1,4-Dioxane → 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)-ethoxy]-3-pyridin-2-ylfuro[3,2-c]pyridin-6-ylamine

Temperature

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-(1,1,1-Tributylstannyl)pyridine (90% pure; 60 μL, 0.17 mmol) was added, and the reaction mixture was heated to 100° C. for 45 min. Further 2-(1,1,1-tributylstannyl)pyridine (90% pure; 30 μL, 0.083 mmol) was added, and the reaction mixture was heated to 100° C. for a total of 2 h. 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 a SCX column (1 g/6 mL cartridge), and the fraction that eluted with NH3/MeOH was concentrated and chromatographed on silica gel [10 g/70 mL cartridge, eluting with DCM→10% EtOAc in DCM→15% EtOAc in DCM→20% EtOAc in DCM→30% EtOAc in DCM]. Fractions containing product were combined and concentrated in vacuo to give the title compound as a foam. 1H NMR (CDCl3, 400 MHz): δ=8.69 (d, J=5.6 Hz, 1H), 8.68 (s, 1H), 7.94 (s, 1H), 7.75 (dd, J=7.6, 7.6 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.29 (dd, J=8.4, 4.4, Hz, 1H), 7.23 (dd, J=7.2, 5.6 Hz, 1H), 7.05 (dd, J=8.4, 8.0 Hz, 1H), 6.56 (q, J=6.8 Hz, 1H), 4.78 (brs, 2H), 1.89 (d, J=6.8 Hz, 3H). MS (ES+): m/z=417.94/419.91/421.93 (100/80/15) [MH+], 228.03 (19) [MH+−3-F-2,6-di-Cl-Ph-CH═CH2]. HPLC: tR=3.27 min (polar—5 min, ZQ3).

1. customwas evacuated
2. additionrefilled with nitrogen (3×)
3. temperaturethe reaction mixture was heated to 100° C. for a total of 2 h
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 a SCX column (1 g/6 mL cartridge)
12. washthe fraction that eluted with NH3/MeOH
13. concentrationwas concentrated
14. customchromatographed on silica gel [10 g/70 mL cartridge, eluting with DCM→10% EtOAc in DCM→15% EtOAc in DCM→20% EtOAc in DCM→30% EtOAc in DCM]
15. additionFractions containing product
16. concentrationconcentrated in vacuo

ORD record

ord-9e53bf7f0e9145939e9000e4c75ff691

Source dataset

uspto-grants-2011_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08022206B2