Streamlined Approach to the Crude Compound Purification to Assay Process

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Abstract
Purification of medicinal chemistry compounds is often the slow step in the drug‐discovery process, particularly for compounds generated through parallel synthesis. To address this bottleneck we have developed a fully automated purification platform using a preparative‐LC/MS with a customized compound analysis requestor and a data tracking‐handling program. The six workstations that comprise the platform are an 8‐channel MUX, a mass‐directed Prep‐LC/MS, a liquid handling system, a balance automator, an evaporation system, and a central PC that runs the core program. The first step involved in the library purification, following the electronic submission of the dry crude synthetic material submitted in a barcoded plate, consists of automatic dissolution of the material and transfer of an aliquot for pre‐purification QC. Subsequent steps involve generation of a sequence list consisting of the methods for the analysis and processing, automatic generation of a sequence of the confirmed wells for LC/MS purification, evaporation, fraction dissolution and pooling, automatic weighing, and calculation of the amount needed to make a specified concentration. The final step involves compound distribution into a solubilization tube for the biochemical assay and plates for post‐purification QC by LC/MS and NMR. Functions incorporated into the core program were written in CSharp (C#) and Microsoft.NET to create a sample sequence list, annotate wells, track purification status, and to enable on‐line retrieval of pre‐ and post‐purification data. This platform enables a complete informatics solution from crude compound in a plate to purified compound ready for storage and assay. The processes and results for compounds purified at the multi‐milligram level by automated Prep‐LC/MS will be described.

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