反应详情

温度

-15 °C

tert-butyl-1H-pyrazole-4-carboxylic acid (5 g, 29.73 mmol) was dissolved in tetrahydrofuran (50 ml) at room temp. In a separate flask was added n-butyllithium (2.5M solution in hexane, 29.73 ml, 74.33 mmol) and was cooled to −15° C. The 1-tert-butyl-1H-pyrazole-4-carboxylic acid solution was added dropwise to the n-Butyllithium solution, maintaining internal temperature below −10° C. The total addition time lasted 30 min. The resulting brownish suspension was stirred and maintained between −10° C. and −15° C. for 40 min. The reaction was then cooled to −15° C. to −20° C. A solution of hexachloroethane (14.08 g, 59.46 mmol) in tetrahydrofuran (50 ml) was added dropwise, maintaining internal temperature below −10° C. The total addition time lasted 20 min. After the addition, the resulting dark brownish solution was stirred at −10° C. to −15° C. for 30 min and was warmed up to room temp. over 1 h. The reaction mixture was then cooled to 15° C. and water (50 ml) was added slowly, maintaining internal temperature below 20° C. 120 ml of organic solvents were distilled under reduced pressure at 25° C. water bath leading to a suspension. Heptane (50 ml) was added leading to a clear brownish biphasic solution. After stirring at room temp. for 15 min, the aqueous layer (pH=11.8) was separated. The organic layer was extracted once with NaOH (1N, 20 ml). The combined aqueous phase was washed with heptane (25 ml) and was cooled in an ice-bath. Hydrochloric acid (6N) was added to adjust pH=2, maintaining internal temperature below 20° C. The suspension was stirred in the ice-bath at 0-5° C. for 1 h and the solid was filtered and washed with water (40 ml). After drying in vacuo at 60° C. for 18 h, 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (5.28 g) was obtained as a light yellow solid.

1. temperaturemaintaining internal temperature below −10° C
2. additionThe total addition time
3. temperaturemaintained between −10° C. and −15° C. for 40 min
4. temperatureThe reaction was then cooled to −15° C. to −20° C
5. temperaturemaintaining internal temperature below −10° C
6. additionThe total addition time
7. waitlasted 20 min
8. additionAfter the addition
9. stirringthe resulting dark brownish solution was stirred at −10° C. to −15° C. for 30 min
10. temperaturewas warmed up to room temp. over 1 h
11. temperatureThe reaction mixture was then cooled to 15° C.
12. temperaturemaintaining internal temperature below 20° C
13. distillation120 ml of organic solvents were distilled under reduced pressure at 25° C. water bath
14. additionHeptane (50 ml) was added
15. stirringAfter stirring at room temp. for 15 min
16. customthe aqueous layer (pH=11.8) was separated
17. extractionThe organic layer was extracted once with NaOH (1N, 20 ml)
18. washThe combined aqueous phase was washed with heptane (25 ml)
19. temperaturewas cooled in an ice-bath
20. additionHydrochloric acid (6N) was added
21. temperaturemaintaining internal temperature below 20° C
22. stirringThe suspension was stirred in the ice-bath at 0-5° C. for 1 h
23. filtrationthe solid was filtered
24. washwashed with water (40 ml)
25. customAfter drying in vacuo at 60° C. for 18 h