N-(5-bromo-2-fluorophenyl)acetamide

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: By the reaction in the same manner as in Example 4-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.50 g), N-(5-bromo-2-fluorophenyl)acetamide (1.17 g) and tetrakis(triphenylphosphine)palladium(0) (0.17 g), the title compound (1.39 g); was obtained as a colorless amorphous powder. By the reaction in the same manner as in Example

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

実験手順: By the reaction in the same manner as in Example 4-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.50 g), N-(5-bromo-2-fluorophenyl)acetamide (1.17 g) and tetrakis(triphenylphosphine)palladium(0) (0.17 g), the title compound (1.39 g); was obtained as a colorless amorphous powder. By the reaction in the same manner as in Example

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

実験手順: 4-Bromo-1-fluoro-2-nitrobenzene (5.81 g), iron powder (6.20 g) and acetic anhydride (5 ml) were stirred in acetic acid (50 ml) at 60° C. for 16 h. Acetic acid was evaporated under reduced pressure and water and ethyl acetate were added. The organic layer was washed with aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (3.56 g) as colorless prism crystals. Acetic acid was evaporated under reduced pressure and water and ethyl acetate were added The organic layer was washed with aqueous sodium hydrogen carbonate and brine dried over magnesium sulfate concentrated under reduced pressure The residue was recrystallized from hexane-ethyl acetate

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

実験手順: The product of Step 1 (5.12 g, 18.7 mmol), cis-2,6-dimethyl piperazine (3.20 g, 28.1 mmol), sodium tert-butoxide (5.39 g, 56.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (343 mg, 0.37 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (444 mg, 1.12 mmol) were heated at reflux for 16 hours in 1,4-dioxane (50 ml). The solution was filtered through celite washing through with ethyl acetate. The filtrate was concentrated in vacuo, and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was washed with water, 50% saturated brine solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (ethyl acetate, then a gradient of dichloromethane to 10% 2M methanolic ammonia in dichloromethane) to afford the title compound. MS (ES+) m/e 266 [M+H]+. The solution was filtered through celite washing through with ethyl acetate The filtrate was concentrated in vacuo the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution The organic phase was washed with water, 50% saturated brine solution, brine dried over anhydrous sodium sulfate concentrated in vacuo The residue was purified by chromatography on silica gel (ethyl acetate

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

実験手順: 5-Bromo-2-fluoroaniline (14.79 g, 78 mmol) was heated at reflux in acetic acid (50 ml) and acetic anhydride (50 ml) for 8 hours. The solution was concentrated in vacuo, azeotroping with toluene. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was washed with water (×3), brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (gradient of hexane to ethyl acetate) to afford the title compound. MS (ES+) m/e 232/234 [M+H]+. The solution was concentrated in vacuo azeotroping with toluene The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution The organic phase was washed with water (×3), brine dried over anhydrous magnesium sulfate concentrated in vacuo The residue was purified by chromatography on silica gel (gradient of hexane to ethyl acetate)

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: The product of Step 1 (5.12 g, 18.7 mmol), cis-2,6-dimethyl piperazine (3.20 g, 28.1 mmol), sodium tert-butoxide (5.39 g, 56.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (343 mg, 0.37 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (444 mg, 1.12 mmol) were heated at reflux for 16 hours in 1,4-dioxane (50 ml). The solution was filtered through celite washing through with ethyl acetate. The filtrate was concentrated in vacuo, and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was washed with water, 50% saturated brine solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (ethyl acetate, then a gradient of dichloromethane to 10% 2M methanolic ammonia in dichloromethane) to afford the title compound. MS (ES+) m/e 266 [M+H]+. The solution was filtered through celite washing through with ethyl acetate The filtrate was concentrated in vacuo the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution The organic phase was washed with water, 50% saturated brine solution, brine dried over anhydrous sodium sulfate concentrated in vacuo The residue was purified by chromatography on silica gel (ethyl acetate

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

実験手順: 5-Bromo-2-fluoroaniline (14.79 g, 78 mmol) was heated at reflux in acetic acid (50 ml) and acetic anhydride (50 ml) for 8 hours. The solution was concentrated in vacuo, azeotroping with toluene. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was washed with water (×3), brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (gradient of hexane to ethyl acetate) to afford the title compound. MS (ES+) m/e 232/234 [M+H]+. The solution was concentrated in vacuo azeotroping with toluene The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution The organic phase was washed with water (×3), brine dried over anhydrous magnesium sulfate concentrated in vacuo The residue was purified by chromatography on silica gel (gradient of hexane to ethyl acetate)

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

実験手順: By the reaction in the same manner as in Example 4-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.50 g), N-(5-bromo-2-fluorophenyl)acetamide (1.17 g) and tetrakis(triphenylphosphine)palladium(0) (0.17 g), the title compound (1.39 g); was obtained as a colorless amorphous powder. By the reaction in the same manner as in Example

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

実験手順: 4-Bromo-1-fluoro-2-nitrobenzene (5.81 g), iron powder (6.20 g) and acetic anhydride (5 ml) were stirred in acetic acid (50 ml) at 60° C. for 16 h. Acetic acid was evaporated under reduced pressure and water and ethyl acetate were added. The organic layer was washed with aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (3.56 g) as colorless prism crystals. Acetic acid was evaporated under reduced pressure and water and ethyl acetate were added The organic layer was washed with aqueous sodium hydrogen carbonate and brine dried over magnesium sulfate concentrated under reduced pressure The residue was recrystallized from hexane-ethyl acetate

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

実験手順: The product of Step 1 (5.12 g, 18.7 mmol), cis-2,6-dimethyl piperazine (3.20 g, 28.1 mmol), sodium tert-butoxide (5.39 g, 56.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (343 mg, 0.37 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (444 mg, 1.12 mmol) were heated at reflux for 16 hours in 1,4-dioxane (50 ml). The solution was filtered through celite washing through with ethyl acetate. The filtrate was concentrated in vacuo, and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was washed with water, 50% saturated brine solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (ethyl acetate, then a gradient of dichloromethane to 10% 2M methanolic ammonia in dichloromethane) to afford the title compound. MS (ES+) m/e 266 [M+H]+. The solution was filtered through celite washing through with ethyl acetate The filtrate was concentrated in vacuo the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution The organic phase was washed with water, 50% saturated brine solution, brine dried over anhydrous sodium sulfate concentrated in vacuo The residue was purified by chromatography on silica gel (ethyl acetate