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Preparation method of clopidogrel and intermediate thereof

A technology for clopidogrel and intermediates, which is applied in the field of preparation of clopidogrel and its intermediates, can solve the problems of long reaction time, racemization of final products, etc., and achieve low cost, easy availability of raw materials, and cost reduction Effect

Active Publication Date: 2014-01-15
SHANDONG LUYAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction raw materials are reduced and the cost is reduced, but the highly toxic sodium cyanide is used in the synthesis process, the reaction time is longer, and the final product faces the problem of racemization

Method used

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  • Preparation method of clopidogrel and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] 1) Synthesis of o-chlorophenylglycine methyl ester hydrochloride

[0028] Add 45.8 g of o-chlorophenylglycine and 180 mL of anhydrous methanol into a 500 mL three-necked flask, and install a reflux device and an acid gas absorption device. Cool down in an ice bath, control the system temperature at 0-5°C, and slowly add 31.7 g of thionyl chloride dropwise. After the dropwise addition was completed, the temperature of the reaction system was raised to 60° C. and kept for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation. Add 50 mL of n-hexane and 200 mL of water, extract and separate, and remove the organic layer. Add 200 mL of dichloromethane to the water layer, add ammonia water dropwise, adjust the pH of the system to 7, stir for half an hour, wash the water layer with 20 mL of dichloromethane respectively, combine the organic phases, dry with anhydrous sodium sulfate, and evaporate the solvent under reduced pressure , to...

Embodiment 2

[0039] 1) Synthesis of o-chlorophenylglycine methyl ester hydrochloride

[0040] Add 45.8 g of o-chlorophenylglycine and 180 mL of anhydrous methanol into a 500 mL three-necked flask, and install a reflux device and an acid gas absorption device. Cool down in an ice bath, control the system temperature at 0-5°C, and slowly add 31.7 g of thionyl chloride dropwise. After the dropwise addition was completed, the temperature of the reaction system was raised to 50° C. and kept for 16 hours. After the reaction was completed, the solvent was removed by rotary evaporation. Add 50 mL of n-hexane and 200 mL of water, extract and separate, and remove the organic layer. Add 200 mL of dichloromethane to the water layer, add ammonia water dropwise, adjust the pH of the system to 7, stir for half an hour, wash the water layer with 20 mL of dichloromethane respectively, combine the organic phases, dry with anhydrous sodium sulfate, and evaporate the solvent under reduced pressure , to obt...

Embodiment 3

[0051] 1) Synthesis of o-chlorophenylglycine methyl ester hydrochloride

[0052] Add 45.8 g of o-chlorophenylglycine and 180 mL of anhydrous methanol into a 500 mL three-necked flask, and install a reflux device and an acid gas absorption device. Cool down in an ice bath, control the system temperature at 0-5°C, and slowly add 31.7 g of thionyl chloride dropwise. After the dropwise addition was completed, the temperature of the reaction system was raised to 70° C. and kept for 8 hours. After the reaction was completed, the solvent was removed by rotary evaporation. Add 50 mL of n-hexane and 200 mL of water, extract and separate, and remove the organic layer. Add 200 mL of dichloromethane to the water layer, add ammonia water dropwise, adjust the pH of the system to 7, stir for half an hour, wash the water layer with 20 mL of dichloromethane respectively, combine the organic phases, dry with anhydrous sodium sulfate, and evaporate the solvent under reduced pressure , to ...

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Abstract

The invention relates to a preparation method of clopidogrel and an intermediate of clopidogrel. The preparation method comprises the following steps: using L-2-chlorophenylglycine as a starting raw material, firstly taking reaction to L-2-chlorophenylglycine with methanol to generate L-2-chlorophenylglycine methyl ester, then using L-(+)-tartaric acid to split L-2-chlorophenylglycine methyl ester to obtain S-(+)-chlorophenylglycine methyl ester and L-(+)-tartrate, taking reaction to the split product with 2-(2-thienyl)-ethanol-p-toluenesulfonate to obtain 2-chlorophenyl-2-thienylethylamine methyl acetate hydrochloride, taking reaction with formaldehyde to close ring to obtain clopidogrel, and carrying out acidification with sulfuric acid to obtain clopidogrel hydrosulfate. The provided synthetic method is simple in route, high in yield, low in cost, and simple to operate. The method for preparing clopidogrel and the intermediate of clopidogrel is easy to industrially produce. During the test process, the method is free from special, toxic and harmful reagents, and beneficial to environment protection. The synthetic process can be operated at normal temperature; the reaction conditions are mild; the processing equipment is simple; the method is easy to realize industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and relates to a preparation method of clopidogrel and its intermediate. Background technique [0002] Clopidogrel is a new generation of platelet aggregation inhibitor researched and developed by Sanofic Company of France in 1986. It can be used clinically to prevent and treat myocardial infarction, ischemic cerebral thrombosis, vasculitis obliterans, and complications caused by atherosclerosis and thromboembolism. disease. Applied to patients with recent stroke, myocardial infarction or confirmed peripheral arterial disease, treatment can reduce the occurrence of atherosclerotic events (myocardial infarction, stroke and vascular death). Compared with other antiplatelet drugs, clopidogrel has the advantages of good curative effect, low cost, and small adverse reactions. In 1998, clopidogrel was first launched in the United States, and then entered Europe, Canada, Australia, Singapor...

Claims

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Application Information

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IPC IPC(8): C07D495/04C07D333/20C07C227/34C07C229/36
CPCC07C227/34C07D333/20C07D495/04C07C229/36
Inventor 刘发文许卫东
Owner SHANDONG LUYAO PHARMA
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