Development of Carbamate Amination Methodology and Synthesis of Levofloxacin

氨基甲酸酯胺化方法的进展及左氧氟沙星的合成

• 批准号: 8320696
• 负责人: Noah Frederick Fine Nathel
• 金额: $ 3.52万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8320696
• 关键词: Amination; Amines; Aniline; Antibiotics; Applications Grants; Aromatic Compounds; Attention; Award; Biochemistry; Biological Factors; Biological Testing; Biology; Boronic Acids; Carbamates; Carbon; Chemicals; Clinical; Complex; Coupling; Development; Disease; Goals; Health; Heterocyclic Amines; Infection; Levaquin; Life; Ligands; Medicine; Metals; Methodology; Methods; Names; Nickel; Nitrogen; Organic Chemistry; Organic Synthesis; Palladium; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Play; Prize; Public Health; Reaction; Role; Solvents; Source; Temperature; Transition Elements; aryl halide; base; drug synthesis; improved; sulfamate; tool

DESCRIPTION (provided by applicant): The specific aim for this proposal describes the development and utility of nickel-catalyzed aminations of aryl carbamates. The health significance of this methodology lies in the synthesis of biologically active natural products and pharmaceutical drugs. Many of these products contain aryl carbon-nitrogen (C-N) bonds and highly substituted aromatic rings. The carbamate moiety is useful in this regard because it can selectively direct functionalization around an aromatic ring prior to undergoing nickel-catalyzed amination to install a C-N bond. With this new methodology, useful quantities of these drugs can be synthesized with ease for biological testing and clinical use. The goals of this proposal will be accomplished through three phases. First, amination methodology that uses nickel(0) and nickel(II) precatalysts will be developed. Having recently developed the amination using nickel(0) precatalysts, optimization of Ni(II) sources will be undertaken by varying ligands, bases, solvents, and temperature. After finding a proper set of conditions, the methodology's substrate scope will be evaluated. A variety of aromatic carbamates including, but not limited to, 2,3, and 4-substituted aryl carbamates and heterocyclic carbamates, will be subjected to the reaction conditions. A selection of amines will also be evaluated, including secondary alkyl amines and anilines. The second phase is the incorporation of unique heterocycles into the scope of these aminations. Heterocycles are ubiquitous in biologically-active compounds and this expansion of scope will improve the methodology's utility. The third and final phase of the specific aim will be the use of the newly developed carbamate amination methodology to synthesize Levofloxacin, an antibiotic used for life-threatening infections. This synthesis will showcase the methodology as a practical tool for the construction of complex, yet biologically significant molecules. PUBLIC HEALTH RELEVANCE: The development of carbamate amination methodology will provide an efficient means to construct aryl carbon-nitrogen bonds and polysubstituted aromatic compounds. Aryl carbon-nitrogen bonds are found in countless biologically active molecules and drug substances, which in turn are active against many classes of disease. Therefore, this new method is expected to be a significant chemical contribution that will ultimately benefit public health.

描述（由申请人提供）：该提案的具体目标描述了镍催化氨基甲酸芳基酯胺化的开发和应用。该方法的健康意义在于合成具有生物活性的天然产物和药物。许多此类产品含有芳基碳-氮 (C-N) 键和高度取代的芳环。氨基甲酸酯部分在这方面很有用，因为它可以在进行镍催化胺化以安装 C-N 键之前选择性地直接围绕芳环进行官能化。通过这种新方法，可以轻松合成有用数量的这些药物，用于生物测试和临床使用。 该提案的目标将通过三个阶段来实现。首先，将开发使用镍（0）和镍（II）预催化剂的胺化方法。最近开发了使用镍 (0) 预催化剂的胺化，将通过改变配体、碱、溶剂和温度来优化 Ni(II) 源。找到一组合适的条件后，将评估该方法的底物范围。多种芳族氨基甲酸酯，包括但不限于2，3和4-取代的芳基氨基甲酸酯和杂环氨基甲酸酯，将经历反应条件。还将评估一系列胺，包括烷基仲胺和苯胺。第二阶段是将独特的杂环纳入这些胺化的范围。杂环化合物在生物活性化合物中普遍存在，范围的扩大将提高该方法的实用性。具体目标的第三个也是最后一个阶段将是使用新开发的氨基甲酸酯胺化方法来合成左氧氟沙星，这是一种用于危及生命的感染的抗生素。该合成将展示该方法作为构建复杂但具有生物学意义的分子的实用工具。 公共卫生相关性：氨基甲酸酯胺化方法的发展将为构建芳基碳氮键和多取代芳香族化合物提供有效的方法。芳基碳氮键存在于无数生物活性分子和药物中，而这些分子和药物又可有效对抗多种疾病。因此，这种新方法有望成为一项重大的化学贡献，最终有利于公众健康。