CN103880848B - 一种双加成富勒烯吡咯烷及其制备方法 - Google Patents
一种双加成富勒烯吡咯烷及其制备方法 Download PDFInfo
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Abstract
本发明公开了双加成富勒烯吡咯烷及其制备方法，涉及药物化学领域。本发明通过环加成，在富勒烯分子上引入两条水溶性的乙二醇臂，得到双加成N-取代富勒烯吡咯烷，不仅增加了其溶解度，而且可以避免聚集，在水溶液中高度均匀分散。其结构式为：有效地解决了现有富勒烯生物相容性差及单加成富勒烯吡咯烷易聚集等问题。
Description
技术领域
本发明涉及药物化学领域，具体的说，涉及一种双加成富勒烯吡咯烷及其制备方法。
背景技术
富勒烯分子是一种由60个碳原子自身结合而形成的闭合网状笼形结构，经研究发现，富勒烯具有清除自由基、DNA裂解、抑制HIV活性、杀伤肿瘤细胞、保护神经等生物学效应。由于整个笼完全由近似sp2杂化的碳原子组成，具有较强的亲电能力，通过光激发后产生单重态氧的效率高达100%,活性氧为高度反应性的,并且可以表现出明显的细胞毒性；C60极易与生物体系产生的游离自由基反应的电化学特性被喻为“吸收游离基的海绵”，能用于治疗一些由于大量产生自由基而致的疾病；亲脂性的富勒烯的碳笼可以与各种酶的活性中心反应，如堵住HlV蛋白酶(HlP)活性中心,抑制HIV，还可以插入生物膜,导致其不稳定,用于抗菌消炎。由此推断,富勒烯可以用于肿瘤的治疗。为此利用富勒烯作为光敏剂开展光动力疗法,使其在肿瘤组织中蓄积,利用光照产生活性氧来选择性的破坏肿瘤组织，是一种优良的光敏剂。
目前,光动力疗法在肿瘤治疗中起到一定的辅助作用,为了更有效地治疗肿瘤,可以使富勒烯作为光动力治疗的光敏剂的同时,作为抗肿瘤药物的载体发挥光动力治疗和化学药物治疗相结合的优势,更好的起到抗肿瘤作用。但由于富勒烯的碳笼结构具有强亲脂性,使其在水等极性溶剂中的溶解度非常有限,限制了其在生物体系中的研究和应用。而且，碳球笼单元仍然太大，在极性溶剂中，疏水性C60球体会聚集在一起形成胶团，而多侧链可以很好的减轻胶束的聚集现象。为此,水溶性好、光敏活性高、毒性小、生物相容性好的药物载体是目前最紧要的目标。
发明内容
本发明的目的是提供一种双加成的富勒烯吡咯烷，提高富勒烯在极性溶液中的溶解度，使其具有良好的抗癌活性。
本发明的另一目的是提供这些化合物的制备方法。
为了实现本发明目的，本发明所述双加成富勒烯吡咯烷其结构式为：
本发明所述的双加成富勒烯吡咯烷的制备方法通过如下步骤实现：
1）在氮气保护下，2-（2－氨乙氧基）乙醇和2-溴乙酸苄酯通过氨解反应合成N-取代氨基乙酸苄酯；
2）以钯碳作为催化剂，N-取代氨基乙酸苄酯经催化氢解反应合成N-取代氨基乙酸；
3）在氮气保护下，C60、多聚甲醛(CH2O)n和N-取代氨基乙酸通过1，3-偶极环加成N-取代双加成富勒烯吡咯烷。
其中，步骤1）中，2-（2－氨乙氧基）乙醇和2-溴乙酸苄酯及三乙胺等体积反应，室温下搅拌3-5小时，反应有机相用蒸馏水100ml和饱和食盐水80ml各萃取3次，加无水硫酸钠静置干燥过夜。
步骤2）中，采用质量百分比10%钯碳作为催化剂，在氢气作用下室温搅拌15-20小时。
步骤3）中，C60与N-取代氨基乙酸及多聚甲醛以1：2:1.66的摩尔比反应，120-140℃油浴，甲苯回流，磁力搅拌反应16-18h,旋蒸后过柱，用200-300目硅胶柱，干法上样，洗脱剂为1:6（v/v）的甲苯与乙酸乙酯的混合溶剂。
本发明制备过程中每步骤均在无水无氧的条件下进行。
本发明所述的双加成富勒烯吡咯烷的合成路线为：
其中，1为N-取代氨基乙酸苄酯，2为N-取代氨基乙酸，3为双加成富勒烯吡咯烷。
本发明通过1，3-偶极环加成反应得到双加成富勒烯吡咯烷，使富勒烯上连上两条乙二醇臂。该化合物大大提高了富勒烯在极性溶液中的溶解度，避免了富勒烯聚集，使其在水溶液中高度均匀分散。开拓了富勒烯吡在生物医学领域的良好应用。
附图说明
图1为本发明双加成富勒烯吡咯烷的TLC点板图；点板的展开剂为甲苯/乙酸乙酯1:6，Rf（trans）；
图2为本发明双加成富勒烯吡咯烷的UV-Vis谱图；图中229.8,266.0,298.6,356.5,425.9nm为C60加成反应特征峰，表明C60与吡咯烷基团相互发生了作用；
图3为本发明双加成富勒烯吡咯烷的红外光谱图；图中522．85为取代C60的标志，1114.50为C-O的伸缩振动，1618.70为C-N的伸缩振动吸收，2922.15为CH2-中CH的拉伸振动峰，3416.60为-OH的伸缩振动，1380.17及1462.11处为C60特征吸收峰；
图4为本发明双加成富勒烯吡咯烷的氢谱图；
图5为本发明双加成富勒烯吡咯烷的质谱图；其理论分子量为983.4414，图中983.1967,由于同位素的原因，质谱中出现M+1、M+2峰。
具体实施方式
以下实施例用于说明本发明，但并非限制本发明的范围。
实施例1双加成富勒烯吡咯烷
1.N-取代氨基乙酸苄酯的合成-氨解作用
250mL带滴液漏斗的三口圆底烧瓶，磁力搅拌下，氮气保护，加入2.5mL(25mmol)2-（2－氨乙氧基）乙醇和用90mLCH2Cl2稀释的2.5mL三乙胺，在0℃下1h内逐滴加入用10mLCH2Cl2溶解稀释的2.5mL(15.9mmol)2-溴乙酸苄酯，室温搅拌4小时，然后将有机相用蒸馏水萃取3次（100mL/次），饱和食盐水萃取3次（80mL/次），用无水Na2SO4干燥过夜，过滤后旋蒸至干，过SiO2硅胶柱（100-200目），99:1v/v乙酸乙酯/甲醇进行洗脱，收集所要组分，旋蒸，真空干燥得灰黄色粘稠油状化合物，即N-取代氨基乙酸苄酯（1.5g,产率37%）。
2．N-取代氨基乙酸的合成-催化氢解作用
带磁性搅拌的250mL三口圆底烧瓶，加1.1g(4.34mmol)N-取代氨基乙酸苄酯用124mL无水乙醇溶解，用氮气换气后加62mg质量百分比10%钯碳，通入氢气，室温催化氢解反应20小时，过滤去除钯碳催化剂，旋蒸干燥得黄色粘稠油状物，即N-取代氨基乙酸（0.79g,产率82%）。
3.双加成富勒烯吡咯烷的合成
称取C60（250mg,0.347mmol）加入装有甲苯（300ml）的三口圆底烧瓶中，超声30min,使之充分溶解。然后固定回流装置，在氮气保护下，迅速加入113mg(0.692mmol)的N-取代氨基乙酸(用少量无水乙醇溶解)和用少量甲苯溶解的52mg多聚甲醛(CH2O)n，130℃油浴、回流、磁力搅拌18小时，TLC监控反应进程，旋蒸后用柱层析分离纯化。
过柱纯化分离：产物进行硅胶(SiO2)柱层析分离，用1:6（v/v）甲苯/乙酸乙酯进行洗脱，旋蒸后真空干燥得深棕色粉末产物3。
本发明紫外-可见吸收光谱UV-Vis采用日本SHIMADIU公司的UV-2450紫外-可见分光光度计测量，以二氯甲烷为溶剂，波长范围为200-700nm；傅利叶红外光谱采用IR-200Spectrometer红外光谱仪，溴化钾KBr压片法制样；氢谱采用瑞士布鲁克公司的AVANCE超导核磁共振波谱仪，以CDCl3为溶剂；质谱采用美国AgilentTechnologies公司的高分辨质谱仪1290/6540。
Claims (1)
1.一种结构式如下的双加成富勒烯吡咯烷的制备方法，其特征在于，通过如下步骤实现：
（1）N-取代氨基乙酸苄酯的合成-氨解作用
250mL带滴液漏斗的三口圆底烧瓶，磁力搅拌下，氮气保护，加入2.5mL即25mmol2-（2－氨乙氧基）乙醇和用90mLCH2Cl2稀释的2.5mL三乙胺，在0℃下1h内逐滴加入用10mLCH2Cl2溶解稀释的2.5mL，即15.9mmol2-溴乙酸苄酯，室温搅拌4小时，然后将有机相用蒸馏水萃取3次，100mL/次，饱和食盐水萃取3次，80mL/次，用无水Na2SO4干燥过夜，过滤后旋蒸至干，过100-200目SiO2硅胶柱，99:1v/v乙酸乙酯/甲醇进行洗脱，收集所要组分，旋蒸，真空干燥得灰黄色粘稠油状化合物，即N-取代氨基乙酸苄酯1.5g,产率37%；
(2)N-取代氨基乙酸的合成-催化氢解作用
带磁性搅拌的250mL三口圆底烧瓶，加1.1g即4.34mmolN-取代氨基乙酸苄酯用124mL无水乙醇溶解，用氮气换气后加62mg质量百分比10%钯碳，通入氢气，室温催化氢解反应20小时，过滤去除钯碳催化剂，旋蒸干燥得黄色粘稠油状物，即N-取代氨基乙酸0.79g，产率82%；
（3）双加成富勒烯吡咯烷的合成
称取C60250mg即0.347mmol加入装有300ml甲苯的三口圆底烧瓶中，超声30min,使之充分溶解；然后固定回流装置，在氮气保护下，迅速加入113mg即0.692mmol的用少量无水乙醇溶解的N-取代氨基乙酸和用少量甲苯溶解的52mg多聚甲醛(CH2O)n，130℃油浴、回流、磁力搅拌18小时，TLC监控反应进程，旋蒸后用柱层析分离纯化；
过柱纯化分离：产物进行SiO2硅胶柱层析分离，用1:6（v/v）甲苯/乙酸乙酯进行洗脱，旋蒸后真空干燥得深棕色粉末产物。
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| CN1450055A (zh) * | 2003-04-22 | 2003-10-22 | 上海大学 | C60吡咯烷类衍生物的制备方法 |
| CN102675655A (zh) * | 2012-06-04 | 2012-09-19 | 郑州大学 | 一种水溶性富勒烯及其制备应用方法 |
| CN102898542A (zh) * | 2012-10-23 | 2013-01-30 | 郑州大学 | 一种水溶性富勒烯及其应用 |
| US20140024839A1 (en) * | 2012-07-17 | 2014-01-23 | Ricoh Company, Ltd. | Fullerene derivative, and method of preparing the same |
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| CN1450055A (zh) * | 2003-04-22 | 2003-10-22 | 上海大学 | C60吡咯烷类衍生物的制备方法 |
| CN102675655A (zh) * | 2012-06-04 | 2012-09-19 | 郑州大学 | 一种水溶性富勒烯及其制备应用方法 |
| US20140024839A1 (en) * | 2012-07-17 | 2014-01-23 | Ricoh Company, Ltd. | Fullerene derivative, and method of preparing the same |
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