Pd-Catalyzed Cyanation of a Bromoaryl Carboxylate En Route to Etrumadenant: Robust Process with Low Catalyst Loading Enabled by Preactivation

Palladium-catalyzed cyanation of aryl bromides is a powerful approach to install a functional group commonly found in active pharmaceutical ingredients starting from readily available precursors. The development of a robust cyanation of a bromo benzoic acid to generate an intermediate en route to etrumadenant is described. Full conversion with catalyst loading as low as 0.13 mol % was enabled by study of the catalyst preactivation step, which was affected by trace water levels. Details of the scale-up of this process to the hundred-kilogram batch size are included.

Automated summary

Palladium-catalyzed cyanation is an important method for installing functional groups commonly found in active pharmaceutical ingredients. In this study, a robust cyanation reaction was developed with full conversion achieved at a catalyst loading as low as 0.13 mol%, which was affected by trace water levels. The scale-up of this process to a hundred-kilogram batch size is also described.