Anticancer Agents, 15. Squaric Acid Diethyl Ester: A New Coupling Reagent for the Formation of Drug Biopolymer Conjugates. Synthesis of Squaric Acid Ester Amides and Diamides

Reaction of squaric acid diethyl ester ( 1 ) with a slight excess of a primary or secondary amine 2 in ethanol, dichloromethane or aqueous buffer (pH 7) at 20°C for 0.3–12 h gives the squaric acid amide esters 3 in mostly excellent yields. Treatment of 3 with amines 2 or 4 in organic solvents in the presence of triethylamine or in aqueous buffer (pH 9) leads to the corresponding symmetrical and unsymmetrical squaric acid diamides 5 , respectively. The reaction can be followed by UV spectroscopy.