General procedure for the synthesis of methyl 2-amino-3-fluorobenzoate from methanol and 2-amino-3-fluorobenzoic acid:
1. a mixture of 2-amino-3-fluorobenzoic acid (559 mg, 3.62 mmol) and 1.7 mL of concentrated H2SO4 in 11 mL of anhydrous methanol was heated and refluxed for 66 hours.
2. After completion of the reaction, it was cooled to room temperature and concentrated under reduced pressure to remove methanol.
3. The residue was dissolved in 30 mL of water and transferred to a dispensing funnel.
4. Slowly add solid sodium carbonate to neutralize to pH 9-10 until no gas escapes. 5.
5. Extract the aqueous layer with ethyl acetate (3 x 40 mL).
6. The organic layers were combined and washed sequentially with 100 mL of saturated aqueous NaHCO3 and 100 mL of brine.
7. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure.
8. The product was purified by column chromatography (eluent: 5% ethyl acetate in hexane) to give Intermediate 10 (491 mg, 80% yield) as a white solid. 9.
9. Characterization of the product: 1H-NMR (CDCl3, 300 MHz) δ: 7.66-7.63 (m, 1H), 7.15-7.08 (m, 1H), 6.60-6.55 (m, 1H), 5.40 (br s, 2H), 3.89 (s, 3H); LCMS m/z [M+H]+ calculated C8H8FNO2: 170.05, measured value. 170.05, measured value: 170.10.
