反应详情

温度

10 °C

An oven dried 300 mL 3-necked round bottomed flask was equipped with a magnetic stirring bar, argon inlet, and drying tube. The flask was charged with 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanoic acid (10 gm, 28.03 mmol) followed by ethanol (100 mL). The resulting solution was cooled using an ice-water bath, the stirring solution was treated with concentrated H2SO4 (0.07 mL, 2.52 meq.). The flask was then removed from the ice-water bath, the argon inlet and drying tube were removed, and the flask was equipped with a condenser and thermocouple. The reaction mixture was heated to reflux and monitored by TLC (using a 1:2:6 MeOH:EtOAc:hexane solvent system). After stirring at reflux for 5 hours, the reaction flask was fitted with a short path distillation apparatus and ethanol was distilled off (70 mL). The resulting residue was cooled to 10° C. and treated dropwise with NaOEt (21 wt %, 37.7 mL, 101.04 mmol). The resulting mixture was then treated with N-methylhydroxylamine hydrochloride (3.51 gm; 42.05 mmol). The reaction flask was then re-equipped with a drying tube and argon inlet, and the reaction was stirred at ambient temperature. b) The reaction was allowed to stir for 18 hours at ambient temperature. TLC analysis (using 50% EtOAc in hexane and 10% methanol in CH2Cl2) showed completion of the reaction. The reaction flask was placed in an ice-water bath, and the reaction mixture was treated dropwise with a cooled (ice-water bath) mixture of glacial acetic acid (3.3 mL; 57.4 mmol) and 33 mL of distilled water. After completion of the addition of the aqueous acetic acid solution, the pH of the mixture was adjusted to between 6.4 to 6.8 with 1N NaOH (litmus). The mixture was then treated with additional distilled water (5 mL) where upon solid began to precipitate out. The reaction flask was then equipped with a short path distillation apparatus, and approximately 27 mL of solvent was removed (80 mm of Hg vacuum at 30-35° C.). The pH of the resulting mixture was re-adjusted to between 6.4 to 6.8, and the mixture was allowed to stir with cooling from an ice-water bath for 30 minutes. The solid was collected by filtration, and the solid product was washed with ice-cold distilled water. The air-dried product was then placed in a vacuum oven and dried for 18 hours at 60° C. under vacuum to give 9.51 gm of tepoxalin (87.9% yield, HPLC wt % purity of 98.6%).

1. customAn oven dried 300 mL 3-necked round bottomed flask
2. customwas equipped with a magnetic stirring bar, argon inlet
3. customdrying tube
4. temperatureThe resulting solution was cooled
5. customThe flask was then removed from the ice-water bath
6. customthe argon inlet and drying tube
7. customwere removed
8. customthe flask was equipped with a condenser
9. temperatureThe reaction mixture was heated
10. temperatureto reflux
11. temperatureat reflux for 5 hours
12. customthe reaction flask was fitted with a short path distillation apparatus and ethanol
13. distillationwas distilled off (70 mL)
14. customThe reaction flask was then re-equipped with a drying tube and argon inlet
15. stirringthe reaction was stirred at ambient temperature
16. stirringto stir for 18 hours at ambient temperature
17. customcompletion of the reaction
18. customThe reaction flask was placed in an ice-water bath
19. additionthe reaction mixture was treated dropwise with
20. temperaturea cooled
21. additionThe mixture was then treated
22. distillationwith additional distilled water (5 mL) where upon solid
23. customto precipitate out
24. customThe reaction flask was then equipped with a short path distillation apparatus, and approximately 27 mL of solvent
25. customwas removed (80 mm of Hg vacuum at 30-35° C.)
26. stirringto stir
27. temperaturewith cooling from an ice-water bath for 30 minutes
28. filtrationThe solid was collected by filtration
29. washthe solid product was washed with ice-cold
30. distillationdistilled water
31. customdried for 18 hours at 60° C. under vacuum