双环醇代谢产物的合成

Synthesis of metabolites of bicyclol

双环醇是我国具有自主知识产权的新一代抗肝炎药,药理作用机制新颖、多环节综合治疗,对慢性乙型肝炎(HBV)临床疗效显著、副作用少,已实现产业化。经药理实验分离出双环醇的代谢产物M 2(4-羟基-4′-甲氧基-2-羟甲基-2′-甲氧羰基-5,6,5,′6′-双亚甲二氧基联苯)和M 3(4′-羟基-4-甲氧基-2-羟甲基-2′-甲氧羰基-5,6,5,′6′-双亚甲二氧基联苯),为进一步研究双环醇的作用机制和保证药物的安全性及有效性,本研究全合成其代谢产物。以苄基分别保护芳香溴代物的羧基和酚羟基,通过分子间不对称U llm ann反应,经催化氢化、硼烷还原制得双环醇的两个代谢产物,经红外、高分辨质谱及氢核磁共振谱确定结构。药理试验结果表明,两个代谢产物对CC l4肝损伤小鼠ALT升高有降低作用,但作用均弱于双环醇。

Bicyclol is a new generation of anti-hepatitis drug with China＇ s own intellectual property rights. The chemical structure of bicyclol is new and original. Pharmacological research showed that it has high clinical efficacy in treating chronic hepatitis （HBV） patients and lower side effects. Two metabolites of bicyclol have been isolated： M2 （4-hydroxy-4＇-methoxy-5, 6, 5＇, 6＇-bis （ methylenedioxy ）-2- hydroxylmethyl-2＇-methoxycarbonyl biphenyl） and M3 （4＇-hydroxy-4-methoxy-5,6,5＇, 6＇-bis （ methyl enedioxy）-2-hydroxylmethyl-2＇-methoxycarbonyl biphenyl）. To further study the mechanism, safety, and effectiveness of bicyclol, the M2 and M3 have been total synthesized. The synthesis route is as following： the carboxyl and phenolic hydroxyl group of the aromatic bromide had been separately protected by bromobenzyl, coupling through the intermolecular asymmetric Ullmann reaction and then catalyst hydrogenated, borane reducted, two metabolites of bicyclol M2 and M3 were obtained. The structures were determined by IR, ^1H NMR, HRMS. Comparison of hepatoprotective activity of bicyclol and the two metabolites on experimental liver injury, the potency of the metabolites were lower than that of bicyclol.