General procedure for the synthesis of methyl 2-fluoro-5-nitrobenzoate from methanol and 2-fluoro-5-nitrobenzoic acid:
1. dissolve 2-fluoro-5-nitrobenzoic acid (3.7 g, 20.0 mmol) in methanol (100 mL) at 0 °C.
2. Slowly add thionyl chloride (5.3 mL, 60.0 mmol) dropwise.
3. The reaction mixture was heated to reflux for 24 hours.
4. Upon completion of the reaction, the solvent was removed by vacuum concentration. 5.
5. The residue was dissolved in ethyl acetate and washed several times with 1.0 M NaOH solution.
6. The organic phase was dried with anhydrous sodium sulfate and the solvent was evaporated in vacuum to give the intermediate methyl 2-fluoro-5-nitrobenzoate (Intermediate 37) as a yellow oil, which crystallized into light yellow needle crystals after standing.
Yield: 90%;
Melting point: 47-49°C;
1H NMR (300MHz, CDCl3) δ= 4.01 (s, 3H, OCH3), 7.35 (t, 1H, H3,3JH3.H4 = 3JH3.F = 9.2Hz), 8.44 (dt, 1H, 3JH4-H3 = 9.2Hz, 4JH4.F = 4JH4-H6 = 3.5Hz), 8.87 (dd, 1H. 4JH6-F = 5.9 Hz, 4JH6-H4 = 2.7 Hz);
13C NMR (75 MHz, CDCl3): δ= 47.7 (OCH3), 113.2 (d, C3,2JC-F = 25.1 Hz), 114.5 (d, C1, 2JC-F = 12.0 Hz), 122.9 (d, C6,3JC-F = 3.3 Hz), 124.3 (d, C4,3JC-F = 10.9 Hz ), 138.6 (C5), 157.4 (d, COOCH3,3JC-F = 3.8 Hz), 159.8 (d, C2,1JC-F = 269.0 Hz).
