Enzymatic Dynamic Kinetic Resolution of 3-Bromo/Methylsulfonyl-dl-Phenylalanine Ethyl Ester in Miniemulsions: A Key Intermediate for Lifitegrast (Xiidra) Synthesis

A scalable enzymatic process has been developed for the preparation of optically pure 3-bromo- or 3-methylsulfonyl-substituted l-phenylalanine (S)-1a–b, which serves as key intermediates in the synthesis of lifitegrast. This method utilizes enzymatic dynamic kinetic resolution (DKR) of the ethyl esters of racemic 3-bromo- or 3-methylsulfonyl-substituted dl-phenylalanine esters (rac-8a–b), catalyzed by the commercially available protease enzyme Alcalase. The reaction was carried out in a miniemulsion system that acts as a nanoreactor with high substrate loading (50% w/v). Notably, the process was completed within 24 h using less than 10% (w/w) of the enzyme. The desired optically pure (S)-isomer was obtained with >90% isolated yield and >99% enantiomeric excess (e.e.) under these conditions. Furthermore, the solvent system, along with the surfactant and enzyme, was successfully recycled, highlighting the sustainability and cost-efficiency of the process.