Acetic Acid → Methyl 2-{(3,4-difluorophenyl)methylene}-3-oxobutyrate

HRID 1250703Notes

Reaction equation

HRID 1250703 reaction equation
[C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1>[F:9][C:10]1[CH:11]=[C:12]([CH:13]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH3:8])=[O:6])[CH:15]=[CH:16][C:17]=1[F:18]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 7757Methyl acetoacetateHCID 8082PiperidineHCID 5880883,4-Difluorobenzaldehyde

Product 1

HCID 54038767Methyl 2-{(3,4-difluorophenyl)methylene}-3-oxobutyrate

Reagents, catalysts & solvents 1

HCID 241BenzeneSolvent

Procedure

To a solution of methyl acetoacetate (8.0 g, 0.069 mol), 3,4-difluorobenzaldehyde (9.8 g, 0.069 mol), acetic acid (0.490 g, 0.008 mole) and piperidine (0.69 g, 0.008 mol) in benzene (1.5 L) were added molecular sieves (37.9 g) and the mixture was stirred at room temperature for 48 h. The molecular sieves were removed by filtration and the solvent was evaporated under reduced pressure. The residue was purified by trituration from hexane to yield the intermediate methyl 2-[(3,4-difluorophenyl)methylene]-3-oxo-butyrate product as a yellow solid as a mixture of cis and trans isomers. A suspension of the methyl 2-[(3,4-difluorophenyl)methylene]-3- oxo-butyrate thus obtained(12 g, 49.9 mmol), O-methylisourea hemisulfate (11.15 g, 67.76 mmol, 1.5 eq.), and sodium bicarbonate (17 g, 203 mmol, 3 eq.) in DMF (110 mL) was stirred at 60° C. for 8 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by chromatography on silica gel eluting with 25%-30% EtOAc/hexane, to give the product as a pale yellow solid. 1H NMR (CDCl3) d 7.2-7.0 (m, 3H), 6.0 (s, 1H), 5.56 (s, 1H), 3.75 (s, 3H), 3.65 (s, 3H), 2.33 (s, 3H),

Workup

  1. customThe molecular sieves were removed by filtration
  2. customthe solvent was evaporated under reduced pressure
  3. customThe residue was purified by trituration from hexane

Sources & evidence

ORD record
ord-83a45cc6309743f9acb23e13b06ccd8a
Source dataset
uspto-grants-2002_01
Patent number
US06339090B1

Reaction notes

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