The key chiral precursor,(S)-1-(2,6-dichloro-3-fluorophenyl)ethan-1-ol,for crizotinib was synthesized asymmetrically using the carbonyl reductase NsCRs19.The asymmetric reduction of 1-(2,6-dichloro-3-fluorophenyl)ethan-1-one by constructing a carbonyl reductase-glucose dehydrogenase dual enzyme catalytic system.The optimum reaction conditions for this catalytic system was determined,and its reaction system was optimized.Under the conditions of(40±2)℃ and pH(7.5±0.5),6％biological enzyme reacted for 24 hours completely reducing 165 g/L(about 0.8 mol/L)1-(2,6-dichloro-3-fluorophenyl)ethan-1-one with conversion>99.2％,yield>93.7％and e.e.(s)>99.9％.The use of biocatalysis in the asymmetric reduction process for the synthesis of the key chiral precursor of crizotinib has shortened the manufacturing process,reduced production costs,avoided chiral separation,and provided reliable support for the enzymatic synthesis of crizotinib.
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