2-bromo-1-morpholin-4-ylethanone

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:0.00; pressure:0.00; stir:

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

Procedure: A glass vial was charged with 4-(bromoacetyl)morpholine (0.05 g, 0.26 mmol, 1.1 eq), 6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-3-ol (0.06 g, 0.23 mmol), DMF (3 mL), and cesium carbonate (0.42 g, 1.3 mmol, 5 eq). The reaction mixture was heated at 90° C. overnight. The reaction was quenched with 30 mL water to provide an off-white precipitate. The solid was collected by vacuum filtration and recrystallized from acetonitrile to provide 0.011 g of 3-(2-morpholin-4-yl-2-oxoethoxy) 10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine, mp 204-206° C. The reaction was quenched with 30 mL water to provide an off-white precipitate The solid was collected by vacuum filtration recrystallized from acetonitrile

Conditions: temp:-25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of bromoacetyl bromide (3.0 mL, 0.034 mol) in dichloromethane (240 mL) was cooled to −25° C. A solution of morpholine (9.0 mL, 0.10 mol) in dichloromethane (20 mL) was slowly added over a period of one hour. After the addition was complete, the reaction was stirred at −25° C. for 15 minutes and then allowed to warm to ambient temperature. Dichloromethane was added, and the resulting solution was washed sequentially with water, 1N aqueous hydrogen chloride, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure to provide 4-(bromoacetyl)morpholine as a colorless oil. After the addition to warm to ambient temperature the resulting solution was washed sequentially with water, 1N aqueous hydrogen chloride, and brine dried over magnesium sulfate filtered and concentrated under reduced pressure

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (11S)-6-amino-11-isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-3-ol (0.30 g, 1.0 mmol) dissolved in 5 mL of DMF was treated with cesium carbonate (1.0 g, 3.0 mmol) and 4-(bromoacetyl)morpholine (0.23 g, 1.1 mmol). After stirring for 18 hours at 65° C., the reaction mixture was concentrated under reduced pressure to give a solid. The solid was dissolved in CH2Cl2 (100 mL) and washed with H2O (100 mL). The organic layer was concentrated under reduced pressure to give a solid. Chromatography (SiO2, 0-15% CMA/CHCl3) gave a white solid which was crystallized from acetonitrile to give 0.18 g of the title compound as white crystals, mp 137-139° C. the reaction mixture was concentrated under reduced pressure to give a solid washed with H2O (100 mL) The organic layer was concentrated under reduced pressure to give a solid was crystallized from acetonitrile

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (11S)-6-amino-11-isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-3-ol (0.30 g, 1.0 mmol) dissolved in 5 mL of DMF was treated with cesium carbonate (1.0 g, 3.0 mmol) and 4-(bromoacetyl)morpholine (0.23 g, 1.1 mmol). After stirring for 18 hours at 65° C., the reaction mixture was concentrated under reduced pressure to give a solid. The solid was dissolved in CH2Cl2 (100 mL) and washed with H2O (100 mL). The organic layer was concentrated under reduced pressure to give a solid. Chromatography (SiO2, 0-15% CMA/CHCl3) gave a white solid which was crystallized from acetonitrile to give 0.18 g of the title compound as white crystals, mp 137-139° C. the reaction mixture was concentrated under reduced pressure to give a solid washed with H2O (100 mL) The organic layer was concentrated under reduced pressure to give a solid was crystallized from acetonitrile

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-2-ol (500 mg, 1.85 mmol) dissolved in 15 mL of DMF was treated with cesium carbonate (1.80 g, 5.55 mmol) and 2-bromo-1-morpholin-4-yl-ethanone (462 mg, 2.03 mmol). After stirring overnight at 75° C., the brown mixture was poured into 150 mL of H2O and stirred for 30 minutes. The reaction mixture was extracted with CHCl3 (3×75 mL) and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give an off-white solid. Chromatography (SiO2, 0-20% CMA/CHCl3) gave an off-white solid which was crystallized from acetonitrile to give 272 mg of the title compound as an off-white solid, mp 226-228° C. stirred for 30 minutes The reaction mixture was extracted with CHCl3 (3×75 mL) the combined extracts were dried over MgSO4 filtered concentrated under reduced pressure to give an off-white solid was crystallized from acetonitrile

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

Procedure: Bromoacetylbromide (20.1 g) was added dropwise to a rapidly stirred solution of morpholine (17.4 g) in ether (200 ml). After stirring overnight, the mixture was washed with water (2×50 ml), dried (MgSO4) and evaporated to afford a colourless oil. 1H NMR (360 MHz, CDCl3) δ3.46 (2H, m, 2×CHHN), 3.63 (2H, m, 2×CHHN), 3.69 (4H, m, 2×CH2O), 3.75 (2H, s, CH2Br). the mixture was washed with water (2×50 ml) dried (MgSO4) evaporated to afford a colourless oil

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (11S)-6-amino-11-isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-3-ol (0.30 g, 1.0 mmol) dissolved in 5 mL of DMF was treated with cesium carbonate (1.0 g, 3.0 mmol) and 4-(bromoacetyl)morpholine (0.23 g, 1.1 mmol). After stirring for 18 hours at 65° C., the reaction mixture was concentrated under reduced pressure to give a solid. The solid was dissolved in CH2Cl2 (100 mL) and washed with H2O (100 mL). The organic layer was concentrated under reduced pressure to give a solid. Chromatography (SiO2, 0-15% CMA/CHCl3) gave a white solid which was crystallized from acetonitrile to give 0.18 g of the title compound as white crystals, mp 137-139° C. the reaction mixture was concentrated under reduced pressure to give a solid washed with H2O (100 mL) The organic layer was concentrated under reduced pressure to give a solid was crystallized from acetonitrile