4-氯-2,6-二氟苯酚

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-chloro-2,6-difluorophenol (5.11 g) was dissolved in DMF (100 ml), ethyl 2-bromo-2-methylpropanoate (14 ml) and potassium carbonate (6.44 g) were added thereto, followed by stirring at 80° C. for 3 hours. The reaction solution was cooled to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a 1M aqueous sodium hydroxide solution and then 1M hydrochloric acid in this order and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=19:1) to obtain a colorless oily product. The oily product thus obtained was dissolved in ethanol (150 ml), a 1M aqueous sodium hydroxide solution (65 ml) was added thereto, followed by stirring at room temperature for one hour. The reaction solution was concentrated under reduced pressure and water was added to the resulting residue, followed by washing with ethyl acetate. 1M hydrochloric acid was added to the aqueous layer, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain a colorless oily product. Acetonitrile (75 ml), WSC•monohydrochloride (7.18 g) and HOBt (5.04 g) were added to the oily product thus obtained, followed by stirring at room temperature for one hour. The resulting reaction solution was added to a mixed solution of hydrazine monohydrate (7.55 ml) and acetonitrile (75 ml), followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine. After drying over anhydrous magnesium sulfate and aeration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to obtain 2-(4-chloro-2,6-difluorophenoxy)-2-methylpropanohydrazide (5.69 g) as a pink oily product. The reaction solution was cooled to room temperature followed by extraction with ethyl acetate The organic layer was washed with a 1M aqueous sodium hydroxide solution 1M hydrochloric acid in this order and dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=19:1) to obtain a colorless oily product The oily product thus obtained by stirring at room temperature for one hour The reaction solution was concentrated under reduced pressure and water was added to the resulting residue by washing with ethyl acetate 1M hydrochloric acid was added to the aqueous layer followed by extraction with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure to obtain a colorless oily product thus obtained by stirring at room temperature for one hour The resulting reaction solution by stirring at room temperature overnight The reaction solution was concentrated under reduced pressure, water was added followed by extraction with chloroform The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine After drying over anhydrous magnesium sulfate and aeration the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate) The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1)

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-chloro-2,6-difluorophenol (5.0 g, 30.4 mmol), 4-fluorobenzaldehyde (3.1 mL, 28.9 mmol) in DMF (30 mL), was added K2CO3 (5.0 g, 36.2 mmol). The mixture was heated at 100° C. overnight. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated, purified by flash chromatography to afford the title compound (5.4 g, 20.10 mmol, 66.1% yield) as a colorless oil. LCMS: rt=3.52 min, [M+H+]=269 After cooling extracted with EA The organic phase was washed with water and brine dried over Na2SO4 concentrated purified by flash chromatography

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-chloro-2,6-difluorophenol (5.11 g) was dissolved in DMF (100 ml), ethyl 2-bromo-2-methylpropanoate (14 ml) and potassium carbonate (6.44 g) were added thereto, followed by stirring at 80° C. for 3 hours. The reaction solution was cooled to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a 1M aqueous sodium hydroxide solution and then 1M hydrochloric acid in this order and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=19:1) to obtain a colorless oily product. The oily product thus obtained was dissolved in ethanol (150 ml), a 1M aqueous sodium hydroxide solution (65 ml) was added thereto, followed by stirring at room temperature for one hour. The reaction solution was concentrated under reduced pressure and water was added to the resulting residue, followed by washing with ethyl acetate. 1M hydrochloric acid was added to the aqueous layer, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain a colorless oily product. Acetonitrile (75 ml), WSC•monohydrochloride (7.18 g) and HOBt (5.04 g) were added to the oily product thus obtained, followed by stirring at room temperature for one hour. The resulting reaction solution was added to a mixed solution of hydrazine monohydrate (7.55 ml) and acetonitrile (75 ml), followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine. After drying over anhydrous magnesium sulfate and aeration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to obtain 2-(4-chloro-2,6-difluorophenoxy)-2-methylpropanohydrazide (5.69 g) as a pink oily product. The reaction solution was cooled to room temperature followed by extraction with ethyl acetate The organic layer was washed with a 1M aqueous sodium hydroxide solution 1M hydrochloric acid in this order and dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=19:1) to obtain a colorless oily product The oily product thus obtained by stirring at room temperature for one hour The reaction solution was concentrated under reduced pressure and water was added to the resulting residue by washing with ethyl acetate 1M hydrochloric acid was added to the aqueous layer followed by extraction with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure to obtain a colorless oily product thus obtained by stirring at room temperature for one hour The resulting reaction solution by stirring at room temperature overnight The reaction solution was concentrated under reduced pressure, water was added followed by extraction with chloroform The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine After drying over anhydrous magnesium sulfate and aeration the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate) The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1)

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-chloro-2,6-difluorophenol (5.0 g, 30.4 mmol), 4-fluorobenzaldehyde (3.1 mL, 28.9 mmol) in DMF (30 mL), was added K2CO3 (5.0 g, 36.2 mmol). The mixture was heated at 100° C. overnight. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated, purified by flash chromatography to afford the title compound (5.4 g, 20.10 mmol, 66.1% yield) as a colorless oil. LCMS: rt=3.52 min, [M+H+]=269 After cooling extracted with EA The organic phase was washed with water and brine dried over Na2SO4 concentrated purified by flash chromatography

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-chloro-2,6-difluorophenol (5.11 g) was dissolved in DMF (100 ml), ethyl 2-bromo-2-methylpropanoate (14 ml) and potassium carbonate (6.44 g) were added thereto, followed by stirring at 80° C. for 3 hours. The reaction solution was cooled to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a 1M aqueous sodium hydroxide solution and then 1M hydrochloric acid in this order and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=19:1) to obtain a colorless oily product. The oily product thus obtained was dissolved in ethanol (150 ml), a 1M aqueous sodium hydroxide solution (65 ml) was added thereto, followed by stirring at room temperature for one hour. The reaction solution was concentrated under reduced pressure and water was added to the resulting residue, followed by washing with ethyl acetate. 1M hydrochloric acid was added to the aqueous layer, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain a colorless oily product. Acetonitrile (75 ml), WSC•monohydrochloride (7.18 g) and HOBt (5.04 g) were added to the oily product thus obtained, followed by stirring at room temperature for one hour. The resulting reaction solution was added to a mixed solution of hydrazine monohydrate (7.55 ml) and acetonitrile (75 ml), followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine. After drying over anhydrous magnesium sulfate and aeration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to obtain 2-(4-chloro-2,6-difluorophenoxy)-2-methylpropanohydrazide (5.69 g) as a pink oily product. The reaction solution was cooled to room temperature followed by extraction with ethyl acetate The organic layer was washed with a 1M aqueous sodium hydroxide solution 1M hydrochloric acid in this order and dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=19:1) to obtain a colorless oily product The oily product thus obtained by stirring at room temperature for one hour The reaction solution was concentrated under reduced pressure and water was added to the resulting residue by washing with ethyl acetate 1M hydrochloric acid was added to the aqueous layer followed by extraction with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure to obtain a colorless oily product thus obtained by stirring at room temperature for one hour The resulting reaction solution by stirring at room temperature overnight The reaction solution was concentrated under reduced pressure, water was added followed by extraction with chloroform The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine After drying over anhydrous magnesium sulfate and aeration the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate) The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1)