Biocatalytic reductive amination from discovery to commercial manufacturing applied to abrocitinib JAK1 inhibitor

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.

Automated summary

Enzymatic reductive amination is an attractive and green method for synthesizing chiral alkylated amines, with the engineered enzyme SpRedAm-R3-V6 showing significant improvement in performance for manufacturing a late-stage drug candidate. This process has successfully been used to manufacture large quantities of amine, demonstrating the potential of RedAm technology for commercial production.