The process development of a new synthetic route leading to an efficient and robust manufacture process for venetoclax is described. The redesigned synthesis features a Buchwald-Hartwig amination reaction to construct the core ester in a convergent fashion by connecting two key building blocks, which is then followed by a uniquely effective saponification reaction of the core ester using anhydrous hydroxide generated <i>in-situ</i>. Finally, the coupling of the penultimate acid with a sulfonamide intermediate furnishes venetoclax with consistently high quality. The challenges and solutions for the key Pd –catalyzed C– N cross–coupling will also be discussed in detail. The improved synthesis overcomes many of the initial scale-up challenges and was accomplished in 46% overall yield. The new process was successfully implemented for producing large quantities of venetoclax with &gt; 99% area purity.

Development of a large-scale synthesis for venetoclax

ACS Spring 2022

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