2-(4-fluorophenyl)aniline

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:

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

実験手順: A stirred solution of 2-iodoaniline (32.6 g, 149 mmol) and 4-fluorophenylboronic acid (20.8 g, 149 mmol) in tetrahydrofuran (1.5 L) was treated under nitrogen with [1,1 ′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (2.20 g, 2.69 mmol) and a 5 N sodium hydroxide solution (60 mL). The reaction mixture was heated at reflux for twelve hours, cooled to room temperature, and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (250 mL) and extracted with a saturated, aqueous, sodium chloride solution (100 mL). The aqueous phase was further extracted with ethyl acetate (2×50 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a brown oil. The brown oil was filtered through a short column of silica gel, and eluted with a mixture of ethyl acetate-hexane (1:4). After evaporation of the solvent in vacuo, a solution of the crude 4′-fluoro-biphenyl-2-ylamine in dichloromethane (75 mL) was treated with pyridine (27.7 mL, 343 mmol), acetic anhydride (15.5 mL, 164 mmol), and 4-(N,N-dimethylamino)pyridine (0.55 g, 4.5 mmol). After stirring for twelve hours at room temperature, the reaction was quenched with a saturated, aqueous, ammonium. chloride solution (250 mL). The separated aqueous phase was extracted with dichloromethane (3×75 mL), and the combined organic phase washed sequentially with a 0.1 N hydrochloric acid solution (2×50 mL), and a saturated, aqueous, sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a second brown oil. After toluene was added and removed in vacuo (3×), the resulting brown solid was crystallized from ethyl acetate-hexane to yield a first crop of the desired product (19.0 g). The mother liquor was concentrated and purified by flash column chromatography on silica gel, eluting with ethyl acetate-hexane (1:4), to obtain a second crop (5.0 g). The combined crops afforded the title compound as a homogeneous, colorless, crystalline, solid (24.0 g, 70%). m.p. 123-124° C.; MS [(+ESI), m/z]: 230 [M+H]+; The reaction mixture was heated at reflux for twelve hours the solvent removed in vacuo The residue was dissolved in ethyl acetate (250 mL) extracted with a saturated, aqueous, sodium chloride solution (100 mL) The aqueous phase was further extracted with ethyl acetate (2×50 mL) The combined organic phase was dried over anhydrous magnesium sulfate filtered concentrated in vacuo to a brown oil The brown oil was filtered through a short column of silica gel eluted with a mixture of ethyl acetate-hexane (1:4) After evaporation of the solvent in vacuo the reaction was quenched with a saturated, aqueous, ammonium The separated aqueous phase was extracted with dichloromethane (3×75 mL) the combined organic phase washed sequentially with a 0.1 N hydrochloric acid solution (2×50 mL) The organic phase was dried over anhydrous sodium sulfate filtered concentrated in vacuo to a second brown oil After toluene was added removed in vacuo (3×) the resulting brown solid was crystallized from ethyl acetate-hexane

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: A stirred solution of 2-iodoaniline (32.6 g, 149 mmol) and 4-fluorophenylboronic acid (20.8 g, 149 mmol) in tetrahydrofuran (1.5 L) was treated under nitrogen with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (2.20 g, 2.69 mmol) and a 5 N sodium hydroxide solution (60 mL). The reaction mixture was heated at reflux for twelve hours, cooled to room temperature, and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (250 mL) and extracted with a saturated, aqueous, sodium chloride solution (100 mL). The aqueous phase was further extracted with ethyl acetate (2×50 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a brown oil. The brown oil was filtered through a short column of silica gel, and eluted with a mixture of ethyl acetate-hexane (1:4). After evaporation of the solvent in vacuo, a solution of the crude 4′-fluoro-biphenyl-2-ylamine in dichloromethane (75 mL) was treated with pyridine (27.7 mL, 343 mmol), acetic anhydride (15.5 mL, 164 mmol), and 4-(N,N-dimethylamino)pyridine (0.55 g, 4.5 mmol). After stirring for twelve hours at room temperature, the reaction was quenched with a saturated, aqueous, ammonium chloride solution (250 mL). The separated aqueous phase was extracted with dichloromethane (3×75 mL), and the combined organic phase washed sequentially with a 0.1 N hydrochloric acid solution (2×50 mL), and a saturated, aqueous, sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a second brown oil. After toluene was added and removed in vacuo (3×), the resulting brown solid was crystallized from ethyl acetate-hexane to yield a first crop of the desired product (19.0 g). The mother liquor was concentrated and purified by flash column chromatography on silica gel, eluting with ethyl acetate-hexane (1:4), to obtain a second crop (5.0 g). The combined crops afforded the title compound as a homogeneous, colorless, crystalline, solid (24.0 g, 70%). m.p. 123-124° C.; The reaction mixture was heated at reflux for twelve hours the solvent removed in vacuo The residue was dissolved in ethyl acetate (250 mL) extracted with a saturated, aqueous, sodium chloride solution (100 mL) The aqueous phase was further extracted with ethyl acetate (2×50 mL) The combined organic phase was dried over anhydrous magnesium sulfate filtered concentrated in vacuo to a brown oil The brown oil was filtered through a short column of silica gel eluted with a mixture of ethyl acetate-hexane (1:4) After evaporation of the solvent in vacuo the reaction was quenched with a saturated, aqueous, ammonium chloride solution (250 mL) The separated aqueous phase was extracted with dichloromethane (3×75 mL) the combined organic phase washed sequentially with a 0.1 N hydrochloric acid solution (2×50 mL) The organic phase was dried over anhydrous sodium sulfate filtered concentrated in vacuo to a second brown oil After toluene was added removed in vacuo (3×) the resulting brown solid was crystallized from ethyl acetate-hexane

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

実験手順: A stirred solution of 2-iodoaniline (32.6 g, 149 mmol) and 4-fluorophenylboronic acid (20.8 g, 149 mmol) in tetrahydrofuran (1.5 L) was treated under nitrogen with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (2.20 g, 2.69 mmol) and a 5 N sodium hydroxide solution (60 mL). The reaction mixture was heated at reflux for twelve hours, cooled to room temperature, and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (250 mL) and extracted with a saturated, aqueous, sodium chloride solution (100 mL). The aqueous phase was further extracted with ethyl acetate (2×50 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a brown oil. The brown oil was filtered through a short column of silica gel, and eluted with a mixture of ethyl acetate-hexane (1:4). After evaporation of the solvent in vacuo, a solution of the crude 4′-fluoro-biphenyl-2-ylamine in dichloromethane (75 mL) was treated with pyridine (27.7 mL, 343 mmol), acetic anhydride (15.5 mL, 164 mmol), and 4-(N,N-dimethylamino)pyridine (0.55 g, 4.5 mmol). After stirring for twelve hours at room temperature, the reaction was quenched with a saturated, aqueous, ammonium chloride solution (250 mL). The separated aqueous phase was extracted with dichloromethane (3×75 mL), and the combined organic phase washed sequentially with a 0.1 N hydrochloric acid solution (2×50 mL), and a saturated, aqueous, sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a second brown oil. After toluene was added and removed in vacuo (3×), the resulting brown solid was crystallized from ethyl acetate-hexane to yield a first crop of the desired product (19.0 g). The mother liquor was concentrated and purified by flash column chromatography on silica gel, eluting with ethyl acetate-hexane (1:4), to obtain a second crop (5.0 g). The reaction mixture was heated at reflux for twelve hours the solvent removed in vacuo The residue was dissolved in ethyl acetate (250 mL) extracted with a saturated, aqueous, sodium chloride solution (100 mL) The aqueous phase was further extracted with ethyl acetate (2×50 mL) The combined organic phase was dried over anhydrous magnesium sulfate filtered concentrated in vacuo to a brown oil The brown oil was filtered through a short column of silica gel eluted with a mixture of ethyl acetate-hexane (1:4) After evaporation of the solvent in vacuo the reaction was quenched with a saturated, aqueous, ammonium chloride solution (250 mL) The separated aqueous phase was extracted with dichloromethane (3×75 mL) the combined organic phase washed sequentially with a 0.1 N hydrochloric acid solution (2×50 mL) The organic phase was dried over anhydrous sodium sulfate filtered concentrated in vacuo to a second brown oil After toluene was added removed in vacuo (3×) the resulting brown solid was crystallized from ethyl acetate-hexane

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

実験手順: Using the same method as in Example 1-(ii), 4′-fluoro-(1,1′-biphenyl)-2-amine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-[((2-[(4′-fluorobiphenyl-2-yl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 60%).

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

実験手順: To a stirred solution of 2-bromoaniline (1.72 g, 10.0 mmol) in diglyme (30 mL) tetrakis(triphenylphosphine)-palladium(0) (0.13 g, 0.3 mmol) and 2.0 M aqueous sodium carbonate solution (15 mL, 30.0 mmol) were added. In a separate flask, 4-fluorophenylboronic acid (2.23 g 16.0 mmol) was dissolved in ethanol (8 mL) and the mixture containing 2-bromoaniline was added to this boronic acid solution. The obtained brown reaction mixture was heated at 80° C. for 6 hours, then cooled, diluted with ethyl acetate and washed with saturated ammonium chloride solution. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and n-hexane:ethyl-acetate=2:1 as eluent to yield after recrystallization from ethanol 1.8 g (60%) of the title compound as white crystals. cooled washed with saturated ammonium chloride solution The organic layer was dried over sodium sulfate filtered concentrated The residue was purified by flash column chromatography ethyl-acetate=2:1 as eluent to yield after recrystallization from ethanol 1.8 g (60%) of the title compound as white crystals

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

実験手順: A mixture of 2-amino-4'-fluorobiphenyl (1.5 g) and benzoylisothiocyanate (1.3 g) in dichloromethane (20 ml) was heated under reflux for 6 hours to yield N-benzoyl-N'-(4'-fluoro-2-biphenylyl)thiourea as a colourless solid (m.p. 123°-124° C.). was heated under reflux for 6 hours

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

実験手順: A stirred solution of 2-iodoaniline (32.6 g, 149 mmol) and 4-fluorophenylboronic acid (20.8 g, 149 mmol) in tetrahydrofuran (1.5 L) was treated under nitrogen with [1,1 ′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (2.20 g, 2.69 mmol) and a 5 N sodium hydroxide solution (60 mL). The reaction mixture was heated at reflux for twelve hours, cooled to room temperature, and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (250 mL) and extracted with a saturated, aqueous, sodium chloride solution (100 mL). The aqueous phase was further extracted with ethyl acetate (2×50 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a brown oil. The brown oil was filtered through a short column of silica gel, and eluted with a mixture of ethyl acetate-hexane (1:4). After evaporation of the solvent in vacuo, a solution of the crude 4′-fluoro-biphenyl-2-ylamine in dichloromethane (75 mL) was treated with pyridine (27.7 mL, 343 mmol), acetic anhydride (15.5 mL, 164 mmol), and 4-(N,N-dimethylamino)pyridine (0.55 g, 4.5 mmol). After stirring for twelve hours at room temperature, the reaction was quenched with a saturated, aqueous, ammonium. chloride solution (250 mL). The separated aqueous phase was extracted with dichloromethane (3×75 mL), and the combined organic phase washed sequentially with a 0.1 N hydrochloric acid solution (2×50 mL), and a saturated, aqueous, sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a second brown oil. After toluene was added and removed in vacuo (3×), the resulting brown solid was crystallized from ethyl acetate-hexane to yield a first crop of the desired product (19.0 g). The mother liquor was concentrated and purified by flash column chromatography on silica gel, eluting with ethyl acetate-hexane (1:4), to obtain a second crop (5.0 g). The combined crops afforded the title compound as a homogeneous, colorless, crystalline, solid (24.0 g, 70%). m.p. 123-124° C.; MS [(+ESI), m/z]: 230 [M+H]+; The reaction mixture was heated at reflux for twelve hours the solvent removed in vacuo The residue was dissolved in ethyl acetate (250 mL) extracted with a saturated, aqueous, sodium chloride solution (100 mL) The aqueous phase was further extracted with ethyl acetate (2×50 mL) The combined organic phase was dried over anhydrous magnesium sulfate filtered concentrated in vacuo to a brown oil The brown oil was filtered through a short column of silica gel eluted with a mixture of ethyl acetate-hexane (1:4) After evaporation of the solvent in vacuo the reaction was quenched with a saturated, aqueous, ammonium The separated aqueous phase was extracted with dichloromethane (3×75 mL) the combined organic phase washed sequentially with a 0.1 N hydrochloric acid solution (2×50 mL) The organic phase was dried over anhydrous sodium sulfate filtered concentrated in vacuo to a second brown oil After toluene was added removed in vacuo (3×) the resulting brown solid was crystallized from ethyl acetate-hexane