Development of a Practical and Scalable Synthetic Route for the Adenosine Monophosphate-Activated Protein Kinase Activator, ASP4132

This paper describes the research and development of a practical and efficient process for making the adenosine monophosphate-activated protein kinase (AMPK) activator, ASP4132 (1). The newly developed process includes an efficient telescoping process consisting of Suzuki–Miyaura coupling and hydrogenation, effective removal of palladium using N-acetyl cysteine and silica gel, and reductive amination with the stable and mild reducing reagent, 2-picoline borane. The need for chromatographic purification was removed from all steps. The overall yield improved from 18% in the medicinal synthetic route to 43% using the new procedure. This highly efficient process was successfully demonstrated on a pilot scale to yield ASP4132 (1) with high quality.