抗糖尿病药物中间体5-氯吡嗪-2-羧酸及其衍生物的合成研究

发布时间：2018-01-21 08:19

本文关键词： 糖尿病药物中间体 5-氯吡嗪-2-羧酸葡萄糖激酶激动剂合成　出处：《重庆医科大学》2014年硕士论文　论文类型：学位论文

【摘要】：在近年来研制的新型抗糖尿病药物中，许多都含有5-氯吡嗪-2-羧酸及其衍生物的结构，例如：葡萄糖激酶激动剂（glucokinase activators，GKAs）、黑色素浓集激素受体拮抗剂（melanin-concentrating hormonereceptor antagonist，MCH）、BACE2抑制剂（Beta-site APP cleavingenzyme2inhibitors）等。为此，以5-氯吡嗪-2-羧酸及其衍生物作为这些新型抗糖尿病药物的重要中间体，得到了越来越多的关注，对5-氯吡嗪-2-羧酸及其衍生物进行深入研究，将具有一定的理论意义和实用价值。本着原料价廉易得、操作简便可行、工艺安全可靠以及易于工业化生产的原则，结合相关文献，本文采用逆合成分析法，确定了以2-乙酰基呋喃作为起始原料合成5-氯吡嗪-2-羧酸的路线。并且在此基础上合成得到了六个相关衍生物，其主要研究与结果如下： 1.建立了一条以2-乙酰基呋喃为起始原料，经二氧化硒氧化、与甘氨酰胺环合、三氯氧磷氯化、高锰酸钾氧化等四步反应合成5-氯吡嗪-2-羧酸的合成路线。该路线具有原料价廉易得、反应条件温和、操作简便等特点。 2.在环合反应中，采用正交实验法得到最优合成条件，使得该步反应收率较文献（27%）提高了23.1%。 3.在5-氯吡嗪-2-羧酸的合成中，使用盐酸酸化乙酸乙酯提取法代使用替价格昂贵的强酸性阳离子交换柱，降低了制备成本。 4.在合成得到5-氯吡嗪-2-羧酸的基础上，合成得到了六个5-氯吡嗪-2-羧酸的衍生物。综上所述，，本文以2-乙酰基呋喃为起始原料，经二氧化硒氧化、与甘氨酰胺环合、三氯氧磷氯化、高锰酸钾氧化等四步反应，建立了一条制备5-氯吡嗪-2-羧酸的合成路线。该路线具有原料价廉易得、操作简便可行、工艺安全可靠等优点。在此基础上合成得到了六个相关衍生物，为新型抗糖尿病药物的研究奠定了一定基础，具有一定的理论意义与实用价值。
[Abstract]:In recent years, many new antidiabetic drugs contain the structure of 5-chloropyrazine-2-carboxylic acid and its derivatives. For example: glucokinase activator GKAs. a glucokinase agonist. Melanin-concentrating hormonereceptor antagonist melanin-concenting hormonereceptor antagonist (MCHs). Beta-site APP cleavingenzyme 2 inhibitors et al. With 5-chloropyrazine-2-carboxylic acid and its derivatives as the important intermediates of these new anti-diabetic drugs, more and more attention has been paid to the study of 5-chloropyrazine-2-carboxylic acid and its derivatives. It will have certain theoretical significance and practical value. Based on the principle of cheap and easy to obtain raw materials, simple and feasible operation, safe and reliable process and easy to industrial production, combined with relevant literature, this paper adopts inverse synthetic analysis method. A route for the synthesis of 5-chloropyrazine-2-carboxylic acid from 2-acetylfuran was established. On this basis, six related derivatives were synthesized. The main research and results are as follows: 1. A starting material of 2-acetylfuran was established, which was oxidized by selenium dioxide, cyclized with glycosaminamide, and chlorinated with phosphorus oxychloride. The synthesis of 5-chloropyrazine-2-carboxylic acid from potassium permanganate oxidation is characterized by its low cost, mild reaction conditions and simple operation. 2. In the cyclization reaction, the optimum synthesis conditions were obtained by orthogonal experiment, and the yield of the step reaction was 23.1g higher than that of the reference (27). 3. In the synthesis of 5-chloropyrazine-2-carboxylic acid, the preparation cost was reduced by the substitution of the expensive strong acid cation exchange column with the extraction of ethyl acetate with acidified hydrochloric acid. 4. Based on the synthesis of 5-chloropyrazine-2-carboxylic acid, six derivatives of 5-chloropyrazine-2-carboxylic acid were synthesized. To sum up, in this paper, 2-acetylfuran was used as the starting material, which was oxidized by selenium dioxide, cyclized with glyamine, chlorinated with phosphorus oxychloride, and oxidized by potassium permanganate. A synthetic route for the preparation of 5-chloropyrazine-2-carboxylic acid was established. This route has the advantages of cheap raw material, simple and feasible operation, safe and reliable process, etc. On this basis, six related derivatives have been synthesized. It lays a foundation for the study of new anti-diabetic drugs and has certain theoretical significance and practical value.
【学位授予单位】：重庆医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914

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