methyl 2-bromo-2-(3-fluorophenyl)acetate

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

実験手順: Methyl 2-bromo-2-(3-fluorophenyl)acetate (310 mg, 1.25 mmol), piperidine (0.15 ml, 1.51 mmol), and DIPEA (0.26 ml, 1.51 mmol) were dissolved in acetonitrile (15 ml) and stirred at room temperature for 16 hours. The solvent was evaporated and the crude was purified by flash chromatography (petroleum ether/EtOAc=9/1) to afford methyl 2-(3-fluorophenyl)-2-(piperidin-1-yl)acetate (224 mg, 71% yield) as a colorless oil. The solvent was evaporated the crude was purified by flash chromatography (petroleum ether/EtOAc=9/1)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 2-bromo-2-(3-fluorophenyl)acetate (I15) (300 mg, 1.21 mmol), DIPEA (0.32 ml, 1.82 mmol), and aniline (0.17 ml, 1.82 mmol) were dissolved in acetonitrile (4 ml) and heated under microwave irradiation at 100° C. for 1 hour. Acetonitrile was evaporated, and the residue was purified by flash chromatography (Petroleum ether/EtOAc=95/5) to obtain intermediate I16 (229 mg, 73% yield). Acetonitrile was evaporated the residue was purified by flash chromatography (Petroleum ether/EtOAc=95/5) to obtain intermediate I16 (229 mg, 73% yield)

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

実験手順: Methyl 2-(3-fluorophenyl)acetate (1.90 g, 11.3 mmol) and N-bromo succinimide (2.01 g, 11.3 mmol) were dissolved in CCl4 (80 ml). HBr (64 ul, 0.56 mmol) was added, and the mixture was stirred under reflux overnight. The mixture was cooled at room temperature, diluted with DCM, and washed with sat. NaHCO3, water and brine. The organic layer was dried (Na2SO4), filtered, and evaporated obtaining intermediate I15 (2.68 g, 96% yield). under reflux overnight washed with sat. NaHCO3, water and brine The organic layer was dried (Na2SO4) filtered evaporated obtaining intermediate I15 (2.68 g, 96% yield)

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

実験手順: Methyl 2-(3-fluorophenyl)acetate (1.90 g, 11.3 mmol) and N-bromo succinimide (2.01 g, 11.3 mmol) were dissolved in CCl4 (80 ml). HBr (64 ul, 0.56 mmol) was added, and the mixture was stirred under reflux overnight. The mixture was cooled at room temperature, diluted with DCM, and washed with sat. NaHCO3, water and brine. The organic layer was dried (Na2SO4), filtered, and evaporated obtaining intermediate I15 (2.68 g, 96% yield). under reflux overnight washed with sat. NaHCO3, water and brine The organic layer was dried (Na2SO4) filtered evaporated obtaining intermediate I15 (2.68 g, 96% yield)

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 2-bromo-2-(3-fluorophenyl)acetate (300 mg, 1.21 mmol) and 3,4,5-trifluoroaniline (268 mg, 1.82 mmol) were dissolved in acetonitrile (4 ml) and stirred under microwave heating into a sealed vial at 120° C. for 1 hours. Some crystals of KI were added, and the resulting mixture was stirred under the same conditions for 1 hour (UPLC-MS: conversion complete). Solvent was evaporated, and the crude residue was purified by flash chromatography (Petroleum ether/EtOAc=9/1) to obtain (3-fluoro-phenyl)-(3,4,5-trifluoro-phenylamino)-acetic acid methyl ester (202 mg, 53% yield). Some crystals of KI were added the resulting mixture was stirred under the same conditions for 1 hour (UPLC-MS: conversion complete) Solvent was evaporated the crude residue was purified by flash chromatography (Petroleum ether/EtOAc=9/1)

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

実験手順: Methyl 2-bromo-2-(3-fluorophenyl)acetate (310 mg, 1.25 mmol), piperidine (0.15 ml, 1.51 mmol), and DIPEA (0.26 ml, 1.51 mmol) were dissolved in acetonitrile (15 ml) and stirred at room temperature for 16 hours. The solvent was evaporated and the crude was purified by flash chromatography (petroleum ether/EtOAc=9/1) to afford methyl 2-(3-fluorophenyl)-2-(piperidin-1-yl)acetate (224 mg, 71% yield) as a colorless oil. The solvent was evaporated the crude was purified by flash chromatography (petroleum ether/EtOAc=9/1)

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

実験手順: A mixture of 2-ethyl-N-(3-fluoro-4-piperazin-1-yl-phenyl)-butyramide dihydrochloride (0.26 g, 0.70 mmol), bromo-(3-fluoro-phenyl)-acetic acid methyl ester (0.23 g, 0.91 mmol), and anhydrous K2CO3 (0.34 g, 2.45 mmol) in DMF (10 mL) was stirred for 20 h. The mixture was diluted with water (100 mL) and extracted with DCM (2×30 mL). The combined organic layers were washed with water, dried (Na2SO4), and concentrated. The residue was purified (SiO2; acetone/DCM) to give the title compound (0.25 g, 78%). MS: mass calcd. for C25H31F2N3O3, 459.23. m/z found, 460.3 [M+H]+. 1H NMR (CDCl3): 7.48-7.43 (m, 1H), 7.35-7.28 (m, 1H), 7.25-7.20 (m, 2H), 7.17 (br s, 1H), 7.12-7.07 (m, 1H), 7.05-6.99 (m, 1H), 6.86 (t, J=9.0, 1H), 4.07 (s, 1H), 3.71 (s, 3H), 3.11-3.04 (m, 4H), 2.70-2.59 (m, 4H), 2.03-1.95 (m, 1H), 1.75-1.66 (m, 2H), 1.59-1.49 (m, 2H), 0.93 (t, J=7.4, 6H). extracted with DCM (2×30 mL) The combined organic layers were washed with water dried (Na2SO4) concentrated The residue was purified (SiO2; acetone/DCM)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Bromo-(3-fluoro-phenyl)-acetic acid methyl ester (I96) (300 mg, 1.21 mmol), DIPEA (0.32 mL, 1.82 mmol), and aniline (0.17 mL, 1.82 mmol) are dissolved in acetonitrile (4 mL) and heated under MW irradiation at 100° C. for 1 hour. Acetonitrile is evaporated and the residue is purified by flash chromatography (Petroleum ether/EtOAc=95/5) to obtain intermediate I145 as a colorless oil (229 mg, 73% yield). Acetonitrile is evaporated the residue is purified by flash chromatography (Petroleum ether/EtOAc=95/5)

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

実験手順: Methyl 2-(3-fluorophenyl)acetate (1.90 g, 11.3 mmol) and N-bromo succinimide (2.01 g, 11.3 mmol) are dissolved in CCl4 (80 mL). HBr (64 ul, 0.56 mmol) is added and the mixture is stirred under reflux overnight. The mixture is cooled at RT, diluted with DCM and washed with sat. NaHCO3, water and brine. The organic layer is dried (Na2SO4), filtered and evaporated obtaining intermediate I144 as a yellow oil (2.68 g, 96% yield). under reflux overnight washed with sat. NaHCO3, water and brine The organic layer is dried (Na2SO4) filtered evaporated

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Bromo-(3-fluoro-phenyl)-acetic acid methyl ester (I96) (300 mg, 1.21 mmol), DIPEA (0.32 mL, 1.82 mmol), and aniline (0.17 mL, 1.82 mmol) are dissolved in acetonitrile (4 mL) and heated under MW irradiation at 100° C. for 1 hour. Acetonitrile is evaporated and the residue is purified by flash chromatography (Petroleum ether/EtOAc=95/5) to obtain intermediate I145 as a colorless oil (229 mg, 73% yield). Acetonitrile is evaporated the residue is purified by flash chromatography (Petroleum ether/EtOAc=95/5)

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

実験手順: Methyl 2-(3-fluorophenyl)acetate (1.90 g, 11.3 mmol) and N-bromo succinimide (2.01 g, 11.3 mmol) are dissolved in CCl4 (80 mL). HBr (64 ul, 0.56 mmol) is added and the mixture is stirred under reflux overnight. The mixture is cooled at RT, diluted with DCM and washed with sat. NaHCO3, water and brine. The organic layer is dried (Na2SO4), filtered and evaporated obtaining intermediate I144 as a yellow oil (2.68 g, 96% yield). under reflux overnight washed with sat. NaHCO3, water and brine The organic layer is dried (Na2SO4) filtered evaporated

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 2-bromo-2-(3-fluorophenyl)acetate (I15) (300 mg, 1.21 mmol), DIPEA (0.32 ml, 1.82 mmol), and aniline (0.17 ml, 1.82 mmol) were dissolved in acetonitrile (4 ml) and heated under microwave irradiation at 100° C. for 1 hour. Acetonitrile was evaporated, and the residue was purified by flash chromatography (Petroleum ether/EtOAc=95/5) to obtain intermediate I16 (229 mg, 73% yield). Acetonitrile was evaporated the residue was purified by flash chromatography (Petroleum ether/EtOAc=95/5) to obtain intermediate I16 (229 mg, 73% yield)