反应详情

温度

-15 °C

Methylhydrazine (319.3 g) was added to methanol (13.931 L) stirred and chilled to −15° C. under nitrogen. Aqueous HCl (37 wt %, 1859.6 g) was then added at a rate sufficiently slow to enable the stirred solution to be maintained at −12 to −7° C. with reactor jacket cooling. As stirring under nitrogen was continued at −10° C., 3-dimethylamino-1-(2′-methoxy-5′-acetamidophenyl)prop-2-en-1-one (4, 1546.9 g) was added as a solid over ten minutes. The resulting homogenous dark brown solution was stirred under nitrogen first at 0° C. for 3 hours and then at 10° C. for 5.5 hours before 33% aqueous ammonia (1090 mL) was added at a rate sufficiently slow (25 minutes) to enable the stirred solution to be maintained at 8.6-15.2° C. with reactor jacket cooling. LC/MS analyses of the reaction mixture before aqueous ammonia treatment revealed 97.3% conversion of 4 to 5 and its other N-methylpyrazole isomer (in 83.3:13.2 ratio) and, after aqueous ammonia treatment, 100% conversion of 4 to 5 and its other N-methylpyrazole isomer (in 87.8:12.2 ratio). The aqueous ammonia addition raised the reaction mixture pH to 8. Methanol (ca. 12 L) was then distilled off the stirred reaction mixture at atmospheric pressure and internal temperatures rising to 74.4° C. Product crystallization, which started at the end of the distillation, was completed by cooling the reaction mixture to −2° C. and holding that temperature with stirring for 44 hours. LC/MS analysis of the crystallization mixture's liquid phase revealed 5 and its other N-methylpyrazole isomer in about 1:3 ratio. (Higher ratios of 5:other isomer in the liquid phase jeopardize product yield, and lower ratios jeopardize product purity. In either case, the crystallization can be repeated by heating the stirred mixture back to reflux at atmospheric pressure and, prior to recrystallization, either distilling off more methanol (if the ratio is high) or adding additional methanol (if the ratio is low).) The reaction mixture was filtered by suction, and the filtered solids were washed with 0° C. water (3 L, then 2×500 mL) and dried at 40° C., <1 mm HgA to provide 5 (1157.7 g, 80.0% yield).

1. temperatureto be maintained at −12 to −7° C. with reactor jacket
2. temperaturecooling
3. stirringAs stirring under nitrogen
4. customwas continued at −10° C.
5. stirringThe resulting homogenous dark brown solution was stirred under nitrogen first at 0° C. for 3 hours
6. temperatureto be maintained at 8.6-15.2° C. with reactor jacket
7. temperaturecooling
8. temperatureraised the reaction mixture pH to 8
9. distillationMethanol (ca. 12 L) was then distilled off
10. customthe stirred reaction mixture at atmospheric pressure and internal temperatures
11. customrising to 74.4° C
12. customProduct crystallization, which
13. distillationstarted at the end of the distillation
14. temperatureby cooling the reaction mixture to −2° C.
15. stirringwith stirring for 44 hours
16. customyield
17. customIn either case, the crystallization
18. temperatureby heating the stirred mixture back
19. temperatureto reflux at atmospheric pressure
20. customto recrystallization
21. distillationdistilling off more methanol (if the ratio
22. additionadding additional methanol (if the ratio
23. filtration) The reaction mixture was filtered by suction
24. washthe filtered solids were washed with 0° C. water (3 L
25. custom2×500 mL) and dried at 40° C.