1H and 13C NMR studies on the oxydimethyleneaminomethyl fragment in six- and eight-membered rings. The solution stereochemistry of N-methyl diastereomers of phendimetrazine (an oxazine anorexic drug) versus nefopam (a benzoxazocine analgesic drug)

✍ Scribed by Robert Glaser

• Publisher: John Wiley and Sons
• Year: 1989
• Tongue: English
• Weight: 621 KB
• Volume: 27
• Category: Article
• ISSN: 0749-1581
• DOI: 10.1002/mrc.1260271207

✦ Synopsis

The 'H NMR spectrum (CD,CI,) of the mesylate analogue of phendimetrazine bitartarate, a central nervous system stimulant and an anorexic drug, showed two isomers (ratio x 17: 1) differing in the stereochemistry of the N+HCH, moiety. A similar diastereomeric ratio was also noted in 13C{1H} NMR spectra recorded in either CD,CI, or in acidic D,O (pD z 1). For the major species in CD,CI, solution, four antiperiplanar vicinal 'H-IH coupling constants indicated a chair-conformation 2,3-trans-1,4-oxazine ring with equatorially oriented 2-pheny1, %methyl and N-methyl substituents. The minor species also has the same chair conformation with equatorially oriented 2-phenyl and Imethyl substituents, since the coupling constant for the minor species vicinal OCH(Ph)CH(Me)N methine protons was also antiperiplanar in magnitude. Axial N-methyl stereochemistry was assigned to the minor species, since chemical shifts of the ring carbons gauche to N-methyl (and of the N-methyl carbon atom itself) were shifted characteristically upfield relative to absorbance for the corresponding carbons in the major [equatorial N-methyl] species. The R-factor method was used to estimate an 0-C-6-C-5-N dihedral angle of 56.0(7)0 for the major equatorial N-methyl species in CD,CI, solution. CP-MAS 13C NMR chemical shifts for solid-state phendimetrazine bitartarate are the same as those for the solution-state equatorial N-methyl diastereomer. The oxydimethyleneaminomethyl fragment in the equatorial N-methyl phendimetrazine chair conformation was used as a model for the corresponding fragment in the eight-membered ring of nefopam. Comparison of -OCH,CH,N+H(equatoriaI CH,+ and -OCH,CH,N+H vicinal coupling constants in the two rings suggests dynamic weighted averaging for those in the octagonal ring of the nefopam Guatorial N-CH, diastereomer.