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

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) eightmembered 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-phenyl–equatorial-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 energy 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.