Mechanochemical preparation of hydantoins from amino esters: application to the synthesis of the antiepileptic drug phenytoin

J Org Chem. 2014 Nov 7;79(21):10132-42. doi: 10.1021/jo5017629. Epub 2014 Oct 17.

Abstract

The eco-friendly preparation of 5- and 5,5-disubstituted hydantoins from various amino ester hydrochlorides and potassium cyanate in a planetary ball-mill is described. The one-pot/two-step protocol consisted in the formation of ureido ester intermediates, followed by a base-catalyzed cyclization to hydantoins. This easy-handling mechanochemical methodology was applied to a large variety of α- and β-amino esters, in smooth conditions, leading to hydantoins in good yields and with no need of purification steps. As an example, the methodology was applied to the "green" synthesis of the antiepileptic drug Phenytoin, with no use of any harmful organic solvent.

MeSH terms

  • Anticonvulsants / chemical synthesis*
  • Anticonvulsants / chemistry
  • Anticonvulsants / pharmacology*
  • Cyclization
  • Esters
  • Hydantoins / chemical synthesis
  • Hydantoins / chemistry
  • Molecular Structure
  • Phenytoin / chemical synthesis*
  • Phenytoin / chemistry*
  • Solvents

Substances

  • Anticonvulsants
  • Esters
  • Hydantoins
  • Solvents
  • Phenytoin