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【结 构 式】 
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【分子编号】30300 【品名】(3aS,7S,7aR)-3a-methyl-3-[(1R)-6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoromethyl)-3-hexynyl]-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol 【CA登记号】 |
【 分 子 式 】C18H22F6O2 【 分 子 量 】384.3618992 【元素组成】C 56.25% H 5.77% F 29.66% O 8.33% |
合成路线1
该中间体在本合成路线中的序号：(III)Condensation of the lithium anion of alkyne (I) with hexafluoroacetone provided the tertiary alcohol (II). Subsequent deprotection of the silyl ether of (II) with tetrabutylammonium fluoride yielded alcohol (III), which was oxidized to ketone (IV) by means of pyridinium chlorochromate. Wittig condensation of (IV) with the ylide resulting from phosphine (V) and BuLi produced diene (VI). Finally, both silyl ethers of (VI) were cleaved with tetrabutylammonium fluoride to furnish the title compound.
| 【1】 Baggiolini, B.J.; Shiuey, S.-J.; Uskokovic, M.R. (F. Hoffmann-La Roche AG); Vitamin D3 fluorinated analogs. US 5451574; US 5753638 . |
| 【2】 Uskokovic, M.R.; Baggiolini, E.G.; Shiuey, S.-J. (F. Hoffmann-La Roche AG); Vitamin D3 fluorinated analogs. EP 0580968 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 30298 | ([(3aS,7S,7aR)-3a-methyl-3-[(1R)-1-methyl-3-butynyl]-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl]oxy)(tert-butyl)dimethylsilane; (3aS,7S,7aR)-3a-methyl-3-[(1R)-1-methyl-3-butynyl]-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl tert-butyl(dimethyl)silyl ether | C21H36OSi | 详情 | 详情 | |
| (II) | 30299 | (6R)-6-((3aS,7S,7aR)-7-[[tert-butyl(dimethyl)silyl]oxy]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl)-1,1,1-trifluoro-2-(trifluoromethyl)-3-heptyn-2-ol | C24H36F6O2Si | 详情 | 详情 | |
| (III) | 30300 | (3aS,7S,7aR)-3a-methyl-3-[(1R)-6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoromethyl)-3-hexynyl]-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol | C18H22F6O2 | 详情 | 详情 | |
| (IV) | 30301 | (3aR,7aS)-7a-methyl-1-[(1R)-6,6,6-trifluoro-5-hydroxy-1,5-dimethyl-3-hexynyl]-3,3a,5,6,7,7a-hexahydro-4H-inden-4-one | C18H23F3O2 | 详情 | 详情 | |
| (V) | 30302 | [2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethyl(diphenyl)phosphine oxide | C32H51O3PSi2 | 详情 | 详情 | |
| (VI) | 30303 | (6R)-6-[(3aS,7aS)-7-[(E)-2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethylidene]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-1,1,1-trifluoro-2-(trifluoromethyl)-3-heptyn-2-ol | C38H60F6O3Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Reduction of the triple bond of compound (I) with LiAlH4 in the presence of NaOMe furnished the E-olefin (II). The secondary alcohol group of (II) was then oxidized to the corresponding ketone (III) by means of pyridinium dichromate in the presence of pyridinium p-toluenesulfonate. Condensation of this ketone with the ylide resulting from phosphine oxide (IV) and n-BuLi produced the silylated cholecalciferol analogue (V). The silyl protecting groups of (V) were finally removed by treatment with tetrabutylammonium fluoride.
| 【1】 Doran, T.I.; Hennessy, B.M.; McLane, J.A.; Pizzolato, G.; Sedarati, F.; Uskokovic, M.R. (F. Hoffmann-La Roche AG); Vitamin D3 analogs. EP 0654467; JP 1995188159; US 5428029 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 30300 | (3aS,7S,7aR)-3a-methyl-3-[(1R)-6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoromethyl)-3-hexynyl]-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol | C18H22F6O2 | 详情 | 详情 | |
| (II) | 44265 | (3aS,7S,7aR)-3a-methyl-3-[(1R,3E)-6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoromethyl)-3-hexenyl]-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol | C18H24F6O2 | 详情 | 详情 | |
| (III) | 44266 | (3aR,7aS)-7a-methyl-1-[(1R,3E)-6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoromethyl)-3-hexenyl]-3,3a,5,6,7,7a-hexahydro-4H-inden-4-one | C18H22F6O2 | 详情 | 详情 | |
| (IV) | 30302 | [2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethyl(diphenyl)phosphine oxide | C32H51O3PSi2 | 详情 | 详情 | |
| (V) | 44267 | (1R,5R)-3-[2-((3aS,7aS)-7a-methyl-1-[(1R,3E)-6,6,6-trifluoro-1-methyl-5-(trifluoromethyl)-5-[(trimethylsilyl)oxy]-3-hexenyl]-3,3a,5,6,7,7a-hexahydro-4H-inden-4-ylidene)ethylidene]-5-[[tert-butyl(dimethyl)silyl]oxy]cyclohexyl tert-butyl(dimethyl)sily; [((1R,5R)-3-[2-((3aS,7aS)-7a-methyl-1-[(1R,3E)-6,6,6-trifluoro-1-methyl-5-(trifluoromethyl)-5-[(trimethylsilyl)oxy]-3-hexenyl]-3,3a,5,6,7,7a-hexahydro-4H-inden-4-ylidene)ethylidene]-5-[[tert-butyl(dimethyl)silyl]oxy]cyclohexyl)oxy](tert-butyl)dimeth | C41H70F6O3Si3 | 详情 | 详情 |