WO1996034861A1

WO1996034861A1 - Novel process for the n2-tritylation of tetrazole ring

Info

Publication number: WO1996034861A1
Application number: PCT/JP1996/001195
Authority: WO
Inventors: Ginro Tokuhara; Tadashi Yamaguchi; Tetsuya Iwasaki; Kazunori Monzen
Original assignee: Chugoku Kayaku Kabushiki Kaisha
Priority date: 1995-05-02
Filing date: 1996-05-01
Publication date: 1996-11-07
Also published as: AU5515796A

Abstract

A process for preparing a 5-substituted-2-trityl-2H-tetrazole of general formula (II), (wherein R is an arbitrary substituent) from a 5-substituted tetrazole of general formula (I), (wherein R is as defined above) and trityl alcohol by the use of an acid as catalyst. Trityl alcohol is easier of handling than triphenylmethyl chloride which has been used as a tritylating agent in the prior art and the unit cost of the former is about one half of that of the latter. Accordingly, the above process enables reduction in the production cost, being industrially advantageous.

Description

Description New method for N2-tritylation of tetrazole ring

The present invention relates to a novel process for producing 5-substituted 1-2-trityl-2H-tetrazole from a 5-substituted tetrazole and trityl alcohol by using an acid as a catalyst. Background art

Conventionally, when performing tritylation of the 2-position N atom of the tetrazole ring (hereinafter, the tritiation of the 2-position N atom is referred to as “N2-tritylation”), tetrazole compounds are converted to alkali (eg, hydroxylated). N2-tritylation was carried out by the action of triphenylmethyl chloride (also known as trifluoromethane or trityl chloride) in sodium, alkylamine, pyridine, etc.).

However, triphenylmethyl chloride is expensive and has a problem that it is difficult to handle because it is sensitive to moisture (decomposes and dissolves in water). Disclosure of the invention

The present invention provides a method for N 2 -tritylation of a tetrazole ring using a trityling agent which is easy to handle and inexpensive.

In view of the above problems of the prior art, the present inventors have conducted intensive studies on a novel industrially superior trityling agent. As a result, the use of trityl alcohol as an acid as a catalyst makes it possible to obtain N 2 of the tetrazole ring. —The inventors have found that tritylation can be industrially advantageously achieved, and have completed the present invention.

That is, the present invention provides a compound represented by the formula (I):

(Wherein, R represents an optional substituent) from a 5-substituted tetrazole represented by the formula:

(Wherein, R represents the above meaning). A method for producing a 5-substituted-12-trityl-2H-tetrazole represented by the following formula: BEST MODE FOR CARRYING OUT THE INVENTION

The kind of the acid used as a catalyst in the present invention may be an inorganic acid or an organic acid, and is not particularly limited. Preferred acids include sulfuric acid (particularly concentrated sulfuric acid), hydrochloric acid, phosphoric acid and the like.

Trityl alcohol used in the present invention is easier to handle (higher stability against water) than triphenylmethyl chloride, and the unit cost is about half, so that the production cost can be reduced. It is industrially very suitable.

The substituent R at the 5-position of the tetrazole represented by the formula (I) may be any substituent and is not particularly limited. For example, R is hydrogen, an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, an alkoxy group which may be substituted, an alkylthio group which may be substituted. , Being replaced Optionally substituted alkoxy group, optionally substituted alkylthio group, optionally substituted alkylsulfinyl group, optionally substituted alkylsulfonyl group, optionally substituted alkylamino group, fully substituted Alkenyloxy group, alkenylthio group which may be substituted, alkoxycarbonyl group which may be substituted, aryl group which may be substituted, aryloxy group which may be substituted, Selected from the group consisting of an optionally substituted aralkyl group, an optionally substituted arylarylalkenyl group, and an optionally substituted heterocyclic group. Examples of the substituent which may be substituted in each of these groups include, for example, halogen (fluoro, chloro, bromo, and sulfide), linear or branched having 1 to 4 carbon atoms. An alkyl group (e.g., a methyl group, an ethyl group, etc.); a linear or branched alkoxy group having 1 to 4 carbon atoms (e.g., a methoxy group, an ethoxy group, etc.); A chain or branched alkylthio group (eg, methylthio group, ethylthio group, etc.), a linear or branched alkylsulfinyl group having 1 to 4 carbon atoms (eg, methanesulfinyl group), carbon A linear or branched alkylsulfonyl group (e.g., mesyl group) of 1 to 4; a nitro group, an amino group, an aldehyde group, a carboxyl group, a 4'-methylbiphenyl-2-yl group And the like. It is 1 or 2 or more. The position of the substituent is not particularly limited, and may be any substitutable position.

Further, specifically, R is hydrogen, a linear or branched alkyl group which may be substituted and has 1 to 4 carbon atoms (for example, a methyl group, an ethyl group, etc.), and 1 to 4 carbon atoms. A straight-chain or branched-chain optionally substituted alkoxy group (for example, a methoxy group or an ethoxyquin group), a straight-chain or branched-chain alkylthio group having 1 to 4 carbon atoms (for example, A methylthio group, an ethylthio group, etc.), a linear or branched alkylsulfinyl group having 1 to 4 carbon atoms (for example, methanesulfinyl group), a linear or branched substitution having 1 to 4 carbon atoms. An alkylsulfonyl group (eg, a methyl group), a funinyl group,

(Wherein, is a halogen (fluoro, chloro, bromo, odo), a linear or branched alkyl group having 1 to 4 carbon atoms (eg, a methyl group, an ethyl group, etc.), a carbon number of 1 to 4 A straight-chain or branched alkoxy group (eg, methoxy group, ethoxyquin group, etc.); a straight-chain or branched alkylthio group having 1 to 4 carbon atoms (eg, methylthio group, ethylthio group) Etc.), a linear or branched alkylsulfinyl group having 1 to 4 carbon atoms (e.g., methanesulfinyl group), a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms (e.g., A mesyl group), a nitro group, an amino group, an aldehyde group, and a carboxyl group).

(Wherein, 1 ^ ₂ and 1 _3, halogen (Furuoro, black hole, bromo, ® one de), linear or branched alkyl group (e.g., methyl group having 1 to 4 carbon atoms, Echiru A straight-chain or branched alkoxy group having 1 to 4 carbon atoms (for example, methoxy group, ethoxy group, etc.), a straight-chain or branched alkylthio group having 1 to 4 carbon atoms. Group (eg, methylthio group, ethylthio group, etc.), linear or branched alkylsulfinyl group having 1 to 4 carbon atoms (eg, methanesulfinyl group), linear or branched group having 1 to 4 carbon atoms. A disubstituted phenyl group represented by a branched alkylsulfonyl group (for example, mesyl group), a nitro group, an amino group, an aldehyde group, or a carboxyl group; Group consisting of methylbiphenyl-1-yl group More choice. In the method of the present invention, a 5-substituted tetrazole compound as a starting material, trityl alcohol and a solvent (eg, benzene, toluene, xylene, etc.) are placed in a reaction vessel equipped with a reflux condenser, and then an acid (eg, (Sulfuric acid) is added, and the reaction is carried out while stirring and heating to reflux. After completion of the reaction, (for example example, MgSO ₄₎ desiccant organic layer existing purpose was dried, the target compound can be obtained and the solvent was distilled off. Example ,

Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to these examples.

Example 1 Synthesis of 5- (4'-methylbiph.zinyl-2-yl) -12-triphenylmethyl-2-H-tetrazole

(4 * —methylbiphenyl-2-yl) tetrazole 1.81 g (7.7 mmo 1), trityl alcohol 1.0 g (3.8 mmo 1), benzene 10 ml, reflux condenser Attached to. Placed in a glass 5 Om 1 reactor. Next, a catalytic amount of concentrated sulfuric acid was added, and the mixture was reacted for about 5 hr while stirring and heating under reflux.

After completion of the reaction, was treated with 5% aqueous alkali, after separated, and the organic layer was dried over MgSO _4, the solvent removed, white crystals of 1. 75 g was obtained. This was recrystallized from hexane / chloroform to give 1.535 g of the product as white crystals. Melting point: 166.3-177.2 ° C. Yield after recrystallization: 83.5% (trityl Alcohol standards). Further, when the aqueous layer is returned to acidic with alkali HC1 using alkali, unreacted (4′-methylbiphenyl-2-yl) and tetrazole can be quantitatively recovered.

Example 2: Synthesis of 5-methyl-12-trifluoromethyl-2H-tetrazole

0.323 g (3.85 mmol) of 5-methyl-1H-tetrazole, 1.0 g (3.85 mmol) of trityl alcohol and 7 ml of benzene were mounted on a thermometer and a reflux cooler. The reactor was charged into a glass 50 ml reactor. A catalytic amount of concentrated sulfuric acid was added thereto, and the mixture was reacted for 5 hours while stirring and heating under reflux.

After completion of the reaction, an excess of diluted HC1 was added, and the mixture was stirred for several hours, and extracted with a solvent such as ethyl acetate or chloroform. MgS0 dried at _4, the solvent was distilled off under reduced pressure, the white crystals 1. 06g (yield: 83.7%) obtained.

Example 3 Synthesis of 5- (4′-methylbiphenyl-2-yl) -12-trifluoromethyl-2-H-tetrazole

(4'-Methylbiphenyl-2-yl) tetrazole 0.8 g (3.81 mm o 1), trityl alcohol 0.503 g (l. 93 mm ol), and benzene 7 m 1 were attached to a reflux condenser. Glass 50m 1 reactor Next, phosphoric acid was added in a catalytic amount, and the mixture was reacted for about 5 hours while stirring and heating under reflux.

After the completion of the reaction, the same post-treatment as in Example 1 was performed to obtain 0.5 g of white crystals. Melting point: 166.3-177.2 ° C. Yield after recrystallization: 91.9% (based on trityl alcohol).

Industrial applicability

Trityl alcohol used in the method of the present invention is easier to handle and has a unit price of about half that of the conventional trityling agent, trifuunylmethyl chloride, so that the production cost can be reduced. It is industrially very suitable.

Claims

Equation (I)

N ヽ N-H

(I)

Contract N

(Wherein R represents an arbitrary substituent) from the 5-substituted-1H-tetrazole and trityl alcohol by using an acid as a catalyst to obtain the compound represented by the formula (II).

(Wherein, R represents the above meaning) A method for producing 5-substituted-2-trityl-2H-tetratolazole represented by the following formula:

2. The method according to claim 1, wherein sulfuric acid, hydrochloric acid or phosphoric acid is used as the acid.

3. R is hydrogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted alkoxy group, an optionally substituted Alkylthio group, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfinyl group, optionally substituted alkylamino group, optionally substituted alkenyloxy group, optionally substituted An alkenylthio group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryl group, an optionally substituted aryloxy group, The method according to claim 1 or 2, wherein the method is selected from the group consisting of an optionally substituted aralkyl group, an optionally substituted arylarylalkenyl group, and an optionally substituted heterocyclic group.

4. R is hydrogen, a linear or branched alkyl group having 1 to 4 carbon atoms which may be substituted, or a linear or branched substituted group having 1 to 4 carbon atoms. An alkoxy group, a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms which may be substituted, a phenyl group,

(Wherein, is a halogen, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, a straight-chain or branched alkoxy group having 1 to 4 carbon atoms, A mono-substituted phenyl group represented by the following formula: selected from the group consisting of a linear or branched alkylsulfonyl group, a nitro group, an amino group, and a carboxyl group;

(Wherein, R ₂ and R ₃ are halogen, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, A linear or branched alkylsulfonyl group having 1 to 4 carbon atoms, independently selected from the group consisting of a nitro group, an amino group, and a carboxyl group); The method according to claim 3, which is selected from the group consisting of —methylbiphenyl-2-yl group.