Highly efficient synthesis of rosuvastatin intermediate using a carbonyl reductase–cofactor co‐immobilized biocatalyst in the non‐aqueous biosystem

Abstract

AbstractBACKGROUNDNon‐aqueous biocatalytic system has exhibited advantages including outstanding substrate solubility, facilitation for product purification, suppression of unwanted water‐dependent side reactions and rare wastewater discharge. However, limited by enzyme stability, selectivity and cofactor recycling, there has been no successful attempt to use carbonyl reductases in non‐aqueous phase.RESULTSIn this study, a non‐aqueous catalytic system of carbonyl reductase was developed for the first time with a carbonyl reductase–cofactor co‐immobilized biocatalyst. Using n‐hexane as the reaction medium, the key chiral diol intermediate of the top‐selling hypolipidemic drug rosuvastatin, tert‐butyl (3R,5S)‐6‐chloro‐3,5‐dihydroxyhexanoate ((3R,5S)‐CDHH) was prepared in a continuous packed‐bed bioreactor, with a total yield of 95.51%, enantiomeric excess (e.e.) > 99.5% and diastereomeric excess (d.e.) > 99.5% in a 44‐batch reaction. The yield of per unit biocatalyst was 34.42 mg U−1, and the space–time yield was 91.01 g h−1 L−1.CONCLUSIONOur work corroborated the valuable potential of carbonyl reductases in non‐aqueous biosynthesis of chiral pharmaceuticals and fine chemicals. © 2021 Society of Chemical Industry (SCI).