4-Fluorobenzoic Acid → 4-Fluoro-N-methoxy-N-methylbenzamide

Temperature

-10 °C

A suspension of 4-fluorobenzoic acid (20 g, 143 mmol) in thionyl chloride (130 g; 1.1 mol) was stirred under reflux for 6 h: vigorous evolution of gas, clear solution after about 10 min, deepening of the color from yellow to orange. Excess thionyl chloride was removed by distillation (initially atmospheric pressure/40° C., then membrane pump vacuum/400° C.). From the distillation residue, 4-fluorobenzoyl chloride was distilled off under membrane pump vacuum at 90° C. over a short column. The reaction product crystallized on storing in a fridge (n20D 1.5315; m.p. 9° C., yield 20 g/89%). Freshly distilled triethylamine (29 ml) was added to a suspension of N,O-dimethylhydroxylamine hydrochloride (9.0 g; 92 mmol) in CH2Cl2 (75 ml). The reaction mixture was stirred at room temperature for 2 h and then cooled to −10° C. With cooling, 4-fluorobenzoyl chloride (13.5 g; 85 mmol) was, over a period of 6 min, added dropwise to the initial charge. After the addition had ended, cooling was removed and the reaction mixture was stirred at room temperature for 1.5 h. The light-brown suspension was poured into H2O (100 ml). The organic phase was removed and the aqueous phase was extracted with diethyl ether (2×). The combined extract was washed with saturated NaCl solution, dried over Na2SO4 and concentrated. The oily brown residue crystallized on cooling and scratching. The crude product was dried using an oil pump (residual triethylamine!) and reacted without further purification.

1. temperatureunder reflux for 6 h
2. customExcess thionyl chloride was removed by distillation (initially atmospheric pressure/40° C.
3. custommembrane pump vacuum/400° C.
4. distillationFrom the distillation residue, 4-fluorobenzoyl chloride was distilled off under membrane pump vacuum at 90° C. over a short column
5. customThe reaction product crystallized on storing in a fridge (n20D 1.5315; m.p. 9° C., yield 20 g/89%)
6. stirringThe reaction mixture was stirred at room temperature for 2 h
7. temperatureWith cooling
8. additionadded dropwise to the
9. additioninitial charge
10. additionAfter the addition
11. temperaturecooling
12. customwas removed
13. stirringthe reaction mixture was stirred at room temperature for 1.5 h
14. additionThe light-brown suspension was poured into H2O (100 ml)
15. customThe organic phase was removed
16. extractionthe aqueous phase was extracted with diethyl ether (2×)
17. extractionThe combined extract
18. washwas washed with saturated NaCl solution
19. dry with materialdried over Na2SO4
20. concentrationconcentrated
21. customThe oily brown residue crystallized
22. temperatureon cooling
23. dry with materialThe crude product was dried
24. customreacted without further purification

ORD record

ord-c92060a6c3d24604a6c5bebcba5922f9

Source dataset

uspto-grants-2009_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07582660B2