Development of a Telescoped Alkylation/Reduction Reaction Sequence and an Asymmetric Hydrogenation to Enable the Kilogram Synthesis of ABBV-3748

Challenges in the synthesis of the cystic fibrosis transmembrane receptor corrector ABBV-3748 were addressed to enable a multikilogram-scale GMP sequence. Implementation of an early-stage telescoped titanium-mediated alkylation and palladium-catalyzed hydrogenation limited the formation of a dimerization impurity and provided consistent yields across reaction scales. Development of late-stage enantioselective hydrogenation installed the stereocenter present in the active pharmaceutical ingredient. Aspects of reagent and catalyst selection, reaction optimization, and crystallization in these two key synthetic steps are described herein.