A rapid and efficient microwave-assisted synthesis of hydantoins and thiohydantoins

Muccioli-GG; Poupaert-JH; Wouters-J; Norberg-B; Poppitz-W; Scriba-GKE; Lambert-DM RP: Lambert, DM;
Catholic Univ Louvain; Fac Med; Ave E Mounier 73; B-1200 Brussels; Belgium IN: Catholic Univ Louvain, Fac Med, Ecole Pharm, Lab Chim Pharmaceut & Radiopharm,CMFA 7340, B-1200 Brussels, Belgium; Fac Univ Notre Dame Paix, Fac Sci, Lab Chim Mol Struct, B-5000 Namur, Belgium; Univ Jena, Dept Inorgan & Analyt Chem, D-07743 Jena, Germany; Univ Jena, Dept Pharmaceut Chem, D-07743 Jena, Germany EM: Lambert, DM: lambert@cmfa.ucl.ac.be

TETRAHEDRON-. FEB 17 2003; 59 (8) : 1301-1307

The present paper describes studies on the synthesis of the antiepileptic drug phenytoin, and of structurally related derivatives. First, the influence of the solvent has been investigated in the microwave-assisted synthesis of the drug, resulting in a yield improvement and a cleaner reaction. Second; a two-step reaction is described to synthesize selectively and in high yields phenytoin. The first step consists in microwave activation of the reaction of benzil with thiourea, the second step includes the conversion of the resulting 2-thiohydantoin to phenytoin using hydrogen peroxide. Moreover, microwave activation is a very convenient method for the synthesis of 3-alkylated phenytoin derivatives, resulting in a much more selective method than the previously reported procedure using alkylating agents.