Ethanol → Valproic Acid

HRID 2225956Notes

Reaction equation

HRID 2225956 reaction equation
O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([C:16]([CH2:27][CH2:28][CH3:29])(C(OCC)=O)[C:17]([O:19]CC)=[O:18])[CH2:14][CH3:15].C(O)C>O>[C:17]([OH:19])(=[O:18])[CH:16]([CH2:27][CH2:28][CH3:29])[CH2:13][CH2:14][CH3:15]

Participants

5

Reactant 3

HCID 702EthanolHCID 80168Diethyl dipropylmalonateHCID 521998p-Toluenesulfonic acid monohydrate

Product 1

HCID 3121Valproic AcidYield 87.8%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent4×

Conditions

Temperature
140 °C

Procedure

A mixture of 70 g of p-toluenesulfonic acid monohydrate, 140 g of diethyl dipropylmalonate and 9 ml of water was heated to reflux in a flask equipped with a distillation column packed with Raschig rings. Ethanol was distilled as it formed and the pot temperature was maintained at 120°-155° C. by periodic addition of water to the pot. After 5 hours, 25 ml of water had been added and the evolution of ethanol had nearly stopped. The mixture was maintained at 140° C. for 18 hours and then was cooled and treated with 100 ml of water. The layers were separated to afford 72.2 g (87.8% yield) of valproic acid as a light brown liquid. The water layer was washed with 50 ml of toluene and the toluene was combined with the crude valproic acid layer. Vacuum distillation afforded a colorless valproic acid fraction (72 g, 87% yield) boiling at 132° C./28" Hg.

Workup

  1. temperaturewas heated
  2. temperatureto reflux in a flask
  3. customequipped with a distillation column
  4. distillationEthanol was distilled as it
  5. customformed
  6. temperaturewas cooled
  7. customThe layers were separated

Sources & evidence

ORD record
ord-09c6eabc5227404cb29c5feb39dd5295
Source dataset
uspto-grants-1994_09
Patent number
US05344975

Reaction notes

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