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 (1.639 mol) of toluene. The reaction was heated to gentle reflux (˜80° C.) and then 19.24 g (0.144 mol) of 98% ethoxy carbonylisothiocyanate was added, and the reaction mixture was heated at gentle reflux (89° C.) for 7 h. The reaction mixture was cooled to 26° C. and allowed to stand overnight. The mixture was heated to 60° C. and then 100 g (5.500 mol) of deionized water was added to the mixture. After heating to reflux (˜69° C.), 9.6 g (0.145 mol) of a 50 wt % aqueous hydroxylamine solution was continuously added over a 1 h period. During the course of the amine addition, the reaction pH rose from 4.00 to 6.67. After completing addition of hydroxylamine, the reaction mixture was heated to 77° C. and then stirred an additional 3 h during which time the reaction pH naturally raised to 7.42. 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 one min period. The reaction pH rose from 7.34 to 7.81 during the sodium sulfite addition. The reaction mixture was stirred an additional 1 h at 77° C. and then cooled to ambient temperature and allowed to stand overnight. The reaction mixture was suction filtered through a medium coarse fritted glass funnel (filtration time was 43 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 dried to afford 19.62 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 83.3% purity of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine active which corresponds to a 67.0% yield.

1. customequipped with a mechanical stirrer
2. temperatureThe reaction was heated
3. temperaturethe reaction mixture was heated
4. temperatureat gentle reflux (89° C.) for 7 h
5. temperatureThe reaction mixture was cooled to 26° C.
6. temperatureThe mixture was heated to 60° C.
7. temperatureAfter heating
8. additionwas continuously added over a 1 h period
9. temperaturethe reaction mixture was heated to 77° C.
10. temperaturepH naturally raised to 7.42
11. stirringThe reaction mixture was stirred an additional 1 h at 77° C.
12. temperaturecooled to ambient temperature
13. waitto stand overnight
14. filtrationfiltered through a medium coarse fritted glass funnel
15. filtration(filtration time was 43 min)
16. washthe reaction vessel was washed with 30 g of deionized water
17. washto wash the isolated product cake
18. washA final displacement wash with 30 g of fresh deionized water
19. customthe product was dried

ORD record

ord-3a411000d91f49b0a442e90fdb05cdc7

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09115135B2