Citric Acid → 2-chloro-1-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)ethanone

Temperatur

-40 °C

To a 10 L four necked flask was charged 1-Isopropyl-3-methyl-1H-1,2,4-triazole 7 (400 g) in THF (2.5 L). The resulting solution was cooled to −40° C. and 2.5 M n-butyllithium BuLi in n-hexanes (1.41 L) was added while keeping the internal temp. below −20° C. The resulting yellow suspension was stirred at −40° C. for 1 hour before being transferred. To a 20 L flask was charged 2-chloro-N-methoxy-N-methylacetamide 10 (485 g) in THF (4 L). The resulting solution was cooled to −40° C. at which point a white suspension was obtained, and to this was added the solution of lithiated triazole 7 keeping the internal temp. below −20° C. At this point a yellow orange solution was obtained which was stirred at −30° C. for 1 hour. Propionic acid (520 mL) was added keeping the internal temp. below −20° C. The resulting off-white to yellowish suspension was warmed to −5° C. over 30 minutes. Citric acid (200 g) in water (0.8 L) was added and after stirring for 5 minutes a clear biphasic mixture was obtained. At this point stirring was stopped and the bottom aqueous layer was removed. The organic phase was washed with 20 w % K3PO4 solution (1 L), 20 w % K2HPO4 solution (2 L), and 20 w % NaCl solution (1 L). The organics was reduced to ca 4 L via distillation under vacuum to afford 2-chloro-1-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)ethanone 13 as a dark amber liquid which was used “as is” in the next step.

1. custombelow −20° C
2. temperatureThe resulting solution was cooled to −40° C. at which point a white suspension
3. customwas obtained
4. custombelow −20° C
5. customAt this point a yellow orange solution was obtained which
6. stirringwas stirred at −30° C. for 1 hour
7. custombelow −20° C
8. temperatureThe resulting off-white to yellowish suspension was warmed to −5° C. over 30 minutes
9. stirringafter stirring for 5 minutes a clear biphasic mixture
10. customwas obtained
11. stirringAt this point stirring
12. customthe bottom aqueous layer was removed
13. washThe organic phase was washed with 20 w % K3PO4 solution (1 L), 20 w % K2HPO4 solution (2 L), and 20 w % NaCl solution (1 L)
14. distillationThe organics was reduced to ca 4 L via distillation under vacuum

ORD-Eintrag

ord-fd028bd8578e464598fc47b9087e7319

Quelldatensatz

uspto-grants-2016_04

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09303043B2