Synthesis
To a round-bottomed flask containing ethyl formate (6 mL, 0.062 mol) and ether (30 mL), sodium metal (1.4 g, 0.062 mol) was slowly added with stirring, followed by the dropwise addition of methyl 2-methoxyacetate (6.5 g, 0.062 mol) under the condition of ice-water bath. The reaction mixture was stirred continuously for 4 hours at room temperature. Upon completion of the reaction, the aqueous phase was isolated by quenching the reaction by adding ice water (25 mL). To the aqueous phase, S-methylisothiourea (5.6 g, 0.062 mol) and potassium hydroxide (2.2 g, 0.062 mol) were sequentially added and the reaction was heated at 65 °C for 1 hour. After cooling, the reaction mixture was neutralized with 37% hydrochloric acid. The crude product was collected by vacuum filtration and recrystallized from 95% ethanol to give Intermediate 2 as white needle-like crystals (4.3 g, 40.1% yield). Intermediate 2 (1.7 g, 0.01 mol) was slowly added to phosphorous trichloride (4.6 g, 0.03 mol) under ice-water bath conditions and the mixture was subsequently heated to 80 °C and kept at 80 °C for 1 h until the reaction was complete. The reaction mixture was cooled to room temperature and neutralized with 25% ammonia. The precipitated solid was filtered, recrystallized with petroleum ether and decolorized with activated charcoal to give Intermediate 3 as a light yellow solid (1.8 g, 95.2% yield) with a melting point of 74-75 °C. Intermediate 3 was dissolved in methanol (10 mL) and 50% hydrazine hydrate solution (1.6 g, 0.015 mol) was added dropwise under ice water bath conditions. The mixture was then heated to 50 °C and the progress of the reaction was monitored by thin layer chromatography (TLC) until completion. After completion of the reaction, the mixture was cooled, the solvent was removed under reduced pressure and the solid was recrystallized with ethyl acetate and petroleum ether to afford 5-methoxy-2-(methylthio)pyrimidin-4-ylhydrazine (4,1.1 g, 96.2% yield) with a melting point of 112-114 °C.
References
[1] Letters in Drug Design and Discovery, 2016, vol. 13, # 4, p. 329 - 334
