Preparation background and overview of 4-bromo-2,6-diethylpyridine
4-Bromo-2,6-diethylpyridine is an organic intermediate that can be prepared in two steps from acetone dicarboxylic acid and propionic anhydride as starting materials.
Preparation of 4-bromo-2,6-diethylpyridine
Preparation step 1 of 4-bromo-2,6-diethylpyridine and preparation of 2,6-diethyl-pyridin-4-ol
Acetone dicarboxylic acid (Aldrich, 165115) (60g, 0.41mol) was rapidly added with deuterated tetrahydrofuran to propionic anhydride (Aldrich, 240311) (170mL, 1.3mol) containing concentrated sulfuric acid (2mL), and the reaction The mixture was heated and stirred at 100°C for 30 minutes. The solution was rapidly cooled in an ice-salt mixture and just when a white solid mass formed, the reaction was added to ice water (500 mL), stirred and immediately filtered. The product was air dried and placed in a 3L flask and treated with aqueous 10% sodium carbonate (600 mL). The resulting paste was stirred with a stirrer and heated at 100°C for 30 minutes. Carbon dioxide is evolved and a pale yellow solution is obtained which is heated at 85-90°C for a further 80 minutes. The solution was cooled and acidified with aqueous 30% acetic acid until no more carbon dioxide was evolved. The white precipitate was filtered, washed with water, air-dried and then added to concentrated hydrochloric acid (120 mL) in a 2 L round bottom flask, and the mixture was heated to reflux for 4 hours. The solution was cooled on ice and neutralized by adding it to a stirred solution of sodium carbonate (115 g) in water (approximately 500 mL). The neutral solution was extracted thoroughly with EtOAc. The extract was dried and the solvent was removed to provide the product 2,6-diethyl-4-pyrone as a brown oil.
The above product was dissolved in 28% NH3 (10 equiv) in H2O, and the reaction was heated at 50°C overnight. The next morning, the solvent was completely removed to yield the title compound as a brown oil.
Preparation step 2 of 4-bromo-2,6-diethylpyridine, 4-bromo-2,6-diethylpyridine
Dissolve 2,6-diethyl-pyridin-4-ol (4g, 26.45mol) in CHCl3 (40mL) and PBr5 (11.43g , within 26.45mmol). The reaction was heated at 60°C for 1 hour and the CHCl3 was evaporated. The residue was heated at 120°C for 8 hours. After cooling, the reaction mixture was carefully added to a solution of water (500 mL) and NaOH pellets (45 g), followed by extraction with 3×EtOAc (100 mL). The combined organic layers were dried over sodium sulfate and concentrated to a brown oil, which was purified via silica plug (sh methyltetrahydrofuran ort plug) using 10% EtOAc/hexanes (×1000 mL).
References
[1] [China invention, China invention authorization] CN200580028091.9 Inhibitors of hepatitis C virus RNA-dependent RNA polymerase, and compositions and therapeutic agents using the inhibitors
