反应详情

温度

100 °C

A mixture of N-{[3-bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (260 mg, 0.400 mmol), 1,1-dimethylethyl (2S)-2-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperazinecarboxylate (166 mg, 0.400 mmol), Na2CO3 (127 mg, 1.199 mmol) and PdCl2(dppf) (29.2 mg, 0.040 mmol)) was diluted in a mixture of 1,4-dioxane (3 mL) and water (1 mL) in a 2-5 mL Biotage microwave reaction tube. The mixture was degassed by bubbling argon through it for 5 minutes and it was then heated in a Biotage microwave at normal absorption for 10 minutes at 100° C. The crude mixture was filtered through a PL-Thiol MP SPE+ and was then washed with ethyl acetate and water. The organic layer was concentrated under vacuum to obtain the crude residue. It was purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were dried using a EZ2 GeneVac evaporator and then combined to give 1,1-dimethylethyl (2S)-4-{[5′-{[({6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinyl}carbonyl)amino]methyl}-2′-(methyloxy)-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate. It was re-dissolved in 25% TFA in DCM (2 mL) and stirred at room temperature for 2 h. Solvent was evaporated under a stream of nitrogen and then the residue was purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 10 to 60% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and converted to the free base with 1 N NaOH, and the basified solution was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-(methyloxy)-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide as a solid (48 mg, 15.8%). LC-MS m/z 760 (M+H)+, 0.80 min (ret time).

1. customThe mixture was degassed
2. customby bubbling argon through it for 5 minutes
3. filtrationThe crude mixture was filtered through a PL-Thiol MP SPE+
4. washwas then washed with ethyl acetate and water
5. concentrationThe organic layer was concentrated under vacuum
6. customto obtain the crude residue
7. customIt was purified with a Gilson HPLC (with 0.1% TFA in the solvents),
8. washeluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min
9. customThe product fractions were dried
10. customa EZ2 GeneVac evaporator