methyl 5-bromo-2-methoxybenzoate

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: 5-Bromo-2-methoxybenzoic acid, methyl ester (5 g, 20.4 mmol), imidazole (1.4 g, 20.6 mmol), and potassium carbonate (2.9 g, 20.7 mmol) were heated to 145° C. in DMF under N2 as cuprous iodide (1.5 g, 7.9 mmol) was added in portions. The reaction was stirred at this temperature for 18 h, allowed to cool, and filtered through a celite plug. The filtered salts were washed extensively with methanol, the filtrate concentrated in vacuo, and the residue taken up in ethyl acetate, washed with water, brine, and dried. Chromatography on SiO2, elution with methanol/ethyl acetate/hexanes (1:1:3) gave 3 g (63%); IR(KBr, ν=cm-1) 3430, 1726, 1512, 1232, 1068; 1H NMR (300 MHz, DMSO-d6) δ3.80 (3H, s), 3.85 (3H, s), 7.07 (1H, s), 7.27 (1H, d, J=8.8 Hz), 7.69 (1H, s), 7.76-7.82 (2H, m) 8.18 (1H, s); MS(DCl)m/z: 233 (MH+). was added in portions to cool filtered through a celite plug The filtered salts were washed extensively with methanol the filtrate concentrated in vacuo washed with water, brine dried Chromatography on SiO2, elution with methanol/ethyl acetate/hexanes (1:1:3) gave 3 g (63%)

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

実験手順: 5-Bromo-2-methoxybenzoic acid, methyl ester (5 g, 20.4 mmol), imidazole (1.4 g, 20.6 mmol), and potassium carbonate (2.9 g, 20.7 mmol) were heated to 145° C. in DMF under N2 as cuprous iodide (1.5 g, 7.9 mmol) was added in portions. The reaction was stirred at this temperature for 18 h, allowed to cool, and filtered through a celite plug. The filtered salts were washed extensively with methanol, the filtrate concentrated in vacuo, and the residue taken up in ethyl acetate, washed with water, brine, and dried. Chromatography on SiO2, elution with methanol/ethyl acetate/hexanes (1:1:3) gave 3 g (63%); IR(KBr, υ=cm−1) 3430, 1726, 1512, 1232, 1068; 1H NMR (300 MHz, DMSO-d6) δ 3.80 (3H, s), 3.85 (3H, s), 7.07 (1H, s), 7.27 (1H, d, J=8.8 Hz), 7.69 (1H, s), 7.76 -7.82 (2H, m) 8.18 (1H, s); MS(DCl)m/z: 233 (MH+). was added in portions to cool filtered through a celite plug The filtered salts were washed extensively with methanol the filtrate concentrated in vacuo washed with water, brine dried Chromatography on SiO2, elution with methanol/ethyl acetate/hexanes (1:1:3) gave 3 g (63%)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 5-bromo-2-methoxybenzoate (29.3 g) obtained in step A of Example 1-1-1, and 33.1 g of zinc cyanide were dissolved in 650 mL of N,N-dimethylformamide. N,N-Dimethylformamide was degassed under reduced pressure, and then the interior of the reactor was purged with nitrogen. After 9.8 g of tetrakistriphenylphosphine palladium was added, N,N-dimethylformamide was deaerated again under reduced pressure, and then the interior of the reactor was purged with argon. This solution was stirred for 2 hours at 100° C., whereafter the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The insolubles were removed by filtration, and washed with ethyl acetate. The filtrate and the washings were combined, water was added, and then the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. After the respective organic layers were combined, the combined organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and then washed with ethyl acetate. The filtrate and the washings were combined, and ethyl acetate was distilled off under reduced pressure. The resulting residue was washed with diethyl ether. The resulting solid was dried under reduced pressure to obtain 13.5 g (42%) of methyl 5-cyano-2-methoxybenzoate. The mother liquor and the washings were combined, and concentrated, whereafter the residue was recrystallized from t-butyl methyl ether. The resulting crystals were separated by filtration, then washed with a 1:1 solvent mixture of n-hexane and diethyl ether, and then dried under reduced pressure to obtain 4.6 g (14%) of methyl 5-cyano-2-methoxybenzoate. N,N-Dimethylformamide was degassed under reduced pressure the interior of the reactor was purged with nitrogen After 9.8 g of tetrakistriphenylphosphine palladium was added the interior of the reactor was purged with argon was distilled off under reduced pressure the residue was dissolved in ethyl acetate The insolubles were removed by filtration washed with ethyl acetate water was added the organic layer was separated The aqueous layer was extracted twice with ethyl acetate the combined organic layer was washed with a saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate The anhydrous sodium sulfate was separated by filtration washed with ethyl acetate ethyl acetate was distilled off under reduced pressure The resulting residue was washed with diethyl ether The resulting solid was dried under reduced pressure

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

実験手順: Methyl 5-bromo-2-methoxybenzoate (14.7 g) obtained in step A was dissolved in 100 mL of methanol. To the solution, 40 mL of a 20% aqueous solution of potassium hydroxide was added, and the mixture was stirred for 2 hours at 80° C. The reaction solution was cooled to 0° C., and then adjusted to pH of about 3 with the use of 11 mL of concentrated hydrochloric acid. The precipitate was separated by filtration, washed with water, and then dried over diphosphorus pentoxide under reduced pressure to obtain 10.9 g (85%) of 5-bromo-2-methoxybenzoic acid. The reaction solution was cooled to 0° C. The precipitate was separated by filtration washed with water dried over diphosphorus pentoxide under reduced pressure

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

実験手順: 5-Bromo-2-hydroxybenzoic acid (25 g) and 40 g of potassium carbonate were suspended in 300 mL of acetone. Dimethyl sulfate (28 mL) was added to the suspension, and the mixture was stirred for 19 hours under reflux with heating. The reaction mixture was cooled to room temperature, whereafter the insolubles were separated by filtration, and washed with ethyl acetate. The filtrate and the washings were combined, and acetone and ethyl acetate were distilled off under reduced pressure. The resulting residue was dissolved in 300 mL of ethyl acetate. Water (300 mL) was added to the solution, and the organic layer was separated; followed by extracting the aqueous layer with 200 mL of ethyl acetate. After the respective organic layers were combined, the combined organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and then washed with ethyl acetate. The filtrate and the washings were combined, and ethyl acetate was distilled off under reduced pressure to obtain 30 g of methyl 5-bromo-2-methoxybenzoate. under reflux with heating were separated by filtration washed with ethyl acetate acetone and ethyl acetate were distilled off under reduced pressure The resulting residue was dissolved in 300 mL of ethyl acetate Water (300 mL) was added to the solution the organic layer was separated by extracting the aqueous layer with 200 mL of ethyl acetate the combined organic layer was washed with a saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate The anhydrous sodium sulfate was separated by filtration washed with ethyl acetate ethyl acetate was distilled off under reduced pressure

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

実験手順: 5-Bromo-2-hydroxybenzoic acid (25 g) and 40 g of potassium carbonate were suspended in 300 mL of acetone. Dimethyl sulfate (28 mL) was added to the suspension, and the mixture was stirred for 19 hours under reflux with heating. The reaction mixture was cooled to room temperature, whereafter the insolubles were separated by filtration, and washed with ethyl acetate. The filtrate and the washings were combined, and acetone and ethyl acetate were distilled off under reduced pressure. The resulting residue was dissolved in 300 mL of ethyl acetate. Water (300 mL) was added to the solution, and the organic layer was separated; followed by extracting the aqueous layer with 200 mL of ethyl acetate. After the respective organic layers were combined, the combined organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and then washed with ethyl acetate. The filtrate and the washings were combined, and ethyl acetate was distilled off under reduced pressure to obtain 30 g of methyl 5-bromo-2-methoxybenzoate. under reflux with heating were separated by filtration washed with ethyl acetate acetone and ethyl acetate were distilled off under reduced pressure The resulting residue was dissolved in 300 mL of ethyl acetate Water (300 mL) was added to the solution the organic layer was separated by extracting the aqueous layer with 200 mL of ethyl acetate the combined organic layer was washed with a saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate The anhydrous sodium sulfate was separated by filtration washed with ethyl acetate ethyl acetate was distilled off under reduced pressure

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 5-bromo-2-methoxybenzoate (29.3 g) obtained in step A of Example 1-1-1, and 33.1 g of zinc cyanide were dissolved in 650 mL of N,N-dimethylformamide. N,N-Dimethylformamide was degassed under reduced pressure, and then the interior of the reactor was purged with nitrogen. After 9.8 g of tetrakistriphenylphosphine palladium was added, N,N-dimethylformamide was deaerated again under reduced pressure, and then the interior of the reactor was purged with argon. This solution was stirred for 2 hours at 100° C., whereafter the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The insolubles were removed by filtration, and washed with ethyl acetate. The filtrate and the washings were combined, water was added, and then the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. After the respective organic layers were combined, the combined organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and then washed with ethyl acetate. The filtrate and the washings were combined, and ethyl acetate was distilled off under reduced pressure. The resulting residue was washed with diethyl ether. The resulting solid was dried under reduced pressure to obtain 13.5 g (42%) of methyl 5-cyano-2-methoxybenzoate. The mother liquor and the washings were combined, and concentrated, whereafter the residue was recrystallized from t-butyl methyl ether. The resulting crystals were separated by filtration, then washed with a 1:1 solvent mixture of n-hexane and diethyl ether, and then dried under reduced pressure to obtain 4.6 g (14%) of methyl 5-cyano-2-methoxybenzoate. N,N-Dimethylformamide was degassed under reduced pressure the interior of the reactor was purged with nitrogen After 9.8 g of tetrakistriphenylphosphine palladium was added the interior of the reactor was purged with argon was distilled off under reduced pressure the residue was dissolved in ethyl acetate The insolubles were removed by filtration washed with ethyl acetate water was added the organic layer was separated The aqueous layer was extracted twice with ethyl acetate the combined organic layer was washed with a saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate The anhydrous sodium sulfate was separated by filtration washed with ethyl acetate ethyl acetate was distilled off under reduced pressure The resulting residue was washed with diethyl ether The resulting solid was dried under reduced pressure

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 5-bromo-2-methoxybenzoate (29.3 g) obtained in step A of Example 1-1-1, and 33.1 g of zinc cyanide were dissolved in 650 mL of N,N-dimethylformamide. N,N-Dimethylformamide was degassed under reduced pressure, and then the interior of the reactor was purged with nitrogen. After 9.8 g of tetrakistriphenylphosphine palladium was added, N,N-dimethylformamide was deaerated again under reduced pressure, and then the interior of the reactor was purged with argon. This solution was stirred for 2 hours at 100° C., whereafter the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The insolubles were removed by filtration, and washed with ethyl acetate. The filtrate and the washings were combined, water was added, and then the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. After the respective organic layers were combined, the combined organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and then washed with ethyl acetate. The filtrate and the washings were combined, and ethyl acetate was distilled off under reduced pressure. The resulting residue was washed with diethyl ether. The resulting solid was dried under reduced pressure to obtain 13.5 g (42%) of methyl 5-cyano-2-methoxybenzoate. The mother liquor and the washings were combined, and concentrated, whereafter the residue was recrystallized from t-butyl methyl ether. The resulting crystals were separated by filtration, then washed with a 1:1 solvent mixture of n-hexane and diethyl ether, and then dried under reduced pressure to obtain 4.6 g (14%) of methyl 5-cyano-2-methoxybenzoate. N,N-Dimethylformamide was degassed under reduced pressure the interior of the reactor was purged with nitrogen After 9.8 g of tetrakistriphenylphosphine palladium was added the interior of the reactor was purged with argon was distilled off under reduced pressure the residue was dissolved in ethyl acetate The insolubles were removed by filtration washed with ethyl acetate water was added the organic layer was separated The aqueous layer was extracted twice with ethyl acetate the combined organic layer was washed with a saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate The anhydrous sodium sulfate was separated by filtration washed with ethyl acetate ethyl acetate was distilled off under reduced pressure The resulting residue was washed with diethyl ether The resulting solid was dried under reduced pressure

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

実験手順: Methyl 5-bromo-2-methoxybenzoate (14.7 g) obtained in step A was dissolved in 100 mL of methanol. To the solution, 40 mL of a 20% aqueous solution of potassium hydroxide was added, and the mixture was stirred for 2 hours at 80° C. The reaction solution was cooled to 0° C., and then adjusted to pH of about 3 with the use of 11 mL of concentrated hydrochloric acid. The precipitate was separated by filtration, washed with water, and then dried over diphosphorus pentoxide under reduced pressure to obtain 10.9 g (85%) of 5-bromo-2-methoxybenzoic acid. The reaction solution was cooled to 0° C. The precipitate was separated by filtration washed with water dried over diphosphorus pentoxide under reduced pressure

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

実験手順: Methyl 5-bromo-2-methoxybenzoate (14.7 g) obtained in step A was dissolved in 100 mL of methanol. To the solution, 40 mL of a 20% aqueous solution of potassium hydroxide was added, and the mixture was stirred for 2 hours at 80° C. The reaction solution was cooled to 0° C., and then adjusted to pH of about 3 with the use of 11 mL of concentrated hydrochloric acid. The precipitate was separated by filtration, washed with water, and then dried over diphosphorus pentoxide under reduced pressure to obtain 10.9 g (85%) of 5-bromo-2-methoxybenzoic acid. The reaction solution was cooled to 0° C. The precipitate was separated by filtration washed with water dried over diphosphorus pentoxide under reduced pressure