Double-protected amino polyethylene glycol and derivatives thereof and methods of making

Abstract

This invention discloses a double-protected amino polyethylene glycol (PEG) and its derivatives, as well as a preparation method thereof, belonging to the field of PEG technology. The double-protected amino PEG and its derivatives have the structure shown in Formula 1, where n is the degree of polymerization, selected from any integer between 10 and 454; and q is the number of methylene groups, selected from any integer between 0 and 6. The double-protected amino PEG has a novel structure and enriches the structural types of double-protected amino-terminated PEG derivatives as an intermediate for their preparation. Furthermore, the synthesis method of the double-protected amino PEG and its derivatives is simple and efficient, with advantages such as high selectivity, high yield, mild reaction, and simple post-processing, making it suitable for large-scale industrial production. This provides a new approach for the synthesis and application of double-terminated PEG derivatives.

Description

Technical Field

[0001] This invention relates to the field of polyethylene glycol technology, and more particularly to a double-protected amino polyethylene glycol and its derivatives and preparation methods. Background Technology

[0002] Polyethylene glycol (PEG) is a widely used water-soluble polymer compound produced by the polymerization of ethylene oxide. PEG possesses good biocompatibility, chemical stability, and low toxicity, making it widely used in pharmaceuticals, cosmetics, food, and other industrial fields.

[0003] Functionalized polyethylene glycol (PEG) is achieved by introducing specific functional groups or chemically modifying the PEG molecular chain, giving it specific functions or properties. This modification can significantly expand the application range of PEG and enhance its performance in various fields. Functional groups are usually located at the ends of the PEG chain (terminal functionalization), and common functional groups include carboxyl, amino, mercapto, azide, and maleimide groups. Among these, the selection of amino groups has attracted widespread attention.

[0004] Amino protection includes both mono-protection and di-protection. Di-protection of amino groups with different protecting groups can protect amino groups under different chemical reaction conditions, thus adapting to a variety of reaction environments. It can also selectively protect specific amino groups in different steps, reducing the impact on other functional groups, thereby improving the selectivity and compatibility of the reaction and reducing adverse effects on other reactions.

[0005] Aberrant polyethylene glycol (PEG) derivatives are an important component of functionalized PEG. Due to the different functional groups at their two ends, aberrant PEG derivatives offer greater synthetic flexibility and diversity, enabling more precise molecular design and modification. They are suitable for constructing complex, multifunctional molecules or materials and have wide applications in biomedicine and materials science. For example, aberrant PEG derivatives can covalently bind to drug molecules, introducing specific targeting groups to improve drug stability, solubility, and bioavailability, thereby achieving targeted drug delivery. This technology improves the precision and efficacy of treatment.

[0006] Amino-protected polyethylene glycol is an important intermediate for anisoterminated polyethylene glycol derivatives, and its synthesis processes include the following:

[0007] 1. Selectively modify one end of polyethylene glycol (PEG), then obtain amino-protected PEG through separation and purification. The disadvantage of this process is poor selectivity and difficulty in separation and purification. For example, patent WO2023059583A selectively introduces a leaving group into one end of PEG, then reacts it with an amino-protecting reagent to obtain amino-monoprotected PEG. Patent CN109096128A uses an amino-protecting reagent with a leaving group to selectively protect one end of PEG, obtaining amino-double-protected PEG.

[0008] However, the two methods mentioned above have poor reaction selectivity, are difficult to separate and purify, and have low yields (12% and 24.9%, respectively).

[0009] 2. Hydroxyl-protected polyethylene glycol (PEG) is obtained through esterification and substitution reactions to form hydroxyl-protected PEG with an amino protecting group. Subsequent removal of the hydroxyl protecting group yields amino-protected PEG. While this method yields high output, the process is lengthy and requires sophisticated experimental techniques. For example, patent CN114409890A uses benzyloxy-terminated PEG with a leaving group at the end, reacting it with an amino protecting agent to obtain amino-protected benzyloxy-terminated PEG. Subsequent removal of the benzyl group yields amino-protected PEG. This route involves four steps, making it cumbersome and demanding.

[0010] 3. Short-chain amino-protected polyethylene glycol (PEG) can be obtained by grafting groups (such as ether bonds, amide bonds, disulfide bonds, etc.), and then the desired long-chain amino-protected PEG can be formed. However, the problem with this process is that the product is unstable, difficult to separate and purify, and difficult to scale up for production. For example, the literature Bioorganic and Medicinal Chemistry Letters, 2012, pp. 586-590 and Eur. J. Org. Chem. 2011, 1641–1644 describes the grafting reaction of short-chain amino-protected PEG with leaving groups at the end with PEG. After 6 steps, long-chain amino-protected PEG is generated, with an overall yield of about 44% and 63%, respectively. This method has a complex reaction route, is difficult to separate and purify, and cannot be scaled up for production.

[0011] Therefore, it is of great significance to research and develop a new amino-double-protected polyethylene glycol, and to synthesize anisoterminated polyethylene glycol derivatives through its simple and efficient method, thereby enriching the variety of anisoterminated polyethylene glycol derivatives and realizing the functional use of polyethylene glycol. Summary of the Invention

[0012] In view of this, the technical problem to be solved by the present invention is to provide a double-protected amino polyethylene glycol and its derivatives, and a method for their preparation. The double-protected amino polyethylene glycol has a novel structure and, as an intermediate for anisoterminated polyethylene glycol derivatives, enriches the structural types of anisoterminated polyethylene glycol derivatives with double-protected amino groups.

[0013] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0014] This invention provides a double-protected amino polyethylene glycol and its derivatives, having the structure shown in Formula 1:

[0015]

[0016] Where n is the degree of aggregation, selected from any integer between 10 and 454;

[0017] q represents the number of methylene groups, selected from any integer between 0 and 6;

[0018] R1 and R2 are independently selected from one or more of the following groups:

[0019]

[0020] R3 is selected from -H, -NH2,

[0021] Preferably, in this invention, n is selected from any integer between 22 and 227;

[0022] Preferably, q is selected from any integer between 0 and 4;

[0023] Preferably, R1 and R2 are selected from... Alternatively, preferably, R1 and R2 are selected from...

[0024] Alternatively, preferably, R1 and R2 are selected from... Alternatively, preferably, R1 and R2 are selected from... Alternatively, preferably, R1 and R2 are selected from... Alternatively, preferably, R1 and R2 are selected from... Alternatively, preferably, R1 and R2 are selected from...

[0025] Alternatively, preferably, R1 and R2 are selected from...

[0026] More preferably, the structure of the double-protected amino polyethylene glycol is shown in Formula 1-1:

[0027]

[0028] More preferably, the structure of the double-protected amino polyethylene glycol derivative is shown in Formulas 1-2:

[0029]

[0030] More preferably, the structure of the double-protected amino polyethylene glycol derivative is shown in Formulas 1-3:

[0031]

[0032] R4 is selected from any of the following structures:

[0033]

[0034] The present invention also provides a method for preparing the above-mentioned double-protected amino polyethylene glycol (structure shown in Formula 1-1), comprising the following steps:

[0035] The double-protected amino polyethylene glycol is obtained by mixing ethylene oxide, alkali and an initiator with the structure shown in Formula 2 under anhydrous conditions.

[0036]

[0037] Where m is any integer between 0 and 4;

[0038] The initiator with the structure shown in Formula 2 above is selected from bis-protected amines, bis-protected amino ethylene glycol, bis-protected amino diethylene glycol, bis-protected amino triethylene glycol, or bis-protected amino tetraethylene glycol, wherein the bis-protecting groups are R1 and R2 as described above.

[0039] R1 and R2 are independently selected from one or more of the following groups:

[0040]

[0041] Preferably, R1 and R2 are selected from...

[0042] Alternatively, preferably, R1 and R2 are selected from...

[0043] Alternatively, preferably, R1 and R2 are selected from...

[0044] Alternatively, preferably, R1 and R2 are selected from...

[0045] Alternatively, preferably, R1 and R2 are selected from...

[0046] Alternatively, preferably, R1 and R2 are selected from...

[0047] Alternatively, preferably, R1 and R2 are selected from...

[0048] Alternatively, preferably, R1 and R2 are selected from...

[0049] In some specific embodiments of the present invention, the initiator of the structure shown in Formula 2 is selected from bis(tert-butoxycarbonyl)amine, bis(benzylmethoxycarbonyl)aminotetraethylene glycol, or N-(tert-butoxycarbonyl)benzylaminodiethylene glycol.

[0050] Preferably, in this invention, the molar ratio of the initiator to the base in the structure shown in Formula 2 is 1:(0.1-10);

[0051] Preferably, the molar ratio of the initiator to ethylene oxide is 1:(10-454).

[0052] Preferably, the reaction temperature is 30℃-150℃.

[0053] Preferably, the reaction pressure is 0.1-2.0 MPa.

[0054] The preferred reaction time is 6-120 hours.

[0055] The alkalis include, but are not limited to, sodium, potassium, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium naphthalene, potassium tert-butoxide, etc.

[0056] The solvents used in the reaction include, but are not limited to, benzene, toluene, xylene, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, dichloromethane, chloroform, etc.

[0057] The above preparation method uses an initiator with the structure shown in Formula 2 to initiate anionic polymerization of ethylene oxide. After the reaction is completed, solid-liquid separation and drying are performed to obtain double-protected amino polyethylene glycol with the structure shown in Formula 1-1.

[0058] This invention also provides a method for preparing the above-mentioned double-protected amino polyethylene glycol derivative (structure shown in Formulas 1-2), comprising the following steps:

[0059] The substituted reagent, base and double-protected amino polyethylene glycol with the structure shown in Formula 1-1 were mixed and reacted under anhydrous conditions. After the reaction was completed, ammonia was added to obtain the double-protected amino polyethylene glycol derivative with the structure shown in Formula 1-2.

[0060] The substituted reagent is selected from one or more of phosphorus oxychloride, thionyl chloride, phosphorus tribromide, methanesulfonyl chloride, and p-toluenesulfonyl chloride.

[0061] The above preparation method yields the double-protected amino polyethylene glycol derivative with the structure shown in Formula 1-2 by evaporating the solvent after the reaction, without the need for further separation and purification, and the reaction yield is high.

[0062] The molar ratio of the substituted reagent to the double-protected amino polyethylene glycol of the structure shown in Formula 1-1 is (1-5):1.

[0063] The molar ratio of the alkali to the double-protected amino polyethylene glycol of the structure shown in Formula 1-1 is (0.01-5):1.

[0064] The solvent in the mixture is selected from one or more of dichloromethane, chloroform, benzene, toluene, dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, and tetrahydrofuran.

[0065] The alkali used in the preparation method is preferably one or more selected from triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium hydride, potassium hydride, sodium, lithium diisopropylamino, lithium hexamethyldisilamino, potassium hexamethyldisilamino, and sodium hexamethyldisilamino. The reaction temperature is -20℃ to 50℃.

[0066] The reaction time is 6-96 hours.

[0067] The above preparation method directly prepares the double-protected amino polyethylene glycol derivative (double-protected amino polyethylene glycol amine) with the structure shown in Formula 1-2 through two substitution reactions of the double-protected amino polyethylene glycol with the structure shown in Formula 1-1. The method is simple and efficient, and has the advantages of high reaction selectivity and high yield.

[0068] In some specific embodiments of the present invention, the dual-protected amino polyethylene glycol derivatives (dual-protected amino polyethylene glycol amines) with the structures shown in Formulas 1-2 include the following structures:

[0069]

[0070] This invention also provides a method for preparing the above-mentioned double-protected amino polyethylene glycol derivatives (structures shown in Formulas 1-3), comprising the following steps:

[0071] The condensation reagent, activating reagent, modifying substance and the double-protected amino polyethylene glycol derivative with the structure shown in Formula 1-2 were mixed and reacted to obtain the double-protected amino polyethylene glycol derivative with the structure shown in Formula 1-3.

[0072] The above preparation method yields the double-protected amino polyethylene glycol derivatives with the structure shown in Formula 1-3 by washing and drying after the reaction. The post-processing is simple and the product yield is high.

[0073] The modifying substance is selected from any of the following structures:

[0074]

[0075] The preferred molar ratio of the double-protected amino polyethylene glycol derivative and the modifying substance in the structure shown in Formula 1-2 is 1:(1-10).

[0076] The preferred molar ratio of the double-protected amino polyethylene glycol derivative and the condensation reagent in the structure shown in Formula 1-2 is 1:(1-5).

[0077] The preferred molar ratio of the double-protected amino polyethylene glycol derivative and the activating agent shown in Formula 1-2 is 1:(1-5).

[0078] The reaction temperature is 0℃~50℃.

[0079] The reaction time is 6 to 48 hours.

[0080] The condensing reagents include, but are not limited to, preferably 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, benzotriazine-1-yl-oxytripyrrolylphosphine hexafluorophosphate, O-benzotriazine-N,N,N',N'-tetramethylureatetrafluoroboric acid, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0081] The activating agent is preferably one or more of N-hydroxybenzotriazole and N-hydroxysuccinamide.

[0082] The solvent for the reaction is selected from one or more of dichloromethane, chloroform, benzene, toluene, dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, and tetrahydrofuran.

[0083] The above preparation method directly prepares the double-protected amino polyethylene glycol derivative with the structure shown in Formula 1-3 through the condensation reaction of the double-protected amino polyethylene glycol derivative (double-protected amino polyethylene glycol amine) with the structure shown in Formula 1-2. The method is simple, has high reaction selectivity, and high product yield.

[0084] In some specific embodiments of the present invention, the double-protected amino polyethylene glycol derivatives with the structures shown in Formulas 1-3 above include the following structures:

[0085]

[0086] The double-protected amino polyethylene glycol derivatives (double-protected amino polyethylene glycol amines) with the structure shown in Formula 1-2 and the double-protected amino polyethylene glycol derivatives with the structure shown in Formula 1-3 of this invention are both heteroterminated polyethylene glycol derivatives. They can also undergo further functionalization modification by removing the amino protecting group to obtain more complex heteroterminated polyethylene glycol derivatives.

[0087] This invention, by designing a double-protected amino polyethylene glycol structure, further enriches the variety of heteroterminated polyethylene glycol derivatives. Furthermore, the preparation methods for double-protected amino polyethylene glycol and heteroterminated polyethylene glycol derivatives are simple and efficient, with mild reaction conditions, simple post-processing, and high product yield, making them suitable for large-scale production.

[0088] Compared with existing technologies, the biprotected amino polyethylene glycol and its derivatives provided by this invention have the structure shown in Formula 1, where n is the degree of polymerization, selected from any integer between 10 and 454; and q is the number of methylene groups, selected from any integer between 0 and 6. The biprotected amino polyethylene glycol has a novel structure and enriches the structural types of biprotected amino-terminated polyethylene glycol derivatives as an intermediate for their preparation. Furthermore, the synthesis method of the biprotected amino polyethylene glycol and its derivatives is simple and efficient, with advantages such as high selectivity, high yield, mild reaction, and simple post-processing, making it suitable for large-scale industrial production. This provides a new approach for the synthesis and application of biprotected polyethylene glycol derivatives. Attached Figure Description

[0089] Figure 1 The 1 kDa NMR spectrum of bis(tert-butyloxycarbonyl)amino polyethylene glycol prepared in Example 1;

[0090] Figure 2 The 1 kDa gel permeation chromatogram of bis(tert-butyloxycarbonyl)amino polyethylene glycol prepared in Example 1;

[0091] Figure 3 The 2kDa NMR spectrum of bis(tert-butyloxycarbonyl)amino polyethylene glycol prepared in Example 2;

[0092] Figure 4 The 2kDa gel permeation chromatogram of bis(tert-butyloxycarbonyl)amino polyethylene glycol prepared in Example 2;

[0093] Figure 5 The 5kDa NMR spectrum of bis(tert-butoxycarbonyl)amino polyethylene glycol prepared in Example 3;

[0094] Figure 6 The 5kDa gel permeation chromatogram of bis(tert-butyloxycarbonyl)amino polyethylene glycol prepared in Example 3;

[0095] Figure 7 The 2kDa NMR spectrum of bis(tert-butyloxycarbonyl)amino polyethylene glycol methanesulfonate prepared in step one of Example 6;

[0096] Figure 8 The 2kDa NMR spectrum of the bis(tert-butyloxycarbonyl)aminopolyethylene glycolamine prepared in Example 6;

[0097] Figure 9The 2kDa gel permeation chromatogram of bis(tert-butyloxycarbonyl)aminopolyethylene glycolamine prepared in Example 6;

[0098] Figure 10 The 5kDa NMR spectrum of bis(tert-butyloxycarbonyl)aminopolyethylene glycolamine prepared in Example 7;

[0099] Figure 11 The 5kDa gel permeation chromatogram of bis(tert-butyloxycarbonyl)aminopolyethylene glycolamine prepared in Example 7;

[0100] Figure 12 The 5kDa NMR spectrum of bis(tert-butyloxycarbonyl)amino polyethylene glycol maleimide prepared in Example 9;

[0101] Figure 13 The 5kDa gel permeation chromatogram of bis(tert-butyloxycarbonyl)amino polyethylene glycol maleimide prepared in Example 9;

[0102] Figure 14 The 2kDa NMR spectrum of bis(tert-butyloxycarbonyl)amino polyethylene glycol cholesterol prepared in Example 11;

[0103] Figure 15 The image shows a 2kDa gel permeation chromatogram of bis(tert-butoxycarbonyl)amino polyethylene glycol cholesterol prepared in Example 11. Detailed Implementation

[0104] To further illustrate the present invention, the following detailed description of the dual-protected amino polyethylene glycol and its derivatives and preparation methods provided by the present invention is provided in conjunction with embodiments.

[0105] Example 1

[0106] Under anhydrous conditions, 434 g of bis(tert-butyloxycarbonyl)amine was dissolved in 3 L of dioxane and added to a 10 L high-pressure reactor. 112 g of sodium hydroxide was added, and the mixture was heated to 60 °C with stirring. 2 kg of ethylene oxide was introduced into the reactor, maintaining a reaction pressure of 2 MPa. The reaction continued for 24 hours, and the pressure was reduced to 0 MPa. A brownish-red reaction liquid was released, and after evaporation, 2.45 kg of a white solid of bis(tert-butyloxycarbonyl)amine polyethylene glycol was obtained. The molecular weight was approximately 1 kDa, and the yield was 96.23%. The specific structural formula is as follows:

[0107]

[0108] Example 2

[0109] Under anhydrous conditions, 217 g of bis(tert-butyloxycarbonyl)amine was dissolved in 2 L of chloroform and added to a 10 L high-pressure reactor. 36 g of potassium hydride was added, and the mixture was heated to 60 °C with stirring. 2 kg of ethylene oxide was introduced into the reactor, maintaining a reaction pressure of 2 MPa. The reaction continued for 24 hours, until the pressure dropped to 0 MPa. A brown reaction liquid was released, and after evaporation, 2.25 kg of a white solid of bis(tert-butyloxycarbonyl)amine polyethylene glycol was obtained. The molecular weight was approximately 2 kDa, and the yield was 98.99%. The specific structural formula is as follows:

[0110]

[0111] Example 3

[0112] Under anhydrous conditions, 86.8 g of bis(tert-butyloxycarbonyl)amine was dissolved in 1 L of tetrahydrofuran and added to a 5 L high-pressure reactor. 22.4 g of potassium hydroxide was added, and the mixture was heated to 60 °C with stirring. 2 kg of ethylene oxide was introduced into the reactor, maintaining a reaction pressure of 1 MPa. The reaction continued for 24 hours, until the pressure dropped to 0 MPa. A yellow reaction liquid was released, and after evaporation to dryness, 2.08 kg of a white solid of bis(tert-butyloxycarbonyl)amine polyethylene glycol was obtained, with a molecular weight of approximately 5 kDa and a yield of 98.62%. The specific structural formula is as follows:

[0113]

[0114] Example 4

[0115] Under anhydrous conditions, 76 g of bis(benzylmethoxycarbonyl)aminotetraethylene glycol was dissolved in 1 L of dimethyl sulfoxide and added to a 5 L high-pressure reactor. 12.4 g of sodium hydride was added, and the mixture was heated to 80 °C with stirring. 2 kg of ethylene oxide was introduced into the reactor, and the reaction pressure was 0.5 MPa. The reaction continued for 72 hours, and the pressure was reduced to 0.05 MPa. A pale yellow reaction liquid was released, and after evaporation, 2.07 kg of a white solid of bis(benzylmethoxycarbonyl)aminopolyethylene glycol was obtained, with a molecular weight of approximately 10 kDa and a yield of 99.14%. The specific structural formula is as follows:

[0116]

[0117] Example 5

[0118] Under anhydrous conditions, 65 g of N-(tert-butyloxycarbonyl)benzylamino diethylene glycol was dissolved in 1 L of dimethyl sulfoxide and added to a 5 L high-pressure reactor. 33.4 g of potassium tert-butoxide was added, and the mixture was heated to 70 °C with stirring. 2 kg of ethylene oxide was introduced into the reactor, and the reaction pressure was 0.7 MPa. The reaction continued for 48 hours, and the pressure was reduced to 0.05 MPa. A yellow reaction liquid was released, and after evaporation, 1.99 kg of a white solid of N-(tert-butyloxycarbonyl)benzylamino polyethylene glycol was obtained. The molecular weight was approximately 7 kDa, and the yield was 94.76%. The specific structural formula is as follows:

[0119]

[0120] Example 6

[0121] Step 1: Under anhydrous conditions, 10g of bis(tert-butyloxycarbonyl)amino polyethylene glycol (2kDa) was dissolved in 50mL of chloroform. 1.44mL of triethylamine was added with stirring, followed by the addition of 1.15g of methanesulfonyl chloride. The reaction was carried out at 25°C for 6 hours. The solution was evaporated to dryness to obtain 10.5g of a white solid, bis(tert-butyloxycarbonyl)amino polyethylene glycol methanesulfonate, with a molecular weight of approximately 2kDa and a yield of 99.5%. The specific structural formula is as follows:

[0122]

[0123] Step 2: Dissolve the bis(tert-butyloxycarbonyl)amino polyethylene glycol methanesulfonate obtained in Step 1 in 30 mL of ammonia water, and react at 30°C for 12 hours. After the reaction is complete, evaporate the solvent to obtain 10 g of a white solid bis(tert-butyloxycarbonyl)amino polyethylene glycol amine with a molecular weight of approximately 2 kDa and a yield of 99%. The specific structural formula is as follows:

[0124]

[0125] Example 7

[0126] Step 1: Under anhydrous conditions, 10g of bis(tert-butyloxycarbonyl)amino polyethylene glycol (5kDa) was dissolved in 100mL of dichloromethane. With stirring, 1.95mL of N,N-diisopropylethylamine was added, followed by the addition of 1.9g of p-toluenesulfonyl chloride. The reaction was carried out at 35°C for 12 hours. The solution was evaporated to dryness to obtain 11.5g of a white solid, bis(tert-butyloxycarbonyl)amino polyethylene glycol p-toluenesulfonate, with a molecular weight of approximately 5kDa and a yield of 96.64%. The specific structural formula is as follows:

[0127]

[0128] Step 2: Dissolve the bis(tert-butyloxycarbonyl)amino polyethylene glycol p-toluenesulfonate obtained in Step 1 in 50 mL of ammonia water, and react at 30°C for 12 hours. After the reaction is complete, evaporate the solvent to obtain 9.9 g of a white solid bis(tert-butyloxycarbonyl)amino polyethylene glycol amine with a molecular weight of approximately 5 kDa and a yield of 99%. The specific structural formula is as follows:

[0129]

[0130] Example 8

[0131] Step 1: Under anhydrous conditions, 10g of bis(benzylmethoxycarbonyl)amino polyethylene glycol (10kDa) was dissolved in 40mL of dichloromethane. 0.05g of diisopropylethylamine was added with stirring, followed by the slow addition of 0.54g of phosphorus tribromide. The reaction was carried out at 0℃ for 12 hours. The mixture was then evaporated to dryness to obtain 10g of bis(benzylmethoxycarbonyl)amino polyethylene glycol, a bromine-yellow solid with a molecular weight of approximately 10kDa and a yield of 99.97%. The specific structural formula is as follows:

[0132]

[0133] Step 2: Dissolve the bis(benzylmethoxycarbonyl)amino polyethylene glycol bromide obtained in Step 1 in 30 mL of ammonia water, and react at 30°C for 12 hours. After the reaction is complete, evaporate the solvent to obtain 9.5 g of a white solid bis(benzylmethoxycarbonyl)amino polyethylene glycol amine with a molecular weight of approximately 10 kDa and a yield of 95.03%. The specific structural formula is as follows:

[0134]

[0135] Example 9

[0136] 0.34 g of maleiminopropionic acid was dissolved in 20 mL of dichloromethane. 0.23 g of N-hydroxysuccinamide and 0.46 g of dicyclohexylcarbodiimide were added, followed by the reaction. Then, 10 g of bis(tert-butyloxycarbonyl)amino polyethylene glycol amine (5 kDa) was added, and the reaction was carried out at 30 °C for 12 hours. The reaction solution was washed with 50 mL of water, and the organic phase was dried with 5 g of anhydrous magnesium sulfate for 2 hours. After filtration and evaporation, 9.7 g of a white solid of bis(tert-butyloxycarbonyl)amino polyethylene glycol maleimide with a molecular weight of approximately 5 kDa and a yield of 93.9% were obtained. The specific structural formula is as follows:

[0137]

[0138] Example 10

[0139] 5.3 g of vitamin E was dissolved in 20 mL of chloroform. 1.15 g of N-hydroxysuccinamide and 1.51 g of N,N'-diisopropylcarbodiimide were added, followed by the addition of 10 g of bis(benzylmethoxycarbonyl)aminopolyethylene glycolamine (1 kDa). The reaction was carried out at 30 °C for 12 hours. The reaction solution was washed with 50 mL of water, and the organic phase was dried over 5 g of anhydrous magnesium sulfate for 2 hours. After filtration and evaporation, 10.1 g of a pale yellow solid of bis(benzylmethoxycarbonyl)aminopolyethylene glycol vitamin E with a molecular weight of approximately 1 kDa and a yield of 70.59% was obtained. The specific structural formula is as follows:

[0140]

[0141] Example 11

[0142] 2.43 g of cholesterol succinate was dissolved in 20 mL of dimethyl sulfoxide. 0.81 g of N-hydroxybenzotriazole and 1.15 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, followed by the addition of 10 g of bis(tert-butyloxycarbonyl)aminopolyethylene glycolamine (2 kDa). The reaction was carried out at 30 °C for 12 hours. The dimethyl sulfoxide was evaporated to dryness, and the residue was dissolved in 20 mL of dichloromethane. The organic phase was washed with 50 mL of water, and dried over 5 g of anhydrous magnesium sulfate for 2 hours. After filtration and evaporation to dryness, 10.2 g of a pale yellow solid of bis(tert-butyloxycarbonyl)aminopolyethylene glycol cholesterol was obtained, with a molecular weight of approximately 2 kDa and a yield of 85.5%. The specific structural formula is as follows:

[0143]

[0144] Example 12

[0145] 1.03 g of lipoic acid was dissolved in 50 mL of N,N-dimethylformamide. 0.58 g of N-hydroxysuccinamide and 1.15 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, followed by the addition of 10 g of N-(tert-butyloxycarbonyl)-p-methoxybenzylaminopolyethylene glycolamine (10 kDa). The reaction was carried out at 45 °C for 36 hours. The N,N-dimethylformamide was evaporated to dryness, and the residue was dissolved in 50 mL of dichloromethane. The reaction solution was washed with 50 mL of water, and the organic phase was dried over 5 g of anhydrous magnesium sulfate for 2 hours. After filtration and evaporation to dryness, 9.9 g of N-(tert-butyloxycarbonyl)-p-methoxybenzylaminopolyethylene glycol lipoic acid, a white solid with a molecular weight of approximately 10 kDa, was obtained, with a yield of 97.06%. The specific structural formula is as follows:

[0146]

[0147] Example 13

[0148] 0.46 g of mercaptoacetic acid was dissolved in 100 mL of toluene. 0.68 g of N-hydroxybenzotriazole and 0.88 g of N,N'-diisopropylcarbodiimide were added, followed by the addition of 10 g of N-(3,4-dimethoxybenzyl)benzylmethoxycarbonylaminopolyethylene glycolamine (20 kDa). The reaction was carried out at 60 °C for 72 hours. The reaction solution was washed with 50 mL of water, and the organic phase was dried over 5 g of anhydrous magnesium sulfate for 2 hours. After filtration and evaporation, 9.3 g of N-(3,4-dimethoxybenzyl)benzylmethoxycarbonylaminopolyethylene glycol mercaptoacetic acid (92.57%) white solid was obtained. The molecular weight was approximately 20 kDa. The yield was 92.57%. The specific structural formula is as follows:

[0149]

[0150] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A double-protected amino polyethylene glycol derivative, characterized in that, It has the structure shown in Equation 1: Formula 1; Where n is the degree of aggregation, selected from any integer between 10 and 454; q represents the number of methylene groups, selected from any integer between 0 and 6; R1 and R2 are independently selected from one or more of the following groups: ； R3 is selected from , , , or .

2. The dual-protected amino polyethylene glycol derivative according to claim 1, characterized in that, The n is selected from any integer between 22 and 227; The q is selected from any integer between 0 and 4; R1 and R2 are selected from ; Alternatively, R1 and R2 are selected from... ; Alternatively, R1 and R2 are respectively selected from and ; Alternatively, R1 and R2 are respectively selected from and ; Alternatively, R1 and R2 are respectively selected from and ; Alternatively, R1 and R2 are respectively selected from and ; Alternatively, R1 and R2 are respectively selected from and ; Alternatively, R1 and R2 are respectively selected from and .

3. The method for preparing the double-protected amino polyethylene glycol derivative according to claim 1 or 2, characterized in that, Includes the following steps: The condensation reagent, activating reagent, modifying substance and the double-protected amino polyethylene glycol derivative with the structure shown in Formula 1-2 were mixed and reacted to obtain the double-protected amino polyethylene glycol derivative with the structure shown in Formula 1. The modifying substance is selected from any of the following structures: ； Equation 1-2.

4. The preparation method according to claim 3, characterized in that, The preparation method of Formula 1-2 includes the following steps: The substituted reagent, base and double-protected amino polyethylene glycol with the structure shown in Formula 1-1 were mixed and reacted under anhydrous conditions. After the reaction was completed, ammonia was added to obtain the double-protected amino polyethylene glycol derivative with the structure shown in Formula 1-2. The substituted reagent is selected from one or more of phosphorus oxychloride, thionyl chloride, phosphorus tribromide, methanesulfonyl chloride, and p-toluenesulfonyl chloride; Equation 1-1.

5. The preparation method according to claim 4, characterized in that, The preparation method of Formula 1-1 includes the following steps: The double-protected amino polyethylene glycol is obtained by mixing ethylene oxide, alkali and an initiator with the structure shown in Formula 2 under anhydrous conditions. Formula 2; Where m is any integer between 0 and 4; R1 and R2 are independently selected from one or more of the following groups: 。 6. The preparation method according to claim 5, characterized in that, The molar ratio of initiator to base in the structure shown in Formula 2 is 1:(0.1-10). The molar ratio of the initiator to ethylene oxide is 1:(10-454).

7. The preparation method according to claim 5, characterized in that, The reaction temperature is 30℃-150℃; The reaction pressure is 0.1-2.0 MPa.

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