2-amino-5-bromo-4-fluorobenzaldehyde

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-morpholinoacetonitrile (1.29 g, 10.26 mmol) in DMSO (13 mL) was added aqueous KOH (11.7 M, 0.276 mL, 3.23 mmol). The reaction was heated at 80° C., and a solution of 2-amino-5-bromo-4-fluorobenzaldehyde (1.41 g, 6.45 mmol) in DMSO (13 mL) was added dropwise over 2.5 h. The reaction mixture was stirred at 80° C. for 14 h. It was then cooled to RT and diluted with water (200 mL) and saturated NH4Cl (5 mL). The aqueous phase was extracted with DCM (2×200 mL). The organic fractions were combined, washed with half-saturated brine (4×300 mL), dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (150 mL) which had been deactivated with TEA (15 mL) eluting with 75:25:1:0.5 EtOAc/hexane/MeOH/Et3N to afford 6-bromo-7-fluoro-3-morpholinoquinolin-2-amine. It was then cooled to RT The aqueous phase was extracted with DCM (2×200 mL) washed with half-saturated brine (4×300 mL) dried over sodium sulfate concentrated The residue was purified by column chromatography on silica gel (150 mL) which eluting with 75:25:1:0.5 EtOAc/hexane/MeOH/Et3N

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-morpholinoacetonitrile (1.29 g, 10.26 mmol) in DMSO (13 mL) was added aqueous KOH (11.7 M, 0.276 mL, 3.23 mmol). The reaction was heated at 80° C., and a solution of 2-amino-5-bromo-4-fluorobenzaldehyde (1.41 g, 6.45 mmol) in DMSO (13 mL) was added dropwise over 2.5 h. The reaction mixture was stirred at 80° C. for 14 h. It was then cooled to RT and diluted with water (200 mL) and saturated NH4Cl (5 mL). The aqueous phase was extracted with DCM (2×200 mL). The organic fractions were combined, washed with half-saturated brine (4×300 mL), dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (150 mL) which had been deactivated with TEA (15 mL) eluting with 75:25:1:0.5 EtOAc/hexane/MeOH/Et3N to afford 6-bromo-7-fluoro-3-morpholinoquinolin-2-amine. It was then cooled to RT The aqueous phase was extracted with DCM (2×200 mL) washed with half-saturated brine (4×300 mL) dried over sodium sulfate concentrated The residue was purified by column chromatography on silica gel (150 mL) which eluting with 75:25:1:0.5 EtOAc/hexane/MeOH/Et3N

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

Procedure: To a suspension of Pt/C (10%, 1.5 g, 0.77 mmol) in DCM (200 mL) and THF (50 mL) was added 5-bromo-4-fluoro-2-nitrobenzaldehyde (9.0 g, 36.3 mmol). The mixture was purged with H2 gas, and was stirred under an atmosphere of H2 gas at ambient temperature for 24 h. The reaction mixture was filtered through celite rinsing with DCM. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (600 mL) eluting with 15% EtOAc/hexane to afford 2-amino-5-bromo-4-fluorobenzaldehyde. The mixture was purged with H2 gas The reaction mixture was filtered through celite rinsing with DCM The filtrate was concentrated the residue was purified by column chromatography on silica gel (600 mL) eluting with 15% EtOAc/hexane

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

Procedure: To a solution of Example 115A (1.0 g, 4.0 mmol) in 1: 1 ethanol-water (50 mL), was added iron-powder (0.6 g) then 6 N hydrochloric acid (1 mL). The reaction mixture was heated to reflux overnight, cooled, neutralized with I N sodium hydroxide, filtered, and the filtrate extracted with ethyl acetate (3x). The organic extracts were dried over magnesium sulfate, filtered and solvent evaporated to provide 0.68 g of 5-bromo-4-fluoro-2-aminobenzaldehyde. To a solution of 2-amino-5-bromo-4-fluorobenzaldehyde (0.68 g, 3.1 mmol) in water (10 mL) at 0 ° C. was added sulfuric acid (2 mL) then slowly a solution of sodium nitrite (0.23 g, 3.4 mmol) in water (10 mL) keeping the temperature below 10 ° C.. After stirring at this temperature for 1 hour this suspension was added to a solution of potassium iodide (0.50 g, 3.1 mmol) in water (20 mL), the reaction mixture stirred at room temperature overnight, extracted with ethyl acetate (3x). The organic extracts were washed with aqueous sodium thiosulfate, 5% sodium bicarbonate solution and water, then dried over magnesium sulfate, filtered and solvent evaporated. The crude residue was purified by flash chromatography over silica gel eluting with ethyl acetate:hexane (1:9) to provide 0.16 g of the title compound as a tan solid. the temperature below 10 ° C. the reaction mixture stirred at room temperature overnight extracted with ethyl acetate (3x) The organic extracts were washed with aqueous sodium thiosulfate, 5% sodium bicarbonate solution and water dried over magnesium sulfate filtered solvent evaporated The crude residue was purified by flash chromatography over silica gel eluting with ethyl acetate:hexane (1:9)

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

Procedure: To a solution of Example 115A (1.0 g, 4.0 mmol) in 1: 1 ethanol-water (50 mL), was added iron-powder (0.6 g) then 6 N hydrochloric acid (1 mL). The reaction mixture was heated to reflux overnight, cooled, neutralized with I N sodium hydroxide, filtered, and the filtrate extracted with ethyl acetate (3x). The organic extracts were dried over magnesium sulfate, filtered and solvent evaporated to provide 0.68 g of 5-bromo-4-fluoro-2-aminobenzaldehyde. To a solution of 2-amino-5-bromo-4-fluorobenzaldehyde (0.68 g, 3.1 mmol) in water (10 mL) at 0 ° C. was added sulfuric acid (2 mL) then slowly a solution of sodium nitrite (0.23 g, 3.4 mmol) in water (10 mL) keeping the temperature below 10 ° C.. After stirring at this temperature for 1 hour this suspension was added to a solution of potassium iodide (0.50 g, 3.1 mmol) in water (20 mL), the reaction mixture stirred at room temperature overnight, extracted with ethyl acetate (3x). The organic extracts were washed with aqueous sodium thiosulfate, 5% sodium bicarbonate solution and water, then dried over magnesium sulfate, filtered and solvent evaporated. The crude residue was purified by flash chromatography over silica gel eluting with ethyl acetate:hexane (1:9) to provide 0.16 g of the title compound as a tan solid. The reaction mixture was heated to reflux overnight cooled filtered the filtrate extracted with ethyl acetate (3x) The organic extracts were dried over magnesium sulfate filtered solvent evaporated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-morpholinoacetonitrile (1.29 g, 10.26 mmol) in DMSO (13 mL) was added aqueous KOH (11.7 M, 0.276 mL, 3.23 mmol). The reaction was heated at 80° C., and a solution of 2-amino-5-bromo-4-fluorobenzaldehyde (1.41 g, 6.45 mmol) in DMSO (13 mL) was added dropwise over 2.5 h. The reaction mixture was stirred at 80° C. for 14 h. It was then cooled to RT and diluted with water (200 mL) and saturated NH4Cl (5 mL). The aqueous phase was extracted with DCM (2×200 mL). The organic fractions were combined, washed with half-saturated brine (4×300 mL), dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (150 mL) which had been deactivated with TEA (15 mL) eluting with 75:25:1:0.5 EtOAc/hexane/MeOH/Et3N to afford 6-bromo-7-fluoro-3-morpholinoquinolin-2-amine. It was then cooled to RT The aqueous phase was extracted with DCM (2×200 mL) washed with half-saturated brine (4×300 mL) dried over sodium sulfate concentrated The residue was purified by column chromatography on silica gel (150 mL) which eluting with 75:25:1:0.5 EtOAc/hexane/MeOH/Et3N

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

Procedure: To a suspension of Pt/C (10%, 1.5 g, 0.77 mmol) in DCM (200 mL) and THF (50 mL) was added 5-bromo-4-fluoro-2-nitrobenzaldehyde (9.0 g, 36.3 mmol). The mixture was purged with H2 gas, and was stirred under an atmosphere of H2 gas at ambient temperature for 24 h. The reaction mixture was filtered through celite rinsing with DCM. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (600 mL) eluting with 15% EtOAc/hexane to afford 2-amino-5-bromo-4-fluorobenzaldehyde. The mixture was purged with H2 gas The reaction mixture was filtered through celite rinsing with DCM The filtrate was concentrated the residue was purified by column chromatography on silica gel (600 mL) eluting with 15% EtOAc/hexane