Pinnick Oxidation on Scale: Process Development of a BDK Inhibitor

The development of a safe and scalable Pinnick oxidation of an aldehyde to a carboxylic acid in the late-stage synthesis of a BDK inhibitor candidate, PF-07208254, is reported. Extensive process safety testing revealed a large exotherm with significant heat accumulation during oxidant addition, which was minimized through careful control of oxidant dosing, and higher dilutions ensured complete solubility of the reactants. The role of atmospheric oxygen in generating sulfuric acid in the product stream, leading to partial decomposition, was identified. The optimized process was safely executed on a kilogram scale to deliver high-quality API for toxicology and clinical studies.