Using another approach, Codexis developed a biocatalytic reduction for MLK-III using a ketoreductase biocatalyst evolved to
reduce MLK-II. Codexis evolved the ketoreductase to increase its activity and stability by more than 2000-fold, replacing
one-third of the amino acids in its active site in the process and under improved reaction conditions: 100 g/L in isopropanol–water–toluene
at 45 °C. Isopropanol is the reductant, which the ketoreductase uses to regenerate its catalytic cofactor, NADPH, producing
acetone as the coproduct. The process runs as a slurry-to-slurry conversion with product precipitation driving the reaction
to completion. The precipitated chiral alcohol is of high chemical purity and stereopurity. Codexis has scaled up the manufacture
of MLK-III using this biocatalytic reduction and has provided samples of MLK-IV to manufacturers of generic montelukast. The
company is planning commercial-scale manufacture on a multiton scale in 2008 (8).
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