Amination of a Green Solvent via Immobilized Biocatalysis for the Synthesis of Nemtabrutinib

Enzymes are capable of unique and selective transformations that can enable efficient chemical production. While many industrial processes have been developed using free enzymes in aqueous solutions, immobilizing enzymes on a solid support can offer considerable advantages, including improved reaction efficiency, enzyme stability, the ability to perform reactions in non-aqueous media, and simplified separation of the product from the enzyme. Herein, we describe the development of a biocatalytic transaminase reaction of Cyrene (2) utilizing an immobilized, evolved transaminase enzyme in an organic solvent to provide amine intermediate 3a en route to Bruton’s tyrosine kinase (BTK) inhibitor nemtabrutinib. Enzyme immobilization is critical to facile isolation of the water-soluble product. Improved reaction kinetics and diastereoselectivity were achieved by bridging directed enzyme evolution with the selection of an optimal reaction solvent and solid support for immobilization, enabling a unified solvent system and direct isolation of 3a as a crystalline salt with dr > 50:1.