Pharmaceutical and Commodity Chemical Synthesis in High-Temperature Water

摘要/ abstract摘要：pi: Philip E. Savage机构：密歇根大学项目编号：0625641题目：高温水中的药物和商品化学合成知识分子优点：高温液态水（HTW）由于其廉价、丰富、无毒、可再生、环保和具有理想的化学性质而成为有机化学合成的反应介质。几种不同的与商业相关的合成已经在HTW中得到证实，但存在更多的机会目标。例如，药物反应是有吸引力的目标，因为化学工业的这一部门通常比任何其他部门单位质量的产品产生更多的废物。在与辉瑞公司的化学家讨论后，PI决定探索HTW中三个特别吸引人的化学反应。这些是用“绿色”路易斯酸催化剂合成四酮酮的弗里德尔-克拉夫特反应，酚甲基醚的脱保护反应，以及铃木偶联反应生成新的碳-碳键。这三个反应与几种不同药品的生产有关。除了上面提到的研究HTW中的新化学物质外，他还将回顾已经在HTW中证明的合成。这些系统包括对二甲苯的部分氧化制对苯二甲酸（与BP合作），醛醇缩合和Friedel-Crafts烷基化。这里的目的是改进这些HTW合成，使它们在经济上与现有工艺具有竞争力。目前制约htw反应技术实施的一个限制是，有机反应物的溶解度往往太低，无法提供与现有工艺在经济上竞争的体积生产速率。然而，最近的一项进展提出了一种可能的途径，可以克服这一障碍，在不牺牲环境效益的情况下提高基于高温钨的工艺的生产率。这一进展表明，在水中获得快速反应速率并不需要在水中的溶解度。事实上，对于某些反应，非均相水-有机体系（大力搅拌不混相的水相和有机相）相对于通常采用的均相条件提供了大大加快的反应速率。迄今为止，这种效应只在接近环境温度的情况下得到证实。PI将探索是否可以将其应用于HTW。本项目将研究对二甲苯的部分氧化生成对苯二甲酸、醛醇缩合、Friedel-Crafts反应、Suzuki偶联和醚水解。如果成功，这项研究将导致化学反应过程至少与目前的化学反应过程一样多产，但对环境更加友好。消除目前HTW中低反应物浓度的障碍将使这些技术进步成为可能。广泛影响：PI将与UM技术转让办公室合作，提供技术进步。这项工作的好处将扩大到化学工业和一般公众（通过减少与制造化学产品有关的环境风险）。该项目还将为一名研究生和约六名本科生提供培训。此外，PI将继续他的实践，将他的研究成果纳入他在密歇根大学教授的本科和研究生课程，因此将有与教学和研究相结合的好处。

ABSTRACTPI: Philip E. Savage Institution: University of MichiganProposal Number: 0625641Title: Pharmaceutical and Commodity Chemical Synthesis in High-Temperature WaterIntellectual Merit: High-temperature liquid water (HTW) is attractive as a reaction medium for organic chemical synthesis because it is inexpensive, abundant, non-toxic, renewable, environmentally benign, and has desirable chemical properties. Several different commercially relevant syntheses have been demonstrated in HTW, but many more targets of opportunity exist. Pharmaceutical reactions, for instance, are attractive targets because this sector of the chemical industry generally produces more waste per unit mass of product than any other sector. After discussions with chemists at Pfizer, the PI has decided to explore three especially attractive chemical reactions in HTW. These are a Friedel-Crafts reaction with "green" Lewis acids catalysts to synthesize tetralone, the deprotection of phenolic methyl ethers, and Suzuki coupling to make new C-C bonds. These three reactions are relevant to the manufacture of several different pharmaceutical products. In addition to the research noted above that examines new chemistries in HTW, he will also revisit syntheses that have already been demonstrated in HTW. These systems include the partial oxidation of p-xylene to make terephthalic acid (in collaboration with BP), aldol condensation, and Friedel-Crafts alkylation. The purpose here is to improve these HTW syntheses so they might become economically competitive with current processes. A limitation currently restraining implementation of HTW-based reaction technologies is that the solubilities of organic reactants are often too low to give volumetric production rates that can compete economically with existing processes. A recent advance, however, has suggested a possible route for overcoming this barrier and increasing the productivity of HTW-based processes without sacrificing the environmental benefits. This advance is the demonstration that solubility in water is not required to get fast reaction rates in water. In fact, for some reactions, heterogeneous aqueous-organic systems (vigorously stirred immiscible aqueous and organic phases) provided greatly accelerated reaction rates relative to the homogeneous conditions typically employed. To date, this effect has only been demonstrated at near ambient temperatures. The PI will explore whether it can be employed in HTW.This project will examine the partial oxidation of p-xylene to make terephthalic acid, aldol condensation, Friedel-Crafts reactions, Suzuki coupling, and ether hydrolysis. If successful, the research will lead to chemical reaction processes that are at least as productive as current ones, but are significantly more environmentally friendly. Removing the current barrier of low reactant concentrations in HTW will allow these technological advances to occur. Broad Impact:The PI will work with the UM Technology Transfer Office to make available the technological advances. The benefit of this work will extend to the chemical industry and the general public (by having less environmental risk associated with the manufacture of chemical products). The project will also provide training for a graduate student and about six undergraduate students. Additionally, the PI will continue his practice of incorporating his research results into the undergraduate and graduate classes he teaches at Michigan, so there will be benefits related to the integration of teaching and research.