利伐沙班合成工艺改进*

目的: 改进利伐沙班的合成工艺,满足产业化生产的要求。方法: 以(S)-N-(2,3-环氧丙基)邻苯二甲酰亚胺和4-(4-氨基苯基)-3-吗啉酮为原料,经过缩合、环合、水解、酰化等反应,最终合成利伐沙班。结果: 研究以甲磺酸代替原专利中的盐酸合成利伐沙班中间体4-4-(5S)-5-(氨甲基)-2-羰基-3-唑烷基]苯基]-3-吗啡啉酮甲磺酸盐,对于路线中的水解、酰化和最终的精制产品的步骤进行了优化,使产品的收率达到96.86 %。结论: 优化后的工艺改善了原研路线中存在的问题和不足,从而极大地提高了操作的安全性以及可行性,更加满足产业化生产的要求。

Improvement of Synthesis Process of Rivaroxaban

Objective: To improve the synthesis process of rivaroxaban while avoiding the patent protection of rivaroxaban. Methods: (S)-(+)-N-(2,3-Epoxypropyl)phthalimide and 4-(4-aMinophenyl)Morpholin-3-one were used as raw materials for the final synthesis of rivaroxaban through condensation, cyclization, hydrolysis and acylation reactions. Results: In the study, the methanesulfonic acid was used instead of hydrochloric acid to synthesize the rivaroxaban intermediate 4-4-(5S)-5(aminomethyl)-2-carbonyl-3-azolidinyl]phenyl]-3-morpholinone methanesulfonate, avoiding patent protection. Also, the steps of hydrolysis, acylation and the final refined product in the route were optimized to achieve a product yield of 96.86 %. Conclusion: The optimized process not only avoids the problems of patent protection in the original route, but also improves the problems in the original route, thus greatly improving the safety and feasibility of the operation, and better meeting the requirements of industrial production.