methyl 2-fluoro-4-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: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:

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

実験手順: To a round bottom containing 2-fluoro-4-hydroxybenzoic acid (5.34 g, 34.19 mmol) (commercially available from Matrix Scientific and TCI America) was added a cold solution of MeOH (50 mL) and sulfuric acid (2.0 mL). The mixture was heated to 80° C. and monitored with TLC. After 20.5 hours, the solvent was removed, and the mixture was diluted with diethyl ether. The organic phase was washed carefully two times with saturated. aqueous NaHCO3, once with brine, and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to yield T31.1 as a white solid (5.82, 85% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.79 (1H, s), 7.75 (1H, t, J=8.8 Hz), 6.69 (1H, dd, J=8.6, 2.3 Hz), 6.62 (1H, dd, J=13.1, 2.2 Hz), 3.78 (3H, s). the solvent was removed the mixture was diluted with diethyl ether The organic phase was washed carefully two times with saturated aqueous NaHCO3, once with brine, and then dried over anhydrous sodium sulfate After filtration the organic solvent was removed in vacuo

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

実験手順: To a round bottom containing 2-fluoro-4-hydroxybenzoic acid (Commercially available from TCI America) (5.34 g, 34.19 mmol) was added a cold solution of MeOH (50 mL) and sulfuric acid (2.0 mL). The mixture was heated to 80° C. and monitored with TLC. After 20.5 hours, the solvent was removed and the residue was diluted with diethyl ether. The organic phase was washed carefully two times with saturated aqueous NaHCO3, once with brine, and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to yield T7.1 as a white solid (5.82, 85% yield). 1H NMR (400 MHz, DMSO-d6) 10.79 (1H, s), 7.75 (1H, t, J=8.8 Hz), 6.69 (1H, dd, J=8.6, 2.3 Hz), 6.62 (1H, dd, J=13.1, 2.2 Hz), 3.78 (3H, s). the solvent was removed the residue was diluted with diethyl ether The organic phase was washed carefully two times with saturated aqueous NaHCO3 once with brine, and then dried over anhydrous sodium sulfate After filtration the organic solvent was 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 2-fluoro-4-hydroxybenzoic acid (50.0 g) and concentrated sulfuric acid (10 mL) in methanol (700 mL) was stirred at 90° C. for 16 hr with heating. The reaction solution was concentrated, and the resulting colorless crystals were washed with water, and dried to give the title compound (51 g, yield 94%) as colorless crystals. with heating The reaction solution was concentrated the resulting colorless crystals were washed with water dried

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-fluoro-4-hydroxybenzoic acid (50.0 g) and concentrated sulfuric acid (10 mL) in methanol (700 mL) was stirred with heating at 90° C. for 16 hr. The reaction solution was concentrated, and the resulting colorless crystals were washed with water, and dried to give the title compound (51 g, yield 94%) as colorless crystals. The reaction solution was concentrated the resulting colorless crystals were washed with water dried

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of methyl 2-fluoro-4-hydroxy-benzoate (2.1 g, 12.4 mmol), potassium carbonate (6.8 g, 49.5 mmol) in dry DMF (13 mL) was added 2-iodopropane (2.5 mL, 24.8 mmol) and the reaction mixture was heated at 60° C. for 2 hours. The reaction was cooled and diluted with ether (50 mL) and filtered over Celite®. The filtrate was washed sequentially with water (3×25 mL) and brine solution (25 mL). The organic layer was separated and dried over MgSO4 and solvent was concentrated in vacuo to give a residue which was purified by silica gel column chromatography using 5-45% EtOAc/hexanes to give methyl 2-fluoro-4-isopropoxybenzoate as a colorless oil (2.2 g, 83%). To a solution of methyl 2-fluoro-4-isopropoxybenzoate (2.2 g, 10.3 mmol) in THF (5.5 mL) was added a suspension of lithium hydroxide (0.9 g, 37.1 mmol) in water (5.5 mL). The reaction mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and the excess LiOH was removed by filtration. The filtrate was diluted with water (9 ml), and washed with ether (2×5 mL). The aqueous layer was separated and cooled to 0° C. and the pH was adjusted to pH 2 by addition of 6 M HCl solution. The aqueous layer was extracted with EtOAc (3×30 mL). The organics were separated and washed sequentially with water and brine. The organic layer was separated, dried and concentrated in vacuo to give 2-fluoro-4-isopropoxy-benzoic acid (2.45 g, 67%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (t, J=8.8 Hz, 1H), 6.69 (ddd, J=15.1, 10.9, 2.0 Hz, 2H), 4.63 (dt, J=12.1, 6.0 Hz, 1H), 1.39 (d, J=6.1 Hz, 6H). The reaction was cooled filtered over Celite® The filtrate was washed sequentially with water (3×25 mL) and brine solution (25 mL) The organic layer was separated dried over MgSO4 and solvent was concentrated in vacuo to give a residue which was purified by silica gel column chromatography

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-fluoro-4-hydroxy-benzoic acid (5.32 g, 34.1 mmol) in methanol (21 mL) was added thionyl chloride (4.86 g, 3 mL, 40.9 mmol) dropwise and the reaction mixture was stirred at 40° C. for 3 hours. The reaction mixture was concentrated in vacuo and diluted with DCM (100 mL) and washed with aqueous saturated NaHCO3 (2×50 mL) solution. The organics were separated and dried with MgSO4, filtered and concentrated in vacuo to give methyl 2-fluoro-4-hydroxy-benzoate (2.3 g, 40%). ESI-MS m/z calc. 170.1. found 171.3 (M+1)+; Retention time: 0.84 minutes (3 min run). The reaction mixture was concentrated in vacuo diluted with DCM (100 mL) washed with aqueous saturated NaHCO3 (2×50 mL) solution The organics were separated dried with MgSO4 filtered concentrated in vacuo

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-fluoro-4-hydroxy-benzoic acid (5.32 g, 34.1 mmol) in methanol (21 mL) was added thionyl chloride (4.86 g, 3 mL, 40.9 mmol) dropwise and the reaction mixture was stirred at 40° C. for 3 hours. The reaction mixture was concentrated in vacuo and diluted with DCM (100 mL) and washed with aqueous saturated NaHCO3 (2×50 mL) solution. The organics were separated and dried with MgSO4, filtered and concentrated in vacuo to give methyl 2-fluoro-4-hydroxy-benzoate (2.3 g, 40%). ESI-MS m/z calc. 170.1. found 171.3 (M+1)+; Retention time: 0.84 minutes (3 min run). The reaction mixture was concentrated in vacuo diluted with DCM (100 mL) washed with aqueous saturated NaHCO3 (2×50 mL) solution The organics were separated dried with MgSO4 filtered concentrated in vacuo