反应详情

温度

100 °C

A solution of 4-(5-bromo-thiazol-2-yl)-morpholine (52.4 mg, 0.210 mmol), 3-(5-chloro-8-fluoroisoquinolin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (BB5) (70 mg, 0.18 mmol), potassium carbonate (77.5 mg, 0.560 mmol), and Pd(PPh3)4 (0.01 g, 0.01 mmol) in previously degassed DME/water (4:1) (1.95 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor to 100° C. for 45 min. The reaction mixture was partitioned between CHCl3 and H2O, and the layers were separated. The aqueous layer was re-extracted with CHCl3 (3×) and the combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 1.5% MeOH in CHCl3] resulting in a yellow solid slightly contaminated with triphenylphosphine oxide. Therefore, this material was dissolved in MeOH/THF and passed through a prewashed 5 g SCX column. The column was washed with 2 volumes of MeOH and 2 volumes of THF then was washed with 1M NH4OH in MeOH upon which the product was released from the resin. The filtrate was concentrated in vacuo, and the resulting material was chromatographed on silica gel [eluting with 0.5% MeOH in CHCl3] resulting in the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=3.37-3.49 (m, 4H), 3.68-3.81 (m, 4H), 7.05 (s, 2H), 7.51-7.62 (m, 2H), 8.03 (dd, J=8.4, 4.8 Hz, 1H), 8.07 (d, J=2.2 Hz, 1H), 8.23 (d, J=2.2 Hz, 1H), 8.36 (s, 1H), 9.64 (s, 1H). MS (ES+): m/z=442.06/444.03 (76/24) [MH+]. HPLC: tR=3.06 min (ZQ2, polar—5 min).

1. customevacuated
2. additioncharged with N2 (2×)
3. customThe reaction mixture was partitioned between CHCl3 and H2O
4. customthe layers were separated
5. extractionThe aqueous layer was re-extracted with CHCl3 (3×)
6. washthe combined organic fractions were washed with brine
7. dry with materialdried over Na2SO4
8. filtrationfiltered
9. concentrationconcentrated in vacuo
10. customThe crude material was purified by chromatography on silica gel [eluting with 1.5% MeOH in CHCl3]
11. customresulting in a yellow solid
12. washThe column was washed with 2 volumes of MeOH and 2 volumes of THF
13. washthen was washed with 1M NH4OH in MeOH upon which the product
14. concentrationThe filtrate was concentrated in vacuo
15. customthe resulting material was chromatographed on silica gel [eluting with 0.5% MeOH in CHCl3]