Sato T, Kawakami Y, Nagai Y, Kawai T, Kozaki T, Nezu Y, Kobayashi T
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
J Nutr Sci Vitaminol (Tokyo). 1990 Aug;36(4):299-309. doi: 10.3177/jnsv.36.4-supplementi_299.
The thermal conversion of 1 alpha-hydroxyprevitamin D3 (1 alpha-OH-previtamin D3) diacetate to 1 alpha-hydroxyvitamin D3 (1 alpha-OH-vitamin D3) diacetate was investigated in five solvents. The fraction of 1 alpha-OH-vitamin D3 diacetate was calculated from the HPLC peak areas (UV detection) of 1 alpha-OH-previtamin D3 diacetate and 1 alpha-OH-vitamin D3 diacetate. When 1 alpha-OH-previtamin D3 diacetate was dissolved in ethanol, benzene, toluene, isopropyl ether, or n-hexane, and heated at 60 degrees C, the yield of 1 alpha-OH-vitamin D3 diacetate increased during the first 4 h, and reached an equilibrium level after 8.5 h. Differences in the ratio of 1 alpha-OH-previtamin D3 diacetate to 1 alpha-OH-vitamin D3 diacetate at thermal equilibrium, and in the rate of the thermal isomerization were observed among these five solvents. Molecular mechanics (MM) calculations were performed in order to estimate solvent effects on conformation for 1 alpha-OH-previtamin D3 diacetate and 1 alpha-OH-vitamin D3 diacetate. The solvent effect was treated by specifying a dielectric constant representative of each of the three solvents: ethanol (polar), n-hexane (nonpolar), and benzene (aromatic). The dielectric constants used were 24.3 for ethanol, 1.5 for n-hexane, and 2.3 for benzene. It is suggested that the conformation of 1 alpha-OH-vitamin D3 diacetate is stabilized in polar solvent. However, the order of conformational stability when solvent effects are included in the calculations is: ethanol greater than benzene greater than n-hexane. This order does not follow the experimental results. The proton NMR chemical shifts of 1 alpha-OH-vitamin D3 diacetate are different in deuterated n-hexane, ethanol, and benzene. The downfield shift of the C-6 vinyl proton of 1 alpha-OH-vitamin D3 diacetate, when compared to the chemical shift in benzene, is 0.15 and 0.11 ppm relative to the chemical shift in n-hexane and ethanol, respectively, and that of the C-7 proton was 0.30 and 0.33 ppm, respectively. No significant proton shift of 1 alpha-OH-previtamin D3 diacetate is recorded in these three solvents. To account for the increased ratio of 1 alpha-OH-vitamin D3 diacetate to 1 alpha-OH-previtamin D3 diacetate ratio in benzene, we suggest that 1 alpha-OH-vitamin D3 diacetate may be stabilized via specific solute-solvent interactions in benzene.
在五种溶剂中研究了1α-羟基维生素D3（1α-OH-维生素D3）二乙酸酯向1α-羟基维生素D3（1α-OH-维生素D3）二乙酸酯的热转化。1α-OH-维生素D3二乙酸酯的比例通过1α-OH-维生素D3二乙酸酯和1α-OH-维生素D3二乙酸酯的HPLC峰面积（紫外检测）计算得出。当将1α-OH-维生素D3二乙酸酯溶解于乙醇、苯、甲苯、异丙醚或正己烷中，并在60℃加热时，1α-OH-维生素D3二乙酸酯的产率在前4小时增加，并在8.5小时后达到平衡水平。在这五种溶剂中观察到了热平衡时1α-OH-维生素D3二乙酸酯与1α-OH-维生素D3二乙酸酯的比例差异以及热异构化速率的差异。进行了分子力学（MM）计算，以估计溶剂对1α-OH-维生素D3二乙酸酯和1α-OH-维生素D3二乙酸酯构象的影响。通过指定代表三种溶剂（乙醇（极性）、正己烷（非极性）和苯（芳香性））中每一种的介电常数来处理溶剂效应。使用的介电常数分别为乙醇24.3、正己烷1.5和苯2.3。表明1α-OH-维生素D3二乙酸酯的构象在极性溶剂中稳定。然而，当计算中包括溶剂效应时，构象稳定性的顺序为：乙醇＞苯＞正己烷。该顺序与实验结果不符。1α-OH-维生素D3二乙酸酯在氘代正己烷、乙醇和苯中的质子核磁共振化学位移不同。与苯中的化学位移相比，1α-OH-维生素D3二乙酸酯的C-6乙烯基质子相对于正己烷和乙醇中的化学位移分别向下位移0.15和0.11 ppm，C-7质子的向下位移分别为0.30和0.33 ppm。在这三种溶剂中未记录到1α-OH-维生素D3二乙酸酯的明显质子位移。为了解释苯中1α-OH-维生素D3二乙酸酯与1α-OH-维生素D3二乙酸酯比例的增加，我们认为1α-OH-维生素D3二乙酸酯可能通过在苯中的特定溶质-溶剂相互作用而稳定。
