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Ketone reductase biocatalysis in the synthesis of chiral intermediates toward generic active pharmaceutical ingredients

Raynbird, Marina Y., Sampson, Joanne B., Smith, Dan A., Forsyth, Siân M., Moseley, Jonathan D. and Wells, Andrew S. 2020. Ketone reductase biocatalysis in the synthesis of chiral intermediates toward generic active pharmaceutical ingredients. Organic Process Research and Development 24 (6) , pp. 1131-1140. 10.1021/acs.oprd.0c00120
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Abstract

A range of generic active pharmaceutical ingredients were examined for potential chiral alcohol motifs and derivatives within their structures that could be employed as key synthetic intermediates. For seven generic active pharmaceutical ingredients (APIs), eight precursor ketones were acquired and then subjected to reduction by >400 commercially available ketone reductases from different suppliers. Positive screening results were achieved for five ketones screened, with multiple ketone reductases available for each successful ketone. Selectivity was typically >99.5% ee in most cases, including for the opposite enantiomer. The three best examples were then optimized and quickly scaled up to 1 L scale in high conversion and isolated yield while retaining selectivity of >99.5% ee for the desired chiral alcohol enantiomer. This work illustrates that where a wide range of enzymes are available, productive enzymes to give either alcohol enantiomer can be readily identified for many ketones and rapidly scaled up to produce chiral alcohols. This approach is particularly applicable to generating chiral API intermediates.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Publisher: American Chemical Society
ISSN: 1083-6160
Date of First Compliant Deposit: 14 July 2020
Date of Acceptance: 2 June 2020
Last Modified: 15 Jul 2020 15:37
URI: http://orca.cf.ac.uk/id/eprint/133438

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