Hydroxyguanidines are a valuable class of molecules in the field of long-acting medications because they can be made to include the structural features of various urea-based drugs, and they are readily attached to drug-polymer conjugate systems as Diels-Alder adducts. A method of converting mono-, di-, and tri-substituted ureas to their corresponding hydroxyguanidines through a thionated intermediate is described. Thionation of each urea can be carried out using 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson’s Reagent) under microwave conditions. Several methods were then employed to complete the substitution of the thiourea with hydroxylamine, including methylation of the thiocarbonyl to form an methanethiol leaving group, oxidation of the thiocarbonyl to form a sulfonate leaving group, and activation using mercury(II) oxide and copper(II) sulfate. Of these methods, the methylation pathway provided the most consistent results. Different protected and unprotected forms of hydroxylamine were also investigated to optimize the condensation reactions to form the desired hydroxyguanidines.<br/>

Conversion of ureas to hydroxyguanidines for conjugation to drug-releasing polymers by nitroso-Diels-Alder reactions

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.