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

作者：Liu, Xu; Guo, Heng; Peng, Peng; Li, Yaping; Yang, Jiangtao; Wu, Chuanjun; Xu, Shengjun; Zhao, Chuanmeng^*; Zhang, Fuli^*

来源：ACS Omega, 2023, 8(21): 19072-19080.

DOI：10.1021/acsomega.3c02188

• ACID

In the present study, a practical method for synthesizingthe keyintermediate 5,7-dichlorotetrahydroisoquinoline-6-carboxylic acid(1) of Lifitegrast was proposed. First, an investigationwas conducted into the utilization of the impurity and recrystallizationmethod in the synthesis of 5,7-dichlorotetrahydroisoquinoline (5 & BULL;HCl) via Friedel-Crafts cyclization. Throughthe screening of different protection groups, a previously unreportedquaternary ammonium salt (13) was isolated with a 95.9%yield and 99.6% purity by simply adjusting the pH during the carboxylationreaction. Subsequently, free state 1 was obtained bycontrolling the pH to 4-5 with HCl-(aq), thereby avoiding theneed for a free operation in the synthesis of the API of Lifitegrast.Further, the triphenylmethanol (TrOH) was recycled to triphenylmethylchloride (TrCl) using CaCl2/HCl-(aq) with 93.0% yield and98.0% purity.

• 单位
  上海医药工业研究院; 上海工程技术大学; 浙江工业大学