5,7-二氯四氢异喹啉-6-羧酸（lifitegrast（Xiidra）的关键中间体）的实用合成方法

Practical Synthesis of 5,7-Dichlorotetrahydroisoquinoline-6-carboxylic Acid-Key Intermediate of Lifitegrast (Xiidra).

作者信息

Liu Xu, Guo Heng, Peng Peng, Li Yaping, Yang Jiangtao, Wu Chuanjun, Xu Shengjun, Zhao Chuanmeng, Zhang Fuli

机构信息

Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Pudong District Shanghai 201203, China.

Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China.

出版信息

ACS Omega. 2023 May 16;8(21):19072-19080. doi: 10.1021/acsomega.3c02188. eCollection 2023 May 30.

In the present study, a practical method for synthesizing the key intermediate 5,7-dichlorotetrahydroisoquinoline-6-carboxylic acid () of Lifitegrast was proposed. First, an investigation was conducted into the utilization of the impurity and recrystallization method in the synthesis of 5,7-dichlorotetrahydroisoquinoline (·HCl) via Friedel-Crafts cyclization. Through the screening of different protection groups, a previously unreported quaternary ammonium salt () was isolated with a 95.9% yield and 99.6% purity by simply adjusting the pH during the carboxylation reaction. Subsequently, free state was obtained by controlling the pH to 4-5 with HCl(aq), thereby avoiding the need for a free operation in the synthesis of the API of Lifitegrast. Further, the triphenylmethanol (TrOH) was recycled to triphenylmethyl chloride (TrCl) using CaCl/HCl(aq) with 93.0% yield and 98.0% purity.

在本研究中，提出了一种合成Lifitegrast关键中间体5,7-二氯四氢异喹啉-6-羧酸（）的实用方法。首先，对杂质利用和重结晶方法在通过傅克环化合成5,7-二氯四氢异喹啉（·HCl）中的应用进行了研究。通过筛选不同的保护基团，通过在羧化反应过程中简单调节pH值，以95.9%的产率和99.6%的纯度分离出一种以前未报道的季铵盐（）。随后，用盐酸水溶液将pH值控制在4-5，得到游离态的，从而避免了Lifitegrast原料药合成中需要进行的游离操作。此外，使用CaCl/盐酸水溶液将三苯甲醇（TrOH）循环转化为三苯甲基氯（TrCl），产率为93.0%，纯度为98.0%。