Catalyst-Free and Scalable Process for Synthesis of Novel MAP4K4 Inhibitor DMX-5804 and Its Glyco-Conjugates

DMX-5804 is a potent and selective mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) inhibitor, which is currently under evaluation for the treatment of myocardial infarction. Here, we report the process development of scalable and practical synthesis of DMX-5804. Process optimization resulted in the following: (1) removal of transition metals from the process and reduced duration of reactions, (2) a streamlined process with significantly improved yields using low-cost raw materials, (3) importantly, microwave-assisted reactions were removed, (4) column purification avoided throughout the process, and (5) crystallized products showed over 95% purity in each step.