Synthesis
4-Amino-2,6-dihydroxypyrimidine (5.18 g, 40.7 mmol) was suspended in hexamethyldisilazane (HMDS, 25 mL) and concentrated sulfuric acid (H2SO4, 0.1 mL) was added. The reaction mixture was heated to reflux for 3 h and subsequently concentrated under vacuum. The residue was dissolved in N,N-dimethylformamide (DMF, 30 mL), iodomethane (MeI, 8.5 mL, 136.5 mmol) was added and stirred continuously for 72 hours at room temperature. Upon completion of the reaction, the mixture was cooled to 0°C and sodium bicarbonate (NaHCO3) was slowly added to neutralize the reaction. Stirring was continued at 0°C until no further gas production was observed. The precipitate was collected by filtration, washed sequentially with methanol (MeOH) and water (H2O), and dried to afford 6-amino-3-methylpyrimidine-2,4(1H,3H)-dione (4.49 g, 78% yield) as a yellow solid, which could be used in the subsequent reaction without further purification. The Rf value of thin layer chromatography (TLC) was 0.23 (Expanding agent: ethyl acetate-methanol-ammonia, 7:2.7:0.3). Nuclear magnetic resonance hydrogen spectrum (1H NMR, 400 MHz, DMSO-d6) δ 10.36 (1H, single peak, NH), 6.16 (2H, single peak, NH2), 4.56 (1H, single peak, H-5), 3.04 (3H, single peak, NCH3). Nuclear magnetic resonance carbon spectrum (13C NMR, 100 MHz, DMSO-d6) δ 163.3 (C-4), 153.5 (C-6), 151.1 (C-2), 74.0 (C-5), 25.9 (NCH3). Melting point (MP): literature value 327°C, measured value 320-323°C.
References
[1] Journal of Agricultural and Food Chemistry, 2016, vol. 64, # 24, p. 5079 - 5084
[2] Patent: WO2017/99612, 2017, A1. Location in patent: Page/Page column 8; 28
[3] Patent: WO2014/143799, 2014, A2. Location in patent: Page/Page column 372
[4] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 5, p. 2001 - 2009
