4-Bromo-3-fluoro-N-methoxy-N-methylbenzamide → 1-(4-Bromo-3-fluorophenyl)ethan-1-one

Temperature

0 °C

To a solution of crude 4-bromo-3-fluoro-N-methoxy-N-methylbenzamide (3, 1106 g, 4.2 mol) in anhydrous tetrahydrofuran (THF, 11 L) was slowly added a 3.0 M solution of methylmagnesium chloride (MeMgCl, 2.5 L, 7.5 mol, 1.7 equiv) in THF at 0° C. The resulting reaction mixture was stirred at 0° C. for 2 h and then quenched very carefully with saturated aqueous ammonium chloride (NH4Cl, 1.5 L). The resulting solution was concentrated under reduced pressure to remove most of THF. The residue was then diluted with ethyl acetate (EtOAc, 5 L) and the resulting solution was washed with water (2 L). The aqueous phase was extracted with ethyl acetate (EtOAc, 2×2 L). The combined organic phases were washed with water (2 L), brine (2 L) and dried over anhydrous sodium sulfate (Na2SO4). The filtered solution was concentrated under reduced pressure and the resulting solid was dried in a vacuum oven at 45° C. to afford 1-(4-bromo-3-fluorophenyl)ethanone (4, 890.8 g, 911.6 g theoretical, 97.7% yield) as a solid which was used in the subsequent reaction without further purification. For 4: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89-7.84 (m, 2H), 7.71 (dd, 1H, J=8.30, 1.87 Hz), 2.57 (s, 3H).

1. customThe resulting reaction mixture
2. customquenched very carefully with saturated aqueous ammonium chloride (NH4Cl, 1.5 L)
3. concentrationThe resulting solution was concentrated under reduced pressure
4. customto remove most of THF
5. additionThe residue was then diluted with ethyl acetate (EtOAc, 5 L)
6. washthe resulting solution was washed with water (2 L)
7. extractionThe aqueous phase was extracted with ethyl acetate (EtOAc, 2×2 L)
8. washThe combined organic phases were washed with water (2 L), brine (2 L)
9. dry with materialdried over anhydrous sodium sulfate (Na2SO4)
10. concentrationThe filtered solution was concentrated under reduced pressure
11. customthe resulting solid was dried in a vacuum oven at 45° C.

ORD record

ord-850f5660ad914ebda9d67d7e0cdb50e5

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08420645B2