苯磺顺阿曲库铵的工艺杂质及结晶条件
Process Impurities and Crystallization Conditions of Cisatracurium Besylate
韩月文 1彭朋 2刘甲甲 3陈香宇 4张福利 3赵传猛3
作者信息
- 1. 上海工程技术大学,上海 201203
- 2. 浙江工业大学长三角绿色制药协同创新中心,浙江杭州 310014
- 3. 中国医药工业研究总院有限公司,上海医药工业研究院有限公司,上海 201203
- 4. 博崤(杭州)生物制药有限公司,浙江杭州 311404
- 折叠
摘要
分析苯磺顺阿曲库铵(1)粗品中8个有关物质的来源,并以(1R,2R)-1-[(3,4-二甲氧基苯基)甲基]-2-[3-(叔丁氧基)-3-氧代丙基]-1,2,3,4-四氢-6,7-二甲氧基-2-甲基异喹啉鎓苯磺酸盐(4)为原料,通过酸解、酯化反应,定向合成了欧洲药典有关物质(杂质A、B、C、D、F、H、O)和非药典杂质(1R,2R)-1-(3,4-二甲氧基苄基)-2-(3-乙氧基-3-氧代丙基)-6,7-二甲氧基-2-甲基-1,2,3,4-四氢异喹啉鎓苯磺酸盐(6),结构均经1HNMR、13C NMR和HRMS确证.同时,通过对1结晶体系的考察,开发了一条杂质去除效果明显的结晶工艺,收率较高,适合工业化生产.
Abstract
The sources of eight related substances in the crude product of cisatracurium besylate(1)were analyzed,and the related substances A,B,C,D,F,H,O included in EP and the non-pharmacopoeial impurity(6),named(1 R,2R)-1-(3,4-dimethoxybenzyl)-2-(3-ethoxy-3-oxo-propyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinium benzenesulfonate were synthesized by the acid hydrolysis and esterification with(1R,2R)-l-[(3,4-dimethoxyphenyl)methyl]-2-[3-(tert-butoxy)-3-oxy-propyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinolinium benzenesulfonate(4)as the starting material.The structures of these compounds were confirmed by 1H NMR,13C NMR and HRMS analyses.Additionally,a crystallization process with obvious impurity removal effect and high yield was developed,which was suitable for indus-trial production.
关键词
苯磺顺阿曲库铵/纯化/有关物质/定向合成/结晶Key words
cisatracurium besylate/purification/related substance/directional synthesis/crystallization引用本文复制引用
出版年
2024
NETL
NSTL
万方数据