Preparation of Deuterium-Labeled Tadalafil and Omeprazole by Carbon Hydrogen-Deuterium Exchange: Hydrogen Scrambling, Acid-Induced Transformation, and LC-MS Applications
Abstract
Rationale: Stable isotope-labeled compounds are indispensable internal standards for reliable liquid chromatography-mass spectrometry (LC-MS) analysis, but their preparation frequently requires multistep synthesis. Base-catalyzed hydrogen-deuterium exchange at carbon centers provides a simple alternative for generating stable isotopologues. Beyond quantitative applications, carbon-bound deuterium may serve as a mechanistic probe for investigating gas-phase fragmentation and chemically induced molecular transformations. In this work, tadalafil and omeprazole were selected as complementary model compounds to evaluate both the analytical applicability of deuterium-labeled standards and the behavior of carbon-bound deuterium during tandem mass spectrometry and acid-induced transformation.
Methods: Deuterium-labeled tadalafil and omeprazole were prepared by base-catalyzed hydrogen-deuterium exchange under optimized reaction conditions. The obtained isotopologue mixtures were characterized using high-resolution ESI-MS, multistage tandem mass spectrometry, 1H NMR spectroscopy, and density functional theory (DFT) calculations. Their chromatographic behavior, short-term isotope stability, and proof-of-concept applicability as LC-MS internal standards were evaluated using chromatographic comparison and analysis of post-dose human urine samples.
Results: Base-catalyzed hydrogen-deuterium exchange produced isotopologue mixtures dominated by tadalafil-d3 and omeprazole-d2.…
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