WO2015081830A1 - 多臂聚乙二醇硬脂酸衍生物和油酸衍生物 - Google Patents

多臂聚乙二醇硬脂酸衍生物和油酸衍生物 Download PDF

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WO2015081830A1
WO2015081830A1 PCT/CN2014/092735 CN2014092735W WO2015081830A1 WO 2015081830 A1 WO2015081830 A1 WO 2015081830A1 CN 2014092735 W CN2014092735 W CN 2014092735W WO 2015081830 A1 WO2015081830 A1 WO 2015081830A1
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polyethylene glycol
arm polyethylene
acid
formula
arm
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PCT/CN2014/092735
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French (fr)
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李俊业
林美娜
陈晓萌
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天津键凯科技有限公司
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Priority to US15/170,909 priority Critical patent/US9890245B2/en

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
    • C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
    • C08G65/3322—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof acyclic
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
    • C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33331—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing imide group
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33331—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing imide group
    • C08G65/33334—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing imide group acyclic
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33331—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing imide group
    • C08G65/33337—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing imide group cyclic
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
    • C08G2650/30—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type branched
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
    • C08G2650/30—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type branched
    • C08G2650/32—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type branched dendritic or similar

Definitions

  • the present invention relates to a multi-arm polyethylene glycol derivative, especially a multi-arm polyethylene glycol derivative having different reactive groups, a stearic acid reactive derivative, an oleic acid active derivative, and a process for the preparation thereof.
  • polyethylene glycol derivatives are widely used in combination with proteins, polypeptides, and other therapeutic agents to prolong the physiological half-life of the drug, reducing its immunogenicity and toxicity.
  • PEG and its derivatives have been widely used as carriers for the preparation of pharmaceutical preparations, and attempts to bind PEG to drug molecules have also been greatly developed in the last decade.
  • the metabolic process of ethylene glycol in the human body is quite clear, and it is a safe, non-side-effect synthetic polymer material.
  • polyethylene glycol is also widely used in the preparation of new medical devices.
  • Baxter's CoSeal, Covidien's SprayGel and DuraSeal are all new medical devices marketed in the US or Europe in recent years, all of which use a multi-arm polyethylene glycol.
  • multi-arm polyethylene glycol has a plurality of end groups relative to linear polyethylene glycol, and thus has the advantage of having multiple drug attachment points and capable of supporting a plurality of drug molecules.
  • multi-arm polyethylene glycol is widely used in the PEGylation modification of polypeptides and small molecule drugs.
  • multi-arm polyethylene glycol can be used as a cross-linking agent in the manufacture of gels. These gels can be used as adhesives, anti-leakage agents, anti-blocking agents and hemostatic materials in medical devices.
  • Patent WO2011075953A1 discloses a novel multi-arm polyethylene glycol having different types of active groups formed by polymerizing ethylene oxide from oligo-pentaerythritol as an initiator, and the terminal active group is selected from the group consisting of hydroxyl group, amino group, sulfhydryl group, A carboxyl group, an ester group, an aldehyde group, an acryl group, and a maleimide group, each of which is a short-chain substituent group.
  • CN101747192B discloses a method for synthesizing polyethylene glycol oleate, which is obtained by using esterification reaction of polyethylene glycol (PEG) and oleic acid as raw materials under the action of an organic acid catalyst, but the method is prepared by the method.
  • Polyethylene glycol polymers have a low degree of polymerization, have a molecular weight of from 400 to 1000, and can only be prepared as oleic acid monoesters or oleic acid diesters.
  • CN103145968A discloses a folic acid-coupled polyethylene glycol monostearate and a preparation method and application thereof, and it can be seen from the molecular structure thereof that the product obtained by the method is only a monostearate, and The limitation of the group, which also only discloses that polyethylene glycol monostearate can be coupled to the drug folic acid.
  • the present application provides a multi-arm polyethylene glycol stearic acid derivative and an oleic acid derivative and a preparation method thereof.
  • An object of the present invention is to provide a multi-arm polyethylene glycol stearic acid derivative and an oleic acid derivative and a preparation method thereof, thereby solving the problem that the linear polyethylene glycol active end group is insufficient and cannot refer to a plurality of functional groups. The problem.
  • Another object of the present invention is to overcome the drawbacks of insufficient loading of stearic acid and oleic acid in polyethylene glycol stearic acid derivatives and oleic acid derivatives.
  • Another object of the present invention is to solve the problem of polyethylene glycol stearic acid derivatives and oleic acid derivatives by simultaneously loading other different active end groups in a multi-arm polyethylene glycol stearic acid derivative and an oleic acid derivative.
  • One aspect of the invention provides a multi-arm polyethylene glycol derivative having the structure of Formula I:
  • Another aspect of the invention provides a multi-arm polyethylene glycol derivative having the structure of the following formula VI:
  • the multi-arm polyethylene glycol derivative of the present invention is of Formula I or Formula VI: the PEG is the same or different -(CH 2 CH 2 O) m -, and the average value of m is 3-250.
  • An integer; l is an integer ⁇ 1; X 1 , X 2 , X 3 , X 4 are linking groups independently selected from the group consisting of: Wherein i is an integer from 0 to 10; F 1 , F 2 , F 3 , and F 4 are terminal groups, and F 1 , F 2 , F 3 , and F 4 may be the same or different, independently selected Free group consisting of the following groups:
  • At least one of F 1 , F 2 , F 3 and F 4 in the formula I is or Or at least one of F 1 , F 2 and F 4 in the formula VI or
  • the average value of m is preferably an integer of from 68 to 250, and more preferably an integer having an average value of m of from 68 to 227.
  • l is preferably an integer of ⁇ 1 and ⁇ 10, more preferably l is an integer of ⁇ 1 and ⁇ 6, and particularly preferably l is An integer of ⁇ 1 and ⁇ 4, in a specific embodiment of the invention, the l may preferably be 1, 2, 3, 4, 5 or 6.
  • i in the X 1 , X 2 , X 3 , X 4 groups are each independently preferably 1-5.
  • the X 2 and/or X 4 are independently preferably or Wherein i is an integer from 1 to 5, preferably an integer from 1 to 3, and in a specific embodiment of the invention, the i is 1, 2 or 3.
  • the X 1 and/or X 3 is preferably Wherein i is an integer from 1 to 5, preferably an integer from 1 to 3, and in a specific embodiment of the invention, the i is 1, 2, and 3.
  • the F 1 , F 2 , F 3 , F 4 may be at least two or In another embodiment of the present invention, at least three of F 1 , F 2 , F 3 , and F 4 are or In another embodiment of the present invention, F 1 , F 2 , F 3 , and F 4 are all or
  • the F 1 , F 2 , F 4 may be at least two or In another embodiment of the invention, F 1 , F 2 , and F 4 are both or
  • F 2 and/or F 4 is preferably -COOH or
  • At least one of F 1 or F 3 is preferably or
  • F 1 is preferably selected from the group consisting of or
  • the F 1 and F 3 are or F 2 and/or F 4 is selected from -COOH or
  • the F 1 is or F 2 and/or F 4 is selected from -COOH or
  • the F 1 , F 2 and F 3 are or F 4 is selected from -COOH or
  • the F 1 and F 2 are or F 4 is selected from -COOH or
  • the multi-arm polyethylene glycol has a molecular weight of 1000 to 80,000 Da, in the present hair In a preferred embodiment, the multi-arm polyethylene glycol has a molecular weight of 3000-20000 Da. In a more preferred embodiment of the invention, the multi-arm polyethylene glycol has a molecular weight of 3000-10000 Da. In a most preferred embodiment of the invention, the multi-arm polyethylene glycol may have a molecular weight of 3000 Da, 10,000 Da, and 20000 Da.
  • the active derivative of the multi-arm polyethylene glycol is a multi-arm polyethylene glycol stearate-monoacetic acid active NHS ester derivative having the structure of Formula II below:
  • the active derivative of the multi-arm polyethylene glycol is a multi-arm polyethylene glycol stearic acid-diacetic acid active NHS ester derivative having the structure of Formula III below:
  • the reactive derivative of the multi-arm polyethylene glycol is a multi-arm polyethylene glycol oleic acid-monoacetic acid active NHS ester derivative having the structure of the following general formula IV:
  • the active derivative of the multi-arm polyethylene glycol is a multi-arm polyethylene glycol oleic acid-diacetic acid active NHS ester derivative having the structure of the following general V:
  • the active derivative of the multi-arm polyethylene glycol is a multi-arm polyethylene glycol stearic acid-monoacetic acid active NHS ester derivative having the structure of the following formula VII:
  • the active derivative of the multi-arm polyethylene glycol is a multi-arm polyethylene glycol stearic acid-diacetic acid active NHS ester derivative having the structure of the following formula VIII:
  • the active derivative of the multi-arm polyethylene glycol is a multi-arm polyethylene glycol oleic acid-monoacetic acid active NHS ester derivative having the structure of the following formula IX:
  • the active derivative of the multi-arm polyethylene glycol is a multi-arm polyethylene glycol oleic acid-diacetic acid active NHS ester derivative having the structure of the general formula X:
  • Another aspect of the invention provides a process for the preparation of a multi-arm polyethylene glycol derivative of formula I or formula VI, comprising the steps of:
  • Another aspect of the invention provides a process for the preparation of a multi-arm polyethylene glycol derivative of formula I or formula VI, comprising the steps of:
  • multi-arm polyethylene glycol oleic acid-monoacetic acid or multi-arm polyethylene glycol oleic acid-monoacetic acid dissolved in a solvent, added with N-hydroxysuccinimide (NHS), N , N'-dicyclohexylcarbodiimide is reacted to obtain a multi-arm polyethylene glycol oleic acid-monoacetic acid active NHS ester or a multi-arm polyethylene glycol oleic acid-diacetic acid active NHS ester.
  • NHS N-hydroxysuccinimide
  • the reactant multi-arm polyethylene glycol amino-monoacetic acid or the multi-arm polyethylene glycol amino-diacetic acid can be commercially available. Obtained or prepared by the method of patent CN102108119A.
  • the solvent may be selected from methanol, ethanol, chloroform, dichloromethane, and the like, which is well known in the art. Acetone, diethyl ether, ethyl acetate, and the like.
  • the multi-arm polyethylene glycol stearic acid derivative and the oleic acid derivative of the present invention can be used for combination with proteins, peptides and pharmaceutically active small molecules to improve targeting and drug efficacy and reduce toxicity.
  • the protein, peptide, and pharmaceutically active small molecule include, but are not limited to, analgesic and anti-inflammatory agents, antacids, anthelmintics, antiarrhythmic agents, antibacterial agents, anticoagulant (blood) agents, antidepressants , antidiabetic agents, antidiarrheal agents, antiepileptic drugs, antifungal agents, anti-gout drugs, antihypertensive drugs, antimalarials, anti-migraine drugs, antimuscarinic agents, antineoplastic agents and immunosuppressants, antigens Insecticides, antirheumatic drugs, antithyroid agents, antiviral agents, anti-anxiety agents, sedatives, eye drops and tranquilizers, beta-blockers, cardiac contractions
  • the multi-arm polyethylene glycol stearic acid derivative and the oleic acid derivative of the present invention are combined with proteins, peptides and pharmaceutically active small molecules, and can be formed by the terminal group and the drug molecule as described in the patent CN102108119A. a conjugate, preferably by -COOH or Combined with proteins, peptides, and pharmaceutically active small molecules.
  • the multi-arm polyethylene glycol stearic acid derivative and the oleic acid derivative of the present invention can be used for preparing liposomes, polymer nanoparticles, solid fats due to loading at least one stearic acid or oleic acid group.
  • Nano-medicine carriers such as nano-particles improve drug efficacy and reduce toxicity.
  • multi-arm polyethylene glycol has multiple end groups, which in turn has multiple functional group introduction points and can support multiple active end groups, making it more flexible. And a larger range of applications.
  • the four-arm polyethylene glycol amino-monoacetic acid used in the examples was supplied by Beijing Key Kai Technology Co., Ltd., and the other reagents used in the following examples were purchased from Beijing Chemical Reagent. Company or other similar mass chemical sales company.
  • Example 1 Synthesis of four-arm polyethylene glycol (3000 Da) stearic acid-monoacetic acid
  • Example 3 Synthesis of eight-arm polyethylene glycol (20000 Da) stearic acid-monoacetic acid
  • Example 7 Synthesis of four-arm polyethylene glycol (10000 Da) oleic acid-monoacetic acid
  • Example 8 Synthesis of four-arm polyethylene glycol (10000 Da) oleic acid-monoacetic acid active NHS ester
  • Example 9 Synthesis of eight-arm polyethylene glycol (hexaglycerol, 10000 Da) oleic acid-monoacetic acid
  • Example 10 Synthesis of eight-arm polyethylene glycol (hexaglycerol, 10000 Da) oleic acid-monoacetic acid active NHS ester
  • Example 11 Synthesis of four-arm polyethylene glycol (3000 Da) oleic acid-diacetic acid
  • Example 12 Four-arm polyethylene glycol (3000 Da) oleic acid-diacetic acid active NHS ester

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  • General Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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Abstract

本发明公开了一种具有通式I或通式VI结构的多臂聚乙二醇衍生物，与直链型聚乙二醇相比，多臂聚乙二醇具有多个端基，进而具有多个功能基团的引入点、可以负载多个活性端基，使其具有更强的灵活性和更大的应用范围。

Description

多臂聚乙二醇硬脂酸衍生物和油酸衍生物 技术领域
本发明涉及多臂聚乙二醇衍生物，尤其是具有不同活性基团的多臂聚乙二醇衍生物，硬脂酸活性衍生物，油酸活性衍生物以及其制备方法。
背景技术
目前，聚乙二醇衍生物被广泛地用于与蛋白质、多肽以及其他治疗药物结合以延长所述药物的生理半衰期，降低其免疫原性和毒性。在临床使用中，PEG及其衍生物作为制作药物制剂的载体已经在很多药品中得到了广泛的应用，而将PEG键合到药物分子的尝试在最近十年里也得到了长足的发展，聚乙二醇在人体内的代谢过程已相当清楚，是一种安全的、无副作用的合成高分子材料。
作为一种安全的、无副作用的合成高分子材料,聚乙二醇也在制备新型医疗器械中得到广泛应用。例如Baxter的CoSeal、Covidien的SprayGel和DuraSeal都是最近几年在美国或欧洲上市的新型医疗器械，它们都应用了一种多臂聚乙二醇。
在药物修饰方面，相对于直链型聚乙二醇，多臂聚乙二醇具有多个端基，进而具有多个药物连接点、可以负载多个药物分子的优势。目前，多臂聚乙二醇广泛应用于多肽和小分子药物的PEG化修饰。在医疗器械应用上，多臂聚乙二醇可以作为交联剂，应用于制作凝胶。这些凝胶可在医疗器械中作为粘合剂、防渗漏剂、防粘连剂和止血材料。
专利WO2011075953A1公开了一种由寡聚季戊四醇作为引发剂聚合环氧乙烷形成的新型的具有不同类型活性基团的多臂聚乙二醇，其端基活性集团选自：羟基、氨基、巯基、羧基、酯基、醛基、丙烯酸基和马来亚酰胺基，其均为短链取代基团。
CN101747192B公开了一种聚乙二醇油酸酯的合成方法，它以聚乙二醇(PEG)和油酸为原料，在有机酸催化剂的作用下进行酯化反应得到，然而该方法制备得到的聚乙二醇聚合物的聚合度较低，分子量为400-1000，并且仅能制备成油酸单酯或油酸双酯。
CN103145968A公开了一种叶酸偶联聚乙二醇单硬脂酸酯及其制备方法和应用，从其分子结构中可以看出，该方法获得产物也仅为单硬脂酸酯化物，并且由于连接基团的限制，其也仅公开聚乙二醇单硬脂酸酯能够与药物叶酸偶联。
为克服现有技术中存在的缺陷，本申请提供一种多臂聚乙二醇硬脂酸衍生物和油酸衍生物及其制备方法。
发明内容
本发明的一个目的是通过提供一种多臂聚乙二醇硬脂酸衍生物和油酸衍生物及其制备方法，解决直链聚乙二醇活性端基不足，无法引用多个功能基团的问题。
本发明的另一个目的是克服聚乙二醇硬脂酸衍生物和油酸衍生物中硬脂酸和油酸的负载不足的缺陷。
本发明的另一个目的是通过在多臂聚乙二醇硬脂酸衍生物和油酸衍生物中同时负载其它不同的活性端基，解决了聚乙二醇硬脂酸衍生物和油酸衍生物灵活性不足，应用范围较窄的问题。
本发明的一方面提供了一种多臂聚乙二醇衍生物，所述的多臂聚乙二醇衍生物具有通式Ⅰ的结构：
Figure PCTCN2014092735-appb-000001
本发明的另一方面提供了一种多臂聚乙二醇衍生物，所述的多臂聚乙二醇衍生物具有以下通式Ⅵ的结构：
Figure PCTCN2014092735-appb-000002
本发明所述的多臂聚乙二醇衍生物通式Ⅰ或通式Ⅵ中：所述的PEG为相同或不同的-(CH2CH2O)m-，m平均值为3-250的整数；l为≥1的整数；X1、X2、X3、X4是连接基团，独立地选自由以下基团组成的组：
Figure PCTCN2014092735-appb-000003
其中i为0-10的整数；F1，F2，F3，F4是端基基团，F1，F2，F3，F4可以是相同的也可以是不同的，独立地选自由以下基团组成的组：
Figure PCTCN2014092735-appb-000004
并且，通式Ⅰ中F1，F2，F3，F4至少一个为
Figure PCTCN2014092735-appb-000005
或
Figure PCTCN2014092735-appb-000006
或者通式Ⅵ中F1，F2，F4至少一个为
Figure PCTCN2014092735-appb-000007
或
Figure PCTCN2014092735-appb-000008
在本发明所述的多臂聚乙二醇衍生物通式Ⅰ或通式Ⅵ中，m平均值优选为68-250的整数，更优选为m平均值为68-227的整数。
在本发明所述的多臂聚乙二醇衍生物通式Ⅰ或通式Ⅵ中，l优选为≥1且≤10的整数，更优选l为≥1且≤6的整数，尤其优选l为≥1且≤4的整数，在本发明的具体实施方式中，所述的l可以优选为1、2、3、4、5或6。
在本发明所述的多臂聚乙二醇衍生物通式Ⅰ或通式Ⅵ中，所述的X1、X2、X3、X4基团中i分别独立地优选为1-5的整数，更优选为1-3的整数，在本发明的具体实施方式中，所述的i为1、2、3、4或5。
在本发明所述的多臂聚乙二醇衍生物通式Ⅰ或通式Ⅵ中，所述的X2和/或X4独立地优选为
Figure PCTCN2014092735-appb-000009
或
Figure PCTCN2014092735-appb-000010
其中i为1-5的整数，优选为1-3的整数，在本发明的具体实施方式中，所述的i为1、2或3。
在本发明所述的多臂聚乙二醇衍生物通式Ⅰ或通式Ⅵ中，所述的X1和/或X3优选为
Figure PCTCN2014092735-appb-000011
其中i为1-5的整数，优选为1-3的整数，在本发明的具体实施方式中，所述的i为1、2、3。
在本发明所述的多臂聚乙二醇衍生物通式Ⅰ中，所述的F1，F2，F3，F4可以至少两个为
Figure PCTCN2014092735-appb-000012
或
Figure PCTCN2014092735-appb-000013
在本发明的另一实施方式中，F1，F2，F3，F4至少三个为
Figure PCTCN2014092735-appb-000014
或
Figure PCTCN2014092735-appb-000015
在本发明的另一实施方式中，F1，F2，F3，F4均为
Figure PCTCN2014092735-appb-000016
或
Figure PCTCN2014092735-appb-000017
在本发明所述的多臂聚乙二醇衍生物通式Ⅵ中，所述的F1，F2，F4可以至少两个为
Figure PCTCN2014092735-appb-000018
或
Figure PCTCN2014092735-appb-000019
在本发明的另一实施方式中，F1，F2，F4均为
Figure PCTCN2014092735-appb-000020
或
Figure PCTCN2014092735-appb-000021
在本发明所述的多臂聚乙二醇衍生物通式Ⅰ或通式Ⅵ中，F2和/或F4优选为-COOH或
Figure PCTCN2014092735-appb-000022
在本发明所述的多臂聚乙二醇衍生物通式Ⅰ中，F1或F3中优选至少一个为
Figure PCTCN2014092735-appb-000023
或
Figure PCTCN2014092735-appb-000024
在本发明所述的多臂聚乙二醇衍生物通式Ⅰ中，F1和F3中优选均为
Figure PCTCN2014092735-appb-000025
或
Figure PCTCN2014092735-appb-000026
在本发明所述的多臂聚乙二醇衍生物通式Ⅵ中，F1优选选自
Figure PCTCN2014092735-appb-000027
或
Figure PCTCN2014092735-appb-000028
在本发明所述的多臂聚乙二醇衍生物通式Ⅰ中，所述的F1和F3为
Figure PCTCN2014092735-appb-000029
或
Figure PCTCN2014092735-appb-000030
F2和/或F4选自-COOH或
Figure PCTCN2014092735-appb-000031
在本发明所述的多臂聚乙二醇衍生物通式Ⅵ中，所述的F1为
Figure PCTCN2014092735-appb-000032
或
Figure PCTCN2014092735-appb-000033
F2和/或F4选自-COOH或
Figure PCTCN2014092735-appb-000034
在本发明所述的多臂聚乙二醇衍生物通式Ⅰ中，所述的F1、F2和F3为
Figure PCTCN2014092735-appb-000035
或
Figure PCTCN2014092735-appb-000036
F4选自-COOH或
Figure PCTCN2014092735-appb-000037
在本发明所述的多臂聚乙二醇衍生物通式Ⅵ中，所述的F1和F2为
Figure PCTCN2014092735-appb-000038
或
Figure PCTCN2014092735-appb-000039
F4选自-COOH或
Figure PCTCN2014092735-appb-000040
在本发明具体的实施方案中，所述多臂聚乙二醇的分子量为1000-80000Da，在本发 明优选的实施方案中，所述的多臂聚乙二醇的分子量为3000-20000Da，在本发明的更为优选的实施方案中，所述的多臂聚乙二醇的分子量为3000-10000Da，在本发明的最优选的实施方案中，所述的多臂聚乙二醇的分子量可以为3000Da、10000Da、20000Da。
在一个具体实施方案中，所述多臂聚乙二醇的活性衍生物是具有以下通式Ⅱ结构的多臂聚乙二醇硬脂酸-单乙酸活性NHS酯衍生物：
Figure PCTCN2014092735-appb-000041
在一个具体的实施方案中，所述的多臂聚乙二醇的活性衍生物是具有以下通式Ⅲ结构的多臂聚乙二醇硬脂酸-二乙酸活性NHS酯衍生物：
Figure PCTCN2014092735-appb-000042
在一个具体实施方案中，所述多臂聚乙二醇的活性衍生物是具有以下通式Ⅳ结构的多臂聚乙二醇油酸-单乙酸活性NHS酯衍生物：
Figure PCTCN2014092735-appb-000043
在一个具体的实施方案中，所述的多臂聚乙二醇的活性衍生物是具有以下通式Ⅴ结构的多臂聚乙二醇油酸-二乙酸活性NHS酯衍生物：
Figure PCTCN2014092735-appb-000044
在一个具体实施方案中，所述多臂聚乙二醇的活性衍生物是具有以下通式Ⅶ结构的多臂聚乙二醇硬脂酸-单乙酸活性NHS酯衍生物：
Figure PCTCN2014092735-appb-000045
在一个具体的实施方案中，所述的多臂聚乙二醇的活性衍生物是具有以下通式Ⅷ结构的多臂聚乙二醇硬脂酸-二乙酸活性NHS酯衍生物：
Figure PCTCN2014092735-appb-000046
在一个具体实施方案中，所述多臂聚乙二醇的活性衍生物是具有以下通式Ⅸ结构的多臂聚乙二醇油酸-单乙酸活性NHS酯衍生物：
Figure PCTCN2014092735-appb-000047
在一个具体的实施方案中，所述的多臂聚乙二醇的活性衍生物是具有以下通式Ⅹ结构的多臂聚乙二醇油酸-二乙酸活性NHS酯衍生物：
Figure PCTCN2014092735-appb-000048
本发明的另一方面提供了一种通式Ⅰ或通式Ⅵ多臂聚乙二醇衍生物的制备方法，包括以下步骤：
(1)将多臂聚乙二醇氨基-单乙酸或多臂聚乙二醇氨基-二乙酸溶于溶剂中，加入氯化亚砜反应1-10h，得到多臂聚乙二醇氨基-单乙酸甲酯或多臂聚乙二醇氨基-二乙酸甲酯；
(2)将多臂聚乙二醇胺基-单乙酸甲酯或多臂聚乙二醇胺基-二乙酸甲酯溶解于溶剂中,加入硬脂酸和三乙胺反应，得到多臂聚乙二醇硬脂酸-单乙酸甲酯或多臂聚乙二醇硬脂 酸-二乙酸甲酯；
(3)将多臂聚乙二醇硬脂酸-单乙酸甲酯或多臂聚乙二醇硬脂酸-二乙酸甲酯，加入NaOH调节pH至10-12，反应1-8h，过滤，用盐酸调节pH至2-3，萃取，分离得到多臂聚乙二醇硬脂酸-单乙酸或多臂聚乙二醇硬脂酸-二乙酸；
任选的，(4)将多臂聚乙二醇硬脂酸-单乙酸或多臂聚乙二醇硬脂酸-单乙酸，溶于溶剂中，加入N-羟基琥珀酰亚胺(NHS)、N,N'-二环己基碳二亚胺反应，得到多臂聚乙二醇硬脂酸-单乙酸NHS酯或多臂聚乙二醇硬脂酸-二乙酸NHS酯。
本发明的另一方面提供了一种通式Ⅰ或通式Ⅵ多臂聚乙二醇衍生物的制备方法，包括以下步骤：
(1)将多臂聚乙二醇氨基-单乙酸或多臂聚乙二醇氨基-二乙酸溶于溶剂中，加入氯化亚砜反应1-10h，得到多臂聚乙二醇氨基-单乙酸甲酯或多臂聚乙二醇氨基-二乙酸甲酯；
(2)将多臂聚乙二醇氨基-单乙酸甲酯或多臂聚乙二醇氨基-二乙酸甲酯溶解于溶剂中,加入油酰氯和三乙胺反应，得到多臂聚乙二醇油酸-单乙酸甲酯或多臂聚乙二醇油酸-二乙酸甲酯。
(3)将多臂聚乙二醇油酸-单乙酸甲酯或多臂聚乙二醇油酸-二乙酸甲酯，加入NaOH调节pH至10-12，反应1-8h，过滤，用盐酸调节pH至2-3，萃取，分离得到多臂聚乙二醇油酸-单乙酸或多臂聚乙二醇油酸-二乙酸。
任选的，(4)将多臂聚乙二醇油酸-单乙酸或多臂聚乙二醇油酸-单乙酸，溶于溶剂中，加入N-羟基琥珀酰亚胺(NHS)、N,N'-二环己基碳二亚胺反应，得到多臂聚乙二醇油酸-单乙酸活性NHS酯或多臂聚乙二醇油酸-二乙酸活性NHS酯。
本发明所述通式Ⅰ或通式Ⅵ多臂聚乙二醇衍生物的制备方法中，反应物多臂聚乙二醇氨基-单乙酸或多臂聚乙二醇氨基-二乙酸可由市售获得，或者通过专利CN102108119A中的方法制备得到。
本发明所述通式Ⅰ或通式Ⅵ多臂聚乙二醇衍生物的制备方法中，所述的溶剂可以使用本领域所述熟知适宜溶剂，选自甲醇、乙醇、氯仿、二氯甲烷、丙酮、乙醚、乙酸乙酯等。
本发明所述的多臂聚乙二醇硬脂酸衍生物和油酸衍生物可以用于与蛋白质、肽、药物活性小分子相结合，提高靶向性和药物疗效，降低毒性。所述的蛋白质、肽、药物活性小分子包括但不限于：镇痛剂和消炎剂、抗酸剂、驱虫药、抗心律不齐药、抗菌剂、抗凝(血)剂、抗抑郁剂、抗糖尿病剂、止泻剂、抗癫痫药、防真菌剂、抗痛风药、抗高血压药、抗疟药、抗偏头痛药、抗毒蕈碱剂、抗瘤剂和免疫抑制剂、抗原虫药、抗风湿药、抗甲状 腺剂、抗病毒剂、抗焦虑剂、镇静剂、安眼药和安定药、β-受体阻断剂、心脏收缩剂、皮质类甾醇、镇咳剂、细胞毒性剂、减充血剂、利尿剂、酶、抗帕金森氏症药、胃肠道药、组胺受体拮抗剂、油脂调节剂、局部麻醉剂、神经肌肉阻断剂、硝酸酯和抗心绞痛药、营养剂、麻醉性镇痛剂、口服疫苗、蛋白、肽和重组药物、性激素和避孕药、杀精子剂、和刺激剂。本发明所述的多臂聚乙二醇硬脂酸衍生物和油酸衍生物与蛋白质、肽、药物活性小分子结合方式，可以如专利CN102108119A所描述，通过其端基与药物分子所形成的结合物，优选通过-COOH或
Figure PCTCN2014092735-appb-000049
与蛋白质、肽、药物活性小分子相结合。
本发明所述的多臂聚乙二醇硬脂酸衍生物和油酸衍生物由于负载有至少一个硬脂酸或油酸基团，可以应用于制备脂质体、聚合物纳米粒、固体脂质纳米粒等纳米药物载体，提高药物疗效，降低毒性。与直链型聚乙二醇相比，多臂聚乙二醇具有多个端基，进而具有多个功能基团的引入点、可以负载多个活性端基，使其具有更强的灵活性和更大的应用范围。
具体实施方式
实施例中用到的四臂聚乙二醇氨基-单乙酸，四臂聚乙二醇氨基-二乙酸由北京键凯科技有限公司提供，以下实施例中其他所使用的试剂购自北京化学试剂公司或其它类似大众化学品销售公司。
实施例1：合成四臂聚乙二醇(3000Da)硬脂酸-单乙酸
Figure PCTCN2014092735-appb-000050
10g四臂聚乙二醇(3000Da)氨基-单乙酸，溶于100mL无水甲醇中，冰水浴，滴加1mL氯化亚砜，室温下反应5h，溶剂用旋转蒸发除去，残留物中添加150ml乙醚冷冻沉淀.过滤，产物真空干燥,得到四臂聚乙二醇(3000Da)氨基-单乙酸甲酯8.5g。
1H NMR(DMSO):3.51(m,272H),2.95(m,6H),4.13(s,2H)。
4.91g四臂聚乙二醇(3000Da)氨基-单乙酸甲酯,溶解于100mL氯仿中,加入0.89mL三乙胺、6.98g硬脂酸，室温搅拌反应过夜，过滤，旋转蒸发除去溶剂，残留物中添加80ml异丙醇热溶解后冷冻沉淀，过滤，溶剂旋转蒸发除去，残留物用80ml乙醚冷冻沉淀，过滤，产物真空干燥，得到四臂聚乙二醇(3000Da)硬脂酸-单乙酸甲酯5.0g。
1H NMR(DMSO):0.82-0.87(t,9H),3.51(m,272H),4.13(s,2H),7.82(m,3H)。
5.0g四臂聚乙二醇(3000Da)硬脂酸-单乙酸甲酯，加入50mL去离子水，用0.5mol/L的NaOH调节体系PH＝12，室温下反应2h，过滤，用1mol/L盐酸调节体系PH＝2-3,加入15％NaCl，用100mL二氯甲烷分三次萃取，合并有机相，用100mLPH＝2-3的饱和食盐水分两次洗涤有机相，有机相用无水硫酸钠干燥，过滤，滤液旋转蒸发除去溶剂，残留物中加入100ml乙醚冷冻沉淀，过滤，产物真空干燥，得到四臂聚乙二醇(3000Da)硬脂酸-单乙酸2.5g。
1H NMR(DMSO):0.82-0.87(t,9H),3.51(m,272H),4.08(s,2H),7.77(m,3H)。
实施例2：合成四臂聚乙二醇(3000Da)硬脂酸-单乙酸活性NHS酯
Figure PCTCN2014092735-appb-000051
3.0g四臂聚乙二醇(3000Da)硬脂酸-单乙酸,溶于30mL二氯甲烷中,加入0.15g N-羟基琥珀酰亚胺(NHS)、0.29g N,N'-二环己基碳二亚胺(DCC)，室温搅拌反应过夜，过滤，旋转蒸发除去溶剂，残留物中添加60ml异丙醇热溶解后冷冻沉淀，过滤，产物真空干燥，得到四臂聚乙二醇(3000Da)硬脂酸-单乙酸活性NHS酯2.0g。
1H NMR(DMSO):0.82-0.87(t,9H),2,81(s,4H),3.51(m,272H),4.60(s,2H),7.77(m,3H)。
实施例3：合成八臂聚乙二醇(20000Da)硬脂酸-单乙酸
Figure PCTCN2014092735-appb-000052
10g八臂聚乙二醇(20000Da)氨基-单乙酸，溶于100mL无水甲醇中，冰水浴，滴加0.3mL氯化亚砜，室温下反应5h，溶剂用旋转蒸发除去，残留物中添加150ml乙醚冷冻沉淀.过滤，产物真空干燥,得到八臂聚乙二醇(20000Da)氨基-单乙酸甲酯9.8g。
1H NMR(DMSO):3.51(m,1818H),2.95(m,14H),4.13(s,2H)。
5g八臂聚乙二醇(20000Da)氨基-单乙酸甲酯,溶解于100mL氯仿中,加入0.27mL三乙胺、2.1g硬脂酸，室温搅拌反应过夜，过滤，旋转蒸发除去溶剂，残留物中添加80ml异丙醇热溶解后冷冻沉淀，过滤，溶剂旋转蒸发除去，残留物用80ml乙醚冷冻沉淀，过滤，产物真空干燥，得到八臂聚乙二醇(20000Da)硬脂酸-单乙酸甲酯4.8g。
1H NMR(DMSO):0.82-0.87(t,21H),3.51(m,1818H),4.13(s,2H),7.82(m,7H)。
4.0g八臂聚乙二醇(20000Da)硬脂酸-单乙酸甲酯，加入40mL去离子水，用0.5mol/L的NaOH调节体系PH＝12，室温下反应2h，过滤，用1mol/L盐酸调节体系PH＝2-3,加入15％NaCl，用80mL二氯甲烷分三次萃取，合并有机相，用80mLPH＝2-3的饱和食盐水分两次洗涤有机相，有机相用无水硫酸钠干燥，过滤，滤液旋转蒸发除去溶剂，残留物中加入80ml乙醚冷冻沉淀，过滤，产物真空干燥，得到八臂聚乙二醇(20000Da)硬脂酸-单乙酸2.5g。
1H NMR(DMSO):0.82-0.87(t,21H),3.51(m,1818H),4.08(s,2H),7.77(m,7H)。
实施例4：合成八臂聚乙二醇(20000Da)硬脂酸-单乙酸活性NHS酯
Figure PCTCN2014092735-appb-000053
3.0g四臂聚乙二醇(3000Da)硬脂酸-单乙酸,溶于30mL二氯甲烷中,加入0.15g N-羟基琥珀酰亚胺(NHS)、0.29g N,N'-二环己基碳二亚胺(DCC)，室温搅拌反应过夜，过滤，旋转蒸发除去溶剂，残留物中添加60ml异丙醇热溶解后冷冻沉淀，过滤，产物真空干燥，得到四臂聚乙二醇(3000Da)硬脂酸-单乙酸活性NHS酯2.0g。
1H NMR(DMSO):0.82-0.87(t,27H),2,81(s,4H),3.51(m,1818H),4.60(s,2H),7.77(m,7H)。实施例5：合成四臂聚乙二醇(3000Da)硬脂酸-二乙酸
Figure PCTCN2014092735-appb-000054
10g四臂聚乙二醇(3000Da)氨基-二乙酸,溶于100mL无水甲醇中,冰水浴,滴加2mL氯化亚砜,室温下反应5h,溶剂旋转蒸发除去,残留物添加150ml乙醚冷冻沉淀、过滤，产物真空干燥,得到四臂聚乙二醇(3000Da)氨基-二乙酸甲酯8.8g。
1H NMR(DMSO):3.51(m,272H),2.95(m,4H),4.13(s,4H)。
5g四臂聚乙二醇(3000Da)氨基-二乙酸甲酯,溶解在100mL氯仿中,加入0.6mL三乙胺、4.74g硬脂酸反应过夜，过滤，旋转蒸发除去溶剂，残留物中添加100ml异丙醇热溶后冷冻沉淀，过滤，溶剂旋转蒸发除去,残留物用100ml乙醚冷冻沉淀、过滤，产物真空干燥,得到四臂聚乙二醇(3000Da)硬脂酸-二乙酸甲酯5.5g。
1H NMR(DMSO):0.82-0.87(t,6H),3.51(m,272H),4.13(s,4H),7.82(m,2H)。
5.0g四臂聚乙二醇硬脂酸-二乙酸甲酯，加入50mL水，用0.5mol/L的NaOH调节体系PH＝12，反应2h，过滤，用1mol/L盐酸调节体系PH＝2-3,加入15％NaCl，用100mL二氯甲烷分三次萃取，合并有机相，用100mLPH＝2-3的饱和食盐水分两次洗涤有机相，有机相用无水硫酸钠干燥，过滤，滤液旋转蒸发除去溶剂，残留物中添加100ml乙醚冷冻沉淀，过滤，产物真空干燥，得到四臂聚乙二醇(3000Da)硬脂酸-二乙酸3.0g。
1H NMR(DMSO):0.82-0.87(t,6H),3.51(m,272H),4.08(s,4H),7.77(m,2H)。
实施例6：合成四臂聚乙二醇(3000Da)硬脂酸-二乙酸活性NHS酯
Figure PCTCN2014092735-appb-000055
3.0g四臂聚乙二醇(3000Da)硬脂酸-二乙酸,溶于30mL二氯甲烷中,加入0.30g N-羟基琥珀酰亚胺(NHS)、0.58g N,N'-二环己基碳二亚胺(DCC)，室温搅拌反应过夜，过滤，旋转蒸发除去溶剂，残留物中添加60ml异丙醇热溶解后冷冻沉淀，过滤，产物真空干燥，得到四臂聚乙二醇(3000Da)硬脂酸-二乙酸活性NHS酯2.2g。
1H NMR(DMSO):0.82-0.87(t,6H),2,81(s,8H),3.51(m,272H),4.15(s,4H),7.77(m,2H)。
实施例7：合成四臂聚乙二醇(10000Da)油酸-单乙酸
Figure PCTCN2014092735-appb-000056
10g四臂聚乙二醇(10000Da)氨基-单乙酸甲酯,溶于120mL甲苯中,升温除水,降至室温，加入0.19mL三乙胺,滴加0.45mL油酰氯,搅拌反应过夜,旋转蒸发除去溶剂，残留物中添加200ml异丙醇热溶后冷冻沉淀，过滤，产物真空干燥,得到四臂聚乙二醇(10000Da)油酸-单乙酸甲酯7.5g。
1H NMR(DMSO):0.82-0.87(t,9H),3.51(m,909H),4.15(s,2H),5.32(t,6H),7.82(m,3H)。
5.0g四臂聚乙二醇(10000Da)油酸-单乙酸甲酯，加入50mL水，用0.5mol/L的NaOH调节体系PH＝12，反应2h，过滤，用1mol/L盐酸调节体系PH＝2-3,加入15％NaCl，用100mL二氯甲烷分三次萃取，合并有机相，有机相用无水硫酸钠干燥，过滤，溶剂旋转蒸发除去，残留物中添加100ml乙醚冷冻沉淀，过滤，产物真空干燥，得到四臂聚乙二醇(10000Da)油酸-单乙酸3.1g。
1H NMR(DMSO):0.82-0.87(t,9H),3.51(m,909H),4.01(s,2H),5.32(t,6H),7.78(m,3H)。
实施例8：合成四臂聚乙二醇(10000Da)油酸-单乙酸活性NHS酯
Figure PCTCN2014092735-appb-000057
3.0g四臂聚乙二醇(10000Da)油酸-单乙酸,溶于30mL二氯甲烷中,加入0.90g N-羟基琥珀酰亚胺(NHS)、0.174g N,N'-二环己基碳二亚胺(DCC)，室温搅拌反应过夜，过滤，旋转蒸发除去溶剂，残留物中添加60ml异丙醇热溶解后冷冻沉淀，过滤，产物真空干燥，得到四臂聚乙二醇(10000Da)硬脂酸-二乙酸活性NHS酯2.2g。
1H NMR(DMSO):0.82-0.87(t,9H),3.51(m,909H),2.83(s,4H),4.60(s,2H),5.32(t,6H),7.78(m,3H)。
实施例9：合成八臂聚乙二醇(六聚甘油，10000Da)油酸-单乙酸
Figure PCTCN2014092735-appb-000058
10g八臂聚乙二醇(六聚甘油，10000Da)氨基-单乙酸甲酯,溶于120mL甲苯中,升温除水,降至室温，加入0.44mL三乙胺,滴加1.05mL油酰氯,搅拌反应过夜,旋转蒸发除去溶剂，残留物中添加200ml异丙醇热溶后冷冻沉淀，过滤，产物真空干燥,得到八臂聚乙二醇(六聚甘油，10000Da)油酸-单乙酸甲酯8.7g。
1H NMR(DMSO):0.82-0.87(t,21H),3.51(m,909H),4.15(s,2H),5.32(t,14H),7.82(m,7H)。
5.0g八臂聚乙二醇(六聚甘油，10000Da)油酸-单乙酸甲酯，加入50mL水，用0.5mol/L的NaOH调节体系PH＝12，反应2h，过滤，用1mol/L盐酸调节体系PH＝2-3,加入15％NaCl，用100mL二氯甲烷分三次萃取，合并有机相，有机相用无水硫酸钠干燥，过滤，溶剂旋转蒸发除去，残留物中添加100ml乙醚冷冻沉淀，过滤，产物真空干燥，得到八臂聚乙二醇(六聚甘油，10000Da)油酸-单乙酸3.1g。
1H NMR(DMSO):0.82-0.87(t,21H),3.51(m,909H),4.01(s,2H),5.32(t,14H),7.78(m,7H)。
实施例10：合成八臂聚乙二醇(六聚甘油，10000Da)油酸-单乙酸活性NHS酯
Figure PCTCN2014092735-appb-000059
3.0g八臂聚乙二醇(六聚甘油，10000Da)油酸-单乙酸,溶于30mL二氯甲烷中,加入0.90g N-羟基琥珀酰亚胺(NHS)、0.174g N,N'-二环己基碳二亚胺(DCC)，室温搅拌反应过夜，过滤，旋转蒸发除去溶剂，残留物中添加60ml异丙醇热溶解后冷冻沉淀，过滤，产物真空干燥，得到八臂聚乙二醇(六聚甘油，10000Da)硬脂酸-二乙酸活性NHS酯2.7g。
1H NMR(DMSO):0.82-0.87(t,21H),3.51(m,909H),2.83(s,4H),4.60(s,2H),5.32(t,14H),7.78(m,7H)。
实施例11：合成四臂聚乙二醇(3000Da)油酸-二乙酸
Figure PCTCN2014092735-appb-000060
10g四臂聚乙二醇(3000Da)氨基-二乙酸甲酯,溶解在120mL甲苯中,升温除水,降至室温，加入0.46mL三乙胺,滴加1.0mL油酰氯,搅拌反应过夜,旋转蒸发除去溶剂，残留物中添加200ml异丙醇热溶后冷冻沉淀，过滤，产物真空干燥,得到四臂聚乙二醇(3000Da)油酸-二乙酸甲酯8.9g。
1H NMR(DMSO):0.82-0.87(t,6H),3.51(m,272H),4.15(s,4H),5.32(t,4H),7.82(m,2H)。
5.0g四臂聚乙二醇(3000Da)油酸-二乙酸甲酯，加入50mL水，用0.5mol/L的NaOH调节体系PH＝12，反应2h，过滤，用1mol/L盐酸调节体系PH＝2-3,加入15％NaCl，用100mL二氯甲烷分三次萃取，合并有机相，有机相用无水硫酸钠干燥，过滤，滤液旋转蒸发除去溶剂，残留物中添加100ml乙醚冷冻沉淀，过滤，产物真空干燥，得到四臂聚乙二醇(3000Da)油酸-二乙酸2.4g。
1H NMR(DMSO):0.82-0.87(t,6H),3.51(m,272H),4.01(s,4H),5.32(t,4H),7.78(m,2H)。
实施例12：四臂聚乙二醇(3000Da)油酸-二乙酸活性NHS酯
Figure PCTCN2014092735-appb-000061
2.0g四臂聚乙二醇(3000Da)油酸-二乙酸,溶于20mL二氯甲烷中,加入0.20g NHS、0.39gDCC，室温搅拌反应过夜，过滤，旋转蒸发除去溶剂，残留物中添加60ml异丙醇热溶解后冷冻沉淀，过滤，产物真空干燥，得到四臂聚乙二醇(3000Da)油酸酸-二乙酸活性NHS酯1.6g。
1H NMR(DMSO):0.82-0.87(t,6H),3.51(m,272H),2.83(s,8H),4.60(s,4H),5.32(t,4H),7.78(m,2H)。

Claims (16)

  1. 一种多臂聚乙二醇衍生物，其特征在于所述多臂聚乙二醇衍生物具有通式Ⅰ或通式Ⅵ的结构：
    Figure PCTCN2014092735-appb-100001
    其中：
    所述的PEG为相同或不同的-(CH2CH2O)m-，m为3-250的整数；
    l为≥1且≤10的整数；
    X1、X2、X3、X4独立地选自由以下基团组成的组：
    Figure PCTCN2014092735-appb-100002
    其中i为0-10的整数；
    F1，F2，F3，F4独立地选自由以下基团组成的组：
    Figure PCTCN2014092735-appb-100003
    并且，通式Ⅰ中F1，F2，F3，F4至少一个为
    Figure PCTCN2014092735-appb-100004
    或
    Figure PCTCN2014092735-appb-100005
    或者通式Ⅵ中F1，F2，F4至少一个为
    Figure PCTCN2014092735-appb-100006
    或
  2. 权利要求1所述的多臂聚乙二醇衍生物，其特征在于，通式Ⅰ中F1，F2，F3，F4至少两个为
    Figure PCTCN2014092735-appb-100008
    或
    Figure PCTCN2014092735-appb-100009
    或者通式Ⅵ中F1，F2，F4至少两个为
    Figure PCTCN2014092735-appb-100010
    或
    Figure PCTCN2014092735-appb-100011
  3. 权利要求1所述的多臂聚乙二醇衍生物，其特征在于，所述的F2和/或F4为-COOH或
    Figure PCTCN2014092735-appb-100012
  4. 权利要求1-3任一项所述的多臂聚乙二醇衍生物，其特征在于，所述的X2、X4选自-(CH2)i-NH-，其中i为1-5的整数。
  5. 权利要求1-3任一项所述的多臂聚乙二醇衍生物，其特征在于，所述的X2、X4选自
    Figure PCTCN2014092735-appb-100013
    其中i为1-5的整数。
  6. 权利要求1-5任一项所述的多臂聚乙二醇衍生物，其特征在于，所述的X1和/或X3为-(CH2)i-NH-，其中i为1-5的整数。
  7. 权利要求1-6任一项所述的多臂聚乙二醇衍生物，其特征在于，所述的多臂聚乙二醇衍生物通式Ⅰ中F1或F3至少一个为
    Figure PCTCN2014092735-appb-100014
    或
    Figure PCTCN2014092735-appb-100015
  8. 权利要求1-6任一项所述的多臂聚乙二醇衍生物，其特征在于，所述的多臂聚乙二醇衍生物通式Ⅰ中，F1和F3中均为
    Figure PCTCN2014092735-appb-100016
    或
    Figure PCTCN2014092735-appb-100017
  9. 权利要求1-6任一项所述的多臂聚乙二醇衍生物，其特征在于，所述的多臂聚乙二醇衍生物通式Ⅵ中，F1为
    Figure PCTCN2014092735-appb-100018
    或
    Figure PCTCN2014092735-appb-100019
  10. 权利要求1-6任一项所述的多臂聚乙二醇衍生物，其特征在于，所述的多臂聚乙二醇衍生物通式Ⅰ中，所述的F1、F3为
    Figure PCTCN2014092735-appb-100020
    或
    Figure PCTCN2014092735-appb-100021
    F2、F4为-COOH或
    Figure PCTCN2014092735-appb-100022
  11. 权利要求1-6任一项所述的多臂聚乙二醇衍生物，其特征在于，所述的多臂聚乙二醇衍生物通式Ⅵ中，所述的F1为
    Figure PCTCN2014092735-appb-100023
    或
    Figure PCTCN2014092735-appb-100024
    F2、F4为-COOH或
    Figure PCTCN2014092735-appb-100025
  12. 权利要求1-6任一项所述的多臂聚乙二醇衍生物，其特征在于，所述的多臂聚乙二醇衍生物通式Ⅰ中，所述的F1、F2和F3选自
    Figure PCTCN2014092735-appb-100026
    或
    Figure PCTCN2014092735-appb-100027
    F4选自-COOH或
    Figure PCTCN2014092735-appb-100028
  13. 权利要求1-6任一项所述的多臂聚乙二醇衍生物，其特征在于，所述的多臂聚乙二醇衍生物通式Ⅵ中，所述的F1和F2选自
    Figure PCTCN2014092735-appb-100029
    或
    Figure PCTCN2014092735-appb-100030
    F4选自-COOH或
    Figure PCTCN2014092735-appb-100031
  14. 权利要求1所述的多臂聚乙二醇衍生物，具有如下通式Ⅱ-Ⅹ之一的结构：
    Figure PCTCN2014092735-appb-100032
    Figure PCTCN2014092735-appb-100033
  15. 权利要求1所述的多臂聚乙二醇衍生物的制备方法，其特征在于，包括以下步骤：
    (1)将多臂聚乙二醇氨基-单乙酸或多臂聚乙二醇氨基-二乙酸溶于溶剂中，加入氯化亚砜反应1-10h，得到多臂聚乙二醇氨基-单乙酸甲酯或多臂聚乙二醇氨基-二乙酸甲酯；
    (2)将多臂聚乙二醇胺基-单乙酸甲酯或多臂聚乙二醇胺基-二乙酸甲酯溶解于溶剂中,加入硬脂酸和三乙胺反应，得到多臂聚乙二醇硬脂酸-单乙酸甲酯或多臂聚乙二醇硬脂酸-二乙酸甲酯；
    (3)将多臂聚乙二醇硬脂酸-单乙酸甲酯或多臂聚乙二醇硬脂酸-二乙酸甲酯，加入NaOH调节pH至10-12，反应1-8h，过滤，用盐酸调节pH至2-3，萃取，分离得到多臂聚乙二醇硬脂酸-单乙酸或多臂聚乙二醇硬脂酸-二乙酸；
    任选的，(4)将多臂聚乙二醇硬脂酸-单乙酸或多臂聚乙二醇硬脂酸-单乙酸，溶于溶剂中，加入N-羟基琥珀酰亚胺(NHS)、N,N'-二环己基碳二亚胺反应，得到多臂聚乙二醇硬脂酸-单乙酸NHS酯或多臂聚乙二醇硬脂酸-二乙酸NHS酯。
  16. 权利要求1所述的多臂聚乙二醇衍生物的制备方法，其特征在于，包括以下步骤：
    (1)将多臂聚乙二醇氨基-单乙酸或多臂聚乙二醇氨基-二乙酸溶于溶剂中，加入氯化亚砜反应1-10h，得到多臂聚乙二醇氨基-单乙酸甲酯或多臂聚乙二醇氨基-二乙酸甲酯；
    (2)将多臂聚乙二醇氨基-单乙酸甲酯或多臂聚乙二醇氨基-二乙酸甲酯溶解于溶剂中,加入油酰氯和三乙胺反应，得到多臂聚乙二醇油酸-单乙酸甲酯或多臂聚乙二醇油酸-二乙酸甲酯；
    (3)将多臂聚乙二醇油酸-单乙酸甲酯或多臂聚乙二醇油酸-二乙酸甲酯，加入NaOH调节pH至10-12，反应1-8h，过滤，用盐酸调节pH至2-3，萃取，分离得到多臂聚乙二醇油酸-单乙酸或多臂聚乙二醇油酸-二乙酸；
    任选的，(4)将多臂聚乙二醇油酸-单乙酸或多臂聚乙二醇油酸-单乙酸，溶于溶剂中，加入N-羟基琥珀酰亚胺(NHS)、N,N'-二环己基碳二亚胺反应，得到多臂聚乙二醇油酸-单乙酸活性NHS酯或多臂聚乙二醇油酸-二乙酸活性NHS酯。
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