An adaptable microplate-integrated purification workflow tailored for high-throughput automated parallel amide syntheses

High-throughput automated parallel amide synthesis is essential in early-phase medicinal chemistry; yet, purification of milligram-scale reaction mixtures remains to be a major operational bottleneck. Conventional approaches, including miniaturized preparative HPLC, provide challenges in scaling for extensive libraries and are limited by sample dilution, analyte-dependent method development, off-plate transfers, and high solvent consumption. Herein, we report a microplate-integrated purification workflow that seamlessly interfaces with automated synthesis platforms using readily available laboratory components. The method employs two consecutively applied, custom slurry-packed hydrophilic PVDF filter plates containing mixed-bed ion-exchange resins and normal-phase silica, facilitating vacuum-assisted cleanup directly from reaction wells. Independent optimization and benchmarking against a recently commercialized single-step alternative demonstrated superior purification efficiency at identical sorbent loadings. Validation across a 24-member amide matrix delivered product purities above 90% in the majority of cases without reaction-specific adjustment of purification conditions. By decoupling ionic scavenging and chromatographic polishing into orthogonal stages, the platform establishes a robust, scalable, and automation-ready purification strategy. This instrument-light approach reduces reliance on chromatographic systems and provides a broadly applicable option for accelerating high-throughput amide synthesis in early drug discovery workflows.