盐酸吉西他滨的合成研究 摘要：盐酸吉西他滨，化学名称为4-氨基-1-(3,3-二氟-4-羟基-5-羟甲基四氢呋喃-2-基)-1H-嘧啶-2-酮盐酸盐，是一种核苷类抗代谢抗肿瘤药物，适用于非小细胞肺癌、胰腺癌、膀胱癌、乳腺癌及其他实体瘤的治疗，但目前国内还不能大规模生产。本课题的研究目的是摸索出一条今后能用于工业化大生产的合成路线，因此要求原料来源充足，反应条件温和，合成步骤少，成本低，环境污染少等。本课题是以2-脱氧-2,2-二氟-D-呋喃核糖-3,5-二苯甲酸酯-1-甲磺酸酯和乙酰胞嘧啶为原料，通过缩合反应、氨甲醇水解反应及成盐反应合成盐酸吉西他滨。通过工艺条件对照实验，本文优化了这几步反应的实验过程，增强了各步反应的稳定性和重复性，提高了产物收率和纯度，降低了实验成本，为今后工业化生产摸索出了一条相对可行的工艺路线。
关键词：盐酸吉西他滨；4-氨基-1-(3,3-二氟-4-羟基-5-羟甲基四氢呋喃-2-基)-1H-嘧啶-2-酮盐酸盐；2-脱氧-2,2-二氟-D-呋喃核糖-3,5-二苯甲酸酯-1-甲磺酸酯；合成
The Research on Synthesis of Gemcitabine Hydrochloride
Abstract: Gemcitabine hydrochloride, chemical name 4-Amino-1-[3,3-difluoro-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl]-1H-pyrimidin-2-one hydrochloride, is a nucleoside antimetabolite antineoplastic agents, which is used for non-small cell lung cancer, pancreatic cancer, bladder cancer, breast cancer and other solid tumors. At present, it can’t be produced on a large scale in our country. The topic is aimed at finding a synthetic process which can be applied for major industrial production in the future, with abundant raw materials, mild reaction condition, few synthetic steps, low cost and less environmental pollution. Gemcitabine hydrochloride is synthesized by condensation reaction and hydrolysis reaction steps based on 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoate-1-methanesulfonic acid ester and acetylcytosine as the starting material. Through the contrast experiment, we optimize experiment condition, enhance stability and reproducibility of each reaction, improve the productivity and purity of product, reduce production cost and determine a relatively feasible process which can be applied for major industrial production in the future.
Key Words: Gemcitabine hydrochloride; 4-Amino-1-[3,3-difluoro-4-hydroxy-5-(hydroxym-ethyl) tetrahydrofuran-2-yl]-1H-pyrimidin-2-one hydrochloride; 2-Deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoate-1-methanesulfonic acid ester; Synthesis
目 录
1 前言1
1.1 盐酸吉西他滨的简介 1
1.2 盐酸吉西他滨的药理学研究 1
1.3 盐酸吉西他滨的临床应用 2
1.4 盐酸吉西他滨的市场2
2 文献综述与方案论证4
2.1 文献综述 4
2.2 方案论证7
2.3 确定实验路线7
3 实验部分 9
3.1 试剂及仪器 9
3.1.1 试剂 9
3.1.2 仪器10
3.2 实验方法 10
3.2.1 2',2'-二氟-2'-脱氧胞嘧啶核苷-3',5'-二苯甲酸酯的合成10
3.2.2吉西他滨的合成 13
3.2.3盐酸吉西他滨的合成 14
3.2.4盐酸吉西他滨的精制15
4 实验讨论18
4.1 2',2'-二氟-2'-脱氧胞嘧啶核苷-3',5'-二苯甲酸酯的合成18
4.1.1 缩合反应 18
4.2 吉西他滨的合成 21
4.2.1水解反应21
4.3 盐酸吉西他滨的合成 23
4.3.1成盐反应23
5 结论25
致谢26
参考文献27
附录28，3568
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