Preparation of Novel Delivery Agents for Delivery of Macromolecular Drugs Using Boric Acid Mediated Amidation of Carboxylic Acids and Amines

摘要

Delivery agents comprising a carboxamide moiety are useful for the delivery of macromolecular drugs to the systemic circulation via oral administration. A practical synthetic pathway to these delivery agents has been developed by the direct amidation between a carboxy ic acid and an amine using a catalytic amount of boric acid as a mediator. Boric acid is nontoxic, environmentally safe, and inexpensive. This method eliminates the preparation of acid chlorides, and is amenable for large-scale preparation providing excellent yields of the desired carboxamides. This boric acid mediated amidation between the carboxylic acids and amines with a variety of functional groups was achieved in a simple, single-step process using an equal molar mix ure of acids and amines. This amidation works well with weakly nucleophilic amine, such as arylamines. The utility of the boric acid mediated amidation will be discussed.