Study On The Synthesis Process Of Clopidogrel

Clopidogrel is a thienopyridine of which S-enantiomer is pharmacologically active. It is a non-competitive inhibitor of adenosine diphosphate(ADP) at the platelet receptors. The activation and aggregation of platelets are inhibited by clopidogrel. It is the main drug of prevention and treatment of atherosclerosis, myocardial infarction, acute coronary syndrome and other thrombotic diseases.The synthetic process of clopidogrel base was optimized and improved in the paper. Synthetic process of clopidogrel base included four steps. The materials were DL-chlorophenylglycine and 2-thiopheneethanol. Many aspects of the synthetic process were studied,such as the mole reaction ratio of materials, the reaction temperature, the reaction time, the reaction solvent and the crystallization process etc. By chemical resolution of starting materials and the intermediates,the enantiomeric excess of the clopidogrel was improved. The amount of R-isomer impurities of clopidogrel was reduced. The chemical structure of the clopidogrel base was confirmed by NMR and MS.The salt forming process of clopidogrel besilate was developed in the paper. As only one crystalline form, the salt forming process of which is relatively easier than the clopidogrel hydrogen sulfate. The reaction optimum conditions are as follows: the reaction solvent is 2-Butanone, the mole reaction ratio of clopidogrel: benzenesulfonic acid is 1:1.05, the reaction temperature is 20~30?, the crystallization temperature is 0~5?.The quality of the intermediate and product of clopidogrel was detected by HPLC. The chemical purity and enantiomeric excess of the clopidogrel base and its besylate were 99.9% and 99.8%. The total yield was more than 60%. This process is beneficial to further development of the industrial process.