Methylhydrazine → 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid

Temperature

-30 °C

At −30° C., difluoroacetyl fluoride (18.7 g, 0.187 mol; 98%) was introduced into a solution of methyl 3-piperidin-1-ylacrylate (99%, 29.0 g, 0.17 mol) and KF (technical grade) (10.7 g, 0.25 mol) in toluene (250 ml). The reaction mixture was stirred at −30° C. for 3 h. The mixture was then, over a period of one hour, warmed to room temperature. The reaction mixture was washed with deionized water (200 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and, under reduced pressure, concentrated to about 300 ml. At −50° C., the reaction solution obtained in this manner was added dropwise to a solution of methylhydrazine (8.79 g, 0.187 mol) in toluene (100 ml). The reaction mixture was stirred at −50° C. for 2 h and then, over a period of one hour, warmed to room temperature. Aqueous sodium hydroxide solution (10% strength, 105.3 g, 0.263 mol) was then added to the reaction mixture, and the mixture was heated under reflux conditions for 2 h. After cooling to room temperature, the phases were separated. The toluene phase was extracted with aqueous sodium hydroxide solution (10% strength, 100 ml). The aqueous phases were combined, adjusted to pH 1 using hydrochloric acid (conc.) and cooled to 0° C. The precipitated solid was filtered off, washed with cyclohexane and dried at 60° C. under reduced pressure. 3-Difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylic acid was obtained in an amount of 29.1 g in a purity of 89.4% (according to quant. HPLC) (yield: 88%). Extraction of the filtrate with ethyl acetate gave a further 1.4 g of a solid which, according to quant. HPLC, consisted to 36% of 3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylic acid.

1. waitover a period of one hour
2. temperaturewarmed to room temperature
3. washThe reaction mixture was washed with deionized water (200 ml)
4. customAfter separation of the phases
5. extractionthe aqueous phase was extracted once with toluene (100 ml)
6. concentrationconcentrated to about 300 ml
7. customAt −50° C., the reaction solution obtained in this manner
8. stirringThe reaction mixture was stirred at −50° C. for 2 h
9. waitover a period of one hour
10. temperaturewarmed to room temperature
11. temperaturethe mixture was heated under reflux conditions for 2 h
12. temperatureAfter cooling to room temperature
13. customthe phases were separated
14. extractionThe toluene phase was extracted with aqueous sodium hydroxide solution (10% strength, 100 ml)
15. temperaturecooled to 0° C
16. filtrationThe precipitated solid was filtered off
17. washwashed with cyclohexane
18. customdried at 60° C. under reduced pressure

ORD record

ord-ea7362d2e4c24f42a68c9acccb92a4d7

Source dataset

uspto-grants-2013_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08586750B2