Purification of Combinatorial Libraries

In the early days of combinatorial chemistry [36], mixtures derived from solidphase split-and-mix libraries [37] as well as nonpurified compounds from solution-

Fig. 6.13. Autosort.

phase synthesis played an important role as test compounds for biological screening, basically because it was a very easy way to produce the promised numbers of compounds. It was soon recognized that those compounds often led to false-positive test results, and that the deconvolution of mixtures and extraction of biologically active molecule in an HTS mode are difficult tasks [38]. This problem resulted in the synthesis of single compounds fulfilling properties such as diversity, drug likeness, and a high degree of purity [39]. Classical purification procedures such as liquid-liquid extraction and chromatography were automated, solid-phase extractions with ion exchangers were adopted, and scavenger reagents for trapping excess starting material or reagents were developed. Automated preparative reversed phase HPLC systems were set up to address high-throughput purification issues.

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