An Improved Commercial\nProcess for the Preparation\nof Lifitegrast

A straightforward,\nefficient, and scalable commercial manufacturing\nprocess was developed for the ophthalmic anti-inflammatory drug lifitegrast\nvia a novel ester intermediate from commercially available starting\nmaterials. Lifitegrast (Xiidra) was approved by the FDA on July 11,\n2016, for the treatment of signs and symptoms of dry eye, a syndrome\ncalled keratoconjunctivitis sicca. The breakthrough step of this new\nprocess is the discovery of an <i>N</i>-Boc deprotection\nreaction that simultaneously transesterifies an intermediate to a\nnew ester by using oxalyl chloride, which has favorable isolation\nproperties. As a result of transesterification, the hydrolysis of\nthe new ester intermediate occurs under milder conditions, which improves\nthe quality of the product by reducing racemization. Lifitegrast prepared\nfrom this new process complied with the quality guidelines, as per\nthe International Council for Harmonization (ICH). By using this new\nprocess, lifitegrast was produced on a 2 kg scale with an overall\nyield of 66%.