| 76% |
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Step B. 3-Bromo-6-methoxy-2-methyl-pyridine. A mixture of 2-methoxy-6-methyl-pyridine (15.2 g, 123 mmol) and 1,3-dibromo-5,5-dimethyl hydantoin (35.3 g, 123 mmol) in THF (1 L) was stirred at rt for 48 h in the dark. The mixture was treated with 10% aq. Na2S2O3 (100 mL) and stirred for 1 h. The mixture was extracted with Et2O. The organic layer was washed with H2O (2*), dried (MgSO4), and concentrated. The residue was purified (SiO2; 0-5% EtOAc/hexanes) to give the title compound (18.7 g, 76%). MS (ESI): mass calcd. for C7H8BrNO, 200.98; m/z found, 202.2 [M+H]+. 1H NMR (CDCl3): 7.60 (d, J=8.6, 1H), 8.45 (d, J=8.7, 1H), 3.90 (s, 3H), 2.54 (s, 3H). |
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With potassium hydroxide; tetraethylammonium chloride; bromine; potassium bromide; In water; at 0 - 20℃; for 17.6667h; |
(2) Synthesis of 3-bromo-6-methoxy-2-methylpyridine 15.3g of 2-methoxy-6-methylpyridine was dissolved in 100ml of potassium bromide aqueous solution, prepared that 50.1g of potassium bromide was dissolved in 200ml of water, 11.9g of potassium hydroxide and 40g of tetraethylammonium chloride were added. The solution of 7.6ml of bromine in 100ml of potassium bromide aqueous solution was added in on ice-cooling to the reaction liquid using a dropping funnel for 40 minutes. After completion of dropping, an ice bath was removed, which was stirred for 17 hours at room temperature. Sodium sulfite aqueous solution and ethyl acetate were added to reaction liquid, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure to give 19.6g of the title compound. 1H-NMR(CDCl3) delta (ppm): 2.56 (s,3H), 3.89 (s, 3H), 6.45 (d, 1H, J=8.0Hz), 7.60(d, 1H, J=8.0Hz). |
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With bromine; In disodium hydrogen phosphate; |
(18-1) 2-Methoxy-6-methylpyridine (10 mL, 81 mmol) was suspended in a 0.15 mol//L disodium hydrogen phosphate aqueous solution (160 mL). Thereafter, a solution prepared by suspending bromine (4.15 mL, 81 mmol) in a 0.15 mol//L disodium hydrogen phosphate aqueous solution (160 mL) was added dropwise to the suspension at room temperature over 1 hour. The reaction solution was stirred at the same temperature as described above overnight. Thereafter, the reaction solution was extracted with methylene chloride (300 mL) three times. Organic layers were gathered. The resultant was dried over anhydrous magnesium sulfate and was then filtrated, followed by vacuum concentration. The obtained residue was distilled away under reduced pressure (91 C.-96 C./16 mmHg), so as to obtain 9.47 g of 3-bromo-6-methoxy-2-methyl-pyridine. |
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