反应详情

温度

115 °C

The mixture of (R)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,1-dimethylurea (222, 330 mg, 1.07 mmol), tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (275, 426 mg, 1.60 mmol), fine-powder cesium carbonate (1.05 g, 3.21 mmol), Pd(OAc)2 (72 mg, 0.32 mmol), BINAP (200 mg, 0.32 mmol) in 60 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 2 hours. The mixture was cooled to RT, diluted with 60 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 6% MeOH in chloroform to isolate (R)-tert-butyl 4-(4-(3-cyano-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (276). It was dissolved in 20 mL MeOH and 4 mL DMSO. To it were added one NaOH solid bead (about 100 mg) and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 2 hours, diluted with 10 mL MeCN, stirred for 5 min, concentrated in vacuo, diluted with EtOAc 150 mL, washed with water ×3, dried, concentrated in vacuo to afford crude (R)-tert-butyl 4-(4-(3-carbamoyl-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (277).

1. customwas degassed with nitrogen stream for 3 min
2. temperatureThe mixture was cooled to RT
3. additiondiluted with 60 mL EtOAc
4. filtrationfiltered
5. concentrationThe filtrate was concentrated in vacuo