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

Abstract

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)COO...