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【结 构 式】 
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【分子编号】68342 【品名】2,6-diethyl-4H-pyran-4-one 【CA登记号】 |
【 分 子 式 】C9H12O2 【 分 子 量 】152.19308 【元素组成】C 71.03% H 7.95% O 21.03% |
合成路线1
该中间体在本合成路线中的序号：(XV)The precursor 4-bromo-2,6-diethylpyridine (V) can be prepared by several methods. Condensation of 3-oxoglutaric acid (XIII) with propionic anhydride (XIV) in the presence of H2SO4, followed by cyclization with HCl at 100 °C leads to 2,6-diethyl-4-pyranone (XV). Subsequent treatment of pyranone (XV) with NH4OH at 50 °C yields 2,6-diethyl-4-pyridinol (XVI) , which is finally brominated with PBr5 in CHCl3 or POBr3 in DMF at 120 °C .
Alternatively, substitution of 2,6-dichloropyridine (XVII) with ethylmagnesium bromide (XVIII) in the presence of NiCl2(dppp) in Et2O gives 2,6-diethylpyridine (XIX), which can also be obtained by Wolff- Kishner reduction of 2,6-diacetylpyridine (XX) with NH2NH2 in the presence of NaOH in diethylene glycol at 120 °C. Oxidation of 2,6-diethylpyridine (XIX) with mCPBA in CHCl3, followed by nitration of the resulting 2,6-diethylpyridine-1-oxide (XXI) with HNO3 and H2SO4 at 90 °C provides the 4-nitro derivative (XXII). Substitution of nitropyridine (XXII) using AcBr in AcOH at 90 °C affords 4-bromo-2,6-diethylpyridin-1-oxide (XXIII), which is finally reduced with PBr3 in CH2Cl2 .
| 【1】 Gonzalez, J., Jewell, T.M., Li, H., Linton, A., Tatlock, J.H. (Pfizer, Inc.; Agouron Pharmaceuticals, Inc.). Inhibitors of hepatitis C virus RNAdependent RNA polymerase, and compositions and treatments using the same. EP 1781662, JP 2008509984, US 2006122399, US 7151105, US 8268835, WO 2006018725. |
| 【2】 Li, H., Tatlock, J., Linton, A. et al. Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-(1,2,4)triazolo(1,5-a)pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor. J Med Chem 2009, 52(5): 1255-8. |
| 【3】 Johnson, S., Drowns, M., Tatlock, J. et al. Synthetic route optimization of PF-00868554, an HCV polymerase inhibitor in clinical evaluation. Synlett 2010(5): 796-800. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 68333 | 4-bromo-2,6-diethylpyridine | 877133-54-5 | C9H12BrN | 详情 | 详情 |
| (XIII) | 15530 | 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid | 542-05-2 | C5H6O5 | 详情 | 详情 |
| (XIV) | 20095 | propionic anhydride | 123-62-6 | C6H10O3 | 详情 | 详情 |
| (XV) | 68342 | 2,6-diethyl-4H-pyran-4-one | C9H12O2 | 详情 | 详情 | |
| (XVI) | 68343 | 2,6-diethyl-4-pyridinol;2,6-diethylpyridin-4-ol | C9H13NO | 详情 | 详情 | |
| (XVII) | 13573 | 2,6-Dichloropyridine | 2402-78-0 | C5H3Cl2N | 详情 | 详情 |
| (XVIII) | 24239 | bromo(ethyl)magnesium；ethylmagnesium bromide | 925-90-6 | C2H5BrMg | 详情 | 详情 |
| (XIX) | 68344 | 2,6-diethylpyridine | 935-28-4 | C9H13N | 详情 | 详情 |
| (XX) | 48515 | 2,6-Diacetylpyridine | 1129-30-2 | C9H9NO2 | 详情 | 详情 |
| (XXI) | 68345 | 2,6-diethylpyridine-1-oxide | C9H13NO | 详情 | 详情 | |
| (XXII) | 68346 | 2,6-diethyl-4-nitropyridine 1-oxide | C9H12N2O3 | 详情 | 详情 | |
| (XXIII) | 68347 | 4-bromo-2,6-diethylpyridin-1-oxide | C9H12BrNO | 详情 | 详情 |