反应详情

温度

100 °C

Process (A). 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 (50 mg, 0.077 mmol), 1,1-dimethylethyl 4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinecarboxylate (24.23 mg, 0.077 mmol), Na2CO3 (24.44 mg, 0.236 mmol) and PdCl2(dppf) (5.62 mg, 7.69 μmol) 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 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 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}-1-piperidinecarboxylate. 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 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′-(4-piperidinylmethyl)-3-biphenylyl]methyl}-2,6-pyridinedicarboxamide as a solid (13 mg, 22.7%). LC-MS m/z 745 (M+H)+, 0.76 min (ret time); 1H NMR (400 MHz, DMSO-d6) δ 1.06-1.26 (m, 7H) 1.32 (t, J=7.28 Hz, 3H) 1.54-1.60 (m, 5H) 1.87-1.94 (m, 2H) 2.52-2.57 (m, 2H) 2.94-3.02 (m, 4H) 3.50-3.58 (m, 2H) 3.72 (s, 3H) 3.82-3.88 (m, 2H) 4.07-4.15 (m, 1H) 4.32 (q, J=7.28 Hz, 2H) 4.55 (d, J=6.02 Hz, 2H) 4.62 (d, J=6.27 Hz, 2H) 6.91 (d, J=7.78 Hz, 1H) 7.01-7.13 (m, 2H) 7.17-7.34 (m, 5H) 8.01 (s, 1H) 8.15-8.31 (m, 3H) 9.50 (t, J=6.27 Hz, 1H) 9.68 (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