Designing chemical systems for precision deuteration of medicinal building blocks
Jonathan D. Dabbs, Caleb C Taylor, Martin Holdren, S. Brewster, Brian T. Quillin, Alvin Q. Meng, Diane A. Dickie, Brooks H. Pate, W. Dean Harman
Abstract
Abstract Methods are lacking that can prepare deuterium-enriched building blocks, in the full range of deuterium substitution patterns at the isotopic purity levels demanded by pharmaceutical use. To that end, this work explores the regio- and stereoselective deuteration of tetrahydropyridine (THP), which is an attractive target for study due to the wide prevalence of piperidines in drugs. A series of d 0 –d 8 tetrahydropyridine isotopomers were synthesized by the stepwise treatment of a tungsten-complexed pyridinium salt with H − /D − and H + /D + . The resulting decomplexed THP isotopomers and isotopologues were analyzed via molecular rotational resonance (MRR) spectroscopy, a highly sensitive technique that distinguishes isotopomers and isotopologues by their unique moments of inertia. In order to demonstrate the medicinal relevance of this approach, eight unique deuterated isotopologues of erythro -methylphenidate were also prepared.