Efficient Synthesis of Crisaborole from <i>m</i>-Cresol: A Practical and Scalable Process

Herein, process improvement work on the phosphodiesterase-4 inhibitor crisaborole is described. The starting material 2-bromo-5-hydroxybenzaldehyde was replaced with the low-cost m-cresol. The process involves the purification of the low-melting-point bromophenol by a cocrystal strategy, selective debromination of the gem-dibromide byproduct, boronation through a telescoped process, and design of experiments optimization in the active pharmaceutical ingredient (API) synthesis stage. The economic, efficient, and practical synthesis of crisaborole was successfully achieved. It is worth noting that filtration unit operations were applied in the scale-up process of Miyaura borylation to address the common issue of incomplete conversion in this process.