Hydroxylamine → 5,8-Dimethoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine

Temperature

80 °C

To a 700 mL jacketed vessel equipped with a mechanical stirrer, a dual pH/temperature probe, a nitrogen inlet, and a reflux condenser was added sequentially 19.4 g (0.125 mol) of 4-amino-2,5-dimethoxypyrimidine followed by 151 g (1.717 mol) of ethyl acetate. The reaction mixture was heated to reflux (˜80° C.) and then 18.7 g (0.143 mol) of ethoxy carbonylisothiocyanate was continuously added via addition funnel over an 8 min period. The addition funnel was rinsed with 1.8 g of ethyl acetate and then the reaction mixture was heated at reflux for 9 h. The reaction mixture was cooled to 25° C. and allowed to stand overnight. The mixture was heated to 60° C. and then 100 g (5.50 mol) of deionized water was added to the mixture. After heating to reflux (˜71° C.), 9.4 g (0.142 mol) of a 50 wt % aqueous hydroxylamine solution was continuously added over a 46 min period. During the course of the amine addition, the reaction pH rose from 4.20 to 6.35. The reaction mixture was then heated an additional 3 h during which time the reaction pH naturally lowered to 6.30. To this reaction mixture was added a solution of 4.5 g (0.036 mol) of sodium sulfite in 20 g (1.110 mol) of deionized water over a 6 min period. The reaction pH rose from 6.35 to 7.51 during the sodium sulfite addition. The reaction mixture was then cooled to 18° C. and allowed to stir an additional 30 min at this temperature. The reaction mixture was suction filtered through a medium coarse fritted glass funnel (filtration time less than 2.0 min), and then the reaction vessel was washed with 30 g of deionized water and this rinse was used to wash the isolated product cake. A final displacement wash with 30 g of fresh deionized water was performed and the product was partially dried by suction for 30 min and then allowed to dry overnight under a gentle stream of nitrogen to afford 19.1 g of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine as a light cream colored wet cake. NMR analysis (using benzyl acetate as an internal standard) indicated a 88.25% purity of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine active which corresponds to a 69.1% yield.

1. customequipped with a mechanical stirrer
2. temperatureThe reaction mixture was heated
3. washThe addition funnel was rinsed with 1.8 g of ethyl acetate
4. temperaturethe reaction mixture was heated
5. temperatureat reflux for 9 h
6. temperatureThe reaction mixture was cooled to 25° C.
7. temperatureThe mixture was heated to 60° C.
8. temperatureAfter heating
9. additionwas continuously added over a 46 min period
10. temperatureThe reaction mixture was then heated an additional 3 h during which time the reaction
11. temperatureThe reaction mixture was then cooled to 18° C.
12. filtrationfiltered through a medium coarse fritted glass funnel
13. filtration(filtration time less than 2.0 min)
14. washthe reaction vessel was washed with 30 g of deionized water
15. washto wash the isolated product cake
16. washA final displacement wash with 30 g of fresh deionized water
17. customthe product was partially dried by suction for 30 min
18. customto dry overnight under a gentle stream of nitrogen

ORD record

ord-2520d547185047378652bc3c18c6f5d7

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09115135B2