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New Chemical Process to Selectively Functionalize Pyridines, Diazines and Pharmaceuticals

选择性功能化吡啶、二嗪和药物的新化学工艺

基本信息

批准号：
10733969
负责人：
Andrew McNally
金额：
$ 31.02万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733969
关键词：
Address Alcohols Alkynes Amides Amination Amines Aminopyridines Ammonia Ammonium Aniline Benzophenones Binding Binding Sites Biological Carbon Cell Respiration Chemicals Chemistry Collection Complex Coupled Coupling Cyclization Cysteine Drug Receptors Electronics Electrons Environment FDA approved Goals Hydrogen Bonding Hydrogenation Imines Ions Isomerism Label Libraries Ligands Mediating Medicine Methods Nitrogen Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phosphines Phosphorus Positioning Attribute Process Property Protocols documentation Pyridones Reaction Reagent Research Resistance Salts Sodium Chloride Structure Sulfhydryl Compounds Sulfonamides Sulfur Thermodynamics Water analog base chemical reaction chlorination design diazine drug discovery drug-like compound functional group nucleophilic addition operation piperidine preference programs pyridine scaffold small molecule thiophenol tool

项目摘要

Project Abstract. The goal of this project is to introduce a new synthetic strategy to functionalize pyridine and diazine heterocycles. Pyridines are the second most common nitrogen heterocycle found in FDA approved drugs, and there are numerous examples of diazines in these structures. The widespread occurrence arises because of a combined effect of the heterocycle and its substituents. The key drug-receptor interaction is often comprised of a hydrogen bond between the heterocycles N-lone pairs and the biological target. These heterocycles are also polar, can engage in p-stacking interactions and are resistant to oxidative metabolism. The substituents enable tuning of the steric and electronic environment of the heterocycle as well as serving as additional binding sites. As such, medicinal chemists require chemical process that can directly and selectively install a range of substituents at various stages of drug discovery from C–H precursors. In this proposal we will develop three different approaches for azine functionalization. First, we will install heterocyclic phosphonium salts and exploit their unique reactivity to develop coupling reactions with amines, thiophenols, cysteine containing molecules and alkynes. Using phosphines with pendant functional groups will enable coupling with water and ammonia. Second, direct coupling reactions between NTf-pyridinium salts and nucleophiles will be exploited for C–Heteroatom bond formation. additionsThis platform will enable direct coupling with aliphatic amines, anilines, amides and sulfonamides. Third, we will use sulfur nucleophile to change the regioselectivity of nucleophilic addition from the 4-position of pyridines to the 2-position of the scaffold. Once embedded in the substrate, these sulfur nucleophiles also serve as versatile functional group the enable other transformations to make C–N, C–O and C–F bonds.

项目摘要。本项目的目标是介绍一种新的合成策略来官能化吡啶和二嗪杂环。吡啶是FDA批准的药物中发现的第二种最常见的氮杂环，这些结构中的二嗪的许多实例。广泛的发生是由于杂环及其取代基的影响。关键的药物-受体相互作用通常由氢组成，杂环N-孤对电子与生物靶标之间的键。这些杂环也是极性的，可以参与p-堆积相互作用，并对氧化代谢有抗性。取代基使得能够调节杂环的空间和电子环境以及作为额外的结合位点。因此，在本发明的一个方面，药物化学家需要能够直接和选择性地将一系列取代基安装在 C-H前体药物发现的各个阶段。在本提案中，我们将开发三种不同的方法用于吖嗪官能化。首先，我们将安装杂环鏻盐并利用其独特的反应性与胺、硫酚、含半胱氨酸的分子和炔发生偶联反应。使用具有侧官能团的膦将能够与水和氨偶联。二、直接耦合 NTf-吡啶盐和亲核试剂之间的反应将用于C-杂原子键的形成。该平台将能够与脂肪胺、苯胺、酰胺和磺酰胺直接偶联。第三，我们将使用含硫亲核试剂来改变亲核加成的区域选择性，将吡啶连接到支架的2-位。一旦嵌入基质中，这些硫亲核试剂还起到作为多功能基团，它们使其他转化成为C-N，C-O和C-F键。