抗HIV-I蛋白酶抑制剂RITONAVIR和碳青霉烯类抗生素重要中间体的合成研究

【作者】 周明伟；

【导师】 杨琍苹；

【作者基本信息】 华东师范大学 ， 有机化学， 2004， 硕士

【摘要】 本论文的第一部分是抗HIV-Ⅰ蛋白酶抑制剂RITONAVIR的合成研究。RITONAVIR是由美国ABBOTT公司开发的一种强效蛋白酶抑制剂，商品名为Norvir，1996年3月首次经美国FDA批准上市，用于治疗早期和进展期HIV感染。 我们以L-苯丙氨酸等为原料，经二十多步反应完成了RITONAVIR的全合成，并对两条合成路线作了优化与探索：通过调整投料比、改变后处理方法提高了中间体20的产率(由70％提高到95％)，并发现中间体20在乙醇中容易形成1：1的络合物以及改变投料比会导致部分外消旋的现象；提出了合成中间体10的不对称还原反应的机理，并通过控制反应条件使目标产物10的含量达到94％；优化了合成5-羟甲基噻唑的反应条件，避免了催化剂中毒、提高了产率；用三光气代替二光气合成出(2S)4-异丙基嗯唑烷-2，5-二酮(11)；发现了中间体13的较佳脱苄条件，使产率提高了10％。我们制备的最终产物RITONAVIR的纯度可达到99.79％。 本论文的第二部分是碳青霉烯类抗生素重要中间体的合成研究。碳青霉烯类抗生素是20世纪70年代发展起来的新型结构的内酰胺类抗生素，具有抗菌谱广、抗菌活性强等特色。其中美洛培南等1β-甲基碳青霉烯类具有更优良的抗菌性能和临床特点。 我们研究了1β-甲基碳青霉烯类重要中间体的合成，从中间体1出发经Reformastky反应、水解反应合成出中间体2；经Reformastky反应、烷基化、Dieckmann环合、烯醇化、酯化合成出中间体3，并对其中各步反应作了优化和探索。同时设计了合成中间体3和36的两条新路线，通过对中间体1和β-酮酯的Reformatsky反应研究经证实得到了两个吡啶酮类的新化合物，其中一个具有潜在的医药价值，并提出了相关反应机理。更多还原

【Abstract】 The first part of this paper relates to a synthetic research of protease inhibitor of HIV-I Ritonavir(marked as Norvir), which is a strong protease inhibitor developed by U. S. A. ABBOTT Company. In March of 1996, the U. S. A. FDA gave approval of Ritonavir for the treatment of patients with advanced HIV disease as well as for patientes with less advanced HIV disease.We synthesized Ritonavir from L-phenylalanine, and have optimized two synthesis routes and researched in detail: Through adjusting the proportion of material and change the treatment of reaction, the yield of enaminone (20) can rise to 95% from 70%. And We find that enaminone (20) is easy to form 1:1 complex compound with ethanol, and change the order of addition will cause to less diastereoselectivity;We put forward the mechanism of asymmetric reduction of enaminones(20) and perfectly explain the result.Through controlling the conditions of reaction, the diastereoselectivity is improved greatly, the content of 10 rised to 94%;Optimizing the process of While formating of 5-hydroxyl thiazole, We can prevent the catalyst from being poisonned and improve the producing rate;Through change the condition of formating of 11, reduce the danger; We find the best conditions of removing the two benzyl groups of intermediate 13. The result is obviously better than document value. The purity of the final product Ritonavir make be up to 99. 79%.The second part of this paper is the synthetic research of pivotal intermediates for carbapenera of antibiotics. Carbapenem antibiotics is a new class of 3-lactam antibiotics, developed in the seventies of the 20th century, have already become an important group of drugs and the object of ongoing pharmaceutical development because of it’s antibiotic activation. Inparticular, carbapenems bearing a 1 P-methyl substituent, examplified by Meropenem, have an excellent spectrum of activity and good resistance to renal dehydropeptidase I(DHP).We researched on the prepartion of pivotal intermediate 2 and 3 for 1 P-methyl carbapenem antibiotics from intermediate 1, which is subjected to Reformastky reaction, N-alkylation, Dieckmann-type cyclisation, enolization, ester condensation etc. in sequence. The synthesis route of document is optimized by us. We tested two new synthesis routes for intermediate 3 and 36. Through reaction of P -keto ester with intermediate 1, We get two compound , which was proved to be new compounds and belong to pyridine, one of them may have potential medical value . And We put forward the mechanism of the reaction.更多还原