3-bromo-2,4-difluoroaniline

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

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

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

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

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

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

Procedure: A mixture of 3-bromo-2,4-difluorophenylamine (prepared according to the procedure described in EP-A-0184384) (12.5 g, 60 mmol), diethyl(3-pyridyl)borane (10.6 g, 72 mmol) and potassium carbonate (16.6 g, 120 mmol) in tetrahydrofuran (150 mL) and water (50 mL) was degassed with nitrogen for 15 min. To this mixture was added tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.8 mmol) and the reaction was heated at reflux for 4 days. The mixture was cooled to ambient temperature and the majority of the tetrahydrofuran removed on a rotary evaporator. The residue was diluted with water (250 mL), extracted with ethyl acetate (300 mL), the organics were washed with water, brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with isohexane (containing 1% triethylamine) on a gradient of ethyl acetate (10-50%) afforded 2,4-difluoro-3-(pyridin-3-yl)phenylamine as a cream-coloured solid (5.8 g, 7%): δH (400 MHz, CDCl3) 3.69 (2H, br), 6.72-6.88 (2H, m), 7.39 (1H, dd, J 8 and 5), 7.80 (1H, d, J 8), 8.62 (1H, dd, J 5 and 1), 8.72 (1H, s). prepared was degassed with nitrogen for 15 min the reaction was heated at reflux for 4 days the majority of the tetrahydrofuran removed on a rotary evaporator The residue was diluted with water (250 mL) extracted with ethyl acetate (300 mL) the organics were washed with water, brine dried over anhydrous magnesium sulfate filtered and pre-adsorbed onto silica Purification by chromatography on silica gel eluting with isohexane (containing 1% triethylamine) on a gradient of ethyl acetate (10-50%)

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

Procedure: A mixture of 3-bromo-2,4-difluorophenylamine (from Example 2, step b) (12.5 g, 60 mmol), diethyl(3-pyridyl)borane (10.6 g, 72 mmol) and potassium carbonate (16.6 g, 120 mmol) in tetrahydrofuran (150 ml) and water (50 ml) was degassed with nitrogen for 15 min. To this mixture was added tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.8 mmol) and the reaction was heated at reflux for 4 days. The mixture was cooled to ambient temperature and the majority of the tetrahydrofuran removed on a rotary evaporator. The residue was diluted with water (250 ml), extracted with ethyl acetate (300 ml), the organics were washed with water, brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography [silica gel, 10–50% EtOAc/isohexane (containing 1% triethylamine)] afforded 5.8 g (47%) of the title compound as a cream-coloured solid: 1H NMR (400 MHz, CDCl3) δ 3.69 (2H, br s), 6.72–6.88 (2H, m), 7.39 (1H, dd, J 8, 5), 7.80 (1H, d, J 8), 8.62 (1H, dd, J 5, 1), 8.72 (1H, s). was degassed with nitrogen for 15 min the reaction was heated at reflux for 4 days the majority of the tetrahydrofuran removed on a rotary evaporator The residue was diluted with water (250 ml) extracted with ethyl acetate (300 ml) the organics were washed with water, brine dried over anhydrous magnesium sulfate filtered and pre-adsorbed onto silica Purification by chromatography [silica gel, 10–50% EtOAc/isohexane (containing 1% triethylamine)]

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

Procedure: A mixture of 3-bromo-2,4-difluorophenylamine (from Example 2, step b) (12.5 g, 60 mmol), diethyl(3-pyridyl)borane (10.6 g, 72 mmol) and potassium carbonate (16.6 g, 120 mmol) in tetrahydrofuran (150 ml) and water (50 ml) was degassed with nitrogen for 15 min. To this mixture was added tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.8 mmol) and the reaction was heated at reflux for 4 days. The mixture was cooled to ambient temperature and the majority of the tetrahydrofuran removed on a rotary evaporator. The residue was diluted with water (250 ml), extracted with ethyl acetate (300 ml), the organics were washed with water, brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography [silica gel, 10–50% EtOAc/isohexane (containing 1% triethylamine)] afforded 5.8 g (47%) of the title compound as a cream-coloured solid: 1H NMR (400 MHz, CDCl3) δ 3.69 (2H, br s), 6.72–6.88 (2H, m), 7.39 (1H, dd, J 8, 5), 7.80 (1H, d, J 8), 8.62 (1H, dd, J 5, 1), 8.72 (1H, s). was degassed with nitrogen for 15 min the reaction was heated at reflux for 4 days the majority of the tetrahydrofuran removed on a rotary evaporator The residue was diluted with water (250 ml) extracted with ethyl acetate (300 ml) the organics were washed with water, brine dried over anhydrous magnesium sulfate filtered and pre-adsorbed onto silica Purification by chromatography [silica gel, 10–50% EtOAc/isohexane (containing 1% triethylamine)]

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-bromo-2,4-difluorophenylamine (from Example 2, step b) (5.2 g, 25 mmol) and 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (7.10 g, 28.8 mmol) in tetrahydrofuran (95 ml) and water (5 ml) was treated with potassium fluoride (4.8 g, 82.5 mmol) and this mixture was degassed with nitrogen for 10 min before adding tris(dibenzylideneacetone)dipalladium(0) (460 mg, 0.5 mmol) and tri-tert-butylphosphine (2.5 ml of a 0.2 M solution in 1,4-dioxane, 0.5 mmol). The reaction was then heated at 50° C. for 2 h then cooled to ambient temperature. The mixture was poured into ice-cold 0.5 N sodium hydroxide (750 ml), stirred for 10 min and the solid collected by filtration. This was triturated with water and dried to afford 3′-amino-4,2′,6′-trifluorobiphenyl-2-carbonitrile as a grey powder (6.6 g), which was used without further purification: 1H NMR (360 MHz, CDCl3) δ 3.74 (2H, br s), 6.79–6.89 (2H, m), 7.36–7.42 (1H, m), 7.45–7.51 (2H, m). this mixture was degassed with nitrogen for 10 min then cooled to ambient temperature the solid collected by filtration This was triturated with water dried

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-bromo-2,4-difluorophenylamine (from Example 2, step b) (5.2 g, 25 mmol) and 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (7.10 g, 28.8 mmol) in tetrahydrofuran (95 ml) and water (5 ml) was treated with potassium fluoride (4.8 g, 82.5 mmol) and this mixture was degassed with nitrogen for 10 min before adding tris(dibenzylideneacetone)dipalladium(0) (460 mg, 0.5 mmol) and tri-tert-butylphosphine (2.5 ml of a 0.2 M solution in 1,4-dioxane, 0.5 mmol). The reaction was then heated at 50° C. for 2 h then cooled to ambient temperature. The mixture was poured into ice-cold 0.5 N sodium hydroxide (750 ml), stirred for 10 min and the solid collected by filtration. This was triturated with water and dried to afford 3′-amino-4,2′,6′-trifluorobiphenyl-2-carbonitrile as a grey powder (6.6 g), which was used without further purification: 1H NMR (360 MHz, CDCl3) δ 3.74 (2H, br s), 6.79–6.89 (2H, m), 7.36–7.42 (1H, m), 7.45–7.51 (2H, m). this mixture was degassed with nitrogen for 10 min then cooled to ambient temperature the solid collected by filtration This was triturated with water dried

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-bromo-2,4-difluorophenylamine (0.6451 g, 3.10 mmol) and 3-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (0.915 g, 3.70 mmol) and potassium fluoride (0.5953 g, 10.2 mmol) in tetrahydrofuran (8 ml) was degassed with nitrogen for 15 min before adding tris(dibenzylideneacetone)dipalladium(0) (56.9 mg, 0.0621 mmol) and tri-tert-butylphosphine (1.24 ml of a 0.1 M solution in 1,4-dioxane, 0.124 mmol). The mixture was degassed for a further 5 min, then heated at 50° C. for 18 h under nitrogen. After cooling to ambient temperature, the mixture was partitioned between water (50 ml) and ethyl acetate (40 ml). The organic layer was washed with saturated aqueous NaCl (20 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography (silica gel, 30% EtOAc/isohexane) to afford 0.5180 g (67%) of the title compound as a yellow solid: 1H NMR (360 MHz, CDCl3) δ 3.70 (2H, br s), 6.84–6.92 (2H, m), 7.44 (1H, t, J 8.4), 7.53 (1H, td, J 8.2, 5.1), 7.61 (1H, d, J 7.3). was degassed with nitrogen for 15 min The mixture was degassed for a further 5 min After cooling to ambient temperature the mixture was partitioned between water (50 ml) and ethyl acetate (40 ml) The organic layer was washed with saturated aqueous NaCl (20 ml) dried (Na2SO4) evaporated in vacuo The residue was purified by chromatography (silica gel, 30% EtOAc/isohexane)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-bromo-1,3-difluoro-4-nitrobenzene (30 g, 130 mmol) and tin(II) chloride dihydrate in 36% hydrochloric acid (150 ml) was heated to 40° C. Diethyl ether (20 ml) was slowly added to bring about solution. Once in solution the reaction proceeded rapidly and the ether boiled away. After heating at 60° C. for 1 h the reaction was cooled and then poured onto ice-water (1.5 l). The solution was made basic (pH 13) with 30% aq. sodium hydroxide keeping the internal temperature below 20° C. The resulting grey slurry was swirled with chloroform (2×500 ml), the organic extracts were combined, washed with water, dried over an-hydrous magnesium sulfate containing 2 g decolourising charcoal, filtered and evaporated to dryness. Trituration with isohexane afforded 23 g (83%) of the title compound as a buff-coloured solid: 1H NMR (360 MHz, CDCl3) δ 3.51 (2H, br), 6.65–6.70 (1H, mn), 6.75-6-80 (1H, m). After heating at 60° C. for 1 h the reaction was cooled poured onto ice-water (1.5 l) the internal temperature below 20° C washed with water dried over an-hydrous magnesium sulfate containing 2 g filtered evaporated to dryness