Streamlined Three-Step Telescope Enabled by a Nonaqueous Suzuki–Miyaura Cross-Coupling Reaction
Rebecca A. Green, Jeishla L. M. Matos, Eric M. Simmons, Bahar Inankur, Brian Lingfeng He, Jennifer Lott, Shasha Zhang, Sergei Kolotuchin, Damián Reyes-Luyanda, Peng Geng, Jason M. Stevens, Jeffrey Nye, M. Kubín, Sha Lou, Albert J. DelMonte, Ling Zhang, Neil A. Strotman
Abstract
The process optimization of a key step in the synthesis of NLRP3 (nucleotide-binding domain and leucine-rich repeat-containing protein 3) agonist BMS-986299 is reported. The step is a convergent three-stage telescope featuring four discrete chemical transformations: a Pd-catalyzed Miyaura borylation, followed by a Suzuki–Miyaura cross-coupling, then a concurrent acid-mediated cyclization and THP (tetrahydropyran) cleavage. Through targeted process development focused on safety, sustainability, and robustness, we developed safer and more robust borylation conditions to generate an aryl boronate ester intermediate that is then taken into a nonaqueous Suzuki–Miyaura reaction via a streamlined telescoped sequence and a subsequent kinetic analysis-driven reactive crystallization to synthesize the imidazole-fused 2-aminoquinoline core of BMS-986299. Overall, the improvements discussed herein resulted in a greener, safer, and more robust process for the synthesis of this intermediate.