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)

Abstract

AbstractThe 1H NMR spectrum (CD2Cl2) of the mesylate analogue of phendimetrazine bitartarate, a central nervous system stimulant and an anorexic drug, showed two isomers (ratio ≈︁ 17:1) differing in the stereochemistry of the N+HCH3 moiety. A similar diastereomeric ratio was also noted in 13C{1H} NMR spectra recorded in either CD2Cl2 or in acidic D2O (pD ≈︁ 1). For the major species in CD2Cl2 solution, four antiperiplanar vicinal 1H1H coupling constants indicated a chair‐conformation 2,3‐trans‐1,4‐oxazine ring with equatorially oriented 2‐phenyl, 3‐methyl and N‐methyl substituents. The minor species also has the same chair conformation with equatorially oriented 2‐phenyl and 3‐methyl 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 absorbances for the corresponding carbons in the major [equatorial N‐methyl] species. The R‐factor method was used to estimate an OC6C5N dihedral angle of 56.0(7)° for the major equatorial N‐methyl species in CD2Cl2 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 OCH2CH2N+H(equatorial CH3)— and OCH2CH2N+H vicinal coupling constants in the two rings suggests dynamic weighted averaging for those in the octagonal ring of the nefopam equatorial NCH3 diastereomer.