Methylhydrazine → 5-Amino-3-cyclohexyl-1-methyl-1H-pyrazole-4-carbonitrile

In a stream of nitrogen, 20.8 g (abt. 60% oil suspension 520 mmol) of sodium hydride was slowly added at 0° C. to a 260 ml tetrahydrofuran solution of 17.2 g (260 mmol) of malononitrile. Then, 35 ml (260 mmol) of cyclohexanecarbonyl chloride was added dropwise at the same temperature. After the dropwise addition, the reactant mixture was brought to room temperature, and stirred for 1.5 hours. Then, 30 ml (312 mmol) of dimethylsulfuric acid was added to the reaction mixture, and the mixture was heated under reflux for 3 hours. Then, 17.4 ml (125 mmol) of triethylamine and 13.8 ml (260 mmol) of methylhydrazine were added with ice cooling, and the mixture was heated under reflux for 1 hour. The reaction mixture was brought to room temperature, and distilled under reduced pressure. Then, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1˜20/1) to obtain crude crystals. The crude crystals were further purified by recrystallization (hexane-ethyl acetate) to obtain 20.7 g (39%) of the captioned compound. Also, the mother liquor was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 11.3 g (21%) of the captioned compound.

1. additionAfter the dropwise addition
2. customwas brought to room temperature
3. temperaturethe mixture was heated
4. temperatureunder reflux for 3 hours
5. temperaturethe mixture was heated
6. temperatureunder reflux for 1 hour
7. customwas brought to room temperature
8. distillationdistilled under reduced pressure
9. additionThen, water was added to the residue
10. extractionthe mixture was extracted with ethyl acetate
11. washThe organic layer was washed with water
12. dry with materiala saturated aqueous solution of sodium chloride, and dried over sodium sulfate
13. distillationThen, the solvent was distilled off under reduced pressure
14. customThe residue was purified by silica gel column chromatography (chloroform/methanol=30/1˜20/1)
15. customto obtain crude crystals
16. customThe crude crystals were further purified by recrystallization (hexane-ethyl acetate)

ORD record

ord-ef2445e36b5843ef8ded605e477d675f

Source dataset

uspto-grants-2007_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07268128B2