NMR studies on conformational and N‐configurational interconversion in 3‐methyl derivatives of the non‐narcotic analgesic drug nefopam

Abstract

AbstractTwo different N‐configurations and two different eight‐membered ring conformations were found in the diastereomeric crystalline (1R,3S)/(1S,3R)‐ and (1S,3R)/(1S,3S)‐3‐methylnefopam hydrochloride salts. 1H and 13C 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.