Direct Synthesis of 1_2_Benzisoxazoles Via Palladium Catalysis

钯催化直接合成 1_2_苯并异恶唑

• 批准号: 8975546
• 负责人: Jeffrey S Bandar
• 金额: $ 5.24万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-04 至 2017-09-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8975546
• 关键词: Address; Alzheimer' s Disease; Biological; Catalysis; Chemicals; Complex; Coupling; Cyclization; Development; Employment; Epilepsy; FDA approved; Foundations; Goals; Health; Isoxazoles; Laboratories; Lead; Left; Ligands; Malignant Neoplasms; Medical; Medicine; Methodology; Methods; Modern Medicine; Nature; Obesity; Palladium; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phosphines; Preparation; Process; Reaction; Recording of previous events; Route; Schizophrenia; Structure; Technology; Work; antimicrobial drug; aryl halide; base; cancer type; chemical synthesis; design; nitrone; obesity treatment; rapid technique; small molecule; trend; ylide

DESCRIPTION (provided by applicant): The 1,2-benzisoxazole heterocycle represents an important chemical motif in modern medicine. Several FDA approved drugs featuring this component, such as Zonisamide and Paliperidone, are widely administered to treat epilepsy and schizophrenia. Other small molecules that contain a 1,2-benzisoxazole are under study for the treatment of Alzheimer's disease, obesity and certain types of cancer. Because these molecules are not found in nature, chemical synthesis is the only route to accessing 1,2-benzisoxazole derivatives. Current methodologies for their laboratory synthesis are chemically and economically inefficient. In order to access new 1,2-benzisoxazole medicines and to optimize derivatives currently under study, a new synthetic method is highly desired. To address this need, a palladium-catalyzed cascade merger of aryl halides and linear nitrones is proposed. This method provides a direct and selective route to 1,2-benzisoxazoles from readily available chemicals. Catalysis allows chemists to prepare complex chemicals under mild reaction conditions; thus, the proposed method will enable the synthesis of 1,2-benzisoxazole derivatives currently inaccessible. This proposal provides strategies inspired by modern technology aided by the rich history of nitrones and palladium catalysis to open new doors for medicinal chemists and ultimately modern medicine.

描述（由申请人提供）：1,2-苯唑恶唑杂环代表现代医学中的重要化学图案。多种FDA批准的具有该成分的药物，例如Zonisamide和Paliperidone，被广泛用于治疗癫痫和精神分裂症。其他包含1,2-苯并唑的小分子正在研究阿尔茨海默氏病，肥胖和某些类型的癌症。由于这些分子在自然界中没有发现，因此化学合成是访问1,2-苯唑恶唑衍生物的唯一途径。其实验室合成的当前方法在化学和经济上效率低下。为了获取新的1,2-苯唑恶唑药物并优化当前正在研究的衍生物，高度需要一种新的合成方法。为了满足这一需求，提出了钯催化的芳基卤化物和线性氮的级联合并。该方法从随时可用的化学物质中提供了直接和选择性的途径到1,2-苯唑恶唑。催化使化学家能够在轻度反应条件下制备复杂的化学物质。因此，所提出的方法将使当前无法访问的1,2-苯唑恶唑衍生物合成。该提案提供了受现代技术启发的策略，在氮和钯催化的悠久历史的帮助下，为药物化学家和最终现代医学打开了新的大门。