聚乙二醇衍生物的合成及其应用研究
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摘要
聚乙二醇(PEG)作为可溶性聚合物载体应用于有机合成,集中了固相反应和经典液相反应的双重优点,既有固相反应的易分离、可循环利用、产物易纯化的特点,又保持了经典液相反应的高反应性、易表征和分析的优点。
本文以PEG作为可溶性聚合物载体,合成了PEG支载的两类树状化合物,并将其应用于去细胞瓣的修饰；以PEG作为可溶性聚合物载体,合成了PEG支载的吡啶叶立德,并将其应用于多取代环丙烷衍生物的合成。
第一章PEG支载树状化合物的合成及其应用
概述了近年来以PEG为可溶性载体支载合成树状化合物的研究进展及其在生物医学领域中的应用。基于PEG支载树状化合物修饰药物、多肽的优点以及本实验室前期工作的基础,提出本课题的设计思路。以不同分子量的线性PEG为原料,5-羟基间苯二甲酸甲酯作为连接基合成活性端基分别为丙烯酰基和琥珀酰亚胺的两种新型的树状化合物PEG-DA4和PEG-NHS4,并将其应用于去细胞瓣的修饰。对修饰条件进行了优化,得出最佳的修饰条件；对不同分子量PEG-DA4修饰效果进行了探讨,通过修饰后去细胞瓣的静态拉伸试验,得知分子量为20000Da时,抗拉强度最大,而弹性模量随分子量的增加而增大,故PEG2oooo-DA4的修饰效果最好；对两种不同活性端基PEG-DA4和PEG-NHS4修饰效果进行了探讨,通过力学测试数据得知PEG-DA4组抗拉强度均高于相同分子量PEG-NHS4组。
第二章PEG支载吡啶叶立德的合成及应用
概述了PEG支载的吡啶叶立德在有机合成中应用。基于本实验室的前期工作提出本课题的设计思路。以PEG支载溴乙酰溴为起始物,与吡啶反应生成PEG支载叶立德,与丙二腈或腈基乙酸乙酯和芳香醛通过Knoevenagel缩合得到的烯类衍生物经加成、环合反应得到14种多取代环丙烷衍生物,总产率为80-87%。同时对这些化合物运用1HNMR、13CNMR、IR等手段进行了分子结构的表征与确认,并由1HNMR确认所得产物均为tran-构型。
PEG在反应过程中担任聚合物载体和保护基,其巨大的反应位阻使关环反应只得到反式产物。相对于经典液相合成,产物产率得到大幅度提高,因此PEG在反应中还起到相转移催化剂的作用,提高了反应的转化率。
Poly(ethylene glycol) (PEG) is applied to organic synthesis as soluble support, which combines the superiorities of solid phase synthesis such as easy separation and purification, recyclable usage, convenient reprocessing and advantages of classical homogeneous reaction such as detecting reactive procedure with routine analytic methods.
In this paper, using PEG as soluble polymer support we synthesized two kinds of PEG-supported dendrimers, and applied them to modify decellularized leaflets; using PEG as soluble polymer support we synthesized PEG-supported pyridine ylide, and applied it to prepare polysubstituted cyclopropanes derivatives.
The first section:synthesis and application of PEG-supported dendrimers.
This section summarized the research progress of PEG-supported dendrimers and their applications in biomedical in recent years. Based on the advantages of PEG-supported dendrimers modifing drugs, peptides and previous work of our laboratory, presented the design idea. Using PEG with different molecular weight as starting materials, dimethyl 5-hydroxyisophthalate as linker, we synthesized two new kinds of dendrimers PEG-DA4 and PEG-NHS4 with acroloyl and NHS as active group respectively, and applied them to modify decellularized leaflets. Optimized the modification conditions, and obtained the best condition; investigated the modification effect of decellularized leaflets modified by different molecular weight of PEG-DA4, with the static tensile test, we reached a decision that PEG20000-DA4 is the best modification agent; investigated the modification effect of decellularized leaflets modified by two kinds of dendrimers PEG-DA4 and PEG-NHS4, with the test of tensile strength, we draw a conclusion that PEG-DA4 is better than PEG-NHS4.
The second section:synthesis and application of PEG-supported pyridine ylide.
This section summarized the applications of PEG-supported pyridine ylide in organic synthesis. Based on the previous work of our laboratory, the synthetical route was presented. PEG-supported acetyl bromide as starting material, reacted with pyridine and obtained PEG-supported pyridine ylide. Then it was treated with olefins generated by Knoevenagel condensation of malononitrile or ethyl cyano group and aromatic aldehydes, and obtained 14 polysubstituted cyclopropanes derivatives. The structure of these compounds was characterized and confirmed by'HNMR,13CNMR, IR. Also these compounds were all trans-configuration, which were confirmed by'HNMR.
PEG acted polymer support and protective group in the whole reaction, and tran-configuration was the only reaction products because of huge steric hindrance of PEG. Compared with classic liquid-phase synthesis, product yield increased greatly, so PEG also played the role of phase transfer catalyst, improving the reaction rate.
本文以PEG作为可溶性聚合物载体,合成了PEG支载的两类树状化合物,并将其应用于去细胞瓣的修饰；以PEG作为可溶性聚合物载体,合成了PEG支载的吡啶叶立德,并将其应用于多取代环丙烷衍生物的合成。
第一章PEG支载树状化合物的合成及其应用
概述了近年来以PEG为可溶性载体支载合成树状化合物的研究进展及其在生物医学领域中的应用。基于PEG支载树状化合物修饰药物、多肽的优点以及本实验室前期工作的基础,提出本课题的设计思路。以不同分子量的线性PEG为原料,5-羟基间苯二甲酸甲酯作为连接基合成活性端基分别为丙烯酰基和琥珀酰亚胺的两种新型的树状化合物PEG-DA4和PEG-NHS4,并将其应用于去细胞瓣的修饰。对修饰条件进行了优化,得出最佳的修饰条件；对不同分子量PEG-DA4修饰效果进行了探讨,通过修饰后去细胞瓣的静态拉伸试验,得知分子量为20000Da时,抗拉强度最大,而弹性模量随分子量的增加而增大,故PEG2oooo-DA4的修饰效果最好；对两种不同活性端基PEG-DA4和PEG-NHS4修饰效果进行了探讨,通过力学测试数据得知PEG-DA4组抗拉强度均高于相同分子量PEG-NHS4组。
第二章PEG支载吡啶叶立德的合成及应用
概述了PEG支载的吡啶叶立德在有机合成中应用。基于本实验室的前期工作提出本课题的设计思路。以PEG支载溴乙酰溴为起始物,与吡啶反应生成PEG支载叶立德,与丙二腈或腈基乙酸乙酯和芳香醛通过Knoevenagel缩合得到的烯类衍生物经加成、环合反应得到14种多取代环丙烷衍生物,总产率为80-87%。同时对这些化合物运用1HNMR、13CNMR、IR等手段进行了分子结构的表征与确认,并由1HNMR确认所得产物均为tran-构型。
PEG在反应过程中担任聚合物载体和保护基,其巨大的反应位阻使关环反应只得到反式产物。相对于经典液相合成,产物产率得到大幅度提高,因此PEG在反应中还起到相转移催化剂的作用,提高了反应的转化率。
Poly(ethylene glycol) (PEG) is applied to organic synthesis as soluble support, which combines the superiorities of solid phase synthesis such as easy separation and purification, recyclable usage, convenient reprocessing and advantages of classical homogeneous reaction such as detecting reactive procedure with routine analytic methods.
In this paper, using PEG as soluble polymer support we synthesized two kinds of PEG-supported dendrimers, and applied them to modify decellularized leaflets; using PEG as soluble polymer support we synthesized PEG-supported pyridine ylide, and applied it to prepare polysubstituted cyclopropanes derivatives.
The first section:synthesis and application of PEG-supported dendrimers.
This section summarized the research progress of PEG-supported dendrimers and their applications in biomedical in recent years. Based on the advantages of PEG-supported dendrimers modifing drugs, peptides and previous work of our laboratory, presented the design idea. Using PEG with different molecular weight as starting materials, dimethyl 5-hydroxyisophthalate as linker, we synthesized two new kinds of dendrimers PEG-DA4 and PEG-NHS4 with acroloyl and NHS as active group respectively, and applied them to modify decellularized leaflets. Optimized the modification conditions, and obtained the best condition; investigated the modification effect of decellularized leaflets modified by different molecular weight of PEG-DA4, with the static tensile test, we reached a decision that PEG20000-DA4 is the best modification agent; investigated the modification effect of decellularized leaflets modified by two kinds of dendrimers PEG-DA4 and PEG-NHS4, with the test of tensile strength, we draw a conclusion that PEG-DA4 is better than PEG-NHS4.
The second section:synthesis and application of PEG-supported pyridine ylide.
This section summarized the applications of PEG-supported pyridine ylide in organic synthesis. Based on the previous work of our laboratory, the synthetical route was presented. PEG-supported acetyl bromide as starting material, reacted with pyridine and obtained PEG-supported pyridine ylide. Then it was treated with olefins generated by Knoevenagel condensation of malononitrile or ethyl cyano group and aromatic aldehydes, and obtained 14 polysubstituted cyclopropanes derivatives. The structure of these compounds was characterized and confirmed by'HNMR,13CNMR, IR. Also these compounds were all trans-configuration, which were confirmed by'HNMR.
PEG acted polymer support and protective group in the whole reaction, and tran-configuration was the only reaction products because of huge steric hindrance of PEG. Compared with classic liquid-phase synthesis, product yield increased greatly, so PEG also played the role of phase transfer catalyst, improving the reaction rate.
引文
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[2]Estelle, D.; Tamis, D. Positive Dendritic Effect in a Peptide Dendrimer-Catalyzed Ester Hydrolysis Reaction[J]. J. Am. Chem. Soc,2004,126,15642-15643
[3]Tang, X. D.; Zhang, Q. Z.; Zhou, Q. F. The paleoenvironmental significance of organic carbon [J]. Chinese Journal of Organic Chemistry,2010,24,585-590
[4]Gernot, A.; Strohmeier, W.; Oliver, K. Synthesis of Functionalized 1,3-Thiazine Libraries Combining Solid-Phase Synthesis[J]. Chem. Eur. J,2004,10,2919-2926
[5]Estelle, D.; Tamis, D. A Strong Positive Dendritic Effect in a Peptide Dendrimer Ester Hydrolysis Reaction[J]. J. Am. Chem. Soc,2004,126,15642-15643
[6]Annunziata, R.; Benaglia, M. Poly(ethylene glycol)-Supported Bisoxazolines as Ligands for Catalytic Enantioselective Synthesis [J]. J. Org. Chem,2001,66,3160-3165
[7]Lubineau, A.; Malleron. A. Recyclable Polymeric Catalyst Effective on Mannich-Type Reaction in Water[J]. J. Chem. Soc. Pekin Trans,2001,2,3815-4195.
[8]Falchi, A.; Taddei, M. A New Soluble Polymer-Supported Scavenger for Alcohols and Phosphine Oxides[J]. PEG-DCT:Org. Lett,2009,2,3429-3431
[9]Hai, H.; Yan, L. PEGylated Poly(amidoamine) dendrimer-based dual-targeting carrier for treating brain tumors[J]. Biomaterials,2011,32,478-487
[10]Inoue, K. Functional dendrimers, hyperbranched and star polymers[J]. Polym. Sci,2000, 25,453-571
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