CC BY 4.0 · Pharmaceutical Fronts 2023; 05(03): e153-e160
DOI: 10.1055/s-0043-1771035
Original Article

An Improved Synthetic Process of Two Key Intermediates and Their Application in the Synthesis of Lifitegrast

Gang-Long Jiang
1   Incubation Centre of S&T Achievements, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
2   Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
,
Xin-Kun Wang
3   College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, People's Republic of China
,
Xiao-Fei Xiao
1   Incubation Centre of S&T Achievements, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
,
Yu Liu
1   Incubation Centre of S&T Achievements, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
2   Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
› Author Affiliations


Abstract

Benzofuran-6-carboxylic acid 2 and 2-(tert-butoxycarbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid 21 are two key intermediates for the synthesis of lifitegrast (1). The present study aimed to obtain lifitegrast from the key intermediates of 2 and 5,7-dichloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (31), which had the same core structure as 21. In this study, the synthetic routes of 2 and 31 were explored. 2 and 31 were synthesized from 4-bromo-2-hydroxybenzaldehyde (25) and 2-(2,4-dichlorophenyl)ethan-1-amine (28), with the yields of 78 and 80%, respectively. The route avoided the harsh reaction conditions of generating 2 in a previous study and could more efficiently achieve the core structure of 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid. Besides, the hydrolysis reaction conditions of preparing lifitegrast were also optimized. In this work, lifitegrast was obtained from 2 and 31 with high purity (>99.9%) and an overall yield of 79%, which was higher than the reported yield of 66%.

Supporting Information

Full experimental detail, as well as 1H, 13C NMR, HRMS spectra of compound 26, 27, 2, 29, 30, 31, 22, 23, 24, and 1 can be found via the ‘[Supporting Information]’ section of this article's webpage.


Supplementary Material



Publication History

Received: 20 February 2023

Accepted: 14 June 2023

Article published online:
03 August 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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