Реакция #41133

Уравнение реакции

Sodium hydroxide

sodium hydroxide

t-butylhydrazine

Tert-butylhydrazine hydrochloride

hydrochloric acid

Formyl-3-oxo-propionic acid ethyl ester

→

1-tert-Butyl-1H-pyrazole-4-carboxylic acid

Растворители

ethanol

Условия реакции

Обработка

1. 1
   ДругоеThe flask was then placed in an ice-bath
2. 2
   Температураto cool it back to 20° C
3. 3
   workup.DISSOLUTIONto fully dissolve
4. 4
   ТемператураThe reaction mixture was cooled in an ice-bath
5. 5
   ДругоеMost of the ethanol was then removed in vacuo and methanol (300 ml)
6. 6
   workup.ADDITIONwas added
7. 7
   Другоеgradually rose to 32° C
8. 8
   ДругоеThe reaction flask was then placed in a water bath
9. 9
   Температураto cool it back to room temp.
10. 10
    workup.STIRRINGto stir at room temp. for 18 h
11. 11
    ДругоеMethanol (300 ml) was then removed in vacuo with the water bath temperature
12. 12
    Другоеkept below 30° C
13. 13
    ТемператураThe reaction mixture was then cooled to 0° C.
14. 14
    workup.ADDITIONhydrochloric acid (6N, 190 ml) was added slowly
15. 15
    Другоеtemperature below 15° C
16. 16
    workup.STIRRINGto stir in the ice-bath for 2 h
17. 17
    Фильтрацияthe solid was filtered
18. 18
    ДругоеAfter drying at 60° C. in vacuo for 2.5 days
19. 19
    Другое1-tert-butyl-1H-pyrazole-4-carboxylic acid (56.06 g) of off-white solid was collected
20. 20
    ЭкстракцияThe mother liquor was extracted 3 times with dichloromethane (200 ml×3)
21. 21
    ПромывкаThe combined organic layer was washed once with brine (100 ml)
22. 22
    Сушкаdried over magnesium sulfate
23. 23
    КонцентрированиеAfter concentrating in vacuo
24. 24
    Другоеdrying
25. 25
    Другое16.5 g of yellowish solid was collected
26. 26
    ДругоеThe crude material was crystallized in hot iso-propyl acetate (25 ml)
27. 27
    ТемператураAfter cooling to room temp
28. 28
    Фильтрацияthe solid was filtered off
29. 29
    Промывкаthe cake was washed with mixed solvent of isopropyl acetate and heptane (1/1 (v/v, 14 ml)
30. 30
    Другоеdried in oven at 60° C. in vacuo for 5 h
31. 31
    ДругоеA second crop of 1-tert-butyl-1H-pyrazole-4-carboxylic acid (7 g) was collected as a white solid

Методика

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.

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