ARYLOXYPROPANOLAMINES FROM 3-AZETIDINOLS AND PHENOLS

3-氮杂二醇在处理时易发生烷基化开环 在高温下与酚类化合物一起生产 芳氧丙醇胺(用于治疗高血压、心绞痛 心绞痛和心律失常)以极好的收益。多数 阻碍这种方法商业化应用的困难一直存在 克服困难。氮杂二酚中起作用的电子因素有 已被实验阐明，最近又被分子阐明 模特儿。尽管如此，苯酚的电子因素 进行了调查，在编写本报告时仍然存在一些困难。 氮杂二酚。拟议研究的具体目的是：1) 提高1-烷基-3-氮杂二醇产率--阻碍 该方法的商业应用，2)获得了更深层次的 对烷基化环开环机理的认识 会产生芳氧基丙醇胺，3)了解 作用于β受体的因素，以及4)研究烷基化 腺嘌呤、奎宁和胞嘧啶由氮杂环丁烷和氮杂环丁醇-- 这些核苷酸的烷基化可能是防止细胞 并可能在治疗癌症和一些 病毒感染。1)准备过程中的主要困难 氮杂二醇似乎与环氧氯丙烷的开环有关。 胺。在胺中起作用的空间和电子因素 目前正在调查环氧氯丙烷的开环情况 高效液相色谱动力学研究。1-氨基-3-氯-2-酮的环合成 丙醇到氮杂环丁烷的研究也将进行，以便进一步 优化产量。2)苯酚对氮杂二酚的开环反应 通过动力学研究和高效液相色谱进行研究。半经验 这方面的计算已接近完成，而且从头算起。 已开始计算。3)分子建模、核磁共振和 将使用FT-IR研究来更全面地阐明 芳氧基丙醇胺类化合物的构象偏好 化合物与β受体结合的机制。4) 虽然不是我们最初研究目标的一部分，但 通过氮杂环丁烷和氮杂二醇烷基化核苷酸将是 调查过了。两名学生和一名技术人员将参与其中 研究。他们将接受高级化学原理方面的培训， 实验室操作、光谱分析和应用 动力学和动力学的分析和解释的色层分析方法 量子力学计算，并获得有价值的技术 沟通技巧。

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.