Yield: 84%

Reaction Conditions:

Stage #1:2,4-difluorophenyl ethyl carbonate with sulfuric acid;nitric acid at 0; for 0.25 h;
Stage #2: with sodium hydrogencarbonate in methanol at 20; for 16 h;

Steps:

A5
To a solution of 2,4-difluorophenyl ethyl carbonate (3.1 g, 16 mmol) in sulphuric acid (10 mL) was added fuming HN0₃ (0.78 ml, 19 mmol) slowly, keeping the internal temperature around 0 °C. After 15 min ice cold water (70 mL) was added, the product was extracted with ethyl acetate (2x50 mL), the combined organic layers were washed with brine, dried (Na₂SC>4) and concentrated to afford the nitro product as a thick syrup. This nitro product was dissolved in methanol (20 mL) and to this solution was added solid NaHC0₃ (4.0 g, 47 mmol) and the resultant mixture was stirred for 16h at RT. The mixture was filtered and the filtrate was concentrated. The resulting solid was dissolved in water (20 ml) and acidified with 3M HC1 solution to pH~5. The product was extracted with CH₂CI₂ (3x25 mL), the combined organic layers were washed with brine, dried ( a₂S0₄) and concentrated to afford 2,4-difluoro-5-nitrophenol (2.34 g, 84% yield). 1H NMR (400 MHz, Acetone-i ₆) δ 9.59 (s, 1H), 7.78 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 10.4 Hz, 1H); MS (ESI) m/z: 176.0 (M+H⁺).

References:

DECIPHERA PHARMACEUTICALS, LLC;FLYNN, Daniel L.;PETILLO, Peter A.;KAUFMAN, Michael D. WO2013/36232, 2013, A2 Location in patent:Paragraph 00224