利非斯特有关物质的合成  

Synthesis of the Related Substances of Lifitegrast

作　　者：蒋港龙 张晓雯 孟冬朔 刁文爽 刘育 JIANG Ganglong;ZHANG Xiaowen;MENG Dongshuo;DIAO Wenshuang;LIU Yu(IncubationCenter of S&T Achievements,Shanghai Institute of Pharmaceutical Industry Co.,Ltd.,China State Institute of Pharmaceutical Industry,Shanghai 201203;Shanghai Engineering Research Center of Pharmaceutical Process,Shanghai 201203)

机构地区：[1]中国医药工业研究总院有限公司,上海医药工业研究总院有限公司,科技成果转化中心,上海201203 [2]上海制药工艺工程研究中心,上海201203

出　　处：《中国医药工业杂志》2023年第10期1442-1449,共8页Chinese Journal of Pharmaceuticals

摘　　要：为优化利非斯特(1)原料药的质量控制,基于原研工艺合成了5个工艺杂质,分别是(S)-2-氨基-3-[3-(甲磺酰基)-苯基]丙酸盐酸盐(有关物质A)、5,7-二氯-1,2,3,4-四氢异喹啉-2,6-二羧酸-6-(3H-[1,2,3]噻唑并[4,5-b]吡啶-3-基)-酯-2-(叔丁基)酯(有关物质B)、(S)-2-(5,7-二氯-1,2,3,4-四氢异喹啉-6-甲酰胺基)-3-[3-(甲磺酰基)苯基]丙酸乙酯盐酸盐(有关物质C)、(S)-2-(5,7-二氯-1,2,3,4-四氢异喹啉-6-甲酰胺基)-3-[3-(甲磺酰基)苯基]丙酸盐酸盐(有关物质D)及2-(苯并呋喃-6-羰基)-5,7-二氯-1,2,3,4-四氢异喹啉-6-甲酸(有关物质E),其中有关物质B与有关物质C未见文献报道。另外,合成了对映异构体(R)-1,过程中得到7个对应的异构体中间体,可作为1原料药质量控制的杂质对照品。To perform the quality control of lifitegrast(1),five process impurities were prepared.These substances were(S)-2-amino-3-[3-(methylsulfonyl)phenyl]propanoic acid hydrochloride(related substance A),6-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-2-(tert-butyl) 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-2,6-dicarboxylate(related substance B),ethyl(S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-[3-(methylsulfonyl)phenyl]-propanoate hydrochloride(related substance C),(S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-[3-(methylsulfonyl)phenyl]propanoic acid hydrochloride(related substance D),2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid(related substance E).The related substances B and C had not been reported in the literature.Meanwhile,seven corresponding isomeric intermediates were synthesized in the preparation of(R)-1.They could be used as the reference substances for the quality control of 1.

关 键 词：利非斯特 有关物质 对映异构体 合成 

分 类 号：R988.1[医药卫生—药品]