Rapid Fluorous Synthesis of Drug-Like Small Molecules

描述(申请人提供)：在许多制药和生物技术公司，合成小分子的方法正在转变中。目前，溶液相平行合成的价值得到了广泛的认可。由50-200个化合物组成的小的靶向(聚焦)文库在先导优化项目中越来越受欢迎，具有高分子多样性的化合物文库在发现文库中得到了更多的考虑。在化合物收集中用于测试或沉积的数量增加到10-50毫克范围，对纯度的要求也越来越高(现在通常为90%或更高)。由于分离耗时且往往很困难，这些需要将当前解决方案阶段的方法发挥到极致。氟技术公司(FTI)正在开发一个基础广泛的技术平台，全面满足现代药物发现环境中苛刻的合成化学需求。在两个成功的第一阶段项目的基础上，目前的第二阶段赠款致力于开发一种用于溶液相平行文库合成的快速氟合成工具包。这项研究的具体目标是：1)开发新的氟清除剂、标签和保护基团，同时扩大范围，包括新的氟试剂、催化剂和反应物；2)扩大微波技术在氟合成中的应用范围；3)通过开发新的氟色层析和平行固相萃取方法，进一步加强氟分离技术；4)结合氟化学品、微波技术和氟硅胶分离，开发“快速氟合成”工具包。该工具包包括三种不同的方案：一小时单一反应、一天一步平行合成和一周多步库合成；5)通过制作5个具有药学意义的支架的原型库来验证溶液相库生产中的快速氟合成，每个样本库包含100-200个类似物，每个10-50 mg，纯度大于90%。

DESCRIPTION (provided by applicant): Methods to synthesize small molecules are in transition in many pharmaceutical and biotechnology companies. The value of solution phase parallel synthesis is now widely recognized. Small targeted (focused) libraries made up of 50-200 compounds are increasingly popular for lead optimization projects, and compound libraries with high molecular diversity are given more consideration for discovery libraries. Quantities for testing or deposition in compound collections are increasing to the 10-50 mg range, and requirements for purity have stiffened (90% or better is now common). These needs tax current solution phase methodology to its limits because of time-consuming and often difficult separations. Fluorous Technologies, Inc. (FTI) is developing a broad-based technology platform that comprehensively addresses the demanding synthetic chemistry needs in a modem drug discovery environment. Based on two successful Phase I projects, the current Phase II grant strives to develop a rapid fluorous synthesis toolkit for solution-phase parallel library synthesis. The specific aims of this research effort are: 1) to develop new fluorous scavengers, tags, and protecting groups while simultaneously expanding the scope to include new fluorous reagents, catalysts, and reactants; 2) to expand the scope of microwave technology in fluorous synthesis; 3) to further strengthen the fluorous separation technology by developing new fluorous chromatographic and parallel SPE methods; 4) to develop a "rapid fluorous synthesis" toolkit by using a combination of fluorous chemicals, microwave technology, and fluorous silica gel-based separations. The toolkit includes three different protocols: a one-hour single reaction, one-day one-step parallel synthesis, and one-week multi-step library synthesis; 5) to validate rapid fluorous synthesis in solution phase library production by making 5 prototype libraries with pharmaceutically interesting scaffolds, containing 100-200 analogs, 10-50 mg each, and in greater than 90% purity.