抗艾滋病药物司它夫定和利托那韦手性中间体的合成-有机化学专业毕业论文.docxVIP

《《如967一一塑里——————————————一 《《如967 一一塑里——————————————一 ／彼鳓刍 摘 要 司它夫定(Stavudine)和利托那韦(Ritonavir)是FDA正式批准的 治疗艾滋瘸的商效抗逆转录病毒治疗(HAA T)药物a本论文工作在文 献的基础上成功地合成了嗣它失定和利托那韦的关键手性中间体，并对它 们豹会成工艺避弦了礤究翱改进。 司它夫定满子核萤类逆转窳酶猕剿裁，结孝勾为2’，3’-聪氧黢氢核萤愆 生物--d4T。以5．甲蓥霖营为起始原料，经挈磺魏纯，郅纯，溪代嚣褥 到关键中闷体2’一溴一3’，甲磺酸酯。溪纯甲磺酸酪在棒，Z；酸述原消除下 得至Ⅱ5’。苯甲酰化的司它夫定，最偌去保护得到最终产品司它夫定，总皎 率42．5％。 利托那韦属于蛋白酶抑制剂，其结构为带有环状结构的肽化合物，其 关键中间体为禽3个手性碳原予的手性氨基醇。本论文的第二部分工作以 (L)～苯嚣氨酸为起始原料制备秘标化合物。酯化苯丙氨酸，再经乙瞎 碳熊襄子驰亲核反应和与辏氏试刹的反应彳寻到中闻体爝跛酮。烯胺嗣经两 步选择性逐暴褥至l露掭产燕，慧收率21．7％+ 关键谣司它夫定；脱裁核替；5一荦蓦深替；零j托郝韦；离散抗逆转录瘸 毒治疗；烯胺酮 摘要Abstract 摘要 Abstract Stavudine and Ritonavir are effective therapeutic agents for the treatment ofAIDS．The present thesis relates to the syntheses of Stavudine and the chiral intermediate of Ritonavir referring to reported synthetic routes and some modification in preparative techniques to be suitable for potential production in industrial scale． Stavudine is a 2’，3-dideoxy一2’，3-didehydro nucleoside analog砸m reverse transcriptase inhibitive activity．The synthesis of Stavudine comprises the following steps：Mesylation of 5-methyluridine gives trimesylated 5-methyluridine．Mesylated 5-methyluridine reacted with sodium benzoate in acetylamine is converted to 5-benzoated-2，2-anhydro-5-methyluridine， which is brominated to give 5-benzoyl-2-bromo-3-mesylthymidine． Zinc-induced reductive elimination provides 5-benzoyl ester of Stavudine． Deprotection of Stavudine ester affords final product in total yied 42．5％． Ritonavir is a protease inhibitor with a chain-typed structure of peptide compound．n圮key intermediate of Ritonavir is a chiral amino alcohol w／tll 3 chiral carbons．Preparation of the chiral amino aleohol starts from (L)-phenylalanine．Esterification of phenylalanine followed by nucleophilic substitution with acetonitrile anion and reaction with Grignard reagent provides an enaminone intermediate．Through enantioselective reduction of the enaminone in two steps，the key chiral intermediate of Ritonavir is formed in 21．7％yield． Keywords：Stavudi