Conformation of Nefopam Hydrochloride, a Novel Analgesic

The solid state structures of (±)- and (+)-nefopam hydro-chloride (3, 4,5,6-tetrahydro-5-methyl-1-phenyl-1 H-2, 5-benzoxazocine hydrochloride, 1) were determined by single crystal X-ray diffraction analysis. (±)-Nefopam hydrochloride gave crystals belonging to mono-clinic P21/c space group, and at 298 K: a=11.766 (1) Å, b=7.741 (1) Å, c=16.907 (3) Å, β=97.43 (1)°, V=1527.0 (7) Å3, Z=4, R=0.0336, and Rw=0.0452. (+)-Nefopam hydrochloride monohydrate gave crystals of the orthorhombic P212121 space group, and at 298 K: a=9.651 (2) Å, b=19.747 (2) Å, c=8.504 (2) Å, V=1620.7(7) Å3, Z=4, R=0.0432, and Rw=0.0690 for the (1 S,5S)-model. The diastereoisomer found in the chiral crystal was also found in the solid racemic modification: (1 S,5S) in the monohydrate of (+)−1 and (1 R,5R)/(1 S,5S) in (±)-1. 1H and 13C{1H} NMR spectroscopy revealed two distinct, major and minor, N-protonated species in CD2Cl2 solution differing in the stereochemistry of the N-methyl group. The molecular structures of the crystals of (±)-1 and (+)−1 · H2O (a) indicate a modified boat-chair conformation of the eight-membered ring with an equatorial N-methyl group, caused by two sp2-hybridized ring atoms, and (b) correspond to the stereochemistry of the minor species in solution.