Dichloromethane → Allyl 3,5-diamino-1H-pyrazole-4-carboxylate

To a suspension of allyl 3-amino-4,4,4-trichloro-2-cyano-but-2-enoate 2 (619 g, 2.297 mol) and KOAc (676.3 g, 6.891 mol) in DMF (2.476 L) at 0° C. was slowly added hydrazine hydrate (172.5 g, 167.6 mL, 3.446 mol) over 15 min. The reaction mixture was then stirred at ambient temperature for 2 h, at which stage 1H NMR shows complete consumption of the starting material. Reaction mixture was then heated overnight at 110° C. before being allowed to cool to ambient and stirred for another 48 h. The mixture was filtered through a sintered glass funnel to remove the precipitated solid and the filtrate was evaporated under reduced pressure to give a thick liquid. DCM (approx 2 L) was added, and the mixture filtered again to remove additional solids that have precipitated. The filtrate was purified through a 1 kg silica gel plug (gradient of DCM/MeOH as an eluent), and the solvent was removed to afford an orange solid which was suspended in acetonitrile and heated at about 70° C. until all the solid went into solution, at which point the solution was allowed to cool to ambient temperature, then to 2° C. The precipitate that formed was isolated by filtration under vacuum, washed with chilled MeCN (˜50 mL) and dried to constant mass in a vacuum oven to furnish the title compound as an off-white powder (171.2 g, 41%). LC-MS (M+H)+ 183.0; 1H NMR (300 MHz, DMSO) δ 10.60 (br s, 1H), 5.95-6.05 (m, 1H), 5.17-5.40 (m, 6H), 4.60 (d, 2H).

1. customover 15 min
2. customconsumption of the starting material
3. customReaction mixture
4. temperaturewas then heated overnight at 110° C.
5. temperatureto cool to ambient and
6. stirringstirred for another 48 h
7. filtrationThe mixture was filtered through a sintered glass funnel
8. customto remove the precipitated solid
9. customthe filtrate was evaporated under reduced pressure
10. customto give a thick liquid
11. filtrationthe mixture filtered again
12. customto remove additional solids that
13. customhave precipitated
14. customThe filtrate was purified through a 1 kg silica gel plug (gradient of DCM/MeOH as an eluent), and the solvent
15. customwas removed
16. customto afford an orange solid which
17. temperatureheated at about 70° C. until all the solid
18. temperatureto cool to ambient temperature
19. customto 2° C
20. customThe precipitate that formed
21. customwas isolated by filtration under vacuum
22. washwashed with chilled MeCN (˜50 mL)
23. customdried to constant mass in a vacuum oven

ORD record

ord-1601d1438fe1470182f1fb7305f4d2c1

Source dataset

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08969360B2