An automated high-throughput liquid-liquid extraction (LLE) methodology has been developed and utilized for the initial purification of the combinatorial library samples containing unreacted amines and other water-soluble byproducts or impurities. Various extraction solvents were evaluated along with different extraction devices. The LLE method was automated using 96-well-format plates and a robotic liquid-handling workstation. In the optimized LLE method, crude combinatorial library samples were dissolved in a water-immiscible organic solvent, butyl acetate, and added to each well in a 96-well-format plate packed with an inert support material coated with hydrochloric acid. Separation occurs based on the partitioning of the compounds between two liquid phases. Product recovery, purity, and amine removal efficiency were determined by HPLC with and without precolumn derivatization. The automated method was successfully applied to the cleanup of some representative combinatorial library samples with greater than 98% amine removal and an average product purity of 90%. The application of the automated high-throughput LLE method should greatly reduce the labor, time, and cost associated with the purification of combinatorial libraries.

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