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【结 构 式】 
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【分子编号】49036 【品名】(Z)-10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-7-decene-1,9-diol 【CA登记号】 |
【 分 子 式 】C13H20F6O2 【 分 子 量 】322.2910192 【元素组成】C 48.45% H 6.25% F 35.37% O 9.93% |
合成路线1
该中间体在本合成路线中的序号：(VII)Synthesis of aldehyde intermediate (IX): The condensation of 1-tert-butoxy-4-chlorobutane (I) with 4-methyl-3-penten-2-one (II) by means of Mg in hot THF gives the 2-octanone (III), which is condensed with hexafluoroacetone (IV) by means of diethyl chlorophosphate and LDA in THF to yield the fluorinated alkynol (V). Hydrogenation of the triple bond of (V) with H2 and Lindlar catalyst affords the cis-alkene (VI), which is deprotected with sulfuric acid to provide the fluorinated diol (VII). Finally, the primary alcohol of (VII) is oxidized to the corresponding aldehyde (VIII) with NaOCl and tempo, which is silylated with Tes-Cl and TEA to afford the desired intermediate (IX).
| 【1】 Wirz, B.; Hilpert, H.; Novel versatile approach to an enantiopure 19-nor, des-C,D vitamin D-3 derivative. Tetrahedron 2001, 57, 4, 681. |
| 【2】 Hilpert, H.; Wirz, B. (F. Hoffmann-La Roche AG); New process for the preparation of retiferol derivs.. EP 1094060 . |
| 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) | 49032 | tert-butyl 4-chlorobutyl ether; 1-(tert-butoxy)-4-chlorobutane | C8H17ClO | 详情 | 详情 | |
| (II) | 42266 | 4-methyl-3-penten-2-one | 141-79-7 | C6H10O | 详情 | 详情 |
| (III) | 49033 | 8-(tert-butoxy)-4,4-dimethyl-2-octanone | C14H28O2 | 详情 | 详情 | |
| (IV) | 44260 | 1,1,1,3,3,3-hexafluoroacetone | 684-16-2 | C3F6O | 详情 | 详情 |
| (V) | 49034 | 10-(tert-butoxy)-1,1,1-trifluoro-6,6-dimethyl-2-(trifluoromethyl)-3-decyn-2-ol | C17H26F6O2 | 详情 | 详情 | |
| (VI) | 49035 | (Z)-10-(tert-butoxy)-1,1,1-trifluoro-6,6-dimethyl-2-(trifluoromethyl)-3-decen-2-ol | C17H28F6O2 | 详情 | 详情 | |
| (VII) | 49036 | (Z)-10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-7-decene-1,9-diol | C13H20F6O2 | 详情 | 详情 | |
| (VIII) | 49037 | (Z)-10,10,10-trifluoro-9-hydroxy-5,5-dimethyl-9-(trifluoromethyl)-7-decenal | C13H18F6O2 | 详情 | 详情 | |
| (IX) | 49038 | (Z)-10,10,10-trifluoro-5,5-dimethyl-9-[(triethylsilyl)oxy]-9-(trifluoromethyl)-7-decenal | C19H32F6O2Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)The reduction of 4,4-dimethyltetrahydropyran-2-one (I) with iBuAlH in THF gives 4,4-dimethyltetrahydropyran-2-ol (II), which is condensed with phosphorane (III) in refluxing acetonitrile to yield the heptenoic ester (IV). The protection of the OH group of (IV) with Tbdms-Cl and imidazole affords the silyl ether (V), which is reduced at the double bond with H2 over Pd/C in ethyl acetate to provide the heptanoate ester (VI). The reduction of the ester group of (VI) with iBu2AlH in THF gives the primary alcohol (VII), which is protected with dihydropyran and PPTS, yielding the tetrahydropyranyl ether (VIII). The desilylation of (VIII) with TBAF in THF affords the heptanol derivative (IX), which by oxidation with tetrapropylammonium perruthenate (TPAP) in dichloromethane is converted into the aldehyde (X). The condensation of (X) with CBr4 and PPh3 in dichloromethane provides the dibromovinyl compound (XI), which is condensed with hexafluoroacetone (XII) by means of BuLi in THF to give the acetylenic alcohol (XIII). The deprotection of (XIII) with pyridinium p-toluenesulfonate (PPTS) in methanol yields the acetylenic diol (XIV), which is selectively reduced with H2 over Pd/C in ethyl acetate to afford the (Z)-ethylenic diol (XV). The oxidation of the primary alcohol of (XV) with pyridinium dichromate in dichloromethane provides the aldehyde (XVI), which is silylated with Tms-Cl, TEA and DMAP in dichloromethane to give the silylated unsaturated aldehyde (XVII).
| 【1】 Mohr, P.; Barbier, P.; Pirson, W.; Muller, M.; Bauer, F. (F. Hoffmann-La Roche AG); Cyclohexanediole derivs.. EP 1056716; WO 9943646 . |
| 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) | 49051 | 4,4-dimethyltetrahydro-2H-pyran-2-one | C7H12O2 | 详情 | 详情 | |
| (II) | 49052 | 4,4-dimethyltetrahydro-2H-pyran-2-ol | C7H14O2 | 详情 | 详情 | |
| (III) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (IV) | 49053 | ethyl (E)-7-hydroxy-5,5-dimethyl-2-heptenoate | C11H20O3 | 详情 | 详情 | |
| (V) | 49054 | ethyl (E)-7-[[tert-butyl(dimethyl)silyl]oxy]-5,5-dimethyl-2-heptenoate | C17H34O3Si | 详情 | 详情 | |
| (VI) | 49055 | ethyl 7-[[tert-butyl(dimethyl)silyl]oxy]-5,5-dimethylheptanoate | C17H36O3Si | 详情 | 详情 | |
| (VII) | 49056 | 7-[[tert-butyl(dimethyl)silyl]oxy]-5,5-dimethyl-1-heptanol | C15H34O2Si | 详情 | 详情 | |
| (VIII) | 49057 | tert-butyl(dimethyl)silyl 3,3-dimethyl-7-(tetrahydro-2H-pyran-2-yloxy)heptyl ether; tert-butyl[[3,3-dimethyl-7-(tetrahydro-2H-pyran-2-yloxy)heptyl]oxy]dimethylsilane | C20H42O3Si | 详情 | 详情 | |
| (IX) | 49058 | 3,3-dimethyl-7-(tetrahydro-2H-pyran-2-yloxy)-1-heptanol | C14H28O3 | 详情 | 详情 | |
| (X) | 49059 | 3,3-dimethyl-7-(tetrahydro-2H-pyran-2-yloxy)heptanal | C14H26O3 | 详情 | 详情 | |
| (XI) | 49060 | 8,8-dibromo-5,5-dimethyl-7-octenyl tetrahydro-2H-pyran-2-yl ether; 2-[(8,8-dibromo-5,5-dimethyl-7-octenyl)oxy]tetrahydro-2H-pyran | C15H26Br2O2 | 详情 | 详情 | |
| (XII) | 44260 | 1,1,1,3,3,3-hexafluoroacetone | 684-16-2 | C3F6O | 详情 | 详情 |
| (XIII) | 49061 | 1,1,1-trifluoro-6,6-dimethyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-(trifluoromethyl)-3-decyn-2-ol | C18H26F6O3 | 详情 | 详情 | |
| (XIV) | 49062 | 10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-7-decyne-1,9-diol | C13H18F6O2 | 详情 | 详情 | |
| (XV) | 49036 | (Z)-10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-7-decene-1,9-diol | C13H20F6O2 | 详情 | 详情 | |
| (XVI) | 49037 | (Z)-10,10,10-trifluoro-9-hydroxy-5,5-dimethyl-9-(trifluoromethyl)-7-decenal | C13H18F6O2 | 详情 | 详情 | |
| (XVII) | 49063 | (Z)-10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-9-[(trimethylsilyl)oxy]-7-decenal | C16H26F6O2Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XV)Alternatively, the intermediate (Z)-ethylenic diol (XV) can also be obtained as follows: The reduction of 5,5-dimethyloxepan-2-one (XX) with iBu2AlH in THF gives 5,5-dimethyloxepan-2-ol (XXI), which is condensed with methyltriphenylphosphonium bromide (XXII) by means of tBu-OK in THF to yield 3,3-dimethyl-6-hepten-1-ol (XXIII). The Swern oxidation of the primary alcohol of (XIII) affords aldehyde (XXIV), which is condensed with CBr4 by means of PPh3 in CH2Cl2 to provide the dibromovinyl compound (XXV). The condensation of (XXV) with hexafluoroacetone (XII) by means of BuLi gives the acetylenic alcohol (XXVI), which is treated with hexylborane in THF to yield the acetylenic diol (XXVII). Finally, this compound is selectively reduced with H2 over Pd/C in EtOAc to afford the desired (Z)-ethylenic diol (XV).
| 【1】 Mohr, P.; Barbier, P.; Pirson, W.; Muller, M.; Bauer, F. (F. Hoffmann-La Roche AG); Cyclohexanediole derivs.. EP 1056716; WO 9943646 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 44260 | 1,1,1,3,3,3-hexafluoroacetone | 684-16-2 | C3F6O | 详情 | 详情 |
| (XV) | 49036 | (Z)-10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-7-decene-1,9-diol | C13H20F6O2 | 详情 | 详情 | |
| (XX) | 49065 | 5,5-dimethyl-2-oxepanone | C8H14O2 | 详情 | 详情 | |
| (XXI) | 49066 | 5,5-dimethyl-2-oxepanol | C8H16O2 | 详情 | 详情 | |
| (XXII) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (XXIII) | 49067 | 3,3-dimethyl-6-hepten-1-ol | C9H18O | 详情 | 详情 | |
| (XXIV) | 49068 | 3,3-dimethyl-6-heptenal | C9H16O | 详情 | 详情 | |
| (XXV) | 49069 | 1,1-dibromo-4,4-dimethyl-1,7-octadiene | C10H16Br2 | 详情 | 详情 | |
| (XXVI) | 49070 | 1,1,1-trifluoro-6,6-dimethyl-2-(trifluoromethyl)-9-decen-3-yn-2-ol | C13H16F6O | 详情 | 详情 | |
| (XXVII) | 49062 | 10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-7-decyne-1,9-diol | C13H18F6O2 | 详情 | 详情 |