Process Development of ABBV-576: A C2 Corrector for the Treatment of Cystic Fibrosis

The development and execution of a second-generation process for the manufacture of ABBV-576, a CFTR C2 corrector for the treatment of cystic fibrosis, are described. Strategic considerations are outlined that address challenges encountered during the manufacture of the phase I-enabling delivery of ABBV-576. The new route features a highly branched-selective Mizoroki–Heck coupling, a Sharpless asymmetric dihydroxylation/cyclization sequence, an alcohol-to-carboxylic acid oxidation on a challenging substrate prone to oxidative decomposition, and an amide coupling to forge the active pharmaceutical ingredient (API). An improved API crystallization addresses issues with solvent removal observed in the original process, and crystallization development work provided insights into a stereoisomeric impurity that was difficult to purge in the penultimate intermediate and API isolations. This paper details the development work performed to establish the second-generation route as well as its execution on a 3 kg scale.