抗凝血药物利伐沙班合成新方法研究

Study on the novel method for the synthesis of anticoagulation drug rivaroxaban

目的研究抗凝血药利伐沙班的化学合成新方法。方法以苯氨基乙醇和氯乙酰氯为主要起始原料,经成环、硝化、还原、合环、叠氮基取代、缩合等步骤得到目标产物利伐沙班。结果与结论以总收率40%(以苯氨基乙醇计)合成了利伐沙班。该合成路线反应步骤简短、操作简便、收率高、反应条件温和,适合工业化生产。

Rivaroxaban, a novel oxazolidinone derivatives as a new class of potent Fxa inhibitors,is a repre- sentative of a new series of anticoagulation agents which have been developed in an attempt to circumvent some of the problems associated with conventional therapies. Rivaroxaban was introduced into the market which led to the need for a high-yielding, economical and environmental sound process. The synthesis of ri- varoxaban has been accomplished from commercially available N-phenylethanolamine and chloroacetyl chlo- ride as starting materials through six steps in 40% overall yield. Treatment of N-phenylethanolamine with chloroacetyl chloride in ethanol afforded 4-（4-phenyl）morpholin-3-one （2）. Treatment of compound 2 with concentrated sulfuric acid and 65 % nitric acid provided 4- （4-nitrophenyl） -morpholin-3-one （ 3 ）, which was followed by hydrogenation. Ring-opening of （R）-epichlorohydrin with 4-（4-aminophenyl）-morpholin-3-one （4） in refluxing iPrOH and successive one-pot cyclization by treatment with N, N＇-carbonyldiimidazole （CDI） afforded the desired enantiopure cycloadduct 5 in 73 % yield over two steps. Then oxazolidinone 5 was smoothly transformed into azide 6 under the treatment of sodium azide in 90% yield. Azide derivative 6 was subjected to hydrogenation and acylation with 5-chlorothiophene-2-carboxylic acid, which provided the desired product rivaroxaban in 88% yield over two steps. The structure of the intermediates and the target compound were confirmed by ^1H-NMR and IR analysis and are in good agreement with those reported. The developed method has some advantages such as simple starting materials, mild reaction conditions, ease oper- ations and high yield.