Early Process Development of PF-07054894, a Squaramide-Based Antagonist of C–C Chemokine Receptor Type 6 (CCR6)

The original synthesis of a CCR6 antagonist and subsequent enablement for kilogram manufacture is presented. Highlighted improvements made in the preparation for the scale-up campaign include (1) a refined route to access a key iodopyrazole which previously suffered from low yield due to poor regioselectivity, (2) optimization of a sulfinimine addition reaction to form a sterically congested amine with high stereocontrol, (3) implementation of a route to an aminopyridine fragment, and (4) efficient construction of the target molecule by sequential substitution of diethyl squarate with two elaborated amines. These enablement efforts have resulted in the successful preparation of >7 kg of crystalline API to perform early toxicological studies and initiate Phase 1 clinical trials.