【作者】 孙博；

【导师】 陆群；

【作者基本信息】 西南交通大学 ， 生物化工， 2010， 硕士

【摘要】 1981年,日本科学家首次证实活性麦角钙化醇类似物具有诱导细胞分化和抑制细胞增殖的功能活性钙化醇受体,其不仅存在于小肠、骨胳和肾脏,还存在于人体的各种组织以及各种癌细胞中。如今,麦角钙化醇类药物可作用于多种靶组织,生理作用也多种多样,因此,广泛用于治疗骨质疏松、甲状旁腺亢进(肾衰)、牛皮癣、癌症以及免疫疾病等。然而,由于麦角钙化醇类药物在治疗中常常引起高钙血症和高磷血症,使其应用受到了限制,而19位缺失的麦角钙化醇化合物在动物实验及临床研究中显示具有相对选择性的药理作用,能安全有效地抑制甲状旁腺激素的分泌及甲状旁腺的增生而很少引起高钙血症和高磷血症,本论文在合成阿法骨化醇,度骨化醇,19-nor麦角钙化醇的基础上,初步合成了化合物la-OH-19-nor麦角钙化醇,并对合成中的关键反应进行了研究。1.合成了阿法骨化醇,并且以麦角钙化醇为原料,与合成阿法骨化醇相似的方法合成了度骨化醇。2.用高锰酸钾双羟基化的方法合成了19-nor麦角钙化醇,以此为模式反应,在生成3,5环合麦角钙化醇后,通过烯丙位氧化,生成1a-OH,后经过酯保护,再加入高锰酸钾氧化生成二醇,用四醋酸铅代替高碘酸钠生成la-OAc-10-oxo化合物,其后反应与19-nor麦角钙化醇相类似,初步得到目标产物粗品,合成路线复杂,且收率较低。我们又尝试在生成10-oxo麦角钙化醇后,通过Triflating Reagent生成了10-OTf-1-烯麦角钙化醇,经醋酸钯还原,用9-BBN进行硼羟基化,生成了1a-OH化合物,最后通过水解来得到目标产物。3.在对3,5环合麦角钙化醇双羟化研究中,通过大量试验,使用高锰酸钾代替剧毒且昂贵的四氧化锇作为氧化剂,取得了较好的效果。4.分别考察了2,6-二甲基吡啶(2,6-Lutidine)、氢化钠(Sodium Hydride)二异丙基胺基锂(LDA)、六甲基二硅基胺基锂(LiHMDS)等作为强碱用于10-oxo-3,5环合麦角钙化醇反应中,初步确定该反应中使用LiHMDS作为强碱副产物少,产率高。更多还原

【Abstract】 In the past, people think the analogues of ergocalciferol were only nutrient that regulated the balance of calcium metabolism; in 1981, Japanese scientists confirmed that analogues of ergocalciferol had the function that inducted cell differentiation and cell proliferation. Analogues of ergocalciferol receptor, not only exists in small intestine, bone and kidney, but also in various organizations as well as a variety of human cancer cells. Today, the drugs of ergocalciferol analogues can target tissue, physiological role is diversity, it is widely used to treat osteoporosis, parathyroid (ARF), psoriasis, cancer and immune diseases. However, Because ergocalciferol analogues in the treatment of hypercalcemia often lead to hypercalcemia and hyperphosphatemia, its application was limited, and 19-methylene missing ergocalciferol analogues compounds in animal experiments and clinical studies have shown the pharmacological effects of relatively selective were safe and effective for its inhibition the secretion of parathyroid hormone and parathyroid gland hyperplasia and rarely cause hypercalcemia and hyperphosphatemia.This paper concentrates on studing the synthesis of ergocalciferol analogues and the key steps of synthesis. New 19-nor ergocalciferol analogues were synthesized by two routines, The content included as following:1. Using similar synthetic method, alfacalcidol and doxercalciferol were synthesized.2. As a model reaction,19-nor ergocalciferol was synthesized. After the synthesis of 3, 5-cycle ergocalciferol, la-OH formed by allylic oxidation, protected through ester, then used potassium permanganate oxidation to generate diol, with lead tetraacetate instead of sodium periodate generated la-OAc-10-oxo compound, followed by reaction with similar to 19-nor ergocalciferol, final crude product was obtained. This route was complex, low yield. Therefore, we attempted another synthesis, starting from 10-oxo ergocalciferol, by triflating reagent to obtain 10-OTf-l-alene ergotcalciferol, reduced to get 1-alene ergotcalciferol by Pd(OAc)2, then by 9-BBN to obtain la-OH compound, and finally through the hydrolysis method to get target product.3. On the research of dihydroxylation of the 3,5-cycle ergocalciferol, we employed potassium permanganate as the oxidant instead of osmium tetroxide which is toxic and expensive, and achieved good and similar result.4. Respectively investigated the synthesis condition on the triflate of 10-oxo-3,5-cycle ergocalciferol by employing different alkali including 2,6-Lutidine、Sodium Hydride、LDA、LiHMDS, experiment showed the best reagent was LiHMDS, it got the less by-product and higher yield.更多还原