Process Optimization Of Clopidogrel Bisulfate And Synthesis Of Related Substances

Clopidogrel bisulfate is a second-generation thienopyridine ADP receptor antagonist that achieves antithrombotic therapy by anti-platelet aggregation,and is commonly used in the treatment of coronary,peripheral and cerebrovascular diseases.Clopidogrel bisulfate contains an asymmetric center and therefore contains two optical isomer compounds.The study found that only(S)-clopidogrel bisulfate had antithrombotic activity.The production process of clopidogrel bisulfate is very complicated.It is of great significance to develop a process route that is economical,safe and efficient,with ideal yield,and the final product quality meets the requirements through process optimization.The research content of this paper is mainly divided into two parts.1.According to the proposed synthetic process route of clopidogrel bisulfate,in addition to the related substances described in the chinese pharmacopoeia,five process related substances that may be produced are analyzed,namely(S)-methyl 2-(2-chlorophenyl)-2-((4-methylphenyl)sulfonamido)acetate(A),(S)-methyl 2-(bis(2-(thiophen-2-yl)ethyl)amino)-2-(2-chlorophenyl)acetate(B),(S)-methyl 2-(2-chlorophenyl)-2-(methyl(2-(thiophen-2-yl)ethyl)amino)acetate(C),(S)-ethyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate(D),(S)-5-(1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-6,7-dihydrothieno[3,2-c]pyridine-5-ammonium(E).We used the readily available materials in the synthesis process route of clopidogrel bisulfate to synthesize these five related substances.The route is simple and the yield is ideal.And established a liquid phase detection method suitable for these five related substances,which can not only analyze their purity,but also separate them from the liquid phase peaks of the standard clopidogrel bisulfate,which lays a foundation for the subsequent process optimization.2.According to the proposed synthetic process route of clopidogrel bisulfate,there are three-step reactions,which are the synthesis of 2-(thiophen-2-yl)ethyl 4-methylbenzenesulfonate,synthesis of(S)-methyl 2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate hydrochloride,and synthesis of clopidogrel bisulfate.We analyze the mechanism of each step of the reaction,and conduct experimental screening through the single-factor experiment method to determine the reaction temperature,reaction solvent,raw material charging ratio,type and amount of acid scavenger,and recrystallization and purification method for each step of the reaction.Finally,a process route with easy operation,ideal yield and promising industrial production was obtained through process optimization.In addition,we analyze the chemical purity and ee value of the product of each step,and finally analyze the related substances of the final product clopidogrel bisulfate through the liquid phase detection method of the above-mentioned related substances.The above-mentioned 5 related substances are not found.The detected and unknown single impurity content is less than 0.1%,and the total impurity content is less than 0.2%.