Discovery and Process Development of a Scalable Biocatalytic Kinetic Resolution toward Synthesis of a Sterically Hindered Chiral Ketone

Wamser Nicole; Wu Hao; Buono FredericBrundage AnthonyRicci FrancescoLorenz Jon C.Wang JunHaddad NizarPaolillo JoshuaLeung Joyce C.Lee HeewonHossain Azad

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Discovery and Process Development of a Scalable Biocatalytic Kinetic Resolution toward Synthesis of a Sterically Hindered Chiral Ketone

机译：Discovery and Process Development of a Scalable Biocatalytic Kinetic Resolution toward Synthesis of a Sterically Hindered Chiral Ketone

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Sterically hindered chiral ketones are useful intermediates in the synthesis of active pharmaceutical ingredients. Here, we report a scalable and highly enantioselective synthesis through a kinetic resolution process promoted by a wild-type ketoreductase (KRED) enzyme. The process was investigated thoroughly, including DoE optimizations and a kinetic study. Scale-up demonstrations on up to 0.8 kg revealed an enzyme aggregation/deactivation challenge, and solutions were provided to obtain the desired enantiomer in high yields and enantiomeric excesses with relatively low enzyme loadings (2-4 wt %).

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来源
《Organic process research & development》 |2022年第6期|1820-1830|共11页
作者
Wamser Nicole; Wu Hao; Buono FredericBrundage AnthonyRicci FrancescoLorenz Jon C.Wang JunHaddad NizarPaolillo JoshuaLeung Joyce C.Lee HeewonHossain Azad;
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Boehringer Ingelheim Pharmaceut Inc;

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正文语种英语
中图分类化学工业;
关键词
ketoreductase; kinetic resolution; biocatalysis; chiral ketone synthesis; scaleup; BRANCHED CYCLIC-KETONES; ASYMMETRIC AMINATION; CARBONYL REDUCTASE; ALKYLATION; KETOREDUCTASE; REGIO;

Discovery and Process Development of a Scalable Biocatalytic Kinetic Resolution toward Synthesis of a Sterically Hindered Chiral Ketone

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