CN100404585C - A kind of polyoxyethylene block polymer ligand and its synthesis method - Google Patents
A kind of polyoxyethylene block polymer ligand and its synthesis method Download PDFInfo
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- CN100404585C CN100404585C CNB2006100261327A CN200610026132A CN100404585C CN 100404585 C CN100404585 C CN 100404585C CN B2006100261327 A CNB2006100261327 A CN B2006100261327A CN 200610026132 A CN200610026132 A CN 200610026132A CN 100404585 C CN100404585 C CN 100404585C
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- 229920003171 Poly (ethylene oxide) Polymers 0.000 title claims abstract description 84
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Abstract
一种聚氧乙烯类嵌段聚合物配体及其合成方法，涉及含苯甲酸及其衍生物的聚氧乙烯/二乙三胺五乙酸(BEN/PEO/DTPA)嵌段聚合物配体及其合成方法，属于医药和化学合成技术领域。本发明的合成路线是：(a)羧基活化的苯甲酸及其衍生物与端胺基嵌段聚氧乙烯改性的配体反应，制得BEN/PEO/DTPA嵌段聚合物配体粗制品；(b)提纯BEN/PEO/DTPA嵌段聚合物配体粗制品，制得BEN/PEO/DTPA嵌段聚合物配体的精制品，乳白色粉末。本发明原料来源丰富，成本低；合成路线简单；产物提纯步骤简单；产物产率高；制成的造影剂在体内停留时间延长；易溶于水，能满足造影剂静脉注射的要求；可作为血池造影剂；可在体内降解；具有生物活性，能用于包覆多肽、蛋白质、DNA或者西药，延长药物半衰期，有利于医疗诊断。
A polyoxyethylene block polymer ligand and a synthesis method thereof, relating to a polyoxyethylene/diethylenetriaminepentaacetic acid (BEN/PEO/DTPA) block polymer ligand containing benzoic acid and its derivatives and The synthesis method belongs to the technical field of medicine and chemical synthesis. The synthetic route of the present invention is: (a) benzoic acid and derivatives thereof activated by the carboxyl group react with the ligand modified by the amino-terminated block polyoxyethylene to prepare the crude product of the BEN/PEO/DTPA block polymer ligand ; (b) Purify the crude product of BEN/PEO/DTPA block polymer ligand to obtain the refined product of BEN/PEO/DTPA block polymer ligand, milky white powder. The invention has abundant sources of raw materials and low cost; the synthesis route is simple; the product purification steps are simple; the product yield is high; the prepared contrast agent has a prolonged residence time in the body; it is easily soluble in water and can meet the requirements of intravenous injection of the contrast agent; it can be used as Blood pool contrast agent; can be degraded in the body; has biological activity, can be used to coat polypeptides, proteins, DNA or western medicines, prolong the half-life of drugs, and is beneficial to medical diagnosis.
Description
技术领域 technical field
本发明涉及一种含苯甲酸及其衍生物的聚氧乙烯/二乙三胺五乙酸(BEN/PEO/DTPA)嵌段聚合物配体及合成方法，属医药和化学合成技术领域。The invention relates to a polyoxyethylene/diethylenetriaminepentaacetic acid (BEN/PEO/DTPA) block polymer ligand containing benzoic acid and its derivatives and a synthesis method, belonging to the technical fields of medicine and chemical synthesis.
背景技术 Background technique
磁共振成像是最新医学影像技术，它所面临的问题是如何提高成像的灵敏度和图像的清晰度，使用磁共振成像造影剂是解决这一问题的有效途径。磁共振成像造影剂一般为顺磁性金属离子的配合物，配体多为含多氨基和多羧基的线形和环状化合物，在金属离子中钆离子的顺磁性最强。大分子顺磁性金属离子配合物与小分子顺磁性金属离子配合物相比，不仅具有弛豫速率较高的优点，而且还可用于血管造影，因而大分子顺磁性金属离子配合物近年来成了一个活跃的研究领域。Magnetic resonance imaging is the latest medical imaging technology. The problem it faces is how to improve the imaging sensitivity and image clarity. The use of magnetic resonance imaging contrast agent is an effective way to solve this problem. Magnetic resonance imaging contrast agents are generally complexes of paramagnetic metal ions, and the ligands are mostly linear and cyclic compounds containing polyamino groups and polycarboxylates. Among metal ions, gadolinium ions have the strongest paramagnetism. Compared with small molecular paramagnetic metal ion complexes, macromolecular paramagnetic metal ion complexes not only have the advantage of higher relaxation rate, but also can be used for angiography. Therefore, macromolecular paramagnetic metal ion complexes have become popular in recent years. an active area of research.
具有靶向性的、半衰期长、弛豫率高的造影剂是近年来的研究热点，这种造影剂可以使待检测器官成像清晰，对临床磁共振检测和病情的诊断有益。在生命科学领域，靶向多肽及靶向药物是否对特殊器官或病变部位具有靶向性，基因治疗方法的早期安全性评估等方面都需要更科学的检测跟踪方法，用磁共振成像可以无需杀死实验动物，长时间跟踪，所以半衰期长、弛豫率高的造影剂已成为一种必不可少的关键药剂。另一方面，大多数多肽、蛋白质、DNA等生化药物具有非常快的代谢速度(plasma clearance)，并且能够被免疫，所以需要经常注射以确保其在病人血液中维持稳定的药理学浓度。这些靶向药物可以与高分子造影剂通过分子间氢键作用，这样高分子既延长造影剂的半衰期、又延长了靶向药物的半衰期、同时又可以进行跟踪监测。Contrast agents with targeting, long half-life, and high relaxation rate have become research hotspots in recent years. This contrast agent can make the images of the organs to be detected clear, and is beneficial to clinical magnetic resonance detection and disease diagnosis. In the field of life sciences, whether targeted peptides and targeted drugs can target specific organs or lesion sites, early safety assessment of gene therapy methods, etc. need more scientific detection and tracking methods. Magnetic resonance imaging can be used without killing Dead experimental animals are followed for a long time, so the contrast agent with long half-life and high relaxation rate has become an essential key agent. On the other hand, most biochemical drugs such as peptides, proteins, and DNA have very fast metabolism (plasma clearance) and can be immunized, so frequent injections are required to ensure that they maintain a stable pharmacological concentration in the patient's blood. These targeted drugs can interact with polymer contrast agents through intermolecular hydrogen bonds, so that the polymers can not only prolong the half-life of contrast agents, but also prolong the half-life of targeted drugs, and can be tracked and monitored at the same time.
聚氧乙烯及其衍生物(PEG)具有两亲性、无毒、免疫原性低、生物相容性好、种类多等优点，常用于蛋白质、多肽生物药物制备、西药添加剂和制备生物医用材料。用PEG改性二乙三胺五乙酸造影剂，有聚氧乙烯的所有优点。带有极性基团的聚氧乙烯对其它分子进行包覆时，有利于形成氢键，可以进行药物的修饰。Polyoxyethylene and its derivatives (PEG) have the advantages of amphiphilicity, non-toxicity, low immunogenicity, good biocompatibility, and various types, and are often used in the preparation of protein and polypeptide biopharmaceuticals, western medicine additives, and the preparation of biomedical materials . PEG-modified diethylenetriaminepentaacetic acid contrast agent has all the advantages of polyoxyethylene. When polyoxyethylene with polar groups coats other molecules, it is conducive to the formation of hydrogen bonds and can be used for drug modification.
专利号和标题分别为US 4,647,447和“Diagnostic Media(诊断媒介物)”的美国专利涉及二乙三胺五乙酸配合物的合成，并且涉及到该配合物与葡甲胺成盐，合成钆喷酸葡胺造影剂。该造影剂已在临床上广泛应用。但是钆喷酸葡胺分子量小，排泄太快，消除半衰期约20～100分钟；这种试剂没有组织和器官选择性，且几乎完全通过肝排泻，对肝胆系统的造影效果不理想；由于代谢速度过快，颅脑及脊髓磁共振成像，需在30分钟内再次给药；判断病人是属于成人病变还是肿瘤复发，需要增加用量；增加了该药物用量，增加了人体排毒量，也提高了负作用的几率；钆喷酸葡胺造影剂不具有靶向性，是一种无专一性分布的对比剂，在各种组织中的分布主要因组织血供和微血管通透性的不同而异；它不能通过完整的血脑屏障，也不能进入毛细血管屏障的其它组织，如脊髓、眼及睾丸等；该对比剂口服不被胃粘膜所吸收，更不能进入红细胞或附着于血红蛋白上，因而只限于在血浆中运输；钆喷酸葡胺不适于在心脏和血管疾病的成像中应用，而通常要用所谓的血池成像对比度增强剂，一般要求这种对比剂的消除速度非常缓慢。U.S. Patent No. and titled US 4,647,447 and "Diagnostic Media (Diagnostic Media)", respectively, relate to the synthesis of diethylenetriaminepentaacetic acid complexes, and to the formation of salts of the complexes with meglumine, and the synthesis of gadopentetate Glumine contrast agent. This contrast agent has been widely used clinically. However, the molecular weight of gadopentetate meglumine is small, the excretion is too fast, and the elimination half-life is about 20 to 100 minutes; this reagent has no tissue and organ selectivity, and is almost completely excreted through the liver, so the imaging effect on the hepatobiliary system is not ideal; If the speed is too fast, the MRI of the brain and spinal cord needs to be administered again within 30 minutes; to judge whether the patient is an adult lesion or a tumor recurrence, it is necessary to increase the dosage; increasing the dosage of the drug increases the amount of detoxification of the human body and improves Possibility of negative effects; gadopentetate dimeglumine contrast agent has no targeting, it is a contrast agent with non-specific distribution, and the distribution in various tissues is mainly due to the difference in tissue blood supply and microvascular permeability different; it cannot pass through the complete blood-brain barrier, nor can it enter other tissues of the capillary barrier, such as the spinal cord, eye and testis; Thus, transport is limited to plasma; gadopentetate dimeglumine is not suitable for use in imaging cardiac and vascular disease, and so-called blood pool imaging contrast-enhancing agents are usually used, which typically require very slow elimination.
发明内容 Contents of the invention
本发明要解决的第一个技术问题是公开一种聚氧乙烯类嵌段聚合物配体，该配体是一种苯甲酸及其衍生物的聚氧乙烯/二乙三胺五乙酸嵌段聚合物配体，即BEN/PEO/DTPA嵌段聚合物配体，该配体具有以下结构，The first technical problem to be solved in the present invention is to disclose a polyoxyethylene block polymer ligand, which is a polyoxyethylene/diethylenetriaminepentaacetic acid block of benzoic acid and its derivatives The polymer ligand, namely the BEN/PEO/DTPA block polymer ligand, has the following structure,
式中，R5代表苯甲酸及其衍生物，In the formula, R represents benzoic acid and derivatives thereof,
R4代表R 4 stands for
式中，R3代表In the formula, R 3 represents
-CH2CH2-(OCH2CH2)n--CH 2 CH 2 -(OCH 2 CH 2 ) n -
或or
R2代表烷基、环烷基或芳环，R1代表烷基-(CH2)m-或环烷基，n代表22～500的整数，m代表2～10的整数，x代表重复单元个数的平均值1～10。R 2 represents alkyl, cycloalkyl or aromatic ring, R 1 represents alkyl-(CH 2 ) m - or cycloalkyl, n represents an integer from 22 to 500, m represents an integer from 2 to 10, and x represents a repeating unit The average value of the number is 1-10.
本发明的BEN/PEO/DTPA嵌段聚合物配体可溶于N，N-二甲基甲酰胺，或二氯甲烷，或氯仿，或二氧六环，或二甲基亚砜，或蒸馏水，或磷酸PBS缓冲溶剂，为白色固体粉末。The BEN/PEO/DTPA block polymer ligand of the present invention is soluble in N, N-dimethylformamide, or methylene chloride, or chloroform, or dioxane, or dimethyl sulfoxide, or distilled water , or phosphate buffered PBS solvent, is a white solid powder.
本发明要解决的第二个技术问题是提供上述BEN/PEO/DTPA嵌段聚合物配体的合成方法。解决该问题的技术方案是采用以下的合成路线：The second technical problem to be solved by the present invention is to provide a synthesis method of the above-mentioned BEN/PEO/DTPA block polymer ligand. The technical solution to solve this problem is to adopt the following synthetic route:
第一步羧基活化的苯甲酸及其衍生物与端胺基嵌段聚氧乙烯改性的配体反应，制得BEN/PEO/DTPA嵌段聚合物配体粗制品。In the first step, the carboxyl-activated benzoic acid and its derivatives are reacted with the ligand modified by the amino-terminated block polyoxyethylene to prepare the crude product of the BEN/PEO/DTPA block polymer ligand.
第二步提纯BEN/PEO/DTPA嵌段聚合物配体粗制品，制得BEN/PEO/DTPA嵌段聚合物的精制品。In the second step, the crude product of the BEN/PEO/DTPA block polymer ligand is purified to obtain a refined product of the BEN/PEO/DTPA block polymer.
其中羧基活化的苯甲酸及其衍生物采用下列方法合成：Wherein the carboxyl-activated benzoic acid and its derivatives are synthesized by the following methods:
A.苯甲酸及其衍生物的羧基与N-羟基琥珀酰亚胺反应，制得羧基活化的苯甲酸；A. the carboxyl of benzoic acid and its derivatives reacts with N-hydroxyl succinimide, makes the benzoic acid of carboxyl activation;
B.提纯羧基活化的苯甲酸及其衍生物，得到精制品；B. purifying benzoic acid and its derivatives activated by carboxyl groups to obtain refined products;
现详细说明本发明的具体操作步骤：Now describe in detail the specific operation steps of the present invention:
第一步BEN/PEO/DTPA嵌段聚合物配体粗制品的制备Preparation of crude product of BEN/PEO/DTPA block polymer ligand in the first step
以羧基活化的苯甲酸及其衍生物精制品为原料，加入端胺基嵌段聚氧乙烯改性的高分子，加入溶剂。溶剂为N，N-二甲基甲酰胺、二氯甲烷、氯仿、二氧六环、蒸馏水。按羧基活化的苯甲酸及其衍生物精制品∶端胺基嵌段聚氧乙烯改性的高分子∶溶剂＝1∶19～60∶170～500重量比量取，在常温～60℃和搅拌下，反应4～48小时，制得BEN/PEO/DTPA嵌段聚合物配体粗制品。端胺基嵌段聚氧乙烯改性的高分子结构式为Carboxyl-activated benzoic acid and refined products of its derivatives are used as raw materials, amino-terminated block polyoxyethylene-modified macromolecules are added, and a solvent is added. The solvents are N,N-dimethylformamide, dichloromethane, chloroform, dioxane, and distilled water. According to carboxyl-activated benzoic acid and its derivative refined products: amino-terminated block polyoxyethylene modified macromolecule: solvent = 1: 19～60: 170～500 weight ratio, at normal temperature～60 ℃ and stirring The crude product of BEN/PEO/DTPA block polymer ligand is obtained by reacting for 4-48 hours under the same conditions. The structural formula of the polymer modified by amino-terminated block polyoxyethylene is
式中，R3代表In the formula, R 3 represents
-CH2CH2-(OCH2CH2)n--CH 2 CH 2 -(OCH 2 CH 2 ) n -
或or
R2代表烷基、环烷基或芳环，R1代表烷基-(CH2)m-或环烷基，n代表22～500的整数，m代表2～10的整数，x代表重复单元个数的平均值1～10。BEN/PEO/DTPA嵌段聚合物配体的结构式为，R 2 represents alkyl, cycloalkyl or aromatic ring, R 1 represents alkyl-(CH 2 ) m - or cycloalkyl, n represents an integer from 22 to 500, m represents an integer from 2 to 10, and x represents a repeating unit The average value of the number is 1-10. The structural formula of the BEN/PEO/DTPA block polymer ligand is,
R5代表苯甲酸及其衍生物，R 5 represents benzoic acid and its derivatives,
R4代表R 4 stands for
第二步BEN/PEO/DTPA嵌段聚合物配体的提纯Purification of the second step BEN/PEO/DTPA block polymer ligand
将第一步制得的产物蒸干，用乙醇重结晶四次，用乙醚洗涤四次，制得BEN/PEO/DTPA嵌段聚合物配体的精制品，产物为乳白色粉末。The product obtained in the first step was evaporated to dryness, recrystallized four times with ethanol, and washed four times with ether to obtain a refined product of BEN/PEO/DTPA block polymer ligand, which was milky white powder.
BEN/PEO/DTPA嵌段聚合物配体可以溶解于水、N，N-二甲基甲酰胺、二氯甲烷、氯仿、二氧六环、二甲基亚砜；不溶于石油醚、乙醚；室温下不溶于乙醇、加热溶解、冷却后析出。BEN/PEO/DTPA block polymer ligands can be dissolved in water, N,N-dimethylformamide, dichloromethane, chloroform, dioxane, dimethyl sulfoxide; insoluble in petroleum ether, ether; Insoluble in ethanol at room temperature, dissolved by heating, and precipitated after cooling.
所述的羧基活化的苯甲酸及其衍生物按如下两步进行：The benzoic acid and derivatives thereof of described carboxyl activation are carried out in the following two steps:
A.羧基活化的苯甲酸及其衍生物的制备A. Preparation of carboxy-activated benzoic acid and its derivatives
苯甲酸及其衍生物为原料，加入N-羟基琥珀酰亚胺、缩合剂和溶剂，按苯甲酸∶N-羟基琥珀酰亚胺∶缩合剂∶溶剂＝1∶5.6～129∶1.1～12∶30～1000重量比量取，在-4℃～常温和搅拌下反应4～48小时，制得羧基活化的苯甲酸及其衍生物的粗制品，苯甲酸衍生物包括甲基苯甲酸、苯乙酸、对溴苯甲酸、对氟苯乙酸等，缩合剂包括二环己基碳化二亚胺(DCC)、1-乙基-(3-(-3-二甲氨丙基)碳二亚胺(EDC)、甲基-1-乙基-(3-(-3-二甲氨丙基)碳二亚胺(MEDC)，溶剂为N，N-二甲基甲酰胺、二氯甲烷、氯仿、二氧六环、蒸馏水。羧基活化的苯甲酸及其衍生物的结构式为，Benzoic acid and its derivatives are raw materials, adding N-hydroxysuccinimide, condensing agent and solvent, according to benzoic acid: N-hydroxysuccinimide: condensing agent: solvent=1: 5.6～129: 1.1～12: Measured at a weight ratio of 30 to 1000, and reacted at -4°C to room temperature for 4 to 48 hours under stirring to obtain crude products of carboxyl-activated benzoic acid and its derivatives. Benzoic acid derivatives include methylbenzoic acid and phenylacetic acid , p-bromobenzoic acid, p-fluorophenylacetic acid, etc., condensing agents include dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-(-3-dimethylaminopropyl) carbodiimide (EDC ), methyl-1-ethyl-(3-(-3-dimethylaminopropyl) carbodiimide (MEDC), the solvent is N,N-dimethylformamide, dichloromethane, chloroform, di Oxyhexane, distilled water. The structural formula of benzoic acid and derivatives thereof activated by the carboxyl group is,
B.羧基活化的苯甲酸及其衍生物的精制B. Purification of carboxyl-activated benzoic acid and its derivatives
将A步制得的产物过滤，除去不溶物，制得羧基活化的苯甲酸及其衍生物的精制品。Filter the product obtained in step A to remove the insoluble matter to obtain refined products of carboxyl-activated benzoic acid and its derivatives.
上述方法中的原料端胺基的高分子配体需自行合成。合成方法见申请号和发明名称分别为200510024217.7和《端胺基嵌段聚氧乙烯改性的钆配合物及其合成方法》的中国专利。In the above method, the polymer ligands with amino-terminated raw materials need to be synthesized by themselves. For the synthesis method, please refer to the Chinese patents with application number and invention name of 200510024217.7 and "Gadolinium Complex Modified by Polyoxyethylene Block with Amino-terminated Block and Its Synthesis Method" respectively.
与背景技术相比，本发明的有益效果为：Compared with background technology, the beneficial effect of the present invention is:
1.本发明的BEN/PEO/DTPA嵌段聚合物是大分子，具有具有两亲性、无毒、免疫原性低、生物相容性好、种类多、稳定、不易粘附于血管壁、半衰期长。1. The BEN/PEO/DTPA block polymer of the present invention is a macromolecule, which has amphiphilicity, non-toxicity, low immunogenicity, good biocompatibility, various types, stability, and is not easy to adhere to the blood vessel wall, Long half-life.
2.由于本发明的BEN/PEO/DTPA嵌段聚合物的大分子中含有易降解的肽键，所以该大分子可以在生物体内降解，毒性小。2. Since the macromolecule of the BEN/PEO/DTPA block polymer of the present invention contains easily degradable peptide bonds, the macromolecule can be degraded in vivo and has low toxicity.
3.由于本发明的BEN/PEO/DTPA嵌段聚合物是大分子含有二乙三胺五乙酸，所以可以用作合成造影剂的配体，并且用它为配体作成的造影剂半衰期长、弛豫率高，可以在计量很小情况下，在体内停留时间延长，使待检测器官成像清晰。3. Since the BEN/PEO/DTPA block polymer of the present invention is macromolecular containing diethylenetriaminepentaacetic acid, it can be used as the part of the synthetic contrast agent, and the contrast agent made of it as the part has a long half-life, The relaxation rate is high, and the residence time in the body can be prolonged with a small amount of measurement, so that the imaging of the organ to be detected is clear.
4.另一方面，由于本发明的BEN/PEO/DTPA嵌段聚合物的半衰期长，因此可以在一段时间内确保其在病人血液中维持稳定的药理学浓度，可以用于血池造影剂。4. On the other hand, due to the long half-life of the BEN/PEO/DTPA block polymer of the present invention, it can ensure that it maintains a stable pharmacological concentration in the patient's blood for a period of time, and can be used as a blood pool contrast agent.
5.由于BEN/PEO/DTPA嵌段聚合物含有极性键，可以与蛋白质、多肽、DNA形成分子间氢键，用于上述药物的包覆，使多肽或者其它药物的半衰期延长。5. Since the BEN/PEO/DTPA block polymer contains polar bonds, it can form intermolecular hydrogen bonds with proteins, polypeptides, and DNA, which can be used for the coating of the above drugs to extend the half-life of polypeptides or other drugs.
6.合成本发明的BEN/PEO/DTPA嵌段聚合物的合成工艺路线简单，操作条件温和，产物提纯步骤简单，产物产率高。6. The synthesis process route for synthesizing the BEN/PEO/DTPA block polymer of the present invention is simple, the operating conditions are mild, the product purification steps are simple, and the product yield is high.
附图说明 Description of drawings
图1是本发明实施例1的BEN/PEO/DTPA嵌段聚合物配体精制品的核磁共振氢谱(1H NMR)。Fig. 1 is the hydrogen nuclear magnetic resonance spectrum ( 1 H NMR) of the refined product of the BEN/PEO/DTPA block polymer ligand in Example 1 of the present invention.
具体实施方式 Detailed ways
实施例1Example 1
(一)羧基活化的苯甲酸的制备(1) Preparation of carboxyl-activated benzoic acid
在反应器中，加入苯甲酸、N-羟基琥珀酰亚胺、二环己基碳化二亚胺(DCC)和N，N-二甲基甲酰胺的量分别为0.244g、0.322g、0.5768g和30ml。苯甲酸、N-羟基琥珀酰亚胺、二环己基碳化二亚胺(DCC)和N，N-二甲基甲酰胺的重量比为1∶1.32∶2.36∶123，常温和搅拌下反应4小时，制得羧基活化的苯甲酸的粗制品。其结构式为：In the reactor, the amount of adding benzoic acid, N-hydroxysuccinimide, dicyclohexylcarbodiimide (DCC) and N,N-dimethylformamide is 0.244g, 0.322g, 0.5768g and 30ml. The weight ratio of benzoic acid, N-hydroxysuccinimide, dicyclohexylcarbodiimide (DCC) and N, N-dimethylformamide is 1: 1.32: 2.36: 123, reacted under normal temperature and stirring for 4 hours , to obtain a crude product of carboxyl-activated benzoic acid. Its structural formula is:
(二)羧基活化的苯甲酸的精制(2) Refining of the benzoic acid of carboxyl activation
将(一)制得的产物过滤，除去不溶物制得羧基活化的苯甲酸的精制品。The product obtained in (1) is filtered, and the insoluble matter is removed to obtain the refined product of carboxyl-activated benzoic acid.
(三)BEN/PEO/DTPA嵌段聚合物配体粗制品的制备(3) Preparation of crude product of BEN/PEO/DTPA block polymer ligand
以(二)制得的羧基活化的苯甲酸精制品为原料，加入端胺基嵌段聚氧乙烯改性的高分子和溶剂N，N-二甲基甲酰胺。羧基活化的苯甲酸精制品、端胺基嵌段聚氧乙烯改性的高分子及N，N-二甲基甲酰胺的加入量分别为0.438g(溶于30mlDMF中)、8.486g和65ml。羧基活化的苯甲酸精制品、端胺基嵌段聚氧乙烯改性的高分子及N，N-二甲基甲酰胺的重量比为1∶19.4∶216，常温和搅拌下反应24小时，制得BEN/PEO/DTPA嵌段聚合物配体粗制品，端胺基嵌段聚氧乙烯改性的高分子，其结构式为The carboxyl-activated benzoic acid refined product obtained in (2) is used as a raw material, and an amino-terminated block polyoxyethylene-modified macromolecule and a solvent N,N-dimethylformamide are added. The amounts of carboxyl-activated benzoic acid refined product, amino-terminated block polyoxyethylene modified polymer and N,N-dimethylformamide were 0.438g (dissolved in 30ml DMF), 8.486g and 65ml, respectively. Carboxyl-activated benzoic acid refined products, amino-terminated block polyoxyethylene-modified macromolecule and N, N-dimethylformamide in a weight ratio of 1:19.4:216 were reacted under normal temperature and stirring for 24 hours to prepare Obtain the crude product of BEN/PEO/DTPA block polymer ligand, the macromolecule of polyoxyethylene modified block of terminal amino group, its structural formula is
式中，R3代表In the formula, R 3 represents
R2代表
BEN/PEO/DTPA嵌段聚合物配体的结构式为，The structural formula of the BEN/PEO/DTPA block polymer ligand is,
R5代表苯甲酸及其衍生物，R4代表R 5 represents benzoic acid and its derivatives, R 4 represents
(四)BEN/PEO/DTPA嵌段聚合物配体的提纯(4) Purification of BEN/PEO/DTPA block polymer ligands
将(三)制得的产物蒸干，用乙醇重结晶四次，用乙醚洗涤四次，制得BEN/PEO/DTPA嵌段聚合物配体的精制品，产物为乳白色粉末6.47g，产率72.5％。The product obtained in (3) was evaporated to dryness, recrystallized four times with ethanol, and washed four times with ether to obtain the refined product of BEN/PEO/DTPA block polymer ligand. The product was milky white powder 6.47g, the yield 72.5%.
实施例1的(一)中的溶剂N，N-二甲基甲酰胺可换成二甲基亚砜、二氯甲烷、氯仿、二氧六环、蒸馏水。The solvent N in the (one) of embodiment 1, N-dimethylformamide can be changed into dimethyl sulfoxide, methylene chloride, chloroform, dioxane, distilled water.
实施例2Example 2
(一)羧基活化的苯甲酸的制备(1) Preparation of carboxyl-activated benzoic acid
在反应器中，加入苯甲酸、N-羟基琥珀酰亚胺、二环己基碳化二亚胺(DCC)和N，N-二甲基甲酰胺的量分别为0.0706g、0.0931g、0.1668g和10ml。苯甲酸、N-羟基琥珀酰亚胺、二环己基碳化二亚胺(DCC)和N，N-二甲基甲酰胺的重量比为1∶1.32∶2.36∶141，常温和搅拌下反应4小时，制得羧基活化的苯甲酸的粗制品，In the reactor, the amounts of benzoic acid, N-hydroxysuccinimide, dicyclohexylcarbodiimide (DCC) and N,N-dimethylformamide were 0.0706g, 0.0931g, 0.1668g and 10ml. The weight ratio of benzoic acid, N-hydroxysuccinimide, dicyclohexylcarbodiimide (DCC) and N, N-dimethylformamide is 1: 1.32: 2.36: 141, reacted under normal temperature and stirring for 4 hours , to obtain a crude product of carboxy-activated benzoic acid,
(二)羧基活化的苯甲酸的精制(2) Refining of the benzoic acid of carboxyl activation
同实施例1，制得羧基活化的苯甲酸的精制品；With embodiment 1, make the refined product of the benzoic acid of carboxyl activation;
(三)BEN/PEO/DTPA嵌段聚合物配体粗制品的制备(3) Preparation of crude product of BEN/PEO/DTPA block polymer ligand
以(二)制得的羧基活化的苯甲酸精制品为原料，加入端胺基嵌段聚氧乙烯改性的高分子和溶剂，溶剂为N，N-二甲基甲酰胺。羧基活化的苯甲酸精制品、端胺基嵌段聚氧乙烯改性的高分子及N，N-二甲基甲酰胺的加入量分别为0.1267g(溶于10mlDMF)、6g和50ml。羧基活化的苯甲酸精制品、端胺基嵌段聚氧乙烯改性的高分子及N，N-二甲基甲酰胺的重量比为1∶47.35∶473，60℃和搅拌下反应5小时，制得BEN/PEO/DTPA嵌段聚合物配体粗制品，端胺基嵌段聚氧乙烯改性的高分子，其结构式为The carboxyl-activated benzoic acid refined product obtained in (2) is used as a raw material, and an amino-terminated block polyoxyethylene-modified macromolecule and a solvent are added, and the solvent is N,N-dimethylformamide. The amounts of carboxyl-activated benzoic acid refined product, amino-terminated block polyoxyethylene-modified macromolecule and N,N-dimethylformamide were 0.1267g (dissolved in 10ml DMF), 6g and 50ml, respectively. The weight ratio of carboxyl-activated benzoic acid refined product, amino-terminated block polyoxyethylene-modified polymer and N, N-dimethylformamide is 1: 47.35: 473, reacted at 60°C for 5 hours under stirring, Obtain the crude product of BEN/PEO/DTPA block polymer ligand, the macromolecule of polyoxyethylene modification of terminal amino group block, its structural formula is
式中，R3代表In the formula, R 3 represents
R2代表
BEN/PEO/DTPA嵌段聚合物配体的结构式为，The structural formula of the BEN/PEO/DTPA block polymer ligand is,
R5代表苯甲酸，R4代表R 5 represents benzoic acid, R 4 represents
(四)BEN/PEO/DTPA嵌段聚合物配体的提纯(4) Purification of BEN/PEO/DTPA block polymer ligands
同实施例1，制得BEN/PEO/DTPA嵌段聚合物配体的精制品，产物为乳白色粉末5.61g，产率91.6％。Same as Example 1, the refined product of BEN/PEO/DTPA block polymer ligand was obtained, the product was 5.61 g of milky white powder, and the yield was 91.6%.
实施例2的(三)中的溶剂N，N-二甲基甲酰胺可换成二甲基亚砜、二氯甲烷、氯仿、二氧六环、蒸馏水。The solvent N in (three) of
实施例3Example 3
(一)羧基活化的苯甲酸的制备(1) Preparation of carboxyl-activated benzoic acid
原料配比等其它条件同实施例1，不同的是在-4℃和搅拌下反应48小时，制得羧基活化的苯甲酸的粗制品。The raw material ratio and other conditions are the same as in Example 1, except that the reaction was carried out at -4°C for 48 hours under stirring to obtain a crude product of carboxyl-activated benzoic acid.
(二)羧基活化的苯甲酸的精制(2) Refining of the benzoic acid of carboxyl activation
同实施例1Same as Example 1
(三)BEN/PEO/DTPA嵌段聚合物配体粗制品的制备(3) Preparation of crude product of BEN/PEO/DTPA block polymer ligand
以(二)制得的羧基活化的苯甲酸精制品为原料，加入端胺基嵌段聚氧乙烯改性的高分子和溶剂N，N-二甲基甲酰胺。羧基活化的苯甲酸精制品、端胺基嵌段聚氧乙烯改性的高分子及N，N-二甲基甲酰胺的加入量分别为0.438g(30mlDMF)、8.486g和45ml。羧基活化的苯甲酸精制品、端胺基嵌段聚氧乙烯改性的高分子及N，N-二甲基甲酰胺的重量比为1∶19.4∶171，60℃和搅拌下反应4小时，制得BEN/PEO/DTPA嵌段聚合物配体粗制品，端胺基嵌段聚氧乙烯改性的高分子，其结构式同实施例1，The carboxyl-activated benzoic acid refined product obtained in (2) is used as a raw material, and an amino-terminated block polyoxyethylene-modified macromolecule and a solvent N,N-dimethylformamide are added. The amounts of carboxyl-activated benzoic acid refined products, amino-terminated block polyoxyethylene-modified macromolecules, and N,N-dimethylformamide were 0.438g (30mlDMF), 8.486g, and 45ml, respectively. Carboxyl-activated benzoic acid refined products, amino-terminated block polyoxyethylene-modified macromolecules and N, N-dimethylformamide have a weight ratio of 1: 19.4: 171, react at 60°C for 4 hours under stirring, Obtain the crude product of BEN/PEO/DTPA block polymer ligand, the macromolecule of polyoxyethylene modification of terminal amino group block, its structural formula is the same as embodiment 1,
(四)BEN/PEO/DTPA嵌段聚合物配体的提纯(4) Purification of BEN/PEO/DTPA block polymer ligands
同实施例1，制得BEN/PEO/DTPA嵌段聚合物配体的精制品，产物为乳白色粉末6.29g，产率70.5％。Same as Example 1, the refined product of BEN/PEO/DTPA block polymer ligand was obtained, the product was 6.29 g of milky white powder, and the yield was 70.5%.
实施例4Example 4
(一)羧基活化的苯甲酸的制备(1) Preparation of carboxyl-activated benzoic acid
在反应器中，加入苯甲酸、N-羟基琥珀酰亚胺、二环己基碳化二亚胺(DCC)和N，N-二甲基甲酰胺的量分别为0.244g、0.322g、0.5768g和7.3ml。苯甲酸、N-羟基琥珀酰亚胺、二环己基碳化二亚胺(DCC)和N，N-二甲基甲酰胺的重量比为1∶1.32∶2.36∶30，-4℃和搅拌下反应48小时，制得羧基活化的苯甲酸的粗制品。In the reactor, the amount of adding benzoic acid, N-hydroxysuccinimide, dicyclohexylcarbodiimide (DCC) and N,N-dimethylformamide is 0.244g, 0.322g, 0.5768g and 7.3ml. The weight ratio of benzoic acid, N-hydroxysuccinimide, dicyclohexylcarbodiimide (DCC) and N, N-dimethylformamide is 1: 1.32: 2.36: 30, react under stirring at -4°C After 48 hours, a crude product of carboxy-activated benzoic acid was obtained.
(二)羧基活化的苯甲酸的精制(2) Refining of the benzoic acid of carboxyl activation
同实施例1，制得羧基活化的苯甲酸的精制品；With embodiment 1, make the refined product of the benzoic acid of carboxyl activation;
(三)BEN/PEO/DTPA嵌段聚合物配体粗制品的制备(3) Preparation of crude product of BEN/PEO/DTPA block polymer ligand
以(二)制得的羧基活化的苯甲酸精制品0.219g(3.6ml N，N-二甲基甲酰胺)为原料，加入端胺基嵌段聚氧乙烯改性的高分子3.528g，加入溶剂32ml，溶剂为N，N-二甲基甲酰胺，羧基活化的苯甲酸精制品、端胺基嵌段聚氧乙烯改性的高分子及溶剂的重量比为1∶16.1∶216，常温和搅拌下反应48小时，制得BEN/PEO/DTPA嵌段聚合物配体粗制品，端胺基嵌段聚氧乙烯改性的高分子，其结构式为With (two) the benzoic acid refined product 0.219g (3.6ml N, N-dimethylformamide) of carboxyl group activation that makes is raw material, add the macromolecule 3.528g that terminal amino group blocks polyoxyethylene modification, add Solvent 32ml, the solvent is N,N-dimethylformamide, carboxyl-activated benzoic acid refined products, amino-terminated block polyoxyethylene modified macromolecule and the weight ratio of solvent is 1:16.1:216, room temperature React under stirring for 48 hours, and obtain the crude product of BEN/PEO/DTPA block polymer ligand, the macromolecule modified by polyoxyethylene with terminal amino group block, its structural formula is
式中，R3代表In the formula, R 3 represents
-CH2CH2-(OCH2CH2)n--CH 2 CH 2 -(OCH 2 CH 2 ) n -
n为76，n is 76,
BEN/PEO/DTPA嵌段聚合物配体的结构式为，The structural formula of the BEN/PEO/DTPA block polymer ligand is,
R5代表苯甲酸，R4代表R 5 represents benzoic acid, R 4 represents
(四)BEN/PEO/DTPA嵌段聚合物配体的提纯(4) Purification of BEN/PEO/DTPA block polymer ligands
同实施例1，制得BEN/PEO/DTPA嵌段聚合物配体的精制品，产物为乳白色粉末2.84g，产率76％。Same as Example 1, the refined product of BEN/PEO/DTPA block polymer ligand was obtained, the product was milky white powder 2.84g, and the yield was 76%.
实施例5Example 5
(一)羧基活化的甲基苯甲酸的制备(1) Preparation of carboxyl-activated methylbenzoic acid
在反应器中，加入甲基苯甲酸、N-羟基琥珀酰亚胺、1-乙基-(3-(-3-二甲氨丙基)碳二亚胺(EDC)和N，N-二甲基甲酰胺的量分别为0.272g、0.322g、0.4346g和7.3ml。甲基苯甲酸、N-羟基琥珀酰亚胺、1-乙基-(3-(-3-二甲氨丙基)碳二亚胺(EDC)和N，N-二甲基甲酰胺的重量比为1∶1.18∶1.60∶26.8。在-4℃和搅拌下反应48小时，制得羧基活化的苯甲酸的粗制品，In the reactor, add toluic acid, N-hydroxysuccinimide, 1-ethyl-(3-(-3-dimethylaminopropyl) carbodiimide (EDC) and N,N-di The amounts of methylformamide were 0.272g, 0.322g, 0.4346g and 7.3ml respectively. Toluic acid, N-hydroxysuccinimide, 1-ethyl-(3-(-3-dimethylaminopropyl ) carbodiimide (EDC) and N, the weight ratio of N-dimethylformamide is 1: 1.18: 1.60: 26.8.React 48 hours under stirring at-4 ℃, make the crude carboxy-activated benzoic acid products,
(二)羧基活化的甲基苯甲酸的精制(2) Refining of methylbenzoic acid activated by carboxyl groups
同实施例1，制得羧基活化的甲基苯甲酸的精制品；With embodiment 1, make the refined product of the toluic acid of carboxyl activation;
(三)BEN/PEO/DTPA嵌段聚合物配体粗制品的制备(3) Preparation of crude product of BEN/PEO/DTPA block polymer ligand
以(二)制得的羧基活化的甲基苯甲酸精制品0.117g(1.8ml N，N-二甲基甲酰胺)为原料，加入端胺基嵌段聚氧乙烯改性的高分子2.589g，加入溶剂32ml，溶剂为N，N-二甲基甲酰胺，羧基活化的甲基苯甲酸精制品、端胺基嵌段聚氧乙烯改性的高分子及溶剂的重量比为1∶22.23∶288，常温和搅拌下反应48小时，制得BEN/PEO/DTPA嵌段聚合物配体粗制品，端胺基嵌段聚氧乙烯改性的高分子，其结构式为Using (2) the carboxyl-activated refined product of methylbenzoic acid 0.117g (1.8ml N,N-dimethylformamide) as raw material, add 2.589g of macromolecules modified by amino-terminated block polyoxyethylene , add solvent 32ml, solvent is N, N-dimethylformamide, and the weight ratio of carboxyl-activated toluic acid refined product, amino-terminated block polyoxyethylene modified macromolecule and solvent is 1: 22.23: 288, reacted for 48 hours under normal temperature and stirring, and obtained the crude product of BEN/PEO/DTPA block polymer ligand, a macromolecule modified by amino-terminated block polyoxyethylene, and its structural formula is
式中，R3代表In the formula, R 3 represents
-CH2CH2-(OCH2cH2)n--CH 2 CH 2 -(OCH 2 cH 2 ) n -
n为113，n is 113,
BEN/PEO/DTPA嵌段聚合物配体的结构式为，The structural formula of the BEN/PEO/DTPA block polymer ligand is,
R5代表甲基苯甲酸，R4代表R 5 represents methyl benzoic acid, R 4 represents
(四)BEN/PEO/DTPA嵌段聚合物配体的提纯(4) Purification of BEN/PEO/DTPA block polymer ligands
同实施例1，制得BEN/PEO/DTPA嵌段聚合物配体的精制品，产物为乳白色粉末2.16g，产率80％。Same as Example 1, the refined product of BEN/PEO/DTPA block polymer ligand was obtained, the product was 2.16 g of milky white powder, and the yield was 80%.
合成的产物潜在用途是用作磁共振造影剂，以及包覆多肽、DNA药物或西药的载体。The potential use of the synthesized product is to be used as a magnetic resonance contrast agent, and a carrier for coating polypeptides, DNA medicines or western medicines.
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| US4647447A (en) * | 1981-07-24 | 1987-03-03 | Schering Aktiengesellschaft | Diagnostic media |
| US4789721A (en) * | 1987-07-27 | 1988-12-06 | Texaco Inc. | Curatives of epoxy resins from dicarboxylic acids, including (1) indane or (2) tert-butylisophtalic derived acids, reacted with polyetherdiamines |
| US5091574A (en) * | 1990-02-06 | 1992-02-25 | Texaco Chemical Company | Polyoxyethylene diamine derivatives of diglycidyl ethers |
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| US4647447A (en) * | 1981-07-24 | 1987-03-03 | Schering Aktiengesellschaft | Diagnostic media |
| US4789721A (en) * | 1987-07-27 | 1988-12-06 | Texaco Inc. | Curatives of epoxy resins from dicarboxylic acids, including (1) indane or (2) tert-butylisophtalic derived acids, reacted with polyetherdiamines |
| US5091574A (en) * | 1990-02-06 | 1992-02-25 | Texaco Chemical Company | Polyoxyethylene diamine derivatives of diglycidyl ethers |
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