The Synthesis Of Cardiovascular Drugs Of Delapril Hydrochloride And Rivaroxaban

The dissertation work includes two chapters.The chapter one is the synthesis of delapril hydrochloride.Delapril hydrochloride is an oral antihypertensive drug,which is mainly used for the treatment of hypertension of light to severe primary,renal and renovascular.We have designed a simple and practical synthetic route for the preparation of delapril hydrochloride.In this chapter,high pure delapril hydrochloride was obtained by using 2-indenone,glycine tert-butyl ester hydrochloride and L-alanine as the raw materials via reductive amination,esterification,Michael addition,reduction,condensation and hydrolysis into hydrochloride.This chapter focused on the the synthesis of N-(2-Indanyl)glycine tert-Butyl Ester,which is the key intermediate of delapril hydrochloride.In the process of reductive amination we using sodium triacetoxyborohyride,instead of highly toxic sodium cyanoborohydride,which has mild reaction condition,high yield,and more importantly has no environment pollution,This chapter studied the impurities of delapril hydrochloride either,to our surprised we finally synthesized two new impurities which were not reported in the literature.In general,this synthetic route has those characteristics of mild reaction condition,simple operation,and low toxicity,which is suitable for industrial production.The chapter two is the synthesis of rivaroxaban.Rivaroxaban is an efficient FXa inhibitor,which is researched and developed by Bayer Company and Johnson&Johnson.It was first listed in Canada in 2008,has excellent vivo activity and bioavailability on preventing venous thromboembolism after hip or knee replacement.At the same time,rivaroxaban has been used in clinical trials of other indications for ascertaining the latent benefits that it's used for the atrial fibrillation and acute coronary syndrome.This chapter made a comprehensive investigation about the synthesis route of rivaroxaban.Rivaroxaban was obtained by using p-nitroaniline as the raw material and(R)-epichlorohydrin as chiral source via substitution,reduction,cyclization,Gabriel reaction,amination and acylation reaction.This route avoids the azides,has milder reaction conditions and is easy to operate.