反应详情

温度

100 °C

A mixture of N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (370 mg, 0.579 mmol), 1,1-dimethylethyl 4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinecarboxylate (233 mg, 0.579 mmol), Na2CO3 (184 mg, 1.738 mmol) and PdCl2(dppf) (42.4 mg, 0.058 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 15 to 80% 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′-fluoro-3-biphenylyl)methyl]-1-piperidinecarboxylate as a solid. 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 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-fluoro-3′-(4-piperidinylmethyl)-3-biphenylyl]methyl}-2,6-pyridinedicarboxamide as a solid (92 mg, 21.7%). LC-MS m/z 733 (M+H)+, 0.87 min (ret time); 1H NMR (400 MHz, DMSO-d6) δ 0.99-1.05 (m, 2H) 1.20 (t, J=7.40 Hz, 3H) 1.32 (t, J=7.15 Hz, 3H) 1.42-1.61 (m, 5H) 1.83-1.96 (m, 2H) 2.32-2.36 (m, 2H) 2.45-2.50 (m, 2H) 2.82-2.89 (m, 2H) 2.97 (q, J=7.28 Hz, 2H) 3.50-3.58 (m, 2H) 3.81-3.88 (m, 2H) 4.06-4.17 (m, 1H) 4.31 (q, J=7.19 Hz, 2H) 4.59-4.65 (m, 4H) 6.92 (d, J=7.53 Hz, 1H) 7.17 (d, J=7.28 Hz, 1H) 7.20-7.39 (m, 5H) 7.42-7.46 (m, 1H) 8.01 (s, 1H) 8.15-8.33 (m, 3H) 9.50 (t, J=6.27 Hz, 1H) 9.74 (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 15 to 80% CH3CN in water at a flow rate of 20 mL/min
9. customThe product fractions were dried
10. customa EZ2 GeneVac evaporator