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(iii) 3-Fluoro-4-methoxybenzonitrile A mixture of 4-bromo-2-fluoro-l -methoxybenzene (107 g, 0.52 mol; see step (ii) above), CuCN (70.4 g, 0.78 mol) in dry DMF (150 mL) was stirred at 12O0C overnight. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over sodium sulfate. Solvent evaporation under reduced pressure, followed by column chromatography over silica gel using 3percent ethyl acetate in petroleum ether as eluent, gave 24.4 g of the sub-title compound as a solid.
In N,N-dimethyl-formamide; at 120℃;
A mixture of 4-bromo-2-fluoro-l -methoxybenzene (107 g, 0.52 mol; see step (ii) above), CuCN (70.4 g, 0.78 mol) in dry DMF (150 mL) was stirred at 12O0C overnight. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water EPO <DP n="36"/>and brine and then dried over sodium sulfate. Solvent evaporation under reduced pressure, followed by column chromatography over silica gel using 3percent ethyl acetate in petroleum ether as eluent, gave 24.4 g of the sub-title compound as a solid.
A mixture of 4-Bromo-2-fluoro-1-methoxybenzene (107 g, 0.5244 mol, from step (ii) above ), CuCN (70.4 g, 0.7866 mol) in dry DMF (150 ml) was stirred at 120 °C overnight. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. Organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by column chromatography over silica gel using 3percent ethyl acetate in petroleum ether gave the sub-title compound (24.4 g) as a solid.
With iron(III) chloride; sodium carbonate; In water; ethyl acetate; N,N-dimethyl-formamide;
20 g of the 2-fluoro-4-bromoanisole thus obtained and 9.8 g of copper cyanide were dissolved in 100 ml of dimethyl formamide and heated under reflux for ten hours. To the reaction mixture, was added an aqueous solution of 20 g of ferric chloride in 100 ml of water. The reaction mixture was allowed to cool to room temperature and the reaction product was extracted with toluene. The organic layer was successively washed with water, a saturated aqueous solution of sodium carbonate and a saturated aqueous solution of common salt. Then the organic layer was separated. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate 10:1) and further recrystallized from ethanol. Thus 10.0 g of 3-fluoro-4-methoxybenzonitrile was obtained. Yield: 68percent.
A mixture of 4-bromo-2-fluoro-l-methoxybenzene (30.0 g, 146 mmol) and CuCN (15.6 g, 174 mmol) in dry DMF (45 mL) was stirred at 120 °C overnight. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The extract was washed with water and brine, dried, and concentrated to give 20.0 g (91percent yield) of the product as a yellow solid. :H NMR (400 MHz, CDC13) delta 7.44 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.36 (dd, J = 10.8 Hz, 2.0 Hz, 1H), 7.02 (dd, J = 8.8 Hz, 8.4 Hz, 1H), 3.96 (s, 3H).
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