2-(2,5-Difluoro-4-nitrophenyl)-2-isobutylmalonic acid diethyl ester → 2-(2,5-Difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid

HRID 385320Notes

Reaction equation

HRID 385320 reaction equation
C([O:3][C:4](=[O:26])[C:5]([C:15]1[CH:20]=[C:19]([F:21])[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=1[F:25])([CH2:11][CH:12]([CH3:14])[CH3:13])C(OCC)=O)C>CC(O)=O.O.CCO>[F:25][C:16]1[CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[C:19]([F:21])=[CH:20][C:15]=1[CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([OH:26])=[O:3]

Participants

3

Reactant 1

HCID 579955742-(2,5-Difluoro-4-nitrophenyl)-2-isobutylmalonic acid diethyl ester

Product 1

HCID 579955592-(2,5-Difluoro-4-nitro-phenyl)-4-methyl-pentanoic acidYield 64.7%

Reagents, catalysts & solvents 1

HCID 86584229Acetic acid ethanol waterSolvent

Procedure

The above 2-(2,5-difluoro-4-nitrophenyl)-2-isobutylmalonic acid diethyl ester (57.0 g, 152.8 mmol) was dissolved in AcOH/H2O/EtOH (400 mL/120 mL/50 mL) and the reaction mixture was heated under reflux for 96 h. After cooling the solvent was evaporated under reduced pressure and water (200 mL) was added. The reaction mixture was extracted with EtOAc (3×100 mL), and the combined extracts were washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). Evaporation of solvent under reduced pressure gave a yellow oil which crystallized on standing to yield 27 g of 2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid. Chromatography of the residual oil (Heptane-EtOAc gradient) gave an additional 3 g of product (72% combined yield). 1H NMR (300 MHz, CDCl3/TMS): δ 9.63 (br s, 1H), 7.82 (dd, J=8.8, 6.0 Hz, 1H), 7.38 (dd, J=11.0, 5.8 Hz, 1H), 4.14-4.08 (m, 1H), 2.05-1.95 (m, 1H), 1.76-1.66 (m, 1H), 1.52-1.43 (m, 1H), 0.95-0.92 (m, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 177.6, 158.2 (d, 1JCF=232.5 Hz), 150.9 (d, 1JCF=262.5 Hz), 136.0, 134.7, 119.0 (d, 2JCF=20.0, Hz), 113.1 (d, 2JCF=29.4 Hz), 41.7, 41.3, 26.0, 22.6, 21.9.

Workup

  1. temperaturethe reaction mixture was heated
  2. temperatureunder reflux for 96 h
  3. temperatureAfter cooling the solvent
  4. customwas evaporated under reduced pressure and water (200 mL)
  5. additionwas added
  6. extractionThe reaction mixture was extracted with EtOAc (3×100 mL)
  7. washthe combined extracts were washed with water (3×100 mL), brine (100 mL)
  8. dry with materialdried (MgSO4)
  9. customEvaporation of solvent under reduced pressure
  10. customgave a yellow oil which
  11. customcrystallized

Sources & evidence

ORD record
ord-2657ac8fcded49aeb4e12477d453dc82
Source dataset
uspto-grants-2013_02
Patent number
US08367863B2

Reaction notes

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