New Fluorous Tags for Combinatorial Synthesis

描述（由申请人提供）：现代药物开发依赖于通过使用组合化学方法快速合成小有机分子（候选药物）。溶液相组合化学方法越来越重要，氟技术平台是一个新的和强大的补充，既加快和利用溶液相合成。然而，由于缺乏市售的氟标记物（保护基），目前诸如氟合成和氟混合物合成的新技术的实用性受到限制，因此迫切需要新的氟标记物。该SBIR提案通过逐步研究（发现）和开发（验证和扩大规模）新的氟标签来满足这一需求。具体目标是： 1)合成Fmoc（9-芴基甲基氨基甲酸酯）、Cbz（苄基氨基甲酸酯）和Bn（苄基）保护基的氟变体。新的氟标记物被设计成使得全氟烷基链将控制标记分子在氟二氧化硅上的分离特性。可以引入一个或多个亚甲基以抵消全氟烷基的电子效应。 2)验证这些新的氟标签在涉及保护、反应和脱保护的合成序列中的使用。对于每个氟基团，在选择在保护和脱保护中模拟母孔并且在氟二氧化硅上具有合适的分离性质的一个或多个候选物之前，将测试几个候选物。 3)优化新型氟标记物的工艺规模合成并合成同系物。这些新标签的合成将在100-200克规模上进行优化。根据需要，该公司将与定制合成公司签订这些新标签的公斤级制备合同。对于这些氟标签中的每一个，将合成一系列具有可变数量的氟的同系物以用于氟混合物合成。

DESCRIPTION (provided by applicant): Modem drug development relies on the rapid synthesis of small organic molecules (drug candidates) by using combinatorial chemistry methods. Solution phase combinatorial chemistry methods are increasingly important, and the fluorous technology platform is a new and powerful addition that both expedites and leverages solution phase synthesis. However, the utility of new techniques like fluorous synthesis and fluorous mixture synthesis is currently limited by the dearth of commercially available fluorous tags (protecting groups), so new fluorous tags are urgently needed. This SBIR proposal addresses this need through a stepwise process of research (discovery) and development (validation and scale up) of new fluorous tags. The specific aims are: 1) To synthesize fluorous variants of Fmoc (9-fluorenylmethylcarbamate), Cbz (benzyl carbamate) and Bn (benzyl) protecting groups. The new fluorous tags are designed such that the perfluoroalkyl chains will control the separation properties of tagged molecules on fluorous silica. One of more methylene groups may be incroporated to offset the electronic effect of the periluoroalkyl groups. 2) To validate the use of these new fluorous tags in a synthetic sequence involving protection, reaction and deprotection. For each fluorous group, several candidates will be tested prior to selecting the one(s) that mimics the parent well in protection and deprotection and have suitable separation properties on fluorous silica. 3) To optimize process scale syntheses of the new fluorous tags and to synthesize homologs. The synthesis of these new tags will be optimized on 100-200 gram scale. As needed, the company will contract for the kg scale preparation of these new tags with custom synthesis companies. For each of these fluorous tags, a series of homologs with variable number of fluorines will be synthesized for the use in fluorous mixture synthesis.