An Improved Commercial Process for the Preparation of Lifitegrast

A straightforward, efficient, and scalable commercial manufacturing process was developed for the ophthalmic anti-inflammatory drug lifitegrast via a novel ester intermediate from commercially available starting materials. Lifitegrast (Xiidra) was approved by the FDA on July 11, 2016, for the treatment of signs and symptoms of dry eye, a syndrome called keratoconjunctivitis sicca. The breakthrough step of this new process is the discovery of an N-Boc deprotection reaction that simultaneously transesterifies an intermediate to a new ester by using oxalyl chloride, which has favorable isolation properties. As a result of transesterification, the hydrolysis of the new ester intermediate occurs under milder conditions, which improves the quality of the product by reducing racemization. Lifitegrast prepared from this new process complied with the quality guidelines, as per the International Council for Harmonization (ICH). By using this new process, lifitegrast was produced on a 2 kg scale with an overall yield of 66%.