ethyl 4-fluoro-3-hydroxybenzoate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-fluoro-3-hydroxy-benzoic acid ethyl ester (2.2 g, 11.95 mmol) in N,N-dimethylformamide (50 ml) was added 60% NaH in mineral oil (0.72 g, 17.93 mmol) and chloropyrazine (1.64 g, 14.34 mmol) and heated at 80° C. for overnight. One more equivalent of chloropyrazine was added and heated at the same temperature for 10 h. The reaction mixture was poured into a flask containing 150 ml of aqueous saturated NaCl solution and 0.6 ml of acetic acid. The mixture was extracted with ethyl acetate (3×100 ml), the combined organic extracts were washed with sat NaCl (150 ml), dried (Na2SO4), filtered and concentrated. The crude product was purified by flash column chromatography using dichloromethane to yield 1.55 g (50%) of product. MS (ESI+) m/z 263 (M+H)+; heated at the same temperature for 10 h The reaction mixture was poured into a flask The mixture was extracted with ethyl acetate (3×100 ml) the combined organic extracts were washed with sat NaCl (150 ml) dried (Na2SO4) filtered concentrated The crude product was purified by flash column chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-fluoro-3-hydroxy-benzoic acid (2 g, 12.81 mmol) in absolute ethanol (30 ml) was added thionyl chloride (1 ml) drop wise at 0° C. After refluxing for overnight, the solvents were driven off, the residue was dissolved in dichloromethane (50 ml), cooled on ice bath, neutralized slowly with 1M NaHCO3, and the layers were separated. The aqueous layer was extracted with dichloromethane (50 ml) for one more time. Combined organic extracts were dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography using dichloromethane to yield 2.2 g (93%) of product. MS (ESI+) m/z 185 (M+H)+. After refluxing for overnight cooled on ice bath the layers were separated The aqueous layer was extracted with dichloromethane (50 ml) for one more time Combined organic extracts were dried (Na2SO4) filtered concentrated purified by flash column chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using the method of Example 3, Step A, ethyl 4-fluoro-3-hydroxybenzoate (2.90 g, 15.8 mmol), 60% sodium hydride in mineral oil (631 mg, 15.8 mmol), and 2-chloro-4-nitropyridine (2.50 g, 15.8 mmol) were reacted to provide ethyl 4-fluoro-3-(2-chloropyridin-4-yloxy)benzoate (4.15 g, 89% yield) as a clear oil. 1H NMR-(CDCl3) δ 8.27 (d, 1H), 8.02 (m, 1H), 7.90 (d, 1H), 7.30 (t, 1H), 6.78-6.83 (m, 2H), 4.39 (q, 2H), 1.40 (t, 3H). were reacted

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-fluoro-3-hydroxy-benzoic acid ethyl ester (2.2 g, 11.95 mmol) in N,N-dimethylformamide (50 ml) was added 60% NaH in mineral oil (0.72 g, 17.93 mmol) and chloropyrazine (1.64 g, 14.34 mmol) and heated at 80° C. for overnight. One more equivalent of chloropyrazine was added and heated at the same temperature for 10 h. The reaction mixture was poured into a flask containing 150 ml of aqueous saturated NaCl solution and 0.6 ml of acetic acid. The mixture was extracted with ethyl acetate (3×100 ml), the combined organic extracts were washed with sat NaCl (150 ml), dried (Na2SO4), filtered and concentrated. The crude product was purified by flash column chromatography using dichloromethane to yield 1.55 g (50%) of product. MS (ESI+) m/z 263 (M+H)+; heated at the same temperature for 10 h The reaction mixture was poured into a flask The mixture was extracted with ethyl acetate (3×100 ml) the combined organic extracts were washed with sat NaCl (150 ml) dried (Na2SO4) filtered concentrated The crude product was purified by flash column chromatography

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-fluoro-3-hydroxy-benzoic acid ethyl ester (2.2 g, 11.95 mmol) in N,N-dimethylformamide (50 ml) was added 60% NaH in mineral oil (0.72 g, 17.93 mmol) and chloropyrazine (1.64 g, 14.34 mmol) and heated at 80° C. for overnight. One more equivalent of chloropyrazine was added and heated at the same temperature for 10 h. The reaction mixture was poured into a flask containing 150 ml of aqueous saturated NaCl solution and 0.6 ml of acetic acid. The mixture was extracted with ethyl acetate (3×100 ml), the combined organic extracts were washed with sat NaCl (150 ml), dried (Na2SO4), filtered and concentrated. The crude product was purified by flash column chromatography using dichloromethane to yield 1.55 g (50%) of product. MS (ESI+) m/z 263 (M+H)+; heated at the same temperature for 10 h The reaction mixture was poured into a flask The mixture was extracted with ethyl acetate (3×100 ml) the combined organic extracts were washed with sat NaCl (150 ml) dried (Na2SO4) filtered concentrated The crude product was purified by flash column chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-fluoro-3-hydroxy-benzoic acid (2 g, 12.81 mmol) in absolute ethanol (30 ml) was added thionyl chloride (1 ml) drop wise at 0° C. After refluxing for overnight, the solvents were driven off, the residue was dissolved in dichloromethane (50 ml), cooled on ice bath, neutralized slowly with 1M NaHCO3, and the layers were separated. The aqueous layer was extracted with dichloromethane (50 ml) for one more time. Combined organic extracts were dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography using dichloromethane to yield 2.2 g (93%) of product. MS (ESI+) m/z 185 (M+H)+. After refluxing for overnight cooled on ice bath the layers were separated The aqueous layer was extracted with dichloromethane (50 ml) for one more time Combined organic extracts were dried (Na2SO4) filtered concentrated purified by flash column chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: K2CO3 (96.9 mmol) and 3-bromo-1-propen (64.6 mmol) are added to a solution of 4-fluoro-3-hydroxy-benzoic acid ethyl ester (32.3 mmol) in acetone (50 mL). The mixture is heated to reflux for 16 h, filtered and cooled to RT. The solvents are removed in vacuo to give the desired product which is used without further purification. LC-MS: tR=1.01 min; [M+CH3CN+H]+=266.0. The mixture is heated to reflux for 16 h filtered The solvents are removed in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 4-fluoro-3-hydroxy-benzoic acid (32.0 mmol) in EtOH (120 mL) is treated with conc. sulfuric acid (25.7 mL) and heated to reflux for 16 h. Water (600 mL), sodium bicarbonate (100 g) and ether (300 mL) are added successively, the layers are separated and the aq. layer is extracted twice with ether. The combined organic layers are washed twice with brine, dried over MgSO4 and concentrated in vacuo to give the desired product which is used without further purification. 1H-NMR (DMSO-d6): δ=7.75 (d, J=8.5 Hz, 1H); 7.58-7.63 (m, 1H); 7.12 (t, J=9.3 Hz, 1H); 6.21 (bs, 1H); 4.39 (q, J=7.0 Hz, 2H); 1.40 (t, J=7.0 Hz, 3H). heated to reflux for 16 h the layers are separated the aq. layer is extracted twice with ether The combined organic layers are washed twice with brine dried over MgSO4 concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of Ethyl 4-fluoro-3-hydroxybenzoate (2.814 g, 15.3 mmol), K2CO3 (1.95 g, 14.1 mmol) in DMF (15 ml) was added 2,6-Dimethylbenzyl chloride (2.21 g, 14.3 mmol) at room temperature under argon. The reaction mixture was stirred for 16 hours at the room temperature, diluted with ethyl acetate and washed with water (2×), and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hexane:ethyl acetate, 4:1) to give the title compound. washed with water (2×), and brine The organic layer was dried over Na2SO4 filtered concentrated purified by flash chromatography on a silica gel column (hexane:ethyl acetate, 4:1)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-fluoro-3-hydroxy-benzoic acid ethyl ester (2.2 g, 11.95 mmol) in N,N-dimethylformamide (50 ml) was added 60% NaH in mineral oil (0.72 g, 17.93 mmol) and chloropyrazine (1.64 g, 14.34 mmol) and heated at 80° C. for overnight. One more equivalent of chloropyrazine was added and heated at the same temperature for 10 h. The reaction mixture was poured into a flask containing 150 ml of aqueous saturated NaCl solution and 0.6 ml of acetic acid. The mixture was extracted with ethyl acetate (3×100 ml), the combined organic extracts were washed with sat NaCl (150 ml), dried (Na2SO4), filtered and concentrated. The crude product was purified by flash column chromatography using dichloromethane to yield 1.55 g (50%) of product. MS (ESI+) m/z 263 (M+H)+; heated at the same temperature for 10 h The reaction mixture was poured into a flask The mixture was extracted with ethyl acetate (3×100 ml) the combined organic extracts were washed with sat NaCl (150 ml) dried (Na2SO4) filtered concentrated The crude product was purified by flash column chromatography