Malonic Acid → (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid

HRID 30674

Reaction equation

HRID 30674 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.[OH-].[Na+]>C1(C)C=CC=CC=1.COCCOCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 867Malonic AcidHCID 8082PiperidineHCID 14798Sodium HydroxideHCID 231574845-(4-fluorophenyl)-1-methyl-1H-pyrazole-4-carbaldehyde

Product 1

HCID 69208981(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylic acidYield 90%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8150DiglymeSolvent

Conditions

Temperature
92.5 °C

Procedure

To a mixture of 5-(4-fluorophenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (3.00 g), malonic acid (1.99 g) and bis(2-methoxyethyl) ether (9 mL) was added dropwise piperidine (1.89 mL) over about 10 min. The mixture was stirred at 90-95° C. for 1 hr. and further at 105-110° C. for 4 hrs. After cooling to 25° C., toluene (12 mL) and 1N aqueous sodium hydroxide solution (15 mL) were added and the mixture was stirred. The aqueous layer was separated and the organic layer was extracted with 1N aqueous sodium hydroxide solution (6 mL). The aqueous layers were combined and washed with toluene. The layers were adjusted to pH 3.5-4.0 with 2N hydrochloric acid at 20-30° C. and water (9 mL) was added dropwise. After stirring at 25° C. for 1 hr., the precipitated crystals were collected by filtration and washed with 20% ethanol to give (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid (3.24 g, yield 90%).

Workup

  1. waitand further at 105-110° C. for 4 hrs
  2. temperatureAfter cooling to 25° C.
  3. stirringthe mixture was stirred
  4. customThe aqueous layer was separated
  5. extractionthe organic layer was extracted with 1N aqueous sodium hydroxide solution (6 mL)
  6. washwashed with toluene
  7. customwere adjusted to pH 3.5-4.0 with 2N hydrochloric acid at 20-30° C.
  8. additionwater (9 mL) was added dropwise
  9. stirringAfter stirring at 25° C. for 1 hr
  10. filtration, the precipitated crystals were collected by filtration
  11. washwashed with 20% ethanol

Sources & evidence

ORD record
ord-db6aa61893614edf9ca87b9570f1139c
Source dataset
uspto-grants-2008_09
Patent number
US07423159B2

Linked notes

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