(4-bromo-2,6-difluorophenyl)methanol

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: To a solution of 4-bromo-2,6-difluorobenzylalcohol (0.200 g, 0.9 mmol) in DCM (4 ml) and DMSO (0.440 ml) was added triethylamine (1 ml, 0.72 mmol) and sulfur trioxide pyridine complex (0.570 g, 3.6 mmol) and the resulting solution was stirred at room temperature for 3 hours. The solution was diluted with Et2O and washed with 0.5M aqueous HCl, 1M sodium bicarbonate solution and brine. The organic phase was dried over MgSO4 and the solvent removed in vacuo to afford 4-bromo-2,6-difluorobenzaldehyde (0.166 g, 0.75 mmol, 84%) as a white solid. 1H NMR (CDCl3) δ 7.22 (2H, d), 10.29 (1H, br. s). LCMS (2) Rt: 2.74 min. washed with 0.5M aqueous HCl, 1M sodium bicarbonate solution and brine The organic phase was dried over MgSO4 the solvent removed in vacuo

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

実験手順: To a solution of (4-bromo-2,6-difluorophenyl)methanol (2 g, 8.97 mmol) in DCM (80 mL) was added tribromophosphine (2.91 g, 10.76 mmol) at 0° C. The resulting mixture was stirred at rt. After LCMS analysis showed the starting material had disappeared, the mixture was washed with aqueous NaHCO3 (40 mL) and brine (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=5/1) to yield a colorless oil of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (1.6 g, 5.48 mmol, 61.2% yield): 1H NMR (400 MHz, CD3OD) δ 7.12 (d, J=6.8 Hz, 2H), 4.47 (s, 2H). the mixture was washed with aqueous NaHCO3 (40 mL) and brine (30 mL) The organic layer was dried over Na2SO4 filtered concentrated The crude material was purified by silica column chromatography (PE/EA=5/1)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-bromo-2,6-difluorobenzoic acid (5 g, 21.10 mmol) in THF (100 mL) was added BH3.DMS (20.03 mL, 211 mmol) dropwise at rt. The resulting mixture was stirred at 60° C. for 16 h. After LCMS analysis showed the starting material had disappeared, the mixture was quenched by MeOH. The solvent was removed in vacuo to yield a white solid of (4-bromo-2,6-difluorophenyl)methanol (4.5 g, 20.02 mmol, 95.2% yield), which was used in the next step without further purification: ES-LCMS m/z 222.1 (M+1). dropwise at rt the mixture was quenched by MeOH The solvent was removed in vacuo

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-bromo-2,6-difluorobenzoic acid (5 g, 21.10 mmol) in THF (100 mL) was added BH3.DMS (20.03 mL, 211 mmol) dropwise at rt. The resulting mixture was stirred at 60° C. for 16 h. After LCMS analysis showed the starting material had disappeared, the mixture was quenched by MeOH. The solvent was removed in vacuo to yield a white solid of (4-bromo-2,6-difluorophenyl)methanol (4.5 g, 20.02 mmol, 95.2% yield), which was used in the next step without further purification: ES-LCMS m/z 222.1 (M+1). dropwise at rt the mixture was quenched by MeOH The solvent was removed in vacuo

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-bromo-2,6-difluorobenzyl alcohol (1.00 g, 4.48 mmol) in dry CH2Cl2 (20 mL) was treated at 0° C. with Et3N (0.81 mL, 5.79 mmol) followed by DMAP (55 mg, 0.45 mmol) and Ms-Cl (0.37 mL, 4.71 mmol). After stirring at 0° C. for 0.5 h and at rt for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-bromo-2,6-difluorophenyl)methyl methanesulfonate as a yellow oil. This material was dissolved in dry DMF (6 mL) and treated with NaN3 (93 mg, 1.41 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(azidomethyl)-4-bromo-2,6-difluorobenzene as a yellow oil. LC-MS-conditions 01: tR=1.00 min. the reaction was quenched with water (10 mL) layer was dried over MgSO4 filtered the solvents were removed under reduced pressure

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-hydroxymethyl-1,3-difluoro-benzene (0.89 g, 4.0 mmol) and 30 wt % of hydrogen bromide in acetic acid was stirred at room temperature for 90 minutes before it was poured into 80 ml of water. The mixture was extracted with pentane (3×50 ml) and the combined organic layers were washed with water (3×20 ml), dried over MgSO4 and concentrated at low pressure to afford the desired product (10.0 g, 98% yield). 1H NMR (CDCl3) δ: 4.47 (s, 2H), 7.09–7.10 (m, 1H), 7.12–7.13 (m, 1H). The mixture was extracted with pentane (3×50 ml) the combined organic layers were washed with water (3×20 ml) dried over MgSO4 concentrated at low pressure

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-hydroxymethyl-1,3-difluoro-benzene (0.89 g, 4.0 mmol) and 30 wt % of hydrogen bromide in acetic acid was stirred at room temperature for 90 minutes before it was poured into 80 ml of water. The mixture was extracted with pentane (3×50 ml) and the combined organic layers were washed with water (3×20 ml), dried over MgSO4 and concentrated at low pressure to afford the desired product (10.0 g, 98% yield). 1H NMR (CDCl3) δ: 4.47 (s, 2H), 7.09–7.10 (m, 1H), 7.12–7.13 (m, 1H). The mixture was extracted with pentane (3×50 ml) the combined organic layers were washed with water (3×20 ml) dried over MgSO4 concentrated at low pressure

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

実験手順: To a solution of 4-bromo-2,6-difluorobenzylalcohol (0.200 g, 0.9 mmol) in DCM (4 ml) and DMSO (0.440 ml) was added triethylamine (1 ml, 0.72 mmol) and sulfur trioxide pyridine complex (0.570 g, 3.6 mmol) and the resulting solution was stirred at room temperature for 3 hours. The solution was diluted with Et2O and washed with 0.5M aqueous HCl, 1M sodium bicarbonate solution and brine. The organic phase was dried over MgSO4 and the solvent removed in vacuo to afford 4-bromo-2,6-difluorobenzaldehyde (0.166 g, 0.75 mmol, 84%) as a white solid. 1H NMR (CDCl3) δ 7.22 (2H, d), 10.29 (1H, br. s). washed with 0.5M aqueous HCl, 1M sodium bicarbonate solution and brine The organic phase was dried over MgSO4 the solvent removed in vacuo

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

実験手順: To a solution of (4-bromo-2,6-difluorophenyl)methanol (2 g, 8.97 mmol) in DCM (80 mL) was added tribromophosphine (2.91 g, 10.76 mmol) at 0° C. The resulting mixture was stirred at rt. After LCMS analysis showed the starting material had disappeared, the mixture was washed with aq NaHCO3 (40 mL) and brine (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=5/1) to yield a colorless oil of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (1.6 g, 5.48 mmol, 61.2% yield): 1H NMR (400 MHz, CD3OD) δ 7.12 (d, J=6.8 Hz, 2H), 4.47 (s, 2H). the mixture was washed with aq NaHCO3 (40 mL) and brine (30 mL) The organic layer was dried over Na2SO4 filtered concentrated The crude material was purified by silica column chromatography (PE/EA=5/1)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-bromo-2,6-difluorobenzoic acid (5 g, 21.10 mmol) in THF (100 mL) was added BH3.DMS (20.03 mL, 211 mmol) dropwise at rt. The resulting mixture was stirred at 60° C. for 16 h. After LCMS analysis showed the starting material had disappeared, the mixture was quenched by MeOH. The solvent was removed in vacuo to yield a white solid of (4-bromo-2,6-difluorophenyl)methanol (4.5 g, 20.02 mmol, 95.2% yield), which was used in the next step without further purification: ES-LCMS m/z 222.1 (M+1). dropwise at rt the mixture was quenched by MeOH The solvent was removed in vacuo