Reaktion #160145

Reaktionsgleichung

methyl 3-fluoro-2-hydroxy-benzoate

2-chloro-2,2-difluoro-acetic acid

potassium carbonate

→

methyl 2-(difluoromethoxy)-3-fluorobenzoate

Ausbeute 41.3%

Lösungsmittel

DMF

water

Reaktionsbedingungen

Aufarbeitung

1. 1
   Extraktionextracted with ether (2×10 mL)
2. 2
   SonstigeThe organics were separated
3. 3
   Waschenwashed sequentially with water (5 mL) and brine solution (5 mL)
4. 4
   TrocknenThe organics were dried (MgSO4)
5. 5
   Einengenconcentrated in vacuo
6. 6
   Sonstigeto give residue which
7. 7
   Sonstigewas purified by silica gel column chromatography

Vorschrift

A mixture of methyl 3-fluoro-2-hydroxy-benzoate (1.5 g, 8.8 mmol), 2-chloro-2,2-difluoro-acetic acid (1.62 g, 1.05 mL, 10.6 mmol) and potassium carbonate (1.46 g, 10.6 mmol) were heated in DMF (5 mL) at 120° C. for 5 hours. The reaction mixture was diluted with water (20 mL) and extracted with ether (2×10 mL). The organics were separated and washed sequentially with water (5 mL) and brine solution (5 mL). The organics were dried (MgSO4) and concentrated in vacuo to give residue which was purified by silica gel column chromatography using 0-30% EtOAc/hexanes as eluent to give methyl 2-(difluoromethoxy)-3-fluorobenzoate (0.8 g, 39%). To methyl 2-(difluoromethoxy)-3-fluorobenzoate (0.8 g, 3.64 mmol) was added 12% aq. NaOH (3 mL) and the reaction mixture was heated at 50° C. for 1 hour. The aqueous layer was extracted with 1:1 ether/hexane (2×5 mL). The aqueous layer was acidified to pH 1 with 6 N HCl solution to give a suspension. The solid was filtered and washed with water, then dried in vacuo to give 2-(difluoromethoxy)-3-fluoro-benzoic acid (555 mg, 31%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=7.8 Hz, 1H), 7.43 (dd, J=13.1, 4.8 Hz, 1H), 7.35 (td, J=8.1, 4.9 Hz, 1H), 6.68 (t, J=74.4 Hz, 1H).

Quelle