New Fluorous Tags for Combinatorial Synthesis

描述(申请人提供)：现代药物开发依赖于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，而氟技术平台是加速和利用溶液相合成的新的、强大的补充。然而，目前氟合成和氟混合物合成等新技术的应用受到商品化氟标签(保护基团)的缺乏的限制，因此迫切需要新的氟标签。这项SBIR建议通过研究(发现)和开发(验证和放大)新的氟标签的逐步过程来满足这一需求。具体目标是： 1)合成含氟保护基Fmoc(9-荧基氨基甲酸酯)、CBZ(氨基甲酸苄酯)和Bn(苄基)保护基。新的氟标签的设计使得全氟烷基链将控制氟二氧化硅上标记分子的分离性能。可以加入一个或多个亚甲基，以抵消二氟代烷基的电子效应。 2)验证这些新的氟标签在包括保护、反应和去保护的合成序列中的使用。对于每个氟基团，在选择在保护和去保护方面与母体很好地模拟并且在氟二氧化硅上具有合适的分离性能的那个(S)之前，将对几个候选基团进行测试。 3)优化新型氟标签的合成工艺，合成同系物。这些新标签的合成将在100-200克范围内进行优化。根据需要，该公司将与定制合成公司签订合同，准备这些新标签的千克规模。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，以用于氟混合物的合成。

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.