立他司特关键中间体的合成工艺优化  

Optimization of the synthetic process for key intermediate of lifitegrast

作　　者：胡怡真 孙嘉伟 刘世超 赵靓靓 杨钰焮 李艳杰[1] HU Yi-zhen;SUN Jia-wei;LIU Shi-chao;ZHAO Liang-liang;YANG Yu-xin;LI Yan-jie(College of Pharmacy,Changchun University of Traditional Chinese Medicine,Changchun 130117,China;Jilin Province Broadwell Pharmaceutical Co.Ltd.,Changchun 130117,China)

机构地区：[1]长春中医药大学药学院,吉林长春130117 [2]吉林省博大伟业药物研究有限公司,吉林长春130117

出　　处：《化学研究与应用》2025年第3期748-752,共5页Chemical Research and Application

基　　金：吉林省辽源市医药健康产业发展项目(202100010)资助。

摘　　要：立他司特是一种治疗干眼症的处方药,本文对其关键中间体5,7-二氯-1,2,3,4-四氢异喹啉-6-甲酸(1)合成工艺进行了改进与优化。以3,5-二氯苯甲酰氯和2-氨基乙醇为起始原料,依次经酰化、还原、FriedelCrafts烷基化、氨基保护、羧基化及脱保护反应制得1。考察了催化剂用量、温度、时间等因素对反应的影响,获得了实施该反应的优化条件。反应总收率49.8%,产品纯度99.4%以上,首步投料量达500克级规模。该工艺路线具有原料易得、收率较高、有利于工业化生产等优点。Lifitegrast is a prescription drug for the treatment of dry eye disease.In this work,the synthetic process of key intermediate of Lifitegrast(1)was improved and optimized.Using 3,5-dichlorobenzoyl chloride and 2-aminoethanol as starting materials,1was obtained by acylation,reduction,Friedel-Crafts alkylation,amino protection,carboxylation and deprotection reaction.The optimal reaction conditions were obtained through the investigation of main influence factors such as catalyst dosage,temperature,and time.Under the optimum conditions,the total yield was 49.8%,the purity of product was more than 99.4%,and the initial feeding amount reached a scale of 500 grams.This synthetic method has the advantages of available starting materials,high yield,and more conducive to industrial production.

关 键 词：立他司特 干眼症 中间体 工艺优化 

分 类 号：O621.3[理学—有机化学]