Acetic Acid → 5-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-carboxaldehyde dimethyl acetal

HRID 271297Notes

Reaction equation

HRID 271297 reaction equation
C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O.[CH3:19][O:20][CH:21]([O:26][CH3:27])[C:22](OC)=O.C(O)(=O)C.[CH3:32][NH:33][NH2:34]>C1COCC1>[CH3:19][O:20][CH:21]([O:26][CH3:27])[C:22]1[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:33]([CH3:32])[N:34]=1

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 6061MethylhydrazineHCID 98284'-FluoroacetophenoneHCID 66647Acetic acid, 2,2-dimethoxy-, methyl esterHCID 2724682Lithium diisopropylamide

Product 1

HCID 586948315-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-carboxaldehyde dimethyl acetal

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
25 °C

Procedure

To a solution of lithium diisopropylamide (1.8M in THF, 160 mL, 0.29 mol) at −78° C. was added 4-fluoroacetophenone (17.6 mL, 0.145 mol) in THF (150 mL), dropwise. The reaction was stirred at −78° C. for 1 h before the addition of methyl dimethoxyacetate (17.7 mL, 0.145 mol) in THF (150 mL). The reaction was warmed to 25° C. and stirred for 16 h. The solvent was removed in vacuo and the residue taken up in EtOH (250 mL), acetic acid (17 mL, 0.3 mol) added, followed by methyl hydrazine (8 mL) and the reaction heated to reflux for 2 h. The ethanol was removed in vacuo and the residue extracted with dichloromethane (×3), the organic layer washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed on silica eluting with 50% ethyl acetate/hexanes to give the title compound (more polar isomer) along with its isomer (less polar). 9 g 1H NMR (360, CDCl3) δ 7.38 (m, 2H), 7.14 (m, 2H), 6.34 (s, 1H), 5.48 (s, 1H), 3.85 (s, 3H), 3.43 (s, 6H).

Workup

  1. customThe solvent was removed in vacuo
  2. temperaturethe reaction heated
  3. temperatureto reflux for 2 h
  4. customThe ethanol was removed in vacuo
  5. extractionthe residue extracted with dichloromethane (×3)
  6. washthe organic layer washed with brine
  7. dry with materialdried over MgSO4
  8. concentrationconcentrated
  9. customThe residue was chromatographed on silica eluting with 50% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-6be534506db34de88a0cdc040fe279f4
Source dataset
uspto-grants-2008_11
Patent number
US07452899B2

Reaction notes

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