Manufacturing Process Development for the Biaryl Ether Fragment of Nemtabrutinib (MK-1026)

MK-1026, also known as nemtabrutinib (1), has been developed as a reversible Bruton’s tyrosine kinase (BTK) inhibitor for the treatment of chronic lymphocytic leukemia. This article describes the two-step manufacturing synthesis and subsequent isolation of biaryl ether (4) en route to MK-1026. First, the esterification step employs unique conditions leveraging dimethyl carbonate as a dual-function reagent, acting as both the solvent and the desiccant to drive the reaction forward. Second, the heterogeneous etherification step requires water content control to achieve acceptable reaction rates and minimize undesired impurities. Finally, isolation from water was developed that addressed oiling issues while also affording effective drying, despite the low melting point (as low as 28 °C) of the biaryl ether.