Acetic Acid → 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine

温度

100 °C

To 4-chloro-2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-bromo-quinazoline (0.19 g, 0.49 mmol) in DMA (1.0 mL) were added 3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (0.30 g, 1.53 mmol) and HOAc (0.065 mL, 1.1 mmol) and the mixture was heated to 100° C. for 5 h. The mixture was allowed to cool to rt and purified by reverse phase HPLC (ammonium acetate modifier). Fraction 1 containing pure product was treated with saturated aq NaHCO3 (2-4 mL) and concentrated under reduced pressure. The aqueous residue was extracted with DCM (3×30 mL) and the combined extracts were washed with sat aqueous NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated to dryness under reduced pressure to afford 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (48 mg, 20%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.22 (br s, 1H), 10.87 (br s, 1H), 8.57-8.81 (m, 2H), 8.24 (d, J=7.5 Hz, 1H), 8.02 (d, J=5.3 Hz, 2H), 7.54 (t, J=7.9 Hz, 1H), 5.95 (s, 1H), 2.17 (s, 3H); LC-MS (ESI) m/z 449/451 (M+H+).

1. temperatureto cool to rt
2. custompurified by reverse phase HPLC (ammonium acetate modifier)
3. additionFraction 1 containing pure product was treated with saturated aq NaHCO3 (2-4 mL)
4. concentrationconcentrated under reduced pressure
5. extractionThe aqueous residue was extracted with DCM (3×30 mL)
6. washthe combined extracts were washed with sat aqueous NaHCO3 (10 mL) and brine (10 mL)
7. dry with materialdried over MgSO4
8. filtrationfiltered
9. concentrationconcentrated to dryness under reduced pressure

ORDレコード

ord-aaba5fb91e7b44c29318f3f896fd3e20

出典データセット

uspto-grants-2014_01

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08633207B2