CN105985516B - 一种具有近红外吸收与自分类聚合特性的双官能团引发剂的合成及应用 - Google Patents
一种具有近红外吸收与自分类聚合特性的双官能团引发剂的合成及应用 Download PDFInfo
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Abstract
本发明公开了一种具有近红外吸收与自分类聚合特性的双官能团分子引发剂及其制备方法及其应用，本发明的引发剂,可“一锅法”杂化聚合异腈与ε‑己内酯单体，具有很好的自分类聚合能力，稳定性好，可用于异腈、ε‑己内酯等单体的活性可控聚合，所得的聚异腈、聚己内酯均聚物及其嵌段共聚物均具有可控的分子量和较窄的分子量分布。
Description
技术领域
本发明涉及聚合物催化合成领域，具体涉及一种具有近红外吸收与自分类聚合特性的双官能团引发剂引发剂及其制备方法及其应用，可“一锅法”杂化聚合异腈与丙交酯或ε-己内酯单体。
背景技术
IR-780具有肿瘤靶向近红外荧光显影特性，为肿瘤靶向诊断治疗药物的研究提供了新的思路和途径。基于前期创新性发现的基础上，本研究提出，IR-780能否作为肿瘤药物的靶向载体，即通过化学连接策略，将抗肿瘤药物与其进行共价连接，在IR-780的靶向转运下，提高药物对肿瘤的特异性作用。由于IR-780具有肿瘤靶向近红外荧光显影特性，还可望同步实现对治疗效果的实时监测，为肿瘤个体化治疗提供新途径花青分子具有明显的吸收波长和光热效应。它广泛提供在工业着色,生物标志物使用,离子的检测等方面有很好的应用。而且具有优越的荧光特性，位于近红外荧光波长范围，具有较强的组织穿透能力以及极大地降低生物组织自身荧光干扰的特点，同时在血清中稳定性好，可用于在生物体内的近红外荧光成像；
20世纪30年代，Carothers教授就合成了内酯的聚合物，并对聚合物制备的条件做了相关的研究。此后许多学者对内酯的聚合机理、动力学、热力学做了深入的研究，为内酯聚合的发展奠定了坚实的基础。聚己内酯、聚丙交酯是一种合成高分子生物医用材料，生物相容性和生物降解性能优越，近年来生物材料在医药领域得到了越来越广泛的应用。
聚异腈(poly isocyanide)是最早发现的具有稳定螺旋构象的高分子之一，其性质稳定、单体易得、聚合方法简单、在溶液中和固态时均能很好的保持螺旋结构。
杂化共聚在高分子合成领域具有重要的意义，它能够基于不同的聚合机理，“一锅法”自分类聚合产生新型的共聚物，为高分子化学及聚合物的应用开拓了新的领域和新的研究方向。然而，杂化聚合的实施也是非常困难的，目前关于这类的报道并不多见。
向异腈和内酯杂化聚合物上引入花青衍生物分子尚属首例，这类聚合物结合了光热分子、聚异腈、聚内酯三者的优秀性能。
综上所述，本领域的技术人员致力于开发一种催化活性高的催化剂用于异腈、ε-己内酯的“一锅法”杂化共聚，合成具有生物相容性、可降解的近红外共聚物。通过近红外的荧光显影变化来跟踪靶细胞，从而为聚异腈、ε-己内酯杂化共聚以及合成生物相容性材料提供新的聚合方法和聚合体系。
发明内容
本发明旨在提供一种双官能团引发剂及其制备方法，本双官能团分子引发剂在分子上引入了近红外基团，可“一锅法”杂化聚合异腈与ε-己内酯单体，具有很好的自分类聚合能力，催化活性高、性质稳定，得到的聚合物依然具有相应的刺激响应性。
本发明采用的技术方案如下:
一种具有近红外吸收与自分类聚合双官能团引发剂，其特征在于：结构式如下：
所述具有近红外吸收与自分类聚合双官能团引发剂的制备方法,其特征在于按以下步骤操作:
a.将IR780-花青素分子与过量的4-氨基苯硫酚按摩尔比例1:1.12充分反应后，分离、洗涤并干燥后得到中间体Ⅰ；
b.将对氨基苯甲酸、无水碳酸钾、溴代丙炔按摩尔比1:2:1.2的比例加入到干燥的乙腈中，在氮气氛围中、室温下搅拌反应22-25h，分离、洗涤并干燥后得到中间体Ⅱ；
c.将所述中间体Ⅱ和碳酸钾、碘化钾按摩尔比1:2:1的比例加入到干燥的乙腈中，滴加过量的溴乙醇，在氮气氛围中，75-80℃反应48-50h，分离、洗涤并干燥后得到中间体Ⅲ；
d.将所述中间体Ⅲ、三乙基磷二氯化钯、氯化亚铜按摩尔比1:1.2:0.12的比例加入到干燥的二乙胺中，在氮气气氛中于室温搅拌反应过夜,旋蒸除去溶剂后经柱层析提纯,真空干燥后得到目标产物Ⅳ；
e.将中间体Ⅰ，Ⅳ，DCC和EDCI按1:1.02:0.8:1的比例加入到氮气气氛中于室温搅拌反应过夜，旋蒸除去溶剂后经柱层析提纯,真空干燥后得到目标产物引发剂Ⅴ。
所述的具有近红外吸收与自分类聚合特性的双官能团引发剂可用于苯异腈或内酯类单体均聚或杂化共聚时作为催化剂的应用。
所述的具有近红外吸收与自分类聚合特性的双官能团引发剂的应用，其特征在于：所述的杂化聚合物，由于存在IR780基团，具有近红外成像能力，可用于生物显影，癌细胞跟踪，以及通过聚酯类物质在生物体内降解，从而达到包裹药物释放的目的。
本发明的引发剂的合成路线如下:
本发明引发剂可用于苯异腈或内酯类单体均聚或杂化共聚时作为催化剂使用。
将本发明引发剂用于引发苯异腈类单体聚合反应，具体步骤如下:
苯异腈类单体聚合在无水无氧条件下进行，在10mL聚合瓶中加入引发剂和苯异腈类单体，引发剂和苯异腈类单体的摩尔比为1:(50-200)，抽真空充氮气3次，加入干燥的氯仿，在60℃回流反应20-24h，加入甲醇终止反应，将所得产物用甲醇(疏水)或正己烷(亲水)洗涤4-5次，真空干燥至质量不变。
本发明所使用的苯异腈单体的结构为:
式R3为长链烷基或手性薄荷醇或亲水链。
将本发明引发剂用于引发己内酯单体聚合反应，具体步骤如下:
己内酯单体聚合在无水无氧条件下进行，在10mL聚合瓶中加入引发剂和己内酯单体，引发剂和己内酯单体的摩尔比为1:60，抽真空充氮气3次，加入干燥的甲苯，在60℃回流反应24h,加入甲醇终止反应，将所得产物用甲醇洗涤4-5次,真空干燥至质量不变。
将本发明引发剂用于引发苯异腈、己内酯单体杂化聚合反应，具体步骤如下:
苯异腈单体、己内酯单体聚合在无水无氧条件下进行，在10mL聚合瓶中加入引发剂和苯异腈、己内酯单体，引发剂和苯异腈、己内酯单体的摩尔比1:30:60，抽真空充氮气3次，加入干燥的甲苯，在60℃回流反应24h，加入甲醇(疏水)或正己烷(亲水)终止反应，将所得产物用甲醇洗涤4-5次，真空干燥至质量不变。
本发明引发剂引发苯异腈、己内酯均聚及杂化共聚的聚合路线如下:
与已有技术相比,本发明的有益效果体现在:
1、可均聚或“一锅法”杂化共聚多种单体，且得到的聚合物也具有响应性。
2、本引发剂引发得到的聚合物分子量均一，分子量分布窄。
3、本发明的聚合物可近红外荧光显影，来达到检测与跟踪的目的。
4、设计的聚合物的亲疏水性质可通过异腈单体的亲疏水性质来进行调控。
5、设计的聚合物，若异腈嵌段亲水，则可形成胶束，来进行包裹物质。
6、设计的聚合物酯的嵌段可通过生物酶水解，来达到包裹药物释放的目的。
一种引发剂，可杂化聚合两种物质，得到近红外吸收的两亲性聚合物，也可得到均聚的聚酯或聚异腈；可“一锅法”杂化聚合异腈与己内酯或ε-己内酯单体，具有很好的自分类聚合能力，合成的杂化聚合物，亲水疏水性可通过单体的选择来进行调控,从而自组装成不同的形貌。
本发明引发剂在空气中具有很好的稳定性，聚合时单体转化率较高，得到的自分类聚合物分子量分布窄，得到的聚合物具有响应性，共聚物可在多种溶剂中自组装。
附图说明
图1是本发明实施例IR780引发剂的红外吸收光谱图。图中，2120cm-1是碳碳叁键的红外特征吸收峰，1675cm-1是羰基的红外特征吸收峰。
图2是本发明实施例780花青引发剂的1H NMR(600M Hz)谱图。
图3是本发明实施例6中“一锅法”聚合聚合物的核磁，对应的化学位移均在谱图中标出。
图4是本发明实施例4聚合亲水异腈，对应的化学位移均在谱图中标出。
图5是本发明实施例3,4中聚合物对应的GPC。
图6是本发明实施例引发剂及聚合物对应的近红外吸收。
具体实施方式
实施例1:IR780引发剂的制备
将IR780的碘化物与过量的对巯基苯胺(按摩尔比为1:1.02加入)在DMF溶液中室温反应24h,旋干后，用硅胶柱层析(甲醇：二氯甲烷＝1:20)，干燥后得到中间体Ⅰ
将对氨基苯甲酸、无水碳酸钾、溴代丙炔按摩尔比1:(1-3):1.2的比例加入到干燥的乙腈中，在氮气氛围中、室温下搅拌反应24h，水洗，饱和NaHCO3洗，盐洗，分离有机相、旋干，粗产品用硅胶柱层析(洗脱液按体积比:石油醚:乙酸乙酯＝4:1)提纯，干燥后得到中间体Ⅱ，结构式如下:
将所述中间体Ⅳ和碳酸钾、碘化钾按摩尔比1:2:1.5的比例加入到干燥的乙腈中，滴加过量的溴乙醇，在氮气氛围中，80℃反应48h，水洗，饱和NaHCO3洗，盐洗，分离有机相、旋干，粗产品用硅胶柱层析(洗脱液按体积比:石油醚:乙酸乙酯＝2:1)提纯，
干燥后得到中间体Ⅲ，结构式如下:
二(三乙基磷)二氯化钯、氯化亚铜和所述中间体Ⅲ按摩尔比1:0.1:1的比例加入到干燥的二乙胺中，在氮气气氛中于室温搅拌反应4-5h，旋蒸除去溶剂后,粗产品用硅胶柱层析(洗脱液按体积比＝石油醚:乙酸乙酯＝3:1)提纯，真空干燥后得到中间体Ⅳ，结构式如下:
将中间体Ⅰ,中间体Ⅳ,HOBT和DCC按摩尔比1:1.01：1:1加入两口反应瓶中，在氮气的保护下反应3小时，旋蒸除去溶剂后,粗产品用硅胶柱层析(甲醇：二氯甲烷＝1:50)提纯，得到IR780引发剂Ⅴ，结构式如下：
实施例1:引发“一锅法”亲水苯异腈与己内酯杂化聚合反应
苯异腈聚合在无水无氧条件下进行，在10mL聚合瓶中加入实施例1制备的引发剂6.8μmol(7.39mg)，苯异腈单体0.60mmol(160.0mg)，己内酯0.14mmol(20.2mg),锌酸亚锡14μmol(2.0mg)抽真空充氮气重复3次，加入干燥的甲苯2.5mL，在60℃回流反应20h后，加入10mL正己烷淬灭，使聚合物沉淀析出，用正己烷洗涤5次，经离心得到棕绿色絮状沉淀，真空干燥至质量不变。得167.3mg聚合物，其数均分子量为2.72×10 4，分子量分布指数为1.22。
本实施例中的单体的结构式为:
实施例2:引发亲水苯异腈聚合反应
苯异腈聚合在无水无氧条件下进行，在10mL聚合瓶中加入实施例1制备的引发剂7.63μmol(8.21mg)，苯异腈单体0.55mmol(160.0mg)，抽真空充氮气重复3次，加入干燥的氯仿2.0mL，在60℃回流反应20h后，加入10mL正己烷淬灭，使聚合物沉淀析出，用正己烷洗涤5次，经离心得到黄色絮状沉淀，真空干燥至质量不变。得150.1mg聚异腈，其数均分子量为2.12×104，分子量分布指数为1.09。
本实施例中的苯异腈单体的结构式为：
Claims (3)
1.一种具有近红外吸收与自分类聚合特性的双官能团引发剂的制备方法，其特征在于：具有近红外吸收与自分类聚合特性的双官能团引发剂结构式如下：
所述具有近红外吸收与自分类聚合特性的双官能团引发剂的制备方法,按以下步骤操作:
a.将IR780-花青素分子与过量的4 - 氨基苯硫酚按摩尔比例1:1.12充分反应后， 分离、洗涤并干燥后得到中间体Ⅰ；
b. 将对氨基苯甲酸、无水碳酸钾、溴代丙炔按摩尔比 1:2:1.2的比例加入到干燥的乙腈中， 在氮气氛围中、 室温下搅拌反应 22-25h， 分离、 洗涤并干燥后得到中间体Ⅱ；
c.将所述中间体Ⅱ和碳酸钾、 碘化钾按摩尔比 1:2:1 的比例加入到干燥的乙腈中，滴加过量的溴乙醇， 在氮气氛围中，75-80℃反应48-50h，分离、洗涤并干燥后得到中间体Ⅲ；
d.将所述中间体Ⅲ、三乙基磷二氯化钯、氯化亚铜按摩尔比 1:1.2:0.12 的比例加入到干燥的二乙胺中，在氮气气氛中于室温搅拌反应过夜,旋蒸除去溶剂后经柱层析提纯,真空干燥后得到目标产物Ⅳ；
e.将中间体Ⅰ，Ⅳ，DCC和EDCl按1:1.02:0.8:1的比例加入到氮气气氛中于室温搅拌反应过夜，旋蒸除去溶剂后经柱层析提纯,真空干燥后得到目标产物引发剂Ⅴ。
2.一种如权利要求1所述的具有近红外吸收与自分类聚合特性的双官能团引发剂用于苯异腈或内酯类单体均聚或杂化共聚时作为催化剂的应用。
3.根据权利要求2所述的应用，其特征在于：所述杂化共聚所得到的聚合物，由于存在IR780基团，具有近红外成像能力，可用于生物显影，癌细胞跟踪，以及通过聚酯类物质在生物体内降解，从而达到包裹药物释放的目的。
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