【结 构 式】 |
【药物名称】ILX-23-7553, Ro-23-7553 【化学名称】1alpha,25-Dihydroxy-16,17,23,23,24,24-hexadehydrocholecalciferol 【CA登记号】118694-43-2 【 分 子 式 】C27H38O3 【 分 子 量 】410.60211 |
【开发单位】Roche (Originator), Ilex Oncology (Licensee) 【药理作用】Oncolytic Drugs, Solid Tumors Therapy, Vitamin D Analogs |
合成路线1
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
Alternatively, the intermediate diol (IX) has been obtained as follows: The condensation of perhydroindene derivative (XIV) with the acetylenic aldehyde (XV) by means of Me3AlCl gives the acetylenic alcohol (XVI), which is esterified to the formate (XVII) or the carbonate (XVIII). The deoxygenation of (XVII) or (XVIII) by means of Pd(acac)2 and P(CH3)3 in hot toluene affords the silylated diol (XIX), which is submitted to desilylation with TBAF to afford the target diol intermediate (IX).
【1】 Radinov, R.; Hutchings, S.D.; Selective palladium-catalyzed hydrogenolysis of a secondary propargylic alcohol in the synthesis of vitamin D analog Ro 23-7553: Substrate and ligand control. Tetrahedron Lett 1999, 40, 51, 8955. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(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 | |
(XIV) | 38695 | (3aR,4S,7aS)-1-[(Z)ethylidene]-7a-methyloctahydro-1H-inden-4-yl trimethylsilyl ether; ([(3aR,4S,7aS)-1-[(Z)ethylidene]-7a-methyloctahydro-1H-inden-4-yl]oxy)(trimethyl)silane | C15H28OSi | 详情 | 详情 | |
(XV) | 38696 | 4-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-2-pentynal | C12H22O2Si | 详情 | 详情 | |
(XVI) | 38697 | (2S)-2-[(3aS,7S,7aR)-3a-methyl-7-[(trimethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-6-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-4-heptyn-3-ol | C27H50O3Si2 | 详情 | 详情 | |
(XVII) | 38698 | 1-((1S)-1-[(3aS,7S,7aR)-3a-methyl-7-[(trimethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]ethyl)-4-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-2-pentynyl formate | C28H50O4Si2 | 详情 | 详情 | |
(XVIII) | 38699 | 1-((1S)-1-[(3aS,7S,7aR)-3a-methyl-7-[(trimethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]ethyl)-4-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-2-pentynyl methyl carbonate | C29H52O5Si2 | 详情 | 详情 | |
(XIX) | 38700 | [((5R)-5-[(3aS,7S,7aR)-3a-methyl-7-[(trimethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-1,1-dimethyl-2-hexynyl)oxy](tert-butyl)dimethylsilane; (5R)-5-[(3aS,7S,7aR)-3a-methyl-7-[(trimethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-1,1-dimethyl-2-hexynyl tert-butyl(dimethyl)silyl ether | C27H50O2Si2 | 详情 | 详情 |