Development of Two Synthetic Approaches to an APJ Receptor Agonist Containing a Tetra-ortho-Substituted Biaryl Pyridone

The development and implementation of two process syntheses to provide BMS-986224, an agonist of the APJ receptor, are reported. The first-generation synthesis of BMS-986224 relied on a key enamine cyclization to construct the pyridone core; however, the overall efficiency of this route was limited by the linear synthesis of the hindered biaryl pyridone. This lack of convergence is solved in a second-generation route that minimizes low-temperature lithiation chemistry, replaces costly Pd coupling with scalable nucleophilic arylation, and reduces step count. The improved synthesis was enabled by a new Negishi coupling method that addresses limitations of the Suzuki–Miyaura literature for tetra-ortho-substituted biaryl pyridones.