Synthesis of 4-(N-cycloalkylamino)-substituted polyfluorobenzoic acids and their esters

When treated with cycloalkylamines (pyrrolidine, piperidine, morpholine, and N-methylpiperazine), polyfluoro-containing benzoic and salicylic acid esters undergo chemoselective nucleophilic aromatic substitution of a fluorine atom in the para position to form 4-(N-cycloalkylamino)-substituted derivatives. The hydrolysis of the latter compounds with alkali in aqueous methanol affords the corresponding acids. Methyl 3,5-difluoro-2-hydroxy-4-(piperidin-1-yl)benzoate exhibits high antibacterial activity against the N. gonorrhoeae strain, which is twice higher than that of the drug spectinomycin. N-Cycloalkyl-substituted polyfluorobenzoic acids do not show analgesic activity. The effect of the esters is comparable with the activity of the drug diclofenac. The studied compounds have a lower acute toxicity compared to the reference drug.