Triethyl phosphonoacetate → Ethyl 3-(3,5-difluorophenyl)propanoate

HRID 1977549Notes

Reaction equation

HRID 1977549 reaction equation
[H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[H][H].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([F:28])[CH:27]=1)[CH:23]=O>C(COC)OC.O>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][CH2:23][C:22]1[CH:21]=[C:20]([F:19])[CH:27]=[C:26]([F:28])[CH:25]=1)[CH3:16]

Participants

7

Reactant 4

HCID 13345Triethyl phosphonoacetateHCID 24758Sodium hydrideHCID 5881603,5-DifluorobenzaldehydeHCID 178418361HCID 178418361, compound

Product 1

HCID 15209345Ethyl 3-(3,5-difluorophenyl)propanoateYield 70.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent3×

Conditions

Temperature
15 °C

Procedure

Dimethoxyethane 350 ml was added to 60% sodium hydride 14.4 g (360 mmol), the mixture was stirred at room temperature while a solution of ethyl diethylphosphonoacetate 80.7 g (360 mmol) in dimethoxyethane (50 ml) was added dropwise. After the generation of hydrogen gas was stopped, the solution was cooled to 15° C., and a solution of 3,5-difluorobenzaldehyde 50.0 g (352 mmol) in dimethoxy ethane (50 ml) was added dropwise keeping the liquid temperature below 25° C. After addition, the mixture was stirred for 30 minutes, the reactant was added to water 300 ml, and the product was extracted with diethylether. The extract was washed with a sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: heptane/ethyl acetate=3/1). Such obtained purified material was hydrogenated in the presence of 5% palladium carbon as a catalyst in ethanol 300 ml. After hydrogenation, the catalyst was filtered off, the solvent was distilled off under reduced pressure to obtain 3-(3,5-difluorophenyl) propionic acid ethyl ester 53.0 g (247 mmol). The yield was 70.2% from 3,5-difluorobenzaldehyde.

Workup

  1. additionwas added dropwise
  2. customthe liquid temperature below 25° C
  3. additionAfter addition
  4. extractionthe product was extracted with diethylether
  5. washThe extract was washed with a sodium chloride aqueous solution
  6. dry with materialdried over anhydrous magnesium sulfate
  7. distillationthe solvent was distilled off under reduced pressure
  8. customThe residue was purified by silica gel column chromatography (eluent: heptane/ethyl acetate=3/1)
  9. customSuch obtained
  10. custompurified material
  11. filtrationAfter hydrogenation, the catalyst was filtered off
  12. distillationthe solvent was distilled off under reduced pressure

Sources & evidence

ORD record
ord-bd0d09302cf44bca9e1c3d7bf075060b
Source dataset
uspto-grants-2001_05
Patent number
US06235355B1

Reaction notes

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