CN116333300A - 三氟甲磺酸稀土活化制备聚四氢呋喃-聚氨基酸嵌段共聚物的方法及其产品 - Google Patents
三氟甲磺酸稀土活化制备聚四氢呋喃-聚氨基酸嵌段共聚物的方法及其产品 Download PDFInfo
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Abstract
本发明公开了一种三氟甲磺酸稀土活化制备聚四氢呋喃‑聚氨基酸嵌段共聚物的方法,以三氟甲磺酸稀土为活化剂,以含有端羟基的聚四氢呋喃为引发剂,在有机溶剂中活化引发α‑氨基酸‑N‑羧酸酐的开环聚合,制备得到聚四氢呋喃‑聚氨基酸嵌段共聚物。本发明公开的三氟甲磺酸稀土活化制备聚四氢呋喃‑聚氨基酸嵌段共聚物的方法,经一步法直接制备得到聚四氢呋喃‑聚氨基酸嵌段共聚物,引发效率高、可控性强;制备得到的共聚物分子量可调、组成可变,且分子量分布窄;除可制备两嵌段共聚物、三嵌段共聚物外,还可制备星型嵌段共聚物。
Description
技术领域
本发明涉及高分子聚合物的技术领域,尤其涉及一种三氟甲磺酸稀土活化制备聚四氢呋喃-聚氨基酸嵌段共聚物的方法及其产品。
背景技术
聚氨基酸(poly(amino acid))是一种以氨基酸残基为主链结构,组成和性质与蛋白质相似的人工合成聚合物,具有良好的生物相容性和可降解性。聚氨基酸的性质可随侧基的不同而表现多样,如刺激响应性、亲疏水性或是自催化性,在工程材料领域、生物医用领域如药物传输、生物传感器、组织工程等前景广阔故而备受关注(Prog.Polym.Sci.,2014,39,330-364)。目前,α-氨基酸-N-羧酸酐(NCA)开环聚合法是最为常用的可控合成聚氨基酸的方法(Chem.Soc.Rev.,2013,42,7373-7390)。
聚四氢呋喃是由四氢呋喃经阳离子开环聚合得到的聚合物,是氨纶、聚氨酯、聚醚酯类弹性体材料中用于调节柔韧性的重要原料之一。聚四氢呋喃柔顺性好、耐水解、抑菌、生物相容性好、化学性质稳定。由于其独特的性质,聚四氢呋喃在纺织、医疗、工程等领域具有广泛的应用前景,尤其在制备高性能弹性材料领域具有举足轻重的作用(精细化工原料及中间体,2008,3,34-37)。
聚氨基酸可以形成无规线团、α螺旋、β折叠等二级结构,因此以聚氨基酸为基底的材料具备良好的力学强度。而聚四氢呋喃主链柔顺性好,两者的嵌段共聚物可以制备以聚氨基酸为硬段、聚四氢呋喃为软段的弹性体,也可以利用聚氨基酸的亲水性与聚四氢呋喃的疏水性制备两亲性嵌段共聚物,为药物传输提供载体。该聚醚聚氨基酸共聚物的合成具有重要的研究和应用价值。
NCA通常由氨基引发聚合,但市售聚四氢呋喃仅带有羟基而不含有氨基,为了得到聚四氢呋喃-聚氨基酸嵌段共聚物,Ling等人设计了将氨基引入聚四氢呋喃链末端的方法,即在四氢呋喃聚合过程中使用终止剂原位将聚四氢呋喃末端氧鎓离子转化成保护的氨基,经脱保后即得到端氨基聚四氢呋喃。随后,该大分子引发剂被用于引发聚合得到聚四氢呋喃-聚氨基酸两嵌段共聚物(ZL 201911376690.X)。这类两嵌段共聚物可以在水溶液中形成胶束,或者用于稳定水/油乳液,在药物递送领域具有应用前景。另外,他们还尝试了将聚四氢呋喃末端羟基转化成氧胺基,用于制备三嵌段聚四氢呋喃-聚氨基酸嵌段共聚物。这类嵌段共聚物形成的胶束可以在酸性条件下发生响应断链,因此可以在药物可控释放和精准医疗领域发挥作用(Chin.J.Chem.,2021,39,2852-2856)。但是这些嵌段共聚物的合成都需要经过端基转化,操作繁琐,步骤冗杂,中间步骤的提纯过程会导致原料损失浪费,缺乏原子经济性,也提高了工业化生产的困难。
发明内容
针对现有技术的不足,本发明公开了一种三氟甲磺酸稀土活化制备聚四氢呋喃-聚氨基酸嵌段共聚物的方法,经一步法直接制备得到聚四氢呋喃-聚氨基酸嵌段共聚物,引发效率高、可控性强;制备得到的共聚物分子量可调、组成可变,且分子量分布窄;除可制备两嵌段共聚物、三嵌段共聚物外,还可制备星型嵌段共聚物。
具体技术方案如下:
一种三氟甲磺酸稀土活化制备聚四氢呋喃-聚氨基酸嵌段共聚物的方法,以三氟甲磺酸稀土为活化剂,以含有端羟基的聚四氢呋喃为引发剂,在有机溶剂中活化引发α-氨基酸-N-羧酸酐的开环聚合,制备得到聚四氢呋喃-聚氨基酸嵌段共聚物。
本发明针对现有技术中以聚四氢呋喃末端羟基直接引发α-氨基酸-N-羧酸酐的聚合效率低,体系中会残留未引发聚合的聚四氢呋喃(该残留物难以从聚四氢呋喃-聚氨基酸嵌段共聚物中分离除去),且聚合反应不可控的问题,首次提出以三氟甲磺酸稀土作为活化剂,稀土元素与聚四氢呋喃的末端羟基配位后将羟基活化,进而引发α-氨基酸-N-羧酸酐的聚合。经试验,本方法可以经一步法直接制备得到聚四氢呋喃-聚氨基酸嵌段共聚物,引发效率高,产物中未检测到聚四氢呋喃的残留;可控性极强,产物的分子量接近理论值,因此通过调控原料的投料比可对产物的分子量进行精确调控;且产物的分子量分布窄。
所述三氟甲磺酸稀土的结构式为RE(OSO2CF3)3;
RE代表稀土元素,选自钪、钇、镧、铈、镨、钕、钐、铕、钆、铽、镝、钬、铒、铥、镱、镥中的一种或多种。
本发明中公开的方法具有较佳的普适性,上述列举的稀土元素组成的三氟甲磺酸稀土对本发明中的端羟基的聚四氢呋喃均具有较佳的活化性能。
所述含有端羟基的聚四氢呋喃,结构式如下式(Ⅰ)或下式(II)所示:
R1与R2独立地选自氢或者对α-氨基酸-N-羧酸酐的开环聚合呈惰性的基团;
m选自1~4的自然数;
n1、n2代表重复单元的数目,与含有端羟基的聚四氢呋喃的数均分子量正相关。
R1与R2基团并不参与反应,因此除H外,还可选择对α-氨基酸-N-羧酸酐的开环聚合呈惰性的基团,具体选自本领域公知的符合上述条件的基团种类即可,没有特殊要求。
具体地:
R1与R2独立地选自氢、C1~C12的饱和脂肪烃基、卤素取代的C1~C12的饱和脂肪烃基、C1~C12的不饱和脂肪烃基、卤素取代的C1~C12的不饱和脂肪烃基、芳香烃基中的一种或多种。
所述芳香烃基选自4-亚甲基-苯基和/或4-亚甲基-联苯基。
式(Ⅰ)中,当R1选自H时,即为双端羟基的聚四氢呋喃;以其活化后制备的最终产物则为三嵌段共聚物。
当R1选自对α-氨基酸-N-羧酸酐的开环聚合呈惰性的基团,如上述的饱和或不饱和、有无卤素取代的脂肪烃基、芳香烃基等时,即为一端羟基的聚四氢呋喃;以其活化后制备的最终产物则为二嵌段共聚物。
式(II)中,m选自1~4的自然数,但具体取值取决于R2基团,举例说明如下:
式(II)可以选自2,2′-[[2-乙基-2-[(环氧乙基甲氧基)甲基]-1,3-联丙基]双(氧亚甲基)]三臂聚四氢呋喃(m=3),结构式如下:
或者3,3-二(2-乙氧基)-1,5-戊二醚基四臂聚四氢呋喃(m=4),结构式如下:
n 3、n4代表重复单元的数目。
优选的,所述含有端羟基的聚四氢呋喃的数均分子量为1000~10000g/mol;经试验发现,采用上述数均分子量,可以保证在聚合过程中聚四氢呋喃链中端羟基的高活性。
所述α-氨基酸-N-羧酸酐,结构式如下式(III)所示:
式中,R3、R4独立地选自氢、C1~C9饱和脂肪烃基、C1~C9不饱和脂肪烃基、芳香烃基、羧基被保护的C1~C6羧烷基(如-R-COOR)、氨基被保护的C1~C6胺烷基(如R-NH-Prot)。
具体地,可选自ε-苄氧羰基赖氨酸NCA、ε-三氟乙酰基赖氨酸NCA、γ-甲基谷氨酸酯NCA、γ-乙基谷氨酸酯NCA、γ-苄基谷氨酸酯NCA、β-苄基天冬氨酸酯NCA、甲硫氨酸NCA、丙氨酸NCA、苯丙氨酸NCA、亮氨酸NCA、异亮氨酸NCA、缬氨酸NCA、甘氨酸NCA、肌氨酸NCA、N-取代甘氨酸NCA中的一种或多种。
(R5选自C2~C9饱和脂肪烃基、C2~C9不饱和脂肪烃基、芳香烃基、羧基被保护的C1~C6羧烷基、氨基被保护的C1~C6胺烷基)
所述有机溶剂的选择很重要,需要满足同时是聚四氢呋喃、α-氨基酸-N-羧酸酐单体以及聚合产物的良溶剂。优选自四氢呋喃、甲基四氢呋喃、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四甲基脲、二甲亚砜、环丁砜、硝基苯、苯甲腈、N-甲基吡咯烷酮、甲苯、二氯甲烷、三氯甲烷中的一种或多种。经试验发现,采用优选的有机溶剂可以在聚合过程中,保证聚四氢呋喃链中端羟基的等活性。
反应体系中,α-氨基酸-N-羧酸酐的浓度为0.1~2mmol/mL,此处浓度的计算以反应体系中所有原料(包括有机溶剂、引发剂、活化剂和单体)的总体积为准。
α-氨基酸-N-羧酸酐与引发剂中羟基的摩尔比为10~500:1;优选为10~100:1。
活化剂与引发剂中羟基的摩尔比为0.01~100:1;优选为0.5~10:1。
所述开环聚合的温度为-10~100℃,时间为1h~10d。
本发明还公开了根据上述的方法制备的聚四氢呋喃-聚氨基酸嵌段共聚物,其数均分子量范围可调,约为2000~80000g/mol;且产物的分子量分布窄,PDI<1.40;且该共聚物中,四氢呋喃嵌段与氨基酸嵌段的比例可以调整,可制备两嵌段共聚物、三嵌段共聚物以及星型嵌段共聚物。
与现有技术相比,本发明具有如下有益效果:
本发明公开了一种一步法制备聚四氢呋喃-聚氨基酸嵌段共聚物的方法,以三氟甲磺酸稀土为活化剂,含有端羟基的聚四氢呋喃为引发剂,该方法的引发效率高,产物中未检测到聚四氢呋喃的残留;可控性极强,共聚产物的分子量分布窄,可通过调整单体与端羟基聚四氢呋喃的比例来调控共聚物中聚氨基酸链段的占比;制备得到的聚四氢呋喃-聚氨基酸嵌段共聚物具有很好的可降解性、生物相容性,能形成囊泡、胶束、乳液等组装体,在生物医用领域和化工生产有着巨大的应用前景。
附图说明
图1为对比例1制备产物的核磁氢谱;
图2为实施例1制备产物的核磁氢谱。
具体实施方式
下面结合实施例和对比例对本发明作进一步详细的描述,但本发明的实施方式不限于此。
聚四氢呋喃-聚氨基酸嵌段共聚物的分子量和结构分别采用凝胶渗透色谱(SEC)和核磁氢谱(1H NMR)测定。
分子量及分子量分布在SEC(Waters 2414)(六氟异丙醇作为流动相,35℃,流速为0.8mL/min)中测定。
核磁共振谱在BrukerAvance DMX 400仪器上测定,用氘代二甲基亚砜(DMSO-d6)或氘代三氯甲烷(CDCl3)作为溶剂,四甲基硅烷作为内标。
对比例1
在反应瓶中加入双端羟基聚四氢呋喃0.1626g(0.16mmol,Mn=1000g/mol),肌氨酸NCA0.1933g(1.67mmol),用3mLDMAc溶解。将反应瓶置于60℃油浴中反应48h后,在正己烷中沉淀并干燥即可得到反应产物。
产物的核磁氢谱(CDCl3)如图1所示。图1中含有肌氨酸聚合后的信号,说明肌氨酸NCA被引发。在3.60ppm处可以观察到聚四氢呋喃原料链端羟甲基的信号,说明聚合后产物中仍然存在未引发聚合的聚四氢呋喃。产物的GPC分子量为13.1kg/mol,远远超过理论值(1.7kg/mol)。
说明,在不添加三氟甲磺酸稀土的情况下,端羟基聚四氢呋喃无法完全引发肌氨酸NCA聚合,且聚合可控性非常差。
实施例1
在反应瓶中加入三氟甲磺酸镥0.0524g(0.0842mmol),肌氨酸NCA0.9662g(8.40mmol)和一端甲基一端羟基的聚四氢呋喃0.3361g(0.168mmol,Mn=2000g/mol),用17mL DMAc溶解。将反应瓶置于60℃油浴中反应48h后,在乙醚中沉淀并将所得沉淀物干燥即可得到聚四氢呋喃-聚肌氨酸两嵌段共聚物,数均分子量为5.7kg/mol,分子量分布为1.28。
产物的核磁氢谱(DMSO-d6)如图2所示。图2中各信号归属明确,证明了聚合产物结构,并且氢谱中不存在羟甲基的信号(对比图1的3.60ppm处信号),说明端羟基聚四氢呋喃完全引发了肌氨酸NCA的聚合。
产物的分子量与理论值接近,说明添加三氟甲磺酸稀土活化端羟基后引发肌氨酸NCA聚合的可控性很好。
实施例2
制备工艺与实施例1基本相同,区别仅在于将引发剂替换为Mn=4000g/mol(0.084mmol)的双端羟基聚四氢呋喃,单体与引发剂中羟基的摩尔比为50:1,所得聚四氢呋喃-聚肌氨酸三嵌段共聚物的分子量为11.8kg/mol,分子量分布为1.32。
实施例3
制备工艺与实施例1基本相同,区别在于:
将单体替换为ε-三氟乙酰基赖氨酸NCA单体;
将引发剂替换为Mn=2000g/mol(0.168mmol)的双端羟基聚四氢呋喃,单体与引发剂中羟基的摩尔比为100:1,所得聚四氢呋喃-聚氨基酸三嵌段共聚物的分子量为43.8kg/mol,分子量分布为1.29。
实施例4
制备工艺与实施例1基本相同,区别仅在于将活化剂替换为等摩尔量的三氟甲磺酸钪,所得聚四氢呋喃-聚氨基酸嵌段共聚物的分子量为5.6kg/mol,分子量分布为1.34。
实施例5
制备工艺与实施例1基本相同,区别在于:
将活化剂替换为等摩尔量的三氟甲磺酸钇;
将单体替换为等摩尔量的γ-苄基谷氨酸酯NCA;
所得聚四氢呋喃-聚氨基酸嵌段共聚物的分子量为13.1kg/mol,分子量分布为1.31。
实施例6
制备工艺与实施例1基本相同,区别在于:
将活化剂替换为0.84mmol的三氟甲磺酸镧,活化剂与引发剂中羟基的摩尔比为5:1;
将单体替换为等摩尔量的甲硫氨酸NCA;
所得聚四氢呋喃-聚氨基酸嵌段共聚物的分子量为9.2kg/mol,分子量分布为1.33。
实施例7
制备工艺与实施例1基本相同,区别在于:
将反应溶剂替换为等体积的四氢呋喃;
将单体替换为ε-苄氧羰基赖氨酸NCA,单体与引发剂中羟基的摩尔比为100:1;
反应温度替换为25℃,反应时间替换为5天;
所得聚四氢呋喃-聚氨基酸嵌段共聚物的分子量为28.2kg/mol,分子量分布为1.27。
实施例9
制备工艺与实施例1基本相同,区别在于:
将反应溶剂替换为等体积的四氢呋喃;
将单体替换为N-乙基甘氨酸NCA,单体与引发剂的摩尔比为50:1;
以2,2′-[[2-乙基-2-[(环氧乙基甲氧基)甲基]-1,3-联丙基]双(氧亚甲基)]三臂聚四氢呋喃(Mn=4000g/mol,0.1mmol)作为引发剂;
聚合反应温度替换为40℃;
所得聚四氢呋喃-聚氨基酸嵌段共聚物的分子量为8.4kg/mol,分子量分布为1.32。
申请人声明,本发明通过上述实施例来说明本发明的详细方法,但本发明并不局限于上述详细方法。
Claims (10)
1.一种三氟甲磺酸稀土活化制备聚四氢呋喃-聚氨基酸嵌段共聚物的方法,其特征在于,以三氟甲磺酸稀土为活化剂,以含有端羟基的聚四氢呋喃为引发剂,在有机溶剂中活化引发α-氨基酸-N-羧酸酐的开环聚合,制备得到聚四氢呋喃-聚氨基酸嵌段共聚物。
2.根据权利要求1所述的三氟甲磺酸稀土活化制备聚四氢呋喃-聚氨基酸嵌段共聚物的方法,其特征在于:
所述三氟甲磺酸稀土的结构式为RE(OSO2CF3)3;
RE代表稀土元素,选自钪、钇、镧、铈、镨、钕、钐、铕、钆、铽、镝、钬、铒、铥、镱、镥中的一种或多种。
4.根据权利要求3所述的三氟甲磺酸稀土活化制备聚四氢呋喃-聚氨基酸嵌段共聚物的方法,其特征在于,R1与R2独立地选自氢、C1~C12的饱和脂肪烃基、卤素取代的C1~C12的饱和脂肪烃基、C1~C12的不饱和脂肪烃基、卤素取代的C1~C12的不饱和脂肪烃基、芳香烃基中的一种或多种。
6.根据权利要求5所述的三氟甲磺酸稀土活化制备聚四氢呋喃-聚氨基酸嵌段共聚物的方法,其特征在于,所述α-氨基酸-N-羧酸酐选自ε-苄氧羰基赖氨酸NCA、ε-三氟乙酰基赖氨酸NCA、γ-甲基谷氨酸酯NCA、γ-乙基谷氨酸酯NCA、γ-苄基谷氨酸酯NCA、β-苄基天冬氨酸酯NCA、甲硫氨酸NCA、丙氨酸NCA、苯丙氨酸NCA、亮氨酸NCA、异亮氨酸NCA、缬氨酸NCA、甘氨酸NCA、肌氨酸NCA、N-取代甘氨酸NCA中的一种或多种。
7.根据权利要求1所述的三氟甲磺酸稀土活化制备聚四氢呋喃-聚氨基酸嵌段共聚物的方法,其特征在于,所述有机溶剂选自四氢呋喃、甲基四氢呋喃、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四甲基脲、二甲亚砜、环丁砜、硝基苯、苯甲腈、N-甲基吡咯烷酮、甲苯、二氯甲烷、三氯甲烷中的一种或多种。
8.根据权利要求1所述的三氟甲磺酸稀土活化制备聚四氢呋喃-聚氨基酸嵌段共聚物的方法,其特征在于:
反应体系中,α-氨基酸-N-羧酸酐的浓度为0.1~2mmol/mL;
α-氨基酸-N-羧酸酐与引发剂中羟基的摩尔比为10~500:1;
活化剂与引发剂中羟基的摩尔比为0.01~100:1。
9.根据权利要求1所述的三氟甲磺酸稀土活化制备聚四氢呋喃-聚氨基酸嵌段共聚物的方法,其特征在于,所述开环聚合的温度为-10~100℃,时间为1h~10d。
10.一种根据权利要求1~9任一项所述的方法制备的聚四氢呋喃-聚氨基酸嵌段共聚物,其特征在于,分子量分布PDI<1.40。
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