Preparation Of High Purity Clopidogrel And Its Bisulfate Crystal Forms

Clopidogrel,a antiplatelet drug developed by French Sanofi,was first introduced in the form of clopidogrel hydrogen sulfate,which has a significant effect and a promising future.The compound belongs to thiophene pyridine chiral compound,and its synthesis technology is quite difficult.The purpose of this study is to optimize the original method for the synthesis of clopidogrel,designed a new synthetic route suitable for industrial production,synthesized the free state of clopidogrel with high optical purity,and studied the synthesis and characterization of three kinds of crystal forms,avoiding the protection of the existing special protection for the crystal type ?,which is clopidic.The research of clopidogrel preparation creates favorable conditions.In this paper,the synthetic route was studied,and three routes were selected.It was found that the self designed route was suitable for industrial production.Therefore,it was defined as a synthetic route,and then three kinds of crystalline forms of its sulfate were explored.Firstly,the synthetic route of clopidogrel is reviewed.On the basis of the existing literature,it is based on the industrial production as a purpose.It uses simple and easy industrial production as the starting material for environmentally friendly and non-toxic products,and develops a mild and easy to industrial production line,and a racemic adjacent chlorobenzene ammonia.Clopidogrel was obtained by the reaction of methylene esterification,nucleophilic substitution with thiophene-2-ethyl p-toluene sulfonic acid,Manihi condensation and separation of paraformaldehyde.NMR,MS,polarimetry and elemental analysis were performed to confirm the molecular structure of S-clopidogrel.Secondly,three types of S-clopidogrel sulfates were selected:?,? and amorphous,and the preparation methods for obtaining high purity free state were studied.Thermal analysis,infrared,powder X-Ray and microscope observation were made to obtain the products,and the respective spectra of three kinds of crystals were obtained.Finally,the experimental conditions for the preparation of the most difficult crystalline 1 were refined.The technological conditions for the preparation of the crystalline ? were studied from the types of solvent,the crystal seed,the reaction temperature and the stirring speed,and the raw material cost of the preparation of the crystalline I was also calculated.According to the synthesis method of this paper,the raw material cost of the clopidogrel hydrogen sulfate crystalline I can be prepared by 1254.08 yuan/kg,the yield is 26%(higher than the literature yield 20%),the purity is higher than 99.95%,and the purity is very high.This article is designed to be an ideal industrial route.