一种磺达肝癸钠中间体的合成方法

发布时间：2018-03-03 16:54

本文选题：磺达肝癸钠　切入点：羟基选择性保护　出处：《苏州大学》2014年硕士论文　论文类型：学位论文

【摘要】：本论文设计了一条磺达肝癸钠重要中间体——单元环A、C、E的合成新路线。磺达肝癸钠是一种选择性抑制因子Xa的抗凝药物，它通过非共价键与抗凝血酶的活化部位特异性结合，加速Xa复合物形成，导致Xa的快速抑制，进而减少凝血酶产生和纤维蛋白形成。磺达肝癸钠于2001年12月13日获得EMEA批准，2002年初获美国FDA批准上市。目前已在法国、英国、德国、中国和美国等国上市，临床上用于治疗和预防深部静脉血栓栓塞。本文设计的新路线以葡萄糖为起始原料，经过乙酰化、1-位对甲苯硫酚取代、去乙酰化、4,6-苯甲缩醛保护、3-位选择性苯甲酰基保护、2-位羟基氧化、选择性还原，完成葡萄糖构型到甘露糖结构的转换，再将羟基转化为叠氮，合成出了单元环A、C、E可以共用的中间体，该中间体经过2至4步的转化合成出单元环A、C、E环,总共17步反应。本文使用葡萄糖合成出了Beta甘露糖硫苷，进而引入叠氮基团生成了关键中间体的方法，，既大大减少了合成此3个单元环的步骤，也避免了像其他文献一样以较贵的甘露糖或氨基葡萄糖为初始原料。
[Abstract]:In this paper, a new route was designed for the synthesis of the important intermediate of fondaparinic sodium, the unit ring Agnocaine E, which is an anticoagulant of selective inhibitory factor Xa, which binds specifically to the activated site of antithrombin by non-covalent bond. Accelerates the formation of Xa complexes, resulting in rapid inhibition of Xa, which in turn reduces thrombin production and fibrin formation. The sodium fondaguein was approved by EMEA in December 13th 2001 and was approved by FDA of the United States in early 2002. It has been approved in France, Britain, Germany, etc. Listed in China and the United States, they are used clinically to treat and prevent deep venous thromboembolism. The new route was designed using glucose as the starting material, substituted by acetylated 1-position p-methylthiophenol, and deacetylated by 4- (4-benzylidene) acetal to protect the 3-position selective benzoyl group to protect 2-position hydroxyl group oxidation and selective reduction. The conversion of glucose configuration to mannose structure was completed, and the hydroxyl group was converted to azide. The intermediate of unit ring Agno Con E was synthesized by 2 to 4 steps of conversion. In this paper, Beta mannose glucosinolate was synthesized using glucose, and the key intermediate was formed by introducing azide group, which greatly reduced the steps of synthesizing these three unit rings. It also avoids starting with more expensive mannose or glucosamine, as in other literature.
【学位授予单位】：苏州大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

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