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

Temperature

87 °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 27.9 g (0.180 mol) of 4-amino-2,5-dimethoxypyrimidine followed by 165.4 g (0.207 mol) of 16.4 wt % ethoxy carbonylisothiocyanate solution in toluene. The reaction mixture was heated to gentle reflux (87° C.) for 7 h at which time liquid chromatographic (LC) analysis indicated ˜95% conversion of starting 4-amino-2,5-dimethoxypyrimidine. The reaction mixture was cooled to 27° C. and allowed to stand overnight. The mixture was heated to 40° C. and then 114.2 g (6.34 mol) of deionized water was added to the mixture. After heating to reflux (˜68° C.), 14.3 g (0.217 mol) of a 50 wt % aqueous hydroxylamine solution was continuously added over a 2 h 15 min period via a peristaltic pump. During the course of the amine addition, the reaction pH rose from 4.44 to 6.95. After complete addition of hydroxylamine, the pump line was flushed with 4.8 g (0.266 mol) of deionized water, the reaction mixture was heated to 81° C., and then stirred an additional 3 h during which time the reaction pH naturally raised to 7.40. The reaction mixture was cooled to ambient temperature (26° C.). The reaction mixture was then suction transferred into a temporary holding vessel. The reactor was washed with two 30 g portions of water. These water washes were combined with the reaction mixture. The combined mixture was suctioned filtered through a coarse Buchner funnel (filtration time about 30 seconds), and the filtrate was collected and filtered a second time through the cake. A final displacement cake wash with ˜40 g of methanol was performed and the product was dried at 60° C. under vacuum (˜<10 mm Hg; 1333 Pa) to afford 25.37 g of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine as a light cream colored solid. NMR analysis (using benzyl acetate as an internal standard) indicated an 97.3% purity of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine active which corresponds to a 70.4% yield.

1. customequipped with a mechanical stirrer
2. temperatureThe reaction mixture was heated
3. temperatureThe reaction mixture was cooled to 27° C.
4. temperatureThe mixture was heated to 40° C.
5. temperatureAfter heating
6. additionwas continuously added over a 2 h 15 min period via a peristaltic pump
7. temperaturethe reaction mixture was heated to 81° C.
8. temperaturepH naturally raised to 7.40
9. temperatureThe reaction mixture was cooled to ambient temperature (26° C.)
10. customsuction transferred into a temporary holding vessel
11. washThe reactor was washed with two 30 g portions of water
12. filtrationThe combined mixture was suctioned filtered through a coarse
13. filtrationBuchner funnel (filtration time about 30 seconds)
14. customthe filtrate was collected
15. filtrationfiltered a second time through the cake
16. washA final displacement cake wash with ˜40 g of methanol
17. customthe product was dried at 60° C. under vacuum (˜<10 mm Hg; 1333 Pa)

ORD record

ord-e9c5cb4c083945c0a04a639c2e17d38b

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09115135B2