3-chloro-2-fluorophenol

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:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Trifluoroacetic acid (0.5 mL) was added to a solution of 3-chloro-2-fluorophenol (750 mg, 5.12 mmol) and N-chlorosuccinimide (684 mg, 5.12 mmol) in acetonitrile (30 mL) and the reaction mixture stirred for 24 h. The mixture was concentrated in vacuo and purified by chromatography on silica gel with heptane:EtOAc (9:1, v/v) as eluent to afford the title compound (440 mg, 48%) as a pale yellow solid. The mixture was concentrated in vacuo purified by chromatography on silica gel with heptane:EtOAc (9:1

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

実験手順: Trifluoroacetic acid (0.5 mL) was added to a solution of 3-chloro-2-fluorophenol (750 mg, 5.12 mmol) and N-chlorosuccinimide (684 mg, 5.12 mmol) in acetonitrile (30 mL) and the reaction mixture stirred for 24 h. The mixture was concentrated in vacuo and purified by chromatography on silica gel with heptane:EtOAc (9:1, v/v) as eluent to afford the title compound (440 mg, 48%) as a pale yellow solid. The mixture was concentrated in vacuo purified by chromatography on silica gel with heptane:EtOAc (9:1

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

実験手順: Trifluoroacetic acid (0.5 mL) was added to a solution of 3-chloro-2-fluorophenol (750 mg, 5.12 mmol) and N-chlorosuccinimide (684 mg, 5.12 mmol) in acetonitrile (30 mL) and the reaction mixture stirred for 24 h. The mixture was concentrated in vacuo and purified by chromatography on silica gel with heptane:EtOAc (9:1, v/v) as eluent to afford the title compound (440 mg, 48%) as a pale yellow solid. The mixture was concentrated in vacuo purified by chromatography on silica gel with heptane:EtOAc (9:1

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3-chloro-2-fluoro-phenol (1.31 g, 8.93 mmol) and ethyl-2-butynoate (2.0 g, 17.83 mmol) in tetrahydrofuran (14 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.4 mL, 9.37 mmol). The reaction was then heated at 130° C. for 2 h. At this time, the reaction was cooled to 25° C. and was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a 1N aqueous sodium hydroxide solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were then dried over magnesium sulfate, filtered, rinsed with dichloromethane, and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% ethyl acetate/hexanes) afforded 3-(3-chloro-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester (1.41 g, 61%) as a white solid: HR-ES-MS m/z calculated for C12H12O3FCl [M+H]+ 259.0532, observed 259.0531; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.1 Hz, 3H), 2.45 (s, 3H), 4.03 (q, J=7.1 Hz, 2H), 4.76 (s, 1H), 7.27-7.39 (m, 2H), 7.50-7.61 (m, 1H). At this time, the reaction was cooled to 25° C. At this time, the reaction was concentrated in vacuo The residue was dissolved in dichloromethane (100 mL) was washed with a 2N aqueous hydrochloric acid solution (1×100 mL) The organics were then dried over magnesium sulfate filtered rinsed with dichloromethane concentrated in vacuo Purification by Analogix flash chromatography (40 g, 1-10% ethyl acetate/hexanes)

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

実験手順: A mixture of 3-chloro-2-fluorophenol (1.5 g, 10.2 mmol), benzyl bromide (1.71 g, 10.0 mmol) and sodium carbonate (1.10 g, 10.38 mmol) in 20 mL ethylene glycol dimethyl ether and 10 mL H2O was stirred at rt for 36 h. The reaction mixture was charged with 20 mL 1N KOH and 50 mL diethyl ether. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the title compound as a white solid which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 5.16 (s, 2Hs) 6.86-7.03 (m, 3Hs) 7.31-7.48 (m, 5Hs). The organic layer was separated washed with brine dried over sodium sulfate concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3-chloro-2-fluoro-phenol (1.31 g, 8.93 mmol) and ethyl-2-butynoate (2.0 g, 17.83 mmol) in tetrahydrofuran (14 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.4 mL, 9.37 mmol). The reaction was then heated at 130° C. for 2 h. At this time, the reaction was cooled to 25° C. and was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a 1N aqueous sodium hydroxide solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were then dried over magnesium sulfate, filtered, rinsed with dichloromethane, and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% ethyl acetate/hexanes) afforded 3-(3-chloro-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester (1.41 g, 61%) as a white solid: HR-ES-MS m/z calculated for C12H12O3FCl [M+H]+ 259.0532, observed 259.0531; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.1 Hz, 3H), 2.45 (s, 3H), 4.03 (q, J=7.1 Hz, 2H), 4.76 (s, 1H), 7.27-7.39 (m, 2H), 7.50-7.61 (m, 1H). At this time, the reaction was cooled to 25° C. At this time, the reaction was concentrated in vacuo The residue was dissolved in dichloromethane (100 mL) was washed with a 2N aqueous hydrochloric acid solution (1×100 mL) The organics were then dried over magnesium sulfate filtered rinsed with dichloromethane concentrated in vacuo Purification by Analogix flash chromatography (40 g, 1-10% ethyl acetate/hexanes)

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

実験手順: A mixture of 3-chloro-2-fluorophenol (1.5 g, 10.2 mmol), benzyl bromide (1.71 g, 10.0 mmol) and sodium carbonate (1.10 g, 10.38 mmol) in 20 mL ethylene glycol dimethyl ether and 10 mL H2O was stirred at rt for 36 h. The reaction mixture was charged with 20 mL 1N KOH and 50 mL diethyl ether. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the title compound as a white solid which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 5.16 (s, 2Hs) 6.86-7.03 (m, 3Hs) 7.31-7.48 (m, 5Hs). The organic layer was separated washed with brine dried over sodium sulfate concentrated in vacuo

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred and cooled solution of 2-fluoro-3-chloro-phenol (21.9 g, 0.15 mol) and succinic anhydride (15.3 g, 0.15 mol) in 1,1,2,2-tetrachloroethane (135 mL) was added anhydrous aluminum chloride (38.7 g, 0.29 mol) portion-wise. The reaction mixture was stirred at room temperature for 3 hours and then heated at 130° C. for 2 hours. After being cooled to room temperature, to the reaction mixture were added concentrated hydrochloric acid and ice alternatively in small portions. The resulting mixture was extracted with ethyl acetate (75 mL×3). The combined organic layers were evaporated. The solid residue was basified by slow addition of an aqueous solution of 2N sodium hydroxide solution under cooling conditions, and then extracted with ethyl acetate (30 mL×3). The aqueous layer was acidified by dropwise addition of concentrated hydrochloric acid to a pH of about 2, and then extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Column chromatography (silica gel, 100-120 mesh, 15% ethyl acetate in hexane) gave 4-(4-chloro-3-fluoro-2-hydroxy-phenyl)-4-oxo-butyric acid (7.0 g, 19%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.59 (t, J=6.26 Hz, 2H), 3.31 (t, J=6.28 Hz, 2H), 7.15 (d, J=6.56 Hz, 1H), 7.74 (d, J=6.56 Hz, 1H), 11.90-12.31 (m, 2H). The reaction mixture was stirred at room temperature for 3 hours After being cooled to room temperature, to the reaction mixture The resulting mixture was extracted with ethyl acetate (75 mL×3) The combined organic layers were evaporated The solid residue was basified by slow addition of an aqueous solution of 2N sodium hydroxide solution under cooling conditions extracted with ethyl acetate (30 mL×3) The aqueous layer was acidified by dropwise addition of concentrated hydrochloric acid to a pH of about 2 extracted with ethyl acetate (50 mL×3) The combined organic layers were dried over sodium sulfate filtered concentrated in vacuo

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred and cooled solution of 2-fluoro-3-chloro-phenol (21.9 g, 0.15 mol) and succinic anhydride (15.3 g, 0.15 mol) in 1,1,2,2-tetrachloroethane (135 mL) was added anhydrous aluminum chloride (38.7 g, 0.29 mol) portion-wise. The reaction mixture was stirred at room temperature for 3 hours and then heated at 130° C. for 2 hours. After being cooled to room temperature, to the reaction mixture were added concentrated hydrochloric acid and ice alternatively in small portions. The resulting mixture was extracted with ethyl acetate (75 mL×3). The combined organic layers were evaporated. The solid residue was basified by slow addition of an aqueous solution of 2N sodium hydroxide solution under cooling conditions, and then extracted with ethyl acetate (30 mL×3). The aqueous layer was acidified by dropwise addition of concentrated hydrochloric acid to a pH of about 2, and then extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Column chromatography (silica gel, 100-120 mesh, 15% ethyl acetate in hexane) gave 4-(4-chloro-3-fluoro-2-hydroxy-phenyl)-4-oxo-butyric acid (7.0 g, 19%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.59 (t, J=6.26 Hz, 2H), 3.31 (t, J=6.28 Hz, 2H), 7.15 (d, J=6.56 Hz, 1H), 7.74 (d, J=6.56 Hz, 1H), 11.90-12.31 (m, 2H). The reaction mixture was stirred at room temperature for 3 hours After being cooled to room temperature, to the reaction mixture The resulting mixture was extracted with ethyl acetate (75 mL×3) The combined organic layers were evaporated The solid residue was basified by slow addition of an aqueous solution of 2N sodium hydroxide solution under cooling conditions extracted with ethyl acetate (30 mL×3) The aqueous layer was acidified by dropwise addition of concentrated hydrochloric acid to a pH of about 2 extracted with ethyl acetate (50 mL×3) The combined organic layers were dried over sodium sulfate filtered concentrated in vacuo