A novel and practical desymmetrization tactic is described to access a new class of pibrentasvir prodrugs. The homotopic benzimidazoles of pibrentasvir (PIB) are differentiated via a one-pot di-Boc/mono-de-Boc selective N-Boc...

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The evolution and development of a commercially viable synthesis of fenleuton, a second-generation 5-lipoxygenase inhibitor, is discussed. Special emphasis is given to the challenges and operational issues encountered on scale-up in the pilot plant. Three separate processes were developed and scaled up, providing valuable information about operational parameters and physical characteristics of the drug substance. A novel displacement reaction was discovered and developed and was incorporated as the key transformation in the final manufacturing process.

An enabling preclinical synthetic route to cystic fibrosis candidate ABBV-2222 is described. Two stereoselective steps provide access to an aminochroman intermediate with excellent control, and a late-stage demethylation/ difluoromethylation sequence provides efficient access to the target molecule.