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

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

doi:10.1021/acsomega.3c02188

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

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

Authors

Xu Liu¹, Heng Guo¹, Peng Peng², Yaping Li³, Jiangtao Yang¹, Chuanjun Wu¹, Shengjun Xu⁴, Chuanmeng Zhao¹, Fuli Zhang¹

Affiliations

¹ Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Pudong District Shanghai 201203, China.
² Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China.
³ School of Chemistry and Chemical Engineering, Shanghai University of Engineering and Science, Songjiang District Shanghai 201620, China.
⁴ Zhejiang Boxiao Biopharmaceutical Co. Ltd, Hangzhou 310014, China.

Abstract

In the present study, a practical method for synthesizing the key intermediate 5,7-dichlorotetrahydroisoquinoline-6-carboxylic acid (1) 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 (5·HCl) via Friedel-Crafts cyclization. Through the screening of different protection groups, a previously unreported quaternary ammonium salt (13) was isolated with a 95.9% yield and 99.6% purity by simply adjusting the pH during the carboxylation reaction. Subsequently, free state 1 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 CaCl₂/HCl(aq) with 93.0% yield and 98.0% purity.