Diisopropylethylamine → 4,4,4-trifluoro-N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(phenylamino)butanamide

To a stirred solution of compound 12 (scheme 3) (100 mg, 0.29 mmol), compound 327 (103 mg, 0.44 mmol) and N,N-diisopropylethylamine (0.18 mL, 1.03 mmol) in dry N,N-dimethylformamide (3 mL) at 0° C. was added HATU reagent (335 mg, 0.88 mmol). The mixture was stirred at room temperature for 16 h. A saturated aqueous solution of sodium bicarbonate was added and the aqueous solution was extracted twice with EtOAc, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent MeOH-dichloromethane, gradient 0:100 to 15:85). The resulting solid was triturated in methanol, filtered off and dried under reduced pressure to afford title compound 324 (81 mg, 0.15 mmol, 50% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.50 (s, 1H), 8.41 (d, J=5.6 Hz, 1H), 7.86 (d, J=1.2 Hz, 1H), 7.81 (dd, J=13.2, 2.0 Hz, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.45 (t, J=8.8 Hz, 1H), 7.37 (dd, J=8.8, 1.6 Hz, 1H), 7.10 (dd, J=8.4, 7.2 Hz, 2H), 6.75 (d, J=8.0 Hz, 2H), 6.61 (t, J=7.2 Hz, 1H), 6.55 (d, J=5.6 Hz, 1H), 6.13 (d, J=9.2 Hz, 1H), 4.75-4.65 (m, 1H), 3.72 (s, 3H), 2.94 (dd, J=15.6, 3.6 Hz, 1H), 2.78 (dd, J=15.9, 9.6 Hz, 1H). LRMS (M+1) 556.0 (100%).

1. extractionthe aqueous solution was extracted twice with EtOAc
2. dry with materialdried over anhydrous sodium sulfate
3. customthe solvent was removed under reduced pressure
4. customThe residue was purified by column chromatography on silica gel (eluent MeOH-dichloromethane, gradient 0:100 to 15:85)
5. customThe resulting solid was triturated in methanol
6. filtrationfiltered off
7. customdried under reduced pressure

ORD-Eintrag

ord-047bd9bdbbea44f5a8b1fae66cac98e1

Quelldatensatz

uspto-grants-2012_12

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08329726B2