|
【结 构 式】 
|
【分子编号】38682 【品名】(3aS,7S,7aR)-3-[(1S)-2-hydroxy-1-methylethyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol 【CA登记号】 |
【 分 子 式 】C13H22O2 【 分 子 量 】210.31648 【元素组成】C 74.24% H 10.54% O 15.21% |
合成路线1
该中间体在本合成路线中的序号：(I)The tosylation of the primary alcohol of the hexahydroindenepropanol (I) with TsCl in pyridine gives the tosylate (II), which is treated with NaCN in DMSO to yield the butyronitrile (II). The reduction of (III) with diisobutylaluminum hydride in dichloromethane affords the butyraldehyde (IV), which is condensed with CBr4 by means of Zn in dichloromethane providing the 1,1-dibromo-1-pentene derivative (V). The dehydrobromination of (V) with n-BuLi in THF/hexane affords the 1-pentyne derivative (VI), which is treated with 1-(trimethylsilyl)imidazole to give the silyl ether (VII). The condensation of (VII) with acetone by means of n-BuLi in THF yields the 3-heptyn-2-ol derivative (VIII), which is desilylated with TBAF in THF affording the diol (IX). The oxidation of the secondary alcohol of (IX) with bipyridinium chlorochromate (BPCC) in dichloromethane provides the corresponding ketone (X), which is protected at the tertiary alcohol with 1-(trimethylsilyl)imidazole giving the silylated ketone (XI). The condensation of (XI) with the phosphorane (XII) by means of n-BuLi in THF yields the protected intermediate (XIII), which is finally deprotected with TBAF in THF.
| 【1】 Baggiolini, E.G.; Hennessy, B.M.; Shiuey, S.-J.; Truitt, G.A.; Uskokovic, M.R. (F. Hoffmann-La Roche AG); Dehydrocholecalciferol derivs.. AU 8928644; EP 0325279; JP 1990009861; US 5087619 . |
| 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) | 38682 | (3aS,7S,7aR)-3-[(1S)-2-hydroxy-1-methylethyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol | C13H22O2 | 详情 | 详情 | |
| (II) | 38683 | (2S)-2-[(3aS,7S,7aR)-7-hydroxy-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]propyl 4-methylbenzenesulfonate | C20H28O4S | 详情 | 详情 | |
| (III) | 38684 | (3R)-3-[(3aS,7S,7aR)-7-hydroxy-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]butanenitrile | C14H21NO | 详情 | 详情 | |
| (IV) | 38685 | (3R)-3-[(3aS,7S,7aR)-7-hydroxy-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]butanal | C14H22O2 | 详情 | 详情 | |
| (V) | 38686 | (3aS,7S,7aR)-3-[(1R)-4,4-dibromo-1-methyl-3-butenyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol | C15H22Br2O | 详情 | 详情 | |
| (VI) | 38687 | (3aS,7S,7aR)-3a-methyl-3-[(1R)-1-methyl-3-butynyl]-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol | C15H22O | 详情 | 详情 | |
| (VII) | 38688 | (3aS,7S,7aR)-3a-methyl-3-[(1R)-1-methyl-3-butynyl]-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl trimethylsilyl ether; ([(3aS,7S,7aR)-3a-methyl-3-[(1R)-1-methyl-3-butynyl]-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl]oxy)(trimethyl)silane | C18H30OSi | 详情 | 详情 | |
| (VIII) | 38689 | (6R)-6-[(3aS,7S,7aR)-3a-methyl-7-[(trimethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-2-methyl-3-heptyn-2-ol | C21H36O2Si | 详情 | 详情 | |
| (IX) | 38690 | (3aS,7S,7aR)-3-[(1R)-5-hydroxy-1,5-dimethyl-3-hexynyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol | C18H28O2 | 详情 | 详情 | |
| (X) | 38691 | (3aR,7aS)-1-[(1R)-5-hydroxy-1,5-dimethyl-3-hexynyl]-7a-methyl-3,3a,5,6,7,7a-hexahydro-4H-inden-4-one | C18H26O2 | 详情 | 详情 | |
| (XI) | 38692 | (3aR,7aS)-1-[(1R)-1,5-dimethyl-5-[(trimethylsilyl)oxy]-3-hexynyl]-7a-methyl-3,3a,5,6,7,7a-hexahydro-4H-inden-4-one | C21H34O2Si | 详情 | 详情 | |
| (XII) | 38693 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](diphenyl)phosphine; tert-butyl(dimethyl)silyl (1R,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-[(E)-2-(diphenylphosphino)ethylidene]-4-methylenecyclohexyl ether | C33H51O2PSi2 | 详情 | 详情 | |
| (XIII) | 38694 | (5R)-5-[(3aS,7aS)-7-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-1,1-dimethyl-2-hexynyl trimethylsilyl ether; [((5R)-5-[(3aS,7aS)-7-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-1,1-dimethyl-2-hexynyl)oxy](trimethyl)silane | C42H74O3Si3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)1-Ethylideneperhydroindan-4-ol (I) reacts with Me2AlCl and paraformaldehyde via an ene process to give the homoallylic diol (II), the primary hydroxyl group of which is tosylated by means of TsCl and DMAP and the secondary hydroxyl group silylated by means of TESOTf and lutidine to yield (III). Conversion of (III) into the corresponding nitrile by means of KCN in DMSO, followed by reduction with DIBALH in toluene, affords the aldehyde (IV) (1), which is further reduced in THF by treatment with DIBALH in hexanes to yield (V). The hydroxy silyl ether (V) is then converted into the iodo derivative (VI) by treatment with PPh3, imidazole and I2 in dichloromethane. The iodo silyl ether (VI) reacts with t-BuSH in the presence of DBU in benzene to afford sulfide (VII), which is then oxidized and deprotected with oxone to provide the hydroxy sulfone (VIII). Oxidation of (VIII) with pyridinium dichromate (PDC) in CH2Cl2 gives the keto sulfone (IX), which reacts with the phosphine oxide derivative (X) in THF in the presence of PhLi. Finally, the protecting silyl ether moiety is removed by means of Bu4NF in THF.
| 【1】 Posner, G.H.; Wang, Q.; Han, G.; et al.; Conceptually new sulfone analogues of the hormone 1alpha,25-dihydroxyvitamin D3: Synthesis and preliminary biological evaluation. J Med Chem 1999, 42, 18, 3425. |
| 【2】 Posner, G.H.; et al.; Noncalcemic, antiproliferative, transcriptionally active, 24-fluorinated hybrid analogues of the hormone 1alpha,25-dihydroxyvitamin D3. Synthesis and preliminary biological evaluation. J Med Chem 1998, 41, 16, 3008. |
| 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) | 42566 | (3aR,4S,7aS)-1-[(Z)ethylidene]-7a-methyloctahydro-1H-inden-4-ol | C12H20O | 详情 | 详情 | |
| (II) | 38682 | (3aS,7S,7aR)-3-[(1S)-2-hydroxy-1-methylethyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol | C13H22O2 | 详情 | 详情 | |
| (III) | 42567 | (2S)-2-[(3aS,7S,7aR)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]propyl 4-methylbenzenesulfonate | C26H42O4SSi | 详情 | 详情 | |
| (IV) | 42568 | (3R)-3-[(3aS,7S,7aR)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]butanal | C20H36O2Si | 详情 | 详情 | |
| (V) | 42569 | (3R)-3-[(3aS,7S,7aR)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-1-butanol | C20H38O2Si | 详情 | 详情 | |
| (VI) | 42570 | ([(3aS,7S,7aR)-3-[(1R)-3-iodo-1-methylpropyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl]oxy)(triethyl)silane; (3aS,7S,7aR)-3-[(1R)-3-iodo-1-methylpropyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl triethylsilyl ether | C20H37IOSi | 详情 | 详情 | |
| (VII) | 42571 | (3aS,7S,7aR)-3-[(1R)-3-(tert-butylsulfanyl)-1-methylpropyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl triethylsilyl ether; ([(3aS,7S,7aR)-3-[(1R)-3-(tert-butylsulfanyl)-1-methylpropyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl]oxy)(triethyl)silane | C24H46OSSi | 详情 | 详情 | |
| (VIII) | 42572 | (3aS,7S,7aR)-3-[(1R)-3-(tert-butylsulfonyl)-1-methylpropyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol | C18H32O3S | 详情 | 详情 | |
| (IX) | 42573 | (3aR,7aS)-1-[(1R)-3-(tert-butylsulfonyl)-1-methylpropyl]-7a-methyl-3,3a,5,6,7,7a-hexahydro-4H-inden-4-one | C18H30O3S | 详情 | 详情 | |
| (X) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Stereoselective addition of formaldehyde to the ethylidene indanol (I) in the presence of dimethylaluminium chloride gave rise to the homoallylic alcohol (II). After tosylation of the primary alcohol of (II) to give tosylate (III) , the secondary hydroxyl group of (III) was silylated with triethylsilyl triflate and lutidine to afford (IV). Displacement of the tosylate group of (IV) with KCN yielded nitrile (V), which was further reduced to aldehyde (VI) by means of DIBAL in cold toluene. A Reformatskii reaction using (VI), ethyl bromodifluoroacetate and activated zinc gave the gem-difluoro ester (VII). Reduction of the free hydroxyl group of (VII) to afford (IX) was achieved via formation of the thianocarbonate (VIII) and then treatment with tributyltin hydride and azobis(isobutyronitrile). Addition of ethyllithium to the ester group of (IX) produced carbinol (X). After desilylation of (X) by treatment with tetrabutylammonium fluoride, the resulting secondary alcohol (XI) was oxidized to ketone (XII) using pyridinium chlorochromate in CH2Cl2.
| 【1】 Posner, G.H.; et al.; Noncalcemic, antiproliferative, transcriptionally active, 24-fluorinated hybrid analogues of the hormone 1alpha,25-dihydroxyvitamin D3. Synthesis and preliminary biological evaluation. J Med Chem 1998, 41, 16, 3008. |
| 【2】 Wang, Q.; Lee, J.K.; Posner, G.H. (Johns Hopkins University); Non-calcemic, antiproliferative, transcriptionally active 24-fluorinated hybrid analogs of 1alpha,25-dihydroxyvitamin D3. US 6043386 . |
| 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) | 42566 | (3aR,4S,7aS)-1-[(Z)ethylidene]-7a-methyloctahydro-1H-inden-4-ol | C12H20O | 详情 | 详情 | |
| (II) | 38682 | (3aS,7S,7aR)-3-[(1S)-2-hydroxy-1-methylethyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol | C13H22O2 | 详情 | 详情 | |
| (III) | 38683 | (2S)-2-[(3aS,7S,7aR)-7-hydroxy-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]propyl 4-methylbenzenesulfonate | C20H28O4S | 详情 | 详情 | |
| (IV) | 42567 | (2S)-2-[(3aS,7S,7aR)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]propyl 4-methylbenzenesulfonate | C26H42O4SSi | 详情 | 详情 | |
| (V) | 44912 | (3R)-3-[(3aS,7S,7aR)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]butanenitrile | C20H35NOSi | 详情 | 详情 | |
| (VI) | 42568 | (3R)-3-[(3aS,7S,7aR)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]butanal | C20H36O2Si | 详情 | 详情 | |
| (VII) | 44913 | ethyl (5R)-5-[(3aS,7S,7aR)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-2,2-difluoro-3-hydroxyhexanoate | C24H42F2O4Si | 详情 | 详情 | |
| (VIII) | 44914 | ethyl (5R)-5-[(3aS,7S,7aR)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-2,2-difluoro-3-[(phenoxycarbothioyl)oxy]hexanoate | C31H46F2O5SSi | 详情 | 详情 | |
| (IX) | 44915 | ethyl (5R)-5-[(3aS,7S,7aR)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-2,2-difluorohexanoate | C24H42F2O3Si | 详情 | 详情 | |
| (X) | 44916 | (7R)-7-[(3aS,7S,7aR)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-3-ethyl-4,4-difluoro-3-octanol | C26H48F2O2Si | 详情 | 详情 | |
| (XI) | 44917 | (3aS,7S,7aR)-3-[(1R)-5-ethyl-4,4-difluoro-5-hydroxy-1-methylheptyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol | C20H34F2O2 | 详情 | 详情 | |
| (XII) | 44918 | (3aR,7aS)-1-[(1R)-5-ethyl-4,4-difluoro-5-hydroxy-1-methylheptyl]-7a-methyl-3,3a,5,6,7,7a-hexahydro-4H-inden-4-one | C20H32F2O2 | 详情 | 详情 |