Syntheses of 2,5- and 2,6-Difluoronorepinephrine, 2,5-Difluoroepinephrine, and 2,6-Difluorophenylephrine: Effect of Disubstitution with Fluorine on Adrenergic Activity

Article abstract of DOI:10.1021/jm00076a024

Synthetic routes to difluorinated analogs of the adrenergic agonists, norepinephrine (NE), epinephrine (E), and phenylephrine (PE) have been developed.The syntheses were based on elaboration of the ethanolamine side chains from the appropriately polyfunctionalized benzaldehydes.The benzaldehydes were prepared from precursor difluorinated benzenes by sequential regioselective lithiations and reaction with electrophiles to introduce hydroxyl and carboxaldehyde functionalities.Binding and functional assay data demonstrate that the 2,6-difluorinated analogs are relatively inactive at both α- and β-adrenergic receptors.These results are consistent with earlier observations that 2-fluoro substitution of adrenergic agonists decreases α-adrenergic activity whereas 6-fluoro substitution decreases β-adrenergic activity.