Pyridine → N-tert-Butyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid ethyl ester

BF3.OEt2 (2.7 ml, 22.0 mmol) was added to a solution of TFEDMA (2.5 ml, 22.0 mmol) in dry dichloromethane (20 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min, before the dichloromethane was removed under reduced pressure. The residue was then taken up in dry acetonitrile (20 ml). In a second Teflon flask, ethyl 4,4,4-trifluoroacetoacetate (2.8 ml, 20.0 mmol) was added to a solution of pyridine (7.1 g, 90.0 mmol) in dry acetonitrile (40 ml) and the mixture was stirred at room temperature for 15 min. To this were added dropwise, at −30° C., the contents of the first flask. The reaction mixture was brought to room temperature in the cold bath and stirred overnight. tert-Butyl hydrazine hydrochloride (3.74 g, 30.0 mmol) was added to a solution of potassium hydroxide (1.68 g, 30 mmol) in methanol (10 ml) and the mixture was stirred at room temperature for 30 minutes. This mixture was then added to the previously prepared intermediate (ethyl 2-(2,2,2-trifluoroacetyl)-3-(dimethylamino)-4,4-difluorobut-2-enoate) and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1). N-tert-Butyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid ethyl ester (3.29 g, 10.5 mmol, 53%) was isolated as a yellow oil.

1. customwas removed under reduced pressure
2. additionTo this were added dropwise, at −30° C.
3. customwas brought to room temperature in the cold bath
4. stirringstirred overnight
5. stirringthe mixture was stirred at room temperature for 30 minutes
6. stirringthe mixture was stirred overnight
7. customThe solvent was removed under reduced pressure
8. customthe residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1)

ORD record

ord-5f528b6499f948dab9f81d7873ffe61c

Source dataset

uspto-grants-2016_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09309202B2