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【结 构 式】 
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【药物名称】 【化学名称】(+)-(22E,24E)-25-(tert-Butylsulfonyl)-1alpha-hydroxy-22,23,24,25-tetradehydro-26,27-dinorvitamin D3 【CA登记号】300344-76-7, 300344-75-6 (diastereomer) 【 分 子 式 】C29H44O4S 【 分 子 量 】488.73563 |
【开发单位】Johns Hopkins University (Originator), M.D. Anderson Cancer Center (Originator), University of Notre Dame (Originator), Virginia Commonwealth University (Originator) 【药理作用】Antineoplastic Enhancing Agents, Modulators of the Therapeutic Activity of Antineoplastic Agents, ONCOLYTIC DRUGS, Vitamin D Analogs |
合成路线1
The intermediate phosphine oxide (XIV) has been obtained as follows: The epoxidation of l-carvone (I) with H2O2 and LiOH in methanol gives the epoxide (II), which is reduced with L-Selectride in THF to yield the alcohol (III). The oxidation of the isopropenyl group of (III) with OsO4, KIO4, MCPBA and HOAc affords the acetate (IV), which is hydrolyzed to the diol (V) with NaOMe in methanol. The protection of the two OH groups of (V) with Tbdms-Cl and imidazole provides the bis-silyl ether (VI), which is oxidized with periodic acid in ethyl ether to give the ketoaldehyde (VII). The aldehyde group of (VII) is subjected to a Wittig condensation with CBr4, PPh3 and Zn in dichloromethane to yield the dibromovinyl compound (VIII), which by treatment with LDA and the triflic imide (IX) in THF affords the acetylenic vinyl triflate (X). The cyclization of (X) by means of Pd(OAc)2 and PPH3, followed by carbonylation in methanol, provides the methyl ester (XI) as a 2:1 mixture of the (Z)- and (E)-isomers. The photoisomerization of this mixture under the Hoffmann-La Roche conditions (presence of 9-fluorenone) gives a high yield of the (Z)-isomer (XII), which is reduced with DIBAL in toluene to give the primary alcohol (XIII). Finally, this compound is converted into the target phosphine oxide (XIV) is performed by known methods.
| 【1】 Mourino, A.; et al.; Efficient and versatile synthesis of A-ring precursors of 1alpha,25-dihydroxyvitamin D3 and analogues. Application to the synthesis of Lythgoe-Roche phosphine oxide. Tetrahedron Lett 1997, 38, 26, 4713. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIa),(XII) | 52149 | methyl 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)acetate | C22H42O4Si2 | 详情 | 详情 | |
| (XIb) | 52150 | methyl 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)acetate | C22H42O4Si2 | 详情 | 详情 | |
| (I) | 13386 | (5R)-5-Isopropenyl-2-methyl-2-cyclohexen-1-one; L-(-)-Carvone | 6485-40-1 | C10H14O | 详情 | 详情 |
| (II) | 52141 | (1R,4R,6R)-4-isopropenyl-1-methyl-7-oxabicyclo[4.1.0]heptan-2-one | C10H14O2 | 详情 | 详情 | |
| (III) | 52550 | 1-methyl-4-(1-methylethenyl)-7-oxabicyclo[4.1.0]heptan-2-ol | C10H16O2 | 详情 | 详情 | |
| (IV) | 52143 | (1R,3S,5S,6S)-5-hydroxy-6-methyl-7-oxabicyclo[4.1.0]hept-3-yl acetate | C9H14O4 | 详情 | 详情 | |
| (V) | 52144 | (1S,2S,4S,6R)-1-methyl-7-oxabicyclo[4.1.0]heptane-2,4-diol | C7H12O3 | 详情 | 详情 | |
| (VI) | 52145 | tert-butyl[((1R,2S,4R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-7-oxabicyclo[4.1.0]hept-2-yl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl (1R,2S,4R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-7-oxabicyclo[4.1.0]hept-2-yl ether | C19H40O3Si2 | 详情 | 详情 | |
| (VII) | 52146 | (3S,5S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-6-oxoheptanal | C19H40O4Si2 | 详情 | 详情 | |
| (VIII) | 52147 | (3S,5R)-8,8-dibromo-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-7-octen-2-one | C20H40Br2O3Si2 | 详情 | 详情 | |
| (IX) | 34685 | N-(5-chloro-2-pyridinyl)(trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 145100-51-2 | C7H3ClF6N2O4S2 | 详情 | 详情 |
| (X) | 52148 | (2S,4R)-2,4-bis[[tert-butyl(dimethyl)silyl]oxy]-1-methylene-6-heptynyl trifluoromethanesulfonate | C21H39F3O5SSi2 | 详情 | 详情 | |
| (XIII) | 47614 | 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)-1-ethanol | C21H42O3Si2 | 详情 | 详情 | |
| (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 |
合成路线2
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 |