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

Temperature

80 °C

To a 700 milliliter (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 grams (g; 0.125 moles (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 a 22 minute (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 hours (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 (5.500 mol) of deionized water was added to the mixture. After heating to reflux (˜71° C.), 9.4 g (0.142 mol) of a 50 weight percent (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 6.60. 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 an 8 min period. The reaction pH rose from 6.30 to 7.44 during the sodium sulfite addition. The reaction mixture was 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 less than 2.0 min), and then the reaction vessel was washed with 150 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 3.5 h to afford 18.01 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 91.6% purity which corresponds to a 67.5% yield. 1H NMR (DMSO-d6, 400 MHz) δ 3.89 (s, 3H), 4.06 (s, 3H), 6.27 (br s, 2H), 7.47 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 55.37, 57.03, 123.06, 138.59, 143.72, 148.49, 166.01.

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 hours (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 1 h 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 ambient temperature
12. waitto stand overnight
13. filtrationfiltered through a medium coarse fritted glass funnel
14. filtration(filtration time less than 2.0 min)
15. washthe reaction vessel was washed with 150 g of deionized water
16. washto wash the isolated product cake
17. washA final displacement wash with 30 g of fresh deionized water
18. customthe product was partially dried by suction for 3.5 h

ORD record

ord-aa857061dfb04b1e914ea27532ab139a

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09115135B2