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【结 构 式】 
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【分子编号】42416 【品名】tert-butyl(dimethyl)[(2S)oxiranylmethoxy]silane; tert-butyl(dimethyl)silyl (2S)oxiranylmethyl ether 【CA登记号】123237-62-7 |
【 分 子 式 】C9H20O2Si 【 分 子 量 】188.3421 【元素组成】C 57.4% H 10.7% O 16.99% Si 14.91% |
合成路线1
该中间体在本合成路线中的序号：(LI)Synthesis of intermediate (LV): The reaction of epoxide (LI) with 2-bromopropenal diethylacetal (LII) by means of BuLi and CuI gives the adduct (LIII), which is treated with TsOH and acetone yielding the aldehydic acetonide (LIV). Finally, this compound is reduced with NaBH4, chlorinated with N-chlorosuccinimide (NCS) and condensed with Bu3Sn-Li in THF to afford the desired stannane intermediate (LV).
| 【1】 Hayward, M.M.; et al.; Total synthesis of altohyrtin A (spongistatin 1): Part 2. Angew Chem. Int Ed Engl 1998, 37, 1-2, 192. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (LI) | 42416 | tert-butyl(dimethyl)[(2S)oxiranylmethoxy]silane; tert-butyl(dimethyl)silyl (2S)oxiranylmethyl ether | 123237-62-7 | C9H20O2Si | 详情 | 详情 |
| (LII) | 42412 | 2-bromo-1-ethoxy-2-propenyl ethyl ether; 2-bromo-3,3-diethoxy-1-propene | 17592-40-4 | C7H13BrO2 | 详情 | 详情 |
| (LIII) | 42413 | (2S)-1-[[tert-butyl(dimethyl)silyl]oxy]-4-(diethoxymethyl)-4-penten-2-ol | C16H34O4Si | 详情 | 详情 | |
| (LIV) | 42414 | 2-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]acrylaldehyde | C9H14O3 | 详情 | 详情 | |
| (LV) | 42415 | tributyl(2-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-2-propenyl)stannane | C21H42O2Sn | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Condensation of 2,4-dinitroimidazole (I) with the silyl-protected (S)-glycidol (II) gave the N-substituted imidazole (III). The free hydroxyl group of (III) was then protected as the tetrahydropyranyl ether (IV) by treatment with dihydropyran and pyridinium tosylate. Desilylation of (IV) by means of tetrabutylammonium fluoride proceeded with concomitant nitro group displacement to afford the pyranoimidazole derivative (V). The tetrahydropyranyl group of (V) was then removed by acidic hydrolysis to provide alcohol (VI). Finally, condensation of (VI) with 4-(trifluoromethoxy)benzyl bromide (VII) under Williamson's ether synthesis conditions provided the title compound.
| 【1】 Baker, W.R.; Shaopei, C.; Keeler, E.L. (PathoGenesis Corp.); Nitroimidazole antibacterial cpds. and methods of use thereof. EP 0866793; JP 1999508270; WO 9701562 . |
| 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) | 56023 | 2,4-dinitro-1H-imidazole | 5213-49-0 | C3H2N4O4 | 详情 | 详情 |
| (II) | 42416 | tert-butyl(dimethyl)[(2S)oxiranylmethoxy]silane; tert-butyl(dimethyl)silyl (2S)oxiranylmethyl ether | 123237-62-7 | C9H20O2Si | 详情 | 详情 |
| (III) | 56024 | (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-(2,4-dinitro-1H-imidazol-1-yl)-2-propanol | C12H22N4O6Si | 详情 | 详情 | |
| (IV) | 56025 | 1-[(2S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-(tetrahydro-2H-pyran-2-yloxy)propyl]-2,4-dinitro-1H-imidazole; tert-butyl(dimethyl)silyl (2S)-3-(2,4-dinitro-1H-imidazol-1-yl)-2-(tetrahydro-2H-pyran-2-yloxy)propyl ether | C17H30N4O7Si | 详情 | 详情 | |
| (V) | 56026 | (6S)-2-nitro-6-(tetrahydro-2H-pyran-2-yloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine; (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl tetrahydro-2H-pyran-2-yl ether | C11H15N3O5 | 详情 | 详情 | |
| (VI) | 56027 | (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ol | C6H7N3O4 | 详情 | 详情 | |
| (VII) | 20308 | 4-(bromomethyl)phenyl trifluoromethyl ether; 1-(bromomethyl)-4-(trifluoromethoxy)benzene | 50824-05-0 | C8H6BrF3O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVIII)Chiral cyclopropanesulfonyl chloride intermediate (VIII) can be prepared as follows. Lithiation of (trimethylsilyl)acetylene (XVII) with t-BuLi in THF at –78 °C, and subsequent coupling with TBDMS-protected (S)-glycidol (XVIII) in the presence of BF3·Et2O at –78 °C affords the (S)-pentynol derivative (XIX). Then, the TMS-protecting group of intermediate (XIX) is selectively removed by means of K2CO3 in MeOH to give alkyne (XX). Iodoboration of alkyne (XX) with B-I-9-BBN in CH2Cl2 at 0 °C followed by deborination with AcOH yields 4-iodo-4-pentene-1,2(S)-diol (XXI). O-Protection of diol (XXI) with TBDMSOTf and pyridine in THF provides the bis-silyl ether (XXII), which is then submitted to Simmons-Smith cyclopropanation with CH2I2 in the presence of Et2Zn and TFA in DCE to produce 1,2-O-bis-TBDMS-3-(1-iodocyclopropyl)propane-1,2(S)-diol (XXIII). Desilylation of compound (XXIII) using HCl in THF gives 3-(1-iodocyclopropyl)propane-1,2(S)-diol (XXIV), which by trans-ketalization with 2,2-dimethoxypropane (XXV) by means of PPTS in CH2Cl2 gives 4(S)-(1-iodocyclopropylmethyl)-2,2-dimethyl-1,3-dioxolane (XXVI). Finally, alkyl iodide (XXVI) is treated with t-BuLi in Et2O at –78 °C, followed by chlorosulfonation with SO2Cl2 in Et2O (3).
Alternatively, deprotonation of dicyclopropyl disulfide (XXVII) with BuLi in THF, followed by alkylation with 4(R)-(bromomethyl)-2,2-dimethyl-1,3-dioxolane (XXVIII) at –78 °C affords the dimeric bis-acetonide (XXIX), which is reductively cleaved to the corresponding thiol monomer (XXX) by treatment with PPh3 and HCl in dioxane/H2O. Air oxidation of cyclopropanethiol derivative (XXX) in the presence of NaOH in DMF gives sodium cyclopropanesulfonate derivative (XXXI), which can also be obtained by direct oxidation of disulfide (XXIX) with H2O2 and NaOAc in AcOH at 80 °C. Finally, sulfonate (XXXI) is chlorinated using POCl3 at 80 °C. Alternatively, sulfonyl chloride (VIII) can be directly obtained from disulfide (XXIX) by oxidative cleavage with NCS in the presence of HCl in MeCN .
| 【1】 Maderna, A., Vernier, J., Barawkar, D., Chamakura, V., El Abdellaoui, H., Hong, Z. (Ardea Biosciences, Inc.). Derivatives of N-(arylamino)sulfonamides as inhibitors of MEK. US 2008058340, US 8101799. |
| 【2】 Maderna, A., Vernier, J.-M., Barawkar, D., Chamakura, V., Abdellaoui, H.E., Hong, Z. (Ardea Biosciences, Inc.). N-(Arylamino)-sulfonamide inhibitors of MEK. EP 1912636, US 2012022076, WO 2007014011 |
| 【3】 Maderna, A., Vernier, J.-M. (Ardea Biosciences, Inc.). Preparation of (R)-and (S)-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2, 3-dihydroxypropyl)cyclopropane-1-sulfonamide and protected derivatives thereof. EP 2462111, JP 2013500242, KR 2012032536, WO 2011009541. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 67911 | (S)-1-((5,5-dimethyltetrahydrofuran-2-yl)methyl)cyclopropane-1-sulfonyl chloride | C10H17ClO3S | 详情 | 详情 | |
| (XVII) | 23897 | ethynyl(trimethyl)silane；trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
| (XVIII) | 42416 | tert-butyl(dimethyl)[(2S)oxiranylmethoxy]silane; tert-butyl(dimethyl)silyl (2S)oxiranylmethyl ether | 123237-62-7 | C9H20O2Si | 详情 | 详情 |
| (XIX) | 67918 | (S)-1-((tert-butyldimethylsilyl)oxy)-5-(trimethylsilyl)pent-4-yn-2-ol | C14H30O2Si2 | 详情 | 详情 | |
| (XX) | 67919 | (S)-1-((tert-butyldimethylsilyl)oxy)pent-4-yn-2-ol | C11H22O2Si | 详情 | 详情 | |
| (XXI) | 67920 | (S)-4-iodopent-4-ene-1,2-diol | C5H9IO2 | 详情 | 详情 | |
| (XXII) | 67922 | (S)-5-(2-iodoallyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane | C17H37IO2Si2 | 详情 | 详情 | |
| (XXIII) | 67921 | 1,2-O-bis-TBDMS-3-(1-iodocyclopropyl) propane-1,2(S)-diol;(S)-5-((1-iodocyclopropyl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane | C18H39IO2Si2 | 详情 | 详情 | |
| (XXIV) | 67923 | 3-(1-iodocyclopropyl)propane-1,2(S)-diol | C6H11O2I | 详情 | 详情 | |
| (XXV) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XXVI) | 67924 | 4(S)-(1-iodocyclopropylmethyl)-2,2-dimethyl- 1,3-dioxolane | C9H15IO2 | 详情 | 详情 | |
| (XXVII) | 67925 | dicyclopropyl disulfide;Dicyclopropyldisulfide | 68846-57-1 | C6H10S2 | 详情 | 详情 |
| (XXVIII) | 67926 | 4(R)-(bromomethyl)-2,2-dimethyl-1,3- dioxolane | 14437-87-7 | C6H11BrO2 | 详情 | 详情 |
| (XXIX) | 67927 | 1,2-bis(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropyl)disulfane | C18H30O4S2 | 详情 | 详情 | |
| (XXX) | 67929 | (R)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropanethiol | C9H16O2S | 详情 | 详情 | |
| (XXXI) | 67928 | sodium (R)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropane-1-sulfonate | C9H15NaO5S | 详情 | 详情 |