New Methods for Site-Selective Trifluoromethylation of Aromatic Heterocycles

芳香杂环的位点选择性三氟甲基化新方法

• 批准号: 8450967
• 负责人: Ryan D Baxter
• 金额: $ 5.22万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450967
• 关键词: Address; Antidepressive Agents; Antineoplastic Agents; Area; Biological Availability; Chemicals; Collaborations; Collection; Communities; Development; Drug Industry; Equipment; Feedback; Gases; Goals; Investigation; Isomerism; Isotopes; Kinetics; Lead; Medical; Metabolic; Metals; Methodology; Methods; Molecular; Pharmacologic Substance; Procedures; Process; Property; Protocols documentation; Reaction; Reporting; Research; Site; System; Testing; Work; base; density; design; functional group; high throughput screening; interest; novel; novel strategies; predictive modeling; programs; scaffold; screening; theories; trifluoromethyl group

DESCRIPTION (provided by applicant): Heterocyclic molecular scaffolds containing the trifluoromethyl functional group have become increasingly common in biologically active compounds targeted by the pharmaceutical industry. Chemotherapeutics ranging from antidepressants to anticancer agents have successfully utilized the incorporation of trifluoromethyl groups due to the unique properties their presence elicits. For this reason, there has been a consistent drive within the chemical community towards the development of chemical methods for the installation of the trifluoromethyl group into pharmaceutically relevant heterocyclic scaffolds. The proposed research aims to develop and refine novel chemical strategies for site-selective trifluoromethylations of aromatic heterocycles through a combination of high-throughput screening and mechanistic analysis. High-throughput screening will efficiently test and push the limits of a recently reported, but underdeveloped trifluoromethylatio protocol that has been show to have significant advantages over previous methods. DFT calculations will be performed in tandem with reaction screens to develop a predictive model of reactivity and site-selectivity based on ground-state substrate properties. Mechanistic investigation involving kinetic analysis and kinetic isotope effect studies will lead to better understanding of this important reaction class, allowing for further development and the discovery of related processes. Finally, the long term goal of the proposed research is the development of a suite of general experimental procedures for the trifluoromethylation of a variety of heterocyclic classes in high yield with high site-selectivity. The development of robust chemical strategies for the selective installation of trifluoromethyl groups into pharmaceutically relevant scaffolds would have a significant and immediate impact on the medical community as trifluoromethyl- containing chemotherapeutics may be targeted more efficiently and in greater numbers by medicinal chemists and pharmaceutical industries.

描述（由申请人提供）：含有三氟甲基官能团的杂环分子支架在制药工业靶向的生物活性化合物中越来越常见。从抗抑郁剂到抗癌剂的化学治疗剂已经成功地利用了三氟甲基基团的掺入，这是由于它们的存在所赋予的独特性质。出于这个原因，在化学界内一直有一致的驱动力，以开发用于将三氟甲基安装到药学相关的杂环支架中的化学方法。拟议的研究旨在通过高通量筛选和机理分析相结合，开发和完善芳族杂环的位点选择性三氟甲基化的新化学策略。高通量筛选将有效地测试和推动最近报道的限制，但欠发达的三氟甲基化协议，已被证明具有显着的优势，比以前的方法。DFT计算将与反应筛选一起进行，以开发基于基态底物性质的反应性和位点选择性的预测模型。涉及动力学分析和动力学同位素效应研究的机制调查将导致更好地理解这一重要的反应类别，允许进一步开发和发现相关过程。最后，所提出的研究的长期目标是开发一套通用的实验程序的三氟甲基化的各种杂环类的高产率与高位点选择性。鲁棒的发展 用于将三氟甲基选择性地安装到药学相关支架中的化学策略将对医学界产生显著和直接的影响，因为含三氟甲基的化学治疗剂可以更有效地被药物化学家和制药工业更大量地靶向。