N-[(2,4-Dimethoxyphenyl)methyl]-1,2,4-thiadiazol-5-amine

Synthesis

The reaction was carried out with 5-amino-1,2,4-thiadiazole (3.3 g, 32.6 mmol) and 2,4-dimethoxybenzaldehyde (5.96 g, 35.9 mmol) in toluene (99 mL) under reflux for 2 hours in a Dean-Stark apparatus. After completion of the reaction, it was cooled to room temperature (about 25 °C) and concentrated under reduced pressure to give the imine intermediate. The intermediate was dissolved in methanol (82 mL) and cooled to 0 °C. Subsequently, NaBH4 (1.85 g, 48.9 mmol) was added in batches, after addition, and stirred at room temperature for 18 hours. At the end of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was back-extracted with ethyl acetate (2 x 150 mL). All organic layers were combined and concentrated under reduced pressure, and the resulting crude product was purified by normal phase chromatography (20-66% ethyl acetate/hexane, 220g ISCO column) to afford the target compounds, N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (1-3), as a white solid (5.9 g, 72% yield).

References

[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 12, p. 2683 - 2688
[2] Patent: WO2012/4714, 2012, A2. Location in patent: Page/Page column 57-58
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 17, p. 7818 - 7839
[4] Patent: US2012/10182, 2012, A1. Location in patent: Page/Page column 35
[5] Patent: WO2012/4706, 2012, A2. Location in patent: Page/Page column 75