¹H and ¹³C NMR conformational studies on quaternary nitrogen derivatives of the analgesic drug nefopam

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 diastereomeric 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 salts 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 methiodide in CD₂Cl₂ solution, 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.