Process Development of a Key Chiral Intermediate toward the Synthesis of ABBV-576

The process development and scale-up of a key intermediate for the synthesis of ABBV-576, a potential treatment for cystic fibrosis, are detailed herein. Challenges associated with the initial synthetic route, including the need for cryogenic conditions and suboptimal chiral purity, were addressed by implementing ketoreductase (KRED)-catalyzed dynamic kinetic resolution (DKR). Through comprehensive medium throughput optimization, the process achieved high selectivity and purity for the desired intermediate. The starting material for the KRED DKR was prepared by an epoxidation Meinwald rearrangement sequence, affording the requisite racemic aldehyde in high yield, and isolated as the bisulfite adduct to ensure stability. The improved route was demonstrated on a multikilogram scale. After the key enzymatic reaction, crystallization with a chiral base was employed to further increase the enantiopurity of the alcohol, which supports future development efforts.