【作者】 李娴洁；

【导师】 徐正；

【作者基本信息】 四川大学 ， 药物化学， 2005， 硕士

【摘要】 米格列奈（MGLN）是2004年首次于日本上市的一种新型治疗Ⅱ型糖尿病的口服降糖药。该药物具有快速促胰岛素分泌的功能,每次餐前服用可迅速降低患者的餐后高血糖,不会引起低血糖反应和β-细胞衰竭,已成为早期及轻度糖尿病患者的一线治疗药物。目前该药国内尚无生产,具有很好的开发价值。 本课题主要对米格列奈的合成进行研究,旨在为国内引进此新药,并为研发该药物的Me-too药物奠定一定的合成基础。由于MGLN的多数合成路线均受到专利保护,故我们首选一条非专利保护路线,以丁二酸二乙酯为原料,在构建目标化合物结构骨架后,经过胺的酰化、催化氢化、光学活性体手性拆分等,合成并得到了目标化合物,其结构经¹H-NMR和¹³C-NMR确证,比旋光值同于文献。此外,我们还考察了另外两条路线的可行性,其中一条除起始原料的手性拆分受专利保护外,其他无特殊要求,现已打通路线;另一条路线因关键步骤的反应产物成分比较复杂且难以纯化,尚在继续研究之中。 MGLN合成中的关键中间体——顺式全氢异吲哚在国内亦元厂家生产。我们选择了两条非专利保护路线,均以邻苯二甲酰亚胺为原料,分别经苄基保护后还原羰基再还原苯环的途径、以及先还原苯环再还原羰基的途径得到该中间体,并进行了工艺研究。其中第二条路线中用四氢铝锂还原六氢邻苯二甲酰亚胺中羰基的方法未见文献报道。目标中间体的结构经¹H-NMR确证。更多还原

【Abstract】 Mitiglinide (MGLN) is a new class of oral hypoglycemic drug for type II diabetes which can spur insulin secreting rapidly and reduce the high lever of postprandial blood sugar sharply and not cause the hypoglycemia or prostration of the pancreatic islets 3 -cell. So it has become the preferred drug for early and low-grade diabetics, which has not been produced in China and has good value.Studying on the synthesis of MGLN is going to introduce it into China and provide a base for further study on its Me-too drugs. In order to avoid the patent protection, we first designed and chose a non-patent route which began from the material diethyl succinate, and obtained the target compound which chemical structure was confirmed by ’H-NMR and 13C-NMR. Furthermore, we also researched two another routes, one was got through and the other is continued.Cis-hexahydroisoidolin is the pivotal intermediate of the MGLN. We chose two non-patent routes to synthesize it and took some improvements and innovations on its technics. The target intermediate was obtained and confirmed by ’H-NMR.更多还原