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

Robert Glaser, Ariel Peleg, Shimona Geresh

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11 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)389-396
Number of pages8
JournalMagnetic Resonance in Chemistry
Volume28
Issue number5
DOIs
StatePublished - 1 Jan 1990

Keywords

  • Analgesic
  • Benzoxazocine
  • C NMR
  • Conformation
  • Difference NOE
  • H NMR
  • H–H coupling constants
  • Methylation
  • Nefopam
  • Oxidation

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