Scalable Process for Making 5,7-Dichlorotetrahydroisoquinoline-6-carboxylic Acid Using Methylene as the Protecting Group

The development of an industrially scalable synthetic route for 5,7-dichlorotetrahydroisoquinoline-6-carboxylic acid (1), a key starting material for lifitegrast, is described. This route includes the following features: (1) tetrahydroisoquinoline 19 was prepared in three steps from readily commercially available 3,5-dichlorobenzoyl chloride and 2-aminoethanol in a high total yield of 76%; (2) formaldehyde instead of triphenylmethyl chloride was employed in the protection of the secondary amine, resulting in much higher atom economy; (3) the target compound 1 was produced in an overall yield of 66% with an HPLC purity of 99% by area.