Methanol → 5-(4-Bromophenyl)-1-methyl-1H-pyrazole

Temperature

110 °C

4-bromoacetophenone (20.0 g; 0.10 mole) and N,N-dimethylformamide dimethylacetal (28.5 mL; 0.20 mole) were mixed together in DMF (12 mL) and heated to 110° C. for 4 hours. The methanol and water that were generated during the reaction were distilled (6.2 mL). The mixture was cooled to 25° C. Methyl t-butyl ether (100 mL) and methylhydrazine (21.2 mL; 0.40 moles) were added and the mixture was stirred over night. The reaction mixture was washed with 1 M aqueous ammonium chloride (3×40 mL) and water (40 mL). The organic phase was dried by azeotropic distillation using a Dean-Stark apparatus. As an alternative to distillation, the solution was dried through an anhydrous magnesium sulfate cartridge. The solution was filtered through a silica gel cartridge (60 g). The product was flushed from the cartridge with methyl t-butyl ether. The fraction(s) containing product were combined and concentrated to about 70 mL by distillation. Heptane (120 mL) was added and distillation was continued until the pot temperature reached 98.4° C. About 100 mL of distillate was collected. The mixture was cooled to 40° C. The mixture was seeded and the temperature was maintained at 40° C. for 30 minutes while crystallization was initiated. The mixture was slowly chilled to 0° C. over 90 minutes. The mixture was held at 0° C. for 30 minutes. The mixture was filtered and the solid was washed (3×) with chilled (0° C.) heptane. The solid was dried on the filter. A cream-colored, crystalline solid (16.3 g; 68% yield) was obtained. The NMR data of the title compound are as per alternative 1.

1. distillationwere distilled (6.2 mL)
2. temperatureThe mixture was cooled to 25° C
3. washThe reaction mixture was washed with 1 M aqueous ammonium chloride (3×40 mL) and water (40 mL)
4. customThe organic phase was dried by azeotropic distillation
5. distillationAs an alternative to distillation
6. dry with materialthe solution was dried through an anhydrous magnesium sulfate cartridge
7. filtrationThe solution was filtered through a silica gel cartridge (60 g)
8. customThe product was flushed from the cartridge with methyl t-butyl ether
9. additionThe fraction(s) containing product
10. concentrationconcentrated to about 70 mL by distillation
11. additionHeptane (120 mL) was added
12. distillationdistillation
13. customreached 98.4° C
14. distillationAbout 100 mL of distillate was collected
15. temperatureThe mixture was cooled to 40° C
16. temperaturethe temperature was maintained at 40° C. for 30 minutes while crystallization
17. temperatureThe mixture was slowly chilled to 0° C. over 90 minutes
18. filtrationThe mixture was filtered
19. washthe solid was washed (3×)
20. temperaturewith chilled (0° C.) heptane
21. customThe solid was dried on the filter
22. customA cream-colored, crystalline solid (16.3 g; 68% yield) was obtained

ORD record

ord-5efb757a0f834f26bf28c5eccdc2db71

Source dataset

uspto-grants-2010_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07772269B2