SYNTHESES OF 2,5-DIFLUORONOREPINEPHRINE, 2,6-DIFLUORONOREPINEPHRINE, 2,5-DIFLUOROEPINEPHRINE, AND 2,6-DIFLUOROPHENYLEPHRINE - EFFECT OF DISUBSTITUTION WITH FLUORINE ON ADRENERGIC ACTIVITY

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 ethanolamin e side chains from the appropriately polyfunctionalized benzaldehydes, The benzaldehydes were prepared from precursor difluorinated benzenes by sequential regioselective lithiations and reaction with electrophi les to introduce hydroxyl and carboxaldehyde functionalities. Binding and functional assay data demonstrate that the 2,6-difluorinated analo gs are relatively inactive at both alpha- and beta-adrenergic receptor s. These results are consistent with earlier observations that 2-fluor o substitution of adrenergic agonists decreases alpha-adrenergic activ ity whereas 6-fluoro substitution decreases beta-adrenergic activity.