Study Of The Synthesis Process Of Antithrombotic Drug Rivaroxaban

Antithrombotic drugs rivaroxaban is manly used for preventing the formation of hip or knee arthroplasty in patients with deep vein thrombosis and pulmonary embolism,and also used for preventing non-valvular atrial fibrillation in patients with stroke and non-CNS embolism,reduce the risk of recurrent coronary artery syndrome.Rivaroxaban is easy to use,so the research on its synthesis technology has important practical significance.We developed a novel synthetic route of rivaroxaban.Rivaroxaban was synthesized from tert-butoxycarbonyl-4-(3-oxo-morpholinyl)aniline and(S)-epichlorohydrin through nucleophilic ring opening,cyclization,debenzylation,chloride,and acylation in 62%overall yield.The effects of process conditions,such as temperature,pressure,catalyst dosage and solvents were investigated.The optimum process conditions for each reaction step were obtained.In addition,the main impurities which was found in synthesis route was prepared.Its chemical structures were determined.And the mechanism of its formation was discussed.Finally,we designed the brief process flow diagram based on this synthesis route,It presented amplification effect of the route,The plan of waste disprosal from production process was given.Rivaroxaban was synthesized through five steps.This synthetic method has some advantages such as cheap available material,mild reaction conditions,high yield,simple operation and high stereoselectivity,which is suitable for the large-scale production.