Synthesis
Step (i) Potassium carbonate (3.70 g, 26.7 mmol) was added to a solution of 4-cyano-2-fluorobenzoic acid (4 g, 24.3 mmol) in N,N-dimethylformamide (DMF, 350 mL). After stirring for 15 min at room temperature, iodomethane (1.66 mL, 26.7 mmol) was slowly added. The reaction vial was sealed and the reaction mixture was stirred at 40 °C for 2 hours. Upon completion of the reaction, most of the DMF was removed by distillation under reduced pressure. the residue was subjected to liquid-liquid partitioning with dichloromethane (DCM, 50 mL) and saturated saline (50 mL). The organic phase was separated and filtered through a short column of silica gel to remove possible solid impurities. Finally, the organic phase was concentrated under reduced pressure to afford methyl 4-cyano-2-fluorobenzoate (4.1 g, 94% yield). Nuclear magnetic resonance hydrogen spectrum (1H NMR, 300 MHz, CDCl3) δ ppm: 3.96 (s, 3H), 7.44-7.48 (m, 1H), 7.49-7.53 (m, 1H), 8.01-8.05 (m, 1H).
References
[1] Patent: WO2015/25164, 2015, A1. Location in patent: Page/Page column 81-82
[2] Patent: US2015/57298, 2015, A1. Location in patent: Paragraph 0551
[3] Patent: US2016/207883, 2016, A1. Location in patent: Paragraph 0916-0918
[4] Patent: WO2009/124962, 2009, A2. Location in patent: Page/Page column 141
