Acetic Acid → 4-(2-Bromo-4-fluorophenyl)-N-(2-chloro-6-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-amine

To a solution of potassium tert-butoxide (0.41 g, 3.3 mmol) in THF (20 mL) at 0° C. was added a solution of 1-(2-bromo-4-fluorophenyl)-2-propanone (i.e. the product of Step A) (0.70 g, 3.0 mmol) in THF (10 mL) over 5 minutes. Stirring was continued for 1 h and then the temperature was reduced to −10° C. A solution of 1-chloro-3-fluoro-2-isothiocyanatobenzene (i.e. the product of Step B) (0.57 g, 3.0 mmol) in THF (10 mL) was added over 6 minutes, and stirring was continued for 15 minutes. Iodomethane (0.54 g, 3.8 mmol) was added, and the cooling bath was removed to provide a reaction mixture containing the intermediate compound α-acetyl-2-bromo-N-(2-chloro-6-fluorophenyl)-4-fluorobenzene-ethanethioamide. After 5 min, water (0.2 mL, 11 mmol), glacial acetic acid (0.53 mL, 9.1 mmol) and methylhydrazine (0.81 mL, 15 mmol) were added in rapid succession, and the reaction mixture was heated to reflux for 6 h. The crude reaction mixture was then concentrated under reduced pressure and purified by MPLC (0 to 100% ethyl acetate in hexanes as eluent) to provide the title product, a compound of the present invention, as an off-white solid (0.55 g).

1. customwas reduced to −10° C
2. stirringstirring
3. waitwas continued for 15 minutes
4. customthe cooling bath was removed
5. customto provide a reaction mixture
6. waitAfter 5 min
7. temperaturethe reaction mixture was heated
8. temperatureto reflux for 6 h
9. customThe crude reaction mixture
10. concentrationwas then concentrated under reduced pressure
11. custompurified by MPLC (0 to 100% ethyl acetate in hexanes as eluent)

ORD record

ord-fcba036166594296a5f55f926b4c00c2

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09107412B2