CN105209520B - 超支化聚甘油的生产方法 - Google Patents
超支化聚甘油的生产方法 Download PDFInfo
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Abstract
本发明涉及一种由甘油生产超支化树枝状聚甘油的方法，所述方法包括以下步骤：(a)在容器中添加甘油和CaO基催化剂；(b)向得到的混合物中灌注惰性气体、优选为二氧化碳，并密封所述反应容器，形成高于大气压1～10巴的压力、优选为高于大气压2～6巴；(c)在至少100℃但低于反应混合物沸点的反应温度下加热所述反应混合物；(d)保持所述反应条件直到至少40wt％的甘油进行缩聚并转化成超支化聚甘油，同时伴随有水的生成；(e)将树枝状聚甘油与混合物中存在的其他组分分离；例如水、催化剂、和诸如羟基酸、通过缩合去质子化的甘油与二氧化碳而得到的甘油碳酸酯以及少量的环状化合物等反应副产物。(i)所述方法的特征在于，所述钙基催化剂为粉末形式的纳米结构的氧化钙，根据ASTM D4464测得的平均粒径小于100nm。
Description
技术领域
本发明涉及一种在特定催化剂的存在下使甘油进行缩聚来生产超支化聚甘油的方法。
背景技术
超支化聚甘油(hbPG)是一种具有惰性聚醚骨架的高度支化的多元醇，其高官能度与其羟基官能度的多面且熟知的反应性相结合形成了各种有用衍生物的基础(参见Frey,H.和Haag,R.的“树枝状聚甘油：一种新型多功能生物相容性材料(DendriticPolyglycerol:A New Versatile Biocompatible Material),”Rev.Mol.Biotech，90(2002)257-267)。每个分支的端部为羟基官能，这使得超支化聚甘油成为高功能性材料；例如，分子量为5,000g·mol–1的分子可具有68个羟基端基。许多聚甘油可商购，应用范围从化妆品到药物控释。例如，聚甘油与脂肪酸部分酯化得到表现为纳米胶囊的两亲材料。这样的纳米胶囊例如可吸收作为客体的极性分子，并且使它们溶解在非极性环境中。生物相容性是包含羟基端基的脂族聚醚结构(包括聚甘油或线性聚乙二醇(PEG))的一个有吸引力的特征，它们被批准用于各种各样的医疗和生物医学应用中。
如今，超支化聚甘油主要通过在缓慢添加单体的情况下使缩水甘油进行阴离子开环多支化聚合来控制甘油的醚化而进行工业化生产。这样的条件得到的聚合物具有低和窄的多分散性(Mw/Mn＝1.2-1.9)，数均分子量(Mn)高达24,000g·mol–1。详细而言，超支化聚甘油通常是利用阳离子或阴离子使缩水甘油进行开环聚合而制备的(参见R.Tokar、P.Kubisa和S.Penczek的“缩水甘油的阳离子缩聚：活性单体和活性链端机理的共存(Cationicpolymerization of glycidol:coexistence of the activated monomer and activechain end mechanism)”,Macromolecules,27(1994)320-322)和A.Sunder、R.Hanselmann、H.Frey、R.Mülhaupt的“通过开环多支化缩聚来受控合成超支化聚甘油(Controlledsynthesis of hyperbranched polyglycerols by ring-opening multibranchingpolymerization)”,Macromolecules,32(1999)4240-4246)。
这种多用途材料的应用数量和范围巨大，并且在日益增加(参见Wilms,D.、Stiriba,S.-E.和Frey,H.的“超支化聚甘油：从受控合成生物相容性聚醚多元醇至综合应用(Hyperbranched Polyglycerols:From the Controlled Synthesis of BiocompatiblePolyether Polyols to Multipurpose Applications)”Acc.Chem.Res.43(2010),129-141)。最近，例如，已经报道了树枝状聚甘油硫酸盐作为有效的炎症抑制剂的性质(参见Haag,R.等人的“树枝状聚甘油硫酸盐作为炎症多价抑制剂(Dendritic polyglycerolsulfates as multivalent inhibitors of inflammation)”Proc.Natl.Acad.Sci.USA107(2010)19679-19684)。
德国专利申请DE10211664A1公开了一种制备这样的聚甘油聚合物的方法，该方法包括在含水介质中在水溶性碱性催化剂的存在下使溶液中的缩水甘油进行聚合的步骤和使聚甘油聚合物具有水溶性的化学变化步骤。WO2009153529公开了另一种制备丙烯醛聚合物的方法，该方法包括在酸催化剂的存在下使甘油从甘油水溶液中脱水的第一步骤，随后在离子催化剂或自由基引发剂的存在下使得到的物质进行聚合。
前述方法的一个缺点在于传统的合成技术始于昂贵的缩水甘油—一种需要使烯丙醇进行环氧化的环状化合物。而且，缩水甘油被列为IARC组2A致癌物质，是一种对皮肤、眼睛、粘膜和上呼吸道有刺激性的有毒化合物。显然，始于无毒的、容易获得的甘油来获得超支化聚甘油的方法的途径会更可取。除了无毒，目前巨大的量(2百万吨/年)的甘油作为生物柴油制造以及来自于脂肪酸盐和游离脂肪酸的生产的副产物获得(参见M.Pagliaro和M.Rossi的“甘油的未来(The Future of Glycerol)；”RSC Publishing,Cambridge:2010)。
回顾上文，所有生产超支化聚甘油的方法都始于缩水甘油的开环多支化聚合(ROMBP)，或者都涉及缩水甘油或缩水甘油衍生物，如甲基丙烯酸缩水甘油酯(参见M.Hu等人的“用于药物递送的具有酯键的生物可降解超支化聚甘油(BiodegradableHyperbranched Polyglycerol with Ester Linkages for Drug Delivery)”,Biomacromolecules 11(2012),3552-3561)。
ROBMP合成方法的另一个缺点在于它仅仅提供最大尺寸约为3～10nm的聚合物，而纳米颗粒生物医学应用的最佳尺寸却是直径为25～100nm。目前，提出了一种通过细乳液模板法将生成树结构(spanning structure)从超支化聚甘油(3nm)扩展成纳米凝胶(32nm)和微凝胶(140mm和220mm)来制备不同长度级别的聚甘油颗粒的方法(参见DirkSteinhilber、Sebastian Seiffert、John A.Heyman、Florian Paulus、David A.WeitzRainer Haag的“纳米和微米级超支化聚甘油(Hyperbranched polyglycerols on thenanometer and micrometer scale),”Biomaterials,32(2011)1311-1316)。
线性聚甘油通常由碱性二元金属氧化物催化甘油醚化获得。例如，WO2010/044531中记载了能够生产高产率的线性聚甘油的CaO基醚化方法。线性聚甘油适合并且被批准作为化妆品或食品添加剂。最近报道了类似的纳米结构的CaO在Ar中、不存在溶剂的情况下、在220℃下使甘油醚化成双甘油的特殊性质(参见A.M.Ruppert、J.D.Meeldijk、B.W.M.Kuipers、B.H.Erné、B.M.Weckhuysen的“甘油醚化高活性CaO基材料：新机理方面以及相关的胶粒形成(Glycerol etherification over highly active CaO-basedmaterials:new mechanistic aspects and related colloidal particle formation)”,Chem.Eur.J.14(2008)2016-2024)，而市售的CaO活性差。据我们所知，尚未报道基于常规的或纳米结构的CaO催化剂获得超支化聚甘油的途径。本发明提供一种生产树枝状聚甘油的方法，该方法便宜、简单、绿色，而且产率高。后文将呈现本发明的这个优点及其他优点。
发明内容
本发明在后附的独立权利要求中限定。优选的实施方式在从属权利要求中限定。特别地，本发明涉及一种由甘油生产超支化聚甘油的方法，所述方法包括以下步骤：
(a)在容器中添加甘油和CaO基催化剂，
(b)向得到的混合物中灌注惰性气体、优选为二氧化碳，并密封所述反应容器，形成高于大气压1～10巴的压力，优选为高于大气压2～6巴；
(c)在至少100℃但低于反应混合物沸点的反应温度下加热所述反应混合物；
(d)保持所述反应条件直到至少40wt％的甘油进行缩聚并转化成超支化聚甘油，同时伴随有水的生成；
(e)将树枝状聚甘油与混合物中存在的其他组分分离；例如水、催化剂、和羟基酸、典型地例如通过缩合去质子化的甘油与二氧化碳而得到的甘油碳酸酯等反应副产物。
(f)所述方法的特征在于，所述钙基催化剂为粉末形式的纳米结构的氧化钙，根据ASTM D4464测得的平均粒径通常小于100nm。在本文中，表述“超支化聚甘油”和“树枝状聚甘油”作为同义词使用，是指结合了以下特征的聚甘油：稳定且生物相容的聚醚骨架，高端基官能度，以及紧凑、明确的树枝状分子结构，即形成反复支化的分子。
优选所述钙基催化剂具有强路易斯酸性，因为这代表高活性。催化剂的路易斯活性可通过测量被吸附的吡啶的C＝C伸缩振动带与气相吡啶的C＝C伸缩振动带的值1580cm-1相比发生的蓝移Δν8a来表征。本发明的氧化钙催化剂的蓝移优选为14～20cm-1、更优选为16～19cm-1、最优选为1.5～18.5cm-1。本发明的纳米结构的CaO催化剂的BET比表面积优选大于50m2/g、更优选为60～100m2/g。所述纳米结构的催化剂呈粉末形式，平均粒径通常小于100nm、优选小于50nm、更优选小于20nm。
在一个实施方式中，所述纳米结构的氧化钙是通过在至少500℃的温度下将Ca(NO3)2·4H2O加热至少50分钟获得。在另一个实施方式中，可以在至少350℃的温度下将Ca(OH)2加热长达12小时。在又一个另外的实施方式中，所述纳米结构的氧化钙是通过以下步骤获得：
·添加水使有机溶剂中处于溶解状态的Ca(OCH3)2水解；
·在高压釜中、在至少200℃的温度和高压下处理水解后的溶液来形成Ca(OH)2；
·在至少300℃和低于10-2托的低压下进行热处理，将得到的Ca(OH)2转变成CaO。
本发明的巨大优势在于将甘油转化成超支化聚甘油可以以液相进行，基本上不含溶剂或含水介质。在优选的实施方式中，相对于甘油和催化剂的总重量，混合物中存在的钙基催化剂的量为4～30mol％、优选为5～25mol％、更优选为10～20mol％。步骤(c)中的反应温度优选为至少120℃、更优选为至少160℃、最优选为至少220℃。所述反应优选在二氧化碳气氛中进行，或在惰性气体如氮气中进行。
根据催化剂的活性和反应条件，步骤(d)中树枝状聚甘油的产率可以为至少50wt％、优选为至少60wt％、更优选为至少80wt％。优选通过过滤将催化剂与步骤(e)中的混合物分离。
由此产生的树枝状聚甘油可溶于水、EtOH、DMF和MeOH，基于表面官能团稍有不同，并且可有利地用作许多应用中的纳米转运体，所述应用包括通过封装高度疏水和亲水的药物或荧光化合物对药品进行非均相催化、以及封装染料、香料和维生素E的化妆品。另外的应用包括但不限于用作洗涤剂或清洗剂中的水软化剂或用于结合使抗体、蛋白质或含有伯胺基团的药物。
附图说明
为了更充分地理解本发明的本质，参考以下结合附图的详细说明，其中：
图1示出了本发明通过催化缩聚甘油形成树枝状聚甘油的反应流程。
图2示出了对由本发明的方法获得的样品测得的NMR谱。
具体实施方式
根据背景技术部分的讨论，迄今为止已知的生产树枝状聚甘油的甘油缩聚方法通常都具有相当低的产率，或者必须以气相进行，或者必须分散在溶剂或含水介质中。本发明提出了一种新的由甘油生产超支化聚甘油的方法，所述方法包括以下步骤：
(a)在容器中添加甘油和CaO基催化剂，
(b)向得到的混合物中灌注惰性气体、优选为二氧化碳，并密封所述反应容器，形成高于大气压1～10巴的压力、优选为高于大气压2～6巴；
(c)在至少100℃但低于反应混合物沸点的反应温度下加热所述反应混合物；
(d)保持所述反应条件直到至少40wt％的甘油进行缩聚并转化成超支化聚甘油，同时伴随有水的生成；
(e)将树枝状聚甘油与混合物中存在的其他组分分离；例如水、催化剂、和羟基酸、通过缩合去质子化的甘油与二氧化碳而得到的甘油碳酸酯以及少量的环状化合物等反应副产物。
图1示出了与本发明的方法有关的反应流程。所述钙基催化剂是本领域已知的纳米结构的氧化钙，是通过处理常规的氧化钙而改变和提高氧化物催化活性而得到的。在Ruppert等人，Chem.Eur.J.,14,(2008)2016-2024中记载了适合于本发明的纳米结构的氧化钙催化剂的实例，该纳米结构的氧化钙催化剂是通过在10-3托的真空下热处理氢氧化钙(Ca(OH)2)得到的，根据以下处理进行了加热：以0.5℃·min-1的速率使温度从25℃升至350℃，然后在350℃的温度下保持1小时；随后以1℃·min-1的速率进一步加热至400℃，再在该温度下保持1小时。在另一个实施方式中，所述催化剂是通过在炉中在350～450℃和大气压下将市售的Ca(OH)2煅烧长达12小时来获得的。不同的温度和不同的反应时间将生成具有不同性质和活性程度的CaO。
Ruppert等人的文献中记载的、适用于本发明的纳米结构的氧化钙催化剂可用另一种方法通过在至少500℃的温度下将Ca(NO3)2·4H2O加热至少50分钟获得。例如，具有优异活性的催化剂可通过将Ca(NO3)2·4H2O以10℃/min的加热速率加热约2小时直至达到保持的温度650-700℃来获得。在又一个另外的制备方法中，溶解在有机溶剂中的Ca(OCH3)2溶液可通过在室温下添加去离子水来进行。特别地，如果有机溶剂包含甲醇，则由此可形成水解的甲醇钙。然后，可在高压釜中在高温和高压下处理该混合物。该温度应至少为200℃、优选至少为220℃，该压力为10～60巴、优选为25～50巴。由此形成的氢氧化钙可通过在大约10-3～10-2托的低压下将Ca(OH)2加热至高达450℃的温度来转变成CaO。
由此获得的纳米结构的CaO的活性基本上比常规的CaO高。特别地，它的路易斯酸性比常规的CaO高。如在A.Travert、A.Vimont等人，Appl.Catal.A,307(2006)98-107(该文献的内容通过引用并入本文)中所示，与气相吡啶的C＝C伸缩振动带的值1580cm-1相比，被吸附的吡啶的C＝C伸缩振动带发生的蓝移Δν8a随着路易斯酸位点与吡啶分子相互作用的强度的增加而增大。对于常规的CaO，发生的蓝移Δν8a通常为1～5cm-1，而本发明的纳米结构的CaO催化剂优选特征在于发生更大的蓝移，其Δν8a值通常为14～20cm-1、优选为16～19cm-1、更优选为17.5～18.5cm-1。本发明的纳米结构的CaO催化剂的比表面积比常规的CaO大，与在R.H.Borgwardt,AIChE Journal,31,(1985)103–111中报道的通常为5～10m2/g的常规CaO的BET比表面积相比，纳米结构的CaO的BET比表面积至少为50m2/g，通常为60～100m2/g、优选为65～90m2/g。本发明的方法中使用的纳米结构的CaO催化剂呈粉末形式，由团聚的CaO纳米颗粒构成，平均粒径通常在1-90μm的范围之间。
所述粉末形式的纳米结构的催化剂的平均粒径通常小于100nm、优选小于50nm、更优选小于20nm。发现为约10nm的平均粒径产生的效果极好。在干燥状态和室温下，所述颗粒可形成微米范围的团聚体，该团聚体在加热甘油时分解。在反应完成且温度降下来后，纳米颗粒聚结以形成较大的聚集体，随时准备催化下一批甘油的缩聚。平均粒径可根据ASTMD4464-10通过激光光散射来方便地测量。当然可使用其他技术。
所述钙基催化剂可以相对于甘油的总重量为4～30mol.％之间的任意量存在于所述混合物中。优选该存在的催化剂的量为5～25mol.％、更优选为10～20mol.％。将催化剂与甘油直接混合，在灌注CO2后可在密闭的容器中将混合物加热至反应温度。
本发明一个大优势在于甘油缩聚以液相进行，而无需任何必须随后除去的溶剂或含水介质，而且反应发生在一个容器中，直接将甘油转化为超支化聚甘油。步骤(c)中的反应温度优选为180～280℃、更优选为200～250℃、最优选为215～225℃。反应优选在二氧化碳气氛(优选为2～6巴)中进行，或者在惰性气氛如氮气或氩气中进行。反应在密闭的容器中进行以使因气相水的释放形成高于大气压的30巴的压力。超支化聚甘油的产率为至少50wt％、优选为至少60wt％；更优选为至少80wt％的产率，可用本发明的方法实现，这远高于包括甘油缩聚在内的大部分现有技术。
图2示出了从根据本发明生产的样品获得的质子NMR谱。将在30mol％的纳米结构的CaO的存在下在220℃进行甘油聚合5小时得到的样品简单地溶解于氘代甲醇中，根据已知技术在Bruker 400MHz波谱仪中记录NMR谱。所述谱图清楚地表明存在超支化聚甘油。A.Sunder等人的“基于聚甘油的超支化聚醚-多元醇：与丙烯氧化物嵌段共聚的极性设计(Hyperbranched polyether-polyols based on polyglycerol:polarity design byblock copolymerization with propylene oxide)”,Macromolecules,33(2000)309-314中使用和记载了一种类似的方法。
除了形成树枝状聚甘油，NMR分析揭示了少量有价值的羟基酸的形成以及将CO2固定于甘油上形成的甘油碳酸酯的形成。在反应结束时，通过简单的离心容易将聚合物与固体催化剂分离开，并根据甘油和聚甘油工业中使用的公知分离技术通过蒸馏容易将其与剩下的副产物分离开。由此生产的树枝状聚甘油可有利地用在包括以下应用的任何应用中：转化成粘合剂和密封剂、作为用于受控递送和释放药物、基因等活性成分的载体、用脂肪酸衍生后用于化妆品中等，如综述这种多用途聚醚树枝状聚合物的多种形式的应用的Frey和合作者在“Hyperbranched Polyglycerols:From the Controlled Synthesis ofBiocompatible Polyether Polyols to Multipurpose Applications”Acc.Chem.Res.,43(2010),129-141”中的记载。
使用纳米结构的CaO作为通过缩聚甘油来生产树枝状聚甘油的催化剂比现有技术的方法更有利，因为：
·反应发生在一个容器中，直接将甘油转化为超支化聚甘油。
·无需必须随后除去的溶剂或含水介质
·反应中没有使用缩水甘油，具有相当大的经济、安全和健康优势
·本发明的方法可实现树枝状聚甘油的约为95％及以上的极高的产率
·可通过过滤或离心简单地实现树枝状聚甘油与固体催化剂和其他副产物的分离来产生适合于任何进一步应用的随时可用的超支化聚甘油。
Claims (14)
1.一种由甘油生产树枝状聚甘油的方法，所述方法包括以下步骤：
(a)在容器中添加甘油和钙基催化剂；
(b)向得到的混合物中灌注惰性气体，并密封反应容器，形成高于大气压1巴～高于大气压10巴的压力；
(c)在至少100℃但低于反应混合物沸点的反应温度下加热所述反应混合物；
(d)保持反应条件直到至少40wt％的甘油被缩聚并转化成超支化聚甘油，同时伴随有水的生成；
(e)将树枝状聚甘油与混合物中存在的其他组分分离；所述其他组分包括：水、催化剂和含有羟基酸、甘油碳酸酯以及少量的环状化合物的反应副产物，
所述方法的特征在于，所述钙基催化剂为粉末形式的纳米结构的氧化钙，根据ASTMD4464测得的平均粒径小于100nm。
2.根据权利要求1所述的方法，其中，与气相吡啶的C＝C伸缩振动带的值1580cm-1相比，所述纳米结构的氧化钙使被吸附的吡啶的C＝C伸缩振动带发生蓝移，蓝移量Δν8a为14～20cm-1。
3.根据权利要求1所述的方法，其中，相对于甘油和催化剂的总重量，所述混合物中存在的所述钙基催化剂的量为4～30mol％。
4.根据权利要求1所述的方法，其中，纳米结构的氧化钙催化剂的BET比表面积大于50m2/g。
5.根据权利要求1所述的方法，其中，所述纳米结构的氧化钙通过在至少500℃的温度下将Ca(NO3)2·4H2O加热至少50分钟来获得，或者通过在至少350℃的温度下将Ca(OH)2加热长达12小时来获得。
6.根据权利要求1所述的方法，其中，所述纳米结构的氧化钙通过以下步骤获得：
(a)添加水使有机溶剂中处于溶解状态的Ca(OCH3)2水解；
(b)在高压釜中，在至少200℃的温度和高压下处理水解后的溶液来形成Ca(OH)2；
(c)在至少300℃和不超过10-2托的低压下进行热处理，将得到的Ca(OH)2转变成CaO。
7.根据权利要求1所述的方法，其中，所述钙基催化剂为平均粒径小于50nm的粉末形式。
8.根据权利要求1所述的方法，其中，所述甘油缩聚以熔融相进行，基本上不含溶剂或除缩聚过程中生成的水以外的其他含水介质。
9.根据权利要求1所述的方法，其中，所述反应温度为至少120℃。
10.根据权利要求1所述的方法，其中，所述反应在氮气气氛或二氧化碳中进行。
11.根据权利要求1所述的方法，其中，树枝状聚甘油的产率为至少50wt％。
12.根据权利要求1所述的方法，其中，通过过滤将所述催化剂与聚甘油分离。
13.根据在前的权利要求中任一项所述的方法，其中，由此获得的树枝状聚甘油被用作活性化合物的受控递送和释放的载体；用脂肪酸衍生后用于化妆品中；被用作洗涤剂或漂洗剂中的水软化剂；或者被用于结合抗体、蛋白质或含有伯胺基团的药物；以及粘合剂或者密封剂。
14.纳米结构的氧化钙催化剂用于生产权利要求1所述方法得到的树枝状聚甘油的用途，其中，与气相吡啶的C＝C伸缩振动带的值1580cm-1相比，所述纳米结构的氧化钙催化剂使被吸附的吡啶的C＝C伸缩振动带发生蓝移，蓝移量Δν8a为14～20cm-1。
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| EP13151096.8 | 2013-01-13 | ||
| EP13151096.8A EP2754684A1 (en) | 2013-01-13 | 2013-01-13 | Method for the production of hyperbranched polyglycerol |
| PCT/EP2014/050438 WO2014108524A1 (en) | 2013-01-13 | 2014-01-13 | Method for the production of hyperbranched polyglycerol |
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| EP3721875B1 (en) | 2014-05-09 | 2023-11-08 | Yale University | Particles coated with hyperbranched polyglycerol and methods for their preparation |
| CN104725627B (zh) * | 2015-01-28 | 2017-07-07 | 浙江大学 | 一种聚甘油结构树枝状大分子及其制备方法和应用 |
| EP3294275B1 (en) | 2015-05-11 | 2024-02-21 | Yale University | Topical formulation of hyperbranched polymer-coated particles |
| EP3416976A2 (en) | 2016-02-16 | 2018-12-26 | Yale University | Compositions for enhancing targeted gene editing and methods of use thereof |
| KR20180116543A (ko) * | 2017-04-17 | 2018-10-25 | (주)아모레퍼시픽 | 신규한 하이퍼브랜치 형태의 폴리글리세롤계 화합물 및 이를 포함하는 화장료 조성물 |
| US20220280656A1 (en) | 2019-07-31 | 2022-09-08 | Yale University | Compositions and methods for treating sickle cell disease |
| CN112126070B (zh) * | 2020-08-27 | 2022-04-26 | 合肥飞木生物科技有限公司 | 一种超支化聚合甘油酯生物基增塑剂及其制备方法和应用 |
| CN114316248A (zh) * | 2020-09-29 | 2022-04-12 | 上海抚佳精细化工有限公司 | 一种改性超支化聚缩水甘油醚、制备方法及其应用 |
| CN113354981B (zh) * | 2021-06-29 | 2022-11-15 | 铜陵晖闪数码科技有限公司 | 一种热转印墨水及其制备方法 |
| WO2023200974A1 (en) | 2022-04-14 | 2023-10-19 | Yale University | Nanoparticles and nanoparticle-releasing vaginal rings |
| WO2023220067A1 (en) | 2022-05-09 | 2023-11-16 | Yale University | Immunotherapy of skin cancer using mpla-loaded hpg nanoparticles |
| WO2024102876A1 (en) | 2022-11-10 | 2024-05-16 | Yale University | Intrathecal nanoparticle delivery for treatment of leptomeningeal tumors with core-shell particles made of hyperbranched polyglycerol and polylactic acid |
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