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

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%.

Keywords

lifitegrast - benzofuran-6-carboxylic acid - 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid - improved synthetic process

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.

Publication History

Received: 20 February 2023

Accepted: 14 June 2023

Article published online:
03 August 2023

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