- Development of Two Synthetic Approaches to an APJ Receptor Agonist Containing a Tetra- ortho-Substituted Biaryl Pyridone
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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.
- Goldfogel, Matthew J.,Jamison, Christopher R.,Savage, Scott A.,Haley, Matthew W.,Mukherjee, Subha,Sfouggatakis, Chris,Gujjar, Manjunath,Mohan, Jayaraj,Rakshit, Souvik,Vaidyanathan, Rajappa
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