1-溴-2-氟-4-甲氧基苯

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-bromo-3-fluoroanisole (10 g, 48.7 mmol, Matrix) in tetrahydrofuran (100 mL) at −78° C. was added lithium diisopropyl amine (32.5 mL, 1.8 M in THF, 58.4 mmol) dropwise during a period of 15 min. The mixture was stirred at −78° C. for another 20 mins. Then N,N-dimethyl-formamide (4.53 mL, 58.4 mmol) was added in one portion. The mixture was stirred at −78° C. for 10 min, then quenched with acetic acid (12 g, 194 mmol) and followed by the addition of water (61 mL). The mixture was partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:4) to give 3-bromo-2-fluoro-6-methoxy-benzaldehyde as a yellow solid (Yield: 10 g, 89%) The mixture was stirred at −78° C. for 10 min The mixture was partitioned between ethyl acetate and water The organic layer was separated concentrated The residue was purified by chromatography (EtOAc:hexanes=1:4)

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-bromo-3-fluoroanisole (10 g, 48.7 mmol, Matrix) in tetrahydrofuran (100 mL) at −78° C. was added lithium diisopropyl amine (32.5 mL, 1.8 M in THF, 58.4 mmol) dropwise during a period of 15 min. The mixture was stirred at −78° C. for another 20 mins. Then N,N-dimethyl-formamide (4.53 mL, 58.4 mmol) was added in one portion. The mixture was stirred at −78° C. for 10 min, then quenched with acetic acid (12 g, 194 mmol) and followed by the addition of water (61 mL). The mixture was partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:4) to give 3-bromo-2-fluoro-6-methoxy-benzaldehyde as a yellow solid (Yield: 10 g, 89%) The mixture was stirred at −78° C. for 10 min The mixture was partitioned between ethyl acetate and water The organic layer was separated concentrated The residue was purified by chromatography (EtOAc:hexanes=1:4)

反应条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a nitrogen atmosphere, metal magnesium (3.9 g) was suspended in THF (5 mL), a solution prepared by dissolving 4-bromo-3-fluoroanisole (30 g) in THF (150 mL) was added at a rate at which the solution was gently refluxed, and stirring was performed at 40° C. for one hour. Subsequently, the reaction liquid was cooled to 5° C. After a solution prepared by dissolving trimethyl borate (19.8 g) in THF (60 mL) was added thereto, stirring was performed at room temperature for one hour. Toluene (150 mL) and 10% hydrochloric acid (100 mL) were added thereto and the mixture was separated. Toluene (100 mL) was added to the resulting aqueous layer and extraction was performed. The obtained organic layers were mixed and washed with a saturated saline solution (100 mL). Anhydrous sodium sulfate was added to perform drying, and the organic solvent was distilled off under reduced pressure. Thus, a crude 2-fluoro-4-methoxyphenylboric acid (26.3 g) was obtained. (3-2) In a nitrogen atmosphere, 5,6,7-trifluoro-2-naphthol (30 g) and pyridine (15.6 g) were dissolved in dichloromethane (150 mL) and cooled to 5° C., and a solution prepared by dissolving trifluoromethanesulfonic acid anhydride (47.0 g) in dichloromethane (150 mL) was added thereto. After stirring was performed at room temperature for one hour, water (200 mL) was added and the mixture was separated. The resulting organic layer was washed with 10% hydrochloric acid (150 mL), an aqueous saturated sodium hydrogen carbonate solution (150 mL), and a saturated saline solution (150 mL). Anhydrous sodium sulfate was added to perform drying, and the organic solvent was distilled off under reduced pressure. Purification was performed by silica gel column chromatography to obtain 5,6,7-trifluoro-2-naphthyl trifluoromethanesulfonate (49.4 g). (3-3) In a nitrogen atmosphere, the 5,6,7-trifluoro-2-naphthyl trifluoromethanesulfonate obtained in (3-2) (40.0 g), tetrakis(triphenylphosphine)palladium (0) (1.4 g), a 2 mol/L aqueous potassium carbonate solution (120 mL), and THF (200 mL) were mixed with each other and heated to 60° C. A solution prepared by dissolving 2-fluoro-4-methoxyphenylboric acid (24.7 g) obtained in (3-1) in THF (100 mL) was added thereto, and stirring was performed at 60° C. for six hours. The temperature was decreased to room temperature. Toluene (150 mL) was added thereto and the mixture was separated. The resulting organic layer was washed with water (100 mL) and a saturated saline solution (100 mL). Anhydrous sodium sulfate was added to perform drying, and the organic solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a crude 2-(2-fluoro-4-methoxyphenyl)-5,6,7-trifluoronaphthalene (35.1 g). (3-4) The crude 2-(2-fluoro-4-methoxyphenyl)-5,6,7-trifluoronaphthalene (35.1 g) obtained in (3-3) was dissolved in dichloromethane (350 mL) and cooled to 5° C., and boron tribromide (14.4 g) was added thereto. After stirring was performed at room temperature for three hours, the temperature was decreased to 5° C. Water (100 mL) was added thereto and the mixture was separated. The resulting organic layer was washed with a saturated saline solution (100 mL) twice. Anhydrous sodium sulfate was added to perform drying, and the organic solvent was distilled off under reduced pressure. The resulting residue was purified by alumina column chromatography and recrystallized using hexane to obtain 4-(5,6,7-trifluoro-2-naphthyl)-3-fluorophenol (25.3 g). (3-5) The subsequent processes were performed by the same method as in Example 1 to obtain [3,5-difluoro-4-(2-fluoro-4-(trans-4-propylcyclohexyl)phenyl)phenyl]-[3-fluoro-4-(5,6,7-trifluoro-2-naphthyl)phenyloxy]difluoromethane (49.9 g). a solution prepared was added at a rate at which the solution was gently refluxed Subsequently, the reaction liquid After a solution prepared was added stirring was performed at room temperature for one hour the mixture was separated Toluene (100 mL) was added to the resulting aqueous layer and extraction The obtained organic layers were mixed washed with a saturated saline solution (100 mL) Anhydrous sodium sulfate was added to perform drying the organic solvent was distilled off under reduced pressure

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred and cooled (0° C.) solution of 4-bromo-3-fluoroanisole (1 g; 4.88 mmol) in anhydrous THF (7 mL) was added isopropyl magnesium chloride (2.0M in THF; 2.22 mL; 4.43 mmol) dropwise. The reaction was stirred at room temperature for 30 min and then cooled to 0° C. 1-benzyl-4-piperidone (0.72 mL; 4.03 mmol) was added dropwise and the reaction was stirred at room temperature for 14 h. The reaction was quenched with saturated NH4Cl and partitioned between EtOAc (50 mL) and H2O (30 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-50% EtOAc/hexanes gradient) to afford 1-benzyl-4-(2-fluoro-4-methoxyphenyl)piperidin-4-ol as a light orange solid. LCMS=315.9 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.38-7.31 (m, 5H), 7.28-7.24 (m, 1H), 6.66 (dd, J=8.7, 2.5 Hz, 1H), 6.61 (dd, J=14.4, 2.5 Hz, 1H), 3.79 (s, 3H), 3.56 (s, 2H), 2.77 (br d, J=10.6 Hz, 2H), 2.54-2.48 (m, 2H), 2.31-2.24 (m, 2H), 1.84 (d, J=12.3 Hz, 2H). The reaction was stirred at room temperature for 30 min the reaction was stirred at room temperature for 14 h The reaction was quenched with saturated NH4Cl partitioned between EtOAc (50 mL) and H2O (30 mL) The aqueous layer was extracted with EtOAc (3×50 mL) the combined extracts were washed with brine (50 mL) dried (MgSO4) filtered concentrated in vacuo The residue was purified by flash silica gel chromatography (0-50% EtOAc/hexanes gradient)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred and cooled (0° C.) solution of 4-bromo-3-fluoroanisole (1 g; 4.88 mmol) in anhydrous THF (7 mL) was added isopropyl magnesium chloride (2.0M in THF; 2.22 mL; 4.43 mmol) dropwise. The reaction was stirred at room temperature for 30 min and then cooled to 0° C. 1-benzyl-4-piperidone (0.72 mL; 4.03 mmol) was added dropwise and the reaction was stirred at room temperature for 14 h. The reaction was quenched with saturated NH4Cl and partitioned between EtOAc (50 mL) and H2O (30 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-50% EtOAc/hexanes gradient) to afford 1-benzyl-4-(2-fluoro-4-methoxyphenyl)piperidin-4-ol as a light orange solid. LCMS=315.9 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.38-7.31 (m, 5H), 7.28-7.24 (m, 1H), 6.66 (dd, J=8.7, 2.5 Hz, 1H), 6.61 (dd, J=14.4, 2.5 Hz, 1H), 3.79 (s, 3H), 3.56 (s, 2H), 2.77 (br d, J=10.6 Hz, 2H), 2.54-2.48 (m, 2H), 2.31-2.24 (m, 2H), 1.84 (d, J=12.3 Hz, 2H). The reaction was stirred at room temperature for 30 min the reaction was stirred at room temperature for 14 h The reaction was quenched with saturated NH4Cl partitioned between EtOAc (50 mL) and H2O (30 mL) The aqueous layer was extracted with EtOAc (3×50 mL) the combined extracts were washed with brine (50 mL) dried (MgSO4) filtered concentrated in vacuo The residue was purified by flash silica gel chromatography (0-50% EtOAc/hexanes gradient)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 4-bromo-3-fluoroanisole, 2-methylphenyl boronic acid, tetrakis(triphenylphosphine) palladium (5% mol) and sodium carbonate (0.23 g, 2.1 mmol) in 20 ml of water/EtOH/toluene (1:2:4) was heated to reflux for 5 h. TLC (EtOAc:hexane/2:98) showed that the reaction was over. The solvents was removed. Water (10 ml) was added. The organic was extracted with methylene chloride (3×50 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after purification with preparative TLC using 2% EtOAc in hexane as the eluant. was heated to reflux for 5 h The solvents was removed Water (10 ml) was added The organic was extracted with methylene chloride (3×50 ml) The combined methylene chloride layers were washed with brine dried over sodium sulfate

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 4-bromo-3-fluoro anisole (500 mg, 2.44 mmol), methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (INTERMEDIATE 37, 875 mg, 3.17 mmol), tetrakis(triphenylphosphine) palladium (282 mg, 5% mol) and Na2CO3 (569 mg, 5.37 mmol) in 20 mL of water/EtOH/toluene (1:2:4) was heated at reflux for 4 h. TLC (CH2Cl2/hexane (1:1)) showed that the reaction was complete. The solvents were removed. Water (10 mL) was added. The organic was extracted with CH2Cl2 (3×10 mL). The combined CH2Cl2 layers were washed with brine and then dried (Na2SO4). The title compound was obtained after flash chromatography using CH2Cl2/hexanes (6:4) as the eluent. 1H NMR (500 MHz, CDCl3): δ 7.98 (s, 1H), 7.92 (dd, J=8.0, 1.5 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.16 (t, J=8.5 Hz, 1H), 6.80 (dd, J=8.5, 2.5 Hz, 1H), 6.77 (dd, J=11.5, 2.5 Hz, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 2.28 (s, 3H). was heated at reflux for 4 h The solvents were removed Water (10 mL) was added The organic was extracted with CH2Cl2 (3×10 mL) The combined CH2Cl2 layers were washed with brine dried (Na2SO4)