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.
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