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 (50 mg, 0.079 mmol), 1-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}piperidine (31.6 mg, 0.079 mmol), Na2CO3 (25.05 mg, 0.236 mmol) and PdCl2(dppf) (5.77 mg, 7.88 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 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 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′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-2,6-pyridinedicarboxamide as a solid (5 mg, 8.54%). LC-MS m/z 743 (M+H)+, 0.87 min (ret time); 1H NMR (400 MHz, CD3OD) δ 1.24-1.30 (m, 5H) 1.37-1.43 (m, 3H) 1.54-1.78 (m, 5H) 1.86-1.93 (m, 2H) 1.98-2.08 (m, 2H) 2.15-2.24 (m, 6H) 2.53 (d, J=7.03 Hz, 2H) 2.76-2.82 (m, 2H) 2.97-3.04 (m, 2H) 3.58-3.65 (m, 2H) 3.98 (d, J=11.54 Hz, 2H) 4.09-4.14 (m, 1H) 4.41 (q, J=7.03 Hz, 2H) 4.60 (s, 2H) 4.75 (s, 2H) 6.96-7.34 (m, 7H) 7.99 (s, 1H) 8.15 (t, J=7.91 Hz, 1H) 8.25-8.31 (m, 1H) 8.36 (dd, J=7.78, 1.00 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. extractionthe basified solution was extracted with ethyl acetate twice
10. washThe combined organic layers were washed with brine
11. dry with materialdried over sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated under vacuum