3-chloro-5-fluorobenzaldehyde

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the mixture of 6-chloro-2-oxindole (4.4 g, 26 mmol) (Crescent) and 3-chloro-5-fluorobenzaldehyde (4.2 g, 26 mmol) (Aldrich) in methanol (200 mL) was added piperidine (2.3 g, 26 mmol) (Aldrich) dropwise. The mixture was then heated at 80° C. for 2 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-5-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 7.5 g, 92%). After cooled to 4° C. the mixture was filtered resulting precipitate was collected dried

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the mixture of 6-chloro-2-oxindole (4.4 g, 26 mmol) (Crescent) and 3-chloro-5-fluorobenzaldehyde (4.2 g, 26 mmol) (Aldrich) in methanol (200 mL) was added piperidine (2.3 g, 26 mmol) (Aldrich) dropwise. The mixture was then heated at 80° C. for 2 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-5-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 7.5 g, 92%). After cooled to 4° C. the mixture was filtered resulting precipitate was collected dried

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

実験手順: Dissolve 3-chloro-5-fluorobenzaldehyde (4.0 g, 25.2 mmol) in glacial acetic acid (15 mL). Add nitromethane (4.1 mL, 75.7 mmol) and ammonium acetate (1.94 g, 25.2 mmol) and heat to reflux for 4 hours. Cool and pour over ice. Dilute with 2 N sodium hydroxide and extract with ethyl acetate, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 1:1 dichloromethane:hexanes) to give the desired compound as a beige solid (2.97 g, 58%). to reflux for 4 hours Cool pour over ice extract with ethyl acetate dry (magnesium sulfate) concentrate purify (silica gel chromatography, eluting with 1:1 dichloromethane:hexanes)

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: Dissolve 3-chloro-5-fluorobenzaldehyde (4.0 g, 25.2 mmol) in glacial acetic acid (15 mL). Add nitromethane (4.1 mL, 75.7 mmol) and ammonium acetate (1.94 g, 25.2 mmol) and heat to reflux for 4 hours. Cool and pour over ice. Dilute with 2 N sodium hydroxide and extract with ethyl acetate, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 1:1 dichloromethane:hexanes) to give the desired compound as a beige solid (2.97 g, 58%). to reflux for 4 hours Cool pour over ice extract with ethyl acetate dry (magnesium sulfate) concentrate purify (silica gel chromatography, eluting with 1:1 dichloromethane:hexanes)

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

実験手順: In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (3.4 g, 20 mmol) was reacted with 3-chloro-5-fluoro-benzaldehyde (Aldrich) (3.77 g, 24 mmol), methanolic solution (25 wt %) of sodium methoxide (4.99 mL, 22 mmol) in methanol (90 mL) at 50° C. for 3 h to give (Z)-3-(3-chloro-5-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (5.5 g, 90%).

反応条件: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-(2-(isopropylamino)-2-oxoethyl)benzamide (Intermediate 7A) (70 mg, 0.20 mmol) was dissolved in ethanol (2 mL) before addition of 3-chloro-5-fluorobenzaldehyde (46.3 mg, 0.29 mmol) followed by 2 drops of acetic acid. The resulting solution was sealed in a Reactivial® and heated at 95° C. for 24 hours. Reaction mixture was then cooled to room temperature and diluted with methanol before loading directly onto a 1 g SCX cartridge. The crude material was purified by SCX and concentrated under reduced pressure. The resultant product was re-dissolved in dichloromethane (2 mL), manganese dioxide (33.8 mg, 0.39 mmol) was added and reaction stirred overnight. The sample was then washed with water (5 mL) and extracted into dichloromethane. The organics were separated using a hydrophobic frit. The solvent was removed under reduced pressure and then re-dissolved in methanol (1 mL) and purified by preparative-HPLC. Purified sample was free-based using 500 mg SCX cartridge to afford 2-(6-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chloro-5-fluorophenyl)-4-oxoquinazolin-3(4H)-yl)-N-isopropylacetamide (9.0 mg, 0.018 mmol) 9% yield. The resulting solution was sealed in a Reactivial® Reaction mixture was then cooled to room temperature The crude material was purified by SCX concentrated under reduced pressure The resultant product was re-dissolved in dichloromethane (2 mL) reaction The sample was then washed with water (5 mL) extracted into dichloromethane The organics were separated The solvent was removed under reduced pressure re-dissolved in methanol (1 mL) purified by preparative-HPLC Purified sample

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the mixture of 6-chloro-2-oxindole (4.4 g, 26 mmol) (Crescent) and 3-chloro-5-fluorobenzaldehyde (4.2 g, 26 mmol) (Aldrich) in methanol (200 mL) was added piperidine (2.3 g, 26 mmol) (Aldrich) dropwise. The mixture was then heated at 80° C. for 2 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-5-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 7.5 g, 92%). After cooled to 4° C. the mixture was filtered resulting precipitate was collected dried

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

実験手順: Dissolve 3-chloro-5-fluorobenzaldehyde (4.0 g, 25.2 mmol) in glacial acetic acid (15 mL). Add nitromethane (4.1 mL, 75.7 mmol) and ammonium acetate (1.94 g, 25.2 mmol) and heat to reflux for 4 hours. Cool and pour over ice. Dilute with 2 N sodium hydroxide and extract with ethyl acetate, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 1:1 dichloromethane:hexanes) to give the desired compound as a beige solid (2.97 g, 58%). to reflux for 4 hours Cool pour over ice extract with ethyl acetate dry (magnesium sulfate) concentrate purify (silica gel chromatography, eluting with 1:1 dichloromethane:hexanes)