ARYLOXYPROPANOLAMINES FROM 3-AZETIDINOLS AND PHENOLS

由 3-氮杂环丁醇和苯酚制备芳氧基丙醇胺

• 批准号: 6338809
• 负责人: ROBERT H HIGGINS
• 金额: $ 3.95万
• 依托单位: FAYETTEVILLE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6338809
• 关键词: alkylation; angina pectoris; antiarrhythmic agent; antihypertensive agents; beta antiadrenergic agent; cardiovascular agents; chemical models; chemical structure function; chemical substitution; computer simulation; conformation; drug design /synthesis /production; high performance liquid chromatography; hypertension; infrared spectrometry; nitrogenous heterocyclic compound; nuclear magnetic resonance spectroscopy; nucleotides; phenols; propanols; receptor binding

3-Azetidinols undergo facile alkylative ring opening when treated with phenols at elevated temperatures to produce aryloxypropanolamines (use in the treatment of hypertension, angina pectoris, and cardiac arrhythmia) in excellent yield. Most difficulties preventing commercial utilization of this method been overcome. The electronic factors operative in the azetidinols have been elucidated by experiment and more recently by molecular modeling. Nevertheless, the phenol's electronic factors have been investigated, and some difficulties remain in the preparation of the azetidinols. The specific aims of the proposed research are to: 1) increase the yields of 1-alky1-3-azetidinols--the hurdle preventing commercial utilization of this method, 2) gain a deeper understanding of the mechanism of the alkylative ring opening which produces the aryloxypropanolamines, 3) understand the factors operative at the beta-receptor, and 4) investigate alkylation of adenine, quinine, and cytosine by azetidines and azetidinols-- alkylation of these nucleotides may be a means of preventing cell division and could have consequences in treating cancer and some viral infections. 1) The primary difficulty in preparation of azetidinols seems to involve ring opening of epichlorohydrin by amines. Steric and electronic factors operative in the amine in the ring opening of epichlorohydrin are currently being investigated by HPLC kinetic studies. Ring closure of 1-amino-3-chloro-2- propanols to azetidines will also be investigated in order to further optimize yields. 2) Ring opening of azetidinols by phenols will be investigated by kinetic studies followed by HPLC. Semi-empirical calculations in this respect are nearing completion, and ab initio calculations have been initiated. 3) Molecular modeling, NMR, and FT-IR investigations will be used to more fully elucidate conformational preferences in aryloxypropanolamines and the mechanism by which compounds bind at the beta-receptor. 4) While not part of our original research goals, the possibility of alkylating nucleotides by means of azetidines and azetidinols will be investigated. Two students and a technician will be involved in this research. They will gain training in advanced chemical principles, laboratory operations, application of spectroscopic and chromatographic methods of analysis, interpretation of kinetic and quantum mechanics calculations, and gain valuable technical communications skills.

3-氮杂环丁烷醇在处理时经历容易的烷基化开环 在高温下与苯酚反应， 芳氧基丙醇胺（用于治疗高血压、心绞痛 心绞痛和心律失常）的良好产量。 最 阻止该方法商业化的困难 克服 在氮杂环丁烷醇中起作用的电子因素有 已经通过实验和最近的分子生物学方法阐明， 建模 然而，苯酚的电子因素已经被 调查，并在准备工作中仍然存在一些困难， 氮杂环丁烷醇。拟议研究的具体目标是：1） 提高1-烷基-3-氮杂环丁烷醇的产率--克服障碍 这种方法的商业利用，2）获得更深的 对烷基化开环机理的认识 它产生芳氧基丙醇胺，3）理解 在β-受体上起作用的因素，以及4）研究烷基化 腺嘌呤，奎宁和胞嘧啶被氮杂环丁烷和氮杂环丁烷醇-- 这些核苷酸的烷基化可以是防止细胞凋亡的一种手段。 分裂，并可能对治疗癌症和一些 病毒感染 1)准备的主要困难是 氮杂环丁烷醇似乎涉及环氧氯丙烷的开环， 胺。 空间和电子因素在胺中起作用， 环氧氯丙烷的开环目前正在研究， HPLC动力学研究。1-氨基-3-氯-2 还将研究丙醇到氮杂环丁烷的反应，以进一步 优化产量。2)通过酚类进行氮杂环丁烷醇的开环将是 通过动力学研究随后通过HPLC进行研究。 半经验 这方面的计算已接近完成，从头算 计算已经开始。 3)分子建模，核磁共振， FT-IR研究将用于更全面地阐明 芳氧基丙醇胺的构象偏好和 化合物与β-受体结合的机制。 四、 虽然不是我们最初的研究目标的一部分， 通过氮杂环丁烷和氮杂环丁烷醇使核苷酸烷基化， 研究了 两名学生和一名技术人员将参与其中 research.他们将接受先进化学原理的培训， 实验室操作，光谱和 色谱分析方法、动力学解释和 量子力学计算，并获得宝贵的技术 沟通技巧。