PFI-RP: Electrochemical Technologies for Pharmaceutical Synthesis via Nickel-Catalyzed Aryl-Alkyl Cross-Coupling

这一由威斯康星大学麦迪逊分校和默克公司领导的创新研究伙伴关系(PFI-RP)项目的更广泛的影响/商业潜力在于为合成活性药物成分及其前体开发了一种新的环境友好型电化学策略。电化学方法通常绕过传统热工艺中使用的昂贵、不安全、有毒和/或对环境有害的化学品的要求。有机合成的电气化有可能给制药制造带来革命性的变化。还原反应涉及到将电子净转移到目标分子上，这在化工生产中很常见。氢气可以利用可再生能源从水中产生，是这些反应的理想电子来源；然而，氢气缺乏完成许多重要还原反应所需的推动力。因此，替代的还原剂，如锌、镁和其他金属，经常被用作电子的来源。这个项目将开发电化学反应器技术，能够利用氢作为电子源来完成还原的交叉偶联反应，这些反应形成在制药和其他工业化学中常见的碳-碳键。拟议的项目旨在开发电化学技术，使镍催化的交叉亲电偶联反应能够以氢(H2)作为电子源。将对几种不同的氢阳极技术进行评估和优化，以便与驱动镍催化还原耦合方法的阴极集成。该项目将利用商用燃料电池中已建立的膜电极组件和气体扩散氢阳极技术。必须解决的技术挑战包括管理跨电化学电池膜迁移的质子和水，这两者都可能干扰催化偶联反应。这些挑战将通过设计和测试各种反应堆配置来克服，这些配置提供了解决这些问题的不同战略。通过结合合成化学家、工程师和制药行业的领先从业者的专业知识，该项目将提高使用氢气作为电子源的电化学碳-碳键形成反应的技术准备水平。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this Partnerships for Innovation – Research Partnerships (PFI-RP) project led by the University of Wisconsin-Madison and Merck & Co. Inc. lies in the development of a new environmentally benign electrochemical strategy for the synthesis of active pharmaceutical ingredients and their precursors. Electrochemical methods often bypass the requirement for costly, unsafe, toxic, and/or environmentally hazardous chemicals used in conventional thermal processes. The electrification of organic synthesis has potential to revolutionize pharmaceutical manufacturing. Reduction reactions involve the net transfer to electrons to a target molecule and they are commonly encountered in chemical manufacturing. Hydrogen gas, which may be produced from water using renewable energy, represents an ideal source of electrons for these reactions; However, hydrogen gas lacks the driving force needed to accomplish many important reduction reactions. Consequently, alternative reductants, such zinc, magnesium, and other metals are often used as a source of electrons. This project will develop electrochemical reactor technologies capable of using hydrogen as a source of electrons to accomplish reductive cross-coupling reactions that form carbon-carbon bonds commonly encountered in pharmaceuticals and other industrial chemicals.The proposed project targets the development of electrochemical technologies that will enable nickel-catalyzed, cross-electrophile coupling reactions to be performed with hydrogen (H2) as the source of electrons. Several different H2-anode technologies will be evaluated and optimized for integration with cathodes that drive the nickel-catalyzed reductive coupling methods. This project will leverage established membrane-electrode assemblies and gas-diffusion hydrogen anode technologies used in commercial fuel cells. Technical challenges that must be addressed include the management of protons and water that migrate across the membrane of the electrochemical cell, both of which could interfere with the catalytic coupling reactions. These challenges will be overcome through the design and testing of various reactor configurations that offer different strategies to address these issues. By combining the expertise of synthetic chemists, engineers and leading practitioners from the pharmaceutical industry, this project will elevate the technology-readiness level of electrochemical carbon-carbon bond forming reactions using H2 as an electron source.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.