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1、 西南交通大学本科毕业设计(论文) 第 I 页西 南 交 通 大 学本科毕业设计（论文）SeO2/t-BuOOH 复合氧化剂对维生素 D31 位 羟基化的工艺研究年 级：2004 级学 号：姓 名：专 业：生物工程指导老师： 2008 年 6 月 西南交通大学本科毕业设计 (论文) 第 II 页摘 要维生素 D 为固醇类衍生物，是一种重要的脂溶性维生素，在体内以其活性代谢物 1,25-二羟基维生素 D 的形式发挥作用，可以提高人体的对钙磷的吸收，促进骨生长和骨骼钙化。维生素 D 主要有维生素 D2 和 D3，以维生素 D3 为主。近年来研究发现 1,25-二羟基维生素 D3 对治疗多种疾病如佝
2、偻病、肾脏骨营养不良、骨质疏松、非白血性白血病、乳腺癌、前列腺癌、艾滋病等有着很高的潜力 。1-羟基维生素 D3 又称阿法骨化醇，是一种重要的维生素 D3 活性代谢物，可不经肾脏由肠道迅速吸收进入血液，经肝脏微粒体 25-羟基化酶作用使侧链 25 位羟基化后生成具有活性的 1,25-二羟基维生素 D3 分布于肠道及骨等靶组织内与受体结合而表现出促进肠道吸收钙的作用、骨盐溶解作用以及骨形成作用等一系列生理活性。国内外报道的阿法骨化醇的合成方法，一般以维生素 D3 为原料，经过酯化、环化、氧化、开环、水解五步最终生成阿法骨化醇。本次毕业设计实验包括三步反应，第一步由维生素 D3 和对甲苯磺酰氯生成
3、维生素 D3 对甲苯磺酸酯；第二步由上步产物与 NaHCO3、无水甲醇生成 3,5-环合维生素D3;第三步用 SeO2/t-BuOOH 做氧化剂，最终合成 1-羟基 3,5-环合维生素 D3，最主要的反应就是第三步氧化反应，这步反应的收率很低，所以本次设计的主要目的就是提高反应的收率。在生产实践和科学实验中，为了寻求最优化生产和实验条件，都需要做许多实验。如果影响实验的因素较多，这时就需要通过正交设计的方法，科学的安排实验，减少实验次数，获得有效的结果。本次设计为了找出氧化反应的最优反应条件，首先做了几组实验，结果显示影响氧化反应的主要因素是反应时间、SeO 2：TBHP 的摩尔比以及反应温度
4、，并由此确定正交设计的因素水平表为三因素三水平表；接着根据因素水平表选择出合适的正交表 L9(34)，最后 进行了 9 组正交试验实验再经过正交分析确定了最佳的实验条件。提高了产物的收率。实验过程中需要用到一些试剂，在进行实验前需要自己制备，如无水甲醇、过氧化叔丁醇（TBHP ） 、无水二氯甲烷等。关键词： 维生素 D3；SeO 2/t-BuOOH；1-羟基维生素 D3；正交设计 西南交通大学本科毕业设计(论文) 第 III 页AbstractVitamin D for the steroid derivatives, is an important fat-soluble vitamin,
5、to play a role in the form of its active metabolition 1,25-dihydroxy vitamin D in body,can improve the bodys absorption of calcium and phosphorus,and promote bone growth and bone calcification.Vitamin D usually contains vitamin D2 and D3, mainly to vitamin D3.In recent years, the study found that 1,
6、25-dihydroxy vitamin D3 has a very high potential in treatment of various diseases such as rickets, malnutrition of kidney, osteoporosis, leukemia, breast cancer, prostate cancer and AIDS. 1-hydroxy vitamin D3 also known as alfacalcidol,is an important active metabolite of vitamin D3, can quickly ab
7、sorbed by the intestine into the bloodstream not through the kidneys, then hydroxyed 25 side chain of activity by the liver microsomal 25-hydroxy enzyme to formate the 1,25-dihydroxyvitamin D3, which distributed in the intestinal tract, bone and other target tissues, binding with the target receptor
8、 and demonstrated to promote calcium absorption of intestine, bone salt dissolution and bone formation as a series of physical activity. The domestic and foreign reports show that the main synthetic method of alfacalcidol , generally takes vitamin D3 as a raw material, after the esterification, the
9、cyclization, the oxidation, the split-ring and the hydrolisis five steps, finally produces the alfacalcidol.The experiment of this graduation project includes three-step reactions, firstly, produces Vitamin D3 para-toluenesulfonic ester by Vitamin D3 and -toluene sulfonyl chloride; the second step g
10、ains 3,5 cyclovitamin D3 by the product of last step, the absolute methanol and NaHCO3; the third step makes SeO2/t-BuOOH as the oxidant to synthesize 1-hydroxyl-3,5 cyclovitamin D3.The main reaction is the third step of reaction, the yield of this step is very low, so the main purpose of this desig
11、n is to raise the yield of reaction.In the production practice and scientific experiments, in order to seek the optimal production and experimental conditions, we need to do many experiments. If the impact of the factors is more, we need to through the orthogonal design methods and scientific experi
12、mental arrangement to reduce the number of experiments, access to effective results. To identify the optimal conditions, first of all, do several group of experiments,the result demonstrates that the major factors influencing oxidizing reaction is the reaction time, the mole ratio of SeO2 and TBHP,a
13、s well as the reaction temperature, and thus determines the level of orthogonal factors to three factors and three levels table, then chooses the appropriate level of the orthogonal L9 (34) according to the factors table,finally carried on 西南交通大学本科毕业设计(论文) 第 IV 页nine group of orthogonal experiments.
14、In the end, to determine the best experimental conditions after the orthogonal analysis.Improve the yield of the product finally.In the course of experiments, some reagents is needed, we have to preparate them before the experiment , such as anhydrous methanol, tert-Butyl hydroperoxide (TBHP), and anhydrous dichloromethane.Key words :Vitamin D3 ; SeO2/t-BuOOH ;1-hydroxy vitamin D3;The orthogonal design 西南交通大学本科毕业设计(论文) 第 V 页目 录第 1 章 绪论 .11.1 维生素 .21.1.1 维生素概述 .21.1.2 维生素的分类 .
