Solid-Supported Solution-Phase Synthesis of 4-Amino-1,2,4,5-tetrahydro-2-benzazepine-3-ones

摘要

Starting from Boc-o-aminomethylphenylalanine,a solution-phase parallel synthesis of 2,4-substituted 4-amino-l,2,4,5-tetrahydro-2-benzazepine-3-ones is described.This heterocycle has two nitrogen functions,which are differentiated and can be selectively substituted.The sources of diversity are aldehydes for the R_1 position and carboxylic acids,sulfonyl chlorides,or isocyanates for the R2 position.High-throughput synthesis and purification of this multistep synthetic sequence was accomplished using polymer-bound reagents and scavengers and liquid-liquid extraction protocols,and a small library of compounds was prepared.Polymer-bound cyanoborohydride was found to work well for the reductive amination.Scavenging of excess of amine was performed by polymer-bound benzaldehyde,and cyclization was performed in the presence of polymer-bound coupling reagent l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC).After Boc-deprotection,the second nitrogen can be acylated using carboxylic acids,sulfonylated or converted to a urea.The acylation is again performed by polymer-bound EDC.Excellent yields and purities were obtained.