Herein, we report the optimization of the first process chemistry route for pilot-plant-scale manufacture of PF-07059013 (1), a noncovalent modulator of hemoglobin for the treatment of sickle cell disease. Five areas of improvement are discussed in detail, namely, an alternative synthetic sequence to install the pyridone functionality before benzylic ether formation, a shorter and safer route to quinoline fragment 9, a tosyl-swap strategy to avoid isolation of a thermally unstable tosylate intermediate, Pd-catalyzed C–O coupling with low catalyst loading and efficient Pd removal, and improved final isolation of the API freebase. The new route was executed in our pilot plant facility to deliver 76 kg of API.

中文翻译：

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血红蛋白非共价调节剂 PF-07059013 通过钯介导的 C-O 偶联治疗镰状细胞病的路线优化，第二部分：中试工厂规模生产

在此，我们报告了用于中试工厂规模生产 PF-07059013 ( 1 ) 的第一个工艺化学路线的优化，PF-07059013 是一种用于治疗镰状细胞病的非共价血红蛋白调节剂。详细讨论了五个改进领域，即在苄基醚形成之前安装吡啶酮功能的替代合成顺序，更短和更安全的喹啉片段 9 的路线，避免分离热不稳定甲苯磺酸酯中间体的甲苯磺酰交换策略， Pd 催化的 C-O 偶联具有低催化剂负载和高效的 Pd 去除，并改进了 API 游离碱的最终分离。新路线在我们的试验工厂设施中执行，以交付 76 公斤的 API。