S-type clopidogrel and preparation method of its salt

Abstract

This invention relates to a preparation method of S - type clopidogrel and its medicinal salt. It includes four steps :( 1) Split racemic Alpha - (2 - thiofuran ethylamino) - Alpha - (2 - chlorphenyl) methyl acetate (II) or its salt to obtain (+) - II and (-) - II or its salt. (2) Racemize (-)- II or its salt to obtain racemic substance II. (3) Repeat first and second step. (4) Adopt (+) - II obtained from first step to prepare S - type clopidogrel and its corresponding salt. This invention use concentrated sulfuric acid to substitute chlorine sulfoxide, reduce toxicant side effect and erosion of equipment.

Description

Technical field: [0001] The invention relates to a preparation method of a compound, especially a method for preparing S-type clopidogrel and a pharmaceutically acceptable salt thereof. Background technique: [0002] Clopidogrel [S(+)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothiophene[3,2-c]pyridine-5)methyl acetate]( Hereinafter referred to as substance I or I), the structural formula is as follows: [0003] [0004] Clopidogrel is a platelet aggregation inhibitor that selectively inhibits the binding of adenosine diphosphate (ADP) to its receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb / IIIa complex, thus inhibiting Platelet aggregation. Clopidogrel was first jointly developed by Japan's Daiichi Pharmaceutical and France's Sanofi (Sanofi), and was launched in the United States in 1998. [0005] European patent EP281459 specifically describes the preparation of the dextroisomer of clopidogrel bisulfate, which has excellent anti-platelet aggr...

AI Technical Summary

Problems solved by technology

[0010] This patent proposes a method that can recycle the isomers or derivatives of the reaction intermediate substance II, but this method also has some defects: 1. It needs to go through a complicated heating and cooling process, which takes a long time. It takes 30-36 hours to complete all the reactions, which consumes a lot of energy and costs

2. During the racemization process, it takes 2-3 hours to react the residue of the mother liquor with the methanol solution of sodium methoxide at 65-70°C. The reaction conditions are harsh, and the resulting product has many impurities and dark color, which affects the quality of the final product clopidogrel

3. In the process of esterification and racemization with thionyl chloride, it is easy to produce a large amount of hydrochloric acid and sulfur dioxide gas, which corrodes the reaction kettle and is very harmful

Images