A tetra-armed peg and a method for preparing the same

Abstract

The application belongs to the technical field of polymer medical materials, and particularly relates to a four-arm PEG and a preparation method thereof. Specifically, the preparation method comprises the following steps: reacting monomethoxy PEG with bromo-pentaerythritol in an alkaline solvent to form four-arm PEG tetramethyl ether; and then removing the methyl groups from the four-arm PEG tetramethyl ether under the conditions of thiol, boron trifluoride ether and the like for a certain time to generate four-arm PEG. The application can effectively overcome the defects in the existing four-arm PEG preparation method, such as high safety risk and high cost caused by the use of ethylene oxide, and crosslinking products caused by the use of double-end PEG raw materials. The method should use safe and easily available raw materials, and the reaction conditions are mild and controllable, so that the directional high-yield synthesis of four-arm PEG is realized, and therefore the method has good practical application value.

Description

Technical Field

[0001] This invention belongs to the field of polymer medical materials technology, specifically relating to a four-armed PEG and its preparation method. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Polyethylene glycol (PEG) is a linear polymer composed of repeating ethylene oxide units. Its unique physicochemical properties (such as good water solubility, non-toxicity, and biocompatibility) have led to its widespread application in surfactants, chemical materials, and medicine. With the development of materials science, branched PEG (such as tetra-armed PEG) has attracted great attention from the scientific and industrial communities due to its higher functionality, better steric hindrance effect, and biological stability brought about by its multi-arm structure.

[0004] Currently, most methods for preparing four-arm PEG rely on the polymerization reaction of pentaerythritol and ethylene oxide under the action of a catalyst. The reaction mechanism is as follows: under the action of a catalyst (such as a basic compound), the four hydroxyl groups of pentaerythritol lose protons to form oxygen anions, which then initiate the ring-opening polymerization of ethylene oxide, ultimately forming a four-arm structure with pentaerythritol as the core and four PEG chains as arms. This method has advantages such as simple steps, controllable molecular weight, and high product purity. However, the inventors discovered that its core drawback lies in the hazardous nature of the raw material, ethylene oxide: ethylene oxide is a gas at room temperature and pressure, possessing strong toxicity, carcinogenicity, and is flammable and explosive. This necessitates extremely high requirements for the airtightness and explosion-proof rating of production equipment, increasing production safety risks and leading to high equipment investment and operating costs, thus limiting the large-scale production and application of four-arm PEG.

[0005] Furthermore, in the existing technology, if dual-functionalized PEG raw materials are used to synthesize four-arm PEG, cross-linking products are easily generated due to the simultaneous reaction of functional groups at both ends of PEG, resulting in reduced purity and yield of the target product, making it difficult to achieve directional synthesis. Summary of the Invention

[0006] The purpose of this invention is to overcome the drawbacks of existing four-arm PEG preparation methods, such as high safety risks and high costs associated with the use of ethylene oxide, and the easy generation of cross-linking products when using dual-terminated PEG raw materials. This invention provides a novel four-arm PEG preparation method. This method uses safe and readily available raw materials, and the reaction conditions are mild and controllable, achieving the directed high-yield synthesis of four-arm PEG. Based on the above research results, this invention is thus completed.

[0007] Specifically, the present invention relates to the following technical solutions: In a first aspect, the present invention provides a method for preparing a four-armed PEG, the method comprising:

[0008] In a second aspect, the present invention provides a four-armed PEG prepared by the above-described method. The molecular weight of the four-armed PEG can be controlled according to the molecular weight of the monomethoxy PEG.

[0009] The beneficial technical effects of the above technical solution are as follows: (1) High safety: Avoid using toxic, flammable and explosive raw materials such as ethylene oxide. The raw materials (halogenated pentaerythritol, monomethoxy PEG, etc.) are safe and easy to store. The reaction does not require closed, high temperature and high pressure equipment. The conditions are mild, which significantly reduces the production safety risk.

[0010] (2) Directed synthesis with high yield: Using PEG (monomethoxy PEG) protected by a single methyl end as raw material, only the terminal hydroxyl group can participate in the reaction, avoiding the cross-linking problem caused by the reaction at both ends of the double-ended PEG, realizing the directed synthesis of four-arm PEG, with high product purity and a yield of 90%~95%.

[0011] (3) Flexible and controllable process: The reaction parameters (such as temperature, time, and raw material ratio) have a wide range and can be adjusted according to the target molecular weight and purity requirements. In addition, there are a variety of reagents such as solvents, alkalis, and thiols to choose from, making it highly adaptable.

[0012] (4) Good economic efficiency: low raw material cost and simple equipment requirements, which is conducive to large-scale production and reduces the application cost of four-arm PEG. Attached Figure Description

[0013] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0014] Figure 1 This is a synthetic route diagram for the four-arm PEG of the present invention.

[0015] Figure 2 The image shows the 1H NMR spectrum of product I (four-arm PEG tetramethyl ether-20k) from Example 4 of this invention.

[0016] Figure 3 The 1H NMR spectrum of product II (four-arm PEG-20k) in Example 4 of this invention is shown.

[0017] Figure 4 The image shows the 1H NMR spectrum of product I (four-arm PEG tetramethyl ether-2k) from Example 8 of this invention.

[0018] Figure 5The image shows the 1H NMR spectrum of product II (four-arm PEG-2k) from Example 8 of this invention.

[0019] Figure 6 The image shows the hydrogen NMR spectrum of the product of Comparative Example 1 of this invention.

[0020] Figure 7 The image shows the hydrogen NMR spectrum of the product of Comparative Example 2 of this invention. Detailed Implementation

[0021] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of this application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains.

[0022] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the exemplary embodiments according to this application. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0023] The present invention will be further illustrated with specific examples. These examples are for illustrative purposes only and do not limit the scope of the invention. Unless otherwise specified, experimental conditions not explicitly stated in the examples are generally performed under conventional conditions or as recommended by the selling company. Materials and reagents used in the examples, unless otherwise specified, are commercially available.

[0024] As introduced in the background section, existing methods for preparing four-arm PEG have drawbacks such as high safety risks and high costs associated with the use of ethylene oxide, and the easy generation of cross-linking products when using dual-ended PEG raw materials. Therefore, developing a preparation method with safe raw materials, mild reaction conditions, and the ability to achieve high-yield directional synthesis of four-arm PEG has become an urgent technical problem to be solved in this field.

[0025] In view of this, in a typical embodiment of the present invention, a method for preparing a four-armed PEG is provided, the method comprising:

[0026] In another specific embodiment of the present invention, the preparation method specifically includes: S1. In an alkaline solvent, monomethoxy PEG is heated and reacted with pentaerythritol haloside to obtain tetramethyl PEG tetraarm PEG; wherein the halogen in pentaerythritol haloside can be any one of Cl, Br or I, without specific limitation.

[0027] S2. Dissolve the tetramethyl PEG obtained in step S1 in thiol, add boron trifluoride diethyl ether, and react to generate tetramethyl PEG.

[0028] The present invention provides a synthetic route diagram of a four-armed PEG as follows: Figure 1 As shown.

[0029] The reaction principle of step S1 is as follows: Under alkaline conditions, the terminal hydroxyl group (-OH) of monomethoxy PEG loses a proton to form an oxygen anion. This oxygen anion acts as a nucleophile to attack the positive carbon center of the pentaerythritol connected to the halogen atom (X), resulting in a nucleophilic substitution reaction. The haloalkane loses its halogen to form an ether bond (-CH2-O-CH2-), and finally, the four monomethoxy PEG chains are attached to the core carbon of pentaerythritol to form a four-armed PEG tetramethyl ether.

[0030] Therefore, the solvent can be selected from aprotic polar solvents (such as N,N-dimethylformamide, dimethyl sulfoxide, toluene, tetrahydrofuran, acetonitrile, acetone) or water. If an organic solvent is used, anhydrous conditions must be ensured to avoid consumption by the reaction of alkali with water; if water is used as the solvent, a phase transfer catalyst (such as quaternary ammonium salts, crown ethers, etc.) needs to be added to promote the contact reaction between the halopentaerythritol in the oil phase and the monomethoxy PEG anion in the aqueous phase.

[0031] In this invention, the base in the alkaline solvent is used to abstract a proton from the terminal hydroxyl group of the monomethoxy PEG to form a nucleophilic oxygen anion. It can be selected from NaH, KH, LDA (lithium diisopropylamino), LHMDS (lithium hexamethyldisilamide), NaHMDS (sodium hexamethyldisilamide), NaOH, Na, K, etc., and is not specifically limited here. It should be noted that since Na and K are active metals, when they come into contact with solvents (such as aprotic polar solvents or water), they can react to generate alkaline substances (such as reacting with water to generate sodium hydroxide or potassium hydroxide), thereby playing a base role in the reaction system (such as abstracting a proton from the terminal hydroxyl group of the monomethoxy PEG, promoting nucleophilic substitution reactions). Therefore, in the application scenario of this application, Na and K are used as bases.

[0032] In step S1, the reaction parameters include: a reaction temperature of 40~150℃, where too low a temperature will reduce the reaction rate and too high a temperature may lead to side reactions; a molar ratio of pentaerythritol halotriethylenetetramol to monomethoxyPEG of 1:4~1:8 to ensure that the four halogenation sites react fully; a reaction time of 6~50 h; and a concentration of monomethoxyPEG in the solvent of 1~300 g / L.

[0033] As mentioned above, in step S1, if water is used as the solvent, a phase transfer catalyst needs to be added; the phase transfer catalyst is selected from at least one of cyclic crown ethers, quaternary ammonium salts, tertiary amines, quaternary ammonium bases, and quaternary phosphine salts; the cyclic crown ethers include at least one of 18-crown 6, 15-crown 5, and cyclodextrin; the quaternary ammonium salts include at least one of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, and tetradecyltrimethylammonium chloride; the tertiary amines include pyridine or tributylamine.

[0034] The amount of the phase transfer catalyst is controlled to be 0-100% of the amount of reactants.

[0035] In this invention, the molecular weight of the monomethoxy PEG can be 200 to 20000, such as 200, 300, 400, 500, 600, 800, 1000, 1500, 2000, 4000, 5000, 6000, 8000, 10000, 20000, etc., and is not specifically limited here.

[0036] The reaction principle of step S2 is as follows: In the tetramethyl PEG of the four-armed PEG, the methoxy group (-OCH3) is reacted with thiol (a nucleophile) and boron trifluoride ether (a Lewis acid catalyst that activates the ether bond). Specifically, under the catalysis of the Lewis acid, the thiol attacks the methyl carbon atom of the tetramethyl PEG of the four-armed PEG, resulting in a bimolecular nucleophilic substitution (SN2) reaction, which leads to the cleavage of the CO bond and the formation of a four-armed PEG and thioether (RSCH3) with a hydroxyl terminus.

[0037] Among them, thiols are nucleophiles, and their activity order is: active aliphatic dithiols > aliphatic monothiols > aromatic thiols. Specifically, they can be selected from benzyl mercaptan, ethylene dithiol, 1-propanethiol, etc.

[0038] Boron trifluoride ethyl ether acts as a catalyst to promote the breaking of ether bonds, and its dosage needs to be matched with that of the four-armed PEG tetramethyl ether and thiol.

[0039] Therefore, the specific reaction conditions for step S2 are as follows: the ratio of tetramethyl PEG ether (mmol): thiol (mL): boron trifluoride ether (mL) is (0.001~2.5): (0.5~100): (0.03~10); the reaction temperature can be 20~80℃, that is, this step can be carried out efficiently at room temperature; the reaction time is 0.5~10 days.

[0040] In another specific embodiment of the present invention, a four-armed PEG prepared by the above-described preparation method is provided. The molecular weight of the four-armed PEG can be controlled according to the molecular weight of the monomethoxy PEG. Further, the molecular weight of the four-armed PEG can be 2000~80000, such as 2000, 4000, 8000, 10000, 20000, 40000, 80000, etc., and is not specifically limited here.

[0041] The technical solution of the present invention will be further described below with reference to specific embodiments.

[0042] Example 1 Step 1: Preparation of four-arm PEG tetramethyl ether-4k 10 g of monomethoxy PEG 1000 was dissolved in 100 mL of anhydrous N,N-dimethylformamide, 0.36 g of NaH was added, and the reaction was carried out for 1 h. Then 0.87 g of tetrabromopentaerythritol was added, and the reaction was heated at 60 °C for 24 h. After cooling to room temperature, the mixture was dialyzed against deionized water for 2 days, and the solvent was removed by rotary evaporation. The solid was purified by recrystallization with anhydrous ethanol to obtain 8.37 g of white solid product (Ⅰ), with a yield of 93%.

[0043] Step 2: Preparation of four-arm PEG-4k 8 g of product (Ⅰ) tetra-armed PEG tetramethyl ether obtained in step 1 was dissolved in 50 mL of benzyl mercaptan, and 0.5 mL of boron trifluoride diethyl ether was added with stirring. The reaction was carried out at room temperature for 2 days, and the reaction was stopped. The product was dialyzed with deionized water for 2 days, and then purified by precipitation, filtration and washing in anhydrous ethanol to obtain product (Ⅱ) 7.36 g, with a yield of 92%.

[0044] Example 2 Step 1: Preparation of four-arm PEG tetramethyl ether-8k 20 g of monomethoxy PEG 2000 was dissolved in 100 mL of anhydrous dimethyl sulfoxide, 0.36 g of NaH was added, and the reaction was carried out for 1 h. Then 0.87 g of tetrabromopentaerythritol was added, and the reaction was heated at 60 °C for 48 h. After cooling to room temperature, the mixture was dialyzed against deionized water for 2 days, and the solvent was removed by rotary evaporation. The solid was purified by recrystallization with anhydrous ethanol to obtain 16.2 g of white solid product (Ⅰ), with a yield of 90%.

[0045] Step 2: Preparation of four-arm PEG-8k 10 g of product (Ⅰ) tetra-armed PEG tetramethyl ether obtained in step 1 was dissolved in 50 mL of benzyl mercaptan, and 1 mL of boron trifluoride diethyl ether was added with stirring. The reaction was carried out at room temperature for 2 days, and the reaction was stopped. The product was dialyzed with deionized water for 2 days, and then purified by precipitation, filtration and washing in anhydrous ethanol to obtain product (Ⅱ) 9.3 g, with a yield of 93%.

[0046] Example 3 Step 1: Preparation of four-arm PEG tetramethyl ether-80k 200 g of monomethoxy PEG 20000 was dissolved in 800 mL of anhydrous acetonitrile, 0.48 g of NaH was added, and the reaction was allowed to proceed for 1 day. Then, 0.87 g of tetrabromopentaerythritol was added, and the mixture was heated at 80 °C for 36 h. After cooling to room temperature, the mixture was dialyzed against deionized water for 2 days, and the solvent was removed by rotary evaporation. The solid was purified by recrystallization from anhydrous ethanol to obtain 153.2 g of white solid product (Ⅰ), with a yield of 85%.

[0047] Step 2: Preparation of four-arm PEG-80k 10 g of product (Ⅰ) tetramethyl PEG obtained in step 1 was dissolved in 40 mL of ethylenedithiol, and 1 mL of boron trifluoride ethyl ether was added with stirring. The reaction was carried out at room temperature for 2 days, and the reaction was stopped. The product was dialyzed with deionized water for 2 days, and then purified by precipitation, filtration and washing in anhydrous ethanol to obtain product (Ⅱ) 9.5 g, with a yield of 95%.

[0048] Example 4 Step 1: Preparation of four-arm PEG tetramethyl ether-20k 50 g of monomethoxy PEG 5000 was dissolved in 200 mL of anhydrous N,N-dimethylformamide, and 0.60 g of KH was added. The reaction was allowed to proceed for 1 h, followed by the addition of 0.89 g of tetraiodopentaerythritol. The mixture was heated at 100 °C for 24 h, cooled to room temperature, dialyzed against deionized water for 2 days, and the solvent was removed by rotary evaporation. The solid was purified by recrystallization from anhydrous ethanol to give 42.75 g of a white solid product (Ⅰ), with a yield of 95%. The 1H NMR spectrum is shown below. Figure 2 At chemical shift 3.40, there are 12 H peaks, which are four CH3 peaks; at chemical shift 3.41, there are 8 H peaks, which are four CH2 peaks originating from pentaerythritol; at chemical shifts 3.50-3.78, there are 1804 H peaks, which are CH2 peaks of PEG (theoretical value 1818). Overall, the results are consistent with the expected structure, indicating that the target product, four-armed PEG tetramethyl ether-20k, has been obtained.

[0049] Step 2: Preparation of four-arm PEG-20k 10 g of product (I) obtained in step 1, tetra-armed PEG tetramethyl ether, was dissolved in 30 mL of 1-propanethiol. 0.2 mL of boron trifluoride diethyl ether was added with stirring. The reaction was carried out at room temperature for 2 days. The reaction was then stopped, and the product was dialyzed against deionized water for 2 days. After precipitation, filtration, and washing in anhydrous ethanol, 9.46 g of product (II) was obtained, with a yield of 95%. The 1H NMR spectrum is shown below. Figure 3The presence of 8 H atoms at chemical shift 3.41 is attributed to the four CH2 peaks of pentaerythritol; the presence of 1790 H atoms at chemical shifts 3.63-3.76 is attributed to the CH2 peaks of PEG (theoretical value 1818). Overall, the results are consistent with the expected structure, indicating that the target product, four-armed PEG-20k, has been obtained.

[0050] Example 5 Step 1: Preparation of four-arm PEG tetramethyl ether-40k 100 g of monomethoxy PEG 10000 was dissolved in 500 mL of anhydrous N,N-dimethylformamide, 0.60 g of KH was added, and the reaction was carried out for 1 h. Then 0.47 g of tetrachloropentaerythritol was added, and the reaction was heated at 150 °C for 48 h. After cooling to room temperature, the mixture was dialyzed against deionized water for 2 days, and the solvent was removed by rotary evaporation. The solid was purified by recrystallization with anhydrous ethanol to obtain 74.72 g of white solid product (Ⅰ), with a yield of 83%.

[0051] Step 2: Preparation of four-arm PEG-40k 10 g of product (Ⅰ) tetramethyl PEG obtained in step 1 was dissolved in 40 mL of 1-propanethiol, and 0.1 mL of boron trifluoride diethyl ether was added with stirring. The reaction was carried out at room temperature for 2 days, and the reaction was stopped. The product was dialyzed with deionized water for 2 days, and then purified by precipitation, filtration and washing in anhydrous ethanol to obtain product (Ⅱ) 9.4 g, with a yield of 94%.

[0052] Example 6 Step 1: Preparation of four-arm PEG tetramethyl ether-4k 10 g of monomethoxy PEG 1000 was dissolved in 100 mL of anhydrous tetrahydrofuran, 1.61 g of LDA was added, and the reaction was carried out for 1 h. Then 0.87 g of tetrabromopentaerythritol was added, and the reaction was heated at 60 °C for 48 h. After cooling to room temperature, the mixture was dialyzed against deionized water for 2 days, and the solvent was removed by rotary evaporation. The solid was purified by recrystallization with anhydrous ethanol to obtain 8.1 g of white solid product (Ⅰ), with a yield of 90%.

[0053] Step 2: Preparation of four-arm PEG-4k 8 g of product (Ⅰ) tetra-armed PEG tetramethyl ether obtained in step 1 was dissolved in 20 mL of ethylenedithiol, and 0.1 mL of boron trifluoride diethyl ether was added with stirring. The reaction was carried out at room temperature for 2 days, and the reaction was stopped. The product was dialyzed with deionized water for 2 days, and then purified by precipitation, filtration and washing in anhydrous ethanol to obtain product (Ⅱ) 7.36 g, with a yield of 90%.

[0054] Example 7 Step 1: Preparation of four-arm PEG tetramethyl ether-4k 10 g of monomethoxy PEG 1000 was dissolved in 100 mL of water containing 20 g of NaOH and reacted for 1 h. Then, 0.87 g of tetrabromopentaerythritol and 0.32 g of tetrabutylammonium bromide were added, and the mixture was heated at 100 °C for 48 h. After cooling to room temperature, the mixture was dialyzed against deionized water for 2 days, and the solvent was removed by rotary evaporation. The solid was purified by recrystallization with anhydrous ethanol to obtain 6.39 g of white solid product (Ⅰ), with a yield of 71%.

[0055] Step 2: Preparation of four-arm PEG-4k 6 g of product (Ⅰ) tetra-armed PEG tetramethyl ether obtained in step 1 was dissolved in 20 mL of benzyl mercaptan, and 0.1 mL of boron trifluoride diethyl ether was added with stirring. The reaction was carried out at room temperature for 2 days, and the reaction was stopped. The product was dialyzed with deionized water for 2 days, and then purified by precipitation, filtration and washing in anhydrous ethanol to obtain product (Ⅱ) 5.4 g, with a yield of 90%.

[0056] Example 8 Step 1: Preparation of four-arm PEG tetramethyl ether-2k 5 g of monomethoxy PEG 500 was dissolved in 20 mL of anhydrous toluene, and 0.60 g of KH was added. The reaction was allowed to proceed for 1 h, followed by the addition of 0.87 g of tetrabromopentaerythritol. The mixture was heated at 110 °C for 36 h, cooled to room temperature, dialyzed against deionized water for 2 days, and the solvent was removed by rotary evaporation. The solid was purified by recrystallization from anhydrous ethanol to give 3.78 g of a white solid product (Ⅰ), with a yield of 84%. The 1H NMR spectrum is shown below. Figure 4 At chemical shift 3.40, there are 12 H peaks, which are four CH3 peaks; at chemical shift 3.42, there are 8 H peaks, which are four CH2 peaks originating from pentaerythritol; at chemical shifts 3.50-3.75, there are 181 H peaks, which are CH2 peaks of PEG (theoretical value 182). Overall, the results are consistent with the expected structure, indicating that the target product, four-armed PEG tetramethyl ether-2k, has been obtained.

[0057] Step 2: Preparation of four-arm PEG-2k 3 g of product (I) obtained in step 1, tetra-armed PEG tetramethyl ether, was dissolved in 10 mL of 1-propanethiol. 0.1 mL of boron trifluoride diethyl ether was added with stirring. The reaction was allowed to proceed at room temperature for 3 days. The reaction was then stopped, and the product was dialyzed against deionized water for 2 days. After precipitation, filtration, and washing in anhydrous ethanol, 2.76 g of product (II) was obtained, with a yield of 92%. The 1H NMR spectrum is shown below. Figure 5 The presence of 8 H atoms at chemical shift 3.41 is attributed to the four CH2 peaks of pentaerythritol; the presence of 175 H atoms at chemical shifts 3.63-3.74 is attributed to the CH2 peaks of PEG (theoretical value 182). Overall, the results are consistent with the expected structure, indicating that the target product, four-armed PEG-2k, has been obtained.

[0058] Comparative Example 1 Preparation of target product: four-arm PEG-24k 60 g of PEG 6000 was dissolved in 100 mL of anhydrous N,N-dimethylformamide, 0.36 g of NaH was added, and the reaction was carried out for 1 h. Then 0.87 g of tetrabromopentaerythritol was added, and the reaction was heated at 80 °C for 24 h. After cooling to room temperature, the product was dialyzed against deionized water for 2 days, and the solvent was removed by rotary evaporation. The solid was purified by recrystallization with anhydrous ethanol to obtain 45.2 g of white solid product.

[0059] See the hydrogen NMR spectrum. Figure 6 The presence of 8 H atoms at chemical shift 3.41 is attributed to the four CH2 peaks of pentaerythritol; the presence of 3282 H atoms at chemical shifts 3.63-3.73 is attributed to the CH2 peaks of PEG, exceeding the theoretical value (2182). This indicates that the terminal hydroxyl groups (-OH) of the product have been further coupled and lengthened, resulting in a significant difference between the NMR results of the product and the target product. In other words, the product exhibits cross-linking. Therefore, under the same conditions, directly using PEG as the reaction raw material will not yield the target product, four-armed PEG-24k.

[0060] Comparative Example 2 Preparation of target product: four-arm PEG-24k 60 g of PEG 6000 was dissolved in 200 mL of water containing 40 g of NaOH and reacted for 1 h. Then, 0.87 g of tetrabromopentaerythritol and 0.32 g of tetrabutylammonium bromide were added, and the mixture was heated at 100 °C for 48 h. After cooling to room temperature, the mixture was dialyzed against deionized water for 2 days, and the solvent was removed by rotary evaporation. The solid was purified by recrystallization with anhydrous ethanol to obtain 40.3 g of white solid product.

[0061] See the hydrogen NMR spectrum. Figure 7 The presence of 8 H atoms at chemical shift 3.44 is attributed to the four CH2 peaks of pentaerythritol; the presence of 7851 H atoms at chemical shifts 3.65-3.73 is attributed to the CH2 peaks of PEG, exceeding the theoretical value (2182). This indicates that the terminal hydroxyl groups (-OH) of the product have been further coupled and lengthened, resulting in a significant difference between the NMR results of the product and the target product. In other words, the product exhibits cross-linking. Therefore, under the same conditions, directly using PEG as the reaction raw material will not yield the target product, four-armed PEG-24k.

[0062] Comparative Example 3 Preparation of four-armed PEG tetramethyl ether-4k 10 g of monomethoxy PEG 1000 was dissolved in 100 mL of anhydrous N,N-dimethylformamide, 0.36 g of NaH was added, and the reaction was carried out for 1 h. Then 0.87 g of tetrabromopentaerythritol was added, and the reaction was carried out at 20 °C for 48 h. After dialyzing with deionized water for 2 days, the solvent was removed by rotary evaporation to obtain the crude product, with a yield of only 17%.

[0063] When the reaction temperature is low, the energy of the reactant molecules is low, making it difficult to reach a sufficient activation energy, which slows down the reaction rate and results in a low product yield. In addition, the activity of the catalyst usually decreases under low temperature conditions, which weakens the acceleration effect of the reaction.

[0064] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing a four-armed PEG, characterized in that, The preparation method includes: 。 2. The preparation method according to claim 1, characterized in that, The preparation method includes: S1. In an alkaline solvent, monomethoxy PEG is heated and reacted with pentaerythritol haloside to obtain tetramethyl PEG tetraarm PEG; wherein the halogen in pentaerythritol haloside is any one of Cl, Br or I. S2. Dissolve the tetramethyl PEG obtained in step S1 in thiol, add boron trifluoride diethyl ether, and react to generate tetramethyl PEG.

3. The preparation method according to claim 2, characterized in that, In step S1, the alkali in the alkaline solvent is selected from any one or more of NaH, KH, LDA, LHMDS, NaHMDS, NaOH, Na, and K; The solvent in the alkaline solvent is selected from aprotic polar solvents or water.

4. The preparation method as described in claim 3, characterized in that, The aprotic polar solvent is selected from any one or more of N,N-dimethylformamide, dimethyl sulfoxide, toluene, tetrahydrofuran, acetonitrile, and acetone.

5. The preparation method according to claim 3, characterized in that, When water is used as a solvent, a phase transfer catalyst is added. Further, the phase transfer catalyst is selected from at least one of cyclic crown ethers, quaternary ammonium salts, tertiary amines, quaternary ammonium bases, and quaternary phosphine salts. The cyclic crown ethers include at least one of 18-crown 6, 15-crown 5, and cyclodextrin. The quaternary ammonium salts include at least one of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, and tetradecyltrimethylammonium chloride. The tertiary amines include pyridine or tributylamine.

6. The preparation method according to claim 2, characterized in that, In step S1, the reaction parameters include: a reaction temperature of 40~150℃; a molar ratio of pentaerythritol halotriethylenetetramol to monomethoxy PEG of 1:4~1:8; a reaction time of 6~50 h; a concentration of monomethoxy PEG in the solvent of 1~300 g / L; wherein the molecular weight of the monomethoxy PEG is 200~20000.

7. The preparation method according to claim 2, characterized in that, In step S2, the thiol is selected from aliphatic dithiols, aliphatic monothiols, and aromatic thiols; further selected from any one or more of benzyl mercaptan, ethylene dithiol, and 1-propanethiol.

8. The preparation method according to claim 2, characterized in that, The specific reaction conditions for step S2 are as follows: the ratio of tetramethyl PEG ether (mmol): thiol (mL): boron trifluoride ether (mL) is (0.001~2.5): (0.5~100): (0.03~10).

9. The preparation method according to claim 2, characterized in that, The reaction temperature in step S2 is 20~80℃; the reaction time is 0.5~10 days.

10. The four-armed PEG prepared by the method according to any one of claims 1-9; further, the molecular weight of the four-armed PEG is 2000-80000.

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