Glaser R, Geresh S, Blumenfeld J, Donnell D, Sugisaka N, Drouin M, Michel A
Department of Chemistry, Ben-Gurion University of the Negev, Beersheva, Israel.
J Pharm Sci. 1993 Mar;82(3):276-81. doi: 10.1002/jps.2600820312.
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) A, V = 2899.5(8) A3, Z = 8, R(F) = 0.045, and Rw(F) = 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 NCH2Ar occupy sterically hindered positions between "boat" and "chair" regions. Dissolution of BfC crystalline 1 in CD2Cl2 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 [-OCH2CH2N- segment] in the 1H NMR spectrum. The solution-state weighted time-averaged 50(1) degrees O-CH2-CH2-N dihedral angle, calculated by the R-ratio method, shows that the BfC conformation is the major contributor to time-averaged structure.
通过单晶X射线衍射分析确定了镇痛药代谢产物（±）-N-去甲基奈福泮盐酸盐（1）的固态结构。化合物1形成属于正交晶系Pcab空间群的晶体棱柱，在室温（293K）下，a = 9.939(2)，b = 14.479(1)，c = 20.148(3) Å，V = 2899.5(8) ų，Z = 8，R(F) = 0.045，Rw(F) = 0.025。晶体1的苯并恶唑嗪环扭曲成船形扁平（椅式）[BfC]构象，苯环位于空间位阻相对较小的外型环位置，而O原子和NCH₂Ar占据“船”和“椅”区域之间的空间位阻位置。BfC晶体1在CD₂Cl₂溶剂中的溶解产生动态构象平衡（涉及假定的扭曲-椅式-扁平（椅式）构象异构体），如¹H NMR谱中的谱线展宽和加权时间平均邻位偶合常数[-OCH₂CH₂N-片段]所示。通过R比率法计算的溶液态加权时间平均50(1)°的O-CH₂-CH₂-N二面角表明，BfC构象是时间平均结构的主要贡献者。
