Synthesis of clopidogrel intermediate (S)-2-(2-thiopheneethylamino)-(2-chlorophenyl)-methyl acetate

Abstract

Belonging to the technical field of medicine, the invention relates to synthesis of a clopidogrel key intermediate (S)-2-(2-thiopheneethylamino)-(2-chlorophenyl)-methyl acetate and a salt thereof. Theinvention discloses a new process for synthesis of the intermediate by taking the succinonitrile as a nucleophilic substitution reaction key solvent for the first time, overcomes many defects of theexisting process, has the advantages of short reaction time, high yield, good product quality, economical efficiency, environmental protection and the like, and is suitable for large-scale industrialproduction.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to the synthesis of (S)-2-(2-thienylethylamino)-(2-chlorophenyl)-acetic acid methyl ester and its salt, a key intermediate of clopidogrel. [0002] technical background [0003] At present, cardiovascular and cerebrovascular diseases have become the number one killer threatening human health and life in the world. According to the report of the World Health Organization, the death toll of cardiovascular and cerebrovascular diseases accounts for 35% of the total death toll in the world. The morbidity and mortality of cardiovascular and cerebrovascular diseases in my country rank first among various diseases, among which the mortality of cardiovascular and cerebrovascular diseases caused by atherosclerosis and thrombosis, such as cerebral apoplexy, hypertension and coronary heart disease, accounts for About 30% of the total mortality. [0004] Clopidogrel (Clopidogrel) is a new type of...

AI Technical Summary

Problems solved by technology

[0010] 1. In the existing synthesis process, the nucleophilic substitution reaction time is too long, some even nearly 3 days;

[0011] 2. The yield is low, between 14% and 94%;

[0012] 3. Most of the product purity has not been reported and is unknown;

[0013] 4. There is a racemization problem in the product, which affects the optical purity and ultimately affects the optical purity of clopidogrel;

[0016] 1. At present, the boiling point of the solvent used in the nucleophilic substitution reaction is generally lower than 100°C. In addition, the reaction time is too long, resulting in a large amount of volatilization loss of the reaction solvent during the long-term heating process. The solvent needs to be replenished during the reaction, which increases the process complexity and cost and pollute the environment

[0017] 2. Solvent-free nucleophilic substitution reaction actually uses thiophene-2-ethyl p-toluenesulfonate as a solvent with a lower melting point. As the reaction progresses, the raw material is continuously consumed and the product continues to increase, resulting in the entire reaction system The viscosity keeps increasing, becoming more and more viscous, the stirring is difficult and uneven in the middle of the reaction, and the material even solidifies and sticks to the reaction vessel, which is not conducive to the mass transfer reaction, and ultimately affects the purity, yield and specific rotation of the product

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