Pharmaceutical and Commodity Chemical Synthesis in High-Temperature Water

菲利普·E·萨维奇研究所：密歇根大学提议编号：0625641题目：高温水中的药物和商品化学合成智能优点：高温液态水(HTW)作为有机化学合成的反应介质具有廉价、丰富、无毒、可再生、环境友好和具有理想的化学性质等优点，因此具有吸引力。HTW已经展示了几种不同的商业上相关的合成，但还有更多的机会目标存在。例如，制药反应是有吸引力的目标，因为化学工业的这一部门通常比其他任何部门产生更多的单位质量产品的废物。在与辉瑞的化学家讨论后，PI决定探索HTW中三个特别吸引人的化学反应。它们是与“绿色”刘易斯酸催化剂进行的Friedel-Craft反应以合成四酮，酚甲基醚的去保护反应，以及Suzuki偶联反应以生成新的C-C键。这三个反应与几种不同药品的生产有关。除了上面提到的检查HTW中的新化学成分的研究外，他还将重新审视已经在HTW中演示的合成。这些体系包括对二甲苯部分氧化生成对苯二甲酸(与BP合作)、羟醛缩合和Friedel-Craft烷基化。这里的目的是改进这些HTW合成，以便它们可能在经济上与当前的工艺相竞争。目前限制基于高温气相沉积的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，无法提供能够在经济上与现有工艺竞争的体积产率。然而，最近的一项进展提出了一条可能的路线，可以在不牺牲环境效益的情况下克服这一障碍，提高基于高温气相沉积的工艺的生产率。这一进展表明，在水中获得快速反应速度并不需要水中的溶解度。事实上，对于某些反应，多相水-有机体系(大力搅拌不相容的水相和有机相)比通常采用的均相条件提供了更快的反应速度。到目前为止，这种效应只在接近环境温度的情况下表现出来。这个项目将研究对二甲苯部分氧化制备对苯二甲酸、羟醛缩合、Friedel-Craft反应、铃木偶联和乙醚水解。如果成功，这项研究将导致化学反应过程至少与目前的过程一样多产，但明显更环保。消除目前HTW中低反应物浓度的障碍将使这些技术进步得以实现。广泛影响：PI将与密歇根大学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普通公众(通过减少与化学产品制造有关的环境风险)。该项目还将为一名研究生和大约六名本科生提供培训。此外，PI将继续他的做法，将他的研究成果纳入他在密歇根大学任教的本科生和研究生班级，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.