反应详情

温度

0 °C

Finely ground 1H-1,2,4-triazole (278 g, 4.02 mol) was mixed with acetonitrile (700 mL), cooled to 0° C., and treated drop-wise with phosphorus oxychloride (62.4 mL, 669 mmol) while maintaining the internal temperature below 15° C. The suspension was stirred for 10 minutes, then slowly treated drop-wise with triethylamine (607 mL, 4.35 mol) under vigorous stirring, while keeping the internal temperature below 48° C. The reaction was stirred for 15 minutes as it cooled to 41° C., and was then treated portion-wise with 7-methyl-5-(1-methyl-1H-pyrazol-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one (77.1 g, 335 mmol). At the completion of the addition, the reaction was warmed to 73° C. for 1 hour, then cooled to room temperature, at which point thin layer chromatography (Eluant: 10% methanol in ethyl acetate) indicated complete conversion to the triazole-substituted intermediate. The reaction slurry was treated successively with triethylamine (279 mL, 2.00 mol) and azetidine hydrochloride (94.0 g, 1.00 mol); over 10 minutes, the internal temperature rose from 18° C. to 38° C. The mixture was stirred for 1 hour, cooled to 15-20° C. and filtered. The filter cake was washed with acetonitrile (600 mL), and the filtrate was concentrated in vacuo. The resulting paste was diluted with water (650 mL) followed by aqueous sodium hydroxide solution (10 N, 450 mL). This slurry was extracted with dichloromethane (3×350 mL), and the combined organic layers were dried over sodium sulfate and filtered. This filtrate was passed through a plug of silica gel (230-400 mesh, 150 g), eluting with dichloromethane (1 L) followed by 10% methanol in ethyl acetate (1 L). The combined eluants containing product were concentrated in vacuo, and the residue was washed with tert-butyl methyl ether (350 mL), collected by filtration, and washed with diethyl ether. This solid was dissolved in water (200 mL) and diluted once more with aqueous sodium hydroxide solution (5 N, 250 mL). The mixture was extracted with dichloromethane (3×250 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The solid was washed with tert-butyl methyl ether (350 mL) and collected by filtration to afford C2 as a pale tan solid. Yield: 82.15 g, 305 mmol, 91%. 1H NMR (500 MHz, CDCl3) δ 2.23-2.30 (m, 2H), 2.65 (s, 3H), 3.96 (s, 3H), 3.98-4.07 (m, 4H), 7.61 (br s, 1H), 7.61 (br s, 1H), 7.85 (s, 1H).

1. temperaturewhile maintaining the internal temperature below 15° C
2. customthe internal temperature below 48° C
3. stirringThe reaction was stirred for 15 minutes as it
4. temperaturecooled to 41° C.
5. additionAt the completion of the addition
6. temperaturethe reaction was warmed to 73° C. for 1 hour
7. waitover 10 minutes
8. customrose from 18° C. to 38° C
9. stirringThe mixture was stirred for 1 hour
10. temperaturecooled to 15-20° C.
11. filtrationfiltered
12. washThe filter cake was washed with acetonitrile (600 mL)
13. concentrationthe filtrate was concentrated in vacuo
14. additionThe resulting paste was diluted with water (650 mL)
15. extractionThis slurry was extracted with dichloromethane (3×350 mL)
16. dry with materialthe combined organic layers were dried over sodium sulfate
17. filtrationfiltered
18. washeluting with dichloromethane (1 L)
19. additionThe combined eluants containing product
20. concentrationwere concentrated in vacuo
21. washthe residue was washed with tert-butyl methyl ether (350 mL)
22. filtrationcollected by filtration
23. washwashed with diethyl ether
24. dissolutionThis solid was dissolved in water (200 mL)
25. additiondiluted once more with aqueous sodium hydroxide solution (5 N, 250 mL)
26. extractionThe mixture was extracted with dichloromethane (3×250 mL)
27. dry with materialthe combined organic layers were dried over sodium sulfate
28. filtrationfiltered
29. concentrationconcentrated in vacuo
30. washThe solid was washed with tert-butyl methyl ether (350 mL)
31. filtrationcollected by filtration