Potassium ethyl malonate → Ethyl 3-(2-chloro-4,5-difluorophenyl)-3-oxopropanoate

HRID 1769268Notes

Reaction equation

HRID 1769268 reaction equation
[C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].C[Mg]Cl.[Cl:14][C:15]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:16]=1C(Cl)=O>O1CCCC1>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([C:16]1[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:15]=1[Cl:14])=[O:5])[CH3:9]

Participants

5

Reactant 3

HCID 3446434Potassium ethyl malonateHCID 101982172-Chloro-4,5-difluorobenzoyl chlorideHCID 178418332HCID 178418332, compound

Product 1

HCID 14423850Ethyl 3-(2-chloro-4,5-difluorophenyl)-3-oxopropanoateYield 92.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A 400 liter glass-lined reactor was charged with 129 liters of dry tetrahydrofuran and 21.7 kg (2.1 equivalents) of potassium ethyl malonate. With slight cooling, 42.4 liters of 3M methyl magnesium chloride was added at a rate to keep the temperature between 20° to 50° C. After a 30 minute stir, the solution was cooled to 0° to -5° C. and 12.8 kg of 2-chloro-4,5-difluorobenzoyl chloride was added at a rate to keep the temperature between 0° and 5° C. The solution was then quenched into 106 liters of 2N HCl. After the addition of 72 liters of toluene, the aqueous layer was removed. The product layer was washed with 53 liters of saturated bicarbonate and salt solution. After removal of the aqueous layer, the product layer was concentrated to an oil and 28 liters of isopropyl alcohol were added. The solution was cooled to -10° to -15° C., granulated and the solids filtered and vacuum dried to give 14.17 Kg (first crop) and 588 g (second crop) of the title compound, 92.8% yield. The high field NMR of the product was typical of that for a mixture of the keto (5%) and enol (95%) forms of the title compound 300 MHz 1H (CDCl3): 12.5 (s, 0.95H), 7.5 (d of d, J=11 Hz, J'=8 Hz, 1H) 7.3 (d of d, J=11 Hz, J'=8 Hz, 1H), 5.6 (s, 0.95H), 4.3 (q, J=6H, 1.9H), 4.2 (q, J=6 Hz, 0.1H), 4.0 (s, 0.1H), 1.4 (t, J=6 Hz,2.85H), 1.2 (t, J=6 Hz, 0.15H).

Workup

  1. custombetween 20° to 50° C
  2. temperaturethe solution was cooled to 0° to -5° C.
  3. customthe temperature between 0° and 5° C
  4. customThe solution was then quenched into 106 liters of 2N HCl
  5. additionAfter the addition of 72 liters of toluene
  6. customthe aqueous layer was removed
  7. washThe product layer was washed with 53 liters of saturated bicarbonate and salt solution
  8. customAfter removal of the aqueous layer
  9. concentrationthe product layer was concentrated to an oil and 28 liters of isopropyl alcohol
  10. additionwere added
  11. temperatureThe solution was cooled to -10° to -15° C.
  12. filtrationthe solids filtered
  13. customvacuum dried

Sources & evidence

ORD record
ord-3f7bf30a9a4d4ca49fb346a94ff62e15
Source dataset
uspto-grants-1995_01
Patent number
US05380860

Reaction notes

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