Leveraging Synergistic Solubility in the Development of a Direct Isolation Process for Nemtabrutinib

We report the process development for the active pharmaceutical ingredient (API) step of the commercial manufacturing route to nemtabrutinib (MK-1026), a reversible Bruton’s Tyrosine Kinase (BTK) inhibitor currently under investigation for the treatment of several hematological malignancies. Significant improvements on process efficiency were achieved by a direct isolation process leveraging optimal reaction conditions and synergistic API solubility in an ethanol/water system. In combination with additional robustness improvements on impurity control, an efficient, practical, and scalable synthesis of nemtabrutinib was developed.