Rapid Fluorous Synthesis of Drug-Like Small Molecules

描述（由申请人提供）：许多制药和生物技术公司正在过渡合成小分子的方法。液相平行合成的价值已得到广泛认可。由50-200种化合物组成的小型靶向（集中）文库越来越受先导化合物优化项目的欢迎，而具有高分子多样性的化合物文库在发现文库中得到更多考虑。用于化合物收集的测试或沉积的量增加到10-50 mg范围，并且对纯度的要求已经加强（90%或更高现在很常见）。这些需要税收目前的解决方案阶段的方法，以其限制，因为费时，往往很难分离。Fluorous Technologies，Inc. (FTI)正在开发一个基础广泛的技术平台，全面解决现代药物发现环境中苛刻的合成化学需求。基于两个成功的第一阶段项目，目前的第二阶段赠款致力于开发一个快速的氟合成工具包，用于溶液相平行库合成。本研究工作的具体目标是：1）开发新的氟清除剂、标记物和保护基团，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）通过开发新的氟色谱和平行SPE方法，进一步加强氟分离技术; 4）通过使用氟化学品、微波技术和基于氟硅胶的分离的组合，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文库合成; 5）通过制备具有药学上感兴趣的支架的5个原型文库来验证溶液相文库生产中的快速氟合成，所述原型文库含有100-200种类似物，每种10-50 mg，并且纯度大于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.