CN103265651B - 一种环糊精胆固醇酰胺的制备方法 - Google Patents

一种环糊精胆固醇酰胺的制备方法 Download PDF

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CN103265651B
CN103265651B CN201310229976.1A CN201310229976A CN103265651B CN 103265651 B CN103265651 B CN 103265651B CN 201310229976 A CN201310229976 A CN 201310229976A CN 103265651 B CN103265651 B CN 103265651B
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金征宇
王金鹏
陶晗
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Jiangnan University
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Abstract

一种环糊精胆固醇酰胺的制备方法，属于环糊精技术领域。本发明以乙二胺环糊精和胆固醇甲酰氯为原料，采用有机合成法制备得到环糊精胆固醇酰胺粗品，经过减压蒸馏，乙醚、水反复洗涤等步骤，制备得到环糊精胆固醇酰胺。本发明方法首次实现了环糊精胆固醇酰胺的制备，扩大了环糊精衍生物的范围，为功能性环糊精的工业制备提供了技术参考，扩大环糊精衍生物在生物活性药物领域的应用，为靶向药物制剂的生产提供一定的参考。

Description

一种环糊精胆固醇酰胺的制备方法
技术领域
一种环糊精胆固醇酰胺的制备方法，属于环糊精技术领域。
背景技术
环糊精具有中空的“分子胶囊”结构，能将一定大小的疏水性客体分子包合形成一种特殊的包合物，在医药行业被广泛地应用。目前国内外研究己不只局限于环糊精与客体分子形成配位包合物，而是趋向于对天然环糊精进行改造，利用其不同的特性，调节主分子的释放速率、时间和位点等作用，克服天然环糊精专一性弱的缺陷。
胆固醇是细胞膜的重要成分之一，占质膜脂类的20%以上。研究表明，温度高时，胆固醇能阻止双分子层的无序化；温度低时又可干扰其有序化，阻止液晶的形成，保持其流动性。此外，它不仅参与形成细胞膜，而且是合成胆汁酸，维生素D以及甾体激素的原料。
本发明首次以乙二胺环糊精和胆固醇甲酰氯为原料，利用酰胺键较高的稳定性，采用有机合成法制备得到环糊精胆固醇酰胺，该技术可为功能性环糊精的工业制备提供技术依据，扩大环糊精衍生物在生物活性药物领域的作用，为靶向药物制剂的开发提供一定的参考。
发明内容
本发明的目的在于提供一种环糊精胆固醇酰胺的制备方法。
本发明的技术方案：一种环糊精胆固醇酰胺的制备方法，以乙二胺环糊精和胆固醇甲酰氯为原料，利用酰胺键较高的稳定性，采用有机合成法制备得到环糊精胆固醇酰胺粗品，经过减压蒸馏，乙醚、水反复洗涤等步骤，制备得到环糊精胆固醇酰胺产品。步骤为：
将乙二胺环糊精溶解于适量干燥的N,N二甲基甲酰胺溶液中，再加入三乙胺和胆固醇甲酰氯，乙二胺环糊精︰三乙胺︰胆固醇甲酰氯的摩尔比为5︰6︰6，N,N二甲基甲酰胺溶液的体积用量mL数与胆固醇甲酰氯的毫摩尔用量mmol数近十倍，于5℃冰浴中搅拌30min，然后将其置于室温下反应17h；反映进程采取TLC法监测，展开剂为三氯甲烷:甲醇体积比为98:2,待乙二胺环糊精反应完全后，停止反应，减压蒸馏除去有机溶剂；然后用乙醚、水反复洗涤，过滤得到白色沉淀，在45℃条件下真空干燥得到环糊精胆固醇酰胺产物，产率42%。
本发明的有益效果：本发明方法首次实现了环糊精胆固醇酰胺的制备，扩大了环糊精衍生物的范围，为功能性环糊精的工业制备提供了技术参考，扩大环糊精衍生物在生物活性药物领域的应用，为靶向药物制剂的生产提供一定的参考。
附图说明
图1：环糊精胆固醇酰胺的近红外光谱图。
图2：环糊精胆固醇酰胺的紫外吸收光谱图。A、乙二胺环糊精，B、胆固醇甲酰氯，C、目标产物环糊精胆固醇酰胺。
图3：环糊精胆固醇酰胺的分子量测定图。
具体实施方式
实施例1环糊精胆固醇酰胺的制备
将0.43g乙二胺环糊精（0.35mmol）溶解于4mL干燥的N,N二甲基甲酰胺溶液中，再加入0.06mL三乙胺（0.42mmol）和0.19g胆固醇甲酰氯（0.42mmol），于5℃冰浴中搅拌30min，然后将其置于室温下反应17h。反应的进程采取TLC法监测（展开剂为三氯甲烷:甲醇体积比=98:2),待乙二胺环糊精反应完全后，停止反应，减压蒸馏除去有机溶剂。然后用乙醚、水反复洗涤，过滤得到白色沉淀，在45℃条件下真空干燥得到环糊精胆固醇酰胺产物（0.1804g），产率42%。
实施例2环糊精胆固醇酰胺的表征
1）红外光谱测定官能团
原理：通过研究物质结构与红外吸收光谱间的关系，根据实验所测绘的红外光谱图的吸收峰位置、强度和形状，利用基团振动频率与分子结构的关系，来确定吸收带的归属，确认分子中所含的基团或键，并推断分子的结构。
（1）取干燥的环糊精胆固醇酰胺试样约1mg于干净的玛瑙研钵中，在红外灯下研磨成细粉，再加入约150mg干燥且已研磨成细粉的KBr一起研磨至二者完全混合均匀。
（2）取适量步骤（1）所得的混合样品于干净的压片模具中，堆积均匀，用手压式压片机用力加压约30s，制成透明试样薄片。
（3）小心取出试样薄片，装在磁性样品架上，放入Nicolet5700傅立叶红外光谱仪的样品室中，测量样品红外光谱图。
表1环糊精胆固醇酰胺的特性吸收及对应基团（KBr压片）
2）双光束紫外分光光度法测定最大吸收波长
原理：利用物质的分子或离子对某一波长范围的光的吸收作用，对物质进行定性分析。
（1）配制1μg·mL-1胆固醇甲酰氯—乙醇，乙二胺环糊精—乙醇，样品—乙醇溶液，以乙醇为参比溶液，分别测定胆固醇甲酰氯，乙二胺环糊精及目标产物的紫外吸收光谱，寻找最大吸收波长λmax。
表2UV最大吸收波长
3）环糊精胆固醇酰胺的分子量的测定
取干燥的环糊精胆固醇酰胺试样约1mg于1mL无水甲醇溶液中，采用液相色谱串联四极杆飞行时间质谱仪测定分离所得环糊精胆固醇酰胺（图3）。
MS(ESI+):m/z1589[M+H+],CalcdforC72H120N2O36Found:1589。

Claims (1)

1.一种环糊精胆固醇酰胺的制备方法，其特征在于：以乙二胺环糊精和胆固醇甲酰氯为原料，采用有机合成法制备得到环糊精胆固醇酰胺粗品，经过减压蒸馏，乙醚、水反复洗涤，制备得到环糊精胆固醇酰胺；步骤为：
将乙二胺环糊精溶解于适量干燥的N,N-二甲基甲酰胺溶液中，再加入三乙胺和胆固醇甲酰氯，乙二胺环糊精：三乙胺：胆固醇甲酰氯的摩尔比为5：6：6，N,N-二甲基甲酰胺溶液的体积用量mL数为胆固醇甲酰氯的毫摩尔用量mmol数的近十倍，于5℃冰浴中搅拌30min，然后将其置于室温下反应17h；反应进程采取TLC法监测，展开剂为三氯甲烷:甲醇体积比为98:2,待乙二胺环糊精反应完全后，停止反应，减压蒸馏除去有机溶剂；然后用乙醚、水反复洗涤，过滤得到白色沉淀，在45℃条件下真空干燥得到环糊精胆固醇酰胺产物。
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