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 on a solid support offer considerable advantages, including improved reaction efficiency, enzyme stability, the ability to perform reactions non-aqueous media, simplified separation product from enzyme. Herein, we describe development biocatalytic transaminase Cyrene (2) utilizing an immobilized, evolved organic solvent provide amine intermediate 3a en route Bruton’s tyrosine kinase (BTK) inhibitor nemtabrutinib. Enzyme immobilization is critical facile isolation water-soluble product. Improved kinetics diastereoselectivity were achieved by bridging directed evolution with selection optimal for immobilization, enabling unified system direct as crystalline salt dr > 50:1.