磷酸西他列汀中间体的合成工艺研究

发布时间：2018-04-10 14:41

本文选题：糖尿病 + 磷酸西他列汀　；参考：《浙江大学》2013年硕士论文

【摘要】：磷酸西他列汀是一种新型二肽基肽酶抑制剂(DPP-IV抑制剂),对2型糖尿病的治疗效果良好。本论文主要是针对磷酸西他列汀主链中间体进行合成研究,文献报道的磷酸西他列汀主链中间体3-氧代-4-(2,4,5-三氟苯基)丁酸乙酯的合成主要是以2,4,5-三氟苯乙酸和2,2-二甲基-1,3-二氧六环-4,6-二酮为原料。本论文设计了一条以1,2,4-三氟苯和丙二酸二乙酯为原料,具有自主知识产权的磷酸西他列汀主链中间体的合成路线。包括五步反应：氯甲基化、制成格式试剂、酯的水解、制成酰氯、格式反应,最终得到纯度为97.5%的3-氧代-4-(2,4,5-三氟苯基)丁酸乙酯。新工艺路线具有起始原料廉价易得,生产成本低,各步骤的反应条件温和,操作安全环保的优点。其中氯甲基化的收率达到85.1%,高于文献的75%。制备格式试剂使用2-甲基四氢呋喃为溶剂,降低偶合副反应的发生,提高了反应的收率,减少了溶剂使用量。另外,对文献报道的以2,4,5-三氟苯乙酸和丙二酸亚异丙酯为原料,得到3-氧代-4-(2,4,5-三氟苯基)丁酸乙酯的工艺,进行了溶剂、反应温度等方面的优化。
[Abstract]:Cetastatin phosphate is a new type of dipeptidyl peptidase inhibitor DPP-IV, which has a good therapeutic effect on type 2 diabetes.In this thesis, the main chain intermediates of cetastatin phosphate were synthesized.The synthesis of ethyl 3-oxo-4-trifluorophenyl 3-oxo-4-trifluorophenyl) -3-oxo-4-difluoro-5-trifluorophenyl) ethyl phosphate was reported in the literature. The synthesis of ethyl butyrate mainly consisted of 2o 4N 5- trifluorophenyl acetic acid and 2o 2 dimethyl-1n 3 dioxane 3 dioxane 6 dione as raw materials.In this paper, a synthetic route of cetaletine phosphate intermediate with independent intellectual property rights was designed, which was made from 1o 2o 4 trifluorobenzene and diethyl malonate.The reaction includes five steps: chloromethylation, preparation of formative reagent, hydrolysis of ester, preparation of acyl chloride, format reaction, and the final synthesis of ethyl 3-oxo-4-trifluorophenyl) butyrate with a purity of 97.5%.The new process has the advantages of cheap raw material, low production cost, mild reaction conditions and safe operation.The yield of chloromethylation was 85.1%, which was higher than that in the literature (75.1%).When 2-methyltetrahydrofuran was used as solvent, the coupling side reaction was reduced, the yield of the reaction was increased, and the amount of solvent was reduced.In addition, the process of synthesis of ethyl 3-oxo-4-trifluorophenyl trifluorophenyl trifluoroacetic acid and isopropyl malonate, which was reported in the literature, was optimized in terms of solvent, reaction temperature and so on.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：TQ463

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