反应详情

温度

0 °C

A 5 L flange-neck round-bottom flask equipped with an air stirrer rod and paddle, thermometer, pressure-equalizing dropping funnel, and nitrogen bubbler is charged with 5-(5-(2-hydroxy-6-methoxy-phenyl)-1H-pyrazol-3-ylamino)-pyrazine-2-carbonitrile (47.0 g, 152 mmol) and anhydrous THF (1.2 L). The stirred suspension, under nitrogen, is cooled to 0° C. A separate 2 L 3-necked round-bottom flask equipped with a large magnetic stirring bar, thermometer, and nitrogen bubbler is charged with triphenylphosphine (44.0 g; 168 mmol) and anhydrous THF (600 mL). The stirred solution, under nitrogen, is cooled to 0° C. and diisopropylazodicarboxylate (34.2 g; 169 mmol) is added and a milky solution is formed. After 3-4 min, a solution of t-butyl-N-(3-hydroxypropyl)-carbamate (30.3 g, 173 mmol) in anhydrous THF (100 mL) is added and the mixture is stirred for 3-4 min. This mixture is then added over 5 min to the stirred suspension of starting material at 0° C. The reaction mixture quickly becomes a dark solution and is allowed to slowly warm up to room temperature. After 6.5 h, more reagents are prepared as above using PPh3 (8 g), DIAD (6.2 g) and carbamate (5.4 g) in anhydrous THF (150 mL). The mixture is added to the reaction mixture, cooled to −5° C. and left to warm up to room temperature overnight. The solvent is removed in vacuo. The resulting viscous solution is loaded onto a pad of silica and product is eluted with ethyl acetate. The concentrated fractions are separately triturated with methanol and resulting solids are collected by filtration. The combined solids are triturated again with methanol (400 mL) and then isolated by filtration and dried in vacuo at 50° C. overnight to give 31.3 g of desired product. LC-ES/MS m/z 466.2 [M+1]+.

1. customA 5 L flange-neck round-bottom flask equipped with an air stirrer rod and paddle
2. customA separate 2 L 3-necked round-bottom flask equipped with a large magnetic stirring bar
3. temperatureThe stirred solution, under nitrogen, is cooled to 0° C.
4. customa milky solution is formed
5. additionThis mixture is then added over 5 min to the stirred suspension of starting material at 0° C
6. temperatureto slowly warm up to room temperature
7. waitAfter 6.5 h
8. custommore reagents are prepared as
9. additionThe mixture is added to the reaction mixture
10. temperaturecooled to −5° C.
11. waitleft
12. temperatureto warm up to room temperature overnight
13. customThe solvent is removed in vacuo
14. washis eluted with ethyl acetate
15. customThe concentrated fractions are separately triturated with methanol
16. customresulting solids
17. filtrationare collected by filtration
18. customThe combined solids are triturated again with methanol (400 mL)
19. customisolated by filtration
20. customdried in vacuo at 50° C. overnight