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) ų, Z = 4, R = 0.0336, and R_w = 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) ų, Z = 4, R = 0.0432, and R_w = 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.