Synthesis
Using 5-amino-3-methylpyridine-2-carbonitrile (18.0 g, 135 mmol) as raw material, a 1.6 M aqueous solution of sodium nitrite (10.3 g, 149 mmol) was slowly added to a mixture of its water (243 mL) and concentrated sulfuric acid (67.5 mL) at 0 °C. The reaction mixture was gradually warmed to room temperature and subsequently stirred at 100 °C for 3 hours. Upon completion of the reaction, it was cooled to room temperature and extracted with ethyl acetate (3 x 75 mL). The organic layers were combined, washed sequentially with water (2 × 75 mL) and saturated aqueous sodium chloride solution (2 × 75 mL), dried, filtered and concentrated under reduced pressure to give 5-hydroxy-3-methylpyridine-2-carbonitrile (16 g, 120 mmol, 89% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 11.07 (brs, 1H) 8.08 (d, J = 2.6Hz, 1H), 7.20 (d, J = 2.3Hz, 1H), 2.40 (s, 3H).
References
[1] Patent: WO2015/155626, 2015, A1. Location in patent: Page/Page column 89; 90
[2] Patent: WO2017/51294, 2017, A1. Location in patent: Page/Page column 57; 58
[3] Patent: WO2017/51303, 2017, A1. Location in patent: Page/Page column 72; 73
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 10, p. 4476 - 4504
[5] Patent: WO2017/51276, 2017, A1. Location in patent: Page/Page column 99; 10016 g
