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

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring suspension of aluminum chloride (8.0 g, 60 mmol) in 1,2-dichloroethane (16 ml) was added bromoacetyl bromide (4.2 ml, 48 mmol) at 0° C. After 30 min, to a suspension was added 5-Fluoro-3,4-dihydroquinolin-2(1H)-one (4.0 g, 24 mmol) portionwise, then the mixture was allowed to warm to 50° C. and stirred for 4 h. After cooling, the solvent was evaporated in vacuo and the residue was quenched with ice-water and extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (hexane/ethyl acetate=1/1) to afford 6-(Bromoacetyl)-5-fluoro-3,4-dihydroquinolin-2(1H)-one (2.0 g) as a yellow solid. After cooling the solvent was evaporated in vacuo the residue was quenched with ice-water extracted with ethyl acetate The extract was dried over sodium sulfate concentrated in vacuo The residue was purified by column chromatography (hexane/ethyl acetate=1/1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The suspension of 3-(2-fluoro-6-nitrophenyl)propanoic acid (6.0 g, 28 mmol) and 10% Pd-C (300 mg) in MeOH was hydrogenated under H2 (4 atm) for 3 h. After filtration, the filtrate was concentrated in vacuo to afford 5-Fluoro-3,4-dihydroquinolin-2(1H)-one (4.6 g) as a slightly brown solid. This crude product was used in the next step without further purification. After filtration the filtrate was concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring suspension of aluminum chloride (8.0 g, 60 mmol) in 1,2-dichloroethane (16 ml) was added bromoacetyl bromide (4.2 ml, 48 mmol) at 0° C. After 30 min, to a suspension was added 5-Fluoro-3,4-dihydroquinolin-2(1H)-one (4.0 g, 24 mmol) portionwise, then the mixture was allowed to warm to 50° C. and stirred for 4 h. After cooling, the solvent was evaporated in vacuo and the residue was quenched with ice-water and extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (hexane/ethyl acetate=1/1) to afford 6-(Bromoacetyl)-5-fluoro-3,4-dihydroquinolin-2(1H)-one (2.0 g) as a yellow solid. After cooling the solvent was evaporated in vacuo the residue was quenched with ice-water extracted with ethyl acetate The extract was dried over sodium sulfate concentrated in vacuo The residue was purified by column chromatography (hexane/ethyl acetate=1/1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The suspension of 3-(2-fluoro-6-nitrophenyl)propanoic acid (6.0 g, 28 mmol) and 10% Pd-C (300 mg) in MeOH was hydrogenated under H2 (4 atm) for 3 h. After filtration, the filtrate was concentrated in vacuo to afford 5-Fluoro-3,4-dihydroquinolin-2(1H)-one (4.6 g) as a slightly brown solid. This crude product was used in the next step without further purification. After filtration the filtrate was concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 5-fluoro-3,4-dihydroquinolin-2(1H)-one (146-4; 0.45 g, 0.00272 mol) in N,N-dimethylformamide (10 mL) was added N-bromosuccinamide (0.53 g, 0.0029 mol). Reaction mass was allowed to stir for overnight. Ice cold water was added to reaction mass. The solid separated was filtered and dried thoroughly to obtain the title compound. MS (M+1): 246.0. Reaction mass Ice cold water was added to reaction mass The solid separated was filtered dried thoroughly

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of diethyl 2-(2-amino-6-fluorobenzyl)malonate (146-3; 2.0 g, 0.00706 mol)) in acetic acid (20 mL) was added hydrochloric acid (20 mL). The reaction mixture was heated at 90° C. for 1 h. The reaction mixture was cooled to room temperature and then poured into ice cold water. It was extracted with ethyl acetate (3×40 mL). The combined organic layer was washed with 10% aqueous sodium hydroxide solution, saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to afford the title compound. 1H NMR (400 MHz, DMSO) δ 10.219 (s, 1H), 7.164-7.108 (q, J=7.6 Hz, 1H), 6.769-6.725 (t, J=8.4 Hz, 1H), 6.684-6.664 (d, J=8.0 Hz, 1H), 2.871-2.832 (t, J=7.6 Hz, 2H), 2.472-2.434 (t, J=8.0 Hz, 2H). MS (M+1): 166.1. The reaction mixture was cooled to room temperature poured into ice cold water It was extracted with ethyl acetate (3×40 mL) The combined organic layer was washed with 10% aqueous sodium hydroxide solution, saturated aqueous sodium chloride solution dried over sodium sulphate concentrated under vacuum

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring suspension of aluminum chloride (8.0 g, 60 mmol) in 1,2-dichloroethane (16 ml) was added bromoacetyl bromide (4.2 ml, 48 mmol) at 0° C. After 30 min, to a suspension was added 5-Fluoro-3,4-dihydroquinolin-2(1H)-one (4.0 g, 24 mmol) portionwise, then the mixture was allowed to warm to 50° C. and stirred for 4 h. After cooling, the solvent was evaporated in vacuo and the residue was quenched with ice-water and extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (hexane/ethyl acetate=1/1) to afford 6-(Bromoacetyl)-5-fluoro-3,4-dihydroquinolin-2(1H)-one (2.0 g) as a yellow solid. After cooling the solvent was evaporated in vacuo the residue was quenched with ice-water extracted with ethyl acetate The extract was dried over sodium sulfate concentrated in vacuo The residue was purified by column chromatography (hexane/ethyl acetate=1/1)