关键词: 利伐沙班, 利伐沙班中间体, 甲磺酸, 原研路线, 工艺优化

Abstract: 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.

Key words: Rivaroxaban, Rivaroxaban intermediate, Patent protection, Process optimization