Phase II Environmentally greener, efficient, and safe synthetic platform for the

二期 更环保、更高效、更安全的合成平台

• 批准号: 8141298
• 负责人: Paul Matthew Herrinton
• 金额: $ 47.54万
• 依托单位: BOROPHARM, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8141298
• 关键词: Address; Area; Benign; Boron; Boronic Acids; Carbon; Cataloging; Catalogs; Characteristics; Chemicals; Chemistry; Client; Development; Disease; Drug Compounding; Drug Costs; Esters; Feedback; Food Supply; Grant; Hepatoprotective Agent; Imidazole-Pyrazole; In Situ; Industrial fungicide; Industry; Insecta; Iridium; Kilogram; Laboratories; Licensing; Malaria; Marketing; Medicine; Methodology; Methods; Michigan; Molecular; Optruma; Outcome; Oxazoles; Pesticides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenols; Process; Production; Provider; Pyrazines; Pyrimidines; Quality of life; Reaction; Rest; Route; Silymarin; Technology; Universities; base; catalyst; combat; cost; drug candidate; drug discovery; functional group; hydroxypyridines; interest; new technology; novel; novel strategies; oxidation; phase 1 study; practical application; professor; public health relevance; pyridine; quinoline; scale up; success

DESCRIPTION (provided by applicant): We propose to continue expanding the study of iridium-catalyzed aromatic C-H activation/borylation in concert with other chemical conversions as a new approach to currently inaccessible chemical building blocks that will be highly useful for variety of practical applications, including pharmaceutical, agro-chemical, materials and fine chemical development. The mildness of the Ir-catalysts and the reaction conditions under which they operate, allows for the borylation of arenes containing a variety of functional groups. Given this substrate tolerance, a wide range of subsequent same-pot reactions is possible, and currently under development. Our newly invented process that "telescopes" C-H activation/borylation with oxidations serves as a prime example of this ability to couple borylation with other chemical transformations in an efficient, scaleable way. This process provides rapid and unique access to new and highly functionalized phenolic building blocks that are currently commercially unavailable or accessible only by protracted, costly, and otherwise unattractive routes. Phenols are commercially important compounds that are extensively utilized, especially in the area of drug discovery, development, and manufacture. Even with an array of methods for their production, there are still many relatively simple examples where the established syntheses are prohibitively long and/or low yielding for practical use. In this proposal BoroPharm aims to combat these difficulties through the commercial development of proprietary technology that has been exclusively licensed to BoroPharm, Inc. Specifically, BoroPharm aims to validate iridium-catalyzed aromatic borylation/oxidation as a commercial route to pharmaceutically relevant phenols and hydroxypyridines. Based on the successful completion of Phase I objectives and industry feedback from BoroPharm's growing client base, the following specific aims will be addressed in this Phase II proposal: 1. Expand the portfolio of borylated pyridine derivatives and add quinolines, pyrazines, pyrimidines, diazenes, imidazoles, pyrazoles, oxazoles, etc. Produce oxidized products (e.g. hydroxyquinolines) where applicable. 2. Explore new boron technologies including the formation and utilization of trifluoroborate, triolate, and MIDA derivatives. 3. Augment the phenol portfolio to make more previously unreported products available. Increase the scale to produce kilogram quantities. 4. Expand upon additional transformations of aryl boronates in the portfolio, and to produce new products where the carbon-boron bonds are either transformed or retained. PUBLIC HEALTH RELEVANCE: The invention of new drugs rests heavily on the chemist's ability to assemble unique compounds from molecular building blocks. In this regard, new pharmaceuticals call for new building blocks, while lower cost drugs will require more efficient and environmentally friendly routes to these key intermediates. Herein we propose to develop the next phase of a novel technology for the creation of unique and versatile chemical building blocks, the invention of which will aid the discovery and development of new medicines. This project is a continuation of a phase I grant that succeeded with positive outcomes. Herein, we will expand upon the breadth, scope and scale of the chemical platform and expand on the synthesis of novel and useful pharmaceutical building blocks.

描述(由申请者提供)：我们建议继续与其他化学转化相结合，扩大Ir离子催化的芳香族C-H活化/硼化反应的研究，作为目前无法获得的化学构件的新方法，这将对各种实际应用非常有用，包括制药、农用化学品、材料和精细化学开发。Ir催化剂的温和和它们的反应条件允许含有各种官能团的芳烃的硼化反应。考虑到底物的耐受性，很大范围的后续同锅反应是可能的，而且目前正在开发中。我们最新发明的“望远镜”C-H活化/硼化与氧化反应的过程是这种能力的一个典型例子，它以一种高效、可扩展的方式将硼化反应与其他化学转化相结合。这一过程提供了快速和独特的途径，以获得新的和高度功能化的酚醛积木，这些积木目前在商业上是不可获得的，或者只能通过漫长、昂贵和没有吸引力的路线才能到达。酚类化合物是一种具有重要商业价值的化合物，在药物的发现、开发和制造等领域有着广泛的应用。即使有一系列的方法来生产它们，仍然有许多相对简单的例子，在这些例子中，已建立的合成对于实际应用来说是令人望而却步的长和/或低产率。在这项提案中，BoroPharm公司旨在通过独家授权给BoroPharm公司的专有技术的商业开发来克服这些困难。具体地说，BoroPharm公司的目标是验证Ir催化的芳香族硼化/氧化作为一种商业路线来获得与药物相关的苯酚和羟基吡啶。基于第一阶段目标的成功完成和BoroPharm不断增长的客户群的行业反馈，第二阶段的提案将涉及以下具体目标：1.扩大硼化吡啶衍生物的产品组合，增加喹啉、吡嗪、嘧啶、双氮烯、咪唑、吡唑、恶唑等。在适用的情况下生产氧化产品(例如羟基喹啉)。2.探索新的硼技术，包括三氟硼酸盐、三聚氰酸酯和MIDA衍生物的形成和利用。3.增加苯酚产品组合，以提供更多以前未报告的产品。增加规模以生产千克数量。4.扩展产品组合中芳基硼酸盐的其他转化，并生产碳-硼键被转化或保留的新产品。 与公共健康相关：新药的发明在很大程度上取决于化学家从分子构件组装独特化合物的能力。在这方面，新的药物需要新的组成部分，而成本较低的药物将需要更有效和更环保的途径来获得这些关键中间体。在此，我们建议开发一种新技术的下一阶段，用于创建独特和多功能的化学构建块，其发明将有助于新药的发现和开发。这一项目是第一阶段赠款的延续，并取得了积极成果。在此，我们将扩展化学平台的广度、范围和规模，并扩展新型和有用的药物构建块的合成。