反应详情

温度

80 °C

To a solution of 3-bromo-pyridin-2-ylamine (9.72 g, 56.2 mmol) in 1,4-dioxane (100 mL) was added dropwise ethoxycarbonyl isothiocyanate (6.70 mL, 56.7 mmol). The mixture was stirred under an atmosphere of nitrogen for 18 hours. The volatiles were evaporated to yield a waxy solid. The recovered material was triturated with hexane (250 mL). N-(3-Bromo-2-pyridinyl)-N′-carboethoxy-thiourea was isolated and was used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 11.46 (s, 1H), 11.43 (s, 1H), 8.49 (dd, J=4.6, 1.5 Hz, 1H), 8.18 (dd, J=8.0, 1.5 Hz, 1H), 7.33 (dd, J=8.0, 4.7 Hz, 1H), 4.23 (q, J=7.1 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H). MS=215 (MH)+. 2b) To a stirred suspension of hydroxylamine hydrochloride (17.4 g, 25.0 mmol) and N,N-diisopropylethylamine (26.0 mL, 14.9 mmol) in a mixture of methanol (70 mL) and ethanol (70 mL) was added N-(3-bromo-2-pyridinyl)-N′-carboethoxy-thiourea. The mixture was stirred for 2 hours at room temperature then heated to 60° C. for 18 hours. The suspension was cooled to room temperature, filtered and rinsed with methanol, water then methanol. 8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was isolated as an off-white solid (8.41 g, 70%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.58 (d, J=6.4 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 6.80 (t, J=7.0 Hz, 1H), 6.25 (s, 2H). MS=213, 215 (MH)+. 2c) An oven dried tube was charged with palladium acetate (0.20 g, 0.89 mmol) and triphenylphosphine (0.60 g, 2.3 mmol). The tube was evacuated under high vacuum and backflushed under a stream of nitrogen for 5 minutes. 1,4-Dioxane (10 mL) was added and the mixture was stirred under nitrogen for 10 minutes. 8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.0 g, 4.7 mmol), 2-methoxybenzeneboronic acid (1.1 g, 7.0 mmol), N,N-dimethylformamide (10 mL) and 1.50 M of sodium carbonate in water (10 mL) were added. The mixture was stirred for 2 minutes at room temperature under nitrogen then the tube was sealed and heated at 80° C. for 18 hours. The mixture was transferred to a round bottom flask and the volatiles were evaporated under reduced pressure. Water (100 mL) was added and the mixture was stirred when a precipitate was formed. The solid was collected by filtration, rinsed with water, air dried, triturated with ether/dichloromethane (4:1; 10 mL), filtered and rinsed with ether. 8-(2-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was isolated (1.0 g, 89%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.50 (d, J=6.5 Hz, 1H), 7.51 (dd, J=7.6, 1.5 Hz, 1H), 7.43-7.36 (m, 2H), 7.13 (d, J=8.1 Hz, 1H), 7.02 (t, J=7.3 Hz, 1H), 6.91 (t, J=7.0 Hz, 1H), 5.96 (br s, 2H), 3.73 (s, 3H). MS=241 (MH)+. 2d) To an oven dried tube was added palladium acetate (10.0 mg, 0.0445 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (75.0 mg, 0.130 mmol), 8-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.4162 mmol), 4-(4-bromo-phenyl)-morpholine (120.0 mg, 0.4956 mmol), cesium carbonate (270 mg, 0.83 mmol) and 1,4-dioxane (5 mL). The tube was evacuated and backflushed with nitrogen three times. The tube was sealed and heated at 80° C. for 72 hours. The mixture was cooled to room temperature, diluted with dichloromethane (10 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated. The material was purified via chromatography utilizing an ISCO automated purification apparatus (amine modified silica gel column 5%→100% ethyl acetate in hexanes). The title compound, [8-(2-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine, was isolated as a pale yellow foam (0.034 g, 20%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.39 (dd, J=6.7, 1.1 Hz, 1H), 7.61 (dd, J=7.5, 1.7 Hz, 1H), 7.51 (dd, J=7.3, 0.9 Hz, 1H), 7.50-7.45 (m, 2H), 7.43-7.37 (m, 1H), 7.12-7.07 (m, 1H), 7.05 (d, J=8.2, 1H), 6.96-6.87 (m, 3H), 6.67 (s, 1H), 3.89-3.85 (m, 4H), 3.81 (s, 3H), 3.12-3.08 (m, 4H). MS=402 (MH)+.

1. dry with material2d) To an oven dried tube
2. customThe tube was evacuated
3. customThe tube was sealed
4. temperatureThe mixture was cooled to room temperature
5. additiondiluted with dichloromethane (10 mL)
6. filtrationfiltered through a plug of diatomaceous earth
7. washrinsed with dichloromethane
8. customevaporated
9. customThe material was purified via chromatography
10. custompurification apparatus (amine modified silica gel column 5%→100% ethyl acetate in hexanes)