Improved Synthesis Of Clopidogrel,Preparation Of Crystal Forms And Synthesis Of Impurity B

This thesis is focusing on improved synthesis of clopidogrel,involving resolution of clopidogel intermediates;clopidogel crystal ?,crystal ? were prepared,optimum condition were established,transformation of high melting point and low melting point was researched;impurity B was synthetized,reaction condition were optimizined.Directly condensation reaction of 2-chlorophenyl glycine methyl ester(8)and 2-(2-thienyl)ethyl toluene-p-sulphonate to give(1)-2-(2-thienylethamino)(2-chlorophenyl)acetate(11),resolved by tartaric acid to give(S)-(±)-2-(2-thienylethamino)(2-chlorophenyl)acetate tartrate(13),yield 25%;benzaldehyde,salicylaldehyde as catalysts were attempted to realize kinetic resolution,the results show that benzaldehyde salicylaldehyde can't catalyze reaction;resolution of 2-(2-thienylethamino)(2-chlorophenyl)acetic acid(14)was attempted to give(S)-(+)-2-(2-thienylethamino)(2-chlorophenyl)acetic acid tartrate,the experiment show that tartaric acid can't resolve it.High melting point crystal I as raw material,methanol as solvent,isopropyl alcohol as antisolvent,solvent dosage and crystallization time were controlled,high melting point crystal I can be transformed into low melting point crystal I;clopidogrel free base as raw material,crystal II was prepared,concentration of the sulfuric acid,temperature of salification and crystallization,solvents were investigated;the optimum condition was established,crystal types were confirmed by XRD,DSC.Thiophene(2)as raw material,3-bromothiophene(4)was prepared by bromination and reduction;reacted with epoxy ethane to give thiophene-3-ethanol(5);clopidogrel impurity B(1)was synthetized by esterification,condensation,cyclization,yield:21.6%.