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Biocatalytic reductive amination from discovery to commercial manufacturing applied to abrocitinib JAK1 inhibitor
Nature Catalysis ( IF 37.8 ) Pub Date : 2021-09-21 , DOI: 10.1038/s41929-021-00671-5
Rajesh Kumar 1 , Michael J. Karmilowicz 1 , Michael P. Burns 1 , Christina G. Connor 1 , Eric Cordi 1 , Nga M. Do 1 , Chad A. Lewis 1 , Carlos A. Martinez 1 , Emma L. McInturff 1 , Robert Pearson 1 , Jeremy Steflik 1 , Anil Rane 1 , John Weaver 1 , Dylan Burke 2 , Leslie A. Clark 2 , David Mangan 2 , Kevin M. Doyle 3 , Steve Hoagland 3 , Kevin Meldrum 4
Affiliation  

Enzymatic reductive amination, being a direct, selective and green methodology, has attracted significant interest in a short period of time and is emerging as a powerful tool for the synthesis of chiral alkylated amines. The discovery of an increasing number of imine reductases with reductive aminase (RedAm) activity has enabled mechanistic and substrate profiling studies. However, their potential for commercial applications has not been realized. Here, we report the discovery of RedAm activity in an imine reductase enzyme for the direct reductive amination of a cyclic ketone with methylamine. We also investigate engineering the enzyme to access a cis-cyclobutyl-N-methylamine for the manufacturing of a late-stage drug candidate, Janus kinase 1 (JAK1) inhibitor abrocitinib. The engineered enzyme, SpRedAm-R3-V6, showed >200-fold improvement in performance over the wild-type enzyme and was successfully used to develop a commercial manufacturing process with 73% isolated yield at 99.5% purity and high selectivity (>99:1 cis:trans). This process has been successfully used to manufacture multi-metric tons of the amine, demonstrating the potential of RedAm technology for commercial manufacturing.



中文翻译:

从发现到商业生产的生物催化还原胺化应用于 abrocitinib JAK1 抑制剂

酶促还原胺化作为一种​​直接、选择性和绿色的方法,在短时间内引起了人们的极大兴趣,并正在成为合成手性烷基化胺的有力工具。越来越多的具有还原氨基酶 (RedAm) 活性的亚胺还原酶的发现使机理和底物分析研究成为可能。然而,它们的商业应用潜力尚未实现。在这里,我们报告了在亚胺还原酶中发现 RedAm 活性,用于环酮与甲胺的直接还原胺化。我们还研究设计酶以获取顺式-环丁基-N-甲胺用于制造晚期候选药物 Janus 激酶 1 (JAK1) 抑制剂 abrocitinib。工程酶Sp RedAm-R3-V6 的性能比野生型酶提高了 200 倍以上,并成功用于开发商业生产工艺,分离产率为 73%,纯度为 99.5%,选择性高(>99 :1顺式:反式)。该工艺已成功用于制造数吨胺,展示了 RedAm 技术在商业制造中的潜力。

更新日期:2021-09-21
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