Leister William, Strauss Kimberly, Wisnoski David, Zhao Zhijian, Lindsley Craig
Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Merck Research Laboratories, PO Box 4, West Point, Pennsylvania 19486, USA.
J Comb Chem. 2003 May-Jun;5(3):322-9. doi: 10.1021/cc0201041.
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.
溶液相平行合成对化合物合成的速度产生了深远影响，能在短时间内提供相对纯净的化合物（>80%）。然而，要建立一个化合物系列的构效关系（SAR），每个库成员最好纯度>95%。从历史上看，对大多数先导化合物发现团队来说，为每个库成员达到并量化如此高的纯度标准被证明是一个缓慢的步骤。为了解决这个问题，对一台商用安捷伦制备型液相色谱/质谱系统进行了重大改进，以实现对各种化合物库的通用质量引导纯化。定制的改进包括：（1）用于纯化溶解性差的样品的“二甲基亚砜段塞”方法；（2）一个有源分流器，以降低系统背压、减少延迟体积并允许可变分流比；（3）一个样品加载泵，用于快速纯化大量稀释样品；（4）一个制备柱选择阀，用于快速改变柱选择性或样品加载；以及（5）一个带有独立流路的分析进样器，用于粗反应或馏分分析。
