Solution- and solid-state conformations of C(α)-alkyl analogues of methylphenidate (Ritalin) salts: Avoidance of gauche + gauche - Interactions

Avital Steinberg, Mark Froimowitz, Damon A. Parrish, Jeffrey R. Deschamps, Robert Glaser

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Alkyl analogues of methylphenidate (Ritalin) salts are slow onset, long duration dopamine reuptake inhibitors with a potential use as a cocaine abuse pharmacotherapy. X-ray crystallographic studies and nuclear magnetic resonance (NMR) investigations strongly suggest that avoidance of sterically unfavorable gauche-gauche+ orientations effectively influences both the C(α)-alkyl side chain conformation and the formation of a predominant rotamer about the CH-CH bond ligating piperidine and C(Ar)R moieties. The favored CH-CH rotamer in D2O and in CD2Cl2 of the pharmacologically interesting i-Bu and CH2-cyc-Pnt (RS,RS)-salts has the same antiperiplanar arrangement that was found in the crystal structures, although there clearly is a fast equilibrium involving smaller amounts of synclinal partners. While the rotamer in the (RS,SR)-i-Bu HCl crystal structure exhibits a synclinal orientation for the vicinal pair of adjacent methine protons, the weighted time-averaged arrangement for these protons becomes almost completely antiperiplanar when the crystals are dissolved in D2O. Increased steric congestion around the CH-CH bond in the analogous N-methyl tertiary ammonium salts seems to augment the quantity of the preferred rotamer within the mixture. The stereochemistry of the species observed via NMR seems to arise from specific combinations of N-methyl orientation and avoidance of sterically unfavorable gauche -gauche+ arrangements.

Original languageEnglish
Pages (from-to)9239-9245
Number of pages7
JournalJournal of Organic Chemistry
Volume76
Issue number22
DOIs
StatePublished - 18 Nov 2011

ASJC Scopus subject areas

  • Organic Chemistry

Fingerprint

Dive into the research topics of 'Solution- and solid-state conformations of C(α)-alkyl analogues of methylphenidate (Ritalin) salts: Avoidance of gauche + gauche - Interactions'. Together they form a unique fingerprint.

Cite this