反应详情

温度

45 °C

A mixture of 5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-7-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (5.02 g, 16.2 mmol) and toluene (100 mL) was treated with phosphorus oxychloride (7.50 mL, 80.5 mmol) and heated to 45° C. N,N-Diisopropylethylamine (17.0 mL, 97.6 mmol) was added in four equal portions, waiting for the exotherm to subside before adding another portion. The reaction mixture was heated to 95° C. for 42 hours, cooled to 35° C. and added to an aqueous solution of potassium phosphate (2.5 M, 45.0 mL), also at 35° C., in four portions; during this addition the temperature rose to 63° C. The resulting mixture was filtered through Celite, which was then rinsed with additional toluene. The organic layer of the filtrate was washed with aqueous citric acid solution (0.57 M, 30 mL), then washed with saturated aqueous sodium chloride solution (25 mL) and dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo to a volume of approximately 100 mL. This was added to a solution of azetidine (2.34 g, 41.0 mmol) in tetrahydrofuran (20 mL), and the reaction mixture was stirred for 1 hour at room temperature, at which time it was poured in four portions into an aqueous sodium bicarbonate solution (0.65 M, 125 mL) with vigorous stirring. The aqueous layer was extracted with toluene (3×50 mL) and the combined organic layers were washed with saturated aqueous sodium chloride solution (25 mL), dried over sodium sulfate, filtered and concentrated in vacuo to a volume of approximately 75 mL. Heptane (100 mL) was added with vigorous stirring, and the mixture was granulated at room temperature for 2 hours, then cooled in an ice bath for 15 minutes. The resulting solid was collected by vacuum filtration to provide C7. Yield: 4.45 g, 12.8 mmol, 79%. 1H NMR (400 MHz, CDCl3) δ 2.24-2.33 (m, 2H), 2.68 (s, 3H), 3.5-4.5 (v br m, 4H), 3.96 (s, 3H), 7.65 (s, 1H), 7.88 (s, 1H).

1. waitwaiting for the exotherm to subside
2. additionbefore adding another portion
3. temperatureThe reaction mixture was heated to 95° C. for 42 hours
4. temperaturecooled to 35° C.
5. additionduring this addition the temperature
6. customrose to 63° C
7. filtrationThe resulting mixture was filtered through Celite, which
8. washwas then rinsed with additional toluene
9. washThe organic layer of the filtrate was washed with aqueous citric acid solution (0.57 M, 30 mL)
10. washwashed with saturated aqueous sodium chloride solution (25 mL)
11. dry with materialdried over sodium sulfate
12. filtrationAfter filtration
13. concentrationthe filtrate was concentrated in vacuo to a volume of approximately 100 mL
14. extractionThe aqueous layer was extracted with toluene (3×50 mL)
15. washthe combined organic layers were washed with saturated aqueous sodium chloride solution (25 mL)
16. dry with materialdried over sodium sulfate
17. filtrationfiltered
18. concentrationconcentrated in vacuo to a volume of approximately 75 mL
19. additionHeptane (100 mL) was added with vigorous stirring
20. waitthe mixture was granulated at room temperature for 2 hours
21. temperaturecooled in an ice bath for 15 minutes
22. filtrationThe resulting solid was collected by vacuum filtration