Study On Synthesis Of Prasugrel

In recent years,the incidence and mortality of cardiovascular disease increased year by year,which has become one of the most important public health problem in our country.Antiplatelet agents can prevent and cure cardiovascular disease through inhibit the platelet adhesion and aggregation,so antiplatelet drugs has become a research hotspot.Prasugrel is a new antiplatelet drug that inhibits P2Y12 receptors on platelets.The drug can reduce the differences between the individual differences and has a rapid onset,a greater reduction in the main ischemic cardiovascular rate because of its higher prodrug to active metabolite conversion and higher bioavailability.This paper developed a new synthetic method of preparing4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride which is an important intermediate of Prasugrel.The synthesis begins from the condensation of2-thiopheneethanol with tosyl chloride in the presence of a acid-binding agent to give 2-(2-thienyl)ethyl tosylate,which was treated with formamide by formic acid as a catalyst to obtain the corresponding N-[2-(2-thienyl)ethyl] formamide.In the subsequent cyclisation step has been carried out with a P2O5/POCl3 system to the corresponding 6,7-dihydrothieno[3,2-c]pyridine,which was reduce with sodium borohydride to 4,5,6,7-tetrahydrothieno[3,2-c] pyridine hydrochloride.The total yield was 72.3% in the optimum conditions.The method avoids the 2-thiopheneethylamine,the raw materials are cheap compared with the original route.The new route we designed provided a new direction for the industrialization of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride.we optimized the synthetic of Prasugrel and obtained some results as bellow.First,the yield was increased from 97% to 99.2% when synthesized5-Trityl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin from 4,5,6,7-Tetrahydrothieno[3,2-c]pyridine hydrochloride.Second,the operation is simplified when synthesized 5,6,7,7a-Tetrahydro-5-(triphenylmethyl)thieno[3,2-c]pyridin-2(4H)-one from 5-Trityl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin.Third,the yield was increased from 97% to 99.5% when synthesized 5,6,7,7a-Tetrahydro-thieno[3,2-c]pyridin-2(4H)-one Hydrochloride from 5,6,7,7a-Tetrahydro-5-(triphenylmethyl)thieno[3,2-c] pyridin-2(4H)-one.Finally,the post processes for the reactions were optimized and the column chromatography purification steps were no longer needed,which made the reaction more suitable for industrial production when we synthesized Prasugrel from 5,6,7,7a-Tetrahydro-thieno[3,2-c]pyridin-2(4H)-one Hydrochloride.In this paper,the total yield of Prasugrel was 41.5%,and the structure wasdetermined by 1HNMR and IR.The purity was 99.8% by HPLC.