Development of a Novel Chemoenzymatic Process for 3-(Methylsulfonyl)-l-phenylalanine Phenylmethyl Ester─A Key Intermediate of Lifitegrast (Xiidra)

Abstract

In the present study, a practical chemoenzymatic method was developed for the synthesis of chiral phenylalanine derivative 1, which is the key intermediate of Lifitegrast. In this established process, a simple and effective Zn/HCl reduction system was employed to obtain N-acetyl-3-bromo-phenylalanine 6, which served as the substrate for the subsequent enzymatic resolution process. Then, the key chiral intermediate, 3-bromo-L-phenylalanine 7, could be obtained using acylase (ACY) AmACY. Upon process optimization, the chemical reaction was executed at a 300 g scale, with a notable substrate concentration reaching up to 100 g/L. The process achieved a yield of 40%, compared to a maximum theoretical yield of 50%, and exhibited an enantiomeric excess (ee) value reaching up to 99.9%. A simple and effective Zn/HCl reduction system was employed to obtain N-acetyl-3-bromophenylalanine 6, which served as the substrate for the subsequent enzymatic resolution process. This synthetic pathway was effectively executed, yielding 1•HCl with a purity of 99.7% and an ee value of 99.9%, culminating in an overall yield of 23.4%. Additionally, the undesired (D)-6 enantiomer was recycled to form (rac)-6, employing an acetanhydride/acetic acid (Ac 2 O/AcOH) system. This recycling process achieved a yield of 47.5%, relative to a maximum theoretical yield of 50%, and a purity level of 99.8%.