The stereochemistry of a nine-membered ring analogue of nefopam, a nonnarcotic analgesic drug

Abstract

The solid-state structure of a (±)-homonefopam hydrogenfumarate salt having an-O(CH₂)₃N-fragment was determined by single-crystal X-ray diffraction analysis. Homonefopam hydrogenfumarate gave crystals belonging to the monoclinicP2₁/c space group, and at ambient temperaturea=10.220(1),b=18.187(2),c=10.687(2)A,Β=94.43(1)‡,V=1980.5(5)å³ Z=4,R(F)=0.039,R _w =0.039,R _W (F)=0.025. The¹H NMR spectrum of homonefopam hydrochloride in CD₂Cl₂ solution showed two species (7:1 ratio) at the prototropic shift-nitrogen inversion slow exchange limit. The solution-state major species has the same conformation andtrans-to-phenyl axial N-methyl disposition found in the crystal as evidenced by three antiperiplanar vicinal³ J (HH) coupling constants in the oxytrimethyleneamino fragment and vicinal coupling constants involving theN-H proton. TheR-ratio method was used to estimate 64(2)‡ O-C(3)-C(4)-C(5) and 75(3)‡ C(3)-C(4)-C(5)-N(6) dihedral angles for the major species in CD₂Cl₂ solution in accord with its proposed structure. The finding of C(3)-C(4) bond time-averaged magnitude³ J (HH) values and severe broadening of signals from other minor species protons suggests conformational heterogeneity for the solution-state minor species.