| 98% |
|
Sodium hydride (25.6 g, 60percent dispersion in oil, 0.64 mol) was added portionwise to a solution of 5-hydroxy-2-methylpyridine (70 g, 0.64 mol) in DMA (700 ml) while keeping the temperature below 40°C. At the end of the addition, the mixture was stirred at room temperature for 1 hour and <strong>[455-88-9]2-fluoro-5-nitrotoluene</strong> (91.3 g, 0. 59 mol) in DMA (100 ml) was added slowly. The mixture was stirred at 80°C for 3 hours and then cooled. The solvents were evaporated under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and then dried over MGS04. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 30percent ethyl acetate in petroleum ether) to give 2-methyl-5- (2-methyl-4-nitrophenoxy) pyridine (141 g, 98percent) as an oil; NMR spectrum (CDC13) ; 2.43 (s, 3H), 2.59 (s, 3H), 6.74 (d, 1H), 7.21 (d, 1H), 7.27 (d, 1H), 8.00 (d, 1H), 8.17 (s, 1H), 8.32 (s, 1H). |
| 98% |
|
Example 51; 2-1[4-(13-Methyl-4-[(6-methylpyridin-3-yl)oxyjphenyllamino)quinazolin-5- yl] oxy} acetamide; A mixture of 1[4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl} amino)quinazolin-5-yl]oxy} acetic acid (120 mg, 0.27 mmol), diisopropylethylamine (72 mul, 0.4 mmol) and HATU (155 mg, 0.41 mmol) was stirred at 50 °C for 18 hours. After cooling, gaseous ammonia was bubbled through the mixture for 15 minutes. After evaporation of the solvents in vacuo, the residue was triturated with water. The pH of the solution was adjusted to 8 by addition of 5percent aqueous sodium bicarbonate solution. The resultant beige precipitate was filtered, washed with water and ether and dried over P205 under high vacuum. The precipitate was stirred in ethyl acetate for 1 hour, filtered and dried under high vacuum at 50 °C to give the title compound as a beige solid (140 mg, 78percent); NMR spectrum: (400 MHz; DMSO-d6 + CF3C02D) 2.29 (s, 3H), 2.71 (s, 3H), 5.01 (s, 2H), 7.24 (d, 1H), 7.30 (d, 1H), 7.48 (d, 1H), 7.86 (m, 1H), 7.93 (m, 2H), 8.09 (m, 2H), 8.74 (s, 1H), 8.96 (s, 1H); Mass spectrum: MH+ 416; The [4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5- yl] oxy}acetic acid used as starting material was obtained as follows: Sodium hydride (25.6 g, 60percent dispersion in oil, 0.64 mol) was added portionwise to a solution of 5-hydroxy-2-methylpyridine (70 g, 0.64 mol) in DMA (700 ml) while keeping the temperature below 40 °C. At the end of the addition, the mixture was stirred at room temperature for 1 hour and <strong>[455-88-9]2-fluoro-5-nitrotoluene</strong> (91.3 g, 0.59 mol) in DMA (100 ml) was added slowly. The mixture was stirred at 80 °C for 3 hours, then cooled. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over MgS04. After evaporation of the solvents, the residue was purified by chromatography on silica gel eluting with 30percent ethyl acetate in petroleum ether to give 2-methyl-5-(2-methyl-4- nitrophenoxy) pyridine as an oil (141 g, 98percent) ; NMR spectrum: (400 MHz; CDC13) 2.43 (s, 3H), 2.59 (s, 3H), 6.74 (d, 1H), 7.21 (d, 1H), 7.27 (d, 1H), 8.00 (d, 1H), 8.17 (s, 1H), 8.32 (s, 1H); A mixture of 2-methyl-5-(2-methyl-4-nitrophenoxy)pyridine (141 g, 0.58 mol) and 10percent palladium on charcoal (13 g) in ethyl acetate (200 ml) and ethanol (700 ml) was stirred under an atmosphere of hydrogen (1.2 bar) for 5 hours. The mixture was then purged with nitrogen and the catalyst was filtered off. The filtrate was evaporated to dryness to give 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline as a white solid (120.6 g, 98percent) ; Mass spectrum: MH+ 215. 3-Methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (6.42 g, 30 mmol) and 4N hydrogen chloride in dioxane (7.55 ml, 30 mmol) were added to a suspension of 4-chloro-5- fluoroquinazoline (obtained as described in Example 1, preparation of starting materials, 5 g, 27.5 mmol) in acetonitrile (100 ml). The mixture was stirred at 80 °C for 2 hours. After cooling, the precipitate was washed with acetonitrile. This precipitate was partitioned between DCM and 5percent aqueous sodium bicarbonate solution and the pH was adjusted to 8. The organic layer was washed with brine and dried over MgS04. Evaporation of the solvents gave 5-fluoro-N {3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl] quinazolin-4- amine as a dark gum (9.3 g, 94percent) which crystallised on standing; NMR spectrum: (400 MHz; CDCl3) 2.30 (s, 3H), 2.54 (s, 3H), 6.93 (d, 1H), 7.15-7.08 (m, 2H), 7.22 (m, 1H), 7.56 (d, 1H), 7.63 (s, 1H), 7.71 (m, 2H), 8.27 (s, 1H), 8.37 (d, 1H), 8.71 (s, 1H); A mixture of 5-fluoro-N- {3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}quinazolin-4-amine (10.8 g, 30 mmol) and sodium methoxide (4.86 g, 90 mmol) in methanol (250 ml) was heated at reflux for 16 hours. After cooling and evaporation of the solvents, the residue was dissolved in dichloromethane. This solution was washed with water and brine and dried over MgS04. Evaporation of the solvents gave 5-methoxy-N- {3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine as a white solid (10.7 g, 96percent) ; NMR spectrum: (400 MHz; CDC13) 2.29 (s, 3H), 2.53 (s, 3H), 4.12 (s, 3H), 6.92 (m, 2H), 7.12 (m, 2H), 7.48 (d, 1H), 7.55 (d, 1H), 7.63 (m, 2H), 8.27 (s, 1H), 8.64 (s, 1H), 9.78 (bs, 1H); A mixture of 5-methoxy-N-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}quinazolin-4-amine (10.04 g, 27 mmol) and pyridine hydrochloride (12.42 g, 108 mmol) in pyridine (100 ml) was heated at reflux for 2 hours. After cooling and evaporation of the solvents, the residue was triturated in 5percent aqueous sodium bicarbonate and the resulting mixture was stirred for 30 minutes. The yellowish precipitate was filtered, washed with water and ether, and dried over P205 under high vacuum to give 5- hydroxy-N- {3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (9.3 g, 96percent) ; NMR spectrum: (400 MHz) 2.20 (s, 3H), 2.44 (s, 3H), 6.71 (m, ... |
| 98% |
|
Sodium hydride (25.6 g, 60percent dispersion in oil, 0.64 mol) was added portion-wise to a solution of 5-hydroxy-2-methylpyridine (70 g, 0.64 mol) in DMA (700 ml) while keeping the temperature below 40°C. At the end of the addition, the mixture was stirred at room temperature for 1 hour and <strong>[455-88-9]2-fluoro-5-nitrotoluene</strong> (91.3 g, 0.59 mol) in DMA (100 ml) was added slowly. The mixture was stirred at 80°C for 3 hours and then cooled. The solvents were evaporated under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over MgSO4. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 30percent ethyl acetate in petroleum ether) to give 2-methyl-5-(2-methyl-4-nitrophenoxy)pyridine as an oil (141 g, 98percent); NMR spectrum (CDCl3): 2.43 (s, 3H), 2.59 (s, 3H), 6.74 (d, IH), 7.21 (d, IH), 7.27 (d, IH), 8.00 (d, IH), 8.17 (s, IH), 8.32 (s, IH). |
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