The Synthesis Of Rivaroxaban: An Blood Coagulation Factor Xa Inhibitor

Venous thromboembolism is an important public health problem in today’s society. It is said the global top three diseases which have the highest morbidity and morbidity with stroke and ischemic heart disease, due to a high mortality and mortality. Because of the long-term complications, it brings the health care system a heavy social and economic burden.Rivaroxaban is the first oral, direct X a factor inhibitor, mainly for the prevention of venous thromboembolism after replacement surgery on knee or hip. Because of having high bioavailability, lasting effect, once-daily medication, a wide therapeutic window, being not need for routine coagulation monitoring and dose adjustment, it is one of the most promising anti-venous thromboembolism drugs.Reviewing the synthesis literature of Rivaroxaban, we proposed two new synthetic routes to build the oxazolidinone of Rivaroxaban.Route one:Rivaroxaban was synthesized from ethanolamine and chlorine ethyl acetate through cyclization, Goldberg coupling, reduction, amino protection, cyclization, nucleophilic substitution, hydrazinolysis and acylation. We got Rivaroxaban through eight steps of reactions and used sodium hydride and lithium chloride instead of expensive organolithium reagent in the cyclization of five-membered ring. This method was easy to operate with mild reaction conditions.Route two:Rivaroxaban was synthesized from ethanolamine and chlorine ethyl acetate through cyclization, Goldberg coupling, bromination, Goldberg coupling, hydrazinolysis and acylation. By Goldberg coupling, we synthesized Rivaroxaban through six steps of reactions. This method was easy to operate and, less synthetic steps and mild reaction conditions.Date of the 1H-NMR,13C-NMR of all products and the optical rotation of the the final product in two synthetic routes are consistent with literatures.