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Dynamic NMR study and theoretical calculations on the conformational exchange of valsartan and related compounds
Author(s) -
Li Fang,
Zhang Huiting,
Jiang Ling,
Zhang Weig,
Nie Jing,
Feng Yuqi,
Yang Minghui,
Liu Maili
Publication year - 2007
Publication title -
magnetic resonance in chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.483
H-Index - 72
eISSN - 1097-458X
pISSN - 0749-1581
DOI - 10.1002/mrc.2072
Subject(s) - chemistry , morpholine , conformational isomerism , valsartan , two dimensional nuclear magnetic resonance spectroscopy , isopropyl , nuclear magnetic resonance spectroscopy , heteronuclear single quantum coherence spectroscopy , nuclear overhauser effect , proton nmr , stereochemistry , computational chemistry , medicinal chemistry , organic chemistry , molecule , medicine , blood pressure , radiology
Abstract Valsartan (1), an antihypertensive drug of the sartan family, and three related compounds, 3‐methyl‐2‐((2′‐(1‐methyl‐1H‐tetrazol‐5‐yl)biphenyl‐4‐ylmethyl) pentanoylamino)butyric acid (2), 3‐isopropyl‐6‐propyl‐4‐(2′‐(1H‐tetrazol‐5‐yl)biphenyl‐4‐ylmethyl) morpholine‐2,5‐dione (3), and 3‐isopropyl‐6‐propyl‐4‐(4′‐(1H‐tetrazol‐5‐yl)biphenyl4‐ylmethyl) morpholine‐2,5‐dione (4), were studied by nuclear magnetic resonance (NMR) spectroscopy. Assignment of 1 H and 13 C NMR resonances for the compounds were completed using COSY, HSQC and HMBC techniques. It was found that each of the compounds 1, 2, and 4 had two sets of 1 H and 13 C resonances, suggesting the presence of two conformers in solution. Based on NOESY experiments at different temperatures, thermodynamic parameters of the conformational exchange process were deduced for these compounds. The exchange barrier was found to be 17.9 ± 0.7, 18.5 ± 0.8, and 17.7 ± 0.6 kcal mol −1 with the corresponding free energy difference ( Δ G ) of 0.32 ± 0.04, 0.23 ± 0.01, and 0.13 ± 0.04 kcal mol −1 for 1, 2, and 4, respectively, at 298 K. Two conformations of valsartan were elucidated by NMR spectroscopy and quantum chemistry calculation. The results showed that two conformers of valsartan interchange via rotation about the C(O)N bond. Copyright © 2007 John Wiley & Sons, Ltd.