降血压药物—昆布氨酸合成方法的研究

发布时间：2018-01-01 17:31

本文关键词：降血压药物—昆布氨酸合成方法的研究　出处：《青岛科技大学》2015年硕士论文　论文类型：学位论文

【摘要】：高血压是中老年人群中最常见的心脑血管疾病。近几年来,由于学习、工作、饮食等各方面原因,高血压也出现在了年轻人群中。海带(又名褐藻)中含有的昆布氨酸是一种具有降血压、降血脂的作用的碱性氨基酸,对预防和治疗高血压和冠心病等心血管疾病作用良好。目前,作为国家一类新药的昆布氨酸,国内外对它的研究都很少,市售的昆布氨酸也还未出现。海带中昆布氨酸的含量极少,提取的方法造价太高而且会造成很大的浪费,因此不适合工业化生产。本课题顺应绿色化学的要求,以安全低毒的“绿色”试剂碳酸二甲酯为甲基化试剂,采用化学全合成的方法制备昆布氨酸,并用响应面法分析影响螯合反应和甲基化反应的各种因素以优化二者的制备工艺,实现降血压药物-昆布氨酸清洁化生产。首先,本课题采用金属离子螯合法保护赖氨酸中的α-NH2。探索了Ca2+、Mg2+、 Cu2+、Zn2+、Ni2+五种金属离子分别与赖氨酸的螫合反应,确定了使用Cu2+对α-NH2进行保护。通过单因素实验确定影响比较大的因素为反应的温度、时间以及体系pH,并通过响应面实验确定了合成赖氨酸铜的最优工艺：反应温度为66℃,反应时间为1.5h,pH值为7.5。以最优方案合成的赖氨酸铜经过80%的乙醇溶液分离提纯,产率可达93.15%。其次,选用碳酸二甲酯做甲基化试剂制备ε-N三甲基赖氨酸。通过单因素实验和响应面实验探索反应温度、时间、催化剂、反应体系、相转移催化剂等对甲基化反应的影响,优化了合成ε-N三甲基赖氨酸的最佳工艺条件：反应温度为111℃、丙酮用量为29%、反应时间为3.5h,最高收率可达54.70%,较前人提高了9%。最后,采用732型阳离子交换树脂对解蔽后的三甲基赖氨酸的反应液分离纯化。通过单因素实验确定了吸附、解吸的最佳反应条件：吸附时间为1.0h、吸附pH=5.0、温度为25℃,初始解吸pH=10.0,洗脱剂为pH=10.8的稀氨水。并通过薄层色谱、熔点测定和红外色谱对目标产物进行了鉴定分析。
[Abstract]:Hypertension is the most common cardiovascular disease in the elderly. In recent years, due to learning, work, all aspects of diet, hypertension also appeared in the young crowd. Kelp (also known as brown algae) laminine contains a basic amino acid have lower blood pressure, blood lipid lowering effect. Good effect on prevention and treatment of hypertension and coronary heart disease and other cardiovascular diseases. At present, as a class of drugs of kelp ammonia acid, researches on it are rarely, commercially available laminine has yet to appear. Very little content of laminine in kelp, the extraction method of cost is too high and will cause a lot of waste, so it is not suitable for industrial production. This paper complies with the requirements of green chemistry, low toxicity to the "green" reagent dimethyl carbonate two as methylating reagent, preparation of laminine by total chemical synthesis, and response Analysis of the influence of various factors chelating reaction and methylation reaction surface method to optimize the preparation process of the two, the blood pressure lowering drug laminine clean production. First of all, this thesis adopts metal ion chelating protection alpha -NH2. lysine of Ca2+, Mg2+, Cu2+, Zn2+, Ni2+ five the metal ions respectively with lysine chelate reaction was determined for alpha -NH2 protection using Cu2+. Through single factor experiments, more important influencing factors as reaction temperature, time and pH system, and to determine the optimal process for the synthesis of Copper Lysine by response surface experiment: reaction temperature is 66 DEG C and the reaction time was 1.5h, pH value of Copper Lysine 7.5. to optimal solution synthesis of 80% ethanol solution after separation and purification, the yield is 93.15%. second, using two methyl carbonate prepared epsilon -N three methyl lysine as methylating reagent. Through single factor experiment and response The response surface experiments to explore the reaction temperature, time, catalyst, reaction system, the effect of phase transfer catalyst reaction of methyl, optimize the synthesis of -N three methyl lysine epsilon optimum conditions of acid ammonia: reaction temperature is 111 DEG C, amount of acetone was 29%, the reaction time is 3.5H, the highest yield of 54.70%, compared with the previous increase 9%. finally, the 732 type cation exchange resin of three methyl demasking after Lai reaction liquid acid ammonia separation and purification. The adsorption was determined by single factor experiment, the optimum reaction conditions were: adsorption time is 1.0h, the adsorption of pH=5.0, the temperature is 25 DEG C, the Initial Desorption of pH=10.0, eluent for dilute ammonia pH=10.8. And by TLC, determination of melting point and infrared spectrum analysis of the target product were identified.

【学位授予单位】：青岛科技大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R914.5

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