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

PFI-RP：通过镍催化芳基-烷基交叉偶联进行药物合成的电化学技术

• 批准号: 2122596
• 负责人: Shannon Stahl
• 金额: $ 55万
• 依托单位: University of Wisconsin-Madison
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2122596&HistoricalAwards=false
• 关键词: PFI; RP; Electrochemical; Technologies; Pharmaceutical

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.

威斯康星大学 - 麦迪逊分校和默克公司领导的这一合作伙伴关系（PFI-RP）项目的更广泛的影响/商业潜力在于开发一种新的环境良性电化学策略，以制定活性药物归纳的合成及其前体。电化学方法通常绕过对常规热过程中使用的昂贵，不安全，有毒和/或环境危险化学物质的要求。有机合成的电化有可能彻底改变药品制造。还原反应涉及到电子向目标分子的净传递，并且在化学制造中通常会遇到它们。可以使用可再生能源从水产生的氢气代表了这些反应的理想电子来源。但是，氢气缺乏完成许多重要还原反应所需的驱动力。因此，替代还原器，例如锌，镁和其他金属通常被用作电子的来源。该项目将开发能够使用氢作为电子来源的电化学反应器技术，以减少交叉耦合反应，形成在药品和其他工业化学化学物质中通常遇到的碳碳键。该提议的项目旨在与电化学技术的开发，以促进镍脉络性互动的近距离脉冲，互联网脉冲脉冲，刺激性脉冲脉络脉冲couplogene couplogene couploplile couploplipecoulloplipecoulloplipecoulloplilectile（电子来源。将评估和优化几种不同的H2阳极技术，以与驱动镍催化的减少耦合方法的阴极集成。该项目将利用已建立的膜电极组件和商业燃料电池中使用的气体扩散氢阳极技术。必须解决的技术挑战包括在整个电池膜上迁移的质子和水的管理，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挑战，这些配置提供了解决这些问题的不同策略。通过结合制药行业的合成化学家，工程师和领先的从业人员的专家，该项目将提高使用H2作为电子资源作为电子资源的电化学碳碳键反应的技术准备水平。该奖项反映了NSF的法定任务，并通过使用基金会的智能范围来评估了NSF的法定任务，并将其视为诚实的支持。

项目成果

Quinone-mediated hydrogen anode for non-aqueous reductive electrosynthesis

• DOI: 10.1038/s41586-023-06534-2
• 发表时间: 2023-08
• 期刊: Nature
• 影响因子: 64.8
• 作者: Jack Twilton;Mathew R. Johnson;Vinayak Sidana;Mareena C. Franke;C. Bottecchia;Dan Lehnherr;F. Lévesque;S. M. Knapp;Luning Wang;James B. Gerken;Cynthia M. Hong;T. Vickery;M. D. Weisel;N. Strotman;D. Weix;T. Root;S. Stahl