Catalytic Aerobic Oxidations for Pharmaceutical Synthesis: Flow-Reaction Methods

描述（由申请人提供）：本提案涉及药物发现、开发和生产的广泛挑战领域（06）使能技术和特定挑战主题06-GM-109绿色化学和工程。开发化学方法和工具，促进药物发现、开发和生产中的绿色化学和工程创新。选择性氧化反应是化学合成中最重要的一类反应。分子氧是最便宜和最环保的化学氧化剂，但它几乎从未用于药物开发和生产，因为有氧氧化反应通常表现出不良的反应选择性和存在无法克服的安全隐患。本提案中描述的项目将建立在金属催化反应性和反应工程创新的最新进展基础上，以实现在药物合成中使用分子氧作为选择性氧化剂的安全和可扩展的方法。流动反应器技术提供了一种将小规模的好氧氧化反应转化为大规模制药过程的方法，其中许多反应在最近的文献中已有报道。操作流动反应器的设计，建造和测试将与Eli Lilly（Indianapolis，IN）的科学家和工程师合作进行，这项工作的目标是开发与均相和非均相反应溶液兼容的反应器。这些反应器将用于系统研究各种因素（催化剂特性、温度、压力、流速等）。其能够将从小规模间歇反应获得的结果有效地转化为成功的基于流动的工艺。最初的研究将集中在钯催化的有氧醇氧化方法，这一直是相当大的合成和机械研究的重点，由PI和他的小组在过去的10年。这些研究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。选择性好氧氧化反应的应用范围不断扩大，这一项目将在推动“绿色化学”的大规模制药生产中发挥重要作用。一旦建立了流动反应方法，它们将用于实现基于流动的好氧醇氧化的两种合成有用的串联转化：（1）通过连续的有氧醇氧化/对映选择性酮氢化将外消旋仲醇会聚成它们的对映体纯形式，和（2）通过连续的有氧醇氧化/（对映选择性）还原胺化反应将醇转化为（手性）胺。在这两类反应中，用O2的氧化反应和用H2的还原反应将在流动中进行。 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友好的氧化剂;然而，基本挑战限制了其在药物合成中的应用。拟议的研究将实施创新的化学（新的催化方法）和工程（流动反应器技术）战略，以克服这一限制，从而使广泛使用一种新的环境友好（“绿色”）的方法来开发和生产药物。

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.