DDP-Ⅳ抑制剂维格列汀的合成工艺研究

发布时间：2018-03-09 01:20

本文选题：抗糖尿病药物　切入点：二肽基肽酶-IV　出处：《天津理工大学》2014年硕士论文　论文类型：学位论文

【摘要】：近年来全球Ⅱ型糖尿病患者人数呈逐年上升的趋势，已成为同心脑血管疾病和癌症一样严重危害人类健康的疾病。DPP-4抑制剂是最具前景的抗Ⅱ型糖尿病药物。DPP-4抑制剂维格列汀作为诺华公司研发的抗糖尿病新型口服药，有其巨大的市场价值和科研意义。论文在总结和研究前人所做相关工作的基础上，，为适合工业化大生产的安全性和可操作性，对维格列汀的合成工艺进行了优化。本路线以廉价的L-脯氨酸为起始原料，无需催化剂，与活泼的氯乙酰氯发生酰胺化反应，生成(S)-1-(2-氯乙酰基)-2-吡咯烷甲酸，此化合物中的甲酸基团采用氨基磺酸作为脱水剂，脲素为氨源，使用分段保温一步法成氰，得到中间体（S）-1-（2-氯乙酰基）-2-腈基吡咯烷；合成中间体3-氨基-1-金刚烷醇时，采用3-氨基-1-金刚烷胺为原料，硝酸钠与硫酸作为硝化剂，硼酸为催化剂进行硝化反应，然后用氢氧化钾亲核取代得到3-氨基-1-金刚烷醇；再将(S)-1-(2-氯乙酰基)-2-吡咯烷甲酸和3-氨基-1-金刚烷醇反应，以碘化钾为催化剂，无水碳酸钾为缚酸剂得到维格列汀。本实验还合成了部分维格列汀杂质。所得目标化合物均使用熔点测定，IR，1HNMR，MS，元素分析等方法确证其结构，并对维格列汀做了粉末衍射确认晶型。此工艺路线提高了产品总收率，达到47.7%。
[Abstract]:In recent years, the number of type 2 diabetes patients in the world is increasing year by year. The DPP-4 inhibitor is the most promising antidiabetic drug. DPP-4 inhibitor is a new oral antidiabetic drug developed by Novartis. Has its huge market value and scientific research significance. On the basis of summarizing and studying the related work done by predecessors, in order to adapt to the safety and maneuverability of large-scale industrial production, the synthesis process of vieglentin was optimized. This route starts with cheap L-proline as the starting material. No catalyst was needed to amidation the active chloroacetyl chloride to form a formic acid, which contained amino sulfonic acid as dehydrating agent and urea as ammonia source to form cyanide by one-step thermal insulation, and the formic group in the compound was formed by one-step method. The amino sulfonic acid was used as dehydrating agent, and urea was used as ammonia source, and the amidation reaction was carried out with active chloroacetyl chloride. The intermediate was synthesized by using 3-amino-1-amantadine as raw material, sodium nitrate and sulfuric acid as nitration agent, and boric acid as catalyst for nitration, and the intermediate was synthesized by using 3-amino-1-adamantanol as raw material, sodium nitrate and sulfuric acid as nitration agent, and boric acid as catalyst for the nitration of pyrrolidine. Then, 3-amino-1-adamantanol was synthesized by nucleophilic substitution of potassium hydroxide, and then reacted with 3-amino-1-adamantanol, and then reacted with 3-amino-1-adamantanol, and was catalyzed by potassium iodide. In this experiment, some impurity of Veglentin was synthesized. The target compounds were characterized by melting point determination, elemental analysis and elemental analysis. The crystal form was confirmed by powder diffraction, and the total yield of the product was increased to 47.7%.
【学位授予单位】：天津理工大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

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