6-fluoro-3,4-dihydro-1H-quinoxalin-2-one

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

実験手順: To a mixture of 1.97 g of 6-fluoro-1,2,3,4-tetrahydroquinoxalin-2-one (EXAMPLE 6), 3.1 ml of diisopropylethylamine, and 11 ml of THF is added 1.4 ml of methyl chloroformate. The reaction is cooled with cool tap water as an exotherm ensued. After 35 min, the mixture is partitioned between ethyl acetate, aq. sodium bicarbonate, and saline. The organic layers are dried over magnesium sulfate, concentrated, and the crude product is crystallized from dichloromethane/methanol/ethyl acetate to give 2.06 g of methyl 6-fluoro-1,2,3,4-tetrahydro-4-(methoxycarbonyl)quinoxaline-2-one; mp 206.5°-207.5°; NMR (CDCl3) 3.86, 4.43, 6.84, 7.48, 8.67 δ. The reaction is cooled the mixture is partitioned between ethyl acetate, aq. sodium bicarbonate, and saline The organic layers are dried over magnesium sulfate concentrated the crude product is crystallized from dichloromethane/methanol/ethyl acetate

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

実験手順: A mixture of N-(5-fluoro-2-nitrophenyl)glycine ethyl ester (XI, EXAMPLE 5, 28.60 g), palladium on carbon (10%, 1.01 g) and methanol (500 ml) is shaken under 45 psi of hydrogen on a Parr shaker. After 2 hr an additional 0.54 g of 10% palladium on carbon catalyst is added. The mixture is shaken for an hour at 42 psi and then the catalyst is removed by filtration. p-Toluenesulfonic acid (0.314 g) is added to the filtrate. The solution is concentrated under reduced pressure to a volume of about 250 ml and then stirred at 20°-25°. The reaction is then further concentrated and dichloromethane is added. The solid that formed is collected and chromatographed on 800 ml of silica gel (column) eluting with dichloromethane/methanol (98/2). The appropriate fractions are pooled and concentrated and triturated with a small amount of dichloromethane. The solid is collected, dried, and triturated a second time with dichloromethane and redried to give the title compound, mp 176.0°-177.5°; NMR (CDCl3) 3.95, 3.99, 6.42, 6.63 and 8.33 δ. the catalyst is removed by filtration p-Toluenesulfonic acid (0.314 g) is added to the filtrate The solution is concentrated under reduced pressure to a volume of about 250 ml stirred at 20°-25° The reaction is then further concentrated dichloromethane is added The solid that formed is collected chromatographed on 800 ml of silica gel (column) eluting with dichloromethane/methanol (98/2) concentrated triturated with a small amount of dichloromethane The solid is collected dried triturated a second time with dichloromethane redried

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

実験手順: To a mixture of 1.97 g of 6-fluoro-1,2,3,4-tetrahydroquinoxalin-2-one (EXAMPLE 6), 3.1 ml of diisopropylethylamine, and 11 ml of THF is added 1.4 ml of methyl chloroformate. The reaction is cooled with cool tap water as an exotherm ensued. After 35 min, the mixture is partitioned between ethyl acetate, aq. sodium bicarbonate, and saline. The organic layers are dried over magnesium sulfate, concentrated, and the crude product is crystallized from dichloromethane/methanol/ethyl acetate to give 2.06 g of methyl 6-fluoro-1,2,3,4-tetrahydro4-(methoxycarbonyl)quinoxaline-2-one; mp 206.5°-207.5°; NMR (CDCl3) 3.86, 4.43, 6.84, 7.48, 8.67 δ. The reaction is cooled the mixture is partitioned between ethyl acetate, aq. sodium bicarbonate, and saline The organic layers are dried over magnesium sulfate concentrated the crude product is crystallized from dichloromethane/methanol/ethyl acetate

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

実験手順: A mixture of N-(5-fluoro-2-nitrophenyl)glycine ethyl ester (XI, EXAMPLE 5, 28.60 g), palladium on carbon (10%, 1.01 g) and methanol (500 ml) is shaken under 45 psi of hydrogen on a Parr shaker. After 2 hr an additional 0.54 g of 10% palladium on carbon catalyst is added. The mixture is shaken for an hour at 42 psi and then the catalyst is removed by filtration. p-Toluenesulfonic acid (0.314 g) is added to the filtrate. The solution is concentrated under reduced pressure to a volume of about 250 ml and then stirred at 20°-25°. The reaction is then further concentrated and dichloromethane is added. The solid that formed is collected and chromatographed on 800 ml of silica gel (column) eluting with dichloromethane/methanol (98/2). The appropriate fractions are pooled and concentrated and triturated with a small amount of dichloromethane. The solid is collected, dried, and triturated a second time with dichloromethane and redried to give the title compound, mp 176.0°-177.5°; NMR (CDCl3) 3.95, 3.99, 6.42, 6.63 and 8.33 δ. the catalyst is removed by filtration p-Toluenesulfonic acid (0.314 g) is added to the filtrate The solution is concentrated under reduced pressure to a volume of about 250 ml stirred at 20°-25° The reaction is then further concentrated dichloromethane is added The solid that formed is collected chromatographed on 800 ml of silica gel (column) eluting with dichloromethane/methanol (98/2) concentrated triturated with a small amount of dichloromethane The solid is collected dried triturated a second time with dichloromethane redried

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

実験手順: To a mixture of 1.97 g of 6-fluoro-1,2,3,4-tetrahydroquinoxalin-2-one (EXAMPLE 6), 3.1 ml of diisopropylethylamine, and 11 ml of THF is added 1.4 ml of methyl chloroformate. The reaction is cooled with cool tap water as an exotherm ensued. After 35 min, the mixture is partitioned between ethyl acetate, aq. sodium bicarbonate, and saline. The organic layers are dried over magnesium sulfate, concentrated, and the crude product is crystallized from dichloromethane/methanol/ethyl acetate to give 2.06 g of methyl 6-fluoro-1,2,3,4-tetrahydro-4-(methoxycarbonyl) quinoxaline-2-one; mp 206.5°-207.5°; NMR (CDCl3) 3.86, 4.43, 6.84, 7.48, 8.67 δ. The reaction is cooled the mixture is partitioned between ethyl acetate, aq. sodium bicarbonate, and saline The organic layers are dried over magnesium sulfate concentrated the crude product is crystallized from dichloromethane/methanol/ethyl acetate

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

実験手順: A mixture of N-(5-fluoro-2-nitrophenyl)glycine ethyl ester (XI, EXAMPLE 5, 28.60 g), palladium on carbon (10%, 1.01 g) and methanol (500 ml) is shaken under 45 psi of hydrogen on a Parr shaker. After 2 hr an additional 0.54 g of 10% palladium on carbon catalyst is added. The mixture is shaken for an hour at 42 psi and then the catalyst is removed by filtration. p-Toluenesulfonic acid (0.314 g) is added to the filtrate. The solution is concentrated under reduced pressure to a volume of about 250 ml and then stirred at 20°-25°. The reaction is then further concentrated and dichloromethane is added. The solid that formed is collected and chromatographed on 800 ml of silica gel (column) eluting with dichloromethane/methanol (98/2). The appropriate fractions are pooled and concentrated and triturated with a small amount of dichloromethane. The solid is collected, dried, and triturated a second time with dichloromethane and redried to give the title compound, mp 176.0°-177.5°; NMR (CDCl3) 3.95, 3.99, 6.42, 6.63 and 8.33 δ. the catalyst is removed by filtration p-Toluenesulfonic acid (0.314 g) is added to the filtrate The solution is concentrated under reduced pressure to a volume of about 250 ml stirred at 20°-25° The reaction is then further concentrated dichloromethane is added The solid that formed is collected chromatographed on 800 ml of silica gel (column) eluting with dichloromethane/methanol (98/2) concentrated triturated with a small amount of dichloromethane The solid is collected dried triturated a second time with dichloromethane redried