反应详情

温度

100 °C

A mixture of N-[(3-bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (100 mg, 0.158 mmol), 1,1-dimethylethyl (2S)-2-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperazinecarboxylate (65.6 mg, 0.158 mmol), Na2CO3 (50.1 mg, 0.473 mmol) and PdCl2(dppf) (11.53 mg, 0.016 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 a 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′-methyl-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-methyl-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide as a solid (10 mg, 8.53%). LC-MS m/z 744 (M+H)+, 1.33 min (ret time); 1H NMR (400 MHz, DMSO-d6) δ 0.91 (d, J=6.27 Hz, 3H) 1.21 (t, J=7.53 Hz, 3H) 1.33 (t, J=7.15 Hz, 3H) 1.47-1.64 (m, 3H) 1.87-1.94 (m, 2H) 2.18 (s, 3H) 2.64-2.68 (m, 6H) 2.94-3.00 (m, 2H) 3.46 (s, 2H) 3.49-3.62 (m, 2H) 3.82-3.87 (m, 2H) 4.08-4.14 (m, 1H) 4.29-4.35 (m, 2H) 4.56-4.59 (m, 4H) 6.90 (d, J=8.53 Hz, 1H) 7.09-7.29 (m, 6H) 7.35 (t, J=7.53 Hz, 1H) 8.01 (s, 1H) 8.13-8.33 (m, 3H) 9.50 (t, J=6.27 Hz, 1H) 9.70 (t, J=6.27 Hz, 1H).

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 a 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