3-ethyl-7-fluoro-3,4-dihydro-1H-quinoxalin-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:; See reaction.notes.procedure_details.

Procedure: To a homogeneous solution of 3-ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one (60.61 g, 312.1 mmol) and 1,4-dioxane (1350 ml) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (75.91 g, 327.7 mmol) and the mixture was stirred using an overhead stirrer at rt for 2.5 h. At this time, the mixture was concentrated under reduced pressure to give a brown residue. The brown residue was suspended in saturated aqueous NaHCO3 (2 L), stirred for 30 min, filtered, washed with saturated aqueous NaHCO3 (1 L) to give a light green solid. The light green solid was re-suspended in saturated aqueous NaHCO3 (500 mL), well mixed, filtered, and washed with saturated aqueous NaHCO3 (500 mL) to give an off-white solid. The off-white solid was suspended in water (500 mL), well mixed, filtered, washed with water (1 L), air-dried overnight, and dried under high vacuum at 22° C. for 2 h to give 3-ethyl-7-fluoroquinoxalin-2(1H)-one (56.87 g, 94.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.36 (br. S, 1H.), 7.76 (dd, J=9.0, 5.9 Hz, 1H), 7.11 (td, J=8.8, 2.7 Hz, 1H), 7.00 (dd, J=9.6, 2.7 Hz, 1H), 2.78 (q, J=7.4 Hz, 2H), 1.20 (t, J=7.4 Hz, 3H) Mass Spectrum (ESI) m/e=193.0 (M+1). at rt for 2.5 h At this time, the mixture was concentrated under reduced pressure to give a brown residue stirred for 30 min filtered washed with saturated aqueous NaHCO3 (1 L) to give a light green solid well mixed filtered washed with saturated aqueous NaHCO3 (500 mL) to give an off-white solid well mixed filtered washed with water (1 L) air-dried overnight dried under high vacuum at 22° C. for 2 h

Conditions: temp:78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The heterogeneous mixture of 2-(4-fluoro-2-nitrophenylamino)butanoic acid (181.7 g, 750.0 mmol), 3 N aq. HCl (750.0 ml, 2250 mmol), and ethanol (1923 ml, 750.0 mmol) in 5-L three neck round bottom flask was added Tin(II) chloride dihydrate (507.7 g, 2250 mmol) and the organe mixture was heated at 78° C. with stirring using an overhead stirrer for 4 h ([Note 1]: The orange heterogeneous mixture became an orange homogeneous mixture and the orange color changed to a red color over ˜2 hour). After 4 h, the mixture was cooled to rt and concentrated under reduced pressure to remove ethanol, and left at rt for 48 h. The resulting yellow precipitate was collected by filtration and washed with water (500 mL). The yellow solid was suspended in ice water (1 L) and the mixture was adjusted ˜pH 13 with KOH (˜250 g). The heterogeneous mixture was extracted with DCM (1 L×3). The combined organic layers were washed with water (1 L×1) and brine (1 L×1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 3-ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one (60.92 g, 41.8% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.26 (s, 1H), 6.68 (dd, J=8.6, 5.5 Hz, 1H), 6.47-6.61 (m, 2H), 5.95 (d, J=1.2 Hz, 1H), 3.62 (ddd, J=6.7, 5.0, 2.0 Hz, 1H), 1.50-1.72 (m, 2H), 0.92 (t, J=7.4 Hz, 3H), Mass Spectrum (ESI) m/e=195.1 (M+1). for 4 h After 4 h the mixture was cooled to rt concentrated under reduced pressure to remove ethanol left at rt for 48 h The resulting yellow precipitate was collected by filtration washed with water (500 mL) The heterogeneous mixture was extracted with DCM (1 L×3) The combined organic layers were washed with water (1 L×1) and brine (1 L×1) dried over Na2SO4 filtered concentrated under reduced pressure

Conditions: temp:78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The heterogeneous mixture of 2-(4-fluoro-2-nitrophenylamino)butanoic acid (181.7 g, 750.0 mmol), 3 N aq. HCl (750.0 ml, 2250 mmol), and ethanol (1923 ml, 750.0 mmol) in 5-L three neck round bottom flask was added Tin(II) chloride dihydrate (507.7 g, 2250 mmol) and the organe mixture was heated at 78° C. with stirring using an overhead stirrer for 4 h ([Note 1]: The orange heterogeneous mixture became an orange homogeneous mixture and the orange color changed to a red color over ˜2 hour). After 4 h, the mixture was cooled to rt and concentrated under reduced pressure to remove ethanol, and left at rt for 48 h. The resulting yellow precipitate was collected by filtration and washed with water (500 mL). The yellow solid was suspended in ice water (1 L) and the mixture was adjusted ˜pH 13 with KOH (˜250 g). The heterogeneous mixture was extracted with DCM (1 L×3). The combined organic layers were washed with water (1 L×1) and brine (1 L×1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 3-ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one (60.92 g, 41.8% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.26 (s, 1H), 6.68 (dd, J=8.6, 5.5 Hz, 1H), 6.47-6.61 (m, 2H), 5.95 (d, J=1.2 Hz, 1H), 3.62 (ddd, J=6.7, 5.0, 2.0 Hz, 1H), 1.50-1.72 (m, 2H), 0.92 (t, J=7.4 Hz, 3H), Mass Spectrum (ESI) m/e=195.1 (M+1). for 4 h After 4 h the mixture was cooled to rt concentrated under reduced pressure to remove ethanol left at rt for 48 h The resulting yellow precipitate was collected by filtration washed with water (500 mL) The heterogeneous mixture was extracted with DCM (1 L×3) The combined organic layers were washed with water (1 L×1) and brine (1 L×1) dried over Na2SO4 filtered concentrated under reduced pressure

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:; See reaction.notes.procedure_details.

Procedure: To a homogeneous solution of 3-ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one (60.61 g, 312.1 mmol) and 1,4-dioxane (1350 ml) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (75.91 g, 327.7 mmol) and the mixture was stirred using an overhead stirrer at rt for 2.5 h. At this time, the mixture was concentrated under reduced pressure to give a brown residue. The brown residue was suspended in saturated aqueous NaHCO3 (2 L), stirred for 30 min, filtered, washed with saturated aqueous NaHCO3 (1 L) to give a light green solid. The light green solid was re-suspended in saturated aqueous NaHCO3 (500 mL), well mixed, filtered, and washed with saturated aqueous NaHCO3 (500 mL) to give an off-white solid. The off-white solid was suspended in water (500 mL), well mixed, filtered, washed with water (1 L), air-dried overnight, and dried under high vacuum at 22° C. for 2 h to give 3-ethyl-7-fluoroquinoxalin-2(1H)-one (56.87 g, 94.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.36 (br. S, 1H), 7.76 (dd, J=9.0, 5.9 Hz, 1H), 7.11 (td, J=8.8, 2.7 Hz, 1H), 7.00 (dd, J=9.6, 2.7 Hz, 1H), 2.78 (q, J=7.4 Hz, 2H), 1.20 (t, J=7.4 Hz, 3H) Mass Spectrum (ESI) m/e=193.0 (M+1). at rt for 2.5 h At this time, the mixture was concentrated under reduced pressure to give a brown residue stirred for 30 min filtered washed with saturated aqueous NaHCO3 (1 L) to give a light green solid well mixed filtered washed with saturated aqueous NaHCO3 (500 mL) to give an off-white solid well mixed filtered washed with water (1 L) air-dried overnight dried under high vacuum at 22° C. for 2 h

Conditions: temp:78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The heterogeneous mixture of 2-(4-fluoro-2-nitrophenylamino)butanoic acid (181.7 g, 750.0 mmol), 3 N aq. HCl (750.0 ml, 2250 mmol), and ethanol (1923 ml, 750.0 mmol) in 5-L three neck round bottom flask was added Tin(II) chloride dihydrate (507.7 g, 2250 mmol) and the organe mixture was heated at 78° C. with stirring using an overhead stirrer for 4 h ([Note 1]: The orange heterogeneous mixture became an orange homogeneous mixture and the orange color changed to a red color over ˜2 hour). After 4 h, the mixture was cooled to rt and concentrated under reduced pressure to remove ethanol, and left at rt for 48 h. The resulting yellow precipitate was collected by filtration and washed with water (500 mL). The yellow solid was suspended in ice water (1 L) and the mixture was adjusted ˜pH 13 with KOH (−250 g). The heterogeneous mixture was extracted with DCM (1 L×3). The combined organic layers were washed with water (1 L×1) and brine (1 L×1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 3-ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one (60.92 g, 41.8% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.26 (s, 1H), 6.68 (dd, J=8.6, 5.5 Hz, 1H), 6.47-6.61 (m, 2H), 5.95 (d, J=1.2 Hz, 1H), 3.62 (ddd, J=6.7, 5.0, 2.0 Hz, 1H), 1.50-1.72 (m, 2H), 0.92 (t, J=7.4 Hz, 3H), Mass Spectrum (ESI) m/e=195.1 (M+1). for 4 h After 4 h the mixture was cooled to rt concentrated under reduced pressure to remove ethanol left at rt for 48 h The resulting yellow precipitate was collected by filtration washed with water (500 mL) The heterogeneous mixture was extracted with DCM (1 L×3) The combined organic layers were washed with water (1 L×1) and brine (1 L×1) dried over Na2SO4 filtered concentrated under reduced pressure

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

Procedure: To a homogeneous solution of 3-ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one (60.61 g, 312.1 mmol) and 1,4-dioxane (1350 ml) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (75.91 g, 327.7 mmol) and the mixture was stirred using an overhead stirrer at rt for 2.5 h. At this time, the mixture was concentrated under reduced pressure to give a brown residue. The brown residue was suspended in saturated aqueous NaHCO3 (2 L), stirred for 30 min, filtered, washed with saturated aqueous NaHCO3 (1 L) to give a light green solid. The light green solid was re-suspended in saturated aqueous NaHCO3 (500 mL), well mixed, filtered, and washed with saturated aqueous NaHCO3 (500 mL) to give an off-white solid. The off-white solid was suspended in water (500 mL), well mixed, filtered, washed with water (1 L), air-dried overnight, and dried under high vacuum at 22° C. for 2 h to give 3-ethyl-7-fluoroquinoxalin-2(1H)-one (56.87 g, 94.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.36 (br. S, 1H.), 7.76 (dd, J=9.0, 5.9 Hz, 1H), 7.11 (td, J=8.8, 2.7 Hz, 1H), 7.00 (dd, J=9.6, 2.7 Hz, 1H), 2.78 (q, J=7.4 Hz, 2H), 1.20 (t, J=7.4 Hz, 3H) Mass Spectrum (ESI) m/e=193.0 (M+1). at rt for 2.5 h At this time, the mixture was concentrated under reduced pressure to give a brown residue stirred for 30 min filtered washed with saturated aqueous NaHCO3 (1 L) to give a light green solid well mixed filtered washed with saturated aqueous NaHCO3 (500 mL) to give an off-white solid well mixed filtered washed with water (1 L) air-dried overnight dried under high vacuum at 22° C. for 2 h