Solution and Solid-State Conformational and Structural Analysis of the N-Methyl Derivatives of (±)-threo-Methylphenidate, (±)-erythro-Methylphenidate, and (±)-threo-p-Methyl-methylphenidate Hydrochloride Salts

The conformational preferences of N-methyl derivatives of the dopamine reuptake blocker threo-methylphenidate [Ritalin] and the p-methyl analogue were determined in the solid state and in solution and that of the erythro isomer in solution. The solid-state structures of (±)-threo-N-methyl-α-phenyl-2-piperidineacetic acid methyl ester hydrochloride [(±)-threo-N-methyl-methylphenidate hydrochloride] (2) and (±)-threo-N,p-dimethyl-α-phenyl-2-piperidineacetic acid methyl ester hydrochloride (5) were determined by single crystal X-ray diffraction analysis. (±)-2 underwent spontaneous resolution to give crystalline chiral plates containing two independent molecules in the asymmetric ring, and at each site there is a disorder involving the N-methylpiperidinyl ring methylene and methyl carbon atoms with a 0.710(7):0.290(7) ratio of occupancy factors. The two (2RS,3RS,4SR) major disordered molecules have similar structures consisting of a chair conformation for the piperidine ring with axial N-methyl and CH(Ph)COOMe groups. The two (2RS,3RS,4RS) minor molecules in the disorder also have similar structures and differ from the major ones by epimerization at nitrogen and inversion of the piperidine ring to afford an axial N-methyl group, and an equatorial CH(Ph)COOMe group. (±)-5 gave crystalline plates also containing diaxially disposed piperidinyl-ring substituents. Dissolution in D2O of either 2 or its erythro-epimer (3) each gives a 5:4 ratio of two species in which the major species exhibits an axial N-methyl group and an equatorial CH(Ph)COOMe group while the minor species has a diequatorial arrangement for both substituents. Both of the axial N-methyl threo or erythro major species in D2O are overwhelmingly conformationally biased in favor of an antiperiplanar H(2)···H(3) disposition and one piperidine ring invertomer. Dissolution of the threo or erythro epimers in CD2Cl2 gives the same axial N-methyl/equatorial CH(Ph)COOMe and diequatorially disposed species but now in a reversed ratio [respectively 3:20 for threo and 4:5 for erythro].