2-amino-5-fluoro-3-methylbenzamide

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

実験手順: A solution of 2-amino-5-fluoro-3-methyl-benzamide (84.1 mg, 0.50 mmol), 4-(4-methyl-piperazin-1-yl)-benzaldehyde (123 mg, 0.60 mmol) and sodium disulfite (97 mg, 0.51 mmol) in N-methyl-pyrrolidone (1 ml) is heated to 150° C. and stirred at this temperature for 16 hours. The reaction mixture is allowed to reach room temperature and poured into ice water. The resulting precipitate is collected by filtration, washed with water and dried. The residue is chromatographed on a silica gel column with methanol/dichloromethane as eluent to afford 6-fluoro-8-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenyl]-3H-quinazolin-4-one as brown powder; HPLC/MS 1.47 min (A), [M+H] 353; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 12.34 (s, 1H), 8.69-7.90 (m, 2H), 7.86-7.26 (m, 2H), 7.28-6.73 (m, 2H), 3.33-3.27 (m, 4H), 2.61 (s, 3H), 2.45 (t, J=5.1 Hz, 4H), 2.23 (s, 3H). to reach room temperature The resulting precipitate is collected by filtration washed with water dried The residue is chromatographed on a silica gel column with methanol/dichloromethane as eluent

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

実験手順: To a solution of 2-amino-5-fluoro-3-methyl-benzoic acid (4.80 g, 28.4 mmol) in THF (60 ml) is added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.9 g, 56.8 mmol), 1-hydroxybenzotriazole hydrate (4.34 g, 28.4 mmol) and ammonia as 5 M solution in dioxane (283 ml, 142 mmol). The resulting slurry is stirred for 3 hours. The reaction mixture is filtered through Celite and washed with THF. The filtrate is evaporated and partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The residue is crystallized from 2-propanol to afford 2-amino-5-fluoro-3-methyl-benzamide as beige crystals; HPLC/MS 1.68 min (B), [M+H] 169. The reaction mixture is filtered through Celite washed with THF The filtrate is evaporated partitioned between water and ethyl acetate The organic phase is dried over sodium sulfate evaporated The residue is crystallized from 2-propanol

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

実験手順: A solution of 2-amino-5-fluoro-3-methyl-benzamide (84.1 mg, 0.50 mmol), 4-(4-methyl-piperazin-1-yl)-benzaldehyde (123 mg, 0.60 mmol) and sodium disulfite (97 mg, 0.51 mmol) in N-methyl-pyrrolidone (1 ml) is heated to 150° C. and stirred at this temperature for 16 hours. The reaction mixture is allowed to reach room temperature and poured into ice water. The resulting precipitate is collected by filtration, washed with water and dried. The residue is chromatographed on a silica gel column with methanol/dichloromethane as eluent to afford 6-fluoro-8-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenyl]-3H-quinazolin-4-one as brown powder; HPLC/MS 1.47 min (A), [M+H] 353; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 12.34 (s, 1H), 8.69-7.90 (m, 2H), 7.86-7.26 (m, 2H), 7.28-6.73 (m, 2H), 3.33-3.27 (m, 4H), 2.61 (s, 3H), 2.45 (t, J=5.1 Hz, 4H), 2.23 (s, 3H). to reach room temperature The resulting precipitate is collected by filtration washed with water dried The residue is chromatographed on a silica gel column with methanol/dichloromethane as eluent

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

実験手順: To a solution of 2-amino-5-fluoro-3-methyl-benzoic acid (4.80 g, 28.4 mmol) in THF (60 ml) is added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.9 g, 56.8 mmol), 1-hydroxybenzotriazole hydrate (4.34 g, 28.4 mmol) and ammonia as 5 M solution in dioxane (283 ml, 142 mmol). The resulting slurry is stirred for 3 hours. The reaction mixture is filtered through Celite and washed with THF. The filtrate is evaporated and partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The residue is crystallized from 2-propanol to afford 2-amino-5-fluoro-3-methyl-benzamide as beige crystals; HPLC/MS 1.68 min (B), [M+H] 169. The reaction mixture is filtered through Celite washed with THF The filtrate is evaporated partitioned between water and ethyl acetate The organic phase is dried over sodium sulfate evaporated The residue is crystallized from 2-propanol