Synthesis
Synthetic route 2.1.5: 2-fluoro-6-methoxybenzonitrile (similar to WO 99/14187): 640.5 g (4.6 mol) of 2,6-difluorobenzonitrile was dissolved in 3.5 L of methanol and subsequently cooled to 0-5 °C. In this temperature range, 828.8 g of 30% sodium methanol solution was slowly added dropwise. After the dropwise addition, the reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was poured into 20 L of water and the precipitate was collected by filtration. The precipitate was washed sequentially twice with water and twice with heptane. The resulting solid was dried under vacuum at 50 °C. A final 740 g of white solid product was obtained in 99% yield of the theoretical value. The product was analyzed by GC and 1H NMR (CDCl3 as solvent) and the purity of the product was >95%.1H NMR data were as follows: δ = 3.95 ppm (single peak, 3H, O-CH3), 6.85 ppm (multiple peaks, 2H, aromatic H), 7.5 ppm (quadruple peak, 1H, aromatic H).
References
[1] Patent: WO2006/56433, 2006, A2. Location in patent: Page/Page column 29
[2] Journal of Heterocyclic Chemistry, 1988, vol. 25, p. 1173 - 1177
[3] Patent: WO2007/93530, 2007, A1. Location in patent: Page/Page column 244
[4] Journal of Medicinal Chemistry, 2012, vol. 55, # 7, p. 3135 - 3143
[5] Patent: WO2017/221092, 2017, A1. Location in patent: Paragraph 00153
