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| - Solution and Solid-State Conformational and Structural Analysisof the N-Methyl Derivatives of (±)-threo-Methylphenidate,(±)-erythro-Methylphenidate, and(±)-threo-p-Methyl-methylphenidate Hydrochloride Salts
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| - The conformational preferences of N-methyl derivativesof the dopamine reuptake blocker threo-methylphenidate [Ritalin] and the p-methyl analogue weredetermined in the solid state and insolution 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-methylphenidatehydrochloride] (2) and(±)-threo-N,p-dimethyl-α-phenyl-2-piperidineaceticacid methyl ester hydrochloride (5) were determined by single crystal X-raydiffraction analysis. (±)-2 underwentspontaneous resolution to give crystalline chiral plates containing twoindependent molecules inthe asymmetric ring, and at each site there is a disorder involving theN-methylpiperidinyl ringmethylene and methyl carbon atoms with a 0.710(7):0.290(7)ratio of occupancy factors. The two(2RS,3RS,4SR) major disorderedmolecules have similar structures consisting of a chairconformation for the piperidine ring with axial N-methyl andCH(Ph)COOMe groups. The two(2RS,3RS,4RS)minor molecules in the disorder also have similar structures and differfrom the major ones byepimerization at nitrogen and inversion of the piperidine ring toafford an axial N-methyl group,and an equatorial CH(Ph)COOMe group.(±)-5 gave crystalline plates also containingdiaxiallydisposed piperidinyl-ring substituents. Dissolution inD2O of either 2 or its erythro-epimer(3) eachgives a 5:4 ratio of two species in which the major species exhibits anaxial N-methyl group and anequatorial CH(Ph)COOMe group while the minorspecies has a diequatorial arrangement for bothsubstituents. Both of the axial N-methylthreo or erythro major species in D2Oare overwhelminglyconformationally biased in favor of an antiperiplanarH(2)···H(3) disposition and one piperidinering invertomer. Dissolution of the threo orerythro epimers in CD2Cl2 givesthe same axialN-methyl/equatorial CH(Ph)COOMe anddiequatorially disposed species but now in a reversedratio[respectively 3:20 for threo and 4:5 forerythro].
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