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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：我们建议继续扩大铱催化芳香族 C-H 活化/硼基化与其他化学转化的研究，作为目前无法获得的化学构件的新方法，这对于各种实际应用非常有用，包括医药、农用化学品、材料和精细化学品开发。 Ir 催化剂的温和性及其运行的反应条件允许含有各种官能团的芳烃的硼化。鉴于这种底物耐受性，多种后续同锅反应是可能的，并且目前正在开发中。我们新发明的“望远镜”C-H 活化/硼化与氧化的工艺是这种以高效、可扩展的方式将硼化与其他化学转化耦合的能力的典型例子。该过程提供了快速而独特的途径来获得新的、高度功能化的酚醛结构单元，这些结构单元目前在商业上无法获得或只能通过长期、昂贵且没有吸引力的途径获得。苯酚是商业上重要的化合物，被广泛使用，特别是在药物发现、开发和制造领域。即使有一系列的生产方法，仍然存在许多相对简单的例子，其中所建立的合成对于实际使用来说太长和/或产率低。在这项提案中，BoroPharm 旨在通过专有技术的商业开发来解决这些困难，该技术已独家授权给 BoroPharm, Inc.。具体来说，BoroPharm 的目标是验证铱催化的芳香硼化/氧化作为制药相关酚类和羟基吡啶的商业途径。基于第一阶段目标的成功完成以及 BoroPharm 不断增长的客户群的行业反馈，第二阶段提案将解决以下具体目标： 1. 扩大硼化吡啶衍生物的产品组合，添加喹啉、吡嗪、嘧啶、二氮烯、咪唑、吡唑、恶唑等。适用时产生氧化产物（例如羟基喹啉）。 2. 探索硼新技术，包括三氟硼酸盐、三油酸盐、MIDA衍生物的形成和利用。 3. 扩大苯酚产品组合，提供更多以前未报告的产品。增加规模以生产公斤数量。 4. 扩展产品组合中芳基硼酸酯的额外转化，并生产碳-硼键被转化或保留的新产品。公共健康相关性：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，新药物需要新的构建模块，而成本较低的药物将需要更有效、更环保的途径来获取这些关键中间体。在此，我们建议开发下一阶段的新技术，用于创建独特且多功能的化学构件，其发明将有助于新药的发现和开发。该项目是第一阶段拨款的延续，该项目已取得积极成果。在此，我们将扩展化学平台的广度、范围和规模，并扩展新颖且有用的药物结构单元的合成。