Hydrochloric Acid → Ethyl 4,4-difluoroacetoacetate

Temperature

25 °C

Add sodium metal (7 kg, 300 mol) in portions to EtOH (53.6 kg) while maintaining the temperature below 60° C. Stir the reaction mixture until the sodium dissolves, then cool the mixture to 20-30° C. Add a solution of ethyl difluoroacetate (34 kg, 274 mol) in EtOAc (63 kg) to the sodium ethoxide at a temperature of 25-40° C. Heat the reaction mixture to 65° C. while stirring. After 2 h cool the mixture to room temperature. Add 10% HCl (30 kg HCl and 204 kg water) to the mixture until the pH of the mixture is 6-7. Extract the mixture with EtOAc (64 kg); separate; and extract the aqueous layer again with EtOAc (60 kg). Combine organic phases, and wash with brine (NaCl (48 kg) in water (136 kg)). Dry the organic phase with 4 A molecular sieve powder (15 kg), and concentrate to give the title compound as a brown-yellow oil (33 kg, 73% yield, 96% GC purity). 1H NMR (500 MHz, CDCl3,) δ 5.91 (t, J=54 Hz, 1H), 4.23 (m, 2H), 3.70 (s, 2H), 1.27 (m, 3H).

1. temperaturewhile maintaining the temperature below 60° C
2. dissolutiondissolves
3. temperatureHeat the reaction mixture to 65° C.
4. temperatureAfter 2 h cool the mixture to room temperature
5. extractionExtract the mixture with EtOAc (64 kg)
6. customseparate
7. extractionand extract the aqueous layer again with EtOAc (60 kg)
8. washCombine organic phases, and wash with brine (NaCl (48 kg) in water (136 kg))
9. dry with materialDry the organic phase with 4 A molecular sieve powder (15 kg)
10. concentrationconcentrate

ORD record

ord-e78623c4cfc546bba6016ec54591dd8f

Source dataset

uspto-grants-2014_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08648200B2