Research On Synthesis Of Anti Platelet Aggregation Drug Prasugrel And Synthesis Of Its Impurity

Prasugrel is an anti-thrombotic drug,which has a good effect on the clinical application.The article mainly introduced the synthetic route of Prasugrel and the application of Vilsmeier–Haack reagent in ring opening reaction of cyclopropyl.This article contains four chapters.The first chapter mainly summarized the synthesis methods of prasugrel reported in the literatures,and the author developed a synthesis route with using cheap materials and brief reaction steps.The second chapter investigated the synthesis routes in detail.The2-fluorophenylacetic acid was used as starting material which reacted with Grignard reagent to obtain 1-cyclopropyl-2-(2-fluorobenzyl)ketone.Then it was brominated to get 2-fluoro-1-cyclopropyl carbonyl benzylbromide by NBS,then reacted with 2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c]pyridinehydrochloride and acetic anhydride in sequence to obtain prasugrel with a overall yield of 30%.A one-pot reaction was developed with combining the condensation reaction and the acetylation reaction.The third chapter introduced the prasugrel impurity,ring opening reaction methods of cyclopropyl and synthesis methods of prasugrel impurity were reviewed.In the fourth chapter,we used the normal ring opening ideas to carry on the ring opening reaction,it was found not effect.The final select of the Vilsmeier-Haack reagent for prasugrel ring opening,the experiments about synthesis of prasugrel impurity were main involved in the fourth chapter.Vilsmeier–Haack reagent was prepared from triphosgene(Bis(trichloromethyl)Carbonate,BTC)and successfully used for cyclopropane opening of prasugrel.Reaction temperature.triphosgene equivalent and reaction time were optimized and the optimum condition is reaction temperature 105 ~oC,triphosgene 0.8equivalents,reaction time of 8 hours,a overall yield of 25%.