1H-BENZO[D][1,3]OXAZIN-2(4H)-ONE

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 2-hydroxymethylaniline (25 g), triethylamine (32 ml) and tetrahydrofuran (250 ml) was introduced phosgene generated from trichloromethyl chloroformate (12.2 ml) and active carbon at room temperature with stirring. After stirring for 1 hour at room temperature, the reaction mixture was filtered off and the filtrate was concentrated. The resulting residue was recrystallized from diethyl ether-n-hexane to give 4H-1,2-dihydro-2-oxo-[3,1]benzoxazine (22.3 g). After stirring for 1 hour at room temperature the reaction mixture was filtered off the filtrate was concentrated The resulting residue was recrystallized from diethyl ether-n-hexane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 2-hydroxymethylaniline (25 g), triethylamine (32 ml) and tetrahydrofuran (250 ml) was introduced phosgene generated from trichloromethyl chloroformate (12.2 ml) and active carbon at room temperature with stirring. After stirring for 1 hour at room temperature, the reaction mixture was filtered off and the filtrate was concentrated. The resulting residue was recrystallized from diethyl ether-n-hexane to give 4H-1,2-dihydro-2-oxo-[3,1]benzoxazine (22.3 g). After stirring for 1 hour at room temperature the reaction mixture was filtered off the filtrate was concentrated The resulting residue was recrystallized from diethyl ether-n-hexane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Following general procedure A, starting from (R)-4-((R)-1-((6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (63 mg), and 1,4,4-trimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,3]oxazin-2(4H)-one (67 mg), 55 mg of 1,4,4-trimethyl-7-(3-methyl-4-4R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1H-benzo[d][1,3]oxazin-2(4H)-one was synthesized.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Following general procedure A, starting from (R)-4-((R)-1-((6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (63 mg), and 1,4,4-trimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,3]oxazin-2(4H)-one (67 mg), 55 mg of 1,4,4-trimethyl-7-(3-methyl-4-4R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1H-benzo[d][1,3]oxazin-2(4H)-one was synthesized.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Methyl chloroformate (1.2 equiv) is added to a solution of a 2-(aminophenyl)alkanol (1 equiv) and DMAP (0.10 equiv) in pyridine (1 M) at 0° C. Additional pyridine is added as needed to keep the precipitates from accumulating. The solution is allowed to warm to room temperature and stirred for 2 hours. Sodium bisulfate (2N) and ethyl acetate are added, resulting in an aqueous layer and a first organic layer. The first organic layer is collected and the aqueous layer extracted with ethyl acetate. The organic layer from that extraction is combined with the first organic layer and that combined organic layer is washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford a solid. To the solid is added potassium carbonate (2 equiv) in DMF (0.5-0.7 M) and that mixture is heated to 100° C. for 1-4 hours. The mixture is cooled and poured into ethyl acetate:water, resulting in a first organic layer and an aqueous layer. The first organic layer is collected and the aqueous layer is extracted with ethyl acetate. The organic layer from that extraction is combined with the collected first organic layer, and the combined organic layers are washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated to afford the 1,4-dihydro-2H-3,1-benzoxazin-2-one. precipitates Sodium bisulfate (2N) and ethyl acetate are added resulting in an aqueous layer The first organic layer is collected the aqueous layer extracted with ethyl acetate The organic layer from that extraction that combined organic layer is washed sequentially with water and brine dried over magnesium sulfate filtered concentrated under reduced pressure to afford a solid that mixture is heated to 100° C. for 1-4 hours The mixture is cooled The first organic layer is collected the aqueous layer is extracted with ethyl acetate The organic layer from that extraction the combined organic layers are washed sequentially with water and brine dried over magnesium sulfate filtered concentrated

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 143 g (0.948 moles) of 2-carbamoyl-benzyl alcohol, 2.3 g (0.0226 moles) of sodium bromide, 6.7 g of Adogen 464 and 806 ml of isopropyl acetate were stirred together in a two liter flask and cooled in a water bath. 504 ml of a 14% w/v solution of sodium hypochlorite (1.0 mole) was added to the stirred mixture over 40 minutes and at 30° C. Vigorous agitation was maintained during the addition and for a further 2 hours. The two-phase reaction mixture was then warmed to 50° C. to dissolve all solids. The organic phase was separated and the medium distilled off. The formed solid was recrystallized from 3 volumes of toluene to form 99 g of the desired product as a pale brown solid; m.p. 112° C.; yield 70%. cooled in a water bath Vigorous agitation was maintained during the addition and for a further 2 hours The two-phase reaction mixture to dissolve all solids The organic phase was separated the medium distilled off The formed solid was recrystallized from 3 volumes of toluene

反应条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The reaction mixture from Stage A was boiled so as to drive off the isopropyl acetate solvent. A solution of 100 g of sodium hydroxide in 100 ml of water was added to the residue, and the whole was refluxed for 2 hours. After cooling to 45° C., the product was extracted with four 270 ml portions of isopropyl acetate. The isopropyl acetate was then distilled off and the product recrystallized from toluene to give 100 g (63% of theoretical) of 97-98% pure 2-amino-benzyl alcohol; m.p. 83°-83.5° C. the whole was refluxed for 2 hours the product was extracted with four 270 ml portions of isopropyl acetate The isopropyl acetate was then distilled off the product recrystallized from toluene

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 2-hydroxymethylaniline (25 g), triethylamine (32 ml) and tetrahydrofuran (250 ml) was introduced phosgene generated from trichloromethyl chloroformate (12.2 ml) and active carbon at room temperature with stirring. After stirring for 1 hour at room temperature, the reaction mixture was filtered off and the filtrate was concentrated. The resulting residue was recrystallized from diethyl ether-n-hexane to give 4H-1,2-dihydro-2-oxo-[3,1]benzoxazine (22.3 g). After stirring for 1 hour at room temperature the reaction mixture was filtered off the filtrate was concentrated The resulting residue was recrystallized from diethyl ether-n-hexane