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

Temperature

60 °C

To a solution of 1,1,2,2-tetrafluoroethyldimethylamine (30 g, 207 mmol) in diethyl ether (90 ml) and dioxane (90 ml) was added dropwise, under a nitrogen atmosphere, at a temperature of from 0 to 5° C., a solution of BF3-etherate (49% BF3, 59.6 ml, 420 mmol). After the addition had ended, the reaction mixture was stirred for 5 min. Subsequently, pyridine (15.9 g, 201 mmol) and methyl 3-methoxyacrylate (22.3 g, 186 mmol) were successively added dropwise to the reaction mixture at a temperature of from 0 to 5° C. After stirring for 6 hours, a greasy solid formed, from which the supernatant solution was decanted off and discarded. The solid was then added at a temperature of from 0 to 5° C. to a mixture of sodium hydroxide (41.4 g, 1.035 mol) and methylhydrazine (38.6 g of a 35% aqueous solution, 288 mmol) in water (665 ml) and then stirred at room temperature for 1 h. Subsequently, the reaction mixture was heated to 60° C. and stirred at this temperature for 0.5 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 solid precipitated at a temperature of 0° C. was isolated by filtration, washed with a little ice-cold water and dried under reduced pressure at a temperature of 40° C. 3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid was obtained as a mixture with 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid with a ratio of 85:15 in an amount of 10.1 g.

1. additionAfter the addition
2. stirringAfter stirring for 6 hours
3. customa greasy solid formed, from which the supernatant solution
4. customwas decanted off
5. stirringstirred at room temperature for 1 h
6. stirringstirred at this temperature for 0.5 h
7. washwashed with ethyl acetate
8. customThe solid precipitated at a temperature of 0° C.
9. customwas isolated by filtration
10. washwashed with a little ice-cold water
11. customdried under reduced pressure at a temperature of 40° C

ORD record

ord-6e3a9bfdce81485d9371c31b5c941269

Source dataset

uspto-grants-2012_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08188295B2