Ethanol → 1-((4-methoxyphenyl)methyl)-1H-pyrazol-5-amine

Temperature

120 °C

Hydrazine hydrate (12.82 g, 400 mmol) was added dropwise to a cooled (<20° C.) solution of 2-propenenitrile (21.76 g, 410 mmol) and ethanol (200 mL). After 16 h stirring the reaction mixture was cooled in an ice water bath and 4-(methyloxy)benzaldehyde (53.8 g, 395 mmol) was added dropwise. The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness. The residue was dissolved in n-butanol (200 mL), sodium hydroxide was added (1 g, 25.00 mmol), and the mixture heated at 120° C. for 6 h. The reaction mixture was concentrated to 50% volume under reduced pressure, poured onto 300 mL of water, and then extracted with Et2O (2×200 mL). The combined ether phases were extracted with 1N HCl (3×100 mL). The combined HCl extracts were combined and cooled in an ice/water bath. Added next was 6N NaOH until basic (pH>12). The contents were extracted with Et2O (4×100 mL), washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (eluent: 0-50% EtOAc:Hex). The final product was collected as 8.94 g (11%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.79 (s, 3 H), 5.14 (s, 2 H), 5.55 (d, J=1.77 Hz, 1 H), 6.81-6.94 (m, 2 H), 7.12 (d, J=8.84 Hz, 2 H), 7.31 (d, J=2.02 Hz, 1 H).

1. temperaturewas cooled in an ice water bath
2. stirringThe mixture was stirred at room temperature for 16 h
3. concentrationThe reaction mixture was concentrated to dryness
4. dissolutionThe residue was dissolved in n-butanol (200 mL)
5. additionsodium hydroxide was added (1 g, 25.00 mmol)
6. concentrationThe reaction mixture was concentrated to 50% volume under reduced pressure
7. additionpoured onto 300 mL of water
8. extractionextracted with Et2O (2×200 mL)
9. extractionThe combined ether phases were extracted with 1N HCl (3×100 mL)
10. temperaturecooled in an ice/water bath
11. additionAdded next
12. extractionThe contents were extracted with Et2O (4×100 mL)
13. washwashed with water
14. dry with materialdried over MgSO4
15. filtrationfiltered
16. concentrationconcentrated under reduced pressure
17. customThe residue was purified via silica gel chromatography (eluent: 0-50% EtOAc:Hex)
18. customThe final product was collected as 8.94 g (11%)

ORD record

ord-7b86f7cd926a4f8b82d043e7c615bf44

Source dataset

uspto-grants-2015_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09073924B2