Studies On The Synthesis Of Clopidogrel Besilate

This paper briefly introduces the research background,mechanism of action,clinical application and market prospect of clopidogrel besilate for the treatment of heart,brain and other arterial circulation disorders caused by high platelet aggregation,and discusses the synthesis of clopidogrel besilate.The original research was introduced in the form of clopidogrel bisulfate by Sanofi of France.Clopidogrel besilate is a generic drug,and as a second-generation adenosine diphosphate receptor antagonist,it has broad market prospects in the field of anti-platelet aggregation therapy.Clopidogrel is the basic drug of clopidogrel besilate.Clopidogrel has a chiral center in its molecular structure.The effective one is(S)-configuration,and the(R)-configuration have no pharmacological effect.The key to synthesis is how to synthesize high purity(S)-clopidogrel.Based on the analysis and comparison of the synthetic route of clopidogrel besilate reported in many literatures,this paper chose the suitable synthetic route for industrial production.Taking(R)-O-chloromandelic acid as the starting material,clopidogrel besilate was obtained through four steps of esterification,sulfonylation,condensation and salt formation,salt exchange.The total molar yield of four steps is more than 44.8% and the purity of clopidogrel besilate is higher than 99.9%.The synthetic route avoids patent protection,no high risk reaction,no high toxicity and high cost materials.The synthetic route parameters of each step were studied,and all intermediates and clopidogrel besilate were characterized by NMR.In addition,the crystal forms of clopidogrel besilate were also studied.The paper had entered the kilogram pilot batch in the foundation of the lab batch.On the basis of successful kilogram pilot batch,the synthetic route verification production was carried out.The sample of clopidogrel besilate obtained by synthetic route verification was performed to confirm the molecular structure of clopidogrel besilate by elemental analysis,nuclear magnetic resonance spectroscopy,and other tests.After research,the synthetic route of clopidogrel besilate suitable for industrial production was obtained,which also laid the foundation for preparation research.