The general procedure for the synthesis of methyl 2-cyano-4-fluorobenzoate from methyl 2-chloro-4-fluorobenzoate is as follows:
Example 123a Synthesis of methyl 2-cyano-4-fluorobenzoate
Step A: In a 100-mL single-necked round-bottomed flask equipped with a magnetic stirrer, methyl 2-chloro-4-fluorobenzoate (10.0 g, 53.0 mmol), copper(I) cyanide (5.22 g, 58.3 mmol), and 2-methylpyrrolidone (30 mL) were added after purging with nitrogen. The reaction mixture was heated at 195 °C for 1.5 h, then cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered and the filter cake was washed with water (100 mL). Subsequently, a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL) was added to the resulting solid and stirred at room temperature for 50 minutes. After that, ethyl acetate (500 mL) was added and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 x 10 mL), the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by fast chromatography to afford the target product methyl 2-cyano-4-fluorobenzoate (123a) in 73% yield (6.99 g) as a white solid with a melting point of 92-93 °C; 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, 1H, J = 9.0, 5.5 Hz), 7.50 (dd, 1H, J = 8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H).
