Research On The Synthesis Of Clopidogrel Hydrosulfate Process

Clopidogrel is one of the new thieno [3,2-c] pyridine derivatives, which caninhibit ADP-induced platelet aggregation.The effect of Clopidogrel is remarkable,butthe production techniques have considerable difficulty.This thesis is mainly focusedon the further study of the synthetic route and process of the Clopidogrel.(1)Three synthetic routes were selected on the basis of the comprehensiveresearch on the literatures and patents about the synthesis of Clopidogrel hydrogensulfate.The first route, e.e. values of Clopidogrel bisulphate confirmed to the Europeanpharmacopoeia standard was synthesized by (R)-2-(2-Chlorophenyl)-2-(hydroxyl)acetic acid as raw material.The cellulose column was first applied for thedetermination of Clopidogrel hydrogen sulfate e.e. values. The yield of (S)-clopidogrel hydrogen sulfate was raised from51%to60%. The crystal form of(S)-Clopidogrel hydrogen sulfate which was synthesized by this route was form-Ⅰ.The second route,(S)-Clopidogrel hydrogen sulfate was synthesized by(S)-methyl-α-amino-α-(2-chl-orophenyl)acetate via four steps reactions includingMannich condensation etc. After optimizing the synthetic conditions，the specificoptical rotation of the intermediate (S)-(+)-methyl-α-[[2-(thien-2-yl]amino]-α-(2-chlorophenyl)acetate is superior to the literature data when this key intermediates wassynthesized.The third route,(RS)-α-amino-α-(2-chlorophenyl)acetic acid was used as rawmaterial. In this route, the reaction conditions of methyl ester reaction,substitutereaction with2-(2-Thieny)ethyl tosylat，Mannich reaction with paraformaldehydeand the chiral separate reaction of racemic (RS)-Clopidogrel etc were mainlyexplored.The intermediate (RS)-(±)-methyl-α-[[2-(thien-2-yl]amino]-α-(2-chlorophenyl)acetate hydrochloride was got in the yield of77.34%,and theconditions of this reaction were potassium carbonate powder as base who has passedthrough the325mesh sieve, acetonitrile as solvent, over a325mesh sieve KI ascatalyst,83℃refluxed for30hours and those conditions were first been reported. After gropping for the resolution conditions of final product (RS)-Clopidogrel,we get(S)-Clopidogrel hydrogen sulfate salt with the e.e. value of98.89%.The total yieldwas25.35%, higher than the yield of19.5%reported in the literature.(2)Finally, quality inspection of the (S)-Clopidogrel hydrogen sulfate werecarried out,including the specific optical rotation,loss on drying,determination ofrelated substances and content determination.All of those indicators were conformedto the state pharmacopoeia commission on new drug obtainment of the provisions ofthe standard-Clopidogrel hydrogen sulfate parts.