反应详情

温度

100 °C

A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-6-ylamine (49.0 mg, 0.117 mmol), KF (44 mg, 0.75 mmol), and Pd(PPh3)4 (13 mg, 0.011 mmol) in 1,4-dioxane (1.0 mL, 13 mmol) in a microwave reactor vial was evacuated and refilled with nitrogen (3×). 2-Tributylstannylthiazole (50 μL, 0.16 mmol) was added, and the reaction mixture was heated to 100° C. for 45 min in a microwave reactor. Further 2-tributylstannylthiazole (50 μL, 0.16 mmol) was added, and the reaction mixture was heated to 100° C. for 45 min. The reaction mixture was diluted with DCM and washed with water. The DCM solution was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was redissolved in MeOH and pre-purified by passing through a thiol SPE cartridge (500 mg/6 mL, PL-Thiol MP SPE+). The material from the thiol SPE treatment was chromatographed on silica gel [10 g/70 mL cartridge, eluting with DCM→10% EtOAc in DCM→15% EtOAc in DCM→20% EtOAc in DCM]. Fractions containing product were combined, concentrated in vacuo, chromatographed on a SCX column (1 g/6 mL cartridge), and the fraction that eluted with NH3/MeOH was concentrated and dried in vacuo to give the title compound as pale yellow film. 1H NMR (CDCl3, 400 MHz): δ=8.61 (s, 1H), 8.00 (s, 1H), 7.91 (d, J=3.2 Hz, 1H), 7.37 (d, J=3.2 Hz, 1H), 7.29 (dd, J=4.4, 8.4 Hz, 1H), 7.06 (dd, J=8.4, 9.2 Hz, 1H), 6.56 (q, J=6.8 Hz, 1H), 4.83 (brs, 2H), 1.89 (d, J=6.8 Hz, 3H). MS (ES+): m/z=423.96/425.90/427.93 (100/95/27) [MH+], 234.03 (30) [MH+−3-F-2,6-di-Cl-Ph-CH═CH2]. HPLC: tR=3.65 min (polar—5 min, ZQ3).

1. customwas evacuated
2. additionrefilled with nitrogen (3×)
3. temperaturethe reaction mixture was heated to 100° C. for 45 min
4. washwashed with water
5. washThe DCM solution was washed with brine
6. dry with materialdried over MgSO4
7. filtrationfiltered
8. concentrationconcentrated
9. dissolutionThe residue was redissolved in MeOH
10. custompre-purified
11. customThe material from the thiol SPE treatment was chromatographed on silica gel [10 g/70 mL cartridge, eluting with DCM→10% EtOAc in DCM→15% EtOAc in DCM→20% EtOAc in DCM]
12. additionFractions containing product
13. concentrationconcentrated in vacuo
14. customchromatographed on a SCX column (1 g/6 mL cartridge)
15. washthe fraction that eluted with NH3/MeOH
16. concentrationwas concentrated
17. customdried in vacuo