Nmr-Studies On Conformational And N-Configurational Interconversion In 3-Methyl Derivatives Of The Nonnarcotic Analgesic Drug Nefopam

Two different N-configurations and two different eight-membered ring conformations were found in the diastereomeric crystalline (1R,3S)/(1S,3R)- and (1R,3R)/(1S,3S)-3-methylnefopam hydrochloride salts. H-1 and C-13 NMR spectroscopy showed that both crystalline epimers undergo N-configurational and eight-membered ring conformational equilibria on dissolution in a solvent (e.g. CD2Cl2). Observation of N-H proton vicinal coupling in both the solution-state major and minor species for each epimer signifies slow exchange limit kinetic regimes for N-configurational interconversion via a prototropic shift-nitrogen inversion. Since previous studies have shown 2,5-benzoxazocine ring inversion to be unfavourable, the finding of weighted time-average vicinal coupling constants for the -OCH(CH3)CH2NH(CH3)CH2- moiety is interpreted in terms of a fast exchange limit (and in some cases fast magnetic site exchange broadening) kinetic regime for eight-membered ring conformational change. For each C-3 epimer; a quantitative estimation was made for the 2n = 4 solution-state diastereomeric forms resulting from the two stereogenic elements of N-configuration and ring conformation. Comparisons were made with the parent nefopam hydrochloride, N-desmethylnefopam hydrochloride metabolite and the nefopam methiodide quaternary ammonium salt.