Selective deuteration of [(pyridylmethyl)sulfinyl]benzimidazole antisecretory drugs. A NMR study where DMSO-d<inf>6</inf>acts as deuteration agent

Jordi Redondo, Carlos Jaime, Albert Marqués

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

© 2016 Elsevier B.V. The use of deuterated drug bioisosteres to obtain superior pharmacokinetic properties or to investigate biotransformations at the molecular level is a growing field of pharmaceutical research. This work presents a NMR study on the deuteration of three structurally related antisecretory proton-pump inhibitors, the sodium salts of esomeprazole, 1, pantoprazole, 2, and rabeprazole, 3. It has been found that the methylene adjacent to the sulfinyl group displays stereoselective deuteration when the sodium salts of these products are dissolved at room temperature in D2O or CD3OD, a process that also occurs very efficiently in DMSO-d6(a solvent considered non-deuterating) if a catalytic amount of NaOH is added. The stereoselectivity of the deuteration is consequence of the asymmetry around the sulfur atom of the sulfinyl group, and the rate of the H-D exchange seems to be mainly related to the polarity of the solvents. In addition, unusually long-range (up to seven bonds) NMR deuterium isotopic effects on proton have been detected. Density Functional Theory (DFT) calculations (DFT/6-31G**) have been performed on the rotamers about the CH2[sbnd]SO bond of 1, as well as about the equivalent bond in its entiol, N-anion, and entiolate. Less conformers than possible were obtained in all cases indicating strong preference for some spatial dispositions. Computed NMR shielding agrees with the experimentally obtained chemical shifts and help in identifying the most accessible diastereotopic hydrogen.
Original languageEnglish
Pages (from-to)454-463
JournalJournal of Pharmaceutical and Biomedical Analysis
Volume131
DOIs
Publication statusPublished - 30 Nov 2016

Keywords

  • Esomeprazole
  • Molecular calculations
  • NMR
  • Pantoprazole
  • Rabeprazole
  • Stereoselective deuteration

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