(5-bromo-2-fluorophenyl)boronic acid

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2,4-dibromofluorobenzene (12.7 g, containing 30% 3,4-dibromofluorobenzene) in dry tetrahydrofuran (THF) (10 ml) is added over 5 min to a stirred suspension of magnesium turnings (1.15 g) in dry THF (50 ml) under an atmosphere of nitrogen and cooled in a water bath. After 1 hour, when all the magnesium has reacted, this reagent is added over 20 min to a stirred solution of trimethoxyborane (7 ml) in dry diethyl ether (80 ml) under an atmosphere of nitrogen and cooled at -78° C. The mixture is stirred at -78° C. for a further 15 min. and glacial acetic acid (6 ml) added followed by water (50 ml). The mixture is warmed to room temperature, extracted with diethyl ether (x3), washed with water, dried and the solvent evaporated under reduced pressure. The residue is stirred with carbon tetrachloride (30 ml) and then cooled at 0° C. The crystals of dihydroxy-(5-bromo-2-fluorophenyl)-borane are filtered off and washed with a little carbon tetrachloride. Yield 2.8 g m.pt. 173°-174° C. cooled in a water bath The mixture is warmed to room temperature extracted with diethyl ether (x3) washed with water dried the solvent evaporated under reduced pressure The residue is stirred with carbon tetrachloride (30 ml) cooled at 0° C The crystals of dihydroxy-(5-bromo-2-fluorophenyl)-borane are filtered off washed with a little carbon tetrachloride

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2,4-dibromofluorobenzene (12.7 g, containing 30% 3,4-dibromofluorobenzene) in dry tetrahydrofuran (THF) (10 ml) is added over 5 min to a stirred suspension of magnesium turnings (1.15 g) in dry THF (50 ml) under an atmosphere of nitrogen and cooled in a water bath. After 1 hour, when all the magnesium has reacted, this reagent is added over 20 min to a stirred solution of trimethoxyborane (7 ml) in dry diethyl ether (80 ml) under an atmosphere of nitrogen and cooled at -78° C. The mixture is stirred at -78° C. for a further 15 min. and glacial acetic acid (6 ml) added followed by water (50 ml). The mixture is warmed to room temperature, extracted with diethyl ether (x3), washed with water, dried and the solvent evaporated under reduced pressure. The residue is stirred with carbon tetrachloride (30 ml) and then cooled at 0° C. The crystals of dihydroxy-(5-bromo-2-fluorophenyl)-borane are filtered off and washed with a little carbon tetrachloride. Yield 2.8 g m.pt. 173°-174° C. cooled in a water bath The mixture is warmed to room temperature extracted with diethyl ether (x3) washed with water dried the solvent evaporated under reduced pressure The residue is stirred with carbon tetrachloride (30 ml) cooled at 0° C The crystals of dihydroxy-(5-bromo-2-fluorophenyl)-borane are filtered off washed with a little carbon tetrachloride

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 6-Bromo-1,2,4-triazin-3-amine (9.1 g, 40.8 mmol), 5-bromo-2-fluorophenylboronic acid (98.9 g, 40.8 mmol), (dppf)PdCl2 (3.0 g, 4.0 mmol), nitrogen-sparged dioxane (81.6 mL), and aq. 2 N K2CO3 (17 mL) were combined and heated in a round bottom flask at 90° C. for 4 h. The hot mixture was filtered through a pad of celite and diluted with EtOAc and washed with water. Concentration followed by trituration with DCM afforded a tan solid (4.5 g), m/z=269.0 [M+H]. The hot mixture was filtered through a pad of celite diluted with EtOAc washed with water Concentration

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 6-Bromo-1,2,4-triazin-3-amine (9.1 g, 40.8 mmol), 5-bromo-2-fluorophenylboronic acid (98.9 g, 40.8 mmol), (dppf)PdCl2 (3.0 g, 4.0 mmol), nitrogen-sparged dioxane (81.6 mL), and aq. 2 N K2CO3 (17 mL) were combined and heated in a round bottom flask at 90° C. for 4 h. The hot mixture was filtered through a pad of celite and diluted with EtOAc and washed with water. Concentration followed by trituration with DCM afforded a tan solid (4.5 g), m/z=269.0 [M+H]. The hot mixture was filtered through a pad of celite diluted with EtOAc washed with water Concentration

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (500 mg, 0.837 mmol) was mixed with (5-bromo-2-fluorophenyl)boronic acid (211 mg, 0.963 mmol), toluene (5 mL), ethanol (278 μL) and sodium carbonate aqueous solution (2M, 0.89 mL, 1.78 mmol). The resulting mixture was stirred at 20° C. for 30 min followed by addition of tetrakis (triphenylphosphine) palladium(0) (43.5 mg, 0.0376 mmol, 4.5 mol %). The reaction mixture was heated in a 90° C. oil bath for 40 hours to complete the reaction. The resulting crude mixture was purified by flash chromatography (SiO2, Biotage 40+M cartridge). The column was eluted by an Ethyl acetate/hexanes mixture. Related fractions were pooled and concentrated in vacuo to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-bromo-2′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=645.02; found=645.94 (M+1)+. The reaction mixture was heated in a 90° C. oil bath for 40 hours the reaction The resulting crude mixture was purified by flash chromatography (SiO2, Biotage 40+M cartridge) The column was eluted by an Ethyl acetate/hexanes mixture concentrated in vacuo

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2,4-dibromofluorobenzene (12.7 g, containing 30% 3,4-dibromofluorobenzene) in dry tetrahydrofuran (THF) (10 ml) is added over 5 min to a stirred suspension of magnesium turnings (1.15 g) in dry THF (50 ml) under an atmosphere of nitrogen and cooled in a water bath. After 1 hour, when all the magnesium has reacted, this reagent is added over 20 min to a stirred solution of trimethoxyborane (7 ml) in dry diethyl ether (80 ml) under an atmosphere of nitrogen and cooled at -78° C. The mixture is stirred at -78° C. for a further 15 min. and glacial acetic acid (6 ml) added followed by water (50 ml). The mixture is warmed to room temperature, extracted with diethyl ether (×3), washed with water, dried and the solvent evaporated under reduced pressure. The residue is stirred with carbon tetrachloride (30 ml) and then cooled at 0° C. The crystals of dihydroxy-(5-bromo-2-fluorophenyl)-borane are filtered off and washed with a little carbon tetrachloride. Yield 2.8 g m.p.t. 173°-174° C. cooled in a water bath The mixture is warmed to room temperature extracted with diethyl ether (×3) washed with water dried the solvent evaporated under reduced pressure The residue is stirred with carbon tetrachloride (30 ml) cooled at 0° C The crystals of dihydroxy-(5-bromo-2-fluorophenyl)-borane are filtered off washed with a little carbon tetrachloride 173°-174° C.

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A cooled (−20° C.) solution of 2,2,6,6-tetramethylpiperidine (28 ml, 165 mmol) in tetrahydrofuran (400 ml) was treated with n-butyllithium (63 ml of a 2.5M solution in hexanes, 157.5 mmol). This mixture was then cooled to −78° C. 1-Bromo-4-fluorobenzene (16.5 ml, 150 mmol) was then added neat and dropwise over 10 min and stirring at −78° C. was continued for 3 h. Triisopropyl borate (40 ml, 172.5 mmol) was then added and stirring at −78° C. continued for 30 min before removing the cooling bath. When the internal temperature of the reaction reached −40° C., 5N hydrochloric acid was added (75 ml) and the mixture was stirred to ambient temperature. After stirring at ambient temp for 1 h the majority of the tetrahydrofuran was removed and the mixture partitioned between ether (500 ml) and 1N hydrochloric acid (500 ml). The organics were then extracted with 2N sodium hydroxide (400 ml) and the organics were discarded. The aqueous was cooled in an ice-water bath and 5N hydrochloric acid (150 ml) was added dropwise over 15 min. The resulting white solid was collected and dried under vacuum to afford 5-bromo-2-fluorobenzeneboronic acid (25 g, 76%). stirring at −78° C. continued for 30 min before removing the cooling bath reached −40° C. 5N hydrochloric acid was added (75 ml) the mixture was stirred to ambient temperature After stirring at ambient temp for 1 h the majority of the tetrahydrofuran was removed the mixture partitioned between ether (500 ml) and 1N hydrochloric acid (500 ml) The organics were then extracted with 2N sodium hydroxide (400 ml) The aqueous was cooled in an ice-water bath 5N hydrochloric acid (150 ml) was added dropwise over 15 min The resulting white solid was collected dried under vacuum

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of lithium diisopropylamide (165 mL of a 2.0 M solution in tetrahydrofuran, 0.33 mol) in tetrahydrofuran (600 mL) at −70° C. is treated with 1-bromo-4-fluorobenzene (33.0 mL, 0.30 mol), stirred at −70° C. for 90 minutes and added to a solution of trimethyl borate (41.0 mL, 0.36 mol) in diethyl ether (300 mL) at −70° C. The resulting solution is stirred at −70° C. for 15 minutes, warmed to 15° C. over 90 minutes, treated with acetic acid (51.5 mL, 0.9 mol) and water (375 mL), and stirred at room temperature for 30 minutes. The organic layer is separated and the aqueous layer is extracted with ether. The organic extracts are combined with the organic layer and the resulting solution is washed sequentially with 10% hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as an off-white solid (65 g, 99% yield). The resulting solution is stirred at −70° C. for 15 minutes warmed to 15° C. over 90 minutes stirred at room temperature for 30 minutes The organic layer is separated the aqueous layer is extracted with ether the resulting solution is washed sequentially with 10% hydrochloric acid and brine dried over anhydrous magnesium sulfate concentrated in vacuo

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

実験手順: A solution of 5-bromo-2-fluorobenzeneboronic acid (25 g, 114 mmol) in tetrahydrofuran was treated with hydrogen peroxide (7.8 ml of a 35 wt % solution in water) then with sodium hydroxide (1.4 ml of a 4N solution in water). A mild exotherm caused the internal temperature to reach 40° C. This mixture was left to stir at ambient temperature for 14 h then treated with manganese dioxide (200 mg) and stirring was continued for 90 min before filtering the reaction (GF/A filter paper). The filtrate was concentrated on a rotary evaporator and the residue partitioned between ether (400 ml) and water. The organics were washed with more water and brine, and dried over anhydrous magnesium sulphate. Filtration and evaporation to dryness afforded 5-bromo-2-fluorophenol (19.7 g, 90%) as a colourless liquid: δH (400 MHz, d6-DMSO) 6.93-6.97 (1H, m), 7.09-7.14 (2H, m), 10.36 (1H, br). to reach 40° C This mixture was left stirring was continued for 90 min before filtering the reaction (GF/A filter paper) The filtrate was concentrated on a rotary evaporator the residue partitioned between ether (400 ml) and water The organics were washed with more water and brine dried over anhydrous magnesium sulphate Filtration and evaporation to dryness

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A cooled (−20° C.) solution of 2,2,6,6-tetramethylpiperidine (28 ml, 165 mmol) in tetrahydrofuran (400 ml) was treated with m-butyllithium (63 ml of a 2.5M solution in hexanes, 157.5 mmol). This mixture was then cooled to −78° C. 1-Bromo-4-fluorobenzene (16.5 ml, 150 mmol) was then added neat and dropwise over 10 min and stirring at −78° C. was continued for 3 h. Triisopropyl borate (40 ml, 172.5 mmol) was then added and stirring at −78° C. continued for 30 min before removing the cooling bath. When the internal temperature of the reaction reached −4° C., 5N hydrochloric acid (75 ml) was added and the mixture was stirred to ambient temperature. After stirring at ambient temp for 1 h the majority of the tetrahydrofuran was removed and the mixture partitioned between ether (500 ml) and 1N hydrochloric acid (500 ml). The organics were then extracted with 2N sodium hydroxide (400 ml) and the organics were discarded. The aqueous was cooled in an ice-water bath and 5N hydrochloric acid (150 ml) was added dropwise over 15 min. The resulting white solid was collected and dried under vacuum to afford 5-bromo-2-fluorobenzeneboronic acid (25 g, 76%). stirring at −78° C. continued for 30 min before removing the cooling bath reached −4° C. 5N hydrochloric acid (75 ml) was added the mixture was stirred to ambient temperature After stirring at ambient temp for 1 h the majority of the tetrahydrofuran was removed the mixture partitioned between ether (500 ml) and 1N hydrochloric acid (500 ml) The organics were then extracted with 2N sodium hydroxide (400 ml) The aqueous was cooled in an ice-water bath 5N hydrochloric acid (150 ml) was added dropwise over 15 min The resulting white solid was collected dried under vacuum

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2,4-dibromofluorobenzene (12.7 g, containing 30% 3,4-dibromofluorobenzene) in dry tetrahydrofuran (THF) (10 ml) is added over 5 min to a stirred suspension of magnesium turnings (1.15 g) in dry THF (50 ml) under an atmosphere of nitrogen and cooled in a water bath. After 1 hour, when all the magnesium has reacted, this reagent is added over 20 min to a stirred solution of trimethoxyborane (7 ml) in dry diethyl ether (80 ml) under an atmosphere of nitrogen and cooled at -78° C. The mixture is stirred at -78° C. for a further 15 min. and glacial acetic acid (6 ml) added followed by water (50 ml). The mixture is warmed to room temperature, extracted with diethyl ether (x3), washed with water, dried and the solvent evaporated under reduced pressure. The residue is stirred with carbon tetrachloride (30 ml) and then cooled at 0° C. The crystals of dihydroxy-(5-bromo-2-fluorophenyl)-borane are filtered off and washed with a little carbon tetrachloride. Yield 2.8 g m.pt. 173°-174° C. cooled in a water bath The mixture is warmed to room temperature extracted with diethyl ether (x3) washed with water dried the solvent evaporated under reduced pressure The residue is stirred with carbon tetrachloride (30 ml) cooled at 0° C The crystals of dihydroxy-(5-bromo-2-fluorophenyl)-borane are filtered off washed with a little carbon tetrachloride