3-chloro-N-(2-fluorophenyl)propanamide

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3-chloro-N-(2-fluorophenyl)propanamide (1-1, 17.2 g, 85.30 mmol) and aluminium trichloride (56.9 g, 427.0 mmol) was heated at 140° C. for 4 h under inert atmosphere. After cooling the reaction mixture down to 0° C., ice cold water (350 mL) was added slowly. The resulting precipitate was collected by filtration and washed with water and hexane. The crude compound was purified by flash chromatography on silica gel to obtain the title compound as a white solid. This intermediate was used directly in the next step without characterization. was added slowly The resulting precipitate was collected by filtration washed with water and hexane The crude compound was purified by flash chromatography on silica gel

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3-chloro-N-(2-fluorophenyl)propanamide (1-1, 17.2 g, 85.30 mmol) and aluminium trichloride (56.9 g, 427.0 mmol) was heated at 140° C. for 4 h under inert atmosphere. After cooling the reaction mixture down to 0° C., ice cold water (350 mL) was added slowly. The resulting precipitate was collected by filtration and washed with water and hexane. The crude compound was purified by flash chromatography on silica gel to obtain the title compound as a white solid. This intermediate was used directly in the next step without characterization. was added slowly The resulting precipitate was collected by filtration washed with water and hexane The crude compound was purified by flash chromatography on silica gel

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

実験手順: A solution of 2-fluoroaniline (20.00 g, 180.0 mmol) in tetrahydrofurane (100 mL) and pyridine (22 mL) was stirred for 15 min and then 3-chloropropionyl chloride (25.14 g, 198 mmol) in tetrahydrofurane (50 ml) was added at 0° C. The mixture was stirred for 18 h at room temperature under inert atmosphere. After the completion of the reaction, the mixture was diluted with water. The aqueous layer was separated and extracted with diethylether. The collected organic parts were washed with water and brine and were then dried over Na2SO4, filtered and concentrated under vacuum to afford the title compound as a white solid. This intermediate was used directly in the next step without further purification and characterization. After the completion of the reaction The aqueous layer was separated extracted with diethylether The collected organic parts were washed with water and brine were then dried over Na2SO4 filtered concentrated under vacuum

反応条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A flame-dried 50-mL flask equipped with a magnetic stirring bar was charged with 3-chloro-N-(2-fluoro-phenyl)-propionamide (5.33 g, 26.5 mmol) and aluminium chloride (5.30 g, 39.7 mmol). In a pre-heated oil bath, the flask was heated at 160° C. for 1.5 hr. After cooling to room temperature, the mixture was treated with ice-water slowly and extracted with EtOAc. The organic layer was washed with water and brine in sequence, dried over anhy. Na2SO4, filtered, and concentrated in vacuo. The resulting residue was then purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to afford title compound (3.1 g, 70% yield) as a solid. MS: 166.0 (M+H)+. A flame-dried 50-mL flask equipped with a magnetic stirring bar After cooling to room temperature extracted with EtOAc The organic layer was washed with water and brine in sequence dried over anhy Na2SO4, filtered concentrated in vacuo The resulting residue was then purified by flash chromatography (silica gel, 30% ethyl acetate in hexane)

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

実験手順: To a solution of 2-fluoroaniline (6.67 g, 60 mmol) and pyridine (5.21 g, 66 mmol) in 1,2-dichloroethane (50 mL) was added 3-chloropropionyl chloride (8.38 g, 66 mmol) dropwise at 15° C. After stirring at room temperature for 2 hr, the mixture was washed with water and then 2N aq. hydrochloric acid. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to afford title compound (10.9 g, 90% yield) as an oil. MS: 202.1 (M+H)+. the mixture was washed with water The organic layer was dried over anhy Na2SO4, filtered concentrated 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 2-fluoroaniline (6.67 g, 60 mmol) and pyridine (5.21 g, 66 mmol) in 1,2-dichloroethane (50 mL) was added 3-chloropropionyl chloride (8.38 g, 66 mmol) dropwise at 15° C. After stirring at room temperature for 2 hr, the mixture was washed with water and then 2N aq. hydrochloric acid. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to afford title compound (10.9 g, 90% yield) as an oil. MS: 202.1 (M+H)+. the mixture was washed with water The organic layer was dried over anhy Na2SO4, filtered concentrated in vacuo

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 8-fluoro-3,4-dihydroquinolin-2(1H)-one (see Example 41 for details), (5 g, 30.3 mmol) in sulfuric acid, cooled to −5° C. was added nitric acid, fuming (1.413 ml, 30.3 mmol) as a 1:1 mixture in water. The resulting mixture was stirred at −5° C. for 20 min. After 20 min the reaction was quenched via addition of ice, precipitating the product which was collected by filtration. The filter cake was dissolved in dichloromethane and a minimal amount of methanol, dried, filtered and concentrated onto silica gel then chromatographed using 0-10% ethyl acetate in dichloromethane to give the desired 8-fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one (5.9 g, 28.1 mmol, 93% yield). 1H NMR (DMSO-d6) δ 10.73 (brs, 1H), 8.03 (m, 1H), 8.02 (m, 1H), 3.08 (t, J=7.5 Hz, 2H), 2.57 (t, J=7.5 Hz, 1H). After 20 min the reaction was quenched via addition of ice precipitating the product which was collected by filtration The filter cake was dissolved in dichloromethane a minimal amount of methanol, dried filtered concentrated onto silica gel then chromatographed

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 8-fluoro-3,4-dihydroquinolin-2(1H)-one (see Example 41 for details) (2 g, 12.11 mmol) in sulfuric acid (12 ml), cooled to −5° C. was added nitric acid, 90% (0.565 ml, 12.11 mmol) as a 1:1 solution in water. The reaction mixture was stirred at −5° C. for 20 min, then quenched via addition of ice, precipitating the product which was collected by filtration. The pale solid was then dissolved in dichloromethane, dried, filtered and concentrated, and then chromatographed on silica gel using 0-10% ethyl acetate in dichloromethane as eluent to give the desired 8-fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one (2.33 g, 11.09 mmol, 92% yield). 1H NMR (DMSO-d6) δ 10.73 (brs, 1H), 8.03 (m, 1H), 8.02 (m, 1H), 3.08 (t, J=7.5 Hz, 2H), 2.57 (t, J=7.5 Hz, 1H). quenched via addition of ice precipitating the product which was collected by filtration The pale solid was then dissolved in dichloromethane dried filtered concentrated chromatographed on silica gel using 0-10% ethyl acetate in dichloromethane as eluent

反応条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Chloro-N-(2-fluorophenyl)propanamide (3.3 g, 16.4 mmol) and aluminum trichloride (10.9 g, 81.8 mmol) were combined in a RB flask with a stirbar and purged with argon. The mixture of the two solids was heated to 160° C. to form a melt, which was stirred for 1.5 h. The mixture was then removed from the heating bath and when it had cooled to below 100° C., was quenched by careful addition of water. The resulting mixture was cooled to room temperature, neutralized with NaOH, and extracted with dichloromethane (3×). The combined organics were dried, filtered and evaporated, then chromatographed on silica gel using 20% EtOAc in hexanes, giving the desired product. 1H NMR showed some impurities. Yield: 2.35 g, 88%. 1H NMR (CDCl3) δ 2.66 (t, 2H, J=7.6 Hz), 3.01 (t, 2H, J=7.6 Hz), 6.96 (m, 3H), 8.11 (brs, 1H). purged with argon The mixture of the two solids to form a melt, which The mixture was then removed from the heating bath and when it had cooled to below 100° C. was quenched by careful addition of water The resulting mixture was cooled to room temperature extracted with dichloromethane (3×) The combined organics were dried filtered evaporated chromatographed on silica gel using 20% EtOAc in hexanes

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

実験手順: 2-Fluoroaniline (2 g, 17.99 mmol) was stirred in acetone (30 mL) and pyridine (2.91 mL, 35.99 mmol) and allowed to dissolve. To this solution was added 3-chloropropanoyl chloride (3.42 g, 26.99 mmol), slowly. The reaction mixture began to reflux, and when the mixture had cooled to room temperature (˜30 min) TLC analysis showed that the reaction was complete. The reaction mixture was then diluted with water and HCl(aq) (1N) and extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated, then chromatographed on silica gel in 30% EtOAc in hexanes. Yield: 3.5 g, 97%. 1H NMR (CDCl3) δ 2.87 (t, 2H, J=6.7 Hz), 3.89 (t, 2H, J=6.7 Hz), 7.10 (m, 3H), 7.52 (brs, 1H), 8.30 (t, 1H, J=7.5 Hz). EI-MS (m/z, %): 201.1 (M+, 22), 111.1 (100). to dissolve to reflux extracted with dichloromethane (3×) The combined organic extracts were dried over sodium sulfate filtered concentrated chromatographed on silica gel in 30% EtOAc in hexanes

反応条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A flame-dried 50-mL flask equipped with a magnetic stirring bar was charged with 3-chloro-N-(2-fluoro-phenyl)-propionamide (5.33 g, 26.5 mmol) and aluminium chloride (5.30 g, 39.7 mmol). In a pre-heated oil bath, the flask was heated at 160° C. for 1.5 hours. After cooling to room temperature, the mixture was treated slowly with ice-water and extracted with EtOAc. The organic layer was washed with water and brine in sequence, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was then purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to afford title compound (3.1 g, 70%) as a solid. MS: 166.0 (M+H+)+. A flame-dried 50-mL flask equipped with a magnetic stirring bar After cooling to room temperature extracted with EtOAc The organic layer was washed with water and brine in sequence dried over anhydrous Na2SO4 filtered concentrated in vacuo The resulting residue was then purified by flash chromatography (silica gel, 30% ethyl acetate in hexane)

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

実験手順: To a solution of 2-fluoroaniline (6.67 g, 60 mmol) and pyridine (5.21 g, 66 mmol) in 1,2-dichloroethane (50 mL) was added 3-chloropropionyl chloride (8.38 g, 66 mmol) dropwise at 15° C. After stirring at room temperature for 2 hours, the mixture was washed with water and then hydrochloric acid (2 N, aqueous). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford title compound (10.9 g, yield: 90%) as an oil. MS: 202.1 (M+H+)+. the mixture was washed with water The organic layer was dried over anhydrous Na2SO4 filtered concentrated in vacuo