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【结 构 式】 
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【分子编号】68674 【品名】(1S,2S,3R,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]-hept-5-ene-2-carboxylic acid 【CA登记号】 |
【 分 子 式 】C10H12O4 【 分 子 量 】196.20288 【元素组成】C 61.22% H 6.16% O 32.62% |
合成路线1
该中间体在本合成路线中的序号：(XXIX)Intermediate (XIb) can also be prepared by the following route. Desymmetrization of cis-5-norbornene-exo-2,3-dicarboxylic anhydride (XXVIII) with MeOH in the presence of quinine in toluene/CCl4 at –55 °C affords (1S,2S,3R,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]-hept-5-ene-2-carboxylic acid (XXIX). Activation of carboxylic acid (XXIX) with ClCOOEt in the presence of Et3N in THF followed by reaction of the resulting mixed anhydride with NaN3 results in the corresponding acyl azide, which then undergoes Curtius rearrangement in refluxing benzene to produce isocyanate (XXX). Without isolation, isocyanate (XXX) is treated with benzyl alcohol in the presence of Et3N in refluxing CH2Cl2 to give the Cbz-protected amine (XXXI). Reduction and deprotection of norbornene derivative (XXXI) with H2 over Pd/C in EtOAc followed by treatment with HCl in Et2O/dioxane gives the saturated amino ester (Vb), which is submitted to reductive alkylation with 4-fluorobenzaldehyde (IX) by means of NaBH3CN and NaOAc in MeOH .
| 【1】 Tran, C.V., Ruebsam, F., Murphy, D.E. et al. (Anadys Pharmaceuticals, Inc.). 5,6-Dihydro-1H-pyridin-2-one compounds. CA 2682584, EP 2129224, JP 2010523586, US 2010034773, US 7939524, US 8101800, US 2012130068, US 8236948, WO 2008124450. |
| 【2】 Dragovich, P.S., Thompson, P.A., Ruebsam, F. (Anadys Pharmaceuticals, Inc.). A method of inhibiting hepatitis C virus by combination of a 5,6-dihydro-1H-pyridin-2-one and one or more additional antiviral compounds. EP 2346329, US 2011229438, WO 2010042834. |
| 【3】 Ruebsam, F., Murphy, D.E., Tran, C.V. et al. Discovery of tricyclic 5,6-dihydro-1H-pyridin-2-ones as novel, potent, and orally bioavailable inhibitors of HCV NS5B polymerase. Bioorg Med Chem Lett 2009, 19(22): 6404-12. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Vb) | 68658 | (±)-(1S,2R,3S,4R)-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride | C9H15NO2.HCl | 详情 | 详情 | |
| (XIb) | 68661 | (1S,2R,3S,4R)-methyl 3-((4-fluorobenzyl)amino)bicyclo[2.2.1]heptane-2-carboxylate | C16H20FNO2 | 详情 | 详情 | |
| (IX) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (XXVIII) | 11171 | (1R,2R,6S,7S)-4-Oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C9H8O3 | 详情 | 详情 | |
| (XXIX) | 68674 | (1S,2S,3R,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]-hept-5-ene-2-carboxylic acid | C10H12O4 | 详情 | 详情 | |
| (XXX) | 68675 | C10H11NO3 | 详情 | 详情 | ||
| (XXXI) | 68676 | (1S,2S,3R,4R)-methyl 3-(((benzyloxy)carbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylate | C17H19NO4 | 详情 | 详情 |