Triethylamine → 4-Bromo-3-fluoro-N-methoxy-N-methylbenzamide

To a suspension of 4-bromo-3-fluorobenzoic acid (1, 967.9 g, 4.4 mol) in dichloromethane (5.9 L) and DMF (21 mL) was slowly added a solution of oxalyl chloride ((COCl)2, 560 mL, 6.4 mol, 1.45 equiv) in dichloromethane (520 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 20 h and then cooled to 0° C. by ice-water bath. N,O-dimethyl hydroxylamine hydrochloride (826 g, 8.4 mol, 1.9 equiv) was added followed by slow addition of triethylamine (TEA, 2.5 L, 17.7 mol, 4.0 equiv) at 0° C. The reaction mixture was then gradually warmed to room temperature and stirred at room temperature overnight. Once the coupling reaction was complete, the reaction mixture was washed with saturated aqueous sodium bicarbonate solution (NaHCO3, 2 L). The aqueous phase was back extracted with dichloromethane (1 L). The combined organic phases were washed with water (1 L), brine (1 L), and concentrated under reduced pressure. The resulting solid residue was dissolved into methyl tert-butyl ether (MTBE, 5 L), washed sequentially with water (5×1 L), brine (1 L), and dried over anhydrous sodium sulfate (Na2SO4). The filtrated solution was concentrated under reduced pressure and the resulting solid was dried in a vacuum oven at 45° C. to afford 4-bromo-3-fluoro-N-methoxy-N-methylbenzamide (3, 1106 g, 1153 g theoretical, 95.9% yield) which was used for the subsequent reaction without further purification. For 3: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.78 (t, 1H, J=7.47 Hz), 7.56 (dd, 1H, J=9.3, 1.6 Hz), 7.18 (d, 1H, J=8.1 Hz), 3.53 (s, 3H), 3.25(s, 3H); C9H9BrFNO2 (MW 262.08), LCMS (EI) m/e 262.0/264.0 (M++H).

1. customThe resulting reaction mixture
2. temperaturecooled to 0° C. by ice-water bath
3. temperatureThe reaction mixture was then gradually warmed to room temperature
4. stirringstirred at room temperature overnight
5. customOnce the coupling reaction
6. washthe reaction mixture was washed with saturated aqueous sodium bicarbonate solution (NaHCO3, 2 L)
7. extractionThe aqueous phase was back extracted with dichloromethane (1 L)
8. washThe combined organic phases were washed with water (1 L), brine (1 L)
9. concentrationconcentrated under reduced pressure
10. dissolutionThe resulting solid residue was dissolved into methyl tert-butyl ether (MTBE, 5 L)
11. washwashed sequentially with water (5×1 L), brine (1 L)
12. dry with materialdried over anhydrous sodium sulfate (Na2SO4)
13. concentrationThe filtrated solution was concentrated under reduced pressure
14. customthe resulting solid was dried in a vacuum oven at 45° C.

ORD record

ord-b0877b9441474674a412d0f4b08ebb41

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08420645B2