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

描述（由申请人提供）：我们建议继续扩大铱催化的芳香族C-H活化/硼基化的研究，与其他化学转化相结合，作为一种新的方法，目前无法获得的化学结构单元，将非常适用于各种实际应用，包括制药，农业化学，材料和精细化学品开发。Ir-催化剂的温和性和它们操作的反应条件允许含有各种官能团的芳烃的硼基化。鉴于这种底物耐受性，广泛的后续同锅反应是可能的，目前正在开发中。我们新发明的方法，“望远镜”C-H活化/硼化与氧化作为这种能力的一个主要例子耦合硼化与其他化学转化在一个有效的，可扩展的方式。这种方法提供了快速和独特的途径，以获得新的和高度官能化的酚类结构单元，这些结构单元目前在商业上不可用或只能通过长期的、昂贵的和其他没有吸引力的途径获得。酚类是广泛使用的商业上重要的化合物，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，仍然有许多相对简单的例子，其中建立的合成是令人望而却步的长和/或低产量的实际应用。在本提案中，BoroPharm旨在通过专有技术的商业开发来克服这些困难，该专有技术已独家授权给BoroPharm，Inc.。具体而言，BoroPharm旨在验证铱催化的芳族硼基化/氧化作为药学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和来自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，并添加喹啉、吡嗪、嘧啶、二氮烯、咪唑、吡唑、恶唑等。2.探索新的硼技术，包括三氟硼酸盐，三硼酸盐和MIDA衍生物的形成和利用。3.扩大苯酚产品组合，使更多以前未报告的产品可用。增加秤以生产千克数量。4.扩展产品组合中芳基硼酸酯的其他转化，并生产碳-硼键转化或保留的新产品。 公共卫生相关性：新药的发明在很大程度上依赖于化学家从分子构件组装独特化合物的能力。在这方面，新的药物需要新的构件，而成本较低的药物将需要更有效和环境友好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，用于创造独特和通用的化学构建模块，其发明将有助于发现和开发新药。该项目是第一阶段赠款的延续，第一阶段赠款取得了积极成果。在此，我们将扩大化学平台的广度，范围和规模，并扩大新型和有用的药物结构单元的合成。

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.