1,3-difluoro-2-methoxybenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 350 ml of tetrahydrofuran was dissolved 22.9 g of 2,6-difluoroanisole, and to the solution was added dropwise 110 ml of a 1.6 M solution of n-butyllithium in n-hexane at -70° C. over a period of 30 minutes. The resulting mixture was stirred at the same temperature for 1 hour, and carbon dioxide was introduced thereinto, after which the mixture was heated to 0° C. over a period of 1 hour. The reaction mixture was added to a mixed solvent of 300 ml of ethyl acetate and 700 ml of water and the pH was adjusted to 1 with 6N hydrochloric acid, after which the organic layer was separated. The organic layer obtained was washed with a saturated aqueous sodium chloride solution, followed by adding thereto a solution of diazomethane in diethyl ether, and the resulting mixture was stirred at room temperature for 10 minutes and distilled under reduced pressure to remove the solvent. The resulting residue was purified by a column chromatography (eluent; n-hexane:ethyl acetate=10:1) to obtain 16.8 g of methyl 2,4-difluoro-3-methoxybenzoate as colorless crystals. after which the organic layer was separated The organic layer obtained was washed with a saturated aqueous sodium chloride solution by adding a solution of diazomethane in diethyl ether, and the resulting mixture was stirred at room temperature for 10 minutes distilled under reduced pressure to remove the solvent The resulting residue was purified by a column chromatography (eluent; n-hexane:ethyl acetate=10:1)

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

Procedure: In 254 ml of N,N-dimethylformamide was dissolved 25.4 g of 2,6-difluorophenol, followed by adding thereto 29.7 g of potassium carbonate and 83.1 g of iodomethane, and the resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was added to a mixed solvent of 200 ml of diethyl ether and 600 ml of water and the organic layer was separated. The organic layer obtained was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by vacuum distillation (43-45° C./20 mmHg) to obtain 22.9 g of 2,6-difluoroanisole as a colorless oil. by adding the organic layer was separated The organic layer obtained was washed with water a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate distilled under reduced pressure to remove the solvent The resulting residue was purified by vacuum distillation (43-45° C./20 mmHg)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 350 ml of tetrahydrofuran was dissolved 22.9 g of 2,6-difluoroanisole, and to the solution was added dropwise 110 ml of a 1.6 M solution of n-butyllithium in n-hexane at -70° C. over a period of 30 minutes. The resulting mixture was stirred at the same temperature for 1 hour, and carbon dioxide was introduced thereinto, after which the mixture was heated to 0° C. over a period of 1 hour. The reaction mixture was added to a mixed solvent of 300 ml of ethyl acetate and 700 ml of water and the pH was adjusted to 1 with 6N hydrochloric acid, after which the organic layer was separated. The organic layer obtained was washed with a saturated aqueous sodium chloride solution, followed by adding thereto a solution of diazomethane in diethyl ether, and the resulting mixture was stirred at room temperature for 10 minutes and distilled under reduced pressure to remove the solvent. The resulting residue was purified by a column chromatography (eluent; n-hexane:ethyl acetate=10:1) to obtain 16.8 g of methyl 2,4-difluoro-3-methoxybenzoate as colorless crystals. after which the organic layer was separated The organic layer obtained was washed with a saturated aqueous sodium chloride solution by adding a solution of diazomethane in diethyl ether, and the resulting mixture was stirred at room temperature for 10 minutes distilled under reduced pressure to remove the solvent The resulting residue was purified by a column chromatography (eluent; n-hexane:ethyl acetate=10:1)

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

Procedure: In 254 ml of N,N-dimethylformamide was dissolved 25.4 g of 2,6-difluorophenol, followed by adding thereto 29.7 g of potassium carbonate and 83.1 g of iodomethane, and the resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was added to a mixed solvent of 200 ml of diethyl ether and 600 ml of water and the organic layer was separated. The organic layer obtained was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by vacuum distillation (43-45° C./20 mmHg) to obtain 22.9 g of 2,6-difluoroanisole as a colorless oil. by adding the organic layer was separated The organic layer obtained was washed with water a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate distilled under reduced pressure to remove the solvent The resulting residue was purified by vacuum distillation (43-45° C./20 mmHg)

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

Procedure: In 254 ml of N,N-dimethylformamide was dissolved 25.4 g of 2,6-difluorophenol, followed by adding thereto 29.7 g of potassium carbonate and 83.1 g of iodomethane, and the resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was added to a mixed solvent of 200 ml of diethyl ether and 600 ml of water and the organic layer was separated. The organic layer obtained was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by vacuum distillation (43-45° C./20 mmHg) to obtain 22.9 g of 2,6-difluoroanisole as a colorless oil. by adding the organic layer was separated The organic layer obtained was washed with water a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate distilled under reduced pressure to remove the solvent The resulting residue was purified by vacuum distillation (43-45° C./20 mmHg)

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Lithium diisopropyl amide (1.5M cyclohexane solution, 5.6 mL) was added dropwise to a THF (10 mL) solution of 2,6-difluoroanisole (1.00 g) at −72° C. under nitrogen atmosphere, and the reaction solution was agitated for 30 minutes. DMF (2.7 mL) was added to the reaction mixture, the reaction solution was agitated for 30 minutes at −78° C., and then agitated at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system) and 433 mg of the title compound was obtained. the reaction solution was agitated for 30 minutes at −78° C. agitated at room temperature for 1 hour the organic layer was partitioned The organic layer was washed with a saturated saline solution dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system)

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

Procedure: Lithium diisopropyl amide (1.5M cyclohexane solution, 5.6 mL) was added dropwise to a THF (10 mL) solution of 2,6-difluoroanisole (1.00 g) at −72° C. under nitrogen atmosphere, and the reaction solution was agitated for 30 minutes. DMF (2.7 mL) was added to the reaction mixture, the reaction solution was agitated for 30 minutes at −78° C., and then agitated at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system) and 433 mg of the title compound was obtained. the reaction solution was agitated for 30 minutes at −78° C. agitated at room temperature for 1 hour the organic layer was partitioned The organic layer was washed with a saturated saline solution dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system)

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

Procedure: Lithium diisopropyl amide (1.5M cyclohexane solution, 5.6 mL) was added dropwise to a THF (10 mL) solution of 2,6-difluoroanisole (1.00 g) at −72° C. under nitrogen atmosphere, and the reaction solution was agitated for 30 minutes. DMF (2.7 mL) was added to the reaction mixture, the reaction solution was agitated for 30 minutes at −78° C., and then agitated at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system) and 433 mg of the title compound was obtained. the reaction solution was agitated for 30 minutes at −78° C. agitated at room temperature for 1 hour the organic layer was partitioned The organic layer was washed with a saturated saline solution dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-bromo-2-chlorobenzoic acid (3.2 g, 13.5 mmol) in dichloromethane (40 mL), oxalyl dichloride (1.7 mL, 27.1 mmol) was added. Then N,N-dimethylformamide (50 mL) was added dropwise. After the vigorous evolution of gas ceased, the mixture was stirred at 25° C. overnight prior to removal of the volatiles under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and cooled to 0° C. Aluminum trichloride (2.7 g, 20.4 mmol) was added in portions, and the mixture was stirred for 10 minutes. Then 1,3-difluoro-2-methoxybenzene (2.0 g, 13.8 mmol) was added, and the mixture was stirred at 0° C. for 2 hours. Then the reaction was allowed to warm to 25° C. overnight. The reaction was quenched with ice-water (30 mL) and extracted with dichloromethane (2×20 mL). The combined organic layers were washed with sodium hydroxide (2 M), water, hydrochloric acid (10%), and brine prior to drying over sodium sulfate. Crude product was obtained after dichloromethane was removed under reduced pressure. The sample was dissolved in tetrahydrofuran/methanol/water (30 mL, v/v/v=2:3:1), and lithium hydroxide monohydrate (700 mg) was added. The mixture was stirred for 1 hour at 25° C. The solvent was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3×30 mL), and the extracts were washed with brine, dried over sodium sulfate, and concentrated to a crude product under reduced pressure. The residue was purified by silica column chromatography to give 1.46 g of white solid (30% yield, purity: 95%). 1H-NMR (CDCl3, 400 MHz): δ 7.59-7.62 (m, 1H), 7.49-7.50 (m, 1H), 7.36-7.42 (m, 3H); HPLC-MS method: Method 2, retention time 3.81 min; MS ES+ (m/z): 345 (M−1)−. to removal of the volatiles under reduced pressure The residue was dissolved in dichloromethane (20 mL) cooled to 0° C the mixture was stirred for 10 minutes the mixture was stirred at 0° C. for 2 hours to warm to 25° C. overnight The reaction was quenched with ice-water (30 mL) extracted with dichloromethane (2×20 mL) The combined organic layers were washed with sodium hydroxide (2 M), water, hydrochloric acid (10%), and brine to drying over sodium sulfate Crude product was obtained after dichloromethane was removed under reduced pressure The sample was dissolved in tetrahydrofuran/methanol/water (30 mL, v/v/v=2:3:1) lithium hydroxide monohydrate (700 mg) was added The mixture was stirred for 1 hour at 25° C The solvent was removed under reduced pressure The aqueous layer was extracted with ethyl acetate (3×30 mL) the extracts were washed with brine dried over sodium sulfate concentrated to a crude product under reduced pressure The residue was purified by silica column chromatography

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

Procedure: 10 g (69.39 mol) of 2,6-difluoroanisole is dissolved in 200 ml of toluene and mixed at room temperature with 5.75 g (83.27 mmol) of isobutyric acid nitrile. 166.5 ml of a 0.5 molar solution of potassium hexamethyldisilazide in toluene is added in drops within 35 minutes. In this case, a slight temperature rise to 27.5° C. takes place. After 16 hours of stirring at room temperature, the reaction mixture is mixed with 200 ml of water and 400 ml of ethyl acetate and acidified with 10% sulfuric acid to a pH of 4. The organic phase is separated, and the aqueous phase is shaken once with ethyl acetate (200 ml). The combined organic extracts are shaken with water and brine. After the solvent is dried, filtered and spun off, the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 7.66 g (57.1%) of the desired compound is isolated. to 27.5° C. The organic phase is separated the aqueous phase is shaken once with ethyl acetate (200 ml) The combined organic extracts are shaken with water and brine After the solvent is dried filtered the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane)