反应详情

温度

130 °C

POCl3 (379.1 g, 2.59 mol) was transferred under nitrogen to a 1 L round bottom flask fitted with a mechanical stirrer, a condenser and a tube connected above the condenser filled with a drying agent (drierite). 1-(2-Fluoro-4-methanesulfonyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (4) (100 g, 0.324 mol) was added to the reaction vessel, the contents were stirred, and a slurry was obtained. Dimethylformamide (DMF; 9.43 g, 0.129 mol) was added, and the reaction mixture was heated to reflux (oil bath set at 130° C.). After refluxing for 3 h, an additional amount of DMF (9.43 g, 0.129 mol) was added. The resulting mixture was refluxed for another 2 h and then gradually cooled to 55° C. Subsequently, acetone (270 mL) was added. The mixture was further cooled to 23° C. and a precipitate was obtained, which was isolated by filtration. The filtrate was quenched by slow dropwise addition into ice water (1.5 L) with stirring. During the quench, the internal temperature was kept at 0° C. or below by cooling with an ice-salt bath. Product 4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (7) crystallized out of the quenched mixtures was isolated by filtration. The solids from both filtrations were combined and washed with water (2×500 mL), 10% aqueous NaHCO3 (2×500 mL), and water (2×500 mL) until the filtrate was neutral. The washed solids were vacuum dried overnight at room temperature and dissolved in methylene chloride (600 mL). The resulting mixture was filtered to remove any residual starting material (4). Hexane (200 mL) was added to the filtrate and methylene chloride was removed by rotary evaporation under reduced pressure. Product crystallized from the hexane solution and was filtered to obtain (7) (95 g; 90%). HPLC analysis, 99.26% (purity, by peak area); 1H NMR (Bruker 400 MHz, CDCl3) δ 8.88 (s, 1H, Ar—H), 8.46 (s, 1H, Ar—H), 7.96 (m, 3H, Ar—H), 3.14 (s, 3H, —SO2CH3); mass spec. (electrospray), m/z 327 (M+H).

1. customfitted with a mechanical stirrer, a condenser and a tube
2. customa slurry was obtained
3. temperaturethe reaction mixture was heated
4. temperatureAfter refluxing for 3 h
5. temperatureThe resulting mixture was refluxed for another 2 h
6. temperaturegradually cooled to 55° C
7. temperatureThe mixture was further cooled to 23° C.
8. customa precipitate was obtained
9. customwhich was isolated by filtration
10. customThe filtrate was quenched by slow dropwise addition into ice water (1.5 L)
11. stirringwith stirring
12. customwas kept at 0° C. or below
13. temperatureby cooling with an ice-salt bath
14. customProduct 4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (7) crystallized out of the quenched mixtures
15. customwas isolated by filtration
16. filtrationThe solids from both filtrations
17. washwashed with water (2×500 mL), 10% aqueous NaHCO3 (2×500 mL), and water (2×500 mL) until the filtrate
18. customdried overnight at room temperature
19. dissolutiondissolved in methylene chloride (600 mL)
20. filtrationThe resulting mixture was filtered
21. customto remove
22. additionHexane (200 mL) was added to the filtrate and methylene chloride
23. customwas removed by rotary evaporation under reduced pressure
24. customProduct crystallized from the hexane solution
25. filtrationwas filtered