Selective deuteration of [(pyridylmethyl)sulfinyl]benzimidazole antisecretory drugs. A NMR study where DMSO-d6acts as deuteration agent.
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 CH2SO 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.
Department of Research and Development, Esteve-Química S.A., Caracas st. 17-19, E08030, Barcelona, Catalonia, Spain. Electronic address: jredondo@eqesteve.com.
Jordi
J
Redondo
Departament de Química, Universitat Autònoma de Barcelona, E08193, Bellaterra, Catalonia, Spain.
Carlos
C
Jaime
Department of Research and Development, Esteve-Química S.A., Caracas st. 17-19, E08030, Barcelona, Catalonia, Spain.
Albert
A
Marqués
D001562:Benzimidazoles / Q000032:analysis* / Q000737:chemistry; D003903:Deuterium / Q000737:chemistry*; D004121:Dimethyl Sulfoxide / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D054328:Proton Pump Inhibitors / Q000032:analysis* / Q000737:chemistry
D001562:Benzimidazoles; D054328:Proton Pump Inhibitors; D003903:Deuterium; D004121:Dimethyl Sulfoxide
Esomeprazole; Molecular calculations; NMR; Pantoprazole; Rabeprazole; Stereoselective deuteration