A commercial KRED has been immobilized and successfully used as biocatalyst in the asymmetric synthesis of (S)-1-(3,5-bis(trifluoromethyl)phenyl)-ethanol (BTPE), an important intermediate for APIs synthesis. The biotransformations were performed under batch and flow conditions obtaining with most samples the complete conversion after 24 hours and ee >99.9 %. The reusability of immobilized KRED samples has been demonstrated in five consecutive reaction cycles.

Abstract

Both enantiomers of 1-(3,5-bis(trifluoromethyl)phenyl)-ethanol (BTPE) constitute important building-blocks for the synthesis of active pharmaceuticals ingredients (APIs). The reduction of 3’,5’-bis(trifluoromethyl)acetophenone (BTAP) performed with soluble and immobilized ketoreductases (KREDs) can be considered as one of the most efficient routes to produce enantiopure BTPE. In the present work, a commercial KRED was employed as biocatalyst after undergoing immobilization processes and it proved to be extremely efficient in the asymmetric synthesis of (S)-BTPE. The immobilization was studied on a set of different commercially available supports. The best results were obtained with samples immobilized via covalent interaction on short chain amino-functionalized support. Two reaction parameters, temperature, and solvent were optimized in the biocatalytic reduction of BTAP in batch conditions. A 90 : 10 (v/v) 2-propanol (IPA): water solvent system and 30 °C proved to be the best reaction conditions in terms of substrate conversion and easy recovery of the product by simple solvent evaporation. Biotransformations were then performed in a flow system under optimized reaction conditions obtaining with most samples complete conversion after 24 hours and excellent enantiomeric excess (>99.9 %). Finally, the reusability of the immobilized biocatalyst was successfully tested in five consecutive reaction cycles, demonstrating the potential of this approach.