Ammonium Chloride → 5-(2,6-difluorophenyl)-1-methyl-1H-pyrazole-3-carbonitrile

Temperature

0 °C

To a mixture of ammonium chloride (0.42 g, 7.52 mmol) in toluene (10 mL) at 0° C. was added dropwise trimethyl aluminum (2 M in toluene, 3.76 mL, 7.52 mmol). After the addition was complete, the reaction mixture was stirred at 0° C. for 1 h, warmed to room temperature, and then a mixture of ethyl 5-(2,6-difluorophenyl)-1-methyl-1H-pyrazole-3-carboxylate (i.e. the product of Step A) (1 g, 3.76 mmol) in toluene (5 mL) was added and the mixture was heated at 110° C. for 4 h. The reaction mixture was allowed to cool to room temperature, partitioned between aqueous hydrochloric acid (1 N) and diethyl ether (about 20 mL) and the organic phase was separated. The aqueous phase was extracted with diethyl ether and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (10 to 20% gradient of ethyl acetate in hexanes) to provide the title compound as a solid (0.4 g).

1. additionAfter the addition
2. temperaturewarmed to room temperature
3. additionwas added
4. temperaturethe mixture was heated at 110° C. for 4 h
5. temperatureto cool to room temperature
6. custompartitioned between aqueous hydrochloric acid (1 N) and diethyl ether (about 20 mL)
7. customthe organic phase was separated
8. extractionThe aqueous phase was extracted with diethyl ether
9. dry with materialthe combined organic layers were dried over magnesium sulfate
10. filtrationfiltered
11. concentrationconcentrated under reduced pressure
12. customThe resulting material was purified by silica gel column chromatography (10 to 20% gradient of ethyl acetate in hexanes)

ORD record

ord-10ac1ed59d4942c2872b92db3adc4c74

Source dataset

uspto-grants-2014_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08754115B2