Piperidines via C-H Activation: An Efficient Route to a Ubiquitous Pharmacophore

通过 C-H 激活的哌啶：获得普遍存在的药效基团的有效途径

• 批准号: 8641060
• 负责人: Joseph John Topczewski
• 金额: $ 5.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8641060
• 关键词: Alzheimer' s Disease; Astemizole; Benchmarking; Benztropine; Catalysis; Chemistry; Communities; Complex; Electrons; Emerging Technologies; FDA approved; Fentanyl; Frequencies; Future; Goals; Haloperidol; Hydrogen Bonding; Hypersensitivity; Literature; Methodology; Methods; Metric; N-methylpiperidine; Nitrogen; Pain; Pain management; Palladium; Parkinson Disease; Petroleum; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Prevention; Production; Property; Reaction; Research; Resources; Route; Schizophrenia; Speed; Staging; Technology; Work; chemical reaction; cost; donepezil; novel; pharmacophore; piperidine; public health relevance; standard care; tool; wasting

DESCRIPTION (provided by applicant): Pharmaceutical agents are a standard treatment for a variety of ailments. The low cost, ease of administration, and efficacy make drugs a near ideal form of prevention or treatment. Regretfully, most of these medications are derived from limited global supplies of petroleum. For this reason, more sustainable methods of manufacturing pharmaceuticals are needed. This proposal aims to develop a novel chemical reaction to synthesize substituted piperidine rings via the activation of otherwise inert C-H bonds. Piperidines are the focus of this work because of their frequency in FDA approved drugs including donepezil (Alzheimer's), benzatropine (Parkinson's), fentanyl (pain), and astemizole (allergies). Because they are common to nearly all organic molecules, the direct functionalization of C-H bonds is a rapid and efficient way to obtain the complex molecules needed to make pharmaceuticals. To activate C-H bonds, this proposal aims to utilize Pd catalysis via a PdII/PdIV catalytic cycle. This proposal avoids the use of superfluously added directing groups by taking direct advantage of the piperidine nitrogen's lone pair electrons. Completion of the proposed research should facilitate a more economical and sustainable method to synthesize piperidine containing pharmaceuticals. This proposal also aims to quantify the efficiency gains of this and other work using green manufacturing metrics. This quantification should provide a benchmark in progress towards making pharmaceutical synthesis sustainable.

描述（由申请人提供）：药剂是多种疾病的标准治疗方法。低成本、易于给药和功效使药物成为近乎理想的预防或治疗形式。遗憾的是，这些药物大多来自全球有限的石油供应。因此，需要更可持续的药品制造方法。该提案旨在开发一种新颖的化学反应，通过激活原本惰性的 C-H 键来合成取代的哌啶环。哌啶是这项工作的重点，因为它们经常出现在 FDA 批准的药物中，包括多奈哌齐（阿尔茨海默病）、苯扎托品（帕金森病）、芬太尼（疼痛）和阿司咪唑（过敏）。由于它们是几乎所有有机分子所共有的，因此 C-H 键的直接官能化是获得制造药物所需的复杂分子的快速有效的方法。为了激活 C-H 键，该提案旨在通过 PdII/PdIV 催化循环利用 Pd 催化作用。该提议通过直接利用哌啶氮的孤对电子来避免使用多余添加的导向基团。完成拟议的研究应有助于更经济和可持续的方法来合成含哌啶的药物。该提案还旨在使用绿色制造指标来量化这项工作和其他工作的效率增益。这种量化应该为药物合成的可持续发展提供一个基准。