Dynamic NMR study and theoretical calculations on the conformational exchange of valsartan and related compounds
Dynamic NMR study and theoretical calculations on the conformational exchange of valsartan and related compounds
复制标题
缬沙坦及相关化合物构象交换的动态核磁共振研究及理论计算
DOI：
10.1002/mrc.2072
复制
发表时间：
2007-11-01
影响因子：
2
通讯作者：
Liu, Maili
中科院分区：
文献类型：
--
作者：
Li, Fang;Zhang, Huiting;Liu, Maili
缬沙坦（Valsartan）（1），一种沙坦家族的抗高血压药物，以及三种相关化合物，3-甲基-2-（（2 '-（1-甲基-1H-四唑-5-基）联苯-4-基甲基）戊酰氨基）丁酸（2），（2 '-（1H-四唑-5-基）联苯-4-基-甲基）吗啉-2，5-二酮（3），和3-异丙基-6-丙基-4-（三氟甲基）苯甲酸酯（3），通过核磁共振（NMR）光谱研究了（4 '-（1H-四唑-5-基）联苯4-基甲基）吗啉-2，5-二酮（4）。利用COSY、HSQC和HMBC技术对化合物的H-1和C-13 NMR共振峰进行了归属。发现化合物1、2和4中的每一个都具有两组H-1和C-13共振，表明溶液中存在两种构象异构体。基于不同温度下的NOESY实验，推导了这些化合物构象交换过程的热力学参数。发现1、2和4的交换势垒分别为17.9 +/- 0.7、18.5 +/- 0.8和17.7 +/- 0.6 kcal mol（-1），相应的自由能差（Δ G）分别为0.32 +/- 0.04、0.23 +/- 0.01和0.13 +/- 0.04 kcal mol（-1），在298 K.通过核磁共振和量子化学计算，确定了缬沙坦的两种构象。结果表明，缬沙坦的两种构象是通过C（O）-N键的旋转进行交换的。版权所有（c）2007约翰威利父子有限公司。
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-yl-methyl) 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 H-1 and C-13 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 H-1 and C-13 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 (Delta 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 (c) 2007 John Wiley & Sons, Ltd.