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

Two different N ‐configurations and two different eight‐membered ring conformations were found in the diastereomeric crystalline (1 R ,3 S )/(1 S ,3 R )‐ and (1 S ,3 R )/(1 S ,3 S )‐3‐methylnefopam hydrochloride salts. 1 H and 13 C NMR spectroscopy showed that both crystalline epimers undergo N ‐configurational and eight‐membered ring conformational equilibria on dissolution in a solvent (e.g. CD 2 Cl 2 ). 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(CH 3 )CH 2 NH(CH 3 )CH 2 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 2 n = 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.