Solution‐ and solid‐state structures of N‐desmethylnefopam hydrochloride, a metabolite of the analgesic drug

Robert Glaser, Shimona Geresh, Jeanine Blumenfeld, David Donnell, Nobuyuki Sugisaka, Marc Drouin, Andre Michela

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8 Scopus citations

Abstract

The solid‐state structure of (±)‐N‐desmethylnefopam hydrochloride (1), a metabolite of the analgesic drug, was determined by single‐crystal X‐ray diffraction analysis. Compound 1 gave crystalline prisms belonging to the orthorhombic Pcab space group, and at ambient temperature (293 K), a = 9.939(2), b = 14.479(1), c = 20.148(3) A, V = 2899.5(8) A3, Z = 8, R(F) = 0.045, and Rw(F) = 0.025. The benzoxazocine ring of crystalline 1 is twisted into the boat‐flattened(chair) [BfC] conformation, the phenyl ring resides in a relatively sterically unhindered exo‐type ring position, whereas the O atom and NCH2Ar occupy sterically hindered positions between “boat” and “chair” regions. Dissolution of BfC crystalline 1 in CD2Cl2 solvent affords a dynamic conformational equilibrium (involving the putative twist‐chair‐flattened(chair) conformer) as shown by line broadening and weighted time‐averaged vicinal coupling constants [‐OCH2CH2N‐ segment] in the 1 H NMR spectrum. The solution‐state weighted time‐averaged 50(1)° O‐CH2‐CH2‐N dihedral angle, calculated by the R‐ratio method, shows that the B/C conformation is the major contributor to time‐averaged structure.

Original languageEnglish
Pages (from-to)276-281
Number of pages6
JournalJournal of Pharmaceutical Sciences
Volume82
Issue number3
DOIs
StatePublished - 1 Jan 1993

ASJC Scopus subject areas

  • Pharmaceutical Science

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