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

• DOI: 10.1021/acs.oprd.3c00358
• Publication Date: 2024-02-14T19:24:27Z
• Authors: Chuanjun Wu; Heng Guo; Jiawei Tang; Lintao Xia; Jianfen Shao; Yongfu He; Fei Chen; Peng Peng; Yuewen Han; Chuanmeng Zhao; Fuli Zhang; Shaoxin Chen
• Keywords: Enantiomeric excess; Derivative (finance)

In the present study, a practical chemoenzymatic method was developed for synthesis of chiral phenylalanine derivative 1, which is key intermediate Lifitegrast. this established process, simple and effective Zn/HCl reduction system employed to obtain N-acetyl-3-bromo-phenylalanine 6, served as substrate subsequent enzymatic resolution process. Then, intermediate, 3-bromo-l-phenylalanine 7, could be obtained using acylase (ACY) AmACY. Upon process optimization, chemical reaction executed at 300 g scale, with notable concentration reaching up 100 g/L. The achieved yield 40%, compared maximum theoretical 50%, exhibited an enantiomeric excess (ee) value 99.9%. A This synthetic pathway effectively executed, yielding 1·HCl purity 99.7% ee 99.9%, culminating in overall 23.4%. Additionally, undesired (D)-6 enantiomer recycled form (rac)-6, employing acetanhydride/acetic acid (Ac2O/AcOH) system. recycling 47.5%, relative level 99.8%.