You are on page 1of 1

The Synthesis of 5,5'=DiphenyIhydantoin

A Novel Benzil-Benzilic Acid Rearrangement


Marvln C. Pankaskie and Laverne Small
College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68105

The application of organic chemistry to the large-scale Although usually applied t o the synthesis of aryl-suhstitut-
commercial production of biologically active, medicinal ed diphenylhydantoins, i t can also he carried out using ali-
agents has in many cases resulted in the discovery of new and phatic diketones or keto acids.
potentially useful reactions or reaction products, using sim-
ple and easily obtainable starting materials. T h e synthesis of Experlmenlal
hvdantoins. such as 5.5'-dinhenvlhvdantoin (ohenvtoin).
from their corresponding l,f-diketones illustratks one such Materials
novel reaction that avoids the use of sodium cvanide charac- bend, reagent grade
teristic of more classical methods of hydantoin synthesis. ethanol, 95%
The mechanism of this transformation closely resembles potassium hydroxide
that of the benzil-henzilic acid rearrangement, except that sulfuric acid, 6N
instead of using hydroxide or alkoxide anion as the nucleo- urea
phile, urea is used to generate the ureide intermediate 1,
which then undergoes cyclization t o the hydantoin 2. Apparatus
round-bottom flask, 250 ml
reflux condenser
heatine +
" mantle voltsee .
.. reeulator
vacuum tllrmtion 8pparstu.i
rnrlring paint apparatus
Procedure'
Dissolve 10.1 g (0.05 mol) of bend, and 6.0 g (0.1 moll of urea in
100 ml of ethanol in a 250-ml round-bottom flask, and add to this a
solution of 16.5g (0.3 mol) ofpotassium hydroxide in 20 mlofwater.
After refluxing the mixture for 2.5 h, the flask is cooled and the
solids2filtered off. The alkaline filtrateis cooled in an ice-water bath
and slowly acidified with 6Nsulfuric acid to pH 3, during which the
hydantoin precipitates out of solution. The product is filtered and
air dried to yield 5,5'-diphenylhydantoin (phenytoin), mp
295-298C with dec~mposition.~ Recrystallization can be aceam-
'Blitz, H.; Seydel, K. Ber. 1911, 44, 411. plished from 95%ethanol, although the product isolated by acidifi-
The small amount of alkali insoluble material is likely the diureide eaton of the filtered reaction mixture is usually better than 95%
of diphenylacetylene, while the hydantoin (pK. 8.3) remains in solu- pure. If time and instrument availability permits, the final product
tion as its potassium salt. can be subjected to tests for identification (IR, UV, and NMR
. . J.:. Hoicomb. I.: Fusari. S. "Analvtical Profiles of Druo
Philio.
Substances"; Fiorey. K.. Ed.: American Pharmaceutical Association:
- spectroscopy) and purity (colorometrie, titrimetric, or chromato-
graphic analysis) and compared to authenic material obtained com-
Washington. 1984; pp 417-438. mer~ially.~

650 Journal of Chemical Education

You might also like