Chem 216 S11 Notes - Dr. Masato Koreeda
Topic: _Experiment 5__ page 1 of 2.
Date: May 10, 2011
Experiment 5. Benzilic Acid Rearrangement: Preparation of Dilantin
Anticonvulsant drugs:
Dilantin Sodium (phenytoin)*
Tegretol (carbazepine)
Phenobarbital
Epilepsy: one of the most common
neurologic disorders, affecting ca. 1% of
the population.
O
H
N
O
N
H
O
O
phenytoin (Dilantin)
*
HN
N
O
NH2
carbamazapine
N
H
O
phenobarbital
http://www.mentalhealth.com/drugs/f33-d05.html
http://www.pfizer.ca/our%20products/pfizer%20pharmaceutical%20group/dilantin/
Benzilic Acid Rearrangement
•Discovered in 1938 by Justus Liebig – one of the first C-C bond migration reactions.
O
O
NaOH
H2O/ethanol
O
Δ
benzil
O
H3O+-workup
O-Na+
HO
OH
HO
benzilic acid
migration!
Reaction mechanism:
O
O
-OH
OH
O
O OH
O
O
O H
bond migration, not bond breakage
O
O
O
H
OR *
H3O+
O
HO
O
OH
HO
benzilic acid
* R = H or C2H5
O
Chem 216 S11 Notes - Dr. Masato Koreeda
Topic: _Experiment 5__ page 2 of 2.
Date: May 10, 2011
Synthesis of Phenytoin (Dilantin)
O
NH2
+
O
NH2
O
benzil
NaOH
H3O+
H
N
H2O/ethanol
O
workup
O
N
O
urea
H
N
N
H
O
Na
phenytoin (Dilantin)
Reation Mechanism:
H
N H
H
OH
* RO-H
N
O
O
O
N H
N H
H
H
N
O
O
O
O
H2N
H
H
N
O
O
O
H2N
pKa ~12
* R = H or C2H5
OR
N
O
H
HO
O
N
H
O
N
O
H
N
HO
H2N
O
O
H2N
OR
a Benzilic acid
rearrangement step!
N
N
O
N
O
H
H
N
H OR
N
O
O
O
N
H
O
O
H
O
O
O
N
H
N
H
N
H3O+-Workup
N
H
O
N
O
N
H
OR
phenytoin (Dilantin)
more acidic N-H