Development of a custom high-throughput preparative liquid chromatography/mass spectrometer platform for the preparative purification and analytical analysis of compound libraries.
Solution-phase parallel synthesis has had a profound impact on the speed of compound synthesis delivering relatively pure compounds (>80%) in short order. However, to develop structure activity relationships (SAR) for a compound series, each library member should preferably be >95% pure. Historically, achieving and quantifying such high-purity criteria for each library member proved to be the slow step for most lead discovery groups. To address this issue, significant modifications have been made to a commercial Agilent preparative LC/MS system to allow for the general mass-guided purification of diverse compound libraries. The custom modifications include (1) the "DMSO slug" approach for the purification of samples with poor solubility; (2) an active splitter to reduce system back-pressure, reduce the delay volume, and allow for a variable split ratio; (3) a sample loading pump for the quick purification of large, dilute samples; (4) a preparative column-selection valve to quickly change column selectivity or sample loading; and (5) an analytical injector with a separate flow path for crude reaction or fraction analyses.
Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Merck Research Laboratories, PO Box 4, West Point, Pennsylvania 19486, USA.
William
W
Leister
Kimberly
K
Strauss
David
D
Wisnoski
Zhijian
Z
Zhao
Craig
C
Lindsley