Catalytic Aerobic Oxidations for Pharmaceutical Synthesis: Flow-Reaction Methods

用于药物合成的催化有氧氧化：流动反应方法

• 批准号: 7820590
• 负责人: Shannon S Stahl
• 金额: $ 45.01万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7820590
• 关键词: Address; Aerobic; Alcohols; Amination; Amines; Area; Benchmarking; Benign; Carbon; Chemicals; Chemistry; Classification; Collaborations; Development; Enabling Factors; Engineering; Environmental Impact; Exhibits; Explosion; Hydrogen Bonding; Hydrogenation; Investigation; Ketones; Literature; Metals; Methodology; Methods; Molecular; Nitrogen; Noble Gases; Oxidants; Oxygen; Palladium; Pharmacologic Substance; Play; Process; Production; Public Health; Reaction; Reagent; Reporting; Research; Role; Route; Safety; Scientist; Solutions; Solvents; System; Technology; Temperature; Testing; Translating; Translations; Universities; Wisconsin; Work; base; catalyst; chemical synthesis; design; design and construction; drug development; drug discovery; hazard; improved; innovation; large scale production; method development; molecular sieving; oxidation; pressure; public health relevance; tertiary amine; tool

DESCRIPTION (provided by applicant): This proposal addresses Broad Challenge Area (06) Enabling Technologies and Specific Challenge Topic 06-GM-109 Green chemistry and engineering for drug discovery, development, and production. Development of chemical methodologies and tools to promote green chemistry and engineering innovation into drug discovery, development, and production. Selective oxidation reactions are among the most important classes of reactions in chemical synthesis. Molecular oxygen is the least expensive and most environmentally benign chemical oxidant available, yet it is virtually never used in drug development and production because aerobic oxidation reactions typically exhibit poor reaction selectivity and present insurmountable safety hazards. The project described in this proposal will build upon recent advances in metal-catalyzed reactivity and innovations in reaction engineering in order to achieve safe and scalable methods for use of molecular oxygen as a selective oxidant in pharmaceutical synthesis. Flow-reactor technology provides a means to translate small-scale aerobic oxidation reactions, many of which have been reported in the recent literature, into large-scale pharmaceutical processes. The design, construction and testing of operational flow reactors will be performed in collaboration with scientists and engineers at Eli Lilly (Indianapolis, IN), and this work will target the development of reactors compatible with both homogeneous and heterogeneous reaction solutions. These reactors will be used for systematic investigation of factors (catalyst identity, temperature, pressure, flow-rate, etc.) that enable effective translation of results obtained from small-scale, batch reactions into successful flow-based processes. Initial studies will focus on palladium-catalyzed methods for aerobic alcohol oxidation, which have been the focus of considerable synthetic and mechanistic investigation by the PI and his group over the past 10 years. The results of these studies should be applicable to the entire scope of aerobic oxidation reactions that have been reported in recent years, including methods for carbon-nitrogen bond formation, allylic acetoxylation and C-H bond functionalization reactions. The expanding scope of selective aerobic oxidation reactions suggests that this project will play an important role in promoting "green chemistry" in large-scale production of pharmaceuticals. Once the flow reaction methods are established, they will be used to achieve two synthetically useful tandem transformations that build upon flow-based aerobic alcohol oxidations: (1) convergence of racemic secondary alcohols into their enantiomerically pure form via sequential aerobic alcohol oxidation/enantioselective ketone hydrogenation, and (2) the conversion of alcohols to (chiral) amines via sequential aerobic alcohol oxidation/(enantioselective) reductive amination reactions. In the both classes of reactions, oxidation reactions with O2 and reduction reactions with H2 will be performed in flow. PUBLIC HEALTH RELEVANCE: Molecular Oxygen is the most abundant and environmentally benign oxidant available for chemical synthesis; however, fundamental challenges limit its utility in pharmaceutical synthesis. The proposed research will implement innovative chemistry (new catalytic methods) and engineering (flow-reactor technology) strategies to overcome this limitation, thereby enabling widespread use of a new environmentally benign ("green") method for the development and production of pharmaceuticals.

描述（由申请人提供）：该提案解决了广泛的挑战领域（06）启用技术和特定挑战主题06-gm-109绿色化学和工程，用于药物发现，开发和生产。开发化学方法和工具，以将绿色化学和工程创新促进药物发现，开发和生产。选择性氧化反应是化学合成中最重要的反应类别之一。分子氧是最便宜，最环保的化学氧化剂，但实际上从未在药物开发和生产中使用它，因为有氧氧化反应通常表现出较差的反应选择性，并且表现出了无法克服的安全隐患。该提案中描述的项目将基于金属催化的反应性和反应工程中的创新的最新进展，以实现使用分子氧作为药物合成中选择性氧化剂的安全可扩展方法。流动反应器技术提供了一种将小规模有氧氧化反应转化的方法，其中许多在最近的文献中已报告为大规模的药物过程。操作流动反应器的设计，构建和测试将与Eli Lilly（印第安纳波利斯，印第安纳州）的科学家和工程师合作进行，这项工作将针对与均匀和异质反应解决方案兼容的反应器的发展。这些反应器将用于系统研究因素（催化剂身份，温度，压力，流量等），以有效地转换从小规模的，批处理反应中获得的成功转化为成功的基于流动的过程。最初的研究将重点介绍用于有氧酒精氧化的钯催化方法，在过去的10年中，PI及其小组的大量合成和机械研究的重点。这些研究的结果应适用于近年来报道的有氧氧化反应的整个范围，包括碳氮键形成，烯丙基乙酰氧基化和C-H键官能化反应的方法。选择性有氧氧化反应的扩大范围表明，该项目将在促进药品生产中促进“绿色化学”中起重要作用。一旦建立了流动反应方法，它们将用于实现两种合成有用的串联转化，这些转换基于基于流动的有氧酒精氧化：（1）外消旋次级酒精通过顺序有氧醇氧化/对照酮的酮酮会收敛于其对映体纯净的形式氢化，以及（2）通过顺序有氧酒精氧化/（对映选择性）还原性胺化反应的醇转化为（手性）胺。在两类反应中，将在流动中进行氧化反应和与H2的还原反应。 公共卫生相关性：分子氧是可用于化学合成的最丰富和环境良性的氧化剂；但是，基本挑战限制了其在药物合成中的效用。拟议的研究将实施创新的化学（新催化方法）和工程（流动反应技术）策略来克服这一局限性，从而实现广泛使用新的环境良性（“绿色”）方法来开发和生产药物。