磷脂酰胆碱、磷脂酰乙醇胺与磷脂酰甘油的全合成的研究.pdf

摘要磷脂是生物膜的重要组成部分,其固有的既具亲水性又具亲脂性的双亲性质使得磷脂能自发在水介质中形成闭合双分子层,成为生物膜骨架。利用该性质发展起来一种新型药物制剂技术一脂质体。脂质体作为药物载体具有靶向性、缓释长效性等特点,在药物的定向输送研究中受到广泛重视。但天然磷脂作为脂质体膜材,由于其寿命短、易被氧化、稳定性差等缺点,应用受到限制。人工合成两亲性材料制备脂质体,稳定性有较大提高,使脂质体研究和应用领域得到拓展。另外,合成磷脂也可用于脂肪乳、微乳等先进载药技术。本文以丙三醇为前体化合物,设计出了含相同碳链的甘油磷脂的全合成路线。采用缩酮,3,4一二甲氧苄基分别作为甘油骨架的二羟基和单羟基的保护基, 以乙酸水溶液、DDQ作为相应的脱保护试剂。分别采用对甲苯磺酸甲酯、叔丁氧羰基和缩酮作为磷脂头基(N、、乙醇胺、甘油)的保护基, 以NaHc03水溶液、三氟乙酸、乙酸作为相应的脱保护试剂,采用萃取、高真空蒸馏、柱层析、制备薄层层析等分离方法,得到了大部分步骤的中间体。先后经过还原、氯化、缩合、双羟基以及单羟基的保护和脱保护、酰化、磷酰化、头基保护、偶联及脱保护等步骤制各出了一定量的二硬脂酸磷脂酰胆碱(DsPc)(产率:45%)、二硬脂酰基甘油(DSPG)(产率:41%)、二硬脂酰基乙醇胺(DSPE) (产率:26%)及一定量的14碳和16碳的双饱和脂肪链的磷脂中间体。最终产物以及部分中间体利用IR、NMR等手段进行了表征。对部分步骤的分离方法进行了简化改进。证明了该合成路线的可行性,为今后利用该合成路线为基础衍生出一系列磷脂产品及工业放大作了前期探索。关键字:磷脂酰胆碱,磷脂酰甘。油,磷脂酰乙醇胺,对甲苯磺酸甲酯,叔丁氧羰基,3,。 The totalsynthesis ofphosphatidylcholine, phosphatidylethanolamine andphosphatidylglycer01 analogOus Abstract Phospholipids aIlalogous are ponents chamcteristic ofphospholipjds isthe锄phiphilic behaVior'depending on which, stablebilayer stmctIITec卸be fkelyfo硼edby jtselfmaking aVeside oflipid bilaycL With thischaractef,a novel dmg preparation tcchn0109y hasdeveloped asliposome, with such mcrits as targeting,duration uSage ofnatllmlph唧holipids was limitedfbrthedisadvantages of shonlifc,fr柚gibility tooxidation ess. Thepmble面啪bc solVed bysyntheticphospholipids,ed thestudying and application ;synthetic phospholjpids can beuscd fbr hn010西es asfatemulsion,microemulsion,卸d so on. The totalsynthetic scheme of舀ycerol phospholipids was designed with tIle ursor百ycemL Ketal,3,4一dimethoxybenzyl were adopted astlleprotecting gfoups of西ycerol skeleton姐d aqueous acetic acidand2,3·dichlom-5,6-dicy强oquinone (DDQ) as the depfotecting reagents respectiVely. Methyl p-toluencsulfonate, tert-butoxycarbonyl, was adopted as the protecting 印ups of N,N—dimethyl —ethanolamine and ethanOlamine rcspectively,锄d aqueous NaHC03,tr硼uOroacetic add as me ting reagenIs ,high Vacuum distillation,