Solution- and Solid-State Structures of N-Desmethylnefopam Hydrochloride, a Metabolite of the Analgesic Drug

The solid-state structure of (±)-N-desmethylnefopam hydrochloride (1), a metabolite of the analgesic drug, was determined by single-crystal X-ray diffraction analysis. Compound 1 gave crystalline prisms belonging to the orthorhombic Pcab space group, and at ambient temperature (293 K), a = 9.939(2), b = 14.479(1), c = 20.148(3) Å, V= 2899.5(8) Å3, Z = 8, R(F) = 0.045, and RJF) = 0.025. The benzoxazocine ring of crystalline 1 is twisted into the boat- flattened(chair) [BfC] conformation, the phenyl ring resides in a relatively sterically unhindered exo-type ring position, whereas the O atom and NCHjAr occupy sterically hindered positions between “boat” and "chair" regions. Dissolution of BfC crystalline 1 in CD2CI2 solvent affords a dynamic conformational equilibrium (involving the putative twist-chair- flattened(chair) conformer) as shown by line broadening and weighted time-averaged vicinal coupling constants [-0CH2CH2N- segment] in the 1H NMR spectrum. The solution-state weighted time-averaged 50(1)° 0-CH2-CH2-N dihedral angle, calculated by the R-ratio method, shows that the B/C conformation is the major contributor to time-averaged structure.