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摘要：西他列汀磷酸盐 (Sitagliptin phosphate)是2006年FDA批准上市的第一个二肽基肽酶-Ⅳ（DPP-4）抑制剂，用于治疗Ⅱ型糖尿病，服用安全，耐受性好，不良反应少。本课题拟以新路线合成西他列汀中间体，并对反应条件进行优化选择。我们总共由两步反应得最终产物，反应第一步，以1-[3-(三氟甲基)-5,6,7,8-四氢-1,2,4-三唑并[4,3-a]吡嗪-7-基]-4-(2,4,5-三氟苯基)丁-2,4-二酮为原料，与L-苯甘氨酰胺和异丙醇反应得到中间产物烯胺，对温度和反应时间进行优化，最终确定反应温度为45℃、反应时间3 h，收率为97.1%。第二步，对化合物烯胺进行不对称还原，其中要对路易斯酸、反应温度、醋酸稀释倍数、加料顺序进行优化选择，最终确定路易斯酸为0.7倍当量氯化锌，反应温度为-60℃，醋酸稀释倍数为2.5，加料顺序为烯胺投入硼氢化锌溶液中得西他列汀中间体，收率为97.2%。23825
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毕业论文关键词： 西他列汀；合成；不对称还原；路易斯酸
The synthesis of asymmetric reduction of Sitagliptin
Abstract: Sitagliptin, the first DPP-IV inhibitor, is a new drug approved by the FDA in October 2006 for the treatment of type 2 diabetes which is safe, good tolerance and has fewer side effects. This topic proposed a new route to synthesize sitagliptin intermediates, and the reaction conditions were optimized selection. We have a total final product obtained from the two-step reaction, the reaction in the first step, 1 - [3 - (trifluoromethyl) -5,6,7,8 - tetrahydro-1 ,2,4 - triazolo [4,3-a] pyrazin-7 - yl] -4 - (2,4,5 - trifluoro-phenyl) butan-2, 4 - dione as starting material, L-phenylglycine amide is reacted with isopropanol to give the intermediate enamine, the reaction temperature and time to optimize,and Ultimately the reaction temperature is 45 ℃, reaction time is 3 h, the yield was 97.1%. The second step, Enamine compound is done by asymmric reduction, in which the Lewis acid, reaction temperature, acid dilution, the addition order was to optimize the selection. We ultimately determine 0.7 equivalents of a Lewis acid chloride, the reaction temperature is -60 ℃, dilution of acetic acid is 2.5, the order of addition is the enamine into the solution of zinc borohydride. Sitagliptin intermediates is obtained,and the yield was 97.2%.
Key Words: sitagliptin; synthesize; asymmric reduction; the Lewis acid
目录
1 绪论 1
1.1 本课题研究背景概述 1
1.1.1 糖尿病药物的国内外概况 1
1.1.2 西他列汀 3
1.2 课题研究现状 4
1.2.1 西他列汀的合成路线 5
1.2.2 本课题的研究目的和意义 7
2 西他列汀关键中间体的合成研究 9
2.1 合成路线设计思路 9
2.1.1 拟采用的总合成路线 9
2.1.2 拟定的合成步骤 10
2.2 使用的材料试剂、仪器设备 10
2.2.1 主要化学原料与试剂 10
2.2.2 仪器设备 11
2.3 化合物烯胺的制备 12
2.3.1 反应方程式 12
2.3.2 实验步骤 12
2.3.3 实验注意事项 12
2.4 烯胺的不对称还原 12
2.4.1 反应方程式 12
2.4.2 实验步骤 12
2.4.3 实验注意事项 13
2.4.4 谱图数据 13
3 实验结果与讨论 15
3.1 合成化合物烯胺条件的优化 15
3.1.1 不同温度对反应产率的影响 15
3.1.2 反应时间对反应产率的影响 16
3.1.3 实验小结 16