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

To a solution of 1,1,2,2-tetrafluoroethyldimethylamine (3.2 g, 22 mmol) in diethyl ether (10 ml) and dioxane (10 ml) was added dropwise, under a nitrogen atmosphere, at a temperature of from 0 to 5° C., a solution of BF3-etherate (49% BF3, 5.6 ml, 44 mmol). After the addition had ended, the reaction mixture was stirred for 5 min. Subsequently, pyridine (1.7 g, 22 mmol) and a solution of ethyl 3-(pyrrolidin-1-yl)acrylate (2.9 g, 20 mmol) in dioxane (2 ml) were successively added dropwise to the reaction mixture at a temperature of from 0 to 5° C. After stirring for 6 hours, the reaction mixture was added at a temperature of from 0 to 5° C. to a mixture of sodium hydroxide (4.4 g, 110 mmol) and methylhydrazine (1.4 g, 30 mmol) in water (75 ml), and then the mixture was stirred at room temperature for 3 h. The reaction mixture was freed of volatile constituents. The resulting residue was taken up in water (50 ml), washed with ethyl acetate and then brought to a pH of 2 with conc. hydrochloric acid. The aqueous phase was decanted off and discarded. The resulting slimy residue was taken up in a mixture of tetrahydrofuran and methyl tert-butyl ether, dried over sodium sulfate, filtered and freed from the solvent under reduced pressure. 3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid was obtained as a mixture with 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid with a ratio of 2:1 in a yield of 60%.

1. additionAfter the addition
2. stirringAfter stirring for 6 hours
3. stirringthe mixture was stirred at room temperature for 3 h
4. washwashed with ethyl acetate
5. customThe aqueous phase was decanted off
6. additionThe resulting slimy residue was taken up in a mixture of tetrahydrofuran and methyl tert-butyl ether
7. dry with materialdried over sodium sulfate
8. filtrationfiltered

ORD record

ord-bbc46165372149b4ae173a6ebc2ad4b7

Source dataset

uspto-grants-2012_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08188295B2