Solid-state stereochemistry of nefopam hydrochloride, a benzoxazocine analgesic drug

Robert Glaser, Gernot Frenking, Gilda H. Loew, David Donnell, Shmuel Cohen, Israel Agranat

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14 Scopus citations

Abstract

The solid-state structures of (±)- and (+)-nefopam hydrochloride (1), an analgesic agent, were determined by single-crystal X-ray diffraction analysis. (±)-Nefopam hydrochloride gave crystals belonging to the monoclinic P21/c space group, and at 298 K: a = 11.766(1), b = 7.741(1), c = 16.907(3) Å, β = 97.43(1)°, V =1 527.0(7) Å3, Z = 4, R(F) = 0.0336, and Rw = 0.0452. (+)-Nefopam hydrochloride monohydrate gave crystals belonging to the orthorhombic P212121, space group, and at 298 K: a = 9.651 (2), b = 19.747(2), c = 8.504(2) Å, V = 1 620.7(7) Å3, Z = 4, R(F) = 0.0432, and Rw = 0.0690 for the (1S,5S)-model versus R(F) = 0.0442, and Rw = 0.0700 for the (1R,5R)-model. The nefopam-HCl diastereoisomer found in the chiral crystal was also found in the racemic modification: (1S,5S) in (+)-(1)·H2O and (1R,5R), (1S,5S) in (±)-(1). The geometry of the nefopam·HCl molecule in both crystals is similar, and is that of a boat-(flattened chair) eight-membered ring. The N-methyl group is in an equatorial-like orientation, the oxydimethyleneamino moiety is in a gauche conformation, and the phenyl group resides in a relatively sterically unhindered exo-type position trans to the methyl. The major difference between the (±)-(1) and (+)-(1) ·H2O molecular geometries is in the pitch of the phenyl ring. Energy minimization calculations on a series of nefopam·HCl boat-(flattened chair), twist-chair-(flattened chair), and twist-boat-(flattened chair) conformations were made by empirical force field methods using the MOLMEC molecular mechanics program. These calculations have shown that the (1R,5R), (1S,5S)-exo-phenylequatorial-methyl boat-(flattened chair) model for nefopam is the lowest energy structure in the series. Its geometry is analogous to that observed for crystalline (±)-(1) and (+)-(1)-H2O. This calculated molecular structure together with that of the axial N-methyl epimer correspond to the stereochemistry of the minor and major N-protonated solution species, respectively, upon dissolution of crystalline (±)-(1) or (+)-(1)·H2O in dichloromethane. The relatively small calculated energv difference (ca. 0.5 kcal mol-1) between the two epimers, which differ via diastereoisomerization through a prototropic shift/nitrogen inversion, is completely consistent with the magnitudes of the n.m.r. observed equilibrium ratios both in acidic aqueous medium or in dichloromethane solution (ca. 1:1 and ca. 3:2, respectively). The other calculated conformational models for nefopam·HCl geometry are not consistent with the n.m.r. data.

Original languageEnglish
Pages (from-to)113-122
Number of pages10
JournalJournal of the Chemical Society. Perkin Transactions 2
Issue number2
DOIs
StatePublished - 1 Jan 1989

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