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To a solution of 5-bromo-N-methoxy-N-methyl-nicotinamide (2.08 g, 8.5 mmol) in THF (20 mL) was added MeMgBr (1.52 g, 12.75 mmol) at −78° C. After the addition, the reaction mixture was stirred at room temperature for 2 hours before quenching with water. After extraction with EtOAC, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash column chromatography to afford the title compound (1.5 g, 88percent).
88%
at -78 - 20℃;
[B] 1 -(5-Bromo-pyridin-3-yl)-ethanoneTo a solution of 5-bromo-N-methoxy-N-methyl-nicotinamide (2.08 g, 8.5 mmol) in THF (20 mL) was added MeMgBr (1.52 g, 12.75 mmol) at -78 °C. After the addition, the reaction mixture was stirred at room temperature for 2 hours before quenching with water. After extraction with EtOAC, the organic layer was washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was then purified by flash column chromatography to afford the title compound (1.5 g, 88percent).
The gas protection Ar, the step a 5-bromo-N-methyl-N-methoxy-nicotinamide (400 mg, 1 . 63mmol) dissolving THF (10 ml), cooled to -20 °C, is dripped slowly into the phenyl magnesium bromide THF solution of (1M, 4.9 ml), is omitted, -20 ° C reaction 1h, slowly to room temperature reaction 4hSaturated NaHC03 aqueous solution was quenched, the THF was distilled off, and the mixture was extracted with ethyl acetate Dried over Na2SO4, filtered, the solvent evaporated, and the residue was chromatographed on a latex gel (260 mg, 61percent).
With triethylamine; In tetrahydrofuran; at 20℃; for 2h;
Reference Example 34; Preparation method of 5-bromo-N-methoxy-N-methylpyridine-3-carboxamide; In an amount of 1.03 g of <strong>[39620-02-5]5-bromonicotinoyl chloride</strong> was dissolved in 10 ml of tetrahydrofuran, successively added with 1.95 ml of triethylamine, and 1.37 g of N,O-dimethylhydroxylamine hydrochloride at room temperature, and stirred under the same condition for 2 hours. The reaction system was added with saturated aqueous ammonium chloride, and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and filtered. Then, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate (3:1 to 1:1)) to obtain 795 mg of the title compound. Physicochemical properties of this compound (1) Molecular formula: C8H9BrN2O2 (2) Mass spectrum (EI): m/z 245 (M)+ (3) 1H NMR spectrum (300 MHz, CDCl3) delta (ppm): 3.40 (s, N(CH3)OCH3), 3.50 (s,N(CH3)OCH3), 8.18 (t, pyridine), 8.76 (d, pyridine), 8.87 (d, pyridine).
Reference Example 35; Preparation method of 5-bromopyridin-3-ylphenyl ketone; In an amount of 245 mg of the compound of Reference Example 34 was dissolved in 4.9 ml of tetrahydrofuran, added with 1.07 ml of a 0.94 N solution of phenyllithium in hexane under ice cooling, and stirred under the same condition for 3.5 hours. The reaction system was adjusted to pH 1 by adding 1 N hydrochloric acid, and washed with ethyl acetate, and then the aqueous layer was neutralized by adding saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and filtered. Then, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate (6:1)) to obtain 136 mg of the title compound. Physicochemical properties of this compound (1) Molecular formula: C12H8BrNO (2) Mass spectrum (EI): m/z 262 (M)+ (3) 1H NMR spectrum (300 MHz, CDCl3) delta (ppm): 7.54 (t, C6H5), 7.67 (tt, C6H5), 7.81 (dd, C6H5), 8.26 (t, pyridine), 8.88 (d, pyridine), 8.89 (d, pyridine).
To a solution of 5-bromo-N-methoxy-N-methyl-nicotinamide (2.08 g, 8.5 mmol) in THF (20 mL) was added MeMgBr (1.52 g, 12.75 mmol) at -78 C. After the addition, the reaction mixture was stirred at room temperature for 2 hours before quenching with water. After extraction with EtOAC, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash column chromatography to afford the title compound (1.5 g, 88%).
88%
In tetrahydrofuran; at -78 - 20℃;
[B] 1 -(5-Bromo-pyridin-3-yl)-ethanoneTo a solution of 5-bromo-N-methoxy-N-methyl-nicotinamide (2.08 g, 8.5 mmol) in THF (20 mL) was added MeMgBr (1.52 g, 12.75 mmol) at -78 C. After the addition, the reaction mixture was stirred at room temperature for 2 hours before quenching with water. After extraction with EtOAC, the organic layer was washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was then purified by flash column chromatography to afford the title compound (1.5 g, 88%).
In tetrahydrofuran; at -20 - 20℃; for 5h;Inert atmosphere;
The gas protection Ar, the step a 5-bromo-N-methyl-N-methoxy-nicotinamide (400 mg, 1 . 63mmol) dissolving THF (10 ml), cooled to -20 C, is dripped slowly into the phenyl magnesium bromide THF solution of (1M, 4.9 ml), is omitted, -20 C reaction 1h, slowly to room temperature reaction 4hSaturated NaHC03 aqueous solution was quenched, the THF was distilled off, and the mixture was extracted with ethyl acetate Dried over Na2SO4, filtered, the solvent evaporated, and the residue was chromatographed on a latex gel (260 mg, 61%).
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