Development of a Practical Enzymatic Process for Preparation of (S)‑2-Chloro-1-(3,4-difluorophenyl)ethanol

(S)-2-Chloro-1-(3,4-difluorophenyl)­ethanol (1) is a vital chiral intermediate for the synthesis of Ticagreloran effective treatment for acute coronary syndromes. A ketoreductase (KRED) KR-01 in our KRED library was screened to transform 2-chloro-1-(3,4-difluorophenyl)­ethanone (2) into the chiral alcohol 1. During process optimization, the bioreduction procedure was performed at a substrate concentration of 500 g/L, giving a near 100% conversion with >99.9% ee. The product 1 was directly obtained by extraction and can be used for the synthesis of (1R,2R)-2-(3,4-difluorophenyl)­cyclo­propane­carboxylic acid ethyl ester (3) with a yield of 98% and >99.9% de, greatly simplifying the original process operation and reducing the safety risk. This process is green and environmentally sound with high productivity of biocatalysis and a space–time yield of 145.8 mmol/L/h. It has an opportunity to be very useful in industrial applications. Additional studies have indicated that KR-01 can also be used to prepare (R)-1-(3,5-bis­(trifluoromethyl)­phenyl)­ethanol (4) with a substrate concentration of 500g/L.