3-bromo-4-formylbenzonitrile

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

実験手順: Formic acid (3.9 mL, 104 mmol) is added to a solution of tert-butyl carbamate (1.90 g, 16.2 mmol), 2-bromo-4-cyanobenzaldehyde (3.41 g, 16.2 mmol) and sodium benzenesulfinate (2.67 g, 16.2 mmol) in a mixture of tetrahydrofuran (7.0 mL) and water (60 mL), and the mixture is stirred at room temperature for 6 days. Water (180 mL) is added, and the precipitate is filtered and washed with water. The precipitate is treated with tert-butyl methyl ether (30 mL), and the mixture is stirred for 30 min. The precipitate is filtered, washed with tert-butyl methyl ether, and dried. Yield: 3.35 g. ESI mass spectrum: [(79Br)-M+H]+=451, [(81Br)-M+H]+=453; Retention time HPLC: 0.66 min (X012_S01). the precipitate is filtered washed with water The precipitate is treated with tert-butyl methyl ether (30 mL) the mixture is stirred for 30 min The precipitate is filtered washed with tert-butyl methyl ether dried 0.66 min (X012_S01)

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

実験手順: 3-Bromo-4-formyl-benzonitrile (intermediate 2, 3.25 g, 14.7 mmol) is stirred with acetylacetone (2.42 mL, 19.1 mmol), 3-(trifluoromethyl)phenylurea (3 g, 14.7 mmol) and polyphosphoric acid (3.02 g, 7.90 mmol) in tetrahydrofurane (80.0 mL) at 60° C. for 48 h. The reaction mixture is concentrated in vacuo and ethyl acetate and water is added and the phases are separated. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over MgSO4 and concentrated. Yield: 7.66 g; ESI mass spectrum: [M+H]+=508; Retention time HPLC: 1.14 min (HPLC method Z018_S04) The reaction mixture is concentrated in vacuo and ethyl acetate and water is added the phases are separated The aqueous phase is extracted twice with ethyl acetate The combined organic phases are washed with saturated sodium chloride solution dried over MgSO4 concentrated 1.14 min (HPLC method Z018_S04)

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

実験手順: 3-Bromo-4-formyl-benzonitrile (intermediate 2, 3.25 g, 14.7 mmol) is stirred with acetylacetone (2.42 mL, 19.1 mmol), 3-(trifluoromethyl)phenylurea (3 g, 14.7 mmol) and polyphosphoric acid (3.02 g, 7.90 mmol) in tetrahydrofurane (80.0 mL) at 60° C. for 48 h. The reaction mixture is concentrated in vacuo and ethyl acetate and water is added and the phases are separated. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over MgSO4 and concentrated. Yield: 7.66 g; ESI mass spectrum: [M+H]+=508; Retention time HPLC: 1.14 min (HPLC method Z018_S04) The reaction mixture is concentrated in vacuo and ethyl acetate and water is added the phases are separated The aqueous phase is extracted twice with ethyl acetate The combined organic phases are washed with saturated sodium chloride solution dried over MgSO4 concentrated 1.14 min (HPLC method Z018_S04)

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

実験手順: 3-Bromo-4-formyl-benzonitrile (intermediate 2, 1.09 g, 4.92 mmol) is stirred with acetylacetone (0.60 mL, 5.88 mmol), 3-(trifluoromethyl)phenylurea (1.00 g, 4.90 mmol) and polyphosphoric acid (3.02 g, 7.90 mmol) in tetrahydrofurane (40.0 mL) at 50° C. overnight. The reaction mixture is concentrated in vacuo, ethyl acetate and water is added and the phases are separated. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over MgSO4 and concentrated. Yield: 2.38 g; ESI mass spectrum: [(79Br)-M+H]+=478, [(81Br)-M+H]+=480; Retention time HPLC: 1.06 min (HPLC method Z018_S04). The reaction mixture is concentrated in vacuo, ethyl acetate and water is added the phases are separated The aqueous phase is extracted twice with ethyl acetate The combined organic phases are washed with saturated sodium chloride solution dried over MgSO4 concentrated 1.06 min (HPLC method Z018_S04)

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

実験手順: 3-Bromo-4-formyl-benzonitrile (intermediate 2, 1.09 g, 4.92 mmol) is stirred with acetylacetone (0.60 mL, 5.88 mmol), 3-(trifluoromethyl)phenylurea (1.00 g, 4.90 mmol) and polyphosphoric acid (3.02 g, 7.90 mmol) in tetrahydrofurane (40.0 mL) at 50° C. overnight. The reaction mixture is concentrated in vacuo, ethyl acetate and water is added and the phases are separated. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over MgSO4 and concentrated. Yield: 2.38 g; ESI mass spectrum: [(79Br)-M+H]+=478, [(81Br)-M+H]+=480; Retention time HPLC: 1.06 min (HPLC method Z018_S04). The reaction mixture is concentrated in vacuo, ethyl acetate and water is added the phases are separated The aqueous phase is extracted twice with ethyl acetate The combined organic phases are washed with saturated sodium chloride solution dried over MgSO4 concentrated 1.06 min (HPLC method Z018_S04)

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

実験手順: 3-Bromo-4-formyl-benzonitrile (20.5 g, 97.7 mmol), benzenesulfinic acid sodium salt (16.03 g, 97.6 mmol) and tert-butylcarbamate (11.4 g, 97.7 mmol) are suspended in water (312 mL) and THF (78 mL). Formic acid (28.8 g, 625 mmol) is added and the solution is stirred at room temperature for 6 days. Water (300 mL) is added and the precipitate is filtered off, washed with water and dried. The crude product is further purified by precipitation from tert-butylmethylether. Yield: 26.8 g; ESI mass spectrum: [M+Na]+=473 (bromine isotope pattern). the precipitate is filtered off washed with water dried The crude product is further purified by precipitation from tert-butylmethylether

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

実験手順: 3-Bromo-4-formyl-benzonitrile (20.5 g, 97.7 mmol), benzenesulfinic acid sodium salt (16.03 g, 97.6 mmol) and tert-butylcarbamate (11.4 g, 97.7 mmol) are suspended in water (312 mL) and THF (78 mL). Formic acid (28.8 g, 625 mmol) is added and the solution is stirred at room temperature for 6 days. Water (300 mL) is added and the precipitate is filtered off, washed with water and dried. The crude product is further purified by precipitation from tert-butylmethylether. Yield: 26.8 g; ESI mass spectrum: [M+Na]+=473 (bromine isotope pattern). the precipitate is filtered off washed with water dried The crude product is further purified by precipitation from tert-butylmethylether

反応条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Trifluoromethylphenylthiourea (12.8 g, 87 mmol), 2-bromo-4-cyanobenzaldehyde (18.3 g, 87 mmol), and methyl acetoacetate (10.4 mL, 96 mmol) were dissolved in THF (300 mL) under an atmosphere of N2 and then trimethylsilylphosphate (18 g) in THF (50 mL) was added, and the mixture heated at 75° C. After 17 hours the reaction mixture was allowed to cool, poured onto 0.5 M HCl (600 mL) and stirred for 30 minutes. The mixture was extracted into EtOAc. The organic phase was washed with water, then brine and dried (Na2SO4) before being concentrated in vacuo. The resulting solid was triturated with Et2O (50 mL), filtered and the solid collected to yield the title compound as a white solid (22.2 g). to cool The mixture was extracted into EtOAc The organic phase was washed with water brine and dried (Na2SO4) before being concentrated in vacuo The resulting solid was triturated with Et2O (50 mL) filtered the solid collected

反応条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Trifluoromethylphenylthiourea (12.8 g, 87 mmol), 2-bromo-4-cyanobenzaldehyde (18.3 g, 87 mmol), and methyl acetoacetate (10.4 mL, 96 mmol) were dissolved in THF (300 mL) under an atmosphere of N2 and then trimethylsilylphosphate (18 g) in THF (50 mL) was added, and the mixture heated at 75° C. After 17 hours the reaction mixture was allowed to cool, poured onto 0.5 M HCl (600 mL) and stirred for 30 minutes. The mixture was extracted into EtOAc. The organic phase was washed with water, then brine and dried (Na2SO4) before being concentrated in vacuo. The resulting solid was triturated with Et2O (50 mL), filtered and the solid collected to yield the title compound as a white solid (22.2 g). to cool The mixture was extracted into EtOAc The organic phase was washed with water brine and dried (Na2SO4) before being concentrated in vacuo The resulting solid was triturated with Et2O (50 mL) filtered the solid collected

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

実験手順: Formic acid (3.9 mL, 104 mmol) is added to a solution of tert-butyl carbamate (1.90 g, 16.2 mmol), 2-bromo-4-cyanobenzaldehyde (3.41 g, 16.2 mmol) and sodium benzenesulfinate (2.67 g, 16.2 mmol) in a mixture of tetrahydrofuran (7.0 mL) and water (60 mL), and the mixture is stirred at room temperature for 6 days. Water (180 mL) is added, and the precipitate is filtered and washed with water. The precipitate is treated with tert-butyl methyl ether (30 mL), and the mixture is stirred for 30 min. The precipitate is filtered, washed with tert-butyl methyl ether, and dried. Yield: 3.35 g. ESI mass spectrum: [(79Br)-M+H]+=451, [(81Br)-M+H]+=453; Retention time HPLC: 0.66 min (X012_S01). the precipitate is filtered washed with water The precipitate is treated with tert-butyl methyl ether (30 mL) the mixture is stirred for 30 min The precipitate is filtered washed with tert-butyl methyl ether dried 0.66 min (X012_S01)

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

実験手順: 3-Bromo-4-formyl-benzonitrile (intermediate 2, 3.25 g, 14.7 mmol) is stirred with acetylacetone (2.42 mL, 19.1 mmol), 3-(trifluoromethyl)phenylurea (3 g, 14.7 mmol) and polyphosphoric acid (3.02 g, 7.90 mmol) in tetrahydrofurane (80.0 mL) at 60° C. for 48 h. The reaction mixture is concentrated in vacuo and ethyl acetate and water is added and the phases are separated. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over MgSO4 and concentrated. Yield: 7.66 g; ESI mass spectrum: [M+H]+=508; Retention time HPLC: 1.14 min (HPLC method Z018_S04) The reaction mixture is concentrated in vacuo and ethyl acetate and water is added the phases are separated The aqueous phase is extracted twice with ethyl acetate The combined organic phases are washed with saturated sodium chloride solution dried over MgSO4 concentrated 1.14 min (HPLC method Z018_S04)

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

実験手順: 3-Bromo-4-formyl-benzonitrile (intermediate 2, 1.09 g, 4.92 mmol) is stirred with acetylacetone (0.60 mL, 5.88 mmol), 3-(trifluoromethyl)phenylurea (1.00 g, 4.90 mmol) and polyphosphoric acid (3.02 g, 7.90 mmol) in tetrahydrofurane (40.0 mL) at 50° C. overnight. The reaction mixture is concentrated in vacuo, ethyl acetate and water is added and the phases are separated. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over MgSO4 and concentrated. Yield: 2.38 g; ESI mass spectrum: [(79Br)-M+H]+=478, [(81Br)-M+H]+=480; Retention time HPLC: 1.06 min (HPLC method Z018_S04). The reaction mixture is concentrated in vacuo, ethyl acetate and water is added the phases are separated The aqueous phase is extracted twice with ethyl acetate The combined organic phases are washed with saturated sodium chloride solution dried over MgSO4 concentrated 1.06 min (HPLC method Z018_S04)