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.

中文翻译：

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由非水铃木-宫浦交叉耦合反应实现的简化三步望远镜


报告了 NLRP3（核苷酸结合结构域和富含亮氨酸重复序列的蛋白 3）激动剂 BMS-986299 合成关键步骤的工艺优化。该步骤是一个会聚的三级望远镜，具有四个离散的化学转变：Pd 催化的 Miyaura 硼化，然后是 Suzuki-Miyaura 交叉偶联，然后是同时的酸介导的环化和 THP（四氢吡喃）裂解。通过专注于安全性、可持续性和稳健性的有针对性的工艺开发，我们开发了更安全、更稳健的硼化条件，以生成芳基硼酸酯中间体，然后通过简化的伸缩序列和随后的动力学分析将其纳入非水铃木-宫浦反应中。驱动反应结晶合成 BMS-986299 的咪唑稠合 2-氨基喹啉核心。总体而言，本文讨论的改进导致了该中间体的合成过程更环保、更安全、更稳健。