SOLUTION AND SOLID-STATE CONFORMATIONAL AND STRUCTURAL-ANALYSIS OF THE N-METHYL DERIVATIVES OF (+ -)-THREO-METHYLPHENIDATE, (+/-)-ERYTHRO-METHYLPHENIDATE, AND (+/-)-THREO-P-METHYL-METHYLPHENIDATE HYDROCHLORIDESALTS/

The conformational preferences of N-methyl derivatives of the dopamine reuptake blocker threo-methylphenidate [Ritalin] and the p-methyl ana logue were determined in the solid state and in solution and that of t he erythro isomer in solution. The solid-state structures /-)-threo-N- methyl-alpha-phenyl-2-piperidineacetic acid methyl ester hydrochloride [(+/-)-threo-N-methyl-methylphenidate hydrochloride] (2) and threo-N, p-dimethyl-alpha-phenyl-2-piperidineacetic acid methyl ester hydrochlo ride (5) were determined by single crystal X-ray diffraction analysis. (+/-)-2 underwent spontaneous resolution to give crystalline chiral p lates containing two independent molecules in the asymmetric ring, and at each site there is a disorder involving the N-methylpiperidinyl ri ng 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 h ave similar structures consisting of a chair conformation for the pipe ridine ring with axial N-methyl and CH(Ph)COOMe groups. The two (2RS,3 RS,4RS) minor molecules in the disorder also have similar structures a nd differ from the major ones by epimerization at nitrogen and inversi on of the piperidine ring to afford an axial N-methyl group, and an eq uatorial CH(Ph)COOMe group. (+/-)-5 gave crystalline plates also conta ining diaxially disposed piperidinyl-ring substituents. Dissolution in D2O of either 2 or its erythro-epimer (3) each gives a 5:4 ratio of t wo 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 die quatorial arrangement for both substituents. Both of the axial N-methy l three or erythro major species in D2O are overwhelmingly conformatio nally biased in favor of an antiperiplanar H(2)... H(3) disposition an d one piperidine ring invertomer. Dissolution of the three or erythro epimers in CD2Cl2 gives the same axial N-methyl/equaterial CH(Ph)COOMe and diequatorially disposed species but now in a reversed ratio [resp ectively 3:20 for three and 4:5 for erythro].