反应详情

温度

90 °C

(328F1): A 1 liter round bottom flask was loaded with 2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (12.05 g, 35.2 mmol, Intermediate 10), methyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)carbamate (10.9 g, 28.5 mmol), Pd(OAc)2 (377 mg, 1.679 mmol), XANTPHOS (990 mg, 1.711 mmol) and Potassium phosphate (17.1 g, 81 mmol). The vial was evacuated and back-filled with nitrogen 4 times. Toluene (320 mL) was added and the flask was again evacuated and back-filled with nitrogen 4 times, and then heated with stirring to 90° C. for 16 hours. LCMS shows product and both starting materials as separate peaks. (˜5:1:1 ratio by UV). The flask was opened under nitrogen, additional palladium(I) acetate (190 mg, 0.846 mmol), XANTPHOS (500 mg, 0.864 mmol) and potassium phosphate tribasic (7.5 g, 35.3 mmol) were added and the flask re-sealed, flushed with nitrogen again and heating continued for additional 6 hours. Celite was added to the reaction mixture. The suspension was stirred briefly, and then filtered through a layer of Celite. Solids were washed with DCM. The filtrate was concentrated to brown foam. (23.9 g). Purification by column chromatography on silica (1500 g) using a gradient from 100% CH2Cl2 to (50% EtOAc+50% CH2Cl2) gave methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (11.2 g).

1. customThe vial was evacuated
2. additionback-filled with nitrogen 4 times
3. additionToluene (320 mL) was added
4. customthe flask was again evacuated
5. additionback-filled with nitrogen 4 times
6. temperatureheated
7. customboth starting materials as separate peaks
8. customthe flask re-sealed
9. customflushed with nitrogen again
10. temperatureheating
11. waitcontinued for additional 6 hours
12. additionCelite was added to the reaction mixture
13. stirringThe suspension was stirred briefly
14. filtrationfiltered through a layer of Celite
15. washSolids were washed with DCM
16. concentrationThe filtrate was concentrated to brown foam
17. customPurification by column chromatography on silica (1500 g)