Preparation of phenytoin derivatives under solvent-free conditions using microwave irradiation

Abstract

Phenytoin or 5,5-diphenylimidazolidine-2,4-dione is an anticonvulsant drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex, where spreading of the seizure activity is inhibited. Phenytoin is indicated for the control of grand mal and psychomotor seizures [1]. Several methods for the preparation of hydantoins have been reported, such as treatment of benzils with urea in ethanolic solution of potassium or sodium hydroxide [2–10]. These methods suffer from some drawbacks, including long reaction times, low yield, difficult operating conditions, and tedious work-up. In the recent years, applications of microwave irra-diation in a variety of organic reactions have rapidly increased due to short reaction time and operational simplicity [11–25]. Taking into account the importance of hydantoin and its derivatives for biological and medicinal chemistry, we decided to optimize methods of synthesis of these compounds. We now report a simple synthetic procedure for the preparation of phenytoin derivatives under microwave irradiation in the presence of sodium hydroxide. To choose the best base among various common bases, comparative study was performed using benzil and urea as representative starting materials (Table 1). Reactant mixtures were irradiated in a microwave oven at a power of 100 W in the presence of different bases. The results showed that sodium hydroxide without solid support ensured the best yield and the shortest reaction time, so that it was selected as base for subsequent experiments. The pres-ence of a base was obligatory, otherwise no reaction occurred. Initially, we synthesized some benzoin derivatives from the corresponding substituted benzaldehydes and converted them into benzil derivatives. A number of phenytoin derivatives were then prepared from substi-tuted benzils and urea under microwave irradiation (100 W) in the presence of NaOH. All reactions were easily performed in a beaker, and their progress was monitored by thin-layer chromatography. The results are summarized in Table 2. The process was accom-panied by formation of an insignificant amount of the corresponding 3a,6a-diarylglycoluril as by-product. The latter can readily be separated by treatment of the reaction mixture with water. The structure of the products was confirmed by physical and spectral data. Their