methyl 4-bromo-3,5-dihydroxybenzoate

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

実験手順: Methyl 4-bromo-3,5-dihydroxybenzoate (10 g) was dissolved in DMF (80 mL), and potassium carbonate (13.2 g) and ethyl iodide (7.6 mL) were added to it, and stirred overnight at room temperature. The reaction liquid was poured into water with cooling with ice, extracted with ethyl acetate, the organic layer was washed with water and saturated saline water, and dried with sodium sulfate. Sodium sulfate was removed through filtration, the filtrate was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=1/0 to 90/10) to obtain the title compound as a white solid. The reaction liquid with cooling with ice extracted with ethyl acetate the organic layer was washed with water and saturated saline water dried with sodium sulfate Sodium sulfate was removed through filtration the filtrate was concentrated under reduced pressure the residue was purified through silica gel column chromatography (hexane/ethyl acetate=1/0 to 90/10)

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

実験手順: In a 2.0-liter egg plant-type flask, a hydrochloric acid/methanol solution (500 mL) of 4-bromo-3,5-dihydroxybenzoic acid (50 g, 0.21 mol) was stirred with heating under reflux for 6 hours. Methanol was removed under reduced pressure to obtain a crude crystal. This was washed with hexane and chloroform to obtain the title compound as a colorless solid. with heating under reflux for 6 hours Methanol was removed under reduced pressure to obtain a crude crystal This was washed with hexane and chloroform

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

実験手順: In a 2.0-liter egg plant-type flask, a hydrochloric acid/methanol solution (500 mL) of 4-bromo-3,5-dihydroxybenzoic acid (50 g, 0.21 mol) was stirred with heating under reflux for 6 hours. Methanol was removed under reduced pressure to obtain a crude crystal. This was washed with hexane and chloroform to obtain the title compound as a colorless solid. with heating under reflux for 6 hours Methanol was removed under reduced pressure to obtain a crude crystal This was washed with hexane and chloroform

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

実験手順: To a mixture of methyl 4-bromo-3,5-dihydroxybenzoate (18.8 g, 76 mmol) and potassium carbonate (5.26 g, 38.1 mmol) in DMF (190 mL) was added benzyl bromide (3.17 mL, 26.6 mmol). The mixture was stirred overnight, diluted with 200 mL water and acidified to pH 1 by slow addition of concentrated hydrochloric acid. The solution was extracted with 1:1 ethyl acetate/ether (6×) and the combined extracts were washed with water (8×), saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to an orange solid. The solids were suspended in DCM (200 mL) and stirred overnight. The solids (primarily unreacted 4-bromo-3,5-dihydroxybenzoate) were removed by filtration and the filtrate was concentrated to an orange oil which was purified by column chromatography (80 g silica gel, 2:1 DCM in heptane elution, followed by DCM elution) to provide methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate (4.66 g). MS (M+1)=337.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.32-7.57 (m, 6H), 7.26 (d, J=1.52 Hz, 1H), 5.77 (s, 1H), 5.22 (s, 2H), 3.93 (s, 3H) as well as the di-benzylated methyl 3,5-bis(benzyloxy)-4-bromobenzoate (1.8 g). The solution was extracted with 1:1 ethyl acetate/ether (6×) the combined extracts were washed with water (8×), saturated sodium bicarbonate, brine dried over magnesium sulfate concentrated to an orange solid stirred overnight The solids (primarily unreacted 4-bromo-3,5-dihydroxybenzoate) were removed by filtration the filtrate was concentrated to an orange oil which was purified by column chromatography (80 g silica gel, 2:1 DCM in heptane elution, followed by DCM elution)

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

実験手順: To a mixture of methyl 4-bromo-3,5-dihydroxybenzoate (18.8 g, 76 mmol) and potassium carbonate (5.26 g, 38.1 mmol) in DMF (190 mL) was added benzyl bromide (3.17 mL, 26.6 mmol). The mixture was stirred overnight, diluted with 200 mL water and acidified to pH 1 by slow addition of concentrated hydrochloric acid. The solution was extracted with 1:1 ethyl acetate/ether (6×) and the combined extracts were washed with water (8×), saturated sodium bicarbonate, brine, then dried over magnesium sulfate and concentrated to provide an orange solid. The solid was suspended in DCM (200 mL) and stirred overnight. The solid (primarily unreacted 4-bromo-3,5-dihydroxybenzoate) was removed by filtration and the filtrate was concentrated to provide an orange oil which was purified by column chromatography (80 g silica gel, 2:1 DCM in heptane elution, followed by DCM elution) to provide methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate (4.66 g). MS (M+1)=337.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.32-7.57 (m, 6H), 7.26 (d, J=1.52 Hz, 1H), 5.77 (s, 1H), 5.22 (s, 2H), 3.93 (s, 3H) as well as the di-benzylated methyl 3,5-bis(benzyloxy)-4-bromobenzoate (1.8 g). The solution was extracted with 1:1 ethyl acetate/ether (6×) the combined extracts were washed with water (8×), saturated sodium bicarbonate, brine dried over magnesium sulfate concentrated to provide an orange solid stirred overnight The solid (primarily unreacted 4-bromo-3,5-dihydroxybenzoate) was removed by filtration the filtrate was concentrated to provide an orange oil which was purified by column chromatography (80 g silica gel, 2:1 DCM in heptane elution, followed by DCM elution)

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

実験手順: Na pieces (41.4 g, 1.82 mol) were added slowly to MeOH (3 L). The resulting mixture was stirred at room temperature for 30 min and then 4-bromo-3,5-dihydroxy-benzoic acid methyl ester (197a) (450 g, 1.82 mol) was added portion wise. The mixture was warmed to 60° C. 3-Chloro-2-methyl-propene (202.5 mL, 2 mol) was added drop wise. The mixture was refluxed for 6 h. TLC (petroleum ether/EtOAc=5/1) showed the reaction was complete. The solvent was removed and the residue was purified by column chromatography (petroleum ether/EtOAc=15/1) to give the title compound (75 g, 13.6% yield). 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H), 7.06(s, 1H), 5.72(s, 1H), 5.11(s, 1H), 4.96(s, 1H), 4.47(s, 2H), 3.84(s, 3H), 1.79(s, 3H). The mixture was warmed to 60° C The mixture was refluxed for 6 h The solvent was removed the residue was purified by column chromatography (petroleum ether/EtOAc=15/1)

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-bromo-3,5-dihydroxy-benzoic acid (450 g, 1.94 mol) in MeOH (3.5 L) was added drop wise conc. H2SO4 (20 mL) at room temperature, and the mixture was refluxed overnight. TLC (petroleum ether/EtOAc=1/1) showed the reaction was complete. MeOH was removed under vacuum to about 250 mL and the resulting solid was filtered. The filter cake was dried under vacuum to give the title compound (450 g, 94% yield) as a white solid the mixture was refluxed overnight MeOH was removed under vacuum to about 250 mL the resulting solid was filtered The filter cake was dried under vacuum

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

実験手順: Na pieces (41.4 g, 1.82 mol) were added slowly to MeOH (3 L). The resulting mixture was stirred at room temperature for 30 min and then 4-bromo-3,5-dihydroxy-benzoic acid methyl ester (197a) (450 g, 1.82 mol) was added portion wise. The mixture was warmed to 60° C. 3-Chloro-2-methyl-propene (202.5 mL, 2 mol) was added drop wise. The mixture was refluxed for 6 h. TLC (petroleum ether/EtOAc=5/1) showed the reaction was complete. The solvent was removed and the residue was purified by column chromatography (petroleum ether/EtOAc=15/1) to give the title compound (75 g, 13.6% yield). 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1 H), 7.06 (s, 1 H), 5.72 (s, 1 H), 5.11 (s, 1 H), 4.96 (s, 1 H), 4.47 (s, 2 H), 3.84 (s, 3 H), 1.79 (s, 3 H). The mixture was warmed to 60° C The mixture was refluxed for 6 h The solvent was removed the residue was purified by column chromatography (petroleum ether/EtOAc=15/1)

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-bromo-3,5-dihydroxy-benzoic acid (450 g, 1.94 mol) in MeOH (3.5 L) was added drop wise conc. H2SO4 (20 mL) at room temperature, and the mixture was refluxed overnight. TLC (petroleum ether/EtOAc=1/1) showed the reaction was complete. MeOH was removed under vacuum to about 250 mL and the resulting solid was filtered. The filter cake was dried under vacuum to give the title compound (450 g, 94% yield) as a white solid the mixture was refluxed overnight MeOH was removed under vacuum to about 250 mL the resulting solid was filtered The filter cake was dried under vacuum

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

実験手順: Methyl 4-bromo-3,5-dihydroxybenzoate (10 g) was dissolved in DMF (80 mL), and potassium carbonate (13.2 g) and ethyl iodide (7.6 mL) were added to it, and stirred overnight at room temperature. The reaction liquid was poured into water with cooling with ice, extracted with ethyl acetate, the organic layer was washed with water and saturated saline water, and dried with sodium sulfate. Sodium sulfate was removed through filtration, the filtrate was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=1/0 to 90/10) to obtain the title compound as a white solid. The reaction liquid with cooling with ice extracted with ethyl acetate the organic layer was washed with water and saturated saline water dried with sodium sulfate Sodium sulfate was removed through filtration the filtrate was concentrated under reduced pressure the residue was purified through silica gel column chromatography (hexane/ethyl acetate=1/0 to 90/10)

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

実験手順: In a 2.0-liter egg plant-type flask, a hydrochloric acid/methanol solution (500 mL) of 4-bromo-3,5-dihydroxybenzoic acid (50 g, 0.21 mol) was stirred with heating under reflux for 6 hours. Methanol was removed under reduced pressure to obtain a crude crystal. This was washed with hexane and chloroform to obtain the title compound as a colorless solid. with heating under reflux for 6 hours Methanol was removed under reduced pressure to obtain a crude crystal This was washed with hexane and chloroform

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-bromo-3,5-dihydroxybenzoic acid (13.89 g, 59.6 mmol) in methanol (50 mL) was added H2SO4 (concentrated, 1 mL). The reaction mixture was heated to reflux overnight. The mixture was quenched with H2O (500 mL) and extracted with 10% MeOH in CH2Cl2 (5×500 mL), dried over MgSO4 and concentrated in vacuo to give a white solid (14.8 g, 100% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 2 H) 7.00 (s, 2 H) 3.80 (s, 3 H); LCMS for C8H7BrO4 m/z 249.10 (M+H)+. The reaction mixture was heated to reflux overnight The mixture was quenched with H2O (500 mL) extracted with 10% MeOH in CH2Cl2 (5×500 mL) dried over MgSO4 concentrated in vacuo