TW491848B - Pyridone carboxylic acid derivatives and the synthetic intermediate thereof - Google Patents

Abstract

Pyridone carboxylic acid derivatives and the synthetic intermediate thereof of the formula wherein R: cycloalkyl optionally substituted by halogen etc., X: H, lower alkyl, hydroxy or amine etc., Y: H or halogen, A: N or C-Z, Z: optionally halogen substituted lower alkoxy etc., R1 and R2: same or different, H etc., R4-R9: same or different, H, halogen or lower alkyl m: 0 or 1, n and p: same or different, 0 or 1, and the pharmaceutical composition containing them, and the direct intermediate bicyclic compound are disclosed.

Description

491848 A7 B7 V. Description of the invention (,) TECHNICAL FIELD The present invention is a novel pyridinonecarboxylic acid derivative and a novel synthetic intermediate thereof which can be used as an anti-sugar agent. BACKGROUND ART Various antibacterial pyridonecarboxylic acid derivatives are known, for example, in Japanese Patent Application Laid-Open No. 6-239857 (corresponding to EP-A-6G3887), compounds of the following formula (A) are shown:

COOR (A) Please read the notes on the back before filling out this page. In the printed format of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, X 1 9 X 2 is the tooth element, Ri is the amine group which may have substituents, etc. 113 and 114 Are H, alkyl, etc., Y is 0, N, or methylene, etc., Z is 0, U, or methylene, etc., a, η are integers from 0 to 2, and the sum is 2 or 3; 1 * is an integer of 0 ~ 3, and the sum is () ~ 3, Α is N or CX (X is Η or halogen, etc.). R is Η and so on. In the compound of the formula (Α), the 7-position dienylamino group is formed from a ring containing N & stomach and a second ring containing 0, etc., but the substitutions ® and & @ on the first sheet Applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 491848 (a 1) (a 2) (a 3) A7 B7 V. Description of the invention (>) Formula (I) The compounds of the present invention are different. In the aforementioned special fair 6- 2 3 98 5 No. 7, the bicyclic amine group at the 7-position in the compound of formula (A) before the description only shows the following three types: · h〇Cn- or Η »-Also in special fair 6- No. 192262 (corresponding to EP-Α-589318), which shows the compound of the following formula (B) (please read the precautions on the back first and fill in this page)

X 1 is tooth element or nitro, X 2 is thallium, amine, etc., printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Ri is an alkyl group, fluorenyl group, etc., R 2 is fluorene, etc., A is N or C-R5 (R5 is η, halogen, etc.), and Z is based on the following formula: This paper size applies to China National Standard (CNS) A4 specifications 2 η N, v scale) 491848 A7 B7 V. Description of the invention (4) R3 'R4

(b 1) (b 2) (b 3) where R2, R4 are H, methyl, etc., but the dichenyl group (Z) of the 7-position substituent of this compound is the first ring containing N and the ring containing 0 The second fused form differs from the compounds of the invention. Presentation of the invention The present invention provides novel pyridonecarboxylic acid derivatives of the following formula (I) (hereinafter sometimes referred to as the compound (I) of the present invention, its esters and salts thereof, (please read the precautions on the back to write this page)- -、 1fan Yinfan, a consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 491848 A7 B7 V. Description of the invention (4) where R is low alkyl, low alkenyl or low cycloalkyl (these groups are sometimes May be substituted with halogen), or phenyl (this group may sometimes be substituted with amine and / or halogen which may be substituted with a low alkyl group), X is H, halogen, hydroxyl, low alkyl, low alkane or Protected amine group, Y is fluorene or halogen, A is N or CZ, Z is H, halogen or cyano, or low alkyl gas group, low alkyl group, low alkylthio group, low alkenyl group or low alkynyl group ( These groups may sometimes be substituted by halogens), or co-form with 8 to form a bridge of -0-CH2-CH (CH3)-, R i and R 2 are the same or different, each being H, lower alkyl or amine protected R 3 is fluorene or lower alkyl, R4 to R9 are the same or different, each is fluorene, dentin or low alkyl, a is 0 or 1, η and P are the same or different, and each is 0 or 1. The present invention also provides novel dihydramine compounds and their salts of the following formula (II) which can be used as synthetic intermediates of the above-mentioned pyridine-carboxylic acid derivatives (please read the notes on the back ^^ write this page) 0. 装 · Order-line · Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 491848 A7 B7 V. Description of invention (JT) (where Ri ~ R9, *, n and P are the same as above). The structure of the compound (I) of the present invention is specifically a 7-position or 7-position equivalent position of a specific pyridone carboxylic acid, and the unidentified bicyclic amine group is as follows:

Where Ri ~ R9, ancestors, η and p. The compound (I) of the present invention having the above-mentioned special emblem has antibacterial activity, and is particularly excellent in antibacterial activity against Gram-positive salamander, and can be used as an antibacterial agent. Hereinafter, the compound of the present invention will be described in detail. In this article, "halogen" can be fluorine, chlorine or bromine, etc. "Low-J, except for the provisions of S, refers to CO printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs." Low-alkyl "refers to straight or branched Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl and the like. "Low alkoxy" refers to a low alkanoyl group having the same alkyl group as above, such as methylamino, ethylamino, propane, isopropyl, butane, and the like. "Lower alkenyl J refers to C2-7 straight or branched alkenyl, such as vinyl, allyl, 1-propenyl, isopropenyl, etc." Low alkynyl "may be ethynyl, 1-propynyl The group "lower cycloalkyl" includes C3_7 cycloalkyl, such as cyclopropyl, cyclobutyl, octyl, cyclohexyl and the like. "Low alkylthio" can be methylthio, ethylthio, etc. Chinese paper standard (CNS) A4 (210X297 mm) for each paper size 491848 A7 _B7____ 5. Description of the invention () Low alkyl Group, low alkenyl group and low cycloalkyl group, which may have 1 to several halogen substitutions. Examples of the above-mentioned halogen substituted groups may be fluoromethyl groups. Please read the precautions before proceeding with difluoromethyl groups and trifluoro groups. Methyl, 2-fluoroethyl, 2-chloroethyl, 2, 2-difluoroethyl, 2-fluorovinyl, fluorovinyl, 2,2-difluorovinyl, 2-fluorocyclopropyl , 2-chlorocyclopropyl and the like. The low fluorene group, low alkyl group, low alkylthio group, low alkenyl group and low alkynyl group defined by Z may also be substituted with 1 to several halogens. The above-mentioned halogen-substituted group may be a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group other than the halogen-substituted low alkyl group and the alkene group described in the above-mentioned R. 2 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, difluoromethylthio, trifluoromethylthio, fluoroethynyl, trifluoropropynyl and the like. "Phenyl (this group may sometimes be substituted with amine and / or halogen which may have a lower alkyl group)" may be 2,4-difluorophenyl, 3-amino-4,6-difluorophenyl, 4-Gas-2-fluorophenyl, 2-Amo-4-fluorophenyl, 3-amino-4-fluorophenyl, 4,6-difluoro-3-methylaminephenyl and the like. "Amine-protecting groups" or "protectable amine groups" can be used as long as they can be easily detached without substantial influence on other structural parts as long as they can be reacted by general deprotection groups such as hydrolysis or hydrogenolysis. Examples of amine-protecting groups (easy-hydrolyzable amine-protecting groups) printed by the employees' cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, such as ethyl carbonyl, the third butoxycarbonyl group of Boc, benzyloxycarbonyl, P-methyl benzyl carbonyl, ethylene carbonyl, p-toluene fluorenyl) ethane carbonyl and other gas carbonyl groups; such as methyl fluorenyl, acetaldehyde, trifluoroacetaldehyde and other fluorenyl groups; such as trimethylsilyl, p. Tributyl dimethylsilyl and other sand bases; tetrahydropyranyl, o-nitrophenylsulfenyl, diphenylphosphinofluorene and the like. -8 A paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 491848 A7 B7 .. --- 5. Description of the invention (7) Amine-protecting group (easy to hydrogen) Hydrolyzable amino-protecting group) can be arylsulfonyl groups such as p-toluenesulfonyl; such as benzyl, trityl, and thylyl methyl or substituted benzyl groups; such as benzylcarbonyl , Aromatic methyl carbonyl fluorene such as o-methylbenzyl carbonyl; etc., such as trichloroethoxycarbonyl fluorene, < The ester of the compound (I) of the present invention is suitably one which can be converted into the compound (I) of the present invention by chemical or enzymatic means for detachment in vivo or in vivo. The esters which can be converted into the corresponding free carboxylic acid by chemical means such as hydrolysis can be lower alkyl esters such as methyl esters and ethyl esters. Not only chemical means, but also enzymatic means can be converted to the corresponding free carboxylic acid esters, such as methyl ethyl acetone, 1-acetaldehyde methyl carbonyl f gas (1 ethyl 2-1X, such as' esters; ethyl amine alkyl methyl Low digas 2 Alkyl alkane; Alkyl esters such as low esters Low methyl gas Carboxaldehyde oxopentane, very low esters Ethyl esters Ethyl esters Ethyl pyridyl methyl esters Ethyl phthalate-2 Ethyl esters Ethyl-5 amine ί etc. 丨 Pyridoxine and other methyl esters, methyl esters, 醯 milk 7 Chirobutene 2Γ 3 Di is-3 base compound Mingfa Benfafluorotriol and salt Xu Rong i Physiochemical salt of sulfonic acid dibutyric acid Milk,,, acid, acid, sugar, salt, such as glucose and acid; acid amine, glutamic acid or organic acid without amine, such as aspartic acid, phosphorus acid, hydrochloric acid, diacid propionate, acid, etc. , Amines and acids; potassium zinc

Deng I. Printing of carbamoyl chloride by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, salt ammonium 〇; The salt of the salt is organic amine triethyl morpholinoformyl methyl sulfide, acetic acid ethyl fluoride For example, the three and the acid can be oxidized, the acid acid I) a (I such as acid and organic compounds, amines and other amines to form acid, plus sulfonic acid benzene, methanoic acid on the machine, this Acid-free sulfonates and adducts combined with amine ring two and \ t * / I / V bio-derived carboxylic acid ketones and ketones. This paper uses China * furniture ratio (cNS) A4 size (210X297 mm). 491848 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () Sometimes it can exist as a hydrate or a vehicle. The compounds of the present invention can also be optically active tritium, stereoisomers (cis, trans) or These mixtures exist in the form. These compounds are included in the present invention. Among the compounds (I) of the present invention, suitable compounds are those in which η is 1 in the foregoing formula (I), and the more preferable ones are in (i) in the foregoing formula (I). ) When R is cyclopropyl, 2-fluorocyclopropyl, etc., it may be substituted by halogen Haloalkyl, or 2,4-difluorophenyl, 3-amino-4, 6-difluorophenyl and other phenyl substituted with halogen and / or amine group, (ii) X is H, such as methyl Equal lower alkyl, hydroxyl or amine groups, (iii) Y is fluorine, (iv) A is N or CZ, where Z is H; halogens such as F, C1, gas groups; methylamino, difluoromethylamino Low alkyl alkanoyl groups which can be substituted by halogen, such as ethyl, 2-fluoroethane, etc .; low alkyl groups such as methyl; low alkylthio groups such as methylsulfide; low alkyl groups such as ethylthio; or acetylene Low alkynyl groups such as (viRiSR2 are the same or different, each is a low alkyl such as methyl, (vi) R 3 is Η, (vii) R4 ~ R9 are the same or different, each η or low as methyl Alkyl. More preferred compounds of the present invention are in formula (I) above, where r is fluorenyl, 2-fluorofluorenyl, 2,4-difluorophenyl or 3-aminoM, 6-difluorophenyl. , Χ is Η, methyl, hydroxyl or amine, Υ is fluorine, A is N or CZ, of which ZgH, F, C1, methylamino, difluoromethyl, ethyl, and 2-fluoroethoxy , Methyl, methylthio, vinyl, ethynyl or cyano, Ri and R2 are the same or different, each H or methyl, H, R4 ~ R9 phase National Standards (CNS) Α4 size (210x297 mm) (Please read the notes on the back before filling out this page) β Pack · 7 and then fill in the wood order 491848 A7 B7 • 0] Xin-6-base)-Bu fifth 2. Description of the invention (9 Identical or different, each of fluorene or methyl, η is 1. More specifically, the compounds of the examples described below. In addition to the compounds of the examples described below, the compounds of the present invention (I) Examples are as follows. In the following names, although three-dimensional structures are not yet determined, the compounds of the following chemical names include all kinds of three-dimensional structures. 7- (8-Amino-2-Ming-6-Azabicyclo [tributyl-6-fluoro-1,4-dihydro-4-oxo-1,8-pyridine-3-carboxylic acid 7- ( 8-Amino-2-Duck-6-B-Yamidine [3 · 3 · 0] oct-6-yl) -1-Third-butyl-6-fluoro-1,4-dihydro-8-methyl Gasoline-4-Gas-B-quinoline-3-carboxylic acid 7- (8-Amino-2-morpho-6-Bammabicyclo [3.3.0] oct-6-yl) -6,8-difluoro- 1- (2-fluoroethyl) -1,4-dihydro-4-gas β morpholine-3-carboxylic acid 7- (8-amino-2-BI-6-azinebicyclo [3.3.0] octyl- 6-yl) -6-fluoro-1,4-dihydro-8-methoxy-4-gas-1-ethylene B quinoline-3-carboxylic acid 7- (4-aminoazinebicyclo [3.2 · 0] heptan-2-yl) -1-fluorenyl-6-fluoro-1,4-dihydro-8-methylamino-4-gas β3-3-carboxylic acid 7- (8-amino -8-Methyl-2-Ming-6-acylbicyclo [3.3.0] oct-6-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methylamino-4 -Ga Itt instructs 3-carboxylic acid 7- (8-amino-4-fluoro-2-ming-6-acylbicyclo [3 · 3 · 0] oct-6-yl) Please read the notes on the back again Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs of the Consumer Cooperative Co., Ltd. ||-2-Fluorodi- 4 4 Tylaminopropyl 8-ring T-Cyclic Digas γ 6 Phosphine if Gas > Acid Carboxyl Propane Fluorohydrodiylcyclomethyl II 6 8 I should be hydrogen 2-one-II 4 * group, 1 × methyl-4 fluoro I p- 6-amino- 8-propaneline url gas 0 6. Carboxylic acid 76-carboxylic acid I-line FI 0 The size of the paper is applicable to the Chinese national standard (CNS "Sigh (2 丨 0 > 29 * 7mm) 491848 A7 B7 V. Description of the invention (~) 7- (8-amino-2-^-6 -Acridinebicyclo [3.3.0] octyl-6-yl) -bucyclopropyl-6-fluoro-1,4-dihydro-5-Cycyl-8-methyl-4-air Acid 1- (3-amino-4,6-difluorophenyl) -7- (8-amino-2- 丨 §-6-azinebicyclo [3.3.0] oct-6-yl) -8- Argon-6-fluoro-1,4-dihydro-4-gas I quinol-3-carboxylic acid 5-amino-1- (3-amino-4,6-difluorophenyl) -7- ( 8 • Amino-2- (|-6_ azinebicyclo [3.3.0] oct-6-yl) -6-fluoro-1,4-dihydro-4-gas-1,8-hexadin-3-carboxyl Acid 7- (9-amino-4,4-difluoro-2-if-7-acylbicyclo [4 · 3 · 0] non-7-yl) -1-cyclopropyl-6-fluoro-1, 4-dihydro-8-methylamino-4-oxo If leaching 3- 3-carboxylic acid 7- (8-aminomethyl-2-1, etc.-6-azinebicyclo [3.3.0] oct-6-yl) -1-Cyclopropyl-6-fluoro-1,4-digas-8-methylamino-4-oxo If 3--3-carboxylic acid 5-amino-7- (8-amino-2-IIII -6-Acridine bicyclo [3 · 3 · 0] oct-6-yl) -1-ring Methyl-6-fluoro-1,4-dihydro-8-methyl-4-ketoline-3-carboxylic acid bucyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7 -(8-Methylamino-2-Ming-6-azinebicyclo [3.3.0] octane-6-yl) -4-gas β-line-3-carboxylic acid 5-amino-1-cyclopropyl-6 -Ga-1,4-dihydro-8-methyl-7- (8-methylamino-2- 丨 etc.-6-B yambicyclo [3.3.0] oct-6-yl) -4 -oxo Lin-3-carboxylic acid 5-amino-1- (4,6-difluoro-3-methylaminephenyl) -6-fluoro-1,4-dihydro-7- (8-methylamino-2 -Ming-6-azinebicyclo [3.3.0] octyl-6-yl) -4-aziridin-3-carboxylic acid 1-cyclopropylethylamino-6-fluoro-1,4-dihydro-7 -(8-Acrolimyl- 2-Ming-6-acylbicyclo [3 · 3 · 0] oct-6-yl) -4-qi 丨 quinoline-3-carboxylic acid-12- This paper is applicable to China Standard (CNS) A4 specification (210X 297 mm) Please read the notes of the back first

t Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 491848 A7 B7 V. Description of the Invention (〇) 5-Amino-1-cyclopropyl-8-ethoxy-6-fluoro-1,4-dihydro-7 -(8 -Methylamino-2-1§-6- (Yabicyclo [3.3.0] oct-6-yl) -4 -GaI®-3-carboxylic acid 1-cyclopropyl-6-fluoro -8- (2-fluoroethoxy) -1,4 -digas-7- (8-methylamino-2H-6-azinebicyclo [3.3.0] oct-6-yl) -4-gas 丨Quinoline-3-carboxylic acid 5-amino-1-cyclopropyl-6-fluoro-8- (2-fluoroethylamino) -1,4-dihydro-7- (8-methylamino-2 -1qin-6-acylbicyclo [3.3.0] oct-6-yl) -4-ketoline-3-carboxylic acid The bicyclic amine compound (II) of the present invention is preferably derived from the corresponding pyridonecarboxylic acid A compound having a substituent at the 7-position of the compound. The compound (I) of the present invention can be produced, for example, by an amination reaction or a ring-closing reaction. The following describes a typical amination reaction. The compound (I) of the present invention, its ester and The salt may be a compound of the following (III), its ester or salt X 0

JL XOOH (Please read the notes on the back and fill in this page)

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

X before * with the bond A and chelation Y boron compound to form R, m-amine, the ring group of the two groups η is this (IL in the formula can be represented by the formula such as oxygen and carboxyl in the formula above Ruler-paper CN / V quasi-standard home country j country one middle school use one suitable 491848 A7 B7

5. Description of the invention (II) In the formula, if R 1 has a boron chelating moiety in the product, this hydrolysis can be used for production. The ionic group L in formula (III) may be halogen, lower alkylthio, lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylsulfonyl, aromatic sulfonyl, etc. Among them, halogens such as F and C1 are preferred. The reaction of the compounds (II) and (III) is generally carried out in an inert solvent, about 10 to 180%, preferably about 20 to 130 ° C, and stirred for about 10 minutes to 7 days, preferably about 30 minutes to 3 days. The inert solvent used may be, for example, water, methanol, ethanol, acetonitrile, aeroform, pyridine, N, N-dimethylformamide, dimethyl sulfene, 1-methyl-2 terminal ketone, and the like. These solvents can be used alone or in combination. In the present reaction, the compound (II) is generally used in an equivalent amount or a slight excess to the compound (III) in the presence of an acid acceptor, but an excess of the compound (II) can also be used as an acid acceptor. The acid acceptor may be 1, 8-Diacylbicyclo [5 · 4 · 0] -7-undecene (DBU), triethylamine, pyridine, Kline, methylpyridine and other organic ages, or such as NaOH, K0Η, potassium sulphate, 硪Inorganic age such as sodium, sodium hydrogen sulfonate, potassium hydrogen sulphate. These acid acceptors are usually used at about 1 to 3 times moles for compound (II). The compound (III) is known, or can be produced following a known method. Bicyclic amination-14- This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) Please read the notes on the back before t Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economy 491848 A7 _____JB7_ V. Invention It is explained that (ii) compound (Π) is novel, and some preparation methods are described later. In the compound (I) of the present invention which can be produced by the amidation reaction of a precursor, if an amine protecting group is present and / or the compound (1) of the present invention is obtained in the form of an ester, these amine protecting groups and / or esters may be Detach or switch as you want, and when you get a free state, you can convert it to salt if you want it, or you can switch to a free state if you get salt. The conversion of the ester to the free state can be effected by hydrolysis. The detachment of the amine-protecting group can be carried out by hydrolysis or hydrogenolysis according to the type of the protective group, thereby leading to the conversion of the amine-protecting group into a compound of the present invention (1). The hydrolysis and hydrogenolysis reactions are described below. The hydrolysis reaction can be carried out by contacting the ester of the compound (I) of the present invention and / or the compound (I) of the present invention having an easily hydrolyzable amine protecting group with water in a suitable solvent. This reaction is to promote the reaction, and is usually carried out at an acid or age. It is carried out in the presence of. Available acids such as osmic acid, hydrobromic acid, sulfuric acid, phosphoric acid and other inorganic acids, such as acetic acid, trifluoroacetic acid, formic acid, p-toluenesulfonic acid and other organic acids. The base may be, for example, HaOH, barium hydrogen etc. Golden hurricane hydrochloride; such as sodium gallate, potassium ferrate, etc .; sodium acetate, etc. The solvent printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs can usually use water. However, the properties of the former compounds can be used with ethanol, ethylene Water-miscible organic solvents such as dimethyl ether and dihenane are used together with water. The reaction temperature is generally about 0 ~ 150eC, preferably about 30 ~ 10ITC. In this reaction, the aforementioned compound is directly heated in the presence of the aforementioned acid, Add water to fruit The dissociation reaction of the hydrogenolytic amine protecting group can be carried out by hydrogenating the compound (I) of the present invention which has an easily hydrogenolytic amine protecting group in the presence of a catalyst in a solvent. It can be used in this reaction The catalyst is platinum, Ruan Laihuan and other hydrogen. 15- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 491848 Α7 Β7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (a) Solvent catalyst. Ethylene glycol, dioxane, N, N-dimethylformamide, ethanol, acetic acid, water, etc. can be used as the solvent. The reaction can be below about 60 eC. It is generally carried out at room temperature. When the hydrogenolytic amino protecting group is benzyl, trityl, benzyl carbonyl, p-toluenesulfonyl, etc., this protecting group can be about -50 ~ -2 in liquid ammonia (TC treated with metal sodium also It can be detached. The compound (I) of the present invention produced by the amidation reaction can be isolated and purified according to a conventional method. These compounds are obtained in the form of a salt, a free state or a hydrate according to the conditions of the isolation and purification, but these The compounds of the present invention can be converted to each other according to the purpose, and can lead to the desired form of the compound. The stereoisomers of compound (I) can be separated by conventional methods, such as stepwise crystallization, chromatography, etc., and the optically active species can be isolated by conventional optical segmentation methods. The obtained compound (I) of the present invention and its homogenate It is a novel compound with excellent antibacterial activity and can be used as an antibacterial agent. The compound (1) and its salt of the present invention can be used as a mandarin for animals other than humans, or can be used as a preservation agent for pesticides, foods, and the like. The ester of the compound (I) of the present invention can be a synthetic raw material of the compound (1) of the present invention. If the compound itself is easily converted into the compound of the present invention (I) in vivo, it can also be used as a prodrug, as well as the compound of the present invention (I). It is used as an antibacterial agent. The compound (11), which is used as a raw material in the amidation reaction of the precursor, can be produced by converting the amine protecting group R10 of the compound of the following formula (IV) into hydrazone, for example:-1 6- (Please read the precautions on the back before filling out this page)-Install · 1T

JI. 本 纸 # ΧΛ 4 User darts (CNS) Α4 specifications (210X297 mm) 491848 A7 B7 V. Description of the invention (

R N- (CH2) m

(Please read the notes on the back before filling this page) (IV) In the formula, Rio is an amine protecting group, Ri ~ R9, », η and p are the same as above. The amine-protecting group Rid may be the easily-hydrolyzable amine-protecting group or the easily-hydrolyzable amine-protecting group as described above. When 1 ^ and / or 112 in the compound (IV) is an amine-protecting group, although the amino-protecting group of Rid and / or the amine-protecting group of R2 can adopt different properties, it is preferable to select one suitable for the subsequent reaction, for example If the amine-protecting group of R1 and / or R2 is an easily hydrolyzable amine-protecting group such as a third butoxycarbonyl group, R10 should preferably select an easily-hydrolyzable amine-protecting group such as benzyl, trityl and the like. The deprotection reaction of the amine protecting group 1110 can be carried out by subjecting the compound (IV) to a hydrogenolysis or hydrolysis reaction as described above. When Ri and / or R2 in the compound obtained from the disengagement reaction printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs is an amine-protecting group, it is also separated as desired and converted to H. If the result is a free state, it may be as needed. It is converted into salt according to the usual method, and if it is obtained, it can be converted into a free state. The obtained stereoisomers of the compound (II) of the present invention can be separated by ordinary methods, such as fractional crystallization, chromatography and the like. The optically active substance can be isolated by the conventional optical division method. The compound (IV) is also novel and can be produced according to the following reaction schemes 1 to 9 or by following this method. -17- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 491848 A7 B7 V. Description of the invention (4) Reverse process

(CH2) q-OR12 〇 T n-ri〇 (CH2) q.〇H 3,

HO,: N ~ R1. (CH2) q-OH 6

(Please read the notes on the back before filling this page)

1T HOm Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 9

P N-R10 (CH2) q R / HN Reaction Scheme 2 PN3, ^ -Ri (CH2) q 10 Rif N /

H2N

N-Ri 11 (CH2) q kg 1. (CH2) q (CH2) q 12 13 -18- This paper size applies to Chinese national standards (c, :: Α4_ 螓 (210X297 mm) 491848

L A7 B7 V. Description of Invention (V7) Reaction Process 3 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

(Please read the precautions on the back before filling this page) Binding _ Order This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 491848 A7 B7 V. Description of Invention (β) Reverse Process 6

Anti * Process 7 (Please read the notes on the back before filling this page)

Reaction Process 8 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

HO R3 · — 1 N-R, (CH2) q 35

33 R ^ HN R3 ^ N-R10 (CH2) q 36 .20 ·

This paper size applies to China National Standard (CNS) A4 (21〇X: N, v f 491848

AT-1 B7, Invention Description (V?) Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Response Process 9

-21- (Please read the notes on the back before filling in this page) 1ΛΙ I. _Binds and bounds are in accordance with the Chinese National Standard (CNS) A4 size (210X297 mm) 491848 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Preparation of A7 ___ ^ ___ B7__ 5. Description of the invention (w) In the formula, Rio is the same as above, R11 is a fermenting protective group such as thallium butyldimethylsilyl, acetamyl, tetrahydropyranyl, and Rl2 is a low alkane Sulfofluorenyl, haloalkanesulfonyl, or aromatic sulfonyl, stilbene is fluorene or low alkyl, R 1 ′ is amine protecting group, R 2, and H 3 are each low alkyl, And χ3 are each a tooth element. Q is an integer of 1 to 3, and r is 0 or 1. The above processes 1 to 9 are briefly explained as follows. [Reaction scheme 1] The known compound 1 or 2 is odorized and then reduced to obtain compound 3 (q = 1 or 2). Compound 3 (q = 3) can be obtained by subjecting Compound 1 to a borohydride reaction. The terminal alcohol portion of compound 3 is sulfonated to form compound 4, and then compound 5 is removed from the alcohol protecting group R1JL, and the ring is closed to obtain compound 7. In addition, the alcohol-protecting group Ru of compound 3 is removed to form compound 6, and this is reacted with a sulfonation reagent in the presence of a base to obtain compound 7. The hydroxyl group of compound 7 is inverted by compound 8 to obtain compound 9. [Reaction scheme 2] After the hydroxy group of the compound 9 obtained above is sulfonated, the compound 10 is substituted with an azide group, and then reduced to obtain the compound 11. The amine group of the compound 11 is protected to obtain the object 12 included in the compound (IV). This compound 12 is alkylated, or the amine protecting group Ri ′ is reduced to lower alkyl 1 {2 Introduction -22- (Please read the precautions on the back before filling this page) +1 -pack-

、 1T This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 491848 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (Η) The amine-based protective group Ri 'must be included in Object 13 of Compound (IV). [Reaction scheme 3] The reaction scheme 2 is completely imitated, and the target compounds 16 and 17 included in the compound (IV) can be obtained from compound 7. [Reaction Scheme 4] The alcohol protecting group RU of compound 18 is removed to form compound 19, and this is treated with a halogenating agent to obtain compound 2 (U. Compound 20 is dehalogenated to obtain compound 21. The hydroxyl group of compound 21 is passed through the compound 22 and reverse to obtain compound 23. [Reaction scheme 5] Completely mimic reaction scheme 2, and obtain the target 26 included in compound (IV) from compound 23. [Reaction scheme 6] Completely mimic reaction scheme 2, from compound 21 can include the target compound 29 in compound (IV). [Reaction-Scheme 7] After the hydroxyl group of compound 7 obtained in the reaction scheme 1 is sulfonated, it is replaced with β nitrogen group to compound 30 and reduced to obtain compound 31. The amine group of the compound 31 is protected to obtain the target 32 of the compound (IV). [Reaction scheme 8] The compound 7 obtained in the reaction scheme 1 is gasified to a compound 33, and then reacted with a low alkyl metal reagent to obtain a compound 34 This reduction yields compound 35. After Rieter reaction, the target 36 of compound (IV) is included. -23- (Please read the precautions on the back before filling this page) 4! 1Τ 本 纸 # 〈Aspiring 4 飔 中 《« Standard (CNS) A4 specification (210 × 297 mm) 491848 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention ("Reaction Scheme 9") Compound 3 (q = 2) obtained in Reaction Scheme 1 is dehydrated and Compound 37 is obtained, and compound 38 (r = 1) is obtained by gasification reaction and halogenation. Compound 38 (r = 1) is obtained by gasification reaction and halogenation of compound 1. After the alcohol-protecting group Ru of compound 38 is released to form compound 39, the ring is closed to obtain compound 40. This was halogenated to obtain compound 41. Thereafter, the reaction scheme 2 is completely imitated, and the objective 44β included in the compound (IV) is obtained from the compound 41. Each of the above reactions is specifically described in Examples A to M described later. The antibacterial activity of the compound (I) of the present invention in a test tube And the effect in vivo is explained by the following data. Table 1 shows the minimum growth inhibitory concentration (MIC: # g /) which is similar to Cheaotherapy 29 (1), 76 (1981). Table 2 shows the effect on mice's systemic overdose disease (ED50, ing / kg). . The effect on systemic infections in mice (EDso, ng / kg) is 5 x 108 嫡 Golden Grape® (S. aureus) 50 7 7 4 for each Stb-ddy male mouse (approximately 20 g). Strains (live bacteria) were used to stain, and the test compound was dissolved in an equivalent NaOH solution and diluted with physiological saline (orally 2 times after infection and 6 hours later). After 14 days of infection, the survival rate of mice was determined according to Probit Method to calculate. The control compound is commercially available enoxacin [1-ethyl-6-fluoro-1,4-dihydro-1-gas- 7- (bupiperinyl) -1,8-pyridine- 3-carboxylic acid, referred to as EHX]. The test compounds in Tables 1 and 1 are specified by the numbers of the examples described later. -24- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the notes on the back before filling out this page) Binding and binding 491848 B7 V. Description of the invention {Η) Central Bureau of Standards, Ministry of Economic Affairs Printed by Employee Consumption Cooperatives Table 1 Test tube meat hangpu (袢 T f:: M g / μ 11 Strain example S. aureus E. coli 50774 MS16405 N1HJ JC-2 No 12 1 S 0.003 0.39 0.013 0.39 2 0.006 0.39 0.013 0.39 3 0.013 1.56 0.006 0.2 4 0.006 0. 39 0.025 0.78 5 S 0.003 0.39 0.025 0.78 6 0.025 1.56 0. 025 1.56 7 0.006 0.39 0.025 0.39 8 0.013 3. 13 0.2 1.56 9 0. 025 1.56 0.05 1.56 10 0.013 0.39 0 · 1 3 · 13 11 0.013 — 0.025 0.39 12 0.013 0.39 0 · 1 1.56 13 0.013 1.56 0.05 0.78 14 0.025 1.56 0.025 1.56 15 0.025 0.78 0.013 0.78 16 0.006 1.56 0 · 1 1.56 17 0.05-0.1 0.78 18 0.025 1.56 0.006 0.39 ENX 0.39 100 0.05 0.78 -25- (Please read the notes on the back before filling this page) This paper size is applicable to China W $: 蠓 瘳 (, \ S) Α4 condition grid (210X297 mm) 491848

-T 7 AB Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (4) Table 1 (continued) Strains 贲 Examples Golden staphylococcus 薗 large intestine 薗 green pus stalk _ 50774 MS16405 NIHJ JC-2 * No 12 19 0.013 0.78 0 · 1 1.56 20 0. 1 3. 13 0.05 1.56 21 S 0.003 0.78 0.013 0.39 22 0.05 one € 0.003 0.39 23 $ 0.003 0.78 0.025 0.78 24 0.013 1.56 0.025 0.78 25 0. 025 1.56 0.025 1.56 26 0.05 — 0.013 0.39 27 0.025 1.56 0.025 1.56 28 0.025 0.78 0.025 1.56 29 0.025 — 0.025 0.39 30 0.013 3. 13 0.05 0.78 31 0.013 0.78 0. 1 0.78 32 0.013 0.78 0 · 1 1.56 33 0.025 1.56 0.05 3. 13 34 0.05 6.25 0.05 1.56 35 0.025 6.25 0 · 1 3. 13 36 0.013 0.78 0.2 3. 13 ENX 0.39 100 «.05 0.78 —26 — 丨 · --S --- ί--mjp · install-- (Please read the precautions on the back before (Fill in this page), 1T J --- Ί · This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 491848 fB7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention 1 Table 1 (Continued) Strain Examples Staphylococcus coliform P. aeruginosa 50774 MS16405 NIHJ JC-2 * No 12 37 0.05 6. 25 0. 1 3. 13 38 0 · 1-0. 05 3. 13 39 0.025 3. 13 0.2 0.78 40 0.025 1.56 0.1 3 13 47 0.013 0.39 0.05 0.78 48 0.013 1.56 0. 05 0.39 49 0.05 1.56 0. 1 3. 13 50 S 0.003 0.39 0.025 0.2 51 ^ 0.003 0.78 0.025 0 · 1 52 0.013 1.56 0.025 1.56 53 0.013 1.56 S 0.003 1.56 54 0.013 0.78 0.025 1.56 55 0.013 1.56 0.05 0.39 57 0.006 0.39 '0.003 0.2 ΕΝχ 0.39 100 0.05 0.78 -27- (Please read the precautions on the back before filling out this page) _Γ · The size of the paper is applicable to the Chinese National Standard (CNS) A4 < 1 is ;:-) 491848 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (4) Table 2 Causes of Pain Caused by the Umbrella of the Mouse (EDm ng / kRi Example Strain Golden «Grape Ball_ 50774 1 0.36 2 0.383 3 0.398 4 0.246 5 0.257 6 0.292 7 0. 331 8 0.345 9 0.415 10 0.465 11 0.579 12 0.715 Example Golden 16 Grape Ball Ball 50774 η 0. 778 14 ^ 0.78 15 1. 12 16 0.78 17 0.78 18 0. 928 19 0. 928 47 0.478 52 0.503 53 0.576 57 1.43 ΕΝχ 9.89 -28- —ϋ ^ ιϋ —ϋ Μϋ II ·· m 11 n (Please read the notes on the back before filling this page) Order --Γ- this The paper size is applicable to the Chinese country * ♦ (Ά84 4 格格 (210X297mm) 491848 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 __ B7 ______ V. Description of the invention (W) As shown in Table 1 and Table 2, The compound (I) of the present invention is excellent in antibacterial activity in a test tube and in vivo. In particular, the compound (1) of the present invention has far stronger antibacterial activity against Gram-positive bacteria than EN X. The compound (I) of the present invention, its ester or physiologically acceptable salt can be used as an antibacterial agent for the treatment of bacterial diseases in humans and animals. When the compound (I) of the present invention is used as an antibacterial agent in humans, the amount of the compound (I) varies depending on age, weight, symptoms, administration route, etc., but it is generally administered once or in portions of 5 ng to 4 g per day. Although the administration route is oral, non-oral or partial administration is acceptable, but oral administration is preferred. Although the compound U) of the present invention can be administered to humans or the like as a precursor, it is usually prepared together with a pharmaceutically acceptable additive to prepare a preparation (pharmaceutical composition) for administration. Such preparations may be lozenges, liquids, capsules, granules, fine granules, powders, syrups, injections, troches, ointments, sprays, eye drops and the like. These preparations can be manufactured by usual methods using usual additives. For example, the oral additives may be starch, mannose, crystalline cellulose, carboxymethylcellulose calcium, water, ethanol and other formulations, and are solid or liquid carriers or diluents that do not react with the compound (I) of the present invention. . Additives for injection can be those commonly used in the field of injections such as water, physiological saline, glucose solution, infusion and the like. The palate spray or soft bud can also be used for the treatment and treatment of otology, throat, or ophthalmology. EXAMPLES The following examples illustrate the present invention. Examples A to M are methods for preparing the blue ring intermediate cyclic bicyclic amine compound (II). Examples 1 to 60 are methods for preparing the compound (I) of the present invention. Example H is There are prescribers. -29- This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) C Please read the notes on the back and fill in this document) 装 • Installation · 1T 491848 A7 B7 V. Description of the invention (W) "It means that the consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed the following" R # J "which is included in the compound name. The three-dimensional structure of the compound is relative and absolute, and the three-dimensional structure of the following structural formula is also the opposite. The abbreviation in the absolute examples is as follows: Boc: the third butanecarbonyl group Me: methyl 2, 4-F 2 Ph: 2, 4-difluorophenyl 3-NH2-4, 6-F2 Ph: 3-amino group -4,6_ Difluorophenyl Example A (-)-(lR *, 5S *, 8R *)-8- (Third butanecarbonylamino group 2-Minga-6-acylbicyclo [3.3.0] Octane (Compound II: βι ^ Boc; R2, R3, U4, R8, R9 = H; brew = 0; n = 1; P = fl) [Process 1] D-tartaric acid is used as raw material, imitating J.Org · CheiuU, lfl3_l () 8 (1995) (3R *, 4S *, 51 ^) · Benzyl-3,4_bis (third butyldimethylsilylamino) -5- (2-hydroxyethyl Base)-125.5 g of pyrrolidone, 60% acetic acid water 1200B1 was added and refluxed overnight. After concentration under reduced pressure, add Concentrated ammonia water 3 0 * 1 and methanol 500b1, after stirring overnight at room temperature, concentrated under reduced pressure on a silica gel column chromatography (chloroform: methanol = 10: 1), to obtain (3R *, 4S *, 5R *)-1- 35 g of benzyl-3,4-dihydroxy-5- (2-hydroxyethylb-2-pyrrolidone. IR (neat) c irr 丨: 3370, 1682 MS (m / z): 252 (MH +) ^ -NMRCCDCla) ^:?. 10-7.32 (m, 5 H). 5. 52 (brs, 2 H), 4.90 (d, 1 H, J = 15.0Hz), 4.50 (d, 1H, J 2 7. Please note first. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (: M * ΝΊ) 491848. Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 / _B7 ^ j_ V. Description of the Invention (Clever) 5Hz), 4.21 (brt, 1 H, J = 7. 5Hz), 3.94 (d, 1 H, J = 15. 〇 Hz), 3.55 (brs, 3H), 2.20 -2.00 (br s, 1 H), 1.86 (brs, 2 H) [Process 2] Add 35 g of the compound obtained in Process 1 to pyridine 4fl0al, add 26.6 g of p-toluenesulfonium gas under ice cooling, stir overnight, add water and chloroform. The organic layer was separated, washed with 10% hydrochloric acid, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain (1R *, 5S *, 8S *)-& benzyl-8-hydroxy-7 -24 g of octane bicyclo [3.3.0] octane. IR (net) ciT1: 3390, 1692 MS (m / z): 234 (MH +) ^ -NMR (CDC 1 a) (5: 7.40-7.18 (m, 5 H). 4. 84 (d, 1 H, J = 15. OHz), 4.49 (br, 1 H), 4.42 (dd, 1 H, J -6. 5, 1. · 7Ηζ), 4.32 (br, 1 H), 4.16-4.06 (m , 2 H), 3. 92-3. 66 (m, 2 H), 1.92-1.82 (m, 2 H) [Process 3] (1) Add 14 g of the compound obtained in Process 2 to dihydromethane 250111, Add pyridine 14.6ial while cooling, and slowly add triflic acid 13.111. After 2 hours, add 550 ml of dimethylformamide and 58.9 g of potassium acetate. After stirring overnight, insoluble matter is filtered off and concentrated under reduced pressure. Water and atmosphere were added, and the organic layer was separated and the solvent was distilled off under reduced pressure to obtain the crude (1IT, 5S *, 8S *)-8-acetamido-6-benzyl-7-gas m-6-acylbicyclic ring. [3 · 3 · 0] Octane. (2) Add ethanol 5G0ral and concentrated ammonia water 20Qb1 to this compound, and stir at room temperature -31- £ ___? 丨 _ ^ _ (Please read the precautions on the back and fill in. (Install-: write this page)

， 1T —ν ^ ϋ ami mntt · This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) 491848 A7 B7 V. Description of the invention (V) Mix overnight, concentrate under reduced pressure, add water and imitate. The organic layer was separated, concentrated under reduced pressure, and subjected to sand-column chromatography (chloroform: methanol: =: 30: 1) to obtain (1 *, 58 *, 8R *, 6_benzylhydroxy_7-gas, and 2-Ming_6-Acridine [3.3.0] 9.2 g of octane. IR (net) c-pass-1: 3381, 1694 MS (m / z): 234 (MH +) ^ -NMR (CDC 1 ο) ά: 7.40-7.20 (m, 5H), 4.93 (d, 1 H, J-15.0Ηζ), 4. 50 (dd, 1 H, J = 6. 0, 5. 0 Hz), 4.28 (d , 1 H, J-6.0 Hz), 4.0 09 (d, 1 H, J = 15.0 Hz), 4.08-3.93 (m, 2 H), 3.80-3.66 (m, 1 H), 3. 22 (brs, 1 H), 2.24-2. 1 1 (m, 1 H), 2. 01-1. 81 (m, 1 H) [Process 4] Process 3 (2) 9.2 g of the obtained compound was added to ioobI dichloromethane, 9.5 nl of pyridine was added with ice cooling, and 91 ml of trifluoromethanesulfonic anhydride was gradually added. After 2 hours, dimethylformamide 300β1 and ft sodium nitride 24.4 g were added. Stir overnight and concentrate under reduced pressure, add water and aerosol, separate the organic layer and wash it with dilute hydrochloric acid, dry over anhydrous magnesium sulfate, and remove the solvent by reducing K to obtain (1R *, 5S *, 8s *)-8 -Azido-6-benzyl-7-qi-7-qi-2-If -6-acridine [3 · 3 · 0] octane 7.4 g. Consumer Co-operation of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the company (please read the precautions on the back before filling in this page) IR (net) ciT1: 2109, 1 6 9 4! H-NMR (CDCI3) δ: 7.40-7.20 (m, 5 Η), 4.93 (d , 1 H, J = 15.0Hz), 4.23 (dd, 1 H, J = 6.0, 1.5 · ζ), 4. 16-4 · 0 2 (m, 3 Η), 3.94-3 · 82 (m , 1 Η), 3 · 8, 3.67 (m, 1 Η), 2.0 · 0-1.80 (m, 2 Η) -32- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 491848 A7 B7 V. Description of the invention (M) [Process 5] (1) Add 7.4 g of tetrahydrofuran compound 3Gflel obtained in process 4, add ice cold 1 + 0 tetrahydrofuran solution 116 »1 of borane-tetrahydrofuran complex, and heat for 30 minutes After that, reflux for 1 night. Cool to room temperature, treat excess borane with ethanol, concentrate under reduced pressure, add 600nl of ethanol, and reflux overnight. It was concentrated under reduced pressure, and 10% hydrochloric acid water was added. The aqueous layer was separated, washed with chloroform, washed with 20% NaOH, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain (1R *, 5R *, 8S *, 8-amino- 6-benzyl-2-Ming-6-azinebicyclo [3 · 3 · 0] -8-amino-6-benzyl-2- 丨 -6-azinebicyclo [3 · 3 · 0] octane 5 · 5 g. (2) After adding this compound to methanol lOflnl and ice-cooling, add 7.2 g of di-tert-butyl diacetate and stir overnight. Concentrate under reduced pressure, and chromatograph on a silica gel column (n-hexane: acetic acid). Ethyl ester = 6: 1), (1R *, 5R *, 8S *)-6-benzyl-8- (third butoxycarbonylamino acyclobicyclo [3 · 3 · 0] octane 7.0 g Melting point: 115-116 ° C (ethyl acetate recrystallization) [cr] 0 ^ + 2-3 ° (c = 1.02, methanol) [Process 6] Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read first) Note on the back side, please fill in this page again.) 5.4 g of the compound obtained in process 5 (2) was dissolved in ethanol 100bI, 5% Pd-C 350ag was added, and the theoretical amount of hydrogen was absorbed at 40 ° C. The solvent was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from diethyl ether isopropyl ether to obtain the target (-)-(lR *, 5S *, 8S *)-8- (third butanecarbonylamino-2-2--6 - 3.5 g of aziridine [3.3.0] octane.

Melting point: 1 1 0-1 1 1 eC -33- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 491848 A7 B7 V. Description of the invention (P) IRUBr) c Zu-1: 3 3 7 7, 3228, 1 68 0 ία) 〇29-4 4. 4 ° (c = 1. 0 3, formazan) ^ H-NMR (CDC 1 3) 5: 4.22 (d, 1 H, J = 5.5 Hz), 4.02-3. 69 (m, 4 Η), 3.15 (dd, 1 H, J = 11.5, 5.0 Hz), 2.84 (dd, 1 H, J-11.5, 3.0Hz ), 2. 19-1.99 (m, 1 H), 1.83-1.68 (m, 2H), 1.45 (s, 9 H)

Example B (-)-(lir, 5S *, 8S *)-8- (third butoxycarbonylamino acyclobicyclo [3.3.0] octane (Compound II: Ri = Boc; R2, R3, R 4 9 R ^ y R 8 9 R 9 == H 5 ffl = 0 > π = 1 j P = 〇) 〇 (1IT, 5S *, 8S *)-6-benzyl obtained in the process 2 of Example A -8-Hydroxy-7-gas-2-ΪΙ-6-acylbicyclo [3 · 3 · 0] octane was treated in the same manner as in process 4 to 6 of Example A to obtain the title compound. [Ct] D w-7 9 · 3 ° (c = 1 · 0 2, methanol) MS (m / z): 229 (MH +)! H ~ NMR (CDC13) δ: 5.17 (br s, 1H), 4.29 (t, employee of Central Bureau of Standards, Ministry of Economic Affairs Printed by a consumer cooperative (please read the precautions on the back before filling this page) 1 H, J = 5.5Hz), 4.04-3.74 (m, 4 H), 3.23 (dd, 1 H, J = 11.5. 7.0Hz) , 2. 50 (t, 1 H, J = 11.5 Hz), 2.26-2.08 (m, 1 H) »1-86 (s, 1 H), 1.88-1.73 (m, 1 H), 1.45 (s, 9 H)

Example C: (+)-(lR *, 5S *, 8R *)-8- (Third butanecarbonylaminoacylbicyclo [3.3.0] octane (Compound II: R 1 = B 〇c 9 R 2 > K 3, R 4 »R 5 9 R θ— H ^ ffl-0} π = 1 -34- This paper size applies the Chinese National Standard (CNS) Α4 specification (210 × 297 mm) 491848 A7 B7 V. Description of the invention (W); P = 〇) 〇

Melting: 1 〇 8-1 Ο 9 ° C IRUBr) c Li-1: 3 3 7 7, 3228, 1680 〔a〕 0 ^ + 44.5 ° (c = 1.01, formazan) 1H-NMR (CDC 1 3 ) (5: 4.22 (d, 1 Η, J = 5.5 Hz), 4.02-3.69 (m, 4 Η), 3.15 (dd, 1 Η, J = 11.5 · 5 ΟΗζ), 2.84 (dd, 1 Η, J = 11.5, 3.0Hz), 2.19-1.99 (m, 1 Η), 1.83-1.68 (m, 2Η), 1.45 (s, 9 Η)

Example D: (+)-(lR *, 5S *, 8S *)-8- (Third butanecarbonylamino group 2- 丨 §-6-azepine bis (3 · 3 · 0) ] Octane (Compound II: R 1 = Boc; R 2 »R 3 9 K 4 9 R 8» R 9 = Η 5 ιβ = 0; π = 1; ρ = 〇) 〇 [cr] (c = 1.00, Methanol) MS (m / z): 229 (MH +) * H-NMR (CDC 1 3) 5: 5. 17 (brs, 1 Η), 4 · 29 (t, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the notes on the back before filling this page)

1 H, J = 5.5 Hz), 4.04-3.74 (m, 4 Η), 3.23 (dd, 1 H, J = 11. 5. 7. OHz), 2.50 (t, 1 H, J = 11.5Hz), 2. 26-2. 08 (m, 1 H), 1.86 (s, 1 H), 1.88-1.73 (m, 1 H), 1.45 (s, 9 H ) Example E (1R *, 6S *, 9R *) _ 9- (Third Butane Carboxamido) -2- 丨 §-7-Acridine [4 · 3 · 0] Nonane (Compound II: Ri = Boc; R2, Ruler 3, Ruler 4, Rs, Re, R7, R 8 9 R 9 = H; ffl = 0 5 n = l; p = l) 〇-35- Paper rule t 钃 * Η'Λ 钃Furniture ratio (CNS) A4 specification (210X297 mm) 491848 A 7 B7 V. Description of invention (M) [Process 1]: Using D-tartaric acid as raw material according to J. Org · Chea.M, 103-108 (1995) (3R *, 4S *, 5R *)-5-allyl-1-benzyl-3,4-bis (third butyldisilylamino) -2-pyrrolidine 100 g After adding to tetrahydrofuran 6 7 0 · 1 and ice-cooling, add a 1.0M-tetrahydrofuran solution 87.1 * 1 of borane-tetrahydrofuran complex, and stir at room temperature for 1 hour • Add 7β1 water dropwise. Add 5N-Na0H once Water 33.4 moved 1. 30% double gas water 33 · 4 · 1 was added at a reaction temperature of 30 to 50 eC, and after stirring overnight, water and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the product was subjected to silica gel column chromatography (chloroform) to obtain (3R *, 4S *, 5R ·) -1-benzyl-3,4-bis (No. Tributyldimethylsilyloxy) -5- (3-hydroxypropyl > -2-pyrrolidine_ 33 · 4 g. IR (net) cm-1: 3444,1697 MS (m / z): 494 (MH +)

^ -NMRCCDCla) ^: 7.40-7.20 (m, 5 H), 4.86 (d, 1 H, J = 15.0Ηζ), 4.20 (d, 1 H, J = 6.0 Hz), 4.12 (d, 1 H, J = 15.0 Hz), 4.12-4.06 (m, lH), 3.65_3.40 (m, 3H), 1.75_l · 25 (m, 4 H), 0.95 (S, 9 H), 0.90 (s , 9 H), 0.23 (s, 3 Η), 0 · 17 (s, 3H), 0. 10 (s, 3 H), 0. 02 (s, 3 H) (Please read the precautions on the back before filling this page) [Process 2]: Add 33.4 g of the compound obtained in the previous process 1 and 10.3 g of triethylamine to 40 Onl dichloromethane. After cooling, 15.5 g of p-toluenesulfonyl chloride was added, and after stirring for 1.5 days, water and chloroform were added, the organic layer was separated and washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (hexane: ethyl acetate- 36- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 491848 A7 B7 V. Description of the Invention (W) Ester = 5: 1), get (31 { *, 481 |, 511 *) _ 1-benzyl-3,4-bis (third butyldimethylsilylamino) _5_ (3_toluenesulfonyloxypropylbopyrrolidone 32.8 g. IR (net) c B-1: 1 7 1 5, 1 3 6 0, 1 2 5 4, 1 1 7 6 MS (m / z): 648 (MH +)! H-NMR (CDC 1 a ) ά: 7.80-7.73 (m, 2 H), 7. 39-7. 19 (m, 7 H), 4.82 (d, 1 H, J = 15.0Hz), 4.15-4.07 (m, 2 H), 4.00 (d, 1H, J = 15.0Hz), 3 · 91-3 · 83 (m, 2H), 3.45-3.35 (m, 1H), 2.47 (s, 3 H), 1.70-1.25 (m , 4 Η), 0.95 (s, 9 H), 0 · 84 (s, 9 H), 0 · 22 (s, 3 H), 0 · 15 (s, 3 H) · 0 · 08 (s, 3H ), -0.03 (s, 3H) [Process 3]: 32.8 g of the compound obtained in the previous process 2 was added to tetrahydrofuran 50 0 * 1, and tetra-n-butylammonium fluoride in 1.0M tetrahydrofuran solution 60 · 7 was added once. -1. After heating under reflux for 30 minutes, add water and ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then subjected to silica gel column chromatography (aerosol · · methanol = 30: 1) to obtain (1R *, 6S *, 9S *, and 7-benzyl-9. -Hydroxy-8-Ga-2-Ming-7-Acridine [4.3.0] nonane 10.6 g. Melting point: 1 3 6-1 3 8 ° CIR (KB r) c nr1: 3 2 9 5 , 1 6 6 4 MS (m / z): 248 (MH +) U] D 3 0 — 9 0 · 6. (C = 1 · 〇〇, methanol) -37- This paper size applies to the national standard UNS; A4 grid (210X 297 mm) ^^^ 1 · mi — ^ ϋ -ϋ · —. Ϋ (Please read the notes on the back before filling out this page) Order J, 491848 A7 B7 V. Description of the invention (4) ] Η-NMK (CDC13) δ: 7.40-7.20 (m, 5H), 4.88 (d, 1 H, J = 15.0Hz), 4.40 (dd, 1 H, J = 2.8, 5.0Hz), 4. 18 ( d, 1 H, J = 15.0 Hz), 4.05 (t, 1 H, J = 5.0 Hz), 3. 82-3. 68 (m, 1 H), 3.65-3.46 (m, 2 H), 3.40 (d, 1 H, J = 2.8Hz), 1.97-1. 78 (m, 1 H), 1.73-1.30 (m, 3 H) [Process 4]: 12.5 g of the compound obtained in the previous process 3 was simulated. Example A is processed in process 3 (1) to obtain (1 R 11, 6 S *, 9 R #)-9 -acetamidinyl-7 -benzyl-8 -oxo-2-fluorene-7-azabicyclo [4 . 3.0] 11.9 g of nonane. IR (net) CUT1: 3564, 1715, 1230 MS (m / z): 290 (MH +) ^ -NMRCCDCla) ^: 7.40-7.20 (m, 5 Η), 5.29 (d, 1 Η, J = 4.2 Hz), 4.95 (d, 1 Η, J 2 15.0Ηζ), 4.28 (dd, 1 Η, J = 2.5, 4 · 5Ηζ), 4.13 (d, 1 Η , J = 15. ΟΗζ), 3.98-3 · 86 (m, 1 Η), 3.44-3.37 (m, 1 Η), 3.33 (dt, 1 Η, J = 2. 5.1.1 · 1Hz), 2.38 (s, 3 Η), 2.38-2.20 (m, 1 Η), 1.74-1.25 (m, 3 Η) [Process 5]: 11.9 g of the compound obtained in the previous process 4 was prepared according to Example A, process 3 (2 ) Processing, get (1R *, 6S *, 9IT) -7-benzyl-9-hydroxy-8-qi-2-ming-7- printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the note on the back first) Please fill in this page for more details) Acridine [4 · 3 · 0] nonane 10 · 8 g. Melting point: 163-165 ° C (recrystallized from dichloromethane-n-hexane) IR (KB r) cm: 3340, 1692 MS (m / z): 248 (MH +) ία) d 20 -55. 7 ° ( c = l. 〇〇 »Formazan) -38- This paper size applies to Chinese National Standard (CNS) A4g (210X297 mm) 491848 A7 B7 V. Description of the invention (W) 'H-NMRCCDCldoJMOUOCmJHhS.OiKd, 1 H, J = 15.0 Hz), 4.26 (br, 1 H), 4. 11 (dd, 1 H, J = 2.8, 4.2Hz), 4.05 (d, 1H, J = 15.0 Hz), 4.00-3.90 (m, 1H), 3.48-3 · 32 (m, 2 H), 2.89 (br, 1 H), 2.25-2.20 (m, 1 H), I. 70-1.30 (m, 3 H) [Process 6] : Processing 10.6 g of the compound obtained in the previous process 5 in the same manner as in the process 4 of Example A to obtain (1R *, 6S *, 9S *)-9-azido-7-benzyl-8-gas-2-ming-7- Acridine [4 · 3 · 0] nonane 9.3g. IR (net) cm: 2107,1698 MS (m / z): 273 (MH +) 'H-NMR (CDC 1 a) (5: 7.40-7.20 (m, 5 H), 4.95 (d, 1 H, J = 15.0Hz), 4. 15 (d, 1 H, J = 3. 9Hz), 4.06 (d, 1 H, J 25.0Hz), 3. 9 and 3.72 (m, 2 H), 3.56- 3.41 (m, 2 Η), 1. 94-1 · 25 (m, 4H) [Process 7]: 9.2 g of the compound obtained in the previous process 6 was processed in the same manner as in process 5 (1) of Example A to obtain (1R * , 6R *, 9S *)-9-Amino-7-benzyl-2-Ming-7-acylbicyclo [4 · 3 · 0] nonane 7.3g. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the notes on the back before filling this page) IR (net) cm · 1: 3372 MS (m / z): 233 (MH +) ^ -NMR (CDC 1 3) 5: 7.38-7.18 (m, 5 Η), 4.01 (d, 1 H, J -15.0Hz), 3.90-3.87 (m, 1 H) 3.58 (d, 1 H, J = 3.6Hz -39- This paper size applies to Chinese National Standard (CNS ) A4 specification (2 丨 heart > 1, ·) 491848 A7 B7 5. Invention description (w)), 3.50-3.25 (m, 3H), 3.28 (d, 1 H, J = 15.〇Hz), 2.62 (dd, 1 H, J = 6.8, 3.8 Hz), 2.15-1.92 (m, 2 H), 1.86 (dd, 1 H, J = 10. 〇r 5.0Hz) 1.80-1.60 (m, 1 Η), 1. 42-1 · 12 (m, 3 H) Process 8]: 7.2 g of the compound obtained in the previous Process 7 was treated in the same manner as in Process 5 (2) of Example A to obtain (1R *, 6R *, 9S *, 7-benzyl-9- (third butanecarbonylamino) -2- 丨 1-7-acylbicyclo [4 · 3 · 0] nonane 10.1 g.

Melting: 1 2 0-1 2 3 ° C I R (KB r) cm-3367, 1683 MS (m / z): 333 (MH +)-U] D 30 + 5 7.8. (C = 1 · 0 1, methanol) ^ -NMR (CDC 1 a) d: 7.38-7.20 (m, 5 H), 4.38 (br, 1 H), 4.05-3.72 (m, 4 H), 3.56- 3.22 (m, 3 H), 2.60-2.47 (m, 1 H), 2.08-1.84 (m, 3 H), 1.80-1.64 (m, 1 H), 1.42 (s, 9 H), 1.39-1.23 ( m, 1 H) '[Process 9]: Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page). 7.4 g of the compound obtained in the previous process 8 is simulated in the process of Example A. 6 treatment, to get the purpose of (1R *, 6S *, 9R *)-9- (third butane carbonylamino) -2- «qin-7-azepine [4.3.0] nonane 4.2g . Melting point: 110-111 ° C (recrystallized from dichloromethane-n-hexane) IR (KB r) cm -1: 3311, 1711, 1687 MS (m / z): 243 (MH +) 〔a〕 D 30 + twenty four. (C 2 1. 0 0, formentase) -40- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 491848 A 7 _B7_ V. Invention Explanation (β)] H ~ NMR (CDC 1 a) 5: 4.53 (br, 1 H), 3.98-3.80 (m, 2H), 3.74-3.55 (m, 2H), 3,36 (dt, 1 H, J = 11.5, 2.5Hz), 3.01-2.92 (m, 1 H), 2.55 (dd, 1 H, J = 12.5 · 3. 8Hz), 2.20-1.58 (m, 5H), 1.44 (s, 9H )

Example F (1R *, 6S *, 9S *)-9- (Third-butanecarbonylamino) -2-fluorene-7-acylbicyclo [4 · 3 · 0] nonane (Compound II ·· R1 = Β Ο C; R 2, R 3, B 4, Rs * R 6) R 7 9 R 8 9 R 9 = H jn = 0; π = 1; ρ = 1) [Process 1]: In Example E, (1R *, 6S *, 9S *) of 7-benzyl-9-hydroxy-8-pyrazine [4.3.0] nonane 10.6 g obtained in the process of Example 3 was processed in the same manner as in the process of Example A to obtain (1R *, 6S ·, 9R *) 9.3 g of 9-azido-7-benzyl-8-oxo-2-ming-7-acylbicyclo [4 · 3 · 0] nonane. IR (net) CIT1: 2108,1694 MS (m / z): 273 (MH +)

^ -NMR (CDC 1 a) 5: 7.40-7.20 (m, 5H), 5.02 (d, 1 H, J = 15.0Hz), 4.15 (dd, 1H, J = 2.7, 4.2Hz), 4.07 ( d, 1 H, J = 15.0 Hz), 4.04-3.92 (m, 1H), 3.87 (d, 1H, J 4.2H z), 3.46-3.31 (m, 2 H), 2.26-2 · 12 (m , 1 H), 1.73-1.28 (m, 3 H) [Process 2]: 9.3 g of the compound obtained in the previous process 1 was processed as in process 5 (1) of Example A to obtain (1R *, 6R *, 9R * ) -9-Amino-7-benzyl_2_ Hum-7- -4 1-This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page ) -ΙΓ · -Installation · 491848 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (and) Acridine [4 · 3 · 0] Nonane 7.2g 0 IR (Net) c 通 -1 : 3 36 5 MS (m / z): 233 (MH +)-NMR (CDC13) (5: 7.40-7. 18 (m, 5 Η), 4 · 10-3 · 97 (m, 1 Η), 3.93 (d, 1 H, J = 15.0 Hz), 3.66 (dd, 1 H, J = 4.2, 2.5 Hz), 3.52-3.33 (m, 3 H), 2.21-1.52 (m, 5 H), 1.40 -1.24 (m, 1 H) [Process 3]: 7.2 g of the compound obtained in the previous process 2 is treated as in the process 5 (2) of Example A to obtain (1R *, 6S *, 9R *)-7-benzyl-9- (third butane carbonylamino) -2-丨 f-7-azinebicyclo [4 · 3 · 0] nonane 9.5 g. Melting point: 82-84 ° CIR (KB r) cm is called: 3446 · 1711 MS (m / z): 333 (MH +) D 30 +41. 3 ° (c = K 00, methanol) ^ -NMR (CDC 1 3) o: 7.38-7.15 (m, 5H) 5,21 (br d, 1 H, J = 8.3Hz), 4.27-4.09 (m, 1 H), 4.07-3.96 (m, 1 H), 3.94 (d, 1H, J = 15.0Hz), 3.83 (dd, 1H, J = 4.8, 2.5Hz), 3.51-3.34 (m, 1H), 3,33 (d, 1 H, J = 15.0Hz), 2.92-2.64 (m , 3 H), 2.21-1.88 (m, 2 H), 1.74-1.24 (m, 2 H), 1.40 (s, 9H) [Process 4]: 9.1 g of the compound obtained in the previous process 3 was simulated as in Example A Process 6 processing, the purpose is (1R *, 6S *, 9S *)-9- (Third Butane Carboxamido) -2- -42- t___ (Please read the precautions on the back before filling and filling- : Write this page)

、 1T .—Aw * The size of the paper ft is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 491848 A7 B7 V. Description of the invention (4ί) Hou-buacic bicyclo [4 · 3 · 0] nonane 5.9 g . IR (net) CBT1: 3 4 51, 1710, 1 1 7 0 MS (m / z): 243 (MH +) U] D 30-4 1 · 1 〇 (c = 1 · 0 3, formazan)! H -NMR (CDC 1 3) (5: 5. 17 (br, 1 Η), 4.30_4 · H) (m, 1 H), 4.01-3.87 (m, lH), 3.69 (dd, 1 H, J = 4.2, 2.2 Hz), 3.44-3.22 (m, 2 H), 3,08 (br, 1H), 2.84 (dd, 1H, J = 11. 0, 7 · 2Ηζ), 2. 00- 1.70 (m, 5 H), 1.45 (s, 9 Η) Example G (1R *, 5S *, 8R * ^) -8-(N- tertiary butane carbonylmethylaminobull 2-beer-6- Acridine [3.3. D 丨] octane (Compound II: Ri * = Βοc; R 2 = Me; R Ξ 3, R /%, R 5 f R 8 f SC) = Η; m = 0; η = = 1; p = 0) [Process 1]: Dissolve 36.7 g of 70% toluene solution of hydrogenated bis (2-methylethane) based on toluene in 120111 and ice-cool, add Example A (1R *, 5R *, 8S *)-6-benzyl-8- (third butanecarbonylamino) -2-1 and other consumer cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Printed (please read the precautions on the back before filling in this page) -8.1 g of 6-acylbicyclo [3 · 3 · 0] octane, slowly heat to 10fl ° C, and stir for 2 hours. After ice-cooling, add ice to decompose excess reagents, add 10% NaOH water, extract with ethyl acetate, dry over anhydrous magnesium sulfate, evaporate the solvent under reduced pressure, add 150al of methanol and di-tert-butyl di-ortho-acid 7 · 2 grams, stirred overnight at room temperature. After concentration under reduced pressure, chromatography on a silica gel column (n-hexane: ethyl acetate = 5: 1) gave (1R *, 5S *, 8R *)-6-benzyl-8- (N-third butanecarbonyl) Methylamino acryl bicyclo [3 · 3 · 0] octane 8β1 -43- This paper size applies to China National Standard (CNS) A4 specification (21 × X: 297 mm) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 491848 A7 B7 V. Description of the invention (0) g. IR (net) Cl · 1: 2972,1698 MS (m / z): 333 (MH +) ^ -NMR (CDC 1 3) (5: 7.38-7.20 (m, 5H), 4.63 (dd, 1 H, J = 6.5, 4.5 Ηζ), 4.18-4.02 (m, 1 Η), 3.98-3.80 (m, 3 Η), 3.41 (d, 1 Η, J = 13.0Hz), 3.35-3.25 (m, 1 Η), 2.95 (dd, 1 Η, J = 9.0, 7.5Ηζ), 2.85 (s, 3Η), 2.42 (dd, 1 Η, J = 10.0, 9.0Hz), 1.86-1.59 (m, 2 Η), 1.43 (s, 9 Η) [Process 2]: Dissolve 8.1 g of the compound obtained in the previous process 1 in 15Gil of ethanol, and add 5% P d-C 8 0 0 bg Absorb the theoretical amount of hydrogen at 40 ° C, remove the solvent, evaporate the solvent under reduced pressure to obtain the target (1R *, 5S *, 8ΙΤ) -8- (N-third butanecarbonylmethylamino)- 21 Qin-6-acylbicyclo [3 · 3 · 0] octane 5.9 g IR (net) CH-1: 3 3 4 8, 2 9 7 3, 1 6 8 2 MS (m / z): 243 (MH +) (a) D 30-5 6. 3 ° (c = 1.0 0.05, methanol) 1H — NMR (CDC 1 3) ά: 4.52 (dd, 1 H, J = 6.0, 3.0 Hz), 4.11 (dt, 1 Η, 7.5, 3. ΟΗζ), 3. 97-3. 74 (m, 3 Η ), 3.21 (dd, 1 Η, J = 11.0, 7.5Ηζ), 2.97 (dd, 1 Η, 11.0, 7.5Hz) 2. 87 (s, 3 Η), 2.11-1.91 (m, 1 Η) , 1.83- 1.67 (m, 1 Η), 1.73 (brs, 1 Η), 1.46 (s, 9 Η) Example Η (lR *, 5 s *, 8S *) -8- (Ν- 三 丁 气Carboxymethylamino)-2-ϊ§ -6-Acridine bicyclic [3.3.0] octane-44- This paper has a wide range of 4 "Chinese paper" "Household Ratio (CNS) A4" (210X 297 mm) !! (Please read the notes on the back before filling this page) Order 491848 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (43) (Compound II: Ri = Boc; R2 = Me; R3, R4, R8, R9 = H; Coarse = 0: 11 = 1: 0 = 0) [Process 1]: Process 1 of Example G is imitated to obtain (1R *, 5S ·, 8S *)-6-benzyl-8- (N-Third butanecarbonylmethylamino) -2-fluorene-6-acylbicyclo [3.3.0] octane. IR (net) car1: 1682 MS (m / z): 333 (MH +)! Η—NMR (CDC13) (5: 7.20-7.38 (m, 5 Η), 4.47-4.56 (m, 1 Η), 4.00-3.84 (m, 2 Η), 3.95 (d, 1 H, J = 15.0Hz), 3. 30 (d, 1H, J = 15.0Hz), 3.25-3.17 (m, 1H), 2.94- 2.85 (m, 1 H), 2.85 (m, 3 H), 2.52-2.35 (m, 1 H), 2.05-1.72 (m, 3H), 1.45 (s, 9H) [Process 2]: 9.5 g of the compound obtained in Process 1 was treated in Process 2 of Example G to obtain the target (lR *, 5S *, 8S *)-8- (N-third butanecarbonylmethylamino) -2- »§ -6-Acridine bicyclo [3 · 3 · 0] octane 5.0 g 〇IR (net) c IT1: 16 9 2 MS (m / z): 243 (MH +) ^ -NMR (CDC 1 3) ά: 4.39 ( t, 1 Η, J = 5.0Hz), 4.29-4. 10 (br, 1 Η), 3.98-3.70 (m, 3 Η), 2.99 (d, 2 Η, J 2 9.0 Hz), 2.93 ( s, 3Η), 2.25-2.07 (m, 1 Η), 1.88-1.74 (m, 1 Η), 1.73-1.64 (br, 1 Η), 1.48 (s, 9 Η) -45- (Please read the back first Please pay attention to this page and fill in this page again). U ___ 9— • Packing _, 1T J --- 5-. This paper is again applicable to China National Standard (CNS) Α4 Specification (2 0 × 297 mm) Employees of the Central Standards Bureau of the Ministry of Economic Affairs Consumer cooperatives 491848 A7 B7 braking five invention is described (uphill)

Example J (1R *, 5S *, 8R *, 8-trimethylacetamido-2-ming-6-azabicyclo [3 · 3 · 0] octane (Compound II: Ri = COCF3; R2, Ra , R4, Rs, Rs, R 9 = H; m = 0; n = 1; p = 0) 〇 [Process 1]: (1R *, 5 ^, 8S *) obtained in the process 5 (1) of Example A 8-amino-6-benzyl-2-fluorene-6-azepine [3 · 3 · 0] octane 4.8g was put into 150nl of dichloromethane, and after ice cooling, 6.9g of anhydrous trifluoroacetic acid was slowly added A 50β1 solution of dichloromethane. After stirring overnight, dichloromethane was added, the organic layer was separated, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the product was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1: 1). The ancestral crystal was recrystallized from a mixture of dichloromethane and n-hexane to obtain (1R *, 5R *, 8S *)-6-benzyl-8-trifluoroacetamido HI-6-azepine [3.3.0 ] 4.7 grams of octane.

Melting point: 1 5 β-1 5 4 ° C I R (KB r) cm-* 1: 3305, 1702, 1180 MS (m / z): 315 (MH +)

Ca) 〇30-4.6 ° (c = 1.0, methanol)! H ~ NMR (CDC 1 a) (5: 7.40-7.20 (m, 5 H), 6. 50 (br, i H) , 4.34 (dd, 1 H, J = 7.0 · 4.0Hz), 4.25-4.11 (m, 1 H), 3.98 -3.76 (m, 3 H), 3.58-3.46 (m, 2 H), 3.15 ( dd, 1H, J = 9.5, 6 · 0Ηζ), 2.33 (dd, 1H, J 2 9.5, 7.0Hz), 1.94-1.64 (m, 2 H) -46- This paper size applies to the Chinese national standard (CNS 蟢i 2iOx 297 mm) (Please read the notes on the back before filling this page)

、 1T # 1 491848 Printed by A7 ____ B7 in the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (4J :), [Process 2] Dissolve 6.0 g of the compound obtained in the previous process 1 in ethanol 100bI, add 10% Pd-C 60 0ttg, after absorbing the theoretical amount of hydrogen at 50 ~ 60 ° C, filter the catalyst, evaporate the solvent under reduced pressure, and recrystallize from chloroform-n-hexane to obtain the target (1R *, 5S *, 8R *)- 8-trifluoroacetaldehyde amino m-6-acylbicyclo [3.3.0] octane 4.0 g. Melting point: 1 0 6-1 10 ° C IR (KBr) cm * 1: 3319, 1706, 1559, 1180 MS (m / z): 225 (MH +) Ca) D 30-40.5. (C = 1, 00, methanol) 1H — NMR (CDC 1 3) δ: 6.69 (br, 1 H), 4.34-4. 21 (m, 2 H), 4. 08-3. 72 (m , 3 H), 3. 28 (dd, 1 H, J = 1L0.5.0Hz), 2.90 (ddd, 1 H, J = 11.0. 3.5, 1.0Hz), 2.24-2.05 (m, 1 H), 1.85 -1.68 (m, 2 H) Example K (1R11,5S *, 8S *)-8- (Third butanecarbonylamino) -3-methyl-2 · 0] Octane (Compound II: Ri = Boc; R2, IΪ3, Rs, R8, ^ 9 = H; R4 = Me; 1 = 0; n = 1; p = 0) [Process 1]: To D-tartaric acid (31 ^, 48 *, 51 ^)-5-allyl-1-benzyl-3,4-bis (31 ^, 48 *, 51 ^) manufactured by J. Org · Chea.U, 103-108 (1995) Tertiary butyl dimethylsilyl gas group)-2-Pyrrolidone 150 g of ethanol 500 ml and concentrated hydrochloric acid 2 Q m 1 of the mixture was stirred and heated at 50 ° C for 2 days, then concentrated under reduced pressure and -47- pack-( Please read the notes on the back before filling in this page) V__ 、 1Τ #, This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 491848 A7 ______B7_ 5. Description of the invention (6) Add water and wash with n-hexane Net, extracted with atmospheric imitation and dried over anhydrous magnesium sulfate, evaporated under reduced pressure After adding ether and n-hexane, the crystals were collected by filtration to obtain (311 *, 48 ||, 511 ||) -5-allyl-1-benzyl-3,4-dihydroxy-2-pyrrolidone 24. 8 grams. Melting point: 9 0-9 3 T: 1 R (KB r) cm -1: 3345, 1682 MS (m / z): 248 (MH +) ^ -NMR (C DC 1 3) δ: 7.38-7.14 (m , 5 H), 5.92-5.64 (m, 1 H), 5.27-4.95 (m, 4 H), 4.53-4.14 (m, 3 H), 3.99 (d, 1 H, J = 15.0 Hz), 3.62 -3.47 (m, 1 H), 2.60-2.26 (m, 2 H) [Process 2]: 15 g of compound obtained in process 1 before dissolving in 50 G ml of dichloromethane, 45 g of sodium iodide and 18-crown-6 5 grams, stir vigorously under ice cold, slowly add 500ul of dichloromethane solution of 19.5 grams of isobenzoic acid, and stir overnight at room temperature, add chloroform and NaOH water, separate the organic layer, and wash with sodium thiosulfate , Dried over anhydrous magnesium sulfate, distilled off the solvent under reduced pressure, and subjected to silica gel column chromatography (chloroform: methanol = 30: 1) to obtain (1R *, 5S ·, 8S *)-6-benzyl employees of the Central Standards Bureau of the Ministry of Economic Affairs Cooperative printed 13.8 g of base-8-hydroxy-3-iodomethyl-7-gas-2-pyrene-6-azepine [3.3.0] octane. IR (net) cm: 3364,1682 MS (m / z): 374 (MH +) ^ -NMRCCDCla) ^: 7.41-7. 19 (m, 5 Η), 4.93 (d, J = 14.5Ηζ) and 4 88 (d, J = 14.5Hz) total 1 Η, 4.64-4.32 (m, 2 Η), 4. 26-3. 84 (m, 3 Η), 3. 52 (brs, 1 Η) , 3. 30-3. 12 (m, 2 Η), 2.30-2. 13 (m, 1 Η), 1.74-1.54 (m, 1 Η)-48- (Please read the precautions on the back before filling (This page) This paper is in accordance with China National Standards (CNS) A4 specifications (21〇X 491848 Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs. 5. Description of the invention (47) [Process 3] The compound obtained in the previous process 2 14 grams dissolved in methanol 200®1, plus 4.9 grams of triethylamine and 1.4 grams of 5% Pd-C. After the theoretical amount of hydrogen was absorbed at room temperature, the catalyst was filtered off, the solvent was distilled off under reduced pressure, and water and chloroform were added. , The organic layer was separated, washed with dilute hydrochloric acid water and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain (1R *, 5S *, 8S *)-6-septyl-8-jingji-3 -Methyl-7-gas- 10.9 g of 2- fluorene-6-acylbicyclo [3 · 3 · 0] octane. IR (net) c-pass-1: 3351,1682 MS (ια / ζ): 2 4 8 (MH +) ^-NMR (CDC 1 3) (5: 7.41-7. 18 (m, 5 Η), 4.90 (d, 1 Η, J = 15.0 Hz), 4.45-4 · 31 (m, 3 Η), 4.18-3.87 (m, 3 Η), 2.20-1.95 (m, 1 Η), 1.48-1.20 (m, 4 Η) [Process 4]: 8.4 g of the compound obtained in the previous Process 3 was treated as in Example A, Process 4 to obtain (IR *, 5S *, 8ΙΤ) -8-dayyl 6.2 g of 6-fluorenyl-3-methyl-7-gas-2-ming-6-acylbicyclo [3.3.0] octane. IR (net) cm: 2108,1694 MS (m / z): 2 7 3 (MH +) 1 H-NHR (CDC1 3) δ: 7 · 4 1-7 · 1 8 (sister, 5Η), 5. 0 5 (d, J = 15 · 0Ηζ) and 4.98 (d, J = 15 · 0Ηζ) are 1H, 4.67 (dd, J = 5.0 6.00Ηζ) and 4.44 (t, J = 6.0Hz) are 1H, 4.24-3.87 (m, 4H), 2,32-2. 11 ( βι, 1Η), 1.74-1.39 (m, lH), 1.29 (d, J = 6.0 Hz) and 1.27 (d, J = 6.0 Hz) are 3H in total) [Process 5]: -49- (Please read the back first Please pay attention to this page and fill in this page again)-Binding and ordering 丨% 丨 4. Paper supply> 1 Qionghua uses the Chinese National Standard (CNS) A4 specification (210X297 mm) 491848 A7 B7_ V. Description of the invention (4) 8.2 g of the compound obtained in Process 4 was treated as in Process 5 of Example A to obtain (1R *, 5R *, 8R *)-6-benzyl-8- (third butanecarbonylamino) -3-methyl -2-1 Qin-6-Ding Shuanghuan [3 · 3 · 0] Xinyuan 10.1g. IR (net) cm · 1: 3447,1714 MS (m / z): 333 (MH +)! H-NMR (CDC 1 a) ： 7.34-7.21 (m, 5 Η), 5. 20 (brm, 1 Η), 4.57 (t, J = 6.0Hz) and 4.35 (t, J = 6.0Hz) are 1 H, 4.26-3.28 (m, 5 H), 2.99-2.45 (m, 2 H), 2.09 -1.60 (m, 2 H), 1.44 (s, 9 Η), 1. 32-1 · 21 (m, 3 H) [Process 6]: 9.7 g of the compound obtained in the previous process 5 is a simulated example The process 6 of A is processed to obtain the target (1R *, 5S *, 8S *)-8- (third butoxycarbonylamino) -3-methyl-2-Bqin-6-acylbicyclo [3.3.0 ] 6.7 grams of octane. IR (net) cm-1: 3317,1714 MS (i / z): 2 4 3 (ΜΗ +) 1 Η-NHR (CDC 1 3): 5 · 1 6 (d, J = 9 · 0 Η ζ) And 5 · 1 8 (d, J = 9 · 0Ηζ) are 1H, 4.19 (dd, J = 6.6, 5. · 4Ηζ) and 4M4 (t, J = 5. · 3Ηζ) are 1H, 3.99 (ddd, J = 9.0, 6_6, 6. · 4Ηζ) and 3.98 (dd, J = 6.6, 5. · 3Ηζ) are 1Η, 3.84 (ddq, J = 10.7, 5.2, 6 · 0 H z) and 4 · 1 0 (ddq, J = 9 · 4, 4 · 8, 6 · 0 H z) are 1 H, 3 · 8 0 (dddd, J = 1 0 · 6, 9 · 0, 6 · 6, 5 · 4 H z) and 3 · 8 9 (dddd, J = 1 0. 0, 9 · 0, 7 · 1, 5 · 3Ηζ) are 1H, 3.16 (dd, J = 11.3, 6.6 Hz) and 3.28 (dd, J = 11 · 3, 7.1Hz) total 1H, 2.54 (dd,

J = 11.3, 10 · 6Ηζ0 and 2.50 (dd, J = 11.3, 10 · 0Ηζ) are 1H-5 0-This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the back Attention, 丨 " " 0 Refill and install the intentions — write this page) Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 491848 A7 B7 V. Description of the invention (49)

, 2-38 (ddd, ί = 12.9m 9 · 〇, 5 · 2Ηζ) and uKddd, j = 12 · 9, 9 · 4, 6 · 6Ηζ) are 1H, 1.83 (s, lH), 1.45 ( s) and I44 (s) are 9H in total, i 26 (d J = 6 〇Hz) and i.23 (d J = 6 〇Hz) are 3H in total, 1 · 2 3 Udd, J = 12 · 9, 10 · 7, 6 · 4Hz) 1 · 97 (dd, J = 12 · 9, 4 · 8ΗZ) are 1H in total Example L UR *, 5S *, 8S *) -8- (Third butanecarbonylamino group) Monomethyl 3-Hydroxy-6-azabicyclo [3 · 3 · 〇] octane (Compound II: Ri: Boc; R2, R3, Re, 1Ϊ9 = H; R4 = Me; ii = 〇 ; N = 1; p = 0) [Process 1]: (1R *, 5S *, 8S *) obtained from Process 3 of Example K-6-benzyl-8-hydroxy-3-methyl-7-gas Uqin-6-azepine [3.3.0] octane 8.7 g was treated in the same manner as in Process A of Example A to obtain (1R *, 5S *, 8R ·) -6-benzyl-8-hydroxy-3 -Methyl-7-qi-2-Ming-6-azepine bicyclo [3 · 3 · 0] octane 6.4 g. Melting point: 98-101 ° CIR (KB r) cm 3388. 1692 MS (m / z): 248 (MH +) ^ -NMR (CDCla) δ: 7.40-7. 15 (m, 5 H), 5.03 (d , J = 15 · 0Ηζ) and 4.95 (d, J = l5.0Hz) are 1H, 4.60 (dd, J = 6.0, 6. · 0 · ζ) and 4.46 (dirty) are 5H, 3.17 (br d, J = 6.0Hz) and 3 · 1 2 (brd, J = 6 · 0 H z) * & 1Η, 2.32-2 · 10 (ιϊ, 1Η), 1.73-1.39 (m, lH), 1.26 ( d, 3H, J = 6.0Hz) -5 1-The size of this paper is applicable to Chinese specifications (2 丨 〇 > < 297 mm) (Please read the precautions on the back before filling this page) i Binding · Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 491848 A7 B7 V. Description of the invention (deduction) [Process 2] Example A is processed in process 4 to obtain (1R *, 5S *, 8S *)-8-azido-6-benzyl-3-methyl-7-gas-2-fluorene-7-acylbicyclo [3 · 3.0] 5.6 grams of nonane. Melting point: 7 0-7 3 X! IR (KB r) cm -1: 2122, 1690 MS (m / z): 273 (MH +) lH-NMR (C DC 1 3) 5: 7.41-7.19 (m, 5 H), 4.97 (d, 1 H, J = 15.flHz), 4.34 (dd, J = 6.0, 1.5 · ζ) and 4.22-3 · 89 (B) are 5H, 2.23-2 · 02 (·, 1Η), 1.48-1.28 (a, 1H), I. 26 (d, J = 6.0Hz) and 1.24 (d, J = 6.0Hz) are 3Η [Process 3]: the previous process 2 5.6 g of the obtained compound was treated in the same manner as in Example 5 to obtain (1R *, 5R *, 8S *)-6-benzyl-8- (third butanylcarbonylamino-3-methyl-2-mingle) -6-Acridine bicyclo [3 · 3 · 0] octane 6.8 g. Melting point: 56-60 X: IR (KB r) cm -1: 3369, 1700 MS (m / z): 333 (MH +) [Process 4]: 6.8 g of the compound obtained in the previous process 3 is processed as in the process 6 of the example A to obtain the target (1R *, 5S *, 8R *)-8- (third butoxycarbonylamino) -3 -methyl 2.8 g of 2-BI-6-acylbicyclo [3 · 3 · 0] octane.

Melting point: 69-72 ° C -52- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) — (Please read the precautions on the back before filling this page) | Binding · Order 491848 Ministry of Economic Affairs Central Standard Bureau Staff Consumer Cooperatives Benben A7 B7 V. Description of Invention (W) IR (KB r) cm 1 1: 3356, 1678 MS (m / z): 243 (MH +) — NMR (CDC 1 3) ά: 4.78 ( brs) Seven 5.23 (brs) are 1Η, 4.10 (β) and 4.37 (dd, J = 5.5, 2.00 · ζ) are 1H, 4.00 (tt) and 3.95U) are 1H, 3.90 (B) And 3.95 (a) are 1H, 3.79 (hep, J = 6.0 Hz) and 4.17 (») are 1H, 3.14 (dd, 1H, J = 11.5, 4.5Hz), 2.86 (br d, J = 1 1 · 5Hz) and 2 · 80 (dd, J = 1 1.5, 4 · 0Ηζ) are 1H, 2.33 (ddd, J = 13.0, 8. · 5, 6 · 0Ηζ) and 1.90 (br dd, J = 13.0, 5.00 · ζ) are 1 共, 1.93 (s, 1Η), 1.44 (s, 9H), 1.26 ((1, J = 6.0Hz), and 1.22 ( d, J = 6.0 Hz) for a total of 3H, 1.20 (ddd, J = 13.0, 10.5, 6 · 0Ηζ) and 1.60 (ddd, J = 13.0, 9.5, 6 · 5 Ηz) for a total of 1 Η Implementation Example M (1R *, 5R *)-8- (Third-butoxyamine methyl) -2-fluorene-6-azinebicyclic [3 · 3 · 0 ] Octane (compound II: Ri = Boc; R2, R3, R4 = H; »= 1; n = 1; p = 0) [Process 1]: obtained from Process 2 of Example A (1R *, 5S * , 8S *) -6-benzyl-8-hydroxy-7-gas-2- 丨 I-6-acylbicyclo [3 · 3 · 0] octane I5g was added to 300ml of dichloromethane, and triethyl under ice cooling Amine 16.3mι1, after adding dropwise methanoic acid 7.5 丨 1 and stirring overnight, water and dichloromethane were added, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain UR ", 5S #, 8S *) -6-Septyl-8-Methanesulfonylamino-7-Ga-2-Side-6-Acetyl-5-3-(Please read the precautions on the back before filling this page) --5 · This paper size applies to Chinese National Standard (CNS) A4 specifications (2 ... *) 491848 A 7 B7 5. Description of the invention (A) [3 · 3 · 0] octane 20 · 6 g. IR (Net) CIT1: 1714 MS (m / z): 312 (MH +) 1H-NMR (CDC13) 5: 7.42- 7.20 (m, 5H), 5.08 (d, 1 H, J = 1.5Hz), 4.91 ( d, 1 H, J = 15.0Hz), 4.61 (dd, 1 H, J = 6.0, 1.5Hz), 4.21-4. 10 (m, 1 H), 4. 12 (d, 1 H, 15.0Hz) , 3.98-3.68 (m, 2H), 3.28 (s, 3 H), 1.99-1.81 (m, 2 H) [Process 2] ·· 23.6 g of the compound obtained in the previous process 1 and 26 g of sodium cyanide and 18-crown-6 40.2 g was put into 800al of acetonitrile, and heated at 45 ° C for 5 days. After concentration under reduced pressure, ethyl acetate and water were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain (1R *, 5R *)-6-benzyl-8. -Cyano-7-gas-2-naphth-6-azabicyclo [3.3.0] nonane 6.3 g. IR (net) chT1: 2210,1714 MS (ι / ζ): 2 4 2 (MH +) — NMR (CDC 1 3): 7,45-7.22 (m, 5 H), 4.95 (d, 1 Η, 15 · 0Ηζ), 4.77 (dd, 1 Η, J = 7.0.0, 1.6 Hz), 4.31 (d, 1 Η, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the Note: Please fill in this page again) J = 15.0Hz), 3.94-3.67 (m, 2Η), 2.94 (dd, J = 7.0, 0.7Ηζ) and 2 · 8 5 (dd, J = 7 · 0, 0 · 7 Η z) is 1 Η, 2 · 6 9 (d, J = 1 · 6 Η z) and 2.6fl (d, J = 1.6 Hz) are 1H, 2.27-1.9 6 (m, 2H) [Process 3 〕 6.3 g of the compound obtained in the previous process 2 was added to tetrahydrofuran 200bi1, and borane-tetrahydrofuran complex 1.0M-tetrahydrofuran solution-54- was added under ice-cooling. This paper size applies Chinese National Standard (CNS) A4 specification (210X297). (Mm) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 491848 A7 B7 V. Description of the Invention (G) 104ml, heated for 30 minutes, and then refluxed overnight. After cooling to room temperature, the excess reagent was treated with ethanol and concentrated under reduced pressure. Ethanol 500 * 1 was added under reflux overnight. After concentrated under reduced pressure, 10% aqueous acid was added. Water leeches were collected separately, washed with ethyl acetate, hydrolyzed with 20% NaOH, extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, methanol 2G0II1 was added, and the mixture was ice-cooled, and then added with di-orthoic acid. 6.8 g of butyl ester was stirred at room temperature overnight, then concentrated under reduced pressure and then subjected to silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain (1IT, 5R *)-6-benzyl-8- ( The third butane carboamino group 2-Ming-6-acylbicyclo [3 · 3 · 0] octane 2. 7 g. IR (net) car1: 3359,1714 MS (m / z): 333 (MH +) ^ -NMR (CDC 1 3) 5: 7.30 (m, 5 Η), 5. 12 (brd, 1 H, J 2 9.0Ηζ), 4 · 18 (brd, 1 H, J = 5.5 Hz), 3 · 98 (ddd, 1H, J = 9.0, 7.7, 3.0Hz), 3.77 (d, 1H, J = 13.0Hz), 3.67 (ddd, 1H, J = 9 · 7, 9 · 0 · 5 · 5Ηζ), 3.50 (brdd, 1 H, J = 13.5, 9.0Hz), 3.35 (d, 1 H, J = 13. 0Hz), 3.14 (dd, 1 H, J = 13.5, 1 · 8Hz ), 2.80 (m, 1 H), 2. 50 (dd, J = 10. 8. 6. Ollz) and 2.46 (dd, J = 10.0, 7. 1Hz) are 1H, 2.14 (ddd, 1 H, J = 12. 5, 9. 7, 7. 5 Hz), 1.70 (m, 2 H), 1.50 (m, 1 H), 1. 46 (s, 9 H) (Process 4 : The resulting compound prior to the process 3 2J g was dissolved in ethanol lGOml, plus 5%

0.25 g of Pd-C, heated at 50 ° C, absorbed theoretical amount of hydrogen, filtered off catalyst, and distilled off the solvent under reduced pressure to obtain the purpose (1R ", 5R *) -8- (third butane carbonyl-55- this Paper size applies Chinese National Standard (CNS) A4 specifications! Door a · 297vt > (Please read the precautions on the back before filling this page) > Equipment · # 1 491848 A7 B7 V. Description of the invention (Kun)

Amine methyl) -2-11-6-azepine bicyclic [3.3.0] 1.8 g of octane Melting point: 5 9-6 7 ° CIR (KB r) cm -1: 3447, 1697 MS (m / z ): 243 (MH +)! H-NMR (CDC 1 3) ά: 5.00 (brs, 1 H), 4. 11 (m, 1 H), 3.94 (m, 1 H), 3. 73 (m , 1 H), 3.25 (m, 2 H), 3.07 (m, 1 H), 2. 98 (m, 1 Η), 2.03 (m, 1 H), 1.90 (m ) And 1.88 (m) are 1 H, 1.80 (m, 1 H), 1.77 (m, 1 Η), 1.63 (brs, 1 Η), 1.44 (s, 9 H). 1 7-[(lR *, 5R *, 8S *)-8-amino-2-fluoren-6-acylbicyclo [3 · 3 · 0] oct-6-yl] -1-cyclopropyl-6- Fluoro-1,4-dihydro-8-methoxy-4-chloroquinoline-3-carboxylic acid (1) The (1R *, 5S *, 8R *)-8- (Third-butyl) obtained in Example A Carboxylamido) -2-Ming-6-azinebicyclo [3.3.0] octane 0.96g and 1-cyclopropyl-6, 7-difluoro-1,4-dihydro-8-methoxy- 4-Gas β commanded 3-glycinic acid-BF 2 chelate 1.2g and triethylamine 0.69ial, added to dimethylarsine 13al, printed on the staff consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the back Note: Please fill in this page again) After stirring at room temperature for 5 days, add water to filter the crystals, add ethanol 60al, water 1 zu 1 and triethylamine 2 al, heated at 80 ° C, stirred overnight, concentrated under reduced pressure, added water and chloroform to separate the organic layer, dried over anhydrous magnesium sulfate, and evaporated the solvent under reduced pressure to obtain 7 _ [(1R *, 5R *, 8S ")- 8- (Third butanecarbonylamino) -2-^-6-azepinebicyclo [3.3.0] oct-6-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-8 -Methylamino-4-aminoquinoline-3-carboxylic acid 1.65 g. (2) Dissolve 1.65 g of the compound obtained in (1) in 4 il of ethanol, add 10% -56- The paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 491848 Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Print A7 B7__V. Description of the invention (β) 15 liters of hydrochloric acid water, stir and heat at 80 ° C for 3.5 hours, evaporate the solvent under reduced pressure, add 10% hydrochloric acid water to completely dissolve, and wash with chloroform. In addition to hydrochloric acid, add concentrated ammonia water until it is completely dissolved, and then wash it with gas imitation. After removing ammonia as much as possible under reduced pressure, neutralize with dilute hydrochloric acid to PH7. It was extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude crystals were recrystallized from a mixture of dichloromethane and ethyl acetate to obtain the target 7- [(1R *, 5R *, 8S *). -8-amino-2-hr-6-ΓΓ bicyclo [3 · 3 · 0] oct-6-yl] -1-cyclopropyl-6-gas-1,4-diaza-8-methylamino -4-Gamm-3-carboxylic acid. Melting point: 1 8 7-1 8 9.0 Example 2 The following compound was obtained by simulating Example 1. 7-[(lR *, 5R *, 8s *)-8-amino-2-carbox-6-azepine [3.3.0] oct-6-yl] -6-fluoro-l-[(lR, 2S) -2-fluorocyclopropyl] -1,4-dihydro-8-methylamino-4-carbazolin-3-carboxylic acid Melting point: 184-187 ° C Example 3 5-amino- 7-[(lR *, 5R *, 8S ·) -8-amino-2-oxo-6-azinebicyclo [3.3.0] oct-6-yl] -1-cyclopropyl-6,8-di Fluoro-1,4-dihydro-4-gas 1 «morpholine-3-carboxylic acid (1) The (1R *, 5S *, 8R *)-8- (third butoxycarbonylamino group) obtained in Example A Bu 2-B§-6-Azabicyclo [3 · 3 · 0] octane 1.5 g 5-amino-1-cyclopropyl-6, 7,8-trifluoro-1,4-dihydro- 4-Gas 1¾ Commands 1.75 g of 3-thanoic acid, 1,8-diazine bicyclic [5 · 4 · 0] -7-H-Sulene (DBU) 920ffig and -57- This paper size applies to Chinese national standards (CNS) A4 specification (210X297 public address) (Please read the precautions on the back--· 0 the remarks and fill in-install — write this page)

, TT -Lr I if 0 491848 A7 B7 V. Description of the invention (a) After heating the mixture of pyridine Ual at 6 (TC 16 hours, 8 (TC hours), the solvent was distilled off under reduced pressure, dissolved in chloroform, followed by cold The diluted acid and saturated brine were washed, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an oily substance. (2) The oily substance of (1) was mixed with 10% hydrochloric acid water 3.5ml and tetrahydrofuran 9ffil, After heating at 8G * C for 2 hours, the solvent was distilled off under reduced pressure, and water and 10% hydrochloric acid water 8nl were added for filtration. The filtrate was washed 3 times with chloroform 10.1, decanted with 10% NaOH water, washed 3 times with chloroform, and 10 % Hydrochloric acid hydrochloride is pH 8-9, extracted with chloroform, dried over anhydrous magnesium sulfate, distilled off the solvent under reduced pressure, and recrystallized from dichloromethane-ethyl acetate to obtain the title substance UlBg. Melting point: 258-263 ° C ( Decomposition) Example 4-38 The following compounds were obtained by simulating Example 1 or 3. (Please read the precautions on the back before filling this page) Binding and printing Remote Myanmar 阄 謇 窣 (CNS) A4 size (210X297 mm) 491848 A7 B7 V. Invention 呓 噚 (β Staff Consumption of Central Standards Bureau, Ministry of Economy Cooperative cooperative printing example ^ # 7 (CH2) VARXW tn B Melting point rc) 4 C-OMe nh2 H2N I in 1 — 253-257 (decomposed) 5 C-OMe ~ < Me H2N || h 1 0.5HC1 244- 247 (decomposition) 6 C-OMe ~ < j H MeHN 1111 1 1 201-203 7 C-OMe —FH H2N I in 1 1 121-125 8 C-OMe-< Me MeHN 1111 1 — 194-196 9 COMe-< nh2 MeHN 1111 1-227-230 10 C-OMe H H2N 丨 | 丨 丨 2 — 205-208 11 N 2,4-F2Ph H H2N || m 1 144-146 (Please read the Please fill in this page again for the matters needing attention) -59--The size of the binding and binding paper is applicable to China National Standard (CNS) Α4 specification (210 × 297 mm) 491848

7 B V. Description of the invention (w) Table 4 Example printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs νγ.Β (CH2) n, ARXW 9 n B Melting point (° c) 12 C-OMe-< nh2 H2N 丨| 丨 丨 2 — 253-255 (decomposition) 13 C-OMe nh2 h2n ► 1 — 260-263 (decomposition) 14 C-OCHF2-< H H2N III 丨 1 182-185 15 C-Cl-< H H2N || n 1 -130-135 16 C-OMe-< Me h2n ► 1 — 230-233 (decomposed) 17 N 2,4-F2Ph H MeHN 1 111 1 0. 1HC1 153-155 18 CF 4 H H2N j | M 1 0. 1HC1 218-223 19 C-OMe < 1 H h2n ► 2 — 196-198 —60— This paper size applies the Chinese National Standard (CNS) AOIL grid (2 丨 0 < 297 mm)丨 --- U --- §--Installation-- (Please read the precautions on the back before filling this page) Order #-• J-. 491848 A7 B7 V. Description of the invention (") Table 5 Ministry of Economy t 矣Printed by the Bureau of Standards and Consumers Cooperatives vAV— 〇 ^ na V · Β (CH2) n, ARXW 9 n B Melting point (° c) 20 C-Cl < H MeHN 1111 1-105-110 (decomposed) 21 CF < NH2 H2N ► 2 — 245-248 22 N < H H2N || n 1 — 230 -233 (decomposition) 23 C-OMe AH h2n ► 1 — 199-201 24 C-Me A Me H2N I III 1 one 205-213 (decomposition) 25 C-Cl -FH H2N || n 1 one 144-148 26 CH H H2N 丨 | 丨 丨 1 — 233-238 (decomposed) 27 CC = CH H H2N || h 1 — 232-234 (decomposed) Please read the note at the back first-61- This paper size applies to Chinese National Standard (CNS ) A4 size (210X297 mm)

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1 4I Bu I 491848

A B V. Description of Invention U. ) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Table 6 実 Example X 0. Ruler Ab (CH2) nf ARXW n 'B Melting point (° C) 28 C-〇Me (1 R. 2 S) H MeHN | | M 1 — 143-146 29 N 2,4-F2Ph H h2n ► 1 HC1 258-261 (decomposition) 30 C-CN Me h2n ► 2 — 260-265 31 C, e-p H h2n ► 1 — * 202-205 (decomposition) 32 C-OMe-< NH2 h2n ► 2 — 272- 276 (decomposed) 33 C-CH = CH2-< H H2N || i 丨 1 — 218-221 34 C-CN < H h2n ► 2 — 223-226 35 C-OMe < H MeHN ^ 1 — 174 -177 -62- (Please read the precautions on the back before filling out this page) This paper size applies Chinese National Standard (CNS) A4 specification (210X297 male * 491848 A7 B7 V. Description of invention (W) Table 7 実 例 例 X 0 wr-FAVc〇〇H 〇 ^ NAV-(CH2) nf ARXW η 'B Melting point (° C) 36 C-OMe < Me h2n ► 2 — 205-208 37 C-ochf2 H h2n ► 1 — 193-196 38 C-CN H H2N 丨 丨 丨 丨 1 — 144-148 (Please read the notes on the back 4 • Items and then fill in. Pack —: Write this page) Order Example 39 The same compound as Example 3 was obtained. 7- [(1R *, 5R *, 8S11, 8-amino-2-11-6-azabicyclo [3 · 3 · 0] oct-6-yl] -1- (2 , 4-difluorophenyl) = 6-fluoro-1,4-dihydro-5-methyl-4 -gas-1,8-leidan-3-caproic acid Melting point: 224-227 T (decomposition) Example 40 The following compound was obtained by imitating Example 1. 7-[(lR *, 5R *, 8R *)-8-amino-3-methyl-2-β-phenyl-6-azinebicyclo [3.3.0] Octyl-6-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methylamino- -4 -gasoline-3-carboxylic acid-63- This paper is applicable to China Standard (CNS) A4 specification (210X 297 mm):-Printed by the Employees 'Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 491848 A7 B7 5. Description of the invention (h) Melting point: 1 6 6-1 6 8 ° C Example 41 Following Example 1, the following compounds were obtained. lO-CUR11, 5ίΤ, 8s *)-8-amino-2-ming-6-acylbicyclo [3.3.0] oct-6-yl] -9-fluoro-2,3-dihydro- (3S)- 3-methyl-7-oxo-7H-pyridine hydrazone [1,2,3-de] [1,4] benzene hydrazone-6-carboxylic acid Melting point: 2 3 1-2 3 3 ° C Example 42 Following Example 3, the following compounds were obtained. 7-[(1R *, 5R *, 8R *)-8-amino-2H-6-azabicyclo [3 · 3 · 0] oct-6-yl] -1-cyclopropyl-6-fluoro-1 , 4-Dihydro-4-gas If leaching-3-carboxylic acid Melting point: 2 3 8-2 4 1 ° C (decomposition) Example 4 3 Following Example 1, the following compounds were obtained. 7-[(1R *, 5R *, 8S *)-8-Amino-2-1qin-6-azinebicyclo [3 · 3 · 0] oct-6-yl] -1-cyclopropyl-6- Fluoro-1,4-diargon-8-methylthio-4-gas B quinoline-3-carboxylic acid Melting point: 226-228 ° C (decomposition) Example 44 The following compound was obtained by simulating Example 3.

1- (3-amino-4,6-difluorophenyl) -7-[(11 **, 51 {*, 83 *)-8-amino-2-fluorene-6-B yambicyclo [3.3 .0] oct-6-yl] -6-gas-1,4-dihydro-4-oxo-1, 8-pyridin-3-carboxylic acid Melting point: 1 6 0-1 6 3 ° C -6 4-This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) (Please read the notes on the back before filling out this page) # 1 J. 491848 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 «B7 V. Description of the invention (W) Example 45 The following compounds were obtained by simulating Example 1. 7-[(ΠΤ, 5R *, 8S *, 8-amino-3-methyl-2-1, etc.-6-azabicyclo [3.3.0] oct-6-yl] -1-cyclopropyl-6 _Fluoro-1,4 -bis-8 _Metrazyl-4-gas 丨 Quinolin-3-carboxylic acid Melting point: 1 0 9-1 1 2 ° C Example 4 6 Imitating Example 3, the following Compound 7-[(lR *, 5R *)-8-Aminemethyl-2-Ming-6-azinebicyclo [3.3.0] oct-6-yl] -1- (2,4-difluorophenyl 6-Fluoro-1,4-dihydro-4-oxo-1,8-pyridine-3-carboxylic acid Melting point: 2 3 0-2 3 3 ° C Example 47 The following compounds were obtained by simulating Example 1. 5-Amino 7-[(lR *, 5R *, 8S *, 8-Amino-2-Ming-6-Azabispyrene [3 · 3 · 0] oct-6-yl] -6-fluoro- l-[(lR, 2S) -2-fluorocyclopropyl] -1, 4 -dihydro-8-methylamino-4-gas Fluoro-3-carboxylic acid Melting point: 2 5 3-2 6 0 ° C (decomposition) Example 48-56 The following compounds were obtained by imitating Example 1 or 3. (Please read the precautions on the reverse side before filling out this page) CNS) A4g (210X297 mm) 491848 A7 B7 V. Description of invention (W) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 8 実 例 X 〇w ^ fotcooh 〇 ^ NAV-(CH2) n, ARXW * n B Melting point (° c) 48 N 3-NH2 ~ 4.6-F2Ph Me IUN 1 2IIC1 266-268 49 CC = CH H H2N 2 one 133-138 (divide angle?) 50 CH 3-NH2-4,6 -F2Ph Me h2n 1 205-207 —66— (Please read the precautions on the back before filling this page) • Installation ·

、 1T # ·· This paper size applies to Chinese National Standard (CNS) A4 specification (210X297mm) 491848 A7 B7 V. Description of the invention Table 9 printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Thousands of Economics ^ NAV-(CH2) n · ARXW% n B Melting point (° c) 51 CH 3-NH2-4, 6-F2Ph nh2 II2N 1 — 200-203 52 C-OC2H5 H H2N 1-97-100 53 C-OCH2 1 CH2F < 1 H h2n 1 HC1 216-219 (decomposition) 54 C-OMe OH h2n 1 HC1 233-236 (decomposition) 55 CH 3-NH2-4. 6-F2Ph NH2 MeHN 1-233-236 (minutes) ) 56 C-OCH2 1 CH2F human NH2 H2N 1 234-237 (decomposed) _6 7 — equipment-(Please read the precautions on the back before filling out this page), 11 This paper is applicable to the standard > A4 specification (210X297 mm) 491848 A7 B7 V. Description of the invention (W) Example 57 Θ 7-[(lR *, 5R * JS *)-8-amino-2-ming-6-azine [3 · 3 · 0] oct-6-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-air βquinol-3-carboxylic acid (1) In an argon stream, mix diisopropylamine 23.8μ1 and tetrahydrofuran 3 0 0 channel 1

At -78 * ^, a solution of n-butyllithium in hexane (1.63M) 100β1 was added dropwise. After stirring for 15 minutes at the same temperature, a mixture of 33.4 g of 2- (2,4,5-trifluorophenyl) -4,4-dimethyloxazoline and tetrahydrofuran 150 »1 was added dropwise. After stirring at the same temperature for 30 minutes, 29nl of ethyl formate was added dropwise. After 1 hour, the temperature was gradually increased, and ammonium vaporization was added at about -10eC. It was extracted with ethyl acetate and washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, isopropyl ether was added, and crystals were collected by filtration to obtain 2- (2,4,5-trifluoro-3- Formamylphenyl) -4,4-dimethyl-2-oxazoline 21 1.6 g. Melting point: 115-117 ° C (recrystallized from ethyl acetate-n-hexane> IR (KB r) cm -1: 1697, 1624 —NMR (CDC 1 3) 5 ·· 10.36 (ηκ 1 Η), 7 · 98 (m, 1 Η), 4.13 (s, 2 Η), 1.40 (s, 6 Η) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the notes on the back before filling out this page (2) A mixture of 15.8 g of the compound obtained in (1) and 220H1 10% hydrochloric acid water was heated under reflux for 4 hours. After cooling, it was extracted with ethyl acetate and washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. N-hexane was added and the crystals were collected by filtration to obtain 12.0 g of 2,4,5-trifluoro-3-methylfluorenylbenzoic acid.

Melting point: 147-148 ° CIR (KB r) cm -1: 3062, 1687, 1618 ^ -NMR (DMSO-de) 5: 13.84-13.64 (br, 1 Η), 10.2 · (0, m, 1 Η), 8.19 (m, 1 H) -68- This paper size applies to the Chinese National Standard (CNS) Α4ϋ 格 (210 X 297 mm) 491848 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Explanation (π) (3) 12.0 g of compound obtained in (2), 8.9 g of potassium sulphate, and methylformamide 120 »1, plus benzyl bromide 7.7.1, at room temperature After stirring for 6 hours, add 10% hydrochloric acid water, extract with ethyl acetate, wash with saturated® acid water and saturated brine, dry with anhydrous sodium sulfate, distill the solvent off, and then use silica gel column chromatography (chloroform). And recrystallized from ethyl acetate-n-hexane to obtain 13.4 g of benzyl 2,4,6-trifluoro-3-formylbenzoate. Melting point: 7 0-7 1 eCI R (KB r) cm -1: 1731, 1710, 1622 ^ -NMR (CDC 1 a) 5: 10.35 (m, 1 Η), 8.05 (m, 1 Η), 7.44 (m, 5H), 5. 46 (s, 2 H) (4) To 100 ml of acetonitrile, add 6.15 g of the compound obtained in (3), obtained from Example A) (11 {*, 5S *, 8R *) -8- (Third butanecarbonylamino) -2-Ming-6-azepine [3.3.0] 5.25 g of octane and 2.8 g of triethylamine. After stirring at room temperature for 7 days, reduce Concentrate under pressure, add water and ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. • Chromatographed on a silica gel column (gas-form: methanol = 50: 1) to obtain 4-[(1ϋ *, 5R *, 8S *)-8- (Third butanecarbonylamino acridine [3.3.0] octane-6-yl] -3 -methylamido-2,5-difluoro-benzoic acid. 9.81 g. Melting point: 6 1-6 3 ° C IR (KBr) ciB " 1: 3368,1712,1681,1619MS (m / z): 503 (MH +)! H-NMR (CDC 1 a) ά: 10.30 (d, 1 H, J = 3 · 0Hz), 7.78 (dd, 1 H, J = 14. 0, 7. 0Hz), 7. 49-7. 33 (m, 5 H), 5. 38 (s, -69- (Please read first (Notes on the back then fill out this page)

、 1T .4 • l ·. This paper size applies to Chinese National Standard (CNS) Λ4ΙΜΙ 2 丨 公 #) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 491848 A7 B7 V. Description of the invention (^) 2 Η), 5. 01 (brs, 1 H), 4. 87 (brs, 1 H), 4. 43 (d, 1 H, J = 4.0 Hz), 4.30 (brs, 1 H), 4. 03-3. 80 (ni, 3 II), 2. 94 (brd, 1 H, J = 12.0 Hz), 2. 09-1 · 86 (m, 1 H), 1. 79-1 · 61 (m, 1 H ), 1.43 (s, 9H) (5) 8.78 g of the compound obtained in (4) was added to 100 ml of methanol, 330 bg of sodium borohydride was added slowly and ice-cooled, and after stirring for 2 hours, acetone was added to concentrate under reduced pressure. Water and ethyl acetate were added. ester. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate and n-hexane were added to obtain 4-[(lR #, 5R *, 8S *)-8- (third butanecarbonylamino group). ) -2-Hydroxy-6-azabispyridyl [3.3.0] oct-6-yl] -2,5-difluoro-3-hydroxymethylbenzoate 4.23 g. The filtrate was subjected to silica gel column chromatography (chloroform: methanol = 100: 1) to obtain 1.3 g of the above compound. Melting point: 1 3 9-1 4 2 ° CIR (KB r) cm -1: 3331, 1681 MS (m / z): 429 (MH +) 1H —NMR (CDC 1 3) ά: 7.58 (dd, 1 H , J 2 13. 0, 7.0 Hz), 4.93-4.76 (m, 3H), 4.68 (t, 1 H, J-5. 0Hz), 4. 44 (d, 1 H, J = 5.0Hz), 4. 17 (brs, 1 H), 4.02-3.82 (m, 3 H),

3.93 (s, 3H), 3.17 (d, 1 H, J 20.0Hz), 2.35 (t, 1 H, J = 5.0Hz), 2.01-1.65 (m, 2 H), 1.45 (s (9H) (6) Add 250g of digas methane to 6.2g of the compound obtained in (5) and 3.12g of triethylamine, add 2.0g of methanesulfonyl chloride in ice-cold, and stir at room temperature overnight, add water and chloroform, Separate the organic layer, dry over anhydrous magnesium sulfate, evaporate the solvent under reduced pressure, and perform column chromatography on silica gel (n-hexane: ethyl acetate = 4: 1) to get -7 0-This paper is in accordance with Chinese National Standards (CNS) A4 specifications (21〇X297 mm) 丨 * ----- £-: (Please read the precautions on the back before filling out this page) • Equipment · 11 491848 A7 __B7_ V. Description of the invention (Μ) 4- [(LR *, 5R *, 8S *)-8- (Third-butanecarbonylamino) -2-pent-6-azabicyclo [3 · 3 · 0] oct-6-yl] -3-chloroform Methyl-2,5-difluorobenzoate 5.81 g. IR (net) ci · 1: 3376, 2979, 1718 MS (ιώ / ζ): 447 (ΜΗ +) ^ -NMR (CDC13) 5: 7.63 (dd, 1 H, J = 13. Ο, 7 · OHz), 4.80 (brd, 1 H, J = 7.0 Hz), 4.71 (d, 2 H, J = 2.0 Hz), 4.66 (brs, 1 H), 4.46 (d, 1 H, J = 5.0Hz), 4.20 (brs, 1 H), 4.02-3.83 (m, 3 H), 3. 93 (s, 3 H), 3.13 (dd, 1 H, J-10.0, 2.0Hz), 2.00 -L68 (m, 2 H), 1.45 (s, 9 H) (7) 5.81 g of compound obtained by dissolving (6) in tetrahydrofuran 2fl0ial and 1.46 g of triethylamine, add 10% Pd-C 3 0 0 ag, in After the theoretical amount of hydrogen was absorbed at 40 ° C, the catalyst was filtered off, the solvent was distilled off under reduced pressure, and water and ethyl acetate were added. The organic layer was fractionated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 4-[(1R *, 5ΙΤ, 8S *)-8- (third butanecarbonylamino) -2- 枵 -6-acryl. 5.6 g of bicyclo [3.3.0] octyl-6-yl] -2,5-difluoro-3-methylbenzoate. IR (net) cm-1: 2977,1715 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) MS (m / z): 413 (MH +), /! H ~ NMR (CDCla) δ: 7.46 (dd, 1 Η, J = 13.0, 7.0 Hz), 4.75 (brs, 1 Η), 4.58 (t, 1 Η, J-5. Ollz), 4.45 ( d, I Η, J = 5. ΟΗζ), 4.18 (brs, 1 Η), 3.99-3.81 (m, 2 Η), 3.91 (s, 3 Η), 3.04 (dd, 1 Η, J = 1〇 · 〇, 2 · ΟΗζ), 2 · 22 (d, 3Η, J 2 · 0Ηζ), 1.92-1.55 (m, 2Η), 1.47 (s, 9Η) -7 1- This paper size applies to China National Standard (CNS) A4 specification (210 × 297 mm) 491848 A7 B7 V. Description of the invention () (8) 5.6 g of compound obtained in (7) plus ethanol 70 · 1 and IN NaOH water 40 pass 1 at room temperature After stirring for 2 days, ethanol was distilled off under reduced pressure, and water was added to make it weakly acidic with 10% acetic acid water under ice-cooling. The crystals were collected by filtration to obtain 4-CUR11, 5R *, 8S *) -8- (Third butanecarbonylamino) U§-6-Azabicyclo [3.3.0] oct-6-yl] -2,5- 3.7 g of difluoro-3-methylbenzoic acid.

Melting point: 1 0 8-1 1 0 eC IR (KB r) cm -1: 3370, 2979, 1698 MS (m / z): 399 (MH +) ^ -NMR (CDCla) δ: 7.50 (dd, 1 H , J = 13. 0, 7. 〇Hz), 4.91-4.52 (br, 2 H), 4.45 (d, 1 H, J = 5.〇Hz), 4.18 (br s, 1 H), 4.05-3.79 (m, 3 H), 3.30-3.00 (br d, 1H, J = 10.0Hz), 2.24 (d, 3H, J = 2.0Hz), 1.98-1.56 (m, 2H), 1.47 (s, 9 H) (9) Dissolve 2.94 g of the compound obtained in (8) and 1.38 g of 1,: T-carbonyldioxazole in tetrahydrofuran 4Dal, stir it at 50 ° C overnight, and inject it with ice-cold potassium potassium malonate A solution of 1.77 g, 1.2 g of magnesium chloride and 2.65 g of triethylamine dissolved in ethyl acetate 40ail and stirred overnight at room temperature. After stirring at room temperature overnight and 5G ° C for 2 hours, ice water was added and acidified with 10% hydrochloric acid. Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Extraction with ethyl acetate and drying over anhydrous magnesium sulfate, evaporation of the solvent under reduced pressure, addition of isopropyl ether, and filtration of the crystals, Obtain 4-[(llT, 5R ", 8S _)-8- (Third-butanecarbonylamino) -2-o-6-azepine [3.3.0] oct-6-yl] -2, 5- Difluoro-3-methylbenzaldehyde ethyl acetate 2.24 g. The filtrate was chromatographed on a silica gel column (aeroform) to obtain 0.25 g of the amidine compound.

Melting point: 1 3 1-1 3 4 ° C -72- Paper body, degree 4 «Medium * W family sample standard (CNS) A4 specification (210X297 mm) 491848 A7 B7 _ V. Description of the invention (V) IR (KB r) cm -1: 3366, 1682, 1526 MS (m / z): 469 (MH +) (10) 2.24 g of compound obtained in (9), 1.07 g of ethyl n-formate and 1.23 of acetic anhydride G, stirred and heated at 150 ° C for 2 hours, concentrated under reduced pressure, added chloroform 2Gb1, and added 0.3 g of cyclopropylamine under ice cooling. After stirring at room temperature overnight, it was heated at 50 ° C for 3 hours. After concentration under reduced pressure, ethyl acetate and water were added. The organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to dissolve in a silica gel column chromatography (aerosol: methanol = 20: 1) to obtain 2-[(lR *, 51T, 8S *)-8- ( Tributylcarbonylaminoacylbicyclo [3 · 3 · 0] oct-6-yl] -2,5-difluoro-3-methylbenzylfluorenyl] -3-fluorenylaminoacrylic acid ethyl ester 2.9 g.

Melting point: 7Z-7 5V IR (KBr) cm -1: 3452, 2977, 1700, 1623 MS (m / z): 536 (MH +) (11) 2.9 g of the compound obtained in (10) and ferric acid Put 1.5 g of potassium into dioxane 4 0 b 1, heat 9 ° C and stir overnight. After concentrating under reduced pressure, add water and chloroform. Separate the organic layer, dry over anhydrous magnesium sulfate, evaporate the solvent under reduced pressure, and place in a silica gel column. Chromatography (chloroform: methanol = 100: 1), get 7-[(1R ·, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) 5R *, 8S *)- 8- (Third Butane Carboxamido) -2-Ban-6- 丨 Yamidine [3.3.0] Octan-6-yl] -1-Cyclopropyl-6-Ga-1,4 -Digas -8-Methyl-4-Gas Bf leaching-3-carboxylic acid ethyl ester 2. 12 g. Melting point: 1 1 5-1 1 8 X: (decomposition) -73- This paper size applies to Chinese national standards (CNS ) Α4 size (210 × 297 mm) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 491848 A 7 B7 V. Description of the invention (W) IR (KB r) cm -1: 3509, 2976, 1700, 1615 MS (m / z): 516 (MH +)! H-NMR (CDC 1 a) ά: 8.67 (s, 1 H), 7.95 (d, 1 H, J = 14 · 0Hz), 4.75 (brs, 1 H), 4.70 (t, 1 H, J-5.0Hz), 4. 48 (d, 1 H, J = 5.0 Hz), 4. 40 (q, 2 H, J = 7. 0Hz), 4.23 (brs, 1 H), 4.07- 3.81 (m, 4 H), 3.08 (dd, 1 H, J 2 10.0, 2.0Hz), 2.63 (s, 3 H), 2.00-1.58 (m, 2 H), 1.47 (s, 9H), 1.42 (t, 3 H, J = 7.0 Hz), 1.38-0.70 (m, 4 H) (12) Put 2.1 g of the compound obtained in (11) into a mixture of ethanol 50 m 1 and 10% hydrochloric acid water 20 b 1, and heat 8G * C and stirred for 4 hours, concentrated under reduced pressure, added water and neutralized with 10% NaOH. After aerated imitation, the organic layer was separated, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and dichloromethane and ethyl acetate were added. Ester, slowly distilling off methane gas. The crystals were collected by filtration, and washed with diethyl ether to obtain the target 7-[(lR *, 5R ·, 8S *)-8-amino-2-^-6-azabicyclo [3.3 .0] octyl-6-yl] -1-fluorenyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid 900nge Melting point: 1 1 4 -1 1 7 ° C Example 58 The following compound was obtained by simulating Example 3. 7-[(lR *, 5R *, 8S *)-8-Amino-Acridinebicyclo [3 · 3 · 0] oct-6-yl] -1- (2,4-difluorophenyl) -6 -Fluoro-5-hydroxy-1,4-dihydro-4-gas-1,8-pyridine-3-carboxylic acid Melting point: 258-263 ° C (decomposition) Example 59 -74- Applicable to this paper size Chinese National Standard (CNS Mil 蟢 (21OX 297 mm) (Please read the notes on the back before filling this page)

491848 A7 B7 V. Description of the invention (W) Following Example 1, the following compounds were obtained. 5-Amino-7-[(lR ·, 5IT, 8S *, 8-Amino-2-Ming-6-Azabicyclo [3 · 3 · 0] oct-6-yl] -1-fluorenyl- 8-Ethyl-6-Ga-1,4-dihydro-4-Ga-Phenolin-3-carboxylic acid Melting point: 2 1 7-2 2 0 ° C Example 60 The following compounds were obtained by imitating Example 3 5-amino-7-[(lR *, 5R *, 8S *)-8-amino-2-fluoren-6-acylbicyclo [3.3.0] oct-6-yl] -1- (2, 4-difluorophenyl) -6-gas-1,4-dihydro-4-oxo-1,8-lean-3-unacid melting point: 2 6 7-2 7 0 ° C (decomposition) Implementation Example N: Method for preparing lozenges 丨 ... ih._ | ^ _ 丨 »1II (Please read the precautions on the back before filling this page) The compound of Example 1 250 grams of corn starch 54 grams of carboxymethyl fiber 40 grams of calcium calcium, 50 grams of microcrystalline cellulose, 6 grams of magnesium stearate, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, and mixed the above ingredients with ethanol. 0 0 0 0 0 lg of tablets 2 0 0 tablets. Industrial applicability The compound (I) of the present invention can be used as an antibacterial agent for humans and animals, and the bicyclic amine compound (II) can be used as a direct compound (I). Synthetic intermediate. -75- Paper size Applicable to China National Standard (CNS) A4 specification (210X297 mm)

Claims (1)

491848 7T. Patent application No. 861 12167 “Pyridonecarboxylic acid derivatives and their synthetic intermediates” (Amended on January 24, 91) Patent application scope: 1. A derivative of pyridonecarboxylic acid of the following formula (I) (I) where R is Ci_3 alkyl or C3_5 cycloalkyl (these groups may be substituted with 1 halogen), or phenyl (the group may be substituted with Ci _ 3 Alkyl-substituted amine and / or halogen), X is fluorene, hydroxy, C 1 _ 3 alkyl or amine, printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) ) X COOH Υ is Η or halogen, Α is N or CZ, Z is H, halogen or cyano, or 1-4 alkoxy which may be substituted by halogen, C1-3 alkyl, 0 ^ -3 alkylthio, C2_3 alkenyl Or C2-3 alkynyl, or a bridge that forms -0-CH2-CH (CH3) _ with R, R! And R2 are the same or different, each is H, or C〗 _3 alkyl, suitable for small paper sizes 491848 A'8 B8 C8 D8 VI. Patent application scope R3 is Η, 114 is Η or C ^ -3 alkyl, (Please read the precautions on the back before filling this page) R5 ~ R9 are Η, ηι is 〇 Or 1, η and ρ are the same or different, each being 0 or 1, but not 0 at the same time. 2. The pyridonecarboxylic acid derivative and its esters and salts according to item 1 of the application, wherein R is a C3_5 cycloalkyl group which may be substituted with one halogen, or a phenyl group substituted with halogen and / or amine. 3. The pyridonecarboxylic acid derivative and its esters and salts according to item 1 of the application, wherein Y is fluorine. 4 · If the pyridonecarboxylic acid derivative and its esters and salts of item 1 of the patent application range, where A is N or CZ and Z is H, halogen, cyano, ~ monoalkoxy, C! _3 alkyl, C2_3 alkenyl or C2_3 alkynyl. 5. The pyridonecarboxylic acid derivative and its esters and salts as described in the first item of the patent application, wherein R4 to R9 are each H. 6. The pyridonecarboxylic acid derivative and its esters and salts according to item 1 of the application, wherein R is cyclopropyl, 2-fluorocyclopropyl, 2,4-difluorophenyl or 3-amino group- 4,6-difluorophenyl, X is fluorene, Shenyl, hydroxy or amine, printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Υ is chlorine 'Α is N or CZ and Z is Η, fluorine, chlorine, cyanide Group, methoxy, difluoromethoxy, ethoxy, 2-fluoroethoxy, methyl, methylthio, vinyl or ethynyl, 1 ^ 1 and R2 are the same or different, each of Η is Methyl, R3 is H, R4 to R9 are each η, and η is 1. 7 · —Bicyclic amine compounds of the following formula (II) or their salts: The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 491848 Αδ Β8 C8 D8 6. Scope of patent application Rl and R2 in the printed format of the Employees' Cooperative in the Intellectual Property Bureau of the Ministry of Economic Affairs are the same or different, each being Η, Cb3 alkyl or an amine protecting group which can be removed by hydrolysis, R3 is Η, and R4 is H or Cl _ 3 alkyl R5 to R9 are each Η, m is 0 or 1, η is the same or different from P, each is 0 or 1, but not 0 at the same time. 8. If the bicyclic amine compound and its acid addition salt of item 7 of the scope of patent application 'are among them! ^ And R2 are the same or different, each is Η, a 0 __3 alkyl group or an amine protecting group which can be removed by hydrolysis, r3 is Η, and R4 to R9 are each Η ′ η is 1. 9. The bicyclic amine compound and its acid addition salt according to item 7 of the scope of patent application, wherein R1 and R2 are the same or different, and each is a fluorene, a methyl group, a third butoxycarbonyl group or a trifluoroethylfluorenyl group, and R3 Is H, R4 ~ R9 are Η, η is (please read the precautions on the back before filling this page), 1T This paper size is applicable to China National Standard (CNS) A4 specification (210 × 297) Chu 491848 A8 B8 C8 D8 Six 2. Application scope of patent 1 〇—A kind of medicinal composition for bacterial diseases of humans or animals, containing pyridonecarboxylic acid derivatives such as the scope of application for patent No. 1 and its ester content is as effective as salt, salt, etc. This or n ϋ I ϋ nnnn II ϋ ϋ · n ϋ n I— nnn one. -n n I ϋ I ϋ I · (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm)