2-(4-bromo-3-oxobutyl)isoindole-1,3-dione

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: 1-Bromo-4-N-phthalimido-2-butanone (50.0 g 0.169 mol) and thiourea (25.71 g, 0.338 mol) were mixed with n-propanol (1000 ml) and concentrated hydrochloric acid (100 ml), and the reaction mixture was heated to reflux for 1.5 hour. After cooling, the precipitate was filtered and washed with n-propanol and ether. After air drying, the title product was obtained as a fluffy white solid (37.51 g, 0.121 mol, 72% yield), m.p. 230°-240° (decomp.). the reaction mixture was heated to reflux for 1.5 hour After cooling the precipitate was filtered washed with n-propanol and ether After air drying

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

実験手順: 1-Bromo-4-N-phthalimido-2-butanone (50.0 g 0.169 mol) and thiourea (25.71 g, 0.338 mol) were mixed with n-propanol (1000 ml) and concentrated hydrochloric acid (100 ml), and the reaction mixture was heated to reflux for 1.5 hour. After cooling, the precipitate was filtered and washed with n-propanol and ether. After air drying, the title product was obtained as a fluffy white solid (37.51 g, 0.121 mol, 72% yield), m.p. 230°-240° (decomp.). the reaction mixture was heated to reflux for 1.5 hour After cooling the precipitate was filtered washed with n-propanol and ether After air drying

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

実験手順: 1-Bromo-4-phthalimidobutan-2-one (23.6 g.) was added to a solution of 2-aminopyridine (7.6 g.) and sodium bicarbonate (6.8 g.) in dimethylformamide (100 ml.) and the mixture was heated at 100° for 1 hour. Cooling followed by addition to water and recrystallisation from ethanol afforded 2-(2-phthalimidoethyl)imidazo [1,2-a]-pyridine (13.4 g.) m.p. 181° - 181.5°. the mixture was heated at 100° for 1 hour Cooling

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

実験手順: 1-Bromo-4-phthalimidobutan-2-one (23.6 g.) was added to a solution of 2-aminopyridine (7.6 g.) and sodium bicarbonate (6.8 g.) in dimethylformamide (100 ml.) and the mixture was heated at 100° for 1 hour. Cooling followed by addition to water and recrystallisation from ethanol afforded 2-(2-phthalimidoethyl)imidazo [1,2-a]-pyridine (13.4 g.) m.p. 181° - 181.5°. the mixture was heated at 100° for 1 hour Cooling

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

実験手順: Reflux formamide (2 mL, 50 mmol) and P2S5 (4.4 g, 10 mmol) dioxane (50 mL) for 2 hours. Add this crude solution to 2-(4-bromo-3-oxobutyl)isoindole-1,3-dione (2.3 g, 7.7 mmol) in dioxane (100 mL) and reflux the resulting reaction solution for 1.5 hours. Add ethyl acetate (100 mL) and 1N sodium hydroxide (100 mL) to the mixture. Separate the organic phase, wash with brine (50 mL), dry (Na2SO4), filter and concentrate in vacuo to an oil. Perform chromatography (silica gel, 7:3 hexane/ethyl acetate) to afford 2-(2-thiazol-4-ylethyl)isoindole-1,3-dione (790 mg). 1H NMR (CDCl3) δ 8.75 (s, 1H), 7.80-7.88 (m, 2H), 7.69-7.75 (m, 2H), 7.08 (s, 1H), 4.10 (t, J=7 Hz, 2H), 3.28 (t, J=7 Hz, 2H). reflux the resulting reaction solution for 1.5 hours Separate the organic phase wash with brine (50 mL) dry (Na2SO4) filter concentrate in vacuo to an oil

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

実験手順: Reflux formamide (2 mL, 50 mmol) and P2S5 (4.4 g, 10 mmol) dioxane (50 mL) for 2 hours. Add this crude solution to 2-(4-bromo-3-oxobutyl)isoindole-1,3-dione (2.3 g, 7.7 mmol) in dioxane (100 mL) and reflux the resulting reaction solution for 1.5 hours. Add ethyl acetate (100 mL) and 1N sodium hydroxide (100 mL) to the mixture. Separate the organic phase, wash with brine (50 mL), dry (Na2SO4), filter and concentrate in vacuo to an oil. Perform chromatography (silica gel, 7:3 hexane/ethyl acetate) to afford 2-(2-thiazol-4-ylethyl)isoindole-1,3-dione (790 mg). 1H NMR (CDCl3) δ 8.75 (s, 1H), 7.80-7.88 (m, 2H), 7.69-7.75 (m, 2H), 7.08 (s, 1H), 4.10 (t, J=7 Hz, 2H), 3.28 (t, J=7 Hz, 2H). reflux the resulting reaction solution for 1.5 hours Separate the organic phase wash with brine (50 mL) dry (Na2SO4) filter concentrate in vacuo to an oil

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

実験手順: Prepare a cold (0° C.) solution of 2-(3-oxobutyl)isoindole-1,3-dione (6.8 g, 31.5 mmol) in methanol (50 mL). Add Br2 (3.2 mL, 63 mmol). Allow the reaction to warm to room temperature and stir for 15 hours. Add 10 M sulfuric acid (26 mL) and stir the mixture for 15 hours. Filter off the solids and dry in vacuo to afford 2-(4-bromo-3-oxobutyl)isoindole-1,3-dione (2.3 g). the reaction stir the mixture for 15 hours Filter off the solids dry in vacuo

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

実験手順: 2-(4-Bromo-3-oxo-butyl)-isoindole-1,3-dione is prepared by condensation of but-1-en-3-one with phthalimide followed by bromination according to known procedures (J. Med. Chem., 35:3239, 1992. A solution of 2-(4-bromo-3-oxo-butyl)-isoindole-1,3-dione (8.9 g, 30.06 mmol) and 2-aminopyridine (2.8 g, 29.75 mmol) in ethanol is heated at reflux for 4 hours. The mixture is cooled to room temperature and concentrated. The residue is purified by chromatography (silica gel, dichloromethane/ethanol 95:5); to give 4.23 g of 2-[2-(imidazo[1,2-a]pyridin-2-yl)ethyl]-isoindole-1,3-dione (49%). at reflux for 4 hours concentrated The residue is purified by chromatography (silica gel, dichloromethane/ethanol 95:5)

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

実験手順: 2-(4-Bromo-3-oxo-butyl)-isoindole-1,3-dione is prepared by condensation of but-1-en-3-one with phthalimide followed by bromination according to known procedures (J. Med. Chem., 35:3239, 1992. A solution of 2-(4-bromo-3-oxo-butyl)-isoindole-1,3-dione (8.9 g, 30.06 mmol) and 2-aminopyridine (2.8 g, 29.75 mmol) in ethanol is heated at reflux for 4 hours. The mixture is cooled to room temperature and concentrated. The residue is purified by chromatography (silica gel, dichloromethane/ethanol 95:5); to give 4.23 g of 2-[2-(imidazo[1,2-a]pyridin-2-yl)ethyl]-isoindole-1,3-dione (49%). at reflux for 4 hours concentrated The residue is purified by chromatography (silica gel, dichloromethane/ethanol 95:5)

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

実験手順: A suspension of 2-(1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H-quinazolin-4-one (1.0 g, 2.93 mmol), 2-(4-bromo-3-oxo-butyl)-isoindole-1,3-dione (867 mg., 2.93 mmol, prepared as described in WO 89/10360), and potassium carbonate (405 mg, 2.93 mmol) in DMF (14 mL) was stirred at room temperature for 80 minutes. The reaction was diluted with water and the resulting white solid (1.6 g) was used in the subsequent step without further purification. the resulting white solid (1.6 g) was used in the subsequent step without further purification

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

実験手順: A suspension of 2-(1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H-quinazolin-4-one (1.0 g, 2.93 mmol), 2-(4-bromo-3-oxo-butyl)-isoindole-1,3-dione (867 mg., 2.93 mmol, prepared as described in WO 89/10360), and potassium carbonate (405 mg, 2.93 mmol) in DMF (14 mL) was stirred at room temperature for 80 minutes. The reaction was diluted with water and the resulting white solid (1.6 g) was used in the subsequent step without further purification. the resulting white solid (1.6 g) was used in the subsequent step without further purification