8-fluoro-3,4-dihydro-1H-quinolin-2-one

反応条件: temp:0.00; 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 (1-2; 8.30 g, 50.10 mmol) in N,N-dimethylformamide (250 mL) was added N-bromosuccinimide (9.80 g, 55.10 mmol) in N,N-dimethylformamide (120 mL) at 0° C. The reaction mixture was stirred at room temperature for 18 h, cooled, and diluted with ice cold water (500 mL). The resulting precipitated was filtered and dried to obtain the title compound as a white solid; 1H NMR (DMSO-D6, 500 MHz) δ=10.20 (s, 1H), 7.37 (dd, J=2.0 Hz, JHF=10.0 Hz, 1H), 7.26 (s, 1H), 2.93 (t, J=7.0 Hz, 2H), 2.47 (t, J=7.5 Hz, 2H). cooled The resulting precipitated was filtered dried

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:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 8-Fluoro-3,4-dihydro-1H-quinolin-2-one [prepared according to the procedure found in EP0524846] (2.62 g, 0.0159 mol) is dissolved in concentrated sulfuric acid (20 ml) and cooled to −5° C. Nitric acid (70%, 1.02 ml, 0.0159 mol) is added dropwise and the reaction stirred at −5° C. for 20 minutes. The mixture is poured onto ice and the resulting precipitate collected by filtration, washed well with water, and dried under vacuum. Purification by flash column chromatography (30% ethyl acetate/hexane) gives the title compound as a light yellow solid (2.50 g, 75%); [M+H]+=211. The mixture is poured onto ice the resulting precipitate collected by filtration washed well with water dried under vacuum Purification by flash column chromatography (30% ethyl acetate/hexane)

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

実験手順: 8-Fluoro-3,4-dihydro-1H-quinolin-2-one [prepared according to the procedure found in EP0524846] (2.62 g, 0.0159 mol) is dissolved in concentrated sulfuric acid (20 ml) and cooled to −5° C. Nitric acid (70%, 1.02 ml, 0.0159 mol) is added dropwise and the reaction stirred at −5° C. for 20 minutes. The mixture is poured onto ice and the resulting precipitate collected by filtration, washed well with water, and dried under vacuum. Purification by flash column chromatography (30% ethyl acetate/hexane) gives the title compound as a light yellow solid (2.50 g, 75%); [M+H]+=211. The mixture is poured onto ice the resulting precipitate collected by filtration washed well with water dried under vacuum Purification by flash column chromatography (30% ethyl acetate/hexane)

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

実験手順: 8-Fluoro-3,4-dihydro-1H-quinolin-2-one [prepared according to the procedure found in EP0524846] (2.62 g, 0.0159 mol) is dissolved in concentrated sulfuric acid (20 ml) and cooled to −5° C. Nitric acid (70%, 1.02 ml, 0.0159 mol) is added dropwise and the reaction stirred at −5° C. for 20 minutes. The mixture is poured onto ice and the resulting precipitate collected by filtration, washed well with water, and dried under vacuum. Purification by flash column chromatography (30% ethyl acetate/hexane) gives the title compound as a light yellow solid (2.50 g, 75%); [M+H]+=211. The mixture is poured onto ice the resulting precipitate collected by filtration washed well with water dried under vacuum Purification by flash column chromatography (30% ethyl acetate/hexane)

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

実験手順: NBS (0.62 g, 3.5 mmol) dissolved in DMF (5 mL) was added to a solution of 8-fluoro-3,4-dihydro-1H-quinolin-2-one (0.52 g, 3.2 mmol) in DMF (5 mL) dropwise at 0° C. The resulting reaction mixture was stirred at room temperature for 12 hr before it was treated with water. The precipitated solid was collected through filtration, washed with ether, and dried over vacuum to afford title compound (0.65 g, 85% yield) as a white solid. MS: 244.1 (M+H)+. The resulting reaction mixture The precipitated solid was collected through filtration washed with ether dried over vacuum

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

実験手順: NBS (0.62 g, 3.5 mmol) dissolved in DMF (5 mL) was added to a solution of 8-fluoro-3,4-dihydro-1H-quinolin-2-one (0.52 g, 3.2 mmol) in DMF (5 mL) dropwise at 0° C. The resulting reaction mixture was stirred at room temperature for 12 hr before it was treated with water. The precipitated solid was collected through filtration, washed with ether, and dried over vacuum to afford title compound (0.65 g, 85% yield) as a white solid. MS: 244.1 (M+H)+. The resulting reaction mixture The precipitated solid was collected through filtration washed with ether dried over 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:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 8-Fluoro-3,4-dihydro-1H-quinolin-2-one [prepared according to the procedure found in EP0524846] (2.62 g, 0.0159 mol) is dissolved in concentrated sulfuric acid (20 ml) and cooled to −5° C. Nitric acid (70%, 1.02 ml, 0.0159 mol) is added dropwise and the reaction stirred at −5° C. for 20 minutes. The mixture is poured onto ice and the resulting precipitate collected by filtration, washed well with water, and dried under vacuum. Purification by flash column chromatography (30% ethyl acetate/hexane) gives the title compound as a light yellow solid (2.50 g, 75%); [M+H]+=211. The mixture is poured onto ice the resulting precipitate collected by filtration washed well with water dried under vacuum Purification by flash column chromatography (30% ethyl acetate/hexane)

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

実験手順: 8-Fluoro-3,4-dihydroquinolin-2(1H)-one (2.31 g, 13.98 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (4.03 g, 27.9 mmol) and potassium carbonate (11.78 g, 85.3 mmol) were combined in a round bottom flask containing a stirbar. The flask was purged with argon and DMF was added. The white suspension was stirred overnight at room temperature. The mixture was then diluted with ethyl acetate and washed with water (5×), then brine (2×). The organic phase was then dried, filtered and concentrated, then chromatographed on silica gel using EtOAc eluent. Yield: 2.86 g, 86%. 1H NMR 7.0 Hz), 4.09 (t, 2H, J=7.0 Hz), 6.98 (m, 3H). ESI-MS: 237 (MH+, 29), 192 (100). (CDCl3) δ 2.24, (s, 6H), 2.51 (t, 2H, J=7.0 Hz), 2.59 (t, 2H, J=7.0 Hz), 2.87 (t, 2H, J= containing a stirbar The flask was purged with argon and DMF was added The mixture was then diluted with ethyl acetate washed with water (5×) The organic phase was then dried filtered concentrated chromatographed on silica gel

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