【作者】 唐果；

【导师】 赵玉芬；

【作者基本信息】 厦门大学 ， 有机化学， 2004， 博士

【摘要】 谷氨酰胺（Gln）是机体内含量非常丰富的一种氨基酸，约占体内游离氨基酸的60％。尽管给危重和营养不良患者补充Gln在生理上具有必要性，但由于Gln在水中溶解度很低以及在溶液中不稳定，加热产生有毒的物质，使其在肠外营养中的应用受到限制。N（2）-L-丙氨酰-L-谷氨酰胺（Ala-Gln）是一种性质稳定且易溶的二肽，进入体内迅速水解成Gln发挥其作用，对大面积的突发性创伤的病人具有重要作用，在非常时期，将对保障军人的健康，提高军队的战斗力有重大作用，使其在肠外营养中的应用日益受到重视，目前是完全依赖进口，在非常时期，将面临无药可买的情况。 在Ala-Gln的合成中，已有N-羧基内酸酐（NCA）偶联法、DCC-HOSu偶联法、通过改变丙氨酸的D-氯代丙酸法和谷氨酸r甲酯法，以上这五种方法都以专利进行保护。 本文以三苯基膦和六氯乙烷为偶联试剂，丙氨酸以N-（O，O-二烷基磷酰基）进行N端保护，在酸性条件下生成活泼酯，然后活泼酯在谷氨酰胺的水溶液中进行偶联，形成N-（O，O-二烷基磷酰化）-L-丙氨酰-L-谷氨酰胺，最后以氯化氢气体脱去保护基，得到N（2）-L-丙氨酰-L-谷氨酰胺二肽。 该方法获得了中国专利：ZL 02123369.1；国际专利公开号：WO03／106481A1。用此方法通过了中试，检验了小试工艺技术的可行性、稳定性；优化了N（2）-L-丙氨酰-L-谷氨酰胺合成反应条件，获得了中试工艺参数，合成出合格的产品，为N（2）-L-丙氨酰-L-谷氨酰胺的国产化奠定了基础，利用中试产品已申报3类原料药，并获受理，闽新药受理号：20030021。 本文利用³¹PNMR，ESI-MS和¹³CNMR进行了反应的跟踪和鉴定，发现偶联试剂（三苯基膦、六氯乙烷）在不同的溶剂中反应生成不同的产物，在乙二醇二甲醚中是五配位共价化合物P婉PC12，在乙睛中是四配位离子型化合物C护乍场C1一，二氧六环中生成含一个二氧六环的五配位离子型化合物Ph3PCI口ioxane)十Cl一。同时还发现偶联试剂与冰乙酸在不同的溶剂中均可以生成活化酷。 利用”PNMR研究了磷保护氨基酸与三苯基嶙及六氯乙烷的反应过程，从磷谱中观察到磷保护的氨基酸几乎可以定量的转化为磷保护氨基酸的活泼醋。该活泼醋与氨基酸甲酷或者氨基酸钠盐可以缩合成肤，经过纯化，可以得到磷保护的二肤醋或二肤酸。 对N（2）一L一丙氨酞一L一谷氨酞胺的合成成功并进行了中试，合成出合格的N（2）一L一丙氨酞一L一谷氨酞胺二肤产品，为N（2）一L一丙氨酞一L一谷氨酞胺二肤的国产化奠定了基础。更多还原

【Abstract】 L-glutamine(Gln) plays important role in the biosynthesis of Adenine, Guanine, Thymine, Cytosine, Uracil. Hence, for the patients, it is essential to provide them the Gln. However, Gln could not be included in currently available amino acid solutions due to its low solubility in water and the releasing of pyroglutamic acid and ammonia when it is under autoclave condition. Therefore, peptides cotaining Gin have taken place of Gln. For example, L-Alanyl-L-glutamine (Ala-Gin) has higer solubility and higher stability than Gin and is used as the infusion component.For the production of AlaGln, there are several kown methods, such as Yasutsugu Shimonishi method, N-carboxyl anhydride (NCA) method, DCC-HOSu method, Y -methyl L-glutamate method and D-2-halopropionic acid method.Recently, organic phosphorous coupling reagents have been applied for the synthesis of peptide derivatives. In this thesis activated ester could be synthesized through the Appel coupling reagents (triphenylphosphine and hexachloroethane) with N-(dialkyloxyphosphoryl)-alanine acid. Then the activated ester solution was added dropwise to the cooled solution of Gln in basic solution to give the product N-(dialkyloxyphosphoryl)-Ala-Gln. Finally the protective group was removed under dry hydrogen chloride to yield the target dipeptide Ala-Gin.In this thesis the reaction mechanism was also investigated. First, the coupling reagents were studied. Hexachloroethane was mixed with triphenylphosphine in different solvents under the protection of dry nitrogen, astraced by 31P-NMR. It was found that in different solvents the coupling reagents gave different chemical shifts. For example, in acetonitrile the reagents mixture gave the 31P NMR shift at 58.5 ppm, a peak at 24.8 ppm in DME, a strong peak at -39 ppm in dioxane. To prove the compositions of the coupling reagents, their MS were analyzed by ESI-MS. It was showed that a penta-coordinated phosphorous compound containing two chloro atoms PhsPCla was found in DME. In dioxane it seems that there was one molecule dioxane incooperated in the new species proposed as Ph3PCl(Dioxane). Second the carboxyl activated intermediates were also studied in the three solvents.Coupling of N-phosphoamino acids and sodium ammo acid by triphenylphosphine and hexachloroethane could produce sodium N-phosphopeptide. Similarly, N-phosphoamino acid, amino acid methyl ester, triphenylphosphine and triethylamine were dissolved in dichloromethane, then hexachloroethane in dichloromethane was added dropwise to the above cooled solution under the protection of dry nitrogen. As traced by 31P NMR, it was found that N-phosphopeptide methyl ester could be synthesized in one pot in reasonable yields.Various effects for scaled up synthesis of the AlaGln dipeptide was also investigated.更多还原