第 51 卷第 4 期 Vol. 51 No. 4 2021 年 8 月 Aug 2021

所属栏目：医药及中间体 利伐沙班的合成工艺改进及其对映异构体杂质的制备

吴世刚，汤 燕，韩爱华，黄 勇，黄 凯* （宿州亿帆药业有限公司，安徽 宿州 234000）

摘　要：改进了利伐沙班（1）的合成工艺。以4-（4-氨基苯基）-3-吗啉酮（2）为起始原料、与R-环氧氯丙烷（7）加成，再与N，N'-羰基二咪唑环合、与邻苯二甲酰亚胺钾（8）取代，然后在水合肼中水解，最后与5-氯噻吩-2-甲酰氯（9）经酰化反应制得利伐沙班成品，总收率达46.1%，产品纯度大于99.8%，最大单杂小于0.1%。为了控制1 的质量，建立1 原料药的质量标准，根据改进的工艺合成路线，将产品的e.e值提高到99%以上，制备了对映异构体杂质（有关物质A），并经MS和NMR确认结构。

关键词：利伐沙班；对映异构体；有关物质

中图分类号：R97　　文献标识码：A　　文章编号：1009-9212（2021）04-0020-04

Improved Synthetic Process for Rivaroxaban and Its Related Substances

WU Shi-gang, TANG Yan, HAN Ai-hua, HUANG Yong, HUANG Kai* (Suzhou Yifan Pharmaceutial Co.,Ltd., Suzhou 234000, China)

Abstract：The synthetic process for Rivaroxaban (1) was improved. 4-(4-aminophenyl)-3-morpholinone (2) was used as the starting material and reacted with R-epichlorohydrin(7) followed by addition, cyclization reaction with N,N'-carbonyldiimidazole; substitution with potassium phthalimide(8); then hydrolyzed in hydrazine hydrate, and finally with 5-chlorothiophene-2-carboxylic acid chloride(9). The final product of rivaroxaban was prepared by acylation reaction with a total yield of 46.1%. A purity of more than 99.8% with the maximum single impurity of less than 0.1% was obtained. In order to control the quality of 1 and establish the quality standard of 1 API, the e.e value of the product was increased to more than 99% according to this improved synthetic process while the enantiomeric impurity (related substance A) was prepared. The enantiomeric impurity was also confirmed by MS and NMR.

Key words：rivaroxaban; enantiomers; related substance

基金项目：安徽省科技重大专项（812116803026）

作者简介：吴世刚（1986—），男，湖南邵阳人，执业药师，硕士，主要从事原料药的研发和产业化生产。

收稿日期：2021-08-26