Effect of solvents on the thermal isomerization of 1 alpha-hydroxyprevitamin D3 diacetate to 1 alpha-hydroxyvitamin D3 diacetate.
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.
Sato
T
T
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Kawakami
Y
Y
Nagai
Y
Y
Kawai
T
T
Kozaki
T
T
Nezu
Y
Y
Kobayashi
T
T
D001554:Benzene / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D000431:Ethanol / Q000494:pharmacology; D004987:Ethers / Q000494:pharmacology; D006586:Hexanes / Q000494:pharmacology; D006358:Hot Temperature; D006887:Hydroxycholecalciferols / Q000737:chemistry*; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D012997:Solvents / Q000494:pharmacology*; D014050:Toluene / Q000494:pharmacology
D004987:Ethers; D006586:Hexanes; D006887:Hydroxycholecalciferols; D012997:Solvents; C026385:n-hexane; D014050:Toluene; D000431:Ethanol; C068156:1-hydroxyvitamin D3 diacetate; C068155:1-hydroxyprevitamin D3 diacetate; C011779:diisopropyl ether; D001554:Benzene; C008088:alfacalcidol