Hydrochloric Acid → 1-tert-Butyl-1H-pyrazole-4-carboxylic acid

Temperatur

32 °C

Formyl-3-oxo-propionic acid ethyl ester (75.85 g, 525.6 mmol) was dissolved in ethanol (1 L) at room temp. Tert-butylhydrazine hydrochloride (65.5 g, 525.6 mmol) was added at room temp and the reaction temperature gradually increased to 32° C. The flask was then placed in an ice-bath to cool it back to 20° C. It took ca. 1 h for t-butylhydrazine to fully dissolve. The solution was stirred at room temp. for 3 h. The reaction mixture was cooled in an ice-bath. Sodium hydroxide (4N, 152.4 g) was added to neutralize the hydrochloric acid. Most of the ethanol was then removed in vacuo and methanol (300 ml) was added followed by additional sodium hydroxide (4N, 304.8 g, 1.05 mol). The internal temperature gradually rose to 32° C. The reaction flask was then placed in a water bath to cool it back to room temp. and the reaction was allowed to stir at room temp. for 18 h. Methanol (300 ml) was then removed in vacuo with the water bath temperature kept below 30° C. The reaction mixture was then cooled to 0° C. and hydrochloric acid (6N, 190 ml) was added slowly to keep internal temperature below 15° C. The solution was adjusted to pH=2. The resulting suspension was allowed to stir in the ice-bath for 2 h, and the solid was filtered. After drying at 60° C. in vacuo for 2.5 days, 1-tert-butyl-1H-pyrazole-4-carboxylic acid (56.06 g) of off-white solid was collected. The mother liquor was extracted 3 times with dichloromethane (200 ml×3). The combined organic layer was washed once with brine (100 ml) and dried over magnesium sulfate. After concentrating in vacuo and drying, 16.5 g of yellowish solid was collected. The crude material was crystallized in hot iso-propyl acetate (25 ml) and heptane (25 ml). After cooling to room temp, the solid was filtered off and the cake was washed with mixed solvent of isopropyl acetate and heptane (1/1 (v/v, 14 ml) and dried in oven at 60° C. in vacuo for 5 h. A second crop of 1-tert-butyl-1H-pyrazole-4-carboxylic acid (7 g) was collected as a white solid.

1. customThe flask was then placed in an ice-bath
2. temperatureto cool it back to 20° C
3. dissolutionto fully dissolve
4. temperatureThe reaction mixture was cooled in an ice-bath
5. customMost of the ethanol was then removed in vacuo and methanol (300 ml)
6. additionwas added
7. customgradually rose to 32° C
8. customThe reaction flask was then placed in a water bath
9. temperatureto cool it back to room temp.
10. stirringto stir at room temp. for 18 h
11. customMethanol (300 ml) was then removed in vacuo with the water bath temperature
12. customkept below 30° C
13. temperatureThe reaction mixture was then cooled to 0° C.
14. additionhydrochloric acid (6N, 190 ml) was added slowly
15. customtemperature below 15° C
16. stirringto stir in the ice-bath for 2 h
17. filtrationthe solid was filtered
18. customAfter drying at 60° C. in vacuo for 2.5 days
19. custom1-tert-butyl-1H-pyrazole-4-carboxylic acid (56.06 g) of off-white solid was collected
20. extractionThe mother liquor was extracted 3 times with dichloromethane (200 ml×3)
21. washThe combined organic layer was washed once with brine (100 ml)
22. dry with materialdried over magnesium sulfate
23. concentrationAfter concentrating in vacuo
24. customdrying
25. custom16.5 g of yellowish solid was collected
26. customThe crude material was crystallized in hot iso-propyl acetate (25 ml)
27. temperatureAfter cooling to room temp
28. filtrationthe solid was filtered off
29. washthe cake was washed with mixed solvent of isopropyl acetate and heptane (1/1 (v/v, 14 ml)
30. customdried in oven at 60° C. in vacuo for 5 h
31. customA second crop of 1-tert-butyl-1H-pyrazole-4-carboxylic acid (7 g) was collected as a white solid

ORD-Eintrag

ord-b6fbe5c47ec6472388d42a50f9e9f172

Quelldatensatz

uspto-grants-2010_06

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07728029B2