Ethyl trifluoroacetate → 1-(2-Amino-5-fluorophenyl)-2,2,2-trifluoroethanone

To an ice-cooled solution of 4.0 g of N-(4-fluorophenyl)-2,2-dimethylpropanamide in 80 mL of dry THF was added dropwise over 30 min 30.8 mL of a 1.6 M solution of n-butyllithium in hexane. After addition was complete, the reaction mixture was stirred an additional 1 h at 0° after which time 5.63 mL of ethyl trifluoroacetate was added quickly dropwise. The cooling bath was removed and the reaction was allowed to proceed at ambient temperature for 40 min. The reaction was quenched by the addition of aqueous ammonium chloride and the reaction mixture was partitioned between ether and water. The ether layer was washed with brine, dried and evaporated to 6.29 g of the title compound as an orange oil. The bulk of this material (6.0 g) was dissloved in ethylene glycol dimethyl ether, 30 mL of 6N HCl was added nd the mixture was heated at reflux for 1.5 h. The cooled reaction mixture was diluted with water, and made basic by the addition of solid sodium carbonate. This was extracted with ether, and the combined extacts were dried and evaporated. The residue was purified by column chromatography over silica gel (elution with 10-20% ethyl acetate in hexanes) affording 2.10 g of the title compound as an orange solid.

1. additionAfter addition
2. additionwas added quickly dropwise
3. customThe cooling bath was removed
4. customThe reaction was quenched by the addition of aqueous ammonium chloride
5. customthe reaction mixture was partitioned between ether and water
6. washThe ether layer was washed with brine
7. customdried
8. customevaporated to 6.29 g of the title compound as an orange oil
9. addition30 mL of 6N HCl was added nd the mixture
10. temperaturewas heated
11. temperatureat reflux for 1.5 h
12. customThe cooled reaction mixture
13. extractionThis was extracted with ether
14. customthe combined extacts were dried
15. customevaporated
16. customThe residue was purified by column chromatography over silica gel (elution with 10-20% ethyl acetate in hexanes)

ORD record

ord-74803482e4bd4b1fac4953f72f490324

Source dataset

uspto-grants-2002_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06489320B1