Solid-state structure of (+)-phendimetrazine bitartarate, an anorexic drug

The anorexic drug (+)-(2 S, 3 S, 4 S)-phendimetrazine-2 ′R, 3 ′R)-bitartarate crystallized in the orthorhombic space group P2₁2₁2₁ and at 293 K:a=7.7710(4), b=13.1379(7), c=15.9913(9) Å, V=1632.6(2) ų, Z=4, R(F)=0.062, and R_w(F)=0.026. A chair conformation 2,3-trans-1,4-oxazine ring with equatorially oriented 2-phenyl,3-methyl, and N-methyl substituents was found as predicted by an earlier reported solid-state CP-MAS¹³C-NMR investigation of crystalline (±)-phendimetrazine bitartarate. The O-CH₂-CH₂-N torsion angle of -58.4(6)° in the solid-state agrees nicely with the 56.0(7)° dihedral angle value estimated by¹H NMR spectroscopy for the major (equatorial N-methyl) phendimetrazine mesylate species in CD₂Cl₂ solution. A common solid-state conformational arrangement was found for (+)-phendimetrazine and a series of six other anorexic drugs structurally analogous to (+)-(2 S, 3 S)-pseudoephedrine. In this arrangement, N CH(Me)CPh has (S)-configuration, there is a (-)-gauche Me-CH-C-Ph torsion angle, an antiperiplanar N-CH-C-Ph torsion angle, and the phenyl ring approximately eclipses the C-H bond of the attached carbon (e.g., H-C-C_ipso-C_ortho ca. 4° for 2,3-transphendimetrazine). Nonbonded interactions involving the 3-methyl and the 2-phenyl groups open up the H-C-C_ipso-C_ortho angle in a series of solid-state structures containing the epimeric (-)-(2 R, 3 S)-ephedrine moiety (e.g., ca. 45° for molecular mechanics calculated 2,3-cis-phendimetrazine model).