Dimethylformamide → Ethyl 2,3-difluoro-4-nitrophenylacetic acid

To a stirred solution of tert-butyl ethyl malonate (5.35 ml, 28.2 mmol) in DMF (150 ml) was added NaH (60% in oil, 3.38 g, 84.7 mmol) at rt. After 20 min, 2,3-difluoronitrobenzene (5 g, 28.2 mmol) in DMF (50 mL) was added dropwise via dropping funnel. Following the addition, the mixture was stirred for 3 hours at rt. The mixture was poured into ice-water and sat. NH4Cl (100 mL). The mixture was extracted with EtOAc and the combined organic layer was washed with 1M HCl and brine, dried over MgSO4, filtered and concentrated. The residue was dissolved to dichloromethane (20 mL), and added TFA (20 mL) at rt. The mixture was refluxed for 18 h. The mixture was evaporated in vacuo, coevaporated with toluene (20 mL×2). The residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient hexane-EtOAc 10:0 to 1:1, φ50 mm×300 mm, 15 mL/min) to give ethyl 2,3-difluoro-4-nitrophenylacetic acid (5.85 g, 85%) as a yellow oil. 1H-NMR (CDCl3) δ1.30 (m, 3H), 3.78 (s, 2H), 4.22 (m, 2H), 7.22 (m, 1H), 7.84 (m, 1H); MS (FAB) m/z 246 (M++1).

1. additionthe addition
2. extractionThe mixture was extracted with EtOAc
3. washthe combined organic layer was washed with 1M HCl and brine
4. dry with materialdried over MgSO4
5. filtrationfiltered
6. concentrationconcentrated
7. dissolutionThe residue was dissolved to dichloromethane (20 mL)
8. additionadded TFA (20 mL) at rt
9. temperatureThe mixture was refluxed for 18 h
10. customThe mixture was evaporated in vacuo
11. customThe residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient hexane-EtOAc 10:0 to 1:1, φ50 mm×300 mm, 15 mL/min)

ORD record

ord-301f39bf3ad54d9b85a848aeed994ddc

Source dataset

uspto-grants-2004_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06756378B2