Synthetic Routes for Venetoclax at Different Stages of Development

We describe the discovery of venetoclax, a selective Bcl-2 inhibitor that has been approved for the treatment of chronic lymphociytic leukemia, and is in clinical studies to treat other forms of leukemia. We begin by briefly discussing the biological rationale for Bcl-2 inhibition and the background of the Bcl-2 family inhibitors program at AbbVie (previously known as Abbott), including earlier projects aimed at discovery of dual Bcl-xL/Bcl-2 inhibitors. Subsequently, we present a synopsis of the later effort to find selective Bcl-2 inhibitors, which culminated in the discovery of venetoclax, and the synthetic route used at that time, with emphasis on the steps responsible for changes to earlier acylsulfonamide series compounds. We then describe how the process team discovered multiple improvements to the initial route and led to the first-generation large-scale synthesis. A new and more efficient synthetic route was then strategically designed to overcome the chemistry challenges associated with the first-generation synthesisIt features a Buchwald-Hartwig amination followed by a uniquely effective saponification reaction using anhydrous hydroxide generated in situ. The new synthesis improved the process convergence, overall yield, and manufacturing robustness. In addition, the new synthesis enabled consistent and reproducible large-scale manufacture of venetoclax to produce high quality active pharmaceutical ingredient (API) with >99% area purity. © 2019 American Chemical Society.