We developed a scalable Suzuki process for the synthesis of lanabecestat (+)-camsylate, an active pharmaceutical ingredient that was recently investigated in a Phase III clinical program for the treatment of early Alzheimer’s disease. The evolution of this process culminated with the use of a stable and crystalline diethanolamine boronic ester that rapidly hydrolyses under the reaction conditions. Herein, we report that the liberated diethanolamine plays an important role in the catalytic process, with supporting evidence for an equilibrium between an unbound and bound palladium complex. Additionally, the diethanolamine acts as an internal scavenger during the crystallization of lanabecestat by increasing the solubility of the palladium species, obviating the need for a discrete scavenging step.

中文翻译：

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用于生产Lanabecestat的Suzuki反应的工艺开发

我们开发了可扩展的Suzuki工艺来合成lanabecestat（+）-camsylate，这是一种活性药物成分，最近在治疗早期阿尔茨海默氏病的III期临床计划中进行了研究。该方法的发展最终通过使用稳定的结晶二乙醇胺硼酸酯在反应条件下迅速水解而达到。在此，我们报道释放的二乙醇胺在催化过程中起着重要作用，并为未结合和结合的钯配合物之间的平衡提供了支持证据。另外，二乙醇胺在拉贝司他的结晶过程中通过增加钯物质的溶解度而起内部清除剂的作用，从而消除了不连续的清除步骤的需要。