Hydrochloric Acid → Diethyl 2-(2,6-difluoro-4-methoxyphenyl)malonate

HRID 1602116Notes

Reaction equation

HRID 1602116 reaction equation
[C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[F:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([F:23])[C:16]=1Br.Cl>[Cu]Br.O1CCOCC1>[F:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([F:23])[C:16]=1[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 7761Diethyl MalonateHCID 24758Sodium hydrideHCID 27249844-Bromo-3,5-difluoroanisole

Product 1

HCID 11174138Diethyl 2-(2,6-difluoro-4-methoxyphenyl)malonateYield 74.1%

Reagents, catalysts & solvents 2

HCID 24593copper(I) bromideCatalystHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
60 °C

Procedure

Diethyl malonate (0.505 mol) is added to a mixture of sodium hydride (0.412 mol) and 1,4-dioxane (230 ml) at 40° C. within 3 hours. The mixture is stirred for 90 minutes at 60° C. and copper(I) bromide (0.402 mol) is added. A mixture of 2,6-difluoro-4-methoxybromobenzene (0.2 mol) and 1,4-dioxane (50 ml) is added. The reaction mixture is heated at 100° C. for 14 hours and cooled to 15° C. Hydrochloric acid (12N, 350 ml) is added slowly at 15 to 20° C. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate (250 ml) and toluene (200 ml). The combined organic phases are concentrated in vacuo. The residue is filtered over silica gel, washed with petroleum ether/ethyl acetate (15:1) and the solvent is distilled off. The residue is distilled in vacuo to yield 44.8 g of the product as an oil, 128-136° C. at 0.018 mbar.

Workup

  1. additionis added
  2. temperatureThe reaction mixture is heated at 100° C. for 14 hours
  3. temperaturecooled to 15° C
  4. customThe organic phase is separated off
  5. extractionthe aqueous phase is extracted with ethyl acetate (250 ml) and toluene (200 ml)
  6. concentrationThe combined organic phases are concentrated in vacuo
  7. filtrationThe residue is filtered over silica gel
  8. washwashed with petroleum ether/ethyl acetate (15:1)
  9. distillationthe solvent is distilled off
  10. distillationThe residue is distilled in vacuo

Sources & evidence

ORD record
ord-8320b4f6287349889a26dc4438ed9b32
Source dataset
uspto-grants-1999_11
Patent number
US05981534

Reaction notes

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