Ethyl Acetoacetate → 2-(2-Fluorophenyl)-5-methyl-2,3-dihydro-1H-pyrazol-3-one

HRID 1478823Notes

Reaction equation

HRID 1478823 reaction equation
Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].C([O:13][C:14](=O)[CH2:15][C:16]([CH3:18])=O)C.[OH-].[Na+]>C(O)(=O)C.O.C(Cl)Cl>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:14](=[O:13])[CH:15]=[C:16]([CH3:18])[NH:10]1

Participants

7

Reactant 3

HCID 8868Ethyl AcetoacetateHCID 14798Sodium HydroxideHCID 2723910Hydrazine, (2-fluorophenyl)-, hydrochloride (1:1)

Product 1

HCID 660216772-(2-Fluorophenyl)-5-methyl-2,3-dihydro-1H-pyrazol-3-one

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
45 °C

Procedure

A stirred suspension of 2-fluorophenylhydrazine hydrochloride (1000 g, 5535 mmol) in acetic acid (1000 ml) and water (1000 ml) was heated at 45° C. Ethylacetoacetate (700 ml) was added dropwise over 30 mins and this was stirred at 88° C. for 2 hr. The resulting mixture was cooled to 5° C. and poured onto ice (3000 g) and DCM (4500 ml). 30% NaOH (aq) (2400 ml) was added and the mixture was stirred for 15 mins, then separated and extracted with DCM (1500 ml). The organic extracts were washed with 1M NaOH (aq) (1500 ml). The aqueous phases were combined and ice (1500 g) and DCM (3600 ml) were added. To the stirred mixture was added 32% HCl (aq) (2400 ml) until the pH was adjusted to pH 1-2. The biphasic mixture was separated, extracted with DCM (1500 ml) and the organic extracts washed with brine/water 4:1 (2000 ml), dried over MgSO4 and evaporated to dryness to give a dark solid. To a stirred solution of the crude product in DCM (2000 ml) was added silica gel (350 g). This was filtered and the filtrate was evaporated. Purification by chromatography with MeOH in EtOAc gave the title compound as a light yellow solid.

Workup

  1. temperatureThe resulting mixture was cooled to 5° C.
  2. stirringthe mixture was stirred for 15 mins
  3. customseparated
  4. extractionextracted with DCM (1500 ml)
  5. washThe organic extracts were washed with 1M NaOH (aq) (1500 ml)
  6. additionice (1500 g) and DCM (3600 ml) were added
  7. additionTo the stirred mixture was added 32% HCl (aq) (2400 ml) until the pH
  8. customThe biphasic mixture was separated
  9. extractionextracted with DCM (1500 ml)
  10. washthe organic extracts washed with brine/water 4:1 (2000 ml)
  11. dry with materialdried over MgSO4
  12. customevaporated to dryness
  13. customto give a dark solid
  14. filtrationThis was filtered
  15. customthe filtrate was evaporated
  16. customPurification by chromatography with MeOH in EtOAc

Sources & evidence

ORD record
ord-2aa23865e87149dcb5215cb183cd7f67
Source dataset
uspto-grants-2016_08
Patent number
US09403833B2

Reaction notes

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