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

Magnesium turnings (4.9 g, 0.20 mol), trimethylsilyl chloride (32.6 g, 0.30 mmol) and anhydrous 1,3-dimethyl-2-imidazolidinone (DMI, 160 ml) were initially charged in a 500 ml three-necked flask fitted with magnetic stirrer and thermometer. After activation of the magnesium with iodine, methyl 2-methoxymethylene-4,4,4-trifluoro-3-oxobutyrate (21.3 g, 0.10 mol) was added in an ice-bath over a period of 30 min, the reaction temperature being kept within a range of from 20 to 30° C. After a further 60 min at room temperature, excess trimethylsilyl chloride was removed under reduced pressure. In a second 500 ml three-necked flask, an aqueous methylhydrazine solution (37%, 14.8 g, 0.12 mol) and methanol (320 ml) were initially charged at −50° C. Over a period of 60 min, the cooled reaction solution of the first reaction was added, with cooling being maintained. After a further 2 hours at −50° C., the reaction mixture was allowed to warm to room temperature and stirred for a further 10 hours. According to GC analysis, the reaction mixture contained methyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate (isomer a) as a mixture with methyl 2-difluoromethyl-1-methylpyrazole-3-carboxylate (isomer b) in an a:b isomer ratio of 90:10. The reaction mixture was then concentrated under reduced pressure. 120 g of 10% strength aqueous sodium hydroxide solution were added to the residue, and the mixture was stirred at 100° C. for 4 h. After acidification of the aqueous solution with hydrochloric acid to pH 1 and repeated extraction with MTBE, an organic solution comprising 13.4 g of the title compound (yield isomer a: 71%) was obtained. The title compound was isolated by crystallization as a light-brown solid.

1. customfitted with magnetic stirrer
2. custombeing kept within a range of from 20 to 30° C
3. customexcess trimethylsilyl chloride was removed under reduced pressure
4. waitOver a period of 60 min
5. customthe cooled reaction solution of the first reaction
6. additionwas added
7. temperaturewith cooling
8. temperaturebeing maintained
9. waitAfter a further 2 hours at −50° C.
10. concentrationThe reaction mixture was then concentrated under reduced pressure
11. addition120 g of 10% strength aqueous sodium hydroxide solution were added to the residue
12. stirringthe mixture was stirred at 100° C. for 4 h
13. extractionextraction with MTBE
14. customyield isomer a: 71%)
15. customwas obtained

ORD record

ord-454cd7fefcf142988fb7df361c9aa7df

Source dataset

uspto-grants-2012_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08115012B2