CN112812098A

CN112812098A - Preparation method and medical application of unsaturated cyclic amine pyridine disulfide derivative

Info

Publication number: CN112812098A
Application number: CN202110040050.2A
Authority: CN
Inventors: 艾海马; 张卫锋; 冯美香; 王磊; 贾晓栋
Original assignee: Beijing Voban Pharmaceutical Technology Co ltd
Current assignee: Beijing Voban Pharmaceutical Technology Co ltd
Priority date: 2021-01-13
Filing date: 2021-01-13
Publication date: 2021-05-18

Abstract

The invention relates to the field of medicinal chemistry, in particular to a series of unsaturated cyclic amine pyridine disulfide derivatives, and also discloses a preparation method and medical application of the compounds. The invention discloses novel unsaturated cyclic amine pyridine disulfide derivatives, a preparation method and application thereof for the first time, and the derivatives are particularly used for treating atherosclerosis diseases, myocardial infarction, stroke, peripheral artery diseases, acute coronary syndrome and thrombosis during anti-angiogenic surgery.

Description

Preparation method and medical application of unsaturated cyclic amine pyridine disulfide derivative

Technical Field

The invention relates to the field of medicinal chemistry, in particular to a series of unsaturated cyclic amine pyridine disulfide derivatives, and also discloses a preparation method and medical application of the compounds.

Background

The cardiovascular and cerebrovascular thrombotic diseases are common diseases, and the incidence rate of the thromboembolic diseases mainly including coronary artery thrombosis and cerebral thrombosis is on the rise in recent years, which seriously harms human health, so the research on the prevention and treatment of the diseases is very important. Platelet aggregation is a key link in the normal coagulation mechanism, but platelet adhesion and aggregation are also the initiation links of thrombus formation. Therefore, drugs that inhibit platelet aggregation play an important role in the treatment of thrombotic diseases (Stroke,1999, 30: 878). Anti-platelet aggregation drugs have been the focus of research.

Clopidogrel (Clopidogrel) developed by Senofura pharmaceutical company, France, is currently the most widely used anti-platelet aggregation drug worldwide. Clopidogrel is a prodrug. Early in vivo metabolism studies showed that clopidogrel undergoes two-step oxidation by the liver P450 enzyme system in vivo, with ring-opening metabolism to produce an active metabolite of an unsaturated cyclic amine structure (shown below). Active metabolites and platelet surface P2Y12 receptors form covalent binding, and inhibit platelet aggregation by antagonizing P2Y12 receptors (Thromb Haemost,2000, 84: 89D. Nippon Sancosmopharmacy company and American Gift pharmaceutical company develop a new generation of antiplatelet Drug Prasugrel (Prasugrel) on the basis of clopidogrel structure, Prasugrel is also a prodrug. early in vivo metabolism research discovers that Prasugrel forms an active metabolite with a saturated cyclic amine structure through esterase hydrolysis and oxidative ring opening of a P450 enzyme system in vivo, and antagonizes antiplatelet P2Y12 receptors (Drug Metab Dispos, 2007, 35: 1096).

In 2012, french researchers found that clopidogrel is metabolized not only into an active metabolite of a saturated cyclic amine structure but also into a metabolite of an unsaturated cyclic amine structure which is transferred with a small amount of double bonds through other esterases in vivo (Chem Res Toxicol,2012, 25: 348). The anti-platelet activity of the metabolites with unsaturated cyclic amine structures in vivo and in vitro is not reported in the literature so far. Clopidogrel, DT678, 2DT678 and unsaturated cyclic amine pyridine disulfide derivatives are metabolized into H4 derivatives in vivo and have anti-platelet activity in vitro and in vivo. The discovery of the Chengqing of the university of Michigan in 2015 shows that the drug effect of disulfide DT-678 formed by combining an active body of clopidogrel and 3-nitropyridine is 10 times that of clopidogrel, but 3-nitropyridine has genotoxicity and reproductive toxicity, and a series of derivatives such as pyridine, high pyridine, nicotinic acid ester and the like are designed to replace 3-nitropyridine, so that the drug effect is improved by 15 times, and the genotoxicity and the reproductive toxicity are avoided.

Based on the structure of saturated cyclic amine metabolites, three companies in Japan have filed a number of patents, such as W098088H, W09943648, and W09943648. These patents protect a series of derivatives with saturated cyclic amine structure and report the situation of anti-platelet activity in vivo and in vitro, but no literature report is available for the research on derivatives with unsaturated cyclic amine structure and anti-platelet activity thereof.

Disclosure of Invention

During the synthesis of saturated cyclic amine derivatives, we have occasionally obtained a series of pyridine disulfide derivatives of unsaturated cyclic amine structure. After testing these compounds for antiplatelet activity, we have surprisingly found that these unsaturated cyclic amine derivatives exhibit more potent antiplatelet activity in animals than prasugrel. Therefore, the unsaturated cyclic amine derivatives are worthy of further research and development.

Based on the structures of clopidogrel and prasugrel metabolites reported in the previous documents, the invention discloses for the first time novel unsaturated cyclic aminopyridine disulfide derivatives, a preparation method and uses thereof, in particular for treating atherosclerotic diseases, myocardial infarction, stroke, peripheral arterial diseases, acute coronary syndromes and thrombosis during anti-angiogenic surgery. S-clopidogrel oxydans is synthesized according to the method provided by US8,536,337B2; the preparation of the final disulfide compound of the formula I, VI was described in the literature (Tetrahedron Lett., 2005,46, 3583-85; Tetrahedron, 2011,67, 8895-.

The invention aims to provide a compound, a pharmaceutically acceptable salt or a solvate of formula I.

Wherein R is₁Represents hydrogen, unsubstituted or X-substituted straight-chain or branched alkyl of 1 to 10 carbons, phenyl or X-substituted phenyl, benzyl or X-substituted benzyl, naphthyl or X-substituted naphthyl, unsubstituted or X-substituted cycloalkyl of 3 to 7 carbons, unsubstituted or X-substituted straight-chain or branched alkoxy of 1 to 10 carbons, unsubstituted or X-substituted cycloalkoxy of 3 to 7 carbons.

R₂Represents hydrogen, fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, straight-chain or branched alkyl group of 1 to 10 carbons, alkenyl group, alkynyl group. X represents fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, aryloxy group, phenyl group or Y-substituted phenyl group; y is fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amido group, sulfamide group, difluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group and ethoxyacyl group, and the Y group is positioned at 2, 3 or 4 positions of the benzene ring.

R₃Represents C1-C10 unsubstituted or X substituted straight or branched chain alkyl, alkenyl, alkynyl, phenyl or X substituted phenyl, benzyl or X substituted benzyl, naphthyl or X substituted naphthyl, C1-C10 unsubstituted or X substituted straight or branched chain alkoxy, C3-C7 unsubstituted or X substituted cycloalkoxy, C1-C10 unsubstituted or X substituted straight or branched chain alkanoyl, unsubstituted or X substituted benzoyl, C3-C7 unsubstituted or X substituted cycloalkanoyl. X represents fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamideA phenyl group substituted with a group, trifluoromethyl, mercapto, hydroxyl, acetoxy, methoxy, ethoxy, carboxyl, methoxyacyl, ethoxyacyl, aryloxy, phenyl or Y; y is fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amido group, sulfamide group, difluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group and ethoxyacyl group, and the Y group is positioned at 2, 3 or 4 positions of the benzene ring.

Preferably, the compound shown in the formula I, the pharmaceutically acceptable salt or the solvate is adopted.

R₁Represents hydrogen, unsubstituted or X-substituted straight-chain or branched alkyl of 1 to 10 carbons, phenyl or X-substituted phenyl, benzyl or X-substituted benzyl, naphthyl or X-substituted naphthyl, unsubstituted or X-substituted cycloalkyl of 3 to 7 carbons, unsubstituted or X-substituted straight-chain or branched alkoxy of 1 to 10 carbons, unsubstituted or X-substituted cycloalkoxy of 3 to 7 carbons.

R₂Represents hydrogen, fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, straight-chain or branched alkyl group of 1 to 10 carbons, alkenyl group, alkynyl group.

X represents fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, aryloxy group, phenyl group or Y-substituted phenyl group; y is fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amido group, sulfamide group, difluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group and ethoxyacyl group, and the Y group is positioned at 2, 3 or 4 positions of the benzene ring.

R₃Represents C1-C10 unsubstituted or X-substituted straight-chain or branched alkyl, alkenyl, alkynyl, phenyl or X-substituted phenyl, benzyl or X-substituted benzyl, naphthyl or X-substituted naphthyl, C1-C10 unsubstituted or X-substituted straight-chain or branched alkoxy, C3-C7 unsubstituted or X-substitutedCycloalkoxy of (a), unsubstituted or X-substituted straight-chain or branched alkanoyl of 1 to 10 carbons, unsubstituted or X-substituted benzoyl, unsubstituted or X-substituted cycloalkanoyl of 3 to 7 carbons. X represents fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, aryloxy group, phenyl group or Y-substituted phenyl group; y is fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amido group, sulfamide group, difluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group and ethoxyacyl group, and the Y group is positioned at 2, 3 or 4 positions of the benzene ring.

Further preferably, the compound of the present invention is selected from:

(Z) -2- (2- (3-carboxymethylenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinic acid

(Z) -2- (2- (3-carboxymethylenyl) -1- (1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinic acid

(Z) -methyl 2- (2- (3-carboxymethylenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio-nicotinate

(Z) -ethyl 2- (2- (3-carboxymethylenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio-nicotinate

(Z) -propyl 2- (2- (3-carboxymethylenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinate

(Z) -2- (2- (3-Carboxymethylenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio-nicotinic acid butyl ester

(Z) -methyl 2- (2- (3-carboxymethylenyl) -1- (1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinate

(Z) -ethyl 2- (2- (3-carboxymethylenyl) -1- (1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinate

(Z) -propyl 2- (2- (3-carboxymethylenyl) -1- (1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) nicotinate

(Z) -2- (2- (3-Carboxymethylenyl) -1- (1- (2-fluorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinic acid butyl ester

(Z) -2- (2- (3-methoxycarbonyl-methyl alkenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxyethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinic acid

(Z) -methyl 2- (2- (3-methoxycarbonyldecenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinate

(Z) -ethyl 2- (2- (3-methoxycarbonyldecenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinate

(Z) -propyl 2- (2- (3-methoxycarbonyldecenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinate

(Z) -2- (2- (3-methoxycarbonyldecenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio-nicotinic acid butyl ester

(Z) -2- (2- (3-ethoxycarbonylmethylenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinic acid

(Z) -methyl 2- (2- (3-ethoxycarbonylmethylenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio-nicotinate

(Z) -ethyl 2- (2- (3-ethoxycarbonylmethylenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio-nicotinate

(Z) -propyl 2- (2- (3-ethoxycarbonylmethylenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinate

(Z) -2- (2- (3-ethoxycarbonylmethylenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio-nicotinic acid butyl ester

(Z) -2- (2- (3-propoxycarbonylmethylenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinic acid

(Z) -methyl 2- (2- (3-propoxycarbonylmethylenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinate

(Z) -ethyl 2- (2- (3-propoxycarbonylmethylenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinate

(Z) -propyl 2- (2- (3-propoxycarbonylmethylenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinate

(Z) -2- (2- (3-Propoxycarbonylmethylene) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio-nicotinic acid butyl ester

(Z) -2- (2- (3-butoxycarbonyl-methyl-alkenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) -nicotinic acid

(Z) -methyl 2- (2- (3-butoxycarbonyldecenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinate

(Z) -ethyl 2- (2- (3-butoxycarbonyl-methyl-alkenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio-nicotinate

(Z) -propyl 2- (2- (3-butoxycarbonyl-methyl-alkenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinate

(Z) -2- (2- (3-Butoxycarbonylmethylene) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio-nicotinic acid butyl ester

Each derivative has 4 optical isomers and 7 chiral 4-position racemic isomers, such as:

(7S,4R) - (Z) -2- (2- (3-carboxymethylenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinic acid

(7R,4S) - (Z) -2- (2- (3-Carboxymethylene) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinic acid

(7S,4S) - (Z) -2- (2- (3-Carboxymethylene) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinic acid

(7R,4R) - (Z) -2- (2- (3-Carboxymethylene) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinic acid

(7S,4 + - (Z) -2- (2- (3-carboxyrnethynyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxyethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinic acid

(7R,4 + - (Z) -2- (2- (3-carboxyrnethynyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxyethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinic acid

The optical isomers of other derivatives are analogized. All of the above compounds are racemic in the 7-and 4-positions.

The present invention provides compounds of formula I having an optical purity of 70%, 100%, preferably 90%, 100%, more preferably 95%, 100%, most preferably 98%, 100%.

The compound shown in the formula I, the pharmaceutically acceptable salt or the solvate is selected from salts formed by the compound shown in the formula I and sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, tartaric acid, fumaric acid, maleic acid, citric acid, acetic acid, formic acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid or succinic acid.

It is another object of the present invention to provide a process for the preparation of the compounds of formula I.

Method (1): preparation of active intermediate by hydrolysis of clopidogrel oxydans

Reacting a compound shown as a formula II or a salt thereof with pyridine in the presence of alkali to obtain a compound shown as a formula I, wherein X represents fluorine, chlorine, bromine, iodine, C1-C10 unsubstituted or X substituted straight chain or branched chain alkyl sulfonyl, phenyl or X substituted benzenesulfonyl.

Wherein, the solvent used in the reaction process is selected from: benzene, toluene, chloroform, N-hexane, cyclohexane, dichloromethane, 1, 2-dichloroethane, methyl tert-butyl ether, carbon tetrachloride, ethyl acetate, propyl acetate, butyl acetate, methanol, ethanol, acetone, tetrahydrofuran, diethyl ether, acetonitrile, N-dimethylformamide or dimethylsulfoxide, preferably methanol or ethanol;

the base is selected from: sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, 1, 8-diazacyclo [5, 4, 0] undecene-7, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate, preferably sodium methoxide, sodium bicarbonate, potassium carbonate, triethylamine;

the reaction temperature is 0 ℃ to 100 ℃, and the preferred temperature is 20 ℃ to 50 ℃;

in the above reaction, R₁、R₂And X is as defined above for compounds of formula I.

Specifically, the preparation method comprises the following steps:

(1) a compound of formula IV or a salt thereof with R₂And (3) reacting OH in the presence of a base to obtain the compound shown in the formula II.

Wherein, the preparation of the compound of formula IV can refer to patent CN102120744, the synthesis method for obtaining the compound of formula 11 by synthesizing the compound of formula IV is disclosed in the literature, and can refer to Chem Res Toxicol,2012, 25: 348.

(2) reacting a compound of formula II or a salt thereof with pyridine in the presence of a base to give a compound of formula I, wherein substituted pyridine 3-Z represents fluorine, chlorine, bromine, iodine, a C1-C10 unsubstituted or X substituted straight or branched chain alkylsulfonyl group, a phenyl group or an X substituted benzenesulfonyl group. The solvent is selected from one or more mixed solvents of benzene, toluene, chloroform, N-hexane, cyclohexane, dichloromethane, 1, 2-dichloroethane, methyl tert-butyl ether, carbon tetrachloride, ethyl acetate, propyl acetate, butyl acetate, methanol, ethanol, acetone, tetrahydrofuran, diethyl ether, acetonitrile, N-dimethylformamide or dimethyl sulfoxide, preferably methanol and ethanol; the base is selected from sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, 1, 8-diazacyclo [5, 4, 0] undecene-7, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate, wherein sodium methoxide, sodium bicarbonate, potassium carbonate and triethylamine are preferred; the reaction temperature is from 0 ℃ to 100 ℃, preferably from 20 ℃ to 50 ℃.

Method (2): preparation of reactive intermediates from piperidones

The method specifically comprises the following steps:

(1) referring to patent CN1192019, the compound of formula V undergoes multi-step reaction to obtain the compound of formula VI, and the specific synthesis method is shown in the examples.

(2) Compounds of formula VI with R₃SK reaction to obtain the compound of formula I.

The reaction conditions for this step are disclosed in patent CN1192019, but in the present invention we found that unsaturated cyclic amine disulfide with double bond transfer can be obtained by using the conditions disclosed in the patent.

In the above reaction, R₁、R₂And R₃As defined above for compounds of formula I.

The compound involved in the production method of the present invention is a known compound, and can be either commercially available or produced by a conventional method.

The invention also aims to provide the application of the compound shown in the formula I in pharmacy.

Pharmacodynamic studies show that the compound of the formula I provided by the invention has a remarkable platelet aggregation inhibiting effect, and the platelet aggregation inhibiting effect is better than that of prasugrel.

The invention provides application of a compound shown in formula I, a pharmaceutically acceptable salt or a solvate in preparation of a medicine for preventing or treating diseases related to thrombus and embolism. In particular to a medicine for preventing or treating atherosclerosis diseases, myocardial infarction, apoplexy, ischemic cerebral thrombosis, peripheral artery diseases, acute coronary syndrome or thrombosis after coronary intervention operation.

The invention also aims to provide a pharmaceutical composition which takes the compound shown in the formula I, the pharmaceutically acceptable salt or the solvate as an active ingredient.

The pharmaceutical composition of the invention comprises 0.1-99.9% of the compound shown in formula I, pharmaceutically acceptable salt or solvate, and the balance of pharmaceutically acceptable carriers.

The pharmaceutical composition of the present invention can be prepared into any pharmaceutically acceptable dosage forms, including: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, buccal agents, granules, pills, powders, ointments, pellets, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches. The formulations of the present invention, preferably oral dosage forms, are: capsule, tablet, oral liquid, granule, pill, powder, pellet, and unguent. Most preferred are capsules.

The pharmaceutical composition of the present invention, its preparation for oral administration, may contain conventional excipients such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents, and the tablet may be coated if necessary.

Suitable fillers include cellulose, mannitol, lactose and other similar fillers. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.

The solid oral compositions can be prepared by conventional methods of mixing, filling, tabletting and the like. Repeated mixing can distribute the active throughout those compositions that use large amounts of filler.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous carriers (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerol, propylene glycol or ethyl alcohol; preservatives, for example p-hydroxybenzyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.

For injections, liquid unit dosage forms are prepared containing the active substances of the invention and a sterile carrier. Depending on the carrier and concentration, the compound may be suspended or dissolved. Solutions are generally prepared by dissolving the active substance in a carrier, filter sterilising before filling it into a suitable vial or ampoule and then sealing. Adjuvants such as a local anaesthetic, preservatives and buffering agents may also be dissolved in the vehicle. To improve its stability, the composition can be frozen after filling into vials and the water removed under vacuum.

The traditional Chinese medicine preparation of the invention can be selectively added with a proper pharmaceutically acceptable carrier when being prepared into a medicament, and the pharmaceutically acceptable carrier is selected from: mannitol, sorbitol, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, pyridine hydrochloride, thioglycolic acid, methionine, vitamin C, EDTA disodium, calcium sodium EDTA, monovalent alkali metal carbonates, acetates, phosphates or aqueous solutions thereof, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acids, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and derivatives thereof, alginates, gelatin, polyvinylpyrrolidone, glycerol, Tween 80, agar, calcium carbonate, calcium bicarbonate, surfactants, polyethylene glycol, cyclodextrin, beta-cyclodextrin, phospholipid-based materials, kaolin, talc, calcium stearate, magnesium stearate, and the like.

Compared with the existing products of clopidogrel and prasugrel, the clopidogrel compound has the following advantages that:

(1) the platelet aggregation inhibition rate is high;

(2) the pharmacokinetics speed is high;

(3) for Asian people lacking P450 enzyme, the medicine is easier to absorb and has better efficacy.

Clopidogrel metabolites and inhibition of platelet receptor activity: because the active ingredients of clopidogrel metabolites are few, the (7S,4R, 2R) dimer or (7S,4 ethylenic bond) unsaturated cyclic amine dithiopyridine derivative with high activity is invented.

Table 1: detection condition of 4 isomers of clopidogrel in human microsome incubation product and in-vitro inhibition³³Activity of P-2MeS-ADP binding to platelet receptors

Detailed Description

The present invention is further illustrated by the following specific examples, which are set forth to better illustrate the invention and are not intended to limit the scope of the invention.

Example 1

Synthesis of 1-trityl-4-piperidone

In 4-piperidone-hydrate hydrochlorideTo a solution of 40g (0.260mol) and 109mL (0.78mol) of triethylamine in 550mL of dimethylformamide was added 72.5g (0.260mol) of chlorotriphenylmethane little by little with stirring at 60 ℃ and then stirred at that temperature for 5 hours, followed by cooling and filtration of the precipitated triethylamine hydrochloride. The filtrate was poured into 2500mL of water, stirred while standing, and then filtered under suction to obtain 77.7g of a white solid with a yield of 70.2%.¹HNMR(500MHz,CDC1₃)：d 7.86-7.06(m，15H，J＝6.5Hz)，2.64(dd，4H，J＝7.1Hz)，2.55(dd，4H，J＝7.1Hz).ESI-MS m/z 364.45[M+Na]⁺。

Example 2

Synthesis of E-2- (4-carbonyl-1-tritylpiperidin-3-enyl) -acetic acid ethyl ester

60g (0.1757mol) of 1-trityl-4-piperidone and 15.8mL (0.1933mol) of pyrrolidine in 600mL of toluene were azeotroped with a water separator under reflux for 3 hours, and after cooling, 20.2mL (0.1933mol) of ethyl glyoxylate was added, followed by azeotropic dehydration under reflux for 2 hours. After cooling, 400mL of water was added, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 49.35g of a pale yellow oil with a yield of 60.2%.¹HNMR(500MHz,CDC1₃)：d 7.51-7.17(m，15H)，6.59(s，1H)，4.10(q，2H，J＝7.1Hz)，3.71(s，2H)，2.79(t，2H，J＝6.OHz)，2.65(s，2H)，1.17(t，2H，J＝7.1Hz).

ESI-MS m/z 448.1[M+Na]⁺

Example 3

Synthesis of E-2- (4-hydroxy-1-tritylpiperidin-3-enyl) -acetic acid ethyl ester

22g (0.0517mol) E-2- (4-carbonyl-1-tritylpiperidin-3-enyl) -acetic acid ethyl ester are dissolved in 50mL dichloromethaneThen, 200mL of methanol was added, and 2.34g (0.0619mol) of sodium borohydride was added little by little under ice-cooling, followed by stirring at room temperature for lh. After the reaction mixture was concentrated under reduced pressure, 150mL of water was added, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give M3-7 as a pale yellow oil, 12.8g, yield 57.9%,¹HNMR(300MHz,CDC1₃):d 7.45(d，6H，J＝7.3Hz)，7.25-7.11(m，9H)，6.05(s，1H)，4.48(s，1H)，4.14-3.96(m，3H)，2.99(s，1H)，2.30-2.22(m，1H)，2.10-2.03(m，1H)，1.93-1.85(m，3H)，1.12(t，3H，J＝7.1Hz)。ESI-MS m/z426.2[M-H]^-。

example 4

Synthesis of E-2- (4-hydroxypiperidin-3-enyl) -acetic acid ethyl ester p-toluenesulfonate

After 8.77g (20.51mmol) of E-2- (4-hydroxy-1-tritylpiperidin-3-enyl) -acetic acid ethyl ester was dissolved in 100mL of tetrahydrofuran, 5.13g (26.97mmol) of p-toluenesulfonic acid monohydrate was added, the mixture was stirred at 50 ℃ for lh, the solvent was evaporated under reduced pressure, the resulting residue was washed with toluene, and after standing, the upper layer was poured out and the lower layer was used in the next reaction.

Example 5

Synthesis of methyl (2S) -2- (2-chlorophenyl) -2- ((E) -3- (2-ethoxy-2-carbonylvinyl) -4-hydroxypiperidin-1-yl) -acetate

E-2- (4-hydroxypiperidin-3-enyl) -acetic acid ethyl ester p-toluenesulfonate was dissolved in 100mL of acetonitrile, and 6.86g (17.77mmol) of (R) -2- (2-chlorophenyl) -2- (4-nitrobenzenesulfonyloxy) -acetic acid methyl ester and 4.44g (44.42mmol) of potassium hydrogencarbonate were added and the mixture was reacted overnight under nitrogen. Vacuum filtering, concentrating the filtrate under reduced pressure, and purifying the obtained residue with silica gel column chromatography to obtain light yellow oil3.47g of substance, two-step yield 46.0%. Specific rotation degree: [ alpha ] to]_D ²⁰5.7 ° (c 5, dissolved in ethanol).¹HNMR(500MHz,CDC1₃)：d 7.59-7.53(m，1H)，7.38-7.35(m，1H)，7.27-7.21(m，2H)，5.98-5.97(m，1H)，4.85-4.81(m，1H)，4.59-4.48(m，1H)，4.10-4.05(m，3H)，3.70-3.68(m，3H)，3.24-3.14(m，1H)，2.91-2.87(m，1H)，2.66-2.50(m，1H)，2.31(s，1H)，2.03-1.97(m，1H)，1.81-1.74(m，2H)，1.23-1.95(m，3H)，ESI-MS m/z 368.1[M+H]⁺。

Example 6

Synthesis of methyl (2S) -2- (2-chlorophenyl) -2- ((E) -3- (2-ethoxy-2-carbonylvinyl) -4-bromopiperidin-1-yl) -acetate

To 35mL of anhydrous dichloromethane were added 2.08g (5.65mmol) of methyl (2S) -2- (2-chlorophenyl) -2- ((E) -3- (2-ethoxy-2-carbonylvinyl) -4-hydroxypiperidin-1-yl) -acetate, 2.25g (6.78mol) of carbon tetrabromide, and 1.78g (6.78mmol) of triphenylphosphine, and the mixture was stirred at room temperature for lh, followed by concentrating the reaction mixture and purifying the resulting residue by silica gel column chromatography to obtain 1.9g of a pale yellow oily substance, and the yield was 79.2%. Specific rotation degree: [ alpha ] to]_D ²⁰10.5 ° (c 5 in ethanol).¹HNMR(500MHz,CDC1₃)：d 7.62-7.58(m，1H)，7.40-7.37(m，1H)，7.29-7.23(m，2H)，5.93(d，1H，J＝4.OHz)，4.89-4.88(m，1H)，4.83(s，1H)，4.65-4.50(m，1H)，4.13-4.05(m，2H)，3.72(d，3H，J＝7.3Hz),3.65-3.55(m，1H)，3.04-2.87(m，1H)，2.80-2.77(m，1H)，2.31(s，1H)，2.09-2.03(m,1H)，1.24(qd,3H,J＝14.1,6.9Hz)，ESI-MS m/z 430.1，[M+H]⁺。

Example 7

Synthesis of(s) -methyl 2- (2-chlorophenyl) -2- (3- (2-ethoxy-2-carbonylethyl) -4-acetylmercapto-dihydropiperidin-1- (2H) -yl) -acetate

2.7g (6.2mmol) of methyl (2S) -2- (2-chlorophenyl) -2- ((E) -3- (2-ethoxy-2-carbonylvinyl) -4-bromopiperidin-1-yl) -acetate and 2.8g (24.5mmol) of potassium thioacetate were dissolved in 80mL of N, N-dimethylformamide or 80mL of dimethyl sulfoxide and all the starting materials disappeared after stirring with heating at 40 ℃ for 48 h. To the reaction solution was added a large amount of water, and the aqueous phase was extracted with ethyl acetate and dried over anhydrous sodium sulfate overnight. Evaporating the organic phase to dryness and then separating the organic phase by a column to obtain a pure product 2.lg, wherein the yield is as follows: 78.9%, specific rotation: [ alpha ] to]_D ²⁰15.8 ° (c ═ 5, dissolved in ethanol).¹HNMR(500MHz,CDC1₃):d 7.66(d，1H,J＝7.OHz)，7.40-7.24(m，3H)，4.86(s，1H)，4.09(q，2H，J＝7.1Hz)，3.71(s,3H)，3.33(ABq,2H,J＝16.5Hz)，3.18(ABq,2H,J＝16.1Hz)，2.79(s，2H)，2.45(s，2H)，2.33(s，3H)，1.22(t，3H，J＝7.1Hz)；¹³CNMR(125MHz,CDC1₃)：d 197.6，193.7，170.9，169.7，137.9，134.6，129.9，129.7，129.4，127.1，124.0，67.2，60.8，54.5，52.1，47.6，38.8，32.5，30.3，29.6，14.0.ESI-MS m/z 426.1[M+H]⁺；HRMS calcd for C20H24N05SClNa[M+H]⁺m/z 448.0916，found 448.0964。

Example 8

(E) Synthesis of (E) -2- (4-acetylmercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-ethenoic acid

Dissolving 2.1g (4.9mmol) of (E) -2- (4-acetylmercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-ethenoic acid ethyl ester in 20mL of methanol, adding 0.7mL of 30% aqueous sodium hydroxide solution (7.3mmol), stirring for 4 days under the protection of nitrogen, allowing the raw materials to disappear completely, adjusting the reaction solution to be neutral or weakly acidic with dilute hydrochloric acid, adding water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate overnight, evaporating the organic phase to obtain a crude product, separating by column to obtain 1.1g of oily matter, wherein the yield is 46.4%, and the specific rotation degree is [ alpha ], [ alpha ] is]_D ²⁰＝23.6(c ═ 5, dissolved in ethanol).¹HNMR(500MHz,CDC13)：δ11.0(w，1H)，7.15(d，1H,J＝7.OHz)，7.02-7.00(m，3H)，6.01(s，1H)，4.74(s，1H)，3.67(s,3H)，3.48(dd，1H，J＝7.1Hz)，3.08-2.98(s，2H)，2.41-2.31(ABq,2H,J＝16.5Hz)，2.33(s，3H)，2.18-1.93(ABq,2H,J＝16.1Hz)；¹³CNMR(75MHz,CDC13)：d 175.67，171.0，134.7，133.1，129.9，129.7，129.6，129.4，127.3，127.1,67.2，54.6，52.1,47.5，37.9，29.6，14.3。ESI-MS m/z 398.9，[M+H]⁺。HRMS calcd forC18H20N05SCl，[M+H]m/z 398.87，found 397.88。

Example 9

(E) Synthesis of (E) -2- (4-mercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-ethenoic acid

3.7g (10mmol) of (E) -2- (4-acetylmercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-ethenoic acid are dissolved in ethyl acetate (20ml), cooled to-5 ℃ and 6% hydrogen chloride in ethyl acetate (25ml) are slowly added dropwise, the reaction is carried out for 10h at 15 ℃ after completion of the dropwise addition, and TLC [ developing solvent dichloromethane: methanol ═ 8: 1%]Indicating that the reaction was complete. Ethyl acetate (20ml) was added to precipitate a large amount of solid, which was filtered, and the filter cake was washed with ethyl acetate (30 ml. times.3) and dried under reduced pressure at 35 ℃ to give 2.7g of a dark yellow solid in a yield of 75.0%. Specific rotation degree: [ alpha ] to]_D ²⁰30.2 ° (c ═ 5, dissolved in ethanol).¹HNMR(500MHz,CDC13)：δ11.0(w，1H)，7.15(d,1H，J＝5.8Hz)，7.02-7.01(m，2H，J＝5.8Hz)，7.00(d，1H，J＝5.8Hz)，5.90(s，1H)，4.74(s，1H)，3.67(s，3H)，3.23(m，1H,J＝16.OHz)，3.08-2.98(s，2H)，2.41-2.31(dd，2H，J＝15.8Hz)，1.82-1.57(m，2H，J＝15.8Hz)，,1.5(d，1H)。¹³CNMR(75MHz,CDC13)：d 171.6，170.6，158.8，135.4，135.1，131.2，129.3，129.0，127.3，113.0，65.8，56.1，51.9，48.9，38.3，33.2。ESI-MS m/z 356.8，[M+H]⁺。HRMS calcd forC16H18N04SCl，[M+H]m/z 356.84，found 356.88。

Example 10

Synthesis of (Z) -2- (4-mercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-ethenoic acid

2.7g (8.2mmol) of (E) -2- (4-mercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidin-3-ethenoic acid are dissolved in acetonitrile (water ═ 1:1(V/V) (30ml), and the reaction is irradiated with a 32W low-pressure mercury lamp at 25 ℃ for 2h, TLC [ developing solvent: dichloromethane: methanol ═ 8: 1-]Indicating that the reaction was complete. Concentrating under reduced pressure, adding ethyl acetate (20ml), precipitating a large amount of solid, filtering, washing the filter cake with ethyl acetate (10ml × 3), and drying under reduced pressure at 45 deg.C to obtain dark yellow solid 2.3g, yield 85.0%. Specific rotation degree: [ alpha ] to]_D ²⁰32.1 ° (c ═ 5, dissolved in ethanol).¹HNMR(500MHz,CDC13)：δ11.0(w，1H)，7.15(d,1H，J＝5.8Hz)，7.02-7.01(m，2H，J＝5.8Hz)，7.00(d，1H，J＝5.8Hz)，5.90(s，1H)，4.74(s，1H)，3.67(s，3H)，3.23(m，1H,J＝16.OHz)，3.08-2.98(s，2H)，2.41-2.31(dd，2H，J＝15.8Hz)，1.82-1.57(m，2H，J＝15.8Hz)，,1.5(d，1H)。¹³CNMR(75MHz,CDC13)：d 171.6，170.6，158.8，135.4，135.1，131.2，129.3，129.0，127.3，113.0，65.8，56.1，51.9，48.9，38.3，33.2。ESI-MS m/z 356.8，[M+H]⁺。HRMS calcd forC16H18N04SCl，[M+H]m/z 356.84，found 356.88。

Example 11

Resolution synthesis of (Z) -2- (4-mercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-ethenoic acid

In a 250mL three-necked flask was placed 3.6g (10mmol) of (Z) -2- (4-mercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-ethenoic acid, dissolved in 50mL of ethyl acetate, and dissolved by heatingDropwise adding a solution of 2.4g (10mmol) of S- (+) -camphor-10-sulfonic acid and 10ml of ethanol at the temperature of 60-70 ℃, stirring and preserving heat for 30 minutes, cooling to 0-10 ℃ for crystallization for 6 hours, filtering, leaching with 10ml of ethyl acetate, resolving with a sodium carbonate solution for crystallization, and drying by blowing at 55 +/-5 ℃ for 4 hours to respectively obtain (7S,4R) and (7S,4S)1.5g of dark yellow solids. Yield: 80.1 percent. Specific rotation of (7S, 4R): [ alpha ] to]_D ²⁰14.5 ° (c ═ 1, dissolved in 6M HCl); specific rotation of (7S, 4S): [ alpha ] to]_D ²⁰15.45 ° (c 1 in 6M HCl).¹HNMR(500MHz,CDC13)：δ11.0(w，1H)，7.15(d,1H，J＝5.8Hz)，7.02-7.01(m，2H，J＝5.8Hz)，7.00(d，1H，J＝5.8Hz)，5.90(s，1H)，4.74(s，1H)，3.67(s，3H)，3.23(m，1H,J＝16.OHz)，3.08-2.98(s，2H)，2.41-2.31(dd，2H，J＝15.8Hz)，1.82-1.57(m，2H，J＝15.8Hz)，,1.5(d，1H)。¹³CNMR(75MHz,CDC13)：d 171.6，170.6，158.8，135.4，135.1，131.2，129.3，129.0，127.3，113.0，65.8，56.1，51.9，48.9，38.3，33.2。ESI-MS m/z 356.8，[M+H]⁺。HRMS calcd forC16H18N04SCl，[M+H]m/z 356.84，found 356.88。

Example 12

Synthesis of methyl (Z) -2- (4-mercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-enoate

Dissolving 3.7g (10mmol) of (Z) -2- (4-mercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-ethenoic acid in methanol (60ml), adding 15ml of thionyl chloride, carrying out reaction reflux at 65 ℃ for 4h until the reaction is completed, concentrating under reduced pressure, adding ethyl acetate (20ml), precipitating a large amount of solid, filtering, washing a filter cake with ethyl acetate (10 ml. times.3), drying under reduced pressure at 45 ℃ to obtain 3.2g of a dark yellow solid, wherein the yield is 87.0 percent, the specific rotation degree is [ alpha. ] [ alpha ]]_D ²⁰36.3 ° (c ═ 5, dissolved in ethanol).¹HNMR(500MHz,CDC13)：δ7.15(d,1H，J＝5.8Hz)，7.02-7.01(m，2H，J＝5.8Hz)，7.00(d，1H，J＝5.8Hz)，5.90(s，1H)，4.74(s，1H)，3.76(s，3H)，3.67(s，3H)，3.23(m，1H,J＝16.OHz)，3.08-2.98(s，2H)，2.41-2.31(dd，2H，J＝15.8Hz)，1.82-1.57(m，2H，J＝15.8Hz)，,1.5(d，1H)。¹³CNMR(75MHz,CDC13)：d 171.6，170.6，158.8，135.4，135.1，131.2，129.3，129.0，127.3，113.0，65.8，56.1，51.9，51.7，48.9，38.3，33.2。ESI-MS m/z 370.8，[M+H]⁺。HRMS calcd forC17H20N04SCl，[M+H]m/z 370.84，found 370.88。

Example 13

Synthesis of ethyl (Z) -2- (4-mercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-enoate

Dissolving 3.8g (10mmol) of (Z) -2- (4-mercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-ethenoic acid in ethanol (60ml), adding 15ml of thionyl chloride, carrying out reaction reflux at 80 ℃ for 4h until the reaction is completed, concentrating under reduced pressure, adding ethyl acetate (20ml), precipitating a large amount of solid, filtering, washing a filter cake with ethyl acetate (10 ml. times.3), drying under reduced pressure at 45 ℃ to obtain 3.3g of a dark yellow solid, wherein the yield is 86.0 percent, and the specific rotation degree is alpha]_D ²⁰29.4 ° (c ═ 5, dissolved in ethanol).¹HNMR(500MHz,CDC13)：δ7.15(d,1H，J＝5.8Hz)，7.02-7.01(m，2H，J＝5.8Hz)，7.00(d，1H，J＝5.8Hz)，5.90(s，1H)，4.74(s，1H)，4.19(q，2H，J＝10.8Hz)，3.67(s，3H)，3.23(m，1H,J＝16.OHz)，3.08-2.98(s，2H)，2.41-2.31(dd，2H，J＝15.8Hz)，1.82-1.57(m，2H，J＝15.8Hz)，1.5(d，1H)，,1.30(t，3H，J＝10.8Hz)。¹³CNMR(75MHz,CDC13)：d 171.6，170.6，158.8，135.4，135.1，131.2，129.3，129.0，127.3，113.0，65.8，61.4，56.1，51.9，48.9，38.3，33.2，14.2。ESI-MS m/z 384.8，[M+H]⁺。HRMS calcd forC18H22N04SCl，[M+H]m/z 384.89，found 383.88。

Example 14

Synthesis of isopropyl (Z) -2- (4-mercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-vinylacetate

3.9g (10mmol) of (Z) -2- (4-mercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-ethenoic acid are dissolved in isopropanol (60ml), 15ml of thionyl chloride is added, the reaction is refluxed for 4 hours at 80 ℃, the reaction is completely performed, reduced pressure concentration is performed, ethyl acetate (20ml) is added, a large amount of solid is separated out, filtration is performed, a filter cake is washed by ethyl acetate (10ml multiplied by 3), reduced pressure drying is performed at 45 ℃, 3.4g of dark yellow solid is obtained, the yield is 86.0 percent, the specific rotation degree is [ alpha ] is]_D ²⁰38.1 ° (c ═ 5, dissolved in ethanol).¹HNMR(500MHz,CDC13)：δ7.15(d,1H，J＝5.8Hz)，7.02-7.01(m，2H，J＝5.8Hz)，7.00(d，1H，J＝5.8Hz)，5.90(s，1H)，4.74(s，1H)，4.31(m，1H，J＝10.8Hz)，3.67(s，3H)，3.23(m，1H,J＝16.OHz)，3.08-2.98(s，2H)，2.41-2.31(dd，2H，J＝15.8Hz)，1.82-1.57(m，2H，J＝15.8Hz)，1.5(d，1H)，1.35(d，6H，J＝10.8Hz)。¹³CNMR(75MHz,CDC13)：d 171.6，170.6，158.8，135.4，135.1，131.2，129.3，129.0，127.3，113.0，69.6，65.8，56.1，51.9，48.9，38.3，33.2，24.2。ESI-MS m/z 398.9，[M+H]⁺。HRMS calcd forC19H24N04SCl，[M+H]m/z 398.92，found397.88。

Example 15

Synthesis of (Z) -2- (4-mercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-vinyl acid tert-butyl ester

Dissolving 4.1g (10mmol) of (Z) -2- (4-mercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-ethenoic acid in tert-butanol (60ml), adding 15ml of thionyl chloride, reacting and refluxing for 4h at 80 ℃, concentrating under reduced pressure, adding ethyl acetate (20ml), precipitating a large amount of solid, filtering, washing a filter cake with ethyl acetate (10 ml. times.3), and drying under reduced pressure at 45 ℃ to obtain a dark yellow solid3.6g, yield 85.0%. Specific rotation degree: [ alpha ] to]_D ²⁰39.2 ° (c ═ 5, in ethanol).¹HNMR(500MHz,CDC13)：δ7.15(d,1H，J＝5.8Hz)，7.02-7.01(m，2H，J＝5.8Hz)，7.00(d，1H，J＝5.8Hz)，5.90(s，1H)，4.74(s，1H)，3.67(s，3H)，3.23(m，1H,J＝16.OHz)，3.08-2.98(s，2H)，2.41-2.31(dd，2H，J＝15.8Hz)，1.82-1.57(m，2H，J＝15.8Hz)，1.5(d，1H)，1.4(s，9H，)。¹³CNMR(75MHz,CDC13)：d 171.6，170.6，158.8，135.4，135.1，131.2，129.3，129.0，127.3，113.0，82.2，65.8，56.1，51.9，48.9，38.3，33.2，28.9。ESI-MS m/z 412.9，[M+H]⁺。HRMS calcd forC20H26N04SCl，[M+H]m/z 412.94，found 411.92。

Example 16

Synthesis of 2- (2- ((Z) -3-carboxymethylethenyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidin-4-yl) dithio) nicotinic acid

In a 50 mL-neck flask equipped with a reflux condenser, stirrer and dropping funnel, 15mL of dry chloroform and 0.262g (1mmol) of triphenylphosphine were added under nitrogen, cooled to 0 ℃ in an ice bath, and then 0.1g of bis (trichloromethyl) carbonate was dissolved in 1mL of dry chloroform and added portionwise with a syringe. After stirring at 0 ℃ for 10min, 0.3mL of triethylamine was added, the temperature was maintained at 0-5 ℃, 1mmol of thiophenol (VIII) and 1mmol of thiophenol 2-mercaptonicotinic acid were added, and after stirring for 1h, the mixture was heated to 65 ℃ and stirred for 5-7 h. And (3) evaporating the solvent in the reaction mixture under reduced pressure, and carrying out column chromatography on the crude product by using silica gel, wherein a developing agent is cyclohexane: ethyl acetate 10:1, column chromatography gave 670mg of oil, which was recrystallized from ethanol to give 493mg of bright yellow solid, yield: 65.8 percent. Specific rotation degree: [ alpha ] to]_D ²⁰16.8 ° (c ═ 5, dissolved in ethanol).¹HNMR(500MHz,CDC13)：¹HNMR(400MHz,CDC13)：δ11.0(w,2H),8.63(d,1H,J＝7.8Hz),8.01(d,1H,J＝7.8Hz),7.28(m,1H,J＝7.8Hz),7.00-7.15(m,4H,J＝5.8Hz)，5.90(s，1H)，4.74(s，1H)，3.67(s，3H)，3.21(dd，J＝15.8.OHz,1H)，3.08,2.98(s，2H)，2.31(dd，2H，J＝16.0Hz)，1.82,1.57(m，2H，J＝16.0Hz)。¹³CNMR(75MHz,CDC13)：d 179.8，171.6，170.6,169.4,158.8,152.1,138.2,135.1，131.2，129.3，129.0，127.3，121.9,121.6，113.0，65.8,55.7，51.9,48.5，42.0，35.0。ESI-MS m/z508.99，[M+Na]⁺。HRMS calcd for C22H21ClN206S2，[M+H]m/z509.9880，found 508.9881。

Comprises a 7-position racemic compound:

2- (2- ((Z) -3-carboxymethylethenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidin-4-yl) dithio) nicotinic acid I₀；

And a chiral compound:

2- (2- ((R, Z) -3-carboxymethylethenyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidin-4-yl) dithio) nicotinic acid;

2- (2- ((S, Z) -3-carboxymethylethenyl) -1- ((S) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidin-4-yl) dithio) nicotinic acid;

2- (2- ((R, Z) -3-carboxymethylethenyl) -1- ((R) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidin-4-yl) dithio) nicotinic acid;

2- (2- ((S, Z) -3-carboxymethylethenyl) -1- ((R) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidin-4-yl) dithio) nicotinic acid.

Example 17

Synthesis of methyl 2- (2- ((Z) -3-carboxymethylethenyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidin-4-yl) dithio) nicotinate

7.1g (20mmol) of (Z) -2- (4-mercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidin-3-ethenoic acid and 3.4g (20mmol) of methyl 2-mercaptonicotinate are dissolved in a solution of acetonitrile water ═ 1:1(V/V) (100ml), 20g (0.1mol) of potassium phosphite are added, the reaction is coupled at 25 to 37 ℃ for 4h, the mixture is concentrated under reduced pressure, ethyl acetate (100ml) is added, a large amount of solid is precipitated, the filtrate is filtered, and the filter cake is washed with ethyl acetate (10 ml. times.3)Vacuum drying at 45 deg.C to obtain dark yellow solid 9.2g with yield of 90.0%. Specific rotation degree: [ alpha ] to]_D ²⁰19.1 ° (c ═ 5, dissolved in ethanol).¹HNMR(500MHz,CDC13)：¹HNMR(400MHz,CDC13)：δ11.0(w,1H),8.63(d,1H,J＝7.8Hz),8.01(d,1H,J＝7.8Hz),7.28(m,1H,J＝7.8Hz),7.00-7.15(m,4H,J＝5.8Hz)，5.90(s，1H)，4.74(s，1H)，3.88(s，3H)，3.67(s，3H)，3.21(dd，J＝15.8.OHz,1H)，3.08,2.98(s，2H)，2.31(dd，2H，J＝16.0Hz)，1.82,1.57(m，2H，J＝16.0Hz)。¹³CNMR(75MHz,CDC13)：d 179.8，171.6，170.6,169.4,158.8,152.1,138.2,135.1，131.2，129.3，129.0，127.3，121.9,121.6，113.0，65.8,55.7，52.0，51.5,48.5，42.0，35.0。ESI-MS m/z523.02，[M+Na]⁺。HRMS calcd for C23H23ClN206S2，[M+H]m/z523.9880，found 523.9881。

Comprises 7-position racemic compound and 4 chiral compounds.

Example 18

Synthesis of ethyl 2- (2- ((Z) -3-carboxymethylethenyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidin-4-yl) dithio) nicotinate

Dissolving 7.1g (20mmol) of (Z) -2- (4-mercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-ethenoic acid and 3.7g (20mmol) of ethyl 2-mercaptonicotinate in a solution of acetonitrile and water (1: 1(V/V) (100ml), adding 20g (0.1mol) of potassium phosphite, reacting and coupling at 25-37 ℃ for 4h, concentrating under reduced pressure, adding ethyl acetate (100ml), precipitating a large amount of solid, filtering, washing the filter cake with ethyl acetate (10 ml. times.3), drying under reduced pressure at 45 ℃ to obtain 9.5g of dark yellow solid, yield 89.0%, specific rotation degree [ alpha. ]]_D ²⁰24.7 ° (c ═ 5, dissolved in ethanol).¹HNMR(500MHz,CDC13)：¹HNMR(400MHz,CDC13)：δ11.0(w,1H),8.63(d,1H,J＝7.8Hz),8.01(d,1H,J＝7.8Hz),7.28(m,1H,J＝7.8Hz),7.00-7.15(m,4H,J＝5.8Hz)，5.90(s，1H)，4.74(s，1H)，4.19(q，2H，J＝10.6Hz)，3.67(s，3H)，3.21(dd，J＝15.8.OHz,1H)，3.08,2.98(s，2H)，2.31(dd，2H，J＝16.0Hz)，1.82,1.57(m，2H，J＝16.0Hz),1.30(t，3H，J＝10.6Hz)。¹³CNMR(75MHz,CDC13)：d 179.8，171.6，170.6,169.4,158.8,152.1,138.2,135.1，131.2，129.3，129.0，127.3，121.9,121.6，113.0，65.8,61.4，55.7，51.9,48.5，42.0，35.0，14.2。ESI-MS m/z523.02，[M+Na]⁺。HRMS calcd for C24H25ClN206S2，[M+H]m/z523.9880，found 523.9881。

Comprises 7-position racemic compound and 4 chiral compounds.

Example 19

Synthesis of isopropyl 2- (2- ((Z) -3-carboxymethylethenyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidin-4-yl) disulfide) nicotinate

Dissolving 7.1g (20mmol) of (Z) -2- (4-mercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-ethenoic acid and 4.0g (20mmol) of isopropyl 2-mercaptonicotinate in 100ml of acetonitrile, water ═ 1:1(V/V), adding 20g (0.1mol) of potassium phosphite, reacting and coupling at 25-37 ℃ for 4h, concentrating under reduced pressure, adding 100ml of ethyl acetate, precipitating a large amount of solid, filtering, washing the filter cake with 10ml of ethyl acetate (3), drying under reduced pressure at 45 ℃ to obtain 7.2g of dark yellow solid, obtaining a yield of 90.0%, and obtaining a specific rotation index [ alpha ]/[ 3 ]]_D ²⁰26.8 ° (c ═ 5, dissolved in ethanol).¹HNMR(500MHz,CDC13)：¹HNMR(400MHz,CDC13)：δ11.0(w,1H),8.77(d,1H,J＝7.8Hz),8.19(d,1H,J＝7.8Hz),7.39(m,1H,J＝7.8Hz),7.00-7.15(m,4H,J＝5.8Hz)，5.90(s，1H)，4.74(s，1H)，4.31(m，1H，J＝16.0Hz)，3.67(s，3H)，3.21(dd，J＝15.8.OHz,1H)，3.08,2.98(s，2H)，2.31(dd，2H，J＝16.0Hz)，1.35(d，6H，J＝16.0Hz)。¹³CNMR(75MHz,CDC13)：d 179.8，171.6，170.6,169.4,158.8,152.1,138.2,135.1，131.2，129.3，129.0，127.3，121.9,121.6，113.0，65.8,55.7，52.0，51.9,48.5，42.0，35.0。ESI-MS m/z551.02，[M+Na]⁺。HRMS calcd for C25H27ClN206S2，[M+H]m/z552.9880，found552.9881。

Comprises 7-position racemic compound and 4 chiral compounds.

Example 20

Synthesis of tert-butyl 2- (2- ((Z) -3-carboxymethylethenyl) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidin-4-yl) dithio) nicotinate

Dissolving 7.1g (20mmol) of (Z) -2- (4-mercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-ethenoic acid and 4.2g (20mmol) of tert-butyl 2-mercaptonicotinic acid in a solution of acetonitrile (water: 1(V/V) (100ml), adding 20g (0.1mol) of potassium phosphite, reacting and coupling at 25-37 ℃ for 4h, concentrating under reduced pressure, adding ethyl acetate (100ml), precipitating a large amount of solid, filtering, washing the filter cake with ethyl acetate (10 ml. times.3), drying under reduced pressure at 45 ℃ to obtain 7.4g of dark yellow solid, yield 91.0%; specific rotation [. alpha. ]]_D ²⁰28.3 ° (c 5 in ethanol).¹HNMR(500MHz,CDC13)：¹HNMR(400MHz,CDC13)：δ11.0(w,1H),8.77(d,1H,J＝7.8Hz),8.19(d,1H,J＝7.8Hz),7.39(m,1H,J＝7.8Hz),7.00-7.15(m,4H,J＝5.8Hz)，5.90(s，1H)，4.74(s，1H)，3.67(s，3H)，3.21(dd，J＝15.8.OHz,1H)，3.08,2.98(s，2H)，2.31(dd，2H，J＝16.0Hz)，1.40(s，9H)。¹³CNMR(75MHz,CDC13)：d 179.8，171.6，170.6,169.4,158.8,152.1,138.2,135.1，131.2，129.3，129.0，127.3，121.9,121.6，113.0，81.7,55.7，52.0，51.9,48.5，42.0，28.8。ESI-MS m/z565.12，[M+Na]⁺。HRMS calcd for C26H29ClN206S2，[M+H]m/z567.9880，found 567.9881。

Comprises 7-position racemic compound and 4 chiral compounds.

Example 21

Synthesis of methyl(s) -2- (2-chlorophenyl) -2- (3- (2-methoxy-2-carbonylethyl) -4-mercapto-5, 6-dihydropyridin-1 (2H) -yl) -acetate

169mg (0.5mmoI) (2S) -2- (2-oxo-7, 7 a-dihydrothieno [3, 2-c)]Pyridin-5 (2H, 4H, 6H) -yl) -2- (2-chlorophenyl) -acetic acid methyl ester was dissolved in 15mL of methanol, and 724mg (5mmol) of anhydrous potassium carbonate was added. The reaction liquid is protected by nitrogen gas, the raw materials are completely disappeared after stirring for 12 hours at room temperature, the reaction liquid is filtered to remove insoluble solids, the pH value is adjusted to be neutral by 2N hydrochloric acid, a large amount of water is added, extraction is carried out by ethyl acetate, the organic phase is washed by saturated salt water, and anhydrous sodium sulfate is dried. Evaporating the organic phase to dryness, and separating by column to obtain oily substance. Specific rotation degree: [ alpha ] to]_D ²⁰35.8 ° (c ═ 5, dissolved in ethanol).¹HNMR(300MHz,CDC1₃)：d 7.65-7.62(m，1H)，7.40-7.38(m，1H)，7.28-7.24(m，2H)，4.79(s，1H)，3.69(s，3H)，3.66(s，3H)，3.24-3.17(m，2H)，3.10(d，2H，J＝15.6Hz)，2.69(t，2H，J＝5.7Hz),2.57(s，1H)，2.38(s，2H)；1HNMR(300MHz,CDC1₃+D₂0)d 7.65-7.62(m，1H)，7.40-7.37(m，1H)，7.28-7.24(m，2H)，4.79(s，1H)，3.69(s，3H)，3.66(s，3H)，3.16-3.10(m，2H)，3.12-3.05(m，2H)，2.69(t，2H，J＝5.7Hz),2.38(s，2H)。¹³C NMR(75MHz,CDC1₃)：d 171.0，170.6，134.6，133.4，129.8，129.7，129.4，127.0，125.1，124.0，67.4，54.4，52.1，47.6，38.3，35.2。ESI-MS m/z 392.l[M+Na]⁺。HRMS calcd for C17H20N04NaSCl[M+Na]⁺m/z 392.0699，found 392.0703。

Example 22

Synthesis of methyl(s) -2- (2-chlorophenyl) -2- (3- (2-methoxy-2-carbonylethyl) -4-mercaptomethyl-5, 6-dihydropyridin-1 (2H) -yl) -acetate

338mg (1mmol) of (2S) -2- (2-oxo-7, 7 a-dihydrothieno [3, 2-c)]Pyridin-5 (2H, 4H, 6H) -yl) -2- (2-chlorophenyl) -acetic acid methyl ester was dissolved in 10mL of methanol, and 1.38g (10mmol) was addedAnhydrous potassium carbonate, and stirring for 12 hours under the protection of nitrogen, wherein all raw materials disappear. After insoluble matter was filtered, the reaction mixture was neutralized or weakly acidic with dilute hydrochloric acid, and 0.18mL (3mmol) of methyl iodide was added thereto and stirred for 0.5 hour. Water was added to the reaction solution, and extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate overnight. The organic phase was evaporated to dryness to give a crude product which was separated by column chromatography to give 282mg of oil, yield: 73.4 percent. Specific rotation degree: [ alpha ] to]_D ²⁰37.4 ° (c ═ 5, in ethanol).¹HNMR(500MHz,CDC1₃)：d 7.65(d，1H,J＝7.2Hz)，7.39-7.38(m,1H)，7.29-7.23(m，3H)，4.80(s，1H)，3.70(s，4H)，3.66(d，3H，J＝9.3Hz),3.37(d，1H，J＝15.7Hz)，3.25-3.20(m，2H)，3.11(d，lH，J＝15.8Hz)，2.72(s，2H)，2.42(s，2H)，2.18(s，3H)。¹³CNMR(125MHz,CDC1₃):d 171.1，171.0，134.6，133.5，129.8，129.7，129.3，129.1，127.7，127.0，67.5，54.7，52.0，51.8，47.6，38.0，29.8，14.3。ESI-MS m/z 406.1[M+Na]⁺。

HRMS calcd for C18H22N04NaSCl[M+Na]⁺:m/z 406.0856，found 406.0860。

Example 23

Synthesis of methyl(s) -2- (1- (1- (2-chlorophenyl) -2-carboxyethyl) -4-mercaptomethyl-1, 2,5, 6-tetrahydropyridin-3-yl) -acetate

233mg (0.61mmol) of(s) -2- (2-chlorophenyl) -2- (3- (2-methoxy-2-carbonylethyl) -4-mercaptomethyl-5, 6-dihydropyridin-1 (2H) -yl) -acetic acid methyl ester were dissolved in 2mL of methanol, 0.07mL of 30% aqueous sodium hydroxide solution (0.73mmol) were added, and after stirring for 4 days under nitrogen, the starting material disappeared completely. The reaction solution was adjusted to neutral or weakly acidic with dilute hydrochloric acid, water was added thereto and extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate overnight. Evaporating the organic phase to dryness to obtain a crude product, and performing column chromatography to obtain an oily substance of 102mg, wherein the yield is as follows: 45.4 percent. Specific rotation degree: [ alpha ] to]_D ²⁰33.6 ° (c ═ 5, in ethanol).¹HNMR(500MHz,CDC13)：d 7.65-7.63(m,1H), 7.40-7.38(m, 1H), 7.29-7.25(m, 2H), 4.84(s, 1H), 3.70(s, 3H), 3.38(d, 1H, J ═ 16, OHz), 3.28-3.25 (m, 2H), 3.13(d, 1H, J ═ 15.8Hz), 2.28-2.75(m, 1H), 2.72-2.69(m, 1H), 2.43(s, 2H), 2.19(s, 3H).¹³CNMR(75MHz,CDC13)：d 175.67，171.0，134.7，133.1，129.9，129.7，129.6，129.4，127.3，127.1,67.2，54.6，52.1,47.5，37.9，29.6，14.3。ESI-MS m/z 370.1，[M+H]⁺。HRMS calcd forC17H21N04SCl，[M+H]m/z 370.0880，found 370.0881。

Example 24

Synthesis of(s) -2- (2- (3-carboxymethyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-carbonylethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) -nicotinic acid

In a 50 mL-neck flask equipped with a reflux condenser, stirrer and dropping funnel, 15mL of dry chloroform and 0.262g (1mmol) of triphenylphosphine were added under nitrogen, cooled to 0 ℃ in an ice bath, and then 0.1g of bis (trichloromethyl) carbonate was dissolved in 1mL of dry chloroform and added portionwise with a syringe. After stirring at 0 ℃ for 10min, 0.3mL of triethylamine are added, the temperature is maintained at 0-5 ℃, 2mmol of thiophenol (II), 2.2mmol of pyridine are added and the mixture is stirred for 1h, the mixture is heated to 65 ℃ and stirred for 5-7 h. And (3) evaporating the solvent in the reaction mixture under reduced pressure, and carrying out column chromatography on the crude product by using silica gel, wherein a developing agent is cyclohexane: ethyl acetate 10:1, column chromatography gave 670mg of oil, which was recrystallized from ethanol to give 493mg of bright yellow solid, yield: 65.8 percent. Specific rotation degree: [ alpha ] to]_D ²⁰7.9 ° (c ═ 5, dissolved in ethanol).¹HNMR(500MHz,CDC13)：¹HNMR(400MHz,CDC13)：δ11.0(w,2H),8.63(d,1H,J＝7.8Hz),8.01(d,1H,J＝7.8Hz),7.28(m,1H,J＝7.8Hz),7.00-7.15(m,4H,J＝5.8Hz)，4.74(s，1H)，3.67(s，3H)，2.90(s，2H)，2.83(s，2H)，2.45(dd，2H，J＝16.0Hz)，2.07(dd，2H，J＝16.0Hz)。¹³CNMR(75MHz,CDC13)：d 179.8，171.6，170.6,169.4,158.8,152.1,138.2,135.1，131.2，129.3，129.0，127.3，121.9,121.6，113.0，65.8,55.7，51.9,48.5，42.0，35.0。ESI-MS m/z508.99，[M+Na]⁺。HRMS calcd for C22H21ClN206S2，[M+H]m/z509.9880，found 508.9881。

Example 25

Preparing a clopidogrel metabolic active substance disulfide derivative by an enzyme method: synthesis of (7S,4R) -2- (2- ((Z) -3-carboxymethylethenyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidin-4-yl) dithio) nicotinic acid

Adding 700L of water into a 750L reaction kettle, starting stirring, and setting the stirring speed to 186 revolutions per minute; taking 14L of purified water, adding KH₂PO₄And NaOH, stirring to dissolve, measuring pH to 7.4 with pH 5.5-9.0, adding MgCl₂.6H₂O, stirring and dissolving, and then adding into a reaction tank; the temperature is set to 30 ℃ for heating, the heating is stopped when the temperature reaches 28 ℃, and the temperature is automatically increased to 30 ℃. Adding 14L of purified water into D-glucose, stirring and dissolving, and then adding into a reaction tank; adding NADP + and G₆The PDH dehydrogenase liquid is set to rotate at 200 r/min, the reaction is started at the temperature of 30 ℃, and the sample is taken after 15min to detect the ultraviolet 340nm value. Introducing air into the reaction tank, dissolving clopidogrel oxydans with DMSO and Tris, adding 70L P450 to oxidize synthetase, and starting reaction. Setting the stirring speed at 186 rpm, reacting at 30 + -0.5 deg.C for 0.5h, adding 6MHCl, measuring pH, discharging, adding ammonium sulfate, stirring for 5min, standing for 2h, filtering, and loading onto resin column. Eluting with 30% and 95% ethanol respectively, and concentrating under reduced pressure to obtain crude product. Then, the resulting product was subjected to preparative chromatography to give (Z) -2(1- (1- (2-chlorophenyl) -2-methoxy-2-carbonylethyl) -4-mercaptopiperidin-3-enyl-acetic acid, 26.6g, yield: 10%, and HPLC, 99.7%.¹HNMR(500MHz,CDC13)：¹HNMR(400MHz,CDC13)：δ11.0(w,2H),8.63(d,1H,J＝7.8Hz),8.01(d,1H,J＝7.8Hz),7.28(m,1H,J＝7.8Hz),7.00-7.15(m,4H,J＝5.8Hz)，5.90(s，1H)，4.74(s，1H)，3.67(s，3H)，3.21(dd，J＝15.8.OHz,1H)，3.08,2.98(s，2H)，2.31(dd，2H，J＝16.0Hz)，1.82,1.57(m，2H，J＝16.0Hz)。¹³CNMR(75MHz,CDC13)：d 179.8，171.6，170.6,169.4,158.8,152.1,138.2,135.1，131.2，129.3，129.0，127.3，121.9,121.6，113.0，65.8,55.7，51.9,48.5，42.0，35.0。ESI-MS m/z508.99，[M+Na]⁺。HRMS calcd for C22H21ClN206S2，[M+H]m/z509.9880，found 508.9881。

Esterification: obtaining methyl ester, ethyl ester, isopropyl ester, tert-butyl ester, pivaloyloxymethyl ester and pirufuralate;

resolution or liquid phase preparation: 4 optical isomers, 7S and 4R are obtained; 7R, 4S; 7S, 4S; 7R, 4R;

example 26

Synthesis of 2- (2- ((Z) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carboxyethyl) -3- (2-methoxy-2-oxovinyl) piperidin-4-yl) -dithio) nicotinic acid

Dissolving 7.4g (20mmol) of methyl (Z) -2- (4-mercapto) -1- ((s) -1- (2-chlorophenyl) -2-methoxy-2-carbonylethylpiperidine-3-enoate and 3.1g (20mmol) of 2-mercaptonicotinic acid in a solution of acetonitrile and water (1: 1(V/V) (100ml), adding 20g (0.1mol) of potassium phosphite, reacting and coupling at 25-37 ℃ for 4h, concentrating under reduced pressure, adding ethyl acetate (100ml), precipitating a large amount of solid, filtering, washing the filter cake with ethyl acetate (10 ml. times.3), drying under reduced pressure at 45 ℃ to obtain 9.2g of dark yellow solid, obtaining a yield of 90.0%, and obtaining a specific rotation degree [ alpha. ] (3) ]]_D ²⁰19.7 ° (c ═ 5, dissolved in ethanol).¹HNMR(500MHz,CDC13)：¹HNMR(400MHz,CDC13)：δ11.0(w,1H),8.63(d,1H,J＝7.8Hz),8.01(d,1H,J＝7.8Hz),7.28(m,1H,J＝7.8Hz),7.00-7.15(m,4H,J＝5.8Hz)，5.90(s，1H)，4.74(s，1H)，3.76(s，3H)，3.67(s，3H)，3.21(dd，J＝15.8.OHz,1H)，3.08,2.98(s，2H)，2.31(dd，2H，J＝16.0Hz)，1.82,1.57(m，2H，J＝16.0Hz)。¹³CNMR(75MHz,CDC13)：d 171.6，170.6,169.4,166.5，158.8,152.1,138.2,135.1，131.2，129.3，129.0，127.3，121.9,121.6，113.0，65.8,55.7，52.0，51.5,48.5，42.0，35.0。ESI-MS m/z523.02，[M+Na]⁺。HRMS calcd for C23H23ClN206S2，[M+H]m/z523.9880，found 523.9881。

Esterification: obtaining methyl ester, ethyl ester, isopropyl ester and tert-butyl ester; comprises 7-position racemic compound and 4 chiral compounds.

Example 27

Anti-platelet aggregation activity assay

Medicine and preparation: the positive drug was prasugrel and the test compound was example 11. The positive drug and the test compound are mixed into a suspension with 0.5% CMC-Na for animal administration.

Animals: male SD rats, weighing around 250 g.

The instrument comprises the following steps: centrifuge, platelet aggregation apparatus, and the like.

The method comprises the following steps: the compounds of the present invention were tested for their pharmacological activity against platelet aggregation by reference to BORN turbidimetry (Nature,1962, 194: 927). Platelet-rich plasma (PRP) is mixed with the addition of the procoagulant Adenosine Diphosphate (ADP) to aggregate the platelets. The aggregation of platelets causes a change in optical density, which can be detected by a spectrophotometer. This assay allows the assessment of platelet aggregation induced by in vivo or in vitro administration of the test compound.

Male SD rats were orally gavaged with prasugrel and test drug (0.5% CMC-Na homogeneous suspension, drug concentration 1mg/ml) at a dose of 3mg/kg, and blank controls were orally gavaged with the same volume of 0.5% CMC-Na. After 2h, blood is taken from the orbit, 3.8 percent of sodium citrate is anticoagulated, and the ratio of the whole blood to the anticoagulant is 9: platelet-rich Plasma (PRI)) was prepared by centrifugation at 1,1000 rpm for 7 min. PRI modulation with Platelet Poor Plasma (PPP) to maintain platelet counts at 2x 10⁶One per ml. PRI) was added to a test cup, incubated at 37 ℃ for 10min, adjusted to zero by PRI), adjusted to 100% by PPP, and then measured for the percentage of platelet aggregation by a platelet aggregation meter by turbidimetry using ADP (final concentration of 5uM) as an inducer, and statistically compared by t-test to obtain the platelet aggregation inhibition (%) [1- (dose tube aggregation percentage/control tube aggregation percentage)]×100％。

As a result: the platelet aggregation rate of the rats after oral administration of the test compound was measured by turbidimetry, and the experimental results are shown in table one. The results indicate that the compound of example 11 shows stronger anti-platelet aggregation activity than prasugrel.

TABLE 2 platelet aggregation inhibition of rats orally administered prasugrel with compounds prepared according to the examples of the present invention

The above tables only show the biological activity data of some compounds of the present invention, and other compounds of the present invention have similar structures and the same or similar activity effects as the above compounds, which are not listed herein due to space limitation.

Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.

Claims

1. A compound of formula I as shown, a pharmaceutically acceptable salt or solvate,

wherein R is₁Represents hydrogen, unsubstituted or X-substituted straight-chain or branched alkyl of 1 to 10 carbons, phenyl or X-substituted phenyl, benzyl or X-substituted benzyl, naphthyl or X-substitutedNaphthyl, unsubstituted or X-substituted cycloalkyl of 3 to 7 carbons, unsubstituted or X-substituted straight or branched alkoxy of 1 to 10 carbons, unsubstituted or X-substituted cycloalkoxy of 3 to 7 carbons;

R₂represents hydrogen, fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, straight-chain or branched alkyl group of 1 to 10 carbons, alkenyl group, alkynyl group;

x represents fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, aryloxy group, phenyl group or Y-substituted phenyl group; y is fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amido group, sulfamide group, difluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group and ethoxyacyl group, and the Y group is positioned at 2, 3 or 4 position of benzene ring;

R₃represents C1-C10 unsubstituted or X-substituted straight-chain or branched alkyl, alkenyl, alkynyl, phenyl or X-substituted phenyl, benzyl or X-substituted benzyl, naphthyl or X-substituted naphthyl, C1-C10 unsubstituted or X-substituted straight-chain or branched alkoxy, C3-C7 unsubstituted or X-substituted cycloalkoxy, C1-C10 unsubstituted or X-substituted straight or branched alkanoyl, unsubstituted or X-substituted benzoyl, C3-C7 unsubstituted or X-substituted cycloalkanoyl, x represents fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, aryloxy group, phenyl group or Y-substituted phenyl group; y is fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amido group, sulfamide group, difluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group and ethoxyacyl group, and the Y group is positioned at 2, 3 or 4 positions of the benzene ring.

2. The compound, pharmaceutically acceptable salt or solvate according to claim 1,

R₁represents hydrogen, unsubstituted or X-substituted straight-chain or branched alkyl of 1 to 10 carbons, phenyl or X-substituted phenyl, benzyl or X-substituted benzyl, naphthyl or X-substituted naphthyl, unsubstituted or X-substituted cycloalkyl of 3 to 7 carbons, unsubstituted or X-substituted straight-chain or branched alkoxy of 1 to 10 carbons, unsubstituted or X-substituted cycloalkoxy of 3 to 7 carbons,

R₂represents hydrogen, fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, straight-chain or branched alkyl group of 1 to 10 carbons, alkenyl group, alkynyl group,

x represents fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, aryloxy group, phenyl group or Y-substituted phenyl group; y is fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amido group, sulfamide group, difluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group and ethoxyacyl group, and the Y group is positioned at 2, 3 or 4 position of benzene ring,

R₃represents C1-C10 unsubstituted or X-substituted straight-chain or branched alkyl, alkenyl, alkynyl, phenyl or X-substituted phenyl, benzyl or X-substituted benzyl, naphthyl or X-substituted naphthyl, C1-C10 unsubstituted or X-substituted straight-chain or branched alkoxy, C3-C7 unsubstituted or X-substituted cycloalkoxy, C1-C10 unsubstituted or X-substituted straight or branched alkanoyl, unsubstituted or X-substituted benzoyl, C3-C7 unsubstituted or X-substituted cycloalkanoyl, x represents fluorine, chlorine, bromine, iodine, nitrile group, nitro group, amino group, amide group, sulfonamide group, trifluoromethyl group, mercapto group, hydroxyl group, acetoxy group, methoxy group, ethoxy group, carboxyl group, methoxyacyl group, ethoxyacyl group, aryloxy group, phenyl group or Y-substituted phenyl group; y is fluorine or chlorineBromine, iodine, nitrile, nitro, amino, amide, sulfonamide, difluoromethyl, mercapto, hydroxy, acetoxy, methoxy, ethoxy, carboxyl, methoxyacyl, ethoxyacyl, and the Y group is in the 2, 3, or 4 position of the phenyl ring.

3. The compound, pharmaceutically acceptable salt or solvate according to claim 1,

(Z) -butyl 2- (2- (3-butoxycarbonyl-methyl-enyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) dithio) nicotinate.

4. A compound, pharmaceutically acceptable salt or solvate according to claim 3,

(7R,4 ±) - (Z) -2- (2- (3-carboxyrnethynyl) -1- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -1,2,5, 6-tetrahydropyridin-4-yl) disulfide) nicotinic acid.

5. The compound, pharmaceutically acceptable salt or solvate according to claim 1,

the salt is selected from salts formed by the compound shown in the formula I and sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, tartaric acid, fumaric acid, maleic acid, citric acid, acetic acid, formic acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid or succinic acid.

6. A process for the preparation of a compound, pharmaceutically acceptable salt or solvate according to claim 1,

Reacting a compound shown as a formula II or a salt thereof with pyridine in the presence of alkali to obtain a compound shown as a formula I, wherein X represents fluorine, chlorine, bromine, iodine, C1-C10 unsubstituted or X substituted straight chain or branched chain alkyl sulfonyl, phenyl or X substituted benzenesulfonyl,

7. A process for the preparation of a compound, pharmaceutically acceptable salt or solvate according to claim 1,

method (2): preparation of reactive intermediates from piperidones

The method specifically comprises the following steps:

(1) referring to patent CN1192019, the compound of formula V is subjected to multi-step reaction to obtain the compound of formula VI,

(2) compounds of formula VI with R₃SK reaction to obtain the compound of formula I,

8. Use of a compound, pharmaceutically acceptable salt or solvate according to claim 1 in the manufacture of a medicament for the prophylaxis or treatment of thrombosis and embolism associated disorders.

9. Use of a compound, pharmaceutically acceptable salt or solvate according to claim 1 in the manufacture of a medicament for the prevention or treatment of atherosclerotic disease, myocardial infarction, stroke, ischemic cerebral thrombosis, peripheral arterial disease, acute coronary syndrome or thrombosis following coronary intervention.

10. A pharmaceutical composition comprises a compound represented by formula I, a pharmaceutically acceptable salt or a solvate as an active ingredient.