Methylhydrazine → Ethyl 3-difluoromethyl-1-methyl-4-pyrazole carboxylate

Temperature

-5 °C

40% Methylhydrazine (565 g, 4.91 moles) in aqueous solution and K2CO3 (237 g, 1.72 moles) are dissolved in water (2134 g) and mixed to make a clear solution. Toluene (2292 g) is added to make a two phase system, and then cooled to −10-0° C. Crude ethyl 2-ethoxymethylenedifluoroacetoacetate (Formula VI) (˜1010 g, ˜4.91 moles) in toluene (1500 g) is then added dropwise with effective agitation while maintaining at the same temperature. The agitation is kept constant for 1-2 hours until GC shows the content of ethyl 2-ethoxymethylenedifluoroacetoacetate <0.2%. Two phases are separated and the organic phase is concentrated until GC shows toluene content <5%. A mixture of toluene (757 g) and petroleum ether (3028 g) (bp. 60-90° C.) is added in and then heated up to 50-60° C. to make a solution. The yellowish solid precipitated after the solution is slowly cooled down to 10-15° C. The solid is collected by filtration and dried in a vacuum oven to give a yellowish solid (828 g, Yield=82.5%). The product only contains 0.01% of the positional isomer of formula XI and 0.01% of the des-difluoro-impurity of Formula XII.

1. additionmixed
2. temperaturewhile maintaining at the same temperature
3. customTwo phases are separated
4. concentrationthe organic phase is concentrated until GC
5. additionA mixture of toluene (757 g) and petroleum ether (3028 g) (bp. 60-90° C.)
6. additionis added in and
7. temperaturethen heated up to 50-60° C.
8. customThe yellowish solid precipitated after the solution
9. temperatureis slowly cooled down to 10-15° C
10. filtrationThe solid is collected by filtration
11. customdried in a vacuum oven

ORD record

ord-f360ae4b9ddb47fa813eb9afb221fa5d

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09139507B2