Synthesis
The general procedure for the synthesis of 2-chloro-5-fluoropyrimidin-4(3H)-one from 2,4-dichloro-5-fluoropyrimidine was as follows: dimethylaniline (195 mL, 1.54 mol) was added to the slurry formed by 5-fluorouracil (99.73 g, 0.77 mol) and phosphoryl chloride (215 mL, 2.31 mol) under nitrogen protection, and the temperature of the reaction was maintained at 95 °C. The reaction mixture was stirred at this temperature for 3.5 hours and then cooled to room temperature and subsequently slowly poured into a stirred mixture of ice (200 g) and 6 M hydrochloric acid (200 mL). The resulting slurry was extracted with dichloromethane (2 x 400 mL), and the combined organic phases were washed with deionized water (4 x 275 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to afford 111.77 g of 5-fluoro-2,4-dichloropyrimidine (87% yield, 98.1% AUC purity as determined by HPLC) as amber oil. Next, 1.34 L of 1 M sodium hydroxide solution was slowly added to a solution of 5-fluoro-2,4-dichloropyrimidine (111.77 g, 0.67 mol) in tetrahydrofuran (377 mL) at 0 °C. The reaction mixture was stirred at room temperature for about 30 min before the pH was slowly adjusted to 6 with 1.0 M hydrochloric acid.The aqueous phase was extracted with ethyl acetate (440 mL) to remove impurities, followed by adjusting the pH to 1 with 1.0 M hydrochloric acid.The acidic aqueous phase was extracted with ethyl acetate (4 x 555 mL).The combined organic phases were washed with brine (111 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 2- chloro-5-fluoro-3H-pyrimidin-4-one 88.35 g (89% yield, 99% AUC purity by HPLC) as an off-white powder.
References
[1] Patent: EP1506967, 2005, A1. Location in patent: Page/Page column 67
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 18, p. 4984 - 4995
[3] Patent: US2007/66636, 2007, A1. Location in patent: Page/Page column 19; 20
[4] Journal of Medicinal Chemistry, 2011, vol. 54, # 2, p. 510 - 524
[5] Patent: US2007/60529, 2007, A1. Location in patent: Page/Page column 14
