

Ethyl acetate was added to the reaction solution, and the ethyl acetate layer was washed with saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The residue was purified by flash silica gel column chromatography (elution solvent; n-hexane:ethyl acetate=20:1-1:1) to obtain 130 mg (75%) of the title compound as a colorless oil.

NMR spectrum (400MHa, CDCl ₃ ) δppm: 5.07 (1H, br.s), 5.68 (1H, br.s), 5.12 (1H, d, J=17.4Hz), 5.05 (1H, d, J=10.6 Hz), 1.48(3H, s), 1.40(9H, s)

Infrared absorption spectrum v _max (CHCl ₃ ) cm ^-1 : 3394, 2980, 1691, 1602, 1483, 1455, 1368, 1253, 1172, 1066, 756

Reference example 1(d)

(-)-(R)-α-Methyl-α-vinylglycine hydrochloride

(2R)-tert-butoxycarbonylamino-2-methyl-3-butenoic acid obtained in 120mg (0.557mmol) of Reference Example 1 (c) was dissolved in 1.5ml of ethanol, and 1.5ml of 4N hydrochloric acid dioxane was added The solution was stirred at room temperature for 18 hours.

The reaction solution was concentrated under reduced pressure, washed with ether, and dried to obtain 72 mg (85%) of a white solid.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 6.07 (1H, dd, J=17.6, 11.0Hz), 5.48 (1H, d, J=11.1Hz), 5.47 (1H, d, J=17.6Hz), 1.66 (3H, s)

Infrared absorption spectrum v _max (KBr)cm ^-1 : 3349, 3029, 1751, 1524, 1200, 954

Optical rotation [α] ³⁶ _D : -18.7° (c=0.70, H ₂ O)

Reference example 1(e)

(-)-(R)-α-Methyl-α-vinylglycine

60 mg (0.40 mmol) of (-)-(R)-α-methyl-α-vinylglycine hydrochloride obtained in Reference Example 1 (d) was dissolved in 1.5 ml of ethanol, and 1.5 ml of 1,2- Propylene oxide was heated to reflux for 2 hours. By filtering the white solid in the reaction solution, 32 mg (70%) of the title compound was obtained as a white solid.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 6.17 (1H, dd, J=17.2, 10.6Hz), 5.56 (1H, d, J=10.6Hz), 5.54 (1H, d, J=17.2Hz), 1.43 (3H, s)

Infrared absorption spectrum v _max (KBr) cm ^-1 : 3600-2500, 1605, 1535, 1455, 1415, 1385, 1360, 1280, 1235, 1150, 1000, 940

Optical rotation [α] ²⁶ _D : -27.6° (c=0.62, H ₂ O)

Reference example 2

(+)-(S)-α-Methyl-α-ethynylglycine

Reference example 2(a)

3-tert-butoxycarbonyl-2,2-dimethyl-(4R)-n-hexanoyloxymethyl-4-methyloxazolidine

Dissolve 10.1 g (33.3 mmol) of (2R)-tert-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol obtained in Example 69 in 152 ml of dichloromethane, and add 16.4 ml (133 mmol) of acetone dimethyl acetal and 172 mg (1.00 mmol) of p-toluenesulfonic acid were stirred at room temperature for 12 hours.

The reaction solution was concentrated, and the residue was purified by flash silica gel column chromatography (elution solvent; n-hexane:ethyl acetate=10:1) to obtain 5.72 g (50%) of the title compound as a colorless oil.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 4.29 (1H, s), 4.18 (1H, s), 3.99 (1H, m), 3.64 (1H, m), 2.28-2.34 (2H, m), 1.26- 1.25(24H, m), 0.89(3H, t)

Optical rotation [α] ²⁵ _D : +17.2° (c=1.50, CHCl ₃ )

Reference example 2(b)

3-tert-butoxycarbonyl-2,2-dimethyl-(4S)-hydroxymethyl-4-methyloxazolidine

13.7 g (39.9 mmol) of 3-tert-butoxycarbonyl-2,2-dimethyl-(4R)-n-hexanoyloxymethyl-4-methyloxazolidine obtained in Reference Example 2 (a) was dissolved In 200ml of dichloromethane, 99ml (99.7mmol) of diisobutylaluminum hydride (1.0M hexane solution) was added dropwise at -78°C.

After stirring at -78°C for 30 minutes, return to room temperature, add 200ml of 10% by weight sodium-potassium tartrate aqueous solution, and stir vigorously for 30 minutes.

The reaction solution was extracted with diethyl ether, the ether layer was dried over anhydrous sodium sulfate, then the residue was concentrated under reduced pressure, and the residue was subjected to flash silica gel column chromatography (elution solvent; n-hexane:ethyl acetate=5:2 ) to afford 10.5 g (100%) of the title compound as white crystals.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 4.49 (1H, br.s), 3.55-3.71 (4H, m), 1.56 (3H, s), 1.49 (12H, s), 1.42 (3H, s)

Optical rotation [α] ²⁵ _D : -1.67° (c=1.45, CHCl ₃ ).

Reference example 2(c)

3-tert-butoxycarbonyl-2,2-dimethyl-(4R)-formyl-4-methyloxazolidine

3-tert-butoxycarbonyl-2,2-dimethyl-(4S)-hydroxymethyl-4-methyloxazolidine obtained in 9.79g (39.9mmol) of reference example 2 (b) was dissolved in 150ml di In methyl chloride, add 13.0g (59.8mmol) pyridinium chlorochromate and 65.0g 4A molecular sieves under ice cooling, and stir at room temperature for 1 hour.

Diethyl ether was added to the reaction solution, and then the reaction solution was filtered through a silica gel column, after which the filtrate was concentrated under reduced pressure, and purified by flash silica gel column chromatography (elution solvent; n-hexane:ethyl acetate=8:1) to obtain 8.07 g (88%) as the title compound as white crystals.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 9.40-9.48 (1H, s), 3.91 (1H, d, J=9.2Hz), 3.67 (1H, d, J=9.2Hz), 1.14-1.66 (18H, m)

Optical rotation [α] ²⁵ _D +20.6° (c=1.25, CHCl ₃ )

Reference example 2(d)

3-tert-butoxycarbonyl-2,2-dimethyl-(4S)-(2,2-dibromo)ethenyl-4-methyloxazolidine

17.3g (65.8mmol) triphenylphosphine was dissolved in 25ml of dichloromethane, and under ice-cooling, a solution formed by dissolving 10.9g (32.9mmol) of carbon tetrabromide in 15ml of dichloromethane was added dropwise. Stir for 5 minutes. Add 4.00g (16.4mmol) 3-tert-butoxycarbonyl-2,2-dimethyl-(4S)-formyl-4-methanol obtained in Reference Example 2(c) to the reaction solution A solution formed by dissolving oxazolidine in 40ml of dichloromethane was stirred at room temperature for 14 hours. After filtering off the insoluble matter in the reaction mixture, the residue was concentrated under reduced pressure to obtain 4.70g (71.2%) as a colorless oil unpurified title compound.

Reference example 2(e)

3-tert-butoxycarbonyl-2,2-dimethyl-(4S)-ethynyl-4-methyloxazolidine

4.70g (11.8mmol) of 3-tert-butoxycarbonyl-2,2-dimethyl-(4S)-(2,2-dibromo)ethenyl-4-methyl obtained in Reference Example 2(d) Oxazolidine was dissolved in 94ml of tetrahydrofuran, and n-butyllithium (1.6N hexane solution) was added dropwise at -78°C under stirring, and stirred at -78°C for 3.5 hours.

100 ml of saturated aqueous ammonium chloride solution was added to the reaction liquid, followed by extraction with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and then the residue was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent; n-hexane:ethyl acetate=15:1) to obtain 2.21 g (78%) as the title compound as white crystals.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 4.13 (1H, d, J = 8.4Hz), 3.84 (1H, d, J = 8.4Hz), 2.32 (1H, s), 1.49-1.69 (18H, m)

Optical rotation [α] ²⁵ _D : +65.6° (c=1.10, CHCl ₃ )

Reference example 2(f)

(2S)-Amino-2-methyl-3-butyn-1-ol

Add 10ml of hydrochloric acid in the 3-tert-butoxycarbonyl-2,2-dimethyl-(4S)-ethynyl-4-methyloxazolidine obtained in 350mg (1.46mmol) of reference example 2 (e), in After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure to obtain 127 mg of the unpurified title compound as a yellow oil.

Reference example 2(g)

(2S)-tert-butoxycarbonylamino-2-methyl-3-butyn-1-ol

127mg (1.28ml) of (2S)-amino-2-methyl-3-butyn-1-alcohol obtained in Reference Example 2 (f) was dissolved in 1ml of water and 5ml of tetrahydrofuran, and 380mg (1.74mmol) of carbonic acid was added Di-tert-butyl ester and 385 mg (3.63 mmol) of anhydrous sodium carbonate were stirred at room temperature for 14 hours.

To the reaction solution was added 6 ml of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous sodium sulfate, and the residue was concentrated under reduced pressure.

The residue was purified by flash silica gel column chromatography (elution solvent; n-hexane:ethyl acetate=1:1) to obtain 154 mg (53%) of the title compound as white crystals.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 5.00 (1H, br.s), 3.78 (1H, dd, J=6.0 and 11.2Hz), 3.67 (1H, dd, J=7.9 and 11.2Hz), 3.20 ( 1H, br.s), 2.40 (1H, s), 1.55 (3H, s), 1.46 (9H, s)

Optical rotation [α] ²⁵ _D : +1.89° (c=0.70, CHCl ₃ )

Reference example 2(h)

(2S)-tert-butoxycarbonylamino-2-methyl-3-butynoic acid

(2S)-tert-butoxycarbonylamino-2-methyl-3-butyn-1-alcohol obtained in 1.20g (6.02mmol) of reference example 2 (g) was dissolved in 30ml of acetone, under ice cooling, add 3.48ml (9.03mmol) of Jones reagent, stirred under ice cooling for 2 hours. Add 3.48ml (9.03mmol) Jones reagent again, stir at room temperature for 14 hours.

5ml of 2-propanol and 30ml of water were added to the reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the residue was concentrated under reduced pressure to obtain 1.38 g of the unpurified title compound as a yellow oil.

Reference example 2(i)

(+)-(S)-α-Methyl-α-ethynylglycine hydrochloride

Dissolve 1.38g (6.02mmol) of (2S)-tert-butoxycarbonylamino-2-methyl-3-butynoic acid obtained in Reference Example 2 (h) in 20ml of tetrahydrofuran, add 10ml of hydrochloric acid, and stir at room temperature 5 hours. The reaction solution was concentrated under reduced pressure, 20 ml of water and 10 ml of ethyl acetate were added, and the aqueous layer was concentrated under reduced pressure to obtain 0.24 g (27%) of the unpurified title compound as yellow crystals.

Reference example 2(j)

(+)-(S)-α-Methyl-α-ethynylglycine

In the (+)-(S)-α-methyl-α-ethynyl glycine hydrochloride obtained in 0.24g (6.02mmol) reference example 2 (i), add 9ml ethanol and 3ml 1,2-propylene oxide , heated to reflux for 2 hours. The reaction solution was filtered, and the solid was washed with diethyl ether to obtain 108 mg (60%) of the title compound as white crystals.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 3.06 (1H, s), 1.77 (3H, s)

Optical rotation [α] ²⁵ _D : +41.7° (c=0.96, H ₂ O)

Reference example 3

(+)-(R)-α-Ethyl-α-vinylglycine

Reference example 3(a)

(2S)-tert-butoxycarbonylamino-2-ethyl-3-n-hexanoyloxy-1-propanal

3g (9.45mmol) of (2R)-tert-butoxycarbonylamino-3-n-hexanoyloxy-2-ethyl-1-propanol obtained in Example 70 was dissolved in 60ml of dichloromethane, and added under ice cooling 20g 4A molecular sieves, 4.07g (18.9mmol) pyridinium chlorochromate, stirred at room temperature for 1 hour. Diethyl ether was added to the reaction solution, insoluble matter in the reaction mixture was filtered off, and the residue was concentrated under reduced pressure.

The residue was purified by flash silica gel column chromatography (elution solvent; n-hexane:ethyl acetate=10:1) to obtain 2.79 g (94%) of the title compound as a colorless oil.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 9.34 (1H, s), 5.29 (1H, br.s), 4.60 (1H, d, J=11.5Hz), 4.40 (1H, d, J=11.5Hz) , 2.28(2H, t, J=7.5Hz), 2.05-2.20(1H, m), 1.70-1.80(1H, m), 1.55-1.65(2H, m), 1.45(9H, s), 1.25-1.40 (4H, m), 0.90 (3H, t, J=7.0Hz), 0.81 (3H, t, J=7.5Hz)

Infrared absorption spectrum v _max (CHCl ₃ )cm ^-1 : 3418, 2979, 2934, 2873, 1737, 1710, 1496, 1369, 1251, 1160

Mass Spectrum (FAB) m/z: 316 ((M+H) ⁺ )

Reference example 3(b)

(2R)-tert-Butoxycarbonylamino-2-ethyl-3-buten-1-ol-n-hexanoate

Suspend 7.90 g (22.0 mmol) of methyltriphenylphosphonium bromide in 25 ml of tetrahydrofuran, add 2.28 g (20.3 mmol) of potassium tert-butoxide under ice cooling, and stir for 1 hour under a nitrogen atmosphere.

Then 2.79g (8.85mmol) of (2S)-tert-butoxycarbonylamino-2-ethyl-3-n-hexanoyloxy-1-propanal obtained in Reference Example 3 (a) was dissolved in 25ml of tetrahydrofuran, and It was added dropwise to the aforementioned reaction liquid under ice-cooling, and stirred for 15 minutes.

Water was added to the reaction liquid, followed by extraction with ethyl acetate, the ethyl acetate layer was washed with saturated brine, and the ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The residue was purified by flash silica gel column chromatography (elution solvent; n-hexane:ethyl acetate=40:1-20:1) to obtain 1.30 g (47%) of the title compound as a colorless oil.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 5.78 (1H, dd, J=17.6, 11.0Hz), 5.22 (1H, d, J=11.0Hz), 5.12 (1H, d, J=17.6Hz), 4.62 (1H, br.s), 4.29 (2H, s), 2.31 (2H, t, J=7.5Hz), 1.83-1.95 (1H, m), 1.55-1.75 (3H, m), 1.44 (9H, s ), 1.25-1.35 (4H, m), 0.83-0.93 (6H, m)

Infrared absorption spectrum v _max (CHCl ₃ )cm ^-1 : 3448, 2972, 2934, 2873, 1721, 1494, 1368, 1249, 1163

Mass spectrum (FAB) m/z: 314 ((M+H) ⁺ )

Reference example 3(c)

(2R)-tert-butoxycarbonylamino-2-ethyl-3-buten-1-ol

(2R)-tert-butoxycarbonylamino-2-ethyl-3-butene-1-alcohol-n-hexanoic acid ester obtained in 1.30g (4.15mmol) of reference example 3 (b) was dissolved in 20ml methanol, in Add 40ml of 1N sodium hydroxide under ice-cooling, and stir at room temperature for 2 hours.

Water was added to the reaction liquid, extracted with diethyl ether, the ether layer was washed with saturated brine, and the ether layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The residue was purified by flash silica gel column chromatography (elution solvent; n-hexane:ethyl acetate=9:1-4:1) to obtain 0.85 g (95%) of the title compound as a white solid.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 5.77 (1H, dd, J=17.0, 10.7Hz), 5.25 (1H, d, J=10.7Hz), 5.16 (1H, d, J=17.0Hz), 4.77 (1H, br.s), 4.10(1H, br.s), 3.65-3.75(2H, m), 1.58-1.83(2H, m), 1.45(9H, s), 0.87(3H, t, J= 7.5Hz)

Infrared absorption spectrum v _max (CHCl ₃ )cm ^-1 : 3348, 3275, 2987, 2969, 2935, 1685, 1541, 1277, 1170, 1053

Mass Spectrum (FAB) m/z: 216 ((M+H) ⁺ )

Optical rotation [α] ²⁴ _D : +2.8° (c=1.03, methanol)

Reference example 3(d)

(2R)-tert-butoxycarbonylamino-2-ethyl-3-butenal

Using (2R)-tert-butoxycarbonylamino-2-ethyl-3-buten-1-alcohol obtained in 0.79g (3.67mmol) of reference example 3 (c), the same operation as reference example 3 (a), This gave 0.63 g (80%) of the title compound as a white solid.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 9.24 (1H, s), 5.83 (1H, dd, J=17.5, 10.7Hz), 5.39 (1H, d, J=10.7Hz), 5.31 (1H, d, J=17.5Hz), 5.29(1H, br.s), 1.85-2.15(2H, m), 1.57(9H, s), 0.85(3H, t, J=7.5Hz)

Infrared absorption spectrum v _max (CHCl ₃ )cm ^-1 : 3443, 3416, 2980, 1712, 1489, 1369, 1249, 1162

Mass Spectrum (FAB) m/z: 214 ((M+H) ⁺ )

Optical rotation [α] ²⁵ _D : +69° (c=1.00, methanol)

Reference example 3(e)

(2R)-tert-butoxycarbonylamino-2-ethyl-3-butenoic acid

(2R)-tert-butoxycarbonylamino-2-ethyl-3-butenal obtained in 0.60g (2.81mmol) of reference example 3 (d) was dissolved in 8ml tert-butanol and 2ml water, added 1.34ml (12.7 mmol) 2-methyl-2-butene, 0.44 g (2.81 mmol) sodium dihydrogen phosphate dihydrate and 0.89 g (9.85 mmol) sodium chlorite were stirred at room temperature for 1 hour.

Ethyl acetate was added to the reaction solution, and the ethyl acetate layer was washed with saturated brine. After drying the ethyl acetate layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.

The residue was purified by flash silica gel column chromatography (elution solvent; n-hexane:ethyl acetate=20:1-1:1) to obtain 0.42 g (65%) of the title compound as a white solid.

NMR spectrum (400MHz, CDCl ₃ ) δppm: 6.05 (1H, dd, J=17.3, 10.7Hz), 5.25-5.35 (3H, m), 1.95-2.20 (2H, m), 1.44 (9H, s), 0.90(3H,t,J=7.4Hz)

Infrared absorption spectrum v _max (CHCl ₃ )cm ^-1 : 3430, 2981, 1713, 1493, 1369, 1252, 1166

Mass spectrum (FAB) m/z: 230 ((M+H) ⁺ )

Optical rotation [α] ²⁵ _D : +19.4° (c=1.00, methanol)

Reference example 3(f)

(+)-(R)-α-Ethyl-α-vinylglycine

(2R)-tert-butoxycarbonylamino-2-ethyl-3-butenoic acid obtained in 379mg (1.65mmol) of reference example 3 (e) was dissolved in 2ml of ethanol, and 2ml of 4N hydrochloric acid dioxane solution was added, Stir at room temperature for 18 hours.

The reaction solution was concentrated under reduced pressure, washed with ether and dried. The obtained white solid was dissolved in 6 ml of ethanol, 2 ml of 1,2-propylene oxide was added, heated to reflux for 2 hours, and the white solid in the reaction solution was filtered to obtain 83 mg of the title compound as a white solid. After the filtrate was concentrated under reduced pressure, the residue was dissolved in water, filtered with Bond Elut HF (C ₁₈ ), and then concentrated under reduced pressure to obtain 61 mg of the title compound (total 144 mg, yield 75%).

NMR spectrum (400MHz, CDCl ₃ ) δppm: 6.08 (1H, dd, J=17.7, 11.1Hz), 5.41 (1H, d, J=11.1Hz), 5.34 (1H, d, J=17.7Hz), 1.82 -2.12(2H, m), 0.95(3H, t, J=7.6Hz)

Infrared absorption spectrum v _max (KBr)cm ^-1 : 3200-2400, 1623, 1605, 1511, 1369

Mass Spectrum (FAB) m/z: 130 ((M+H) ⁺ )

Optical rotation [α] ²⁸ _D : +20.6° (c=1.00, H ₂ O)

Reference example 4

5-(4-fluorophenyl)pent-1-yne

Suspend 2.11 g (48.4 mmol) of sodium hydride in 60 ml of anhydrous tetrahydrofuran, add dropwise 10.84 g (48.4 mmol) of ethyl diethylphosphonoacetate under ice cooling, and stir for 10 minutes. Subsequently, a solution of 5.00 g (40.3 mmol) of 4-fluorobenzaldehyde dissolved in 60 ml of anhydrous tetrahydrofuran was added dropwise at the same temperature. The reaction solution was stirred for 3 hours, poured into 150 ml of ice water, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent; hexane:ethyl acetate=10:1-3:1) to obtain 6.69 g of (86%) ethyl 4-fluorocinnamate as a colorless oil.

6.52 g (33.6 mmol) of this ester was dissolved in 100 ml of ethyl acetate, 1.30 g of 5% rhodium/alumina was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 8 hours. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 30 ml of anhydrous tetrahydrofuran. Under ice-cooling, this solution was added dropwise to a suspension obtained by suspending 1.26 g (33.2 mmol) of lithium aluminum hydride in 60 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred at the same temperature for 30 minutes, then a saturated aqueous sodium sulfate solution was added, and stirred at room temperature for 10 minutes. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash silica gel column chromatography (eluting solvent; hexane:ethyl acetate=5:1-1:1) to obtain 4.86 g (95%) of a colorless oil of 4-fluorophenylpropan-1-ol.

Dissolve 4.83g (31.3mmol) of the resulting 4-fluorophenylpropan-1-ol in 50ml of dichloromethane, add 6.55ml (47.0mmol) of triethylamine and 2.91ml (37.6mmol) of methanesulfonyl chloride under ice cooling , stirred under nitrogen atmosphere for 30 minutes. The reaction mixture was diluted with 50 ml of dichloromethane, washed successively with ice-cooled 10% hydrochloric acid, saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in 100 ml of acetone. Next, 9.39 g (62.6 mmol) of sodium iodide was added, and the mixture was stirred at 50° C. for 2 hours in a nitrogen atmosphere. The reaction mixture was diluted with 250 ml of ethyl acetate, then washed successively with 10% aqueous sodium thiosulfate solution, saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash silica gel column chromatography (eluting solvent; hexane:ethyl acetate=5:1-2:1) to obtain 7.12 g (86%) of a pale yellow oil 4-Fluorophenyl-1-iodopropane.

Add 50ml of sodium acetylide (18% xylene suspension) to 20ml of hexamethylphosphoramide, under ice cooling, add 7.00g (26.5mmol) of previously obtained 4-fluorophenyl-1-iodopropane dissolved in 20ml of A solution formed in water dimethylformamide. The reaction mixture was stirred at room temperature for 2 hours. Under ice cooling, ice water was very carefully poured thereinto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent; hexane) to obtain 2.67 g (62%) of the title compound as a colorless oil.

NMR spectrum (400MHz, CDCl ₃ ): δ1.82(2H, m), 1.99(1H, t, J=2.6Hz), 2.19(2H, m), 2.71(2H, t, J=7.5Hz), 6.97(2H, m), 7.14(2H, m)

Mass spectrum (EI) m/z: 162 (M ⁺ )

Reference example 5

5-(4-Methoxyphenyl)pent-1-yne

The title compound was obtained using 3-(4-methoxyphenyl)-1-iodopropane and sodium acetylide in the same manner as in Reference Example 4.

NMR spectrum (500MHz, CDCl ₃ ): δ1.78-1.88(2H, m), 1.98(1H, t, J=2.6Hz), 2.15-2.22(2H, m), 2.67(2H, t, J= 7.5 Hz), 3.79 (3H, s), 6.83 (2H, d, J=8.6Hz), 7.11 (2H, d, J=8.6Hz)

Mass Spectrum (EI) m/z: 174 (M ⁺ )

Reference example 6

5-Phenylpent-1-yne

The title compound was obtained using 3-phenyl-1-iodopropane and sodium acetylide in the same manner as in Reference Example 4.

NMR spectrum (400MHz, CDCl ₃ ): δ 1.81-1.89 (2H, m), 1.99 (1H, t, J=2.8Hz), 2.21 (2H, dt, J=2.8, 7.6Hz), 2.74 (2H, t, J=7.6 Hz), 7.16-7.23 (3H, m), 7.26-7.32 (2H, m)

Mass Spectrum (EI) m/z: 144 (M ⁺ )

Reference example 7

5-cyclohexylpent-1-yne

The title compound was obtained using 3-cyclohexyl-1-sulfopropane and sodium acetylide in the same manner as in Reference Example 4.

NMR spectrum (400MHz, CDCl ₃ ): δ0.75-1.38(13H, m), 1.48-1.59(2H, m), 1.94(1H, t, J=2.8Hz), 2.16(2H, dt, J= 2.8, 7.2Hz)

Mass Spectrum (EI) m/z: 150 (M ⁺ )

Reference example 8

4-(4-fluorophenoxy)but-1-yne

Dissolve 5.00g (44.6mmol) of 4-fluorophenol, 3.38ml (44.6mmol) of 3-butyn-1-ol, 17.5g (66.9mmol) of triphenylphosphine in 100ml of tetrahydrofuran, and add 11.7g (66.9 mmol) diethyl azodicarboxylate, stirred at room temperature for 18 hours. The solvent was concentrated under reduced pressure, then 200 ml of hexane and 20 ml of ethyl acetate were added, the precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by flash silica gel column chromatography (elution solvent; hexane:ethyl acetate=1:0) to obtain the title compound.

NMR spectrum (400MHz, CDCl ₃ ): δ2.05(1H, t, J=2.7Hz), 2.63-2.70(2H, m), 4.07(2H, t, J=7.0Hz), 6.82-6.90(2H , m), 6.94-7.02 (2H, m)

Mass Spectrum (EI) m/z: 164 (M ⁺ )

Reference example 9

3-(4-Methylphenoxy)-1-propyne

In the same manner as in Reference Example 8, the title compound was obtained using 4-methylphenol and propargyl alcohol.

NMR spectrum (400MHz, CDCl ₃ ): δ2.29(3H, s), 2.50(1H, t, J=2.4Hz), 4.67(2H, d, J=2.4Hz), 6.88(2H, d, J =8.4Hz), 7.10 (2H, d, J = 8.4Hz)

Mass Spectrum (EI) m/z: 146 (M ⁺ )

Reference example 10

3-[(4-Methylthio)phenoxy]-1-propyne

In the same manner as in Reference Example 8, the title compound was obtained using 4-(methylthio)phenol and propargyl alcohol.

NMR spectrum (400MHz, CDCl ₃ ): δ2.45(3H, s), 2.52(1H, t, J=2.4Hz), 4.68(2H, d, J=2.4Hz), 6.93(2H, d, J =8.9Hz), 7.27 (2H, d, J = 8.9Hz)

Mass Spectrum (EI) m/z: 178 (M ⁺ )

Reference example 11

3-(3-Methoxyphenoxy)-1-propyne

In the same manner as in Reference Example 8, the title compound was obtained using 3-methoxyphenol and propargyl alcohol.

NMR spectrum (400MHz, CDCl ₃ ): δ2.52 (1H, t, J=2.4Hz), 3.79 (3H, s), 4.67 (2H, d, J=2.4Hz), 6.53-6.60 (3H, m ), 7.16-7.23 (1H, m)

Mass spectrum (EI) m/z: 162 (M ⁺ )

Reference example 12

3-(3,4-Dimethylphenoxy)-1-propyne

In the same manner as in Reference Example 8, the title compound was obtained using 3,4-dimethylphenol and propargyl alcohol.

NMR spectrum (400MHz, CDCl ₃ ): δ2.20(3H, s), 2.24(3H, s), 2.49(1H, t, J=2.4Hz), 4.65(2H, d, J=2.4Hz), 6.72(1H,dd,J=2.4,8.0Hz), 6.78(1H,d,J=2.4Hz), 7.04(1H,d,J=8.0Hz)

Mass Spectrum (EI) m/z: 160 (M ⁺ )

Reference example 13

4-(4-Methylphenoxy)but-1-yne

In the same manner as in Reference Example 8, the title compound was obtained using 4-methylphenol and 3-butyn-1-ol.

NMR spectrum (400MHz, CDCl ₃ ): δ2.03(1H, t, J=2.8Hz), 2.28(3H, s), 2.66(2H, dt, J=2.8, 7.2Hz), 4.07(2H, t , J=7.2Hz), 6.81 (2H, d, J=8.8Hz), 7.08 (2H, d, J=8.8Hz)

Mass Spectrum (EI) m/z: 160 (M ⁺ )

Reference example 14

4-Cyclohexyloxybut-1-yne

Add 32ml (0.31mol) cyclohexanone, 33.5ml (0.46mol) 1,3-propanediol, 51.5ml (0.31mol) triethyl orthoformate, 1.44g (6.18mmol) Zirconium, stirred at room temperature under nitrogen atmosphere for 1 hour. Add 1.5 L of ice-cooled 1N aqueous sodium hydroxide solution, extract with dichloromethane, and wash the dichloromethane layer with water. The dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by distillation under reduced pressure to obtain 26.8 g (55%) of cyclohexanone trimethylketal.

Under a nitrogen atmosphere, 20.5 g (0.54 mmol) of sodium borohydride was slowly added to a suspension obtained by suspending 24.9 g (0.11 mol) of zirconium chloride in 500 ml of tetrahydrofuran, followed by stirring at room temperature for 20 minutes. Under nitrogen atmosphere and ice-cooling, 170 ml of tetrahydrofuran solution containing 16.9 g (0.11 mol) of cyclohexanone trimethyl ketal obtained previously was added dropwise thereto, and after the dropwise addition was completed, it was stirred at room temperature for a whole day and night. Under ice-cooling, 600 ml of ice-cooled 2N hydrochloric acid was added to terminate the reaction, and tetrahydrofuran was distilled off under reduced pressure. The remaining aqueous phase was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1-5:2) to obtain 13.4 g (78%) of 3-cyclohexyloxypropan-1-ol.

11.5g (72.9mmol) of gained 3-cyclohexyloxypropan-1-alcohol was dissolved in 240ml of dichloromethane, and 58g of 4A molecular sieves, 23.8g (0.11mol) of pyridinium chlorochromate were added under ice cooling, and in a nitrogen atmosphere Stirring was continued for 1 hour and 40 minutes. Diethyl ether was added to the reaction solution, and filtered through celite. Celite was washed with diethyl ether, and the filtrates were combined, and the solvent was distilled off under reduced pressure. The residue was crudely purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=20:1-10:1) to obtain 8.60 g of crude 3-cyclohexyloxypropanal.

In a nitrogen atmosphere, under ice cooling, add dropwise 120ml of methylene chloride containing 57.7g (0.22mol) of triphenylphosphine in 120ml of methylene chloride containing 36.5g (0.11mol) of carbon tetrabromide, and then stir 5 minutes. 90 ml of dichloromethane containing 8.60 g of the obtained crude 3-cyclohexyloxypropanal was added dropwise thereto under ice-cooling in a nitrogen atmosphere, and stirred for 25 minutes after the dropwise addition was completed. The reaction solution was diluted with dichloromethane, and washed with saturated aqueous sodium bicarbonate solution and saturated brine. The dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=100:1-33:1) to obtain 12.6 g (55%, 2 steps) of 4-cyclohexyloxy-1,1- Dibromobut-1-ene.

In a nitrogen atmosphere at -78°C, add 54ml (81.0mmol) of 1.5N n-butyl dropwise to 130ml of tetrahydrofuran containing 12.6g (40.4mmol) of the resulting 4-cyclohexyloxy-1,1-dibromobut-1-ene Lithium hexane solution. After the dropwise addition was completed, the mixture was stirred for 1 hour, and then the temperature was slowly raised to room temperature. After stirring at room temperature for 50 minutes, water was added under ice cooling to terminate the reaction. It was extracted with diethyl ether, and the diethyl ether layer was washed with saturated brine. The diethyl ether layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=100:1-50:1) to obtain 4.35 g (71%) of the title compound.

NMR spectrum (400MHz, CDCl ₃ ): δ1.13-1.36 (5H, m), 1.48-1.58 (1H, m), 1.67-1.81 (2H, m), 1.85-1.95 (2H, m), 1.97 ( 1H, t, J=2.8Hz), 2.45(2H, dt, J=2.8, 7.2Hz), 3.23-3.32(1H, m), 3.59(2H, t, J=7.2Hz)

Mass Spectrum (EI) m/z: 153 (M+H) ⁺

test case 1

Determination of Inhibitory Activity on Rat HvGR (Graft Versus Host Response)

(1) Two strains of rats [Lewis (male, 6 weeks old, Japan Charles River Co., Ltd.) and WKAH/Hkm (male, 7 weeks old) Japan SLC Co., Ltd.] were used. Five rats (hosts) per group were used.

(2) Induction of HvGR

Spleen cells were isolated from the spleen of WKAH/Hkm rats or Lewis rats, and suspended in RPMI1640 medium (LIFE TECHNOLOGIES, Rockville MD USA) at a concentration of 1×10 ⁸ cells/ml. 100 μl (the number of spleen cells is 1×10 ⁷ ) of spleen cell suspension of WKAH/Hkm rats or Lewis rats was subcutaneously injected into the foot pads of both hind limbs of Lewis rats.

(3) Administration of compounds

Compounds were suspended in 0.5% tragacanth gum solution. The compound after the suspension was in the ratio of 5ml/kg, once a day, and the compound administration group (Lewis large rats injected with WKAH/Hkm rat spleen cells and given the test compound) was orally administered for 4 consecutive days from the spleen cell injection day, once a day. mouse). Orally administered 0.5% tragacanth gum solution to the same-strain group (Lewis rat group injected with Lewis rat spleen cells) and control group (Lewis rats injected with WKAH/Hkm rat spleen cells but not administered test compound) rather than the test compound.

(4) Determination of inhibitory activity to HvGR

Subtract the mean popliteal lymph node weight of the same-strain group ("popliteal lymph node weight induced by HvGR") from the popliteal lymph node weight of each rat, relative to the average "popliteal lymph node weight induced by HvGR" of the control group, and the The inhibition rate was calculated from the "weight of popliteal lymph node induced by HvGR" in each rat. The inhibitory activity of the compound was expressed by the ID50 value (mg/kg) calculated from the dose of the compound and the inhibitory rate by the least square method.

[table 5]

In the above table, comparative compound 1 is the compound described in Example 29 in WO 94/08943 publication.

test case 2

Determination of inhibitory activity against the onset of adjuvant arthritis

1. Preparation of adjuvants

The preparation is as follows: the dead bacteria of Mycobacterium butyricum are suspended in liquid paraffin to make the ratio reach 2 mg/ml, and ultrasonic treatment is performed.

2. Preparation of Test Compounds

Test compounds were suspended or dissolved in 0.5% tragacanth gum solution.

3. Adjuvant Arthritis Induction

0.05 ml of the adjuvant prepared in 1 was injected intradermally into the right hind paw of rats (usually Lewis strain). Usually 1 group is 5. Group 1 was set as a group not injected with adjuvant (normal group).

4. Administration of compounds

From the day of adjuvant injection, the compound prepared in 2 was orally administered once a day at a ratio of 5 ml per 1 kg of rat body weight for 21 consecutive days. A 0.5% tragacanth gum solution was administered to group 1 administered with the adjuvant (control group) and a group not injected with the adjuvant.

5. Calculation of the inhibitory activity of the compound on the pathogenesis

One day after the final administration, the volume of the right hind limb was measured with a foot plantar measuring device, and the average value of the normal group was subtracted from the value of each rat, and this value was regarded as the swelling volume. The inhibition rate was calculated from the swelling volume of each rat administered with the compound relative to the average swelling volume of the control group. ID50 values were calculated from the doses of the compounds administered and the respective (group average) inhibition rates.

The test results show that the compound of the present invention has excellent inhibitory activity.

[Table 6]

In the above table, comparative compound 1 is the compound described in Example 29 in WO 94/08943 publication.

Claims (9)

1. By general formula (La) or (Lb) expression compound:

   

   In the formula,

   R ¹And R ²Identical or different, the expression hydrogen atom or as the protecting group of the amino of giving a definition;

   R ^3aThe expression hydrogen atom or as the protecting group of the hydroxyl of giving a definition, perhaps work as R ¹During for hydrogen atom, R ²And R ^3aTogether expression-(C=O)-group;

   R ^4aExpression C ₁-C ₆Alkyl;

   M represents the integer of 0-4;

   The benzothienyl that Ar represents thienyl, is selected from thienyl that the substituting group as the substituting group group a that gives a definition replaces, benzothienyl or replaced by 1-4 substituting group that is selected from as the substituting group group a that gives a definition by 1-4;

   Substituting group group a by halogen atom, as the low alkyl group of giving a definition, as the lower alkoxy of giving a definition, as giving a definition lower alkylthio, carboxyl and as the rudimentary aliphatic acidyl of giving a definition form;

   The protecting group of described amino is selected from as the lower alkoxycarbonyl of giving a definition or can chooses wantonly by the lower alkoxycarbonyl as giving a definition of halogen atom or the replacement of three low alkyl group silyls, and wherein each low alkyl group is as giving a definition;

   The protecting group of described hydroxyl is selected from as rudimentary aliphatic acidyl of giving a definition and the aromatic acyl group as giving a definition;

   Described low alkyl group is that carbonatoms is the straight or branched alkyl of 1-6;

   Described lower alkoxy is that carbonatoms is the straight or branched alkoxyl group of 1-6;

   Described lower alkylthio is that carbonatoms is the alkylthio of 1-6;

   Described rudimentary aliphatic acidyl is the carbonyl that links to each other with hydrogen atom or above-mentioned low alkyl group;

   Described lower alkoxycarbonyl is the carbonyl that links to each other with lower alkoxy as defined above;

   Described aromatic acyl group for comprise that carbonatoms is the carbonyl that the aryl of the aromatic hydrocarbon of 6-10 links to each other.
2. 2. the compound of claim 1, it has general formula (La).
3. 3. claim 1 or 2 compound, wherein R ¹Be hydrogen atom.
4. 4. claim 1 or 2 compound, wherein R ²And R ^3aBe together formula-(C=O)-group.
5. 5. claim 1 or 2 compound, wherein R ^3aBe hydrogen atom.
6. 6. claim 1 or 2 compound, wherein R ^4aBe methyl or ethyl.
7. 7. claim 1 or 2 compound, wherein Ar is thienyl or the thienyl that replaced by 1-4 substituting group that is selected from as the substituting group group a of claim 1 definition.
8. 8. claim 1 or 2 compound, wherein Ar is benzothienyl or the benzothienyl that replaced by 1-4 substituting group that is selected from as the substituting group group a of claim 1 definition.
9. 9. claim 1 or 2 compound, wherein m is 0.