1H and 13C NMR Conformational Studies on Quaternary Nitrogen Derivatives of the Analgesic Drug Nefopam

Article abstract of DOI:10.1002/mrc.1260280503

Nitrogen quaternization in the analgesic nefopam <(+/-)-3,4,5,6-tetrahydro-5-methyl-1-phenyl-1H-2,5-benzoxazocine hydrochloride> by either N-trideuteriomethylation or N-oxidation affords reaction product diastereoisomeric mixtures differing in N-configuration.The axial to equatorial N-CH3 product ratios were found to be ca. 3 : 2 (N-trideuteriomethylation) and approximately equimolar (ca. 48 : 52, N-oxidation).Both diastereomeric N-oxides have boat-(flattened chair) conformations of the octagonal ring in which the phenyl group is exo-oriented.The quaternary ammonium salt showed considerable line broadening in the 1H NMR spectrum owing to rapid conformational equilibration.The same boat-(flattened chair) conformation is clearly the preponderant contributor to the time-averaged structure of nefopam methioiodide in CD2Cl2 solutions, similar to the case for the equatorial N-methyl isomer of the parent hydrochloride salt.Conformational assignments were based on the vicinal coupling constants in the -OCH2CH2N- fragment and on the finding of an NOE intensity enhancement for the benzhydrylic-H on irradiation of the equatorially oriented -OCH.