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【结 构 式】 
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【分子编号】52151 【品名】(1R,3aR,4S,7aR)-1-[(1S)-2-hydroxy-1-methylethyl]-7a-methyloctahydro-1H-inden-4-ol 【CA登记号】 |
【 分 子 式 】C13H24O2 【 分 子 量 】212.33236 【元素组成】C 73.54% H 11.39% O 15.07% |
合成路线1
该中间体在本合成路线中的序号：(XV)Synthesis of ketone (XXIV): Reaction of the known diol (XV) obtained by degradation of vitamin D2 with TsOH in pyridine gives, regioselectively, the monotosylate (XVI), which is protected at the secondary OH group by silylation with TBDMS-Cl and imidazole to yield the silyl ether (XVII). Oxidation of the tosyloxy group of (XVII) with O2 and t-BuOK in DMSO/t-BuOH affords ketone (XVIII), which is reduced with K and i-PrOH providing alcohol (XIX). Condensation of compound (XIX) with ethyl prop-ynoate (XX) by means of NMM in benzene gives the alkoxyacrylate (XXI), which is reduced with H2 over Pd/C in EtOH to yield the alkoxypropionate (XXII). Deprotection of the OH group of (XXII) with HF in acetonitrile affords alcohol (XXIII), which is oxidized with pyridinium dichromate (PDC) in CH2Cl2 providing ketone (XXIV). Wittig-Horner condensation of ketone (XXIV) with phosphine oxide (XIV) by means of BuLi in THF yields the corresponding adduct (XXV), which is submitted to a Grignard reaction with MeLi in THF to give the protected maxacalcitol precursor (XXVI). Finally, this compound is desilylated by means of TBAF in THF.
| 【1】 Vidal, B.; Fall, Y.; Mourino, A.; Gonzalez, V.; Stereoselective synthesis of 22-oxacalcitriol (OCT) and analogues modified at C25. Tetrahedron Lett 2002, 43, 3, 427. |
| 【2】 Fall, Y.; A new approach to the synthesis of the 25-hydroxy-22-oxa-vitamin D3 side chain. Tetrahedron Lett 1997, 38, 27, 4909. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 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 | |
| (XV) | 52151 | (1R,3aR,4S,7aR)-1-[(1S)-2-hydroxy-1-methylethyl]-7a-methyloctahydro-1H-inden-4-ol | C13H24O2 | 详情 | 详情 | |
| (XVI) | 52152 | (2S)-2-[(1R,3aR,4S,7aR)-4-hydroxy-7a-methyloctahydro-1H-inden-1-yl]propyl 4-methylbenzenesulfonate | C20H30O4S | 详情 | 详情 | |
| (XVII) | 52153 | (2S)-2-((1R,3aR,4S,7aR)-4-[[tert-butyl(dimethyl)silyl]oxy]-7a-methyloctahydro-1H-inden-1-yl)propyl 4-methylbenzenesulfonate | C26H44O4SSi | 详情 | 详情 | |
| (XVIII) | 52154 | 1-((1S,3aR,4S,7aS)-4-[[tert-butyl(dimethyl)silyl]oxy]-7a-methyloctahydro-1H-inden-1-yl)-1-ethanone | C18H34O2Si | 详情 | 详情 | |
| (XIX) | 52155 | (1S)-1-((1S,3aR,4S,7aR)-4-[[tert-butyl(dimethyl)silyl]oxy]-7a-methyloctahydro-1H-inden-1-yl)-1-ethanol | C18H36O2Si | 详情 | 详情 | |
| (XX) | 35333 | ethyl propiolate | 623-47-2 | C5H6O2 | 详情 | 详情 |
| (XXI) | 52156 | ethyl (E)-3-[[(1S)-1-((1S,3aR,4S,7aR)-4-[[tert-butyl(dimethyl)silyl]oxy]-7a-methyloctahydro-1H-inden-1-yl)ethyl]oxy]-2-propenoate | C23H42O4Si | 详情 | 详情 | |
| (XXII) | 52157 | ethyl 3-[[(1S)-1-((1S,3aR,4S,7aR)-4-[[tert-butyl(dimethyl)silyl]oxy]-7a-methyloctahydro-1H-inden-1-yl)ethyl]oxy]propanoate | C23H44O4Si | 详情 | 详情 | |
| (XXIII) | 52158 | ethyl 3-([(1S)-1-[(1S,3aR,4S,7aS)-4-hydroxy-7a-methyloctahydro-1H-inden-1-yl]ethyl]oxy)propanoate | C17H30O4 | 详情 | 详情 | |
| (XXIV) | 52159 | ethyl 3-([(1S)-1-[(1S,3aR,7aR)-7a-methyl-4-oxooctahydro-1H-inden-1-yl]ethyl]oxy)propanoate | C17H28O4 | 详情 | 详情 | |
| (XXV) | 52160 | ethyl 3-[((1S)-1-[(1S,3aS,7aS)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]ethyl)oxy]propanoate | C38H68O5Si2 | 详情 | 详情 | |
| (XXVI) | 11724 | 4-[((1S)-1-[(1S,3aS,7aS)-4-[(E)-2-((3S,5R)-3,5-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]ethyl)oxy]-2-methyl-2-butanol | C38H70O4Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXII)The intermediate phosphonate (XXI) has been obtained as follows: The reaction of tert-butyl mercaptan (XV) with allyl bromide (XVI) by means of NaOH in ethanol gives the sulfide (XVII), which is oxidized with Oxone in methanol/water to yield the sulfone (XVIII). The bromination of (XVIII) with Br2 in CCl4 followed by dehydrobromination with TEA affords the bromosulfone (XIX), which is finally condensed with tributyl phosphite (XX) by heating at 130 C to provide the target intermediate phosphonate (XXI). The silylation of the known diol (XXII) (obtained by degradation of vitamin D2) with Tes-OTf and lutidine gives the bis silyl ether (XXIII), which is submitted to a Swern oxidation ((COCl)2), yielding the carbaldehyde (XXIV). The Wadsworth-Emmons condensation of aldehyde (XXIV) with the intermediate phosphonate (XXI) by means of tBu-OLi affords the diinsaturated sulfone (XXV), which is desilylated with HF in THF to provide the alcohol (XXVI). The oxidation of (XXVI) with TPAP and NMO furnishes the ketone (XXVII), which is submitted to a Wittig-Horner condensation with the intermediate phosphine oxide (XIV) by means of PhLi, giving the silylated precursor (XXVIII). Finally, this compound is desilylated with HF in ethanol to afford the target vitamin D3 analogue.
| 【1】 Posner, G.H.; et al.; A non-calcemic sulfone version of the vitamin D3 analogue seocalcitol (EB 1089): Chemical synthesis, biological evaluation and potency enhancement of the anticancer drug adriamycin. Bioorg Med Chem 2001, 9, 9, 2365. |
| 【2】 Fall, Y.; A new approach to the synthesis of the 25-hydroxy-22-oxa-vitamin D3 side chain. Tetrahedron Lett 1997, 38, 27, 4909. |
| 【3】 Lee, J.K.; Crawford, K.R.; Wang, Q.; Posner, G.H.; Han, G. (Johns Hopkins University); Non-calcemic, antiproliferative, transcriptionally active sulfur-containing analogs of 1alpha,25-dihydroxyvitamin D3. US 6380408; WO 0059513 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 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 | |
| (XV) | 52551 | tert-Butyl mercaptan; 2-Methyl-2-propanethiol | 75-66-1 | C4H10S | 详情 | 详情 |
| (XVI) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XVII) | 52552 | 1,1-dimethylethyl 2-propenyl sulfide; 3-[(1,1-dimethylethyl)sulfanyl]-1-propene | C7H14S | 详情 | 详情 | |
| (XVIII) | 52553 | (1,1-dimethylethyl)(dioxo)2-propenyl-lambda~6~-sulfane; 1,1-dimethylethyl 2-propenyl sulfone | C7H14O2S | 详情 | 详情 | |
| (XIX) | 52554 | (3-bromo-1-propenyl)(1,1-dimethylethyl)dioxo-lambda~6~-sulfane; 3-bromo-1-propenyl 1,1-dimethylethyl sulfone | C7H13BrO2S | 详情 | 详情 | |
| (XX) | 52555 | Tri-n-butylphosphite; Tributyl phosphite; Phosphorous acid Tri-N-butyl ester | 102-85-2 | C12H27O3P | 详情 | 详情 |
| (XXI) | 52556 | dibutyl 3-[(1,1-dimethylethyl)sulfonyl]-2-propenylphosphonate | C15H31O5PS | 详情 | 详情 | |
| (XXII) | 52151 | (1R,3aR,4S,7aR)-1-[(1S)-2-hydroxy-1-methylethyl]-7a-methyloctahydro-1H-inden-4-ol | C13H24O2 | 详情 | 详情 | |
| (XXIII) | 52557 | 7a-methyl-1-{1-methyl-2-[(triethylsilyl)oxy]ethyl}octahydro-1H-inden-4-yl triethylsilyl ether; [(7a-methyl-1-{1-methyl-2-[(triethylsilyl)oxy]ethyl}octahydro-1H-inden-4-yl)oxy](triethyl)silane | C25H52O2Si2 | 详情 | 详情 | |
| (XXIV) | 52558 | 2-{7a-methyl-4-[(triethylsilyl)oxy]octahydro-1H-inden-1-yl}propanal | C19H36O2Si | 详情 | 详情 | |
| (XXV) | 52559 | [(1-{5-[(1,1-dimethylethyl)sulfonyl]-1-methyl-2,4-pentadienyl}-7a-methyloctahydro-1H-inden-4-yl)oxy](triethyl)silane; 5-{7a-methyl-4-[(triethylsilyl)oxy]octahydro-1H-inden-1-yl}-1,3-hexadienyl 1,1-dimethylethyl sulfone | C26H48O3SSi | 详情 | 详情 | |
| (XXVI) | 52560 | 1-{5-[(1,1-dimethylethyl)sulfonyl]-1-methyl-2,4-pentadienyl}-7a-methyloctahydro-1H-inden-4-ol | C20H34O3S | 详情 | 详情 | |
| (XXVII) | 52561 | 1-{5-[(1,1-dimethylethyl)sulfonyl]-1-methyl-2,4-pentadienyl}-7a-methyloctahydro-4H-inden-4-one | C20H32O3S | 详情 | 详情 | |
| (XXVIII) | 52562 | (1,1-dimethylethyl)({3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-[2-(1-{5-[(1,1-dimethylethyl)sulfonyl]-1-methyl-2,4-pentadienyl}-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene]-4-methylidenecyclohexyl}oxy)dimethylsilane; 5-{4-[2-(3,5-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methylidenecyclohexylidene)ethylidene]-7a-methyloctahydro-4H-inden-1-yl}-1,3-hexadienyl 1,1-dimethylethyl sulfone | C41H72O4SSi2 | 详情 | 详情 |