Desymmetrization of pibrentasvir for efficient prodrug synthesis |
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Authors: | Eric A. Voight Stephen N. Greszler John Hartung Jianguo Ji Russell C. Klix John T. Randolph Bhadra H. Shelat Jan E. Waters David A. DeGoey |
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Affiliation: | Drug Discovery Science & Technology, AbbVie, Inc., 1 North Waukegan Road, North Chicago Illinois 60064-1802 USA.; Process Research and Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago Illinois 60064-1802 USA |
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Abstract: | 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 protection and formaldehyde adduct formation sequence, both enabled by crystallization-induced selectivity. The first step represents the only known application of the Horeau principle of statistical amplification for C2-symmetric polyheterocycle regioselective functionalization. The resulting versatile intermediate is employed in the high-yielding preparation of several pibrentasvir prodrug candidates.Horeau principle statistical amplification and solubility-driven selectivities allow C2-desymmetrization of pibrentasvir without typically required internal functionalization or steric proximity effects. |
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