Synthesis
Ammonium acetate (79.3 mg, 1.03 mmol) and acetic acid (0.6 mL) were added to anhydrous toluene (12.4 mL) as 4,4-dimethoxy-2-butanone (2.0 g, 15.13 mmol) and cyanoacetamide (1.6 g, 18.92 mmol) in an anhydrous toluene (12.4 mL) assembled in a Dean-Stark device and stirred and refluxed for 8 hr to remove the resulting water. Upon completion of the reaction, the solvent was removed by evaporation under reduced pressure, and the residual oily substance was cooled to room temperature and ethanol (7.0 mL) was added at 25 °C with stirring. Subsequently, 50% sulfuric acid (2.6 mL) was added slowly and the mixture was heated at 50 °C with stirring for 3 hours. After the reaction mixture was cooled to 5 °C, water (1.3 mL) was slowly added. The resulting brown solid was purified by crystallization in ethanol to give 2-hydroxy-3-cyano-4-methylpyridine (0.900 g, yield: 45%); melting point: 233-236 °C. 1H NMR (400 MHz, DMSO-d6): δ 12.58 (br s, 1H, NH), 8.04 (d, J = 7.4 Hz, 1H, H-6), 6.24 ( d, J = 7.4 Hz, 1H, H-5), 2.31 (s, 3H, CH3).
References
[1] European Journal of Medicinal Chemistry, 2018, vol. 154, p. 155 - 171
