Working Toward Process Simplification for the Synthesis of Crisaborole

The development of a concise synthesis of crisaborole (1), a phosphodiesterase 4 (PDE4) inhibitor, is described. There are several challenges with the initial commercial synthesis that were drivers for process redesign and simplification, most notably the need for protection/deprotection steps. Key bond disconnections and reordering of steps were evaluated to streamline the process focusing on greener options for manufacture and eliminating protecting groups. The resulting alternate synthesis features a similar Miyaura borylation to install the key boron atom but provides a more direct route to crisaborole through an important crystalline intermediate for impurity purge. Other challenges addressed by the alternate route include avoiding environmentally undesirable reagents DMF and boric acid (both included on the REACH list of substances of very high concern), reducing palladium usage, and eliminating the use of a palladium scavenging treatment. Successful demonstration of the alternate route for crisaborole has been achieved at pilot plant scale and ultimately has been validated at commercial scale consistent with ICH Q11 principles. The route was approved for commercial use to supply crisaborole in 2023 and to date has produced approximately 750 kg of the crisaborole drug substance.