Biocatalytic Reductive Amination- Discovery to Commercial Manufacturing applied to Abrocitinib JAK1 inhibitor

Abstract

Enzymatic reductive amination being highly novel, selective and green methodology has attracted significant interest in a short period of time. This article describes, discovery of novel RedAm activity and enzyme engineering to improve its performance over >200-fold, to make it suitable for commercial scale manufacturing. The enzymatic process was successfully implemented on commercial scale to make multi metric ton of a key intermediate for Abrocitinib manufacturing. This is the first application of RedAm technology for commercial scale manufacturing of a secondary amine via direct reductive amination of a ketone with methyl amine. This work contributes to the rapidly developing field of enzyme catalysis that is emerging as a critical strategy as a sustainable alternative to existing methods.

Upgrading heterogeneous Ni catalysts with thiol modification

“…More importantly, the simple thiol modification strategy can be well extended to various Ni nanomaterial systems (ie, Raney Ni, supported Ni nanoparticles, and even Ni carbide) to fabricate cost-effective practical Ni catalysts toward the green synthesis of a wide range of functional primary amines via the reductive amination of aldehydes or ketones. 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 …”

The Evolving Nature of Biocatalysis in Pharmaceutical Research and Development

“…The team at Pfizer developed an enzymatic reductive amination of ketone 31 with methylamine which was utilized in the synthetic route to abrocitinib (XIII) (CIBINQOⓇ). 57,58 A wild-type reductive aminase (RedAm) was identified from initial screening and subjected to several rounds of engineering.…”

A growth selection system for the directed evolution of amine-forming or converting enzymes

“…Recent discoveries and developments of transaminases 11 – 15 , monoamine oxidases 16 , amine dehydrogenases 17 , imine reductases 18 , and ammonia lyases 19 provide a versatile biocatalyst toolbox to access chiral amines. Since many synthetically useful chiral intermediates are new to these natural enzymes, extensive and time-consuming directed evolution 20 – 23 is usually required to tailor natural enzymes for the production of specific non-natural chiral amine targets 24 – 26 . Therefore, high-throughput screening methods have been developed for specific classes of enzymes 27 , 28 .…”