R. Glaser, S. Cohen, D. Donnell
Aug 1, 1986
Citations
0
Influential Citations
24
Citations
Journal
Journal of pharmaceutical sciences
Abstract
The solid state structures of (+/-)- and (+)-nefopam hydrochloride (3,4,5,6-tetrahydro-5-methyl-1-phenyl-1H-2,5-benzoxazocine hydrochloride, 1) were determined by single crystal X-ray diffraction analysis. (+/-)-Nefopam hydrochloride gave crystals belonging to monoclinic P21/c space group, and at 298 K: a = 11.766 (1) A, b = 7.741 (1) A, c = 16.907 (3) A, beta = 97.43 (1) degrees, V = 1527.0 (7) A3, Z = 4, R = 0.0336, and Rw = 0.0452. (+)-Nefopam hydrochloride monohydrate gave crystals of the orthorhombic P2(1)2(1)2(1) space group, and at 298 K: a = 9.651 (2) A, b = 19.747 (2) A, c = 8.504 (2) A, V = 1620.7(7) A3, Z = 4, R = 0.0432, and Rw = 0.0690 for the (1S,5S)-model. The diastereoisomer found in the chiral crystal was also found in the solid racemic modification: (1S,5S) in the monohydrate of (+)-1 and (1R,5R)/(1S,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 X 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.