Selective Functionalization of Pyridines and Diazines via Heterocyclic Phosphonium Salts

通过杂环鏻盐选择性官能化吡啶和二嗪

• 批准号: 10300452
• 负责人: Andrew McNally
• 金额: $ 28.05万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300452
• 关键词: Aldehyde oxidase; Alkylation; Anions; Carbonates; Catalysis; Chemicals; Cobalt; Complex; Coupling; Deuterium; Drug Industry; Electrons; FDA approved; Gases; Goals; Hydrogen; Ions; Isotope Labeling; Isotopes; Laboratories; Ligands; Mediating; Metabolism; Metals; Methods; Nickel; Nitrogen; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phosphines; Phosphorus; Positioning Attribute; Process; Protocols documentation; Pyrazines; Pyridazines; Pyrimidines; Reaction; Reagent; Research; Salts; Science; Scientist; Sodium Chloride; Source; Therapeutic; Transition Elements; Translating; Tritium; base; catalyst; diazine; drug discovery; functional group; interest; novel strategies; pharmacophore; programs; pyridine; small molecule; tool

Project Abstract. The aim of this proposal is to develop a general process to functionalize pyridines and diazines so that biologically active molecules can be accessed in an accelerated fashion. Pyridines are the second most common nitrogen heterocycle observed in FDA approved drugs and related diazines (pyrimidines, pyrazines and pyridazines) are also widely found. Traditional methods to functionalize these heterocycles are limited by functional group tolerance, poor regiocontrol and lack of applicability to complex substrates. Our strategy to functionalize these heterocycles will install a versatile functional group that enables a number of subsequent bond-forming reactions. Specifically, we will transform pyridines and diazines into phosphonium salts and use the unique reactivity of the phosphonium ion to make medicinally relevant derivatives. The 4-selective reaction to make phosphonium salts will use common reagents, be trivial to perform and have a broad substrate scope. We also propose to use this approach for late-stage functionalization of pharmaceuticals. Transforming phosphonium salts into important pyridine and diazine derivatives will occur through distinct mechanistic pathways. Direct reactions with nucleophiles will form C–C, C–O, C–S, C–N, and C–Hal bonds that occur via SNAr processes or ligand coupling at the phosphorus center. Metal-catalyzed cross-coupling, using nickel and cobalt catalysts, will be exploited for arylation and alkylation reactions. Base-mediated fragmentation reactions form heteroaryl anions that will be used to install deuterium and tritium isotopes and form organometallics. A conceptually new approach to make important bis-heterobiaryls will be developed base on phosphorus ligand coupling processes. Collectively, this program will provide rapid access to pyridine and diazine derivatives that have multiple applications in the pharmaceutical sciences. The long-term objective is for these methods to be used as routine tools by medicinal chemists.

项目摘要。 该提案的目的是开发一个一般过程来使吡啶和雄性氮嗪官能化，以便 可以以加速的方式访问具有生物活性的分子。吡啶是第二常见的 在FDA批准的药物和相关的雄性胺（嘧啶，吡啶和吡啶和 吡啶嗪）也被广泛发现。功能化这些杂环的传统方法受到限制 功能组的耐受性，差的降级控制和缺乏对复杂底物的适用性。我们的策略 功能化这些杂环将安装一个多功能功能组，以实现许多随后的功能 特别是，我们将将吡啶和大直就是磷盐转化为磷盐并使用 磷离子具有药物相关衍生物的独特反应性。四选择性反应 为了制作磷盐将使用常见试剂，要执行并具有广泛的底物范围。 我们还建议将这种方法用于药物的晚期功能化。转型 将磷盐进入重要的吡啶和丁胺衍生物将通过不同的机械出现 途径。与核phobile的直接反应将形成CC，C – O，C – S，C – N和C – HAL键通过 在磷中心的SNAR过程或配体耦合。金属催化的交叉耦合，使用镍和 将探索钴催化剂，以进行芳基化和酗酒反应。碱介导的碎裂反应 形成杂种阴离子，该阴离子将用于安装氘和tri同位素并形成器官。一个 从概念上讲，将基于磷配体的新方法来制造重要的双螺旋体 耦合过程。总的来说，该计划将提供快速访问吡啶和二嗪衍生物的访问 在药物科学中有多个应用。长期目标是使这些方法成为 用作药剂师的常规工具。