Spacer-modified crosslinked copolymer beads for the solid phase synthesis of an amide

Abstract

The goal of this research was to synthesize an amide using the reaction of a polymer-supported active ester with a primary amine. A new type of the polymer support for an active ester was prepared from poly( ω-bromobutylstyrene-co-divinylbenzene) beads ( 1). Bromine atoms in 1 were replaced by mercapto groups upon treatment with thiourea and subsequent alkaline hydrolysis. Following this, N-hydroxymaleimide was reacted with the polymer ( 3). This reaction introduced N-hydroxysuccinimide moieties into the polymer beads via Michael addition, yielding a resin ( 4). Resin 4 was reacted with a model carboxylic acid in the presence of a water-soluble esterification reagent (WSC). This yielded resin ( 5), which contained polymer-bound active ester groups. Reaction of 5 with a primary amine gave the objective amide. Resulting amides had a higher purity than those prepared by solid phase synthesis using the corresponding polymer support, which was derived with poly(chloromethylstyrene-co-divinylbenzene) beads and a traditional liquid phase synthesis. Resin 5, after use in the amide synthesis, was regenerated into the active ester form for the repeated use.