Dimethylformamide → 6-amino-3-bromo-2-fluoro-N-methylbenzamide

Temperature

0 °C

NBS (9.42 g, 52.9 mmol) was added to a cold (0° C.) solution of 5-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (Compound 27E, 9.2 g, 50.8 mmol) in DCM and DMF (120 mL+60 mL) over the course of 40 min. The reaction mixture was stirred at 0° C. for 2 h then allowed to warm to RT. After 30 min, the DCM was removed in vacuo. The remaining reaction mixture was cooled −10° C., treated with a solution of 2M methyl amine in THF (50.8 mL, 101.6 mmol) and allowed to stir for overnight at room temperature. The reaction mixture was poured to water (240 mL) and the resulting suspension was extracted with ethyl acetate (3×100 mL). The combined ethyl acetate layer was washed with water (3×100 mL), dried (Na2SO4) and concentrated to give crude residue which was purified by column chromatography (20% ethyl acetate/hexanes) to afford 4 g of the title compound (32% over two steps). 1H NMR (CDCl3, 500 MHz) δ=2.98 (d, J=4.5 Hz, 3H), 5.90 (brs, 2H), 6.38 (d, J=9.0 Hz, 1H), 6.55 (brs, 1H), 7.24-7.27 (m, 1H).

1. temperatureto warm to RT
2. waitAfter 30 min
3. customthe DCM was removed in vacuo
4. customThe remaining reaction mixture
5. temperaturewas cooled −10° C.
6. stirringto stir for overnight at room temperature
7. extractionthe resulting suspension was extracted with ethyl acetate (3×100 mL)
8. washThe combined ethyl acetate layer was washed with water (3×100 mL)
9. dry with materialdried (Na2SO4)
10. concentrationconcentrated
11. customto give crude residue which
12. customwas purified by column chromatography (20% ethyl acetate/hexanes)

ORD record

ord-17356bd015694b649c48d6651cd6b31d

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09133224B2