反应详情

To a microwave vial was added a mixture of Example 53 (750 mg, 2.99 mmol), 4-fluorophenylboronic acid (1674 mg, 11.97 mmol), Cs2CO3 (1170 mg, 3.59 mmol) and N,N-dimethylformamide (6.5 mL). Then tri-tert-butylphosphine (0.179 mL, 0.179 mmol, 1.0 M in toluene), palladium(II) acetate (20.15 mg, 0.09 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.067 mL, 0.449 mmol) subsequently were added under nitrogen. The vial was sealed, and this mixture was then irradiated in a Biotage Initiator™ 2.0 microwave instrument for 50 minutes at 150° C. Reaction completion was monitored by LC/MS. Another batch was done at same scale. After the reactions were cooled to room temperature, the two reaction mixtures were combined and diluted with ethyl acetate and then filtered through a pad of diatomaceous earth. The filtrate was washed with saturated brine (2×), and the combined aqueous phases were extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, then concentrated, and purified by flash column chromatography with methanol in dichloromethane (0-20%, 0.5% triethylamine). A solid was obtained, which was purified again by crystallization from ethyl acetate to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.07 (d, J=2.1, 1H), 8.03 (s, 1H), 7.74-7.66 (m, 3H), 7.34-7.22 (m, 3H), 3.34-3.21 (m, 2H), 3.19-3.04 (m, 2H), 2.93 (dd, J=8.9, 10.3, 1H), 2.71-2.59 (m, 2H), 2.39 (s, 3H), 2.30-2.14 (m, 1H); MS (ESI+) m/z 310.9 [M+H]+.

1. customThe vial was sealed
2. customthis mixture was then irradiated in a Biotage Initiator™ 2.0 microwave instrument for 50 minutes at 150° C
3. customReaction completion
4. customthe two reaction mixtures
5. filtrationfiltered through a pad of diatomaceous earth
6. washThe filtrate was washed with saturated brine (2×)
7. extractionthe combined aqueous phases were extracted with ethyl acetate
8. dry with materialThe combined organic layers were dried over Na2SO4
9. concentrationconcentrated
10. custompurified by flash column chromatography with methanol in dichloromethane (0-20%, 0.5% triethylamine)
11. customA solid was obtained
12. customwhich was purified again by crystallization from ethyl acetate