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

Temperature

-30 °C

At −30° C., trifluoroacetyl fluoride (18.3 g, 0.16 mol; 99.5%) was introduced into a solution of methyl 3-piperidin-1-ylacrylate (97%, 25 g, 0.14 mol) and KF (12.5 g, 0.51 mol) in toluene (250 ml). The reaction mixture was stirred at −30° C. for 3 h and then, over a period of one hour, warmed to room temperature. The reaction mixture was washed with deionized water (400 ml). After phase separation, the aqueous phase was extracted once with toluene (200 ml). The toluene phases were combined and, under reduced pressure, concentrated to about 600 ml. The reaction solution obtained in this manner was, at −50° C., added dropwise to a solution of methylhydrazine (7.4 g, 0.16 mol) in toluene (150 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, 69.4 g, 0.17 mol) was then added, and the reaction 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, at 60° C., dried under reduced pressure. 3-trifluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylic acid was obtained in an amount of 21.8 g and a purity of 98% (according to 1H-NMR) (yield: 0.12 mol, 81%).

1. waitover a period of one hour
2. temperaturewarmed to room temperature
3. washThe reaction mixture was washed with deionized water (400 ml)
4. customAfter phase separation
5. extractionthe aqueous phase was extracted once with toluene (200 ml)
6. concentrationconcentrated to about 600 ml
7. customThe reaction solution obtained in this manner
8. customwas, at −50° C.
9. stirringThe reaction mixture was stirred at −50° C. for 2 h
10. waitover a period of one hour
11. temperaturewarmed to room temperature
12. temperaturethe reaction mixture was heated under reflux conditions for 2 h
13. temperatureAfter cooling to room temperature
14. customthe phases were separated
15. extractionThe toluene phase was extracted with aqueous sodium hydroxide solution (10% strength, 100 ml)
16. temperaturecooled to 0° C
17. filtrationThe precipitated solid was filtered off
18. washwashed with cyclohexane and, at 60° C.
19. customdried under reduced pressure

ORD record

ord-f8e6dde68d644896bea52a9e8bdea92c

Source dataset

uspto-grants-2013_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08586750B2