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CN-122011360-A - Method for preparing two-arm PEG modifier

CN122011360ACN 122011360 ACN122011360 ACN 122011360ACN-122011360-A

Abstract

The invention provides a synthesis method of a two-arm PEG modifier, which comprises the step of reacting mPEG-SC with lysine in a mixed solvent system of an organic solvent and water. Compared with the existing preparation process, the reaction coupling efficiency and the yield of the final product of the two-arm PEG lysine are greatly improved, the applicability of the process to mPEG-SC with different molecular weights is expanded, and the method is suitable for industrialized production of the two-arm PEG lysine.

Inventors

  • Lou Xiyu
  • JIN LEI
  • LIU QINGYIN
  • LIU YU
  • HUANG QIANG
  • San Jinglong
  • ZHANG XU
  • XU XUEYU
  • LIU YANG
  • YIN XUEQIANG

Assignees

  • 吉林省金派格药业有限责任公司

Dates

Publication Date
20260512
Application Date
20251224
Priority Date
20250926

Claims (9)

  1. 1. A process for preparing two-arm PEG lysine as shown in formula (II) includes such steps as reacting mPEG-SC as shown in formula (I) with lysine or its salt in the mixture of organic solvent A and water under alkaline condition, Wherein n is an integer between 4 and 500.
  2. 2. The method of claim 1, wherein n is an integer between 200-500; preferably, where n is an integer between 300 and 500, for example n is an integer of 450.
  3. 3. The method of any one of claims 1-2, wherein the lysine salt is lysine dihydrochloride.
  4. 4. A process according to any one of claims 1 to 3, wherein the organic solvent a comprises, but is not limited to, one or more of an alcoholic solvent, a ketone solvent, an ether solvent, an ester solvent, a sulfone or sulfoxide solvent, a halogenated hydrocarbon solvent, a nitrile solvent; Preferably, the organic solvent A is selected from one or more of alcohol solvents, ketone solvents, ether solvents, ester solvents, sulfoxide solvents, halogenated hydrocarbon solvents and nitrile solvents; Preferably, the organic solvent A is selected from one or more of methanol, ethanol, propanol, isopropanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, dichloromethane and acetonitrile; preferably, according to an embodiment of the present invention, the organic solvent a is selected from one or more of isopropanol, acetone, tetrahydrofuran, acetonitrile, methanol, dimethyl sulfoxide, ethanol; More preferably, the organic solvent a is selected from acetonitrile or dimethyl sulfoxide.
  5. 5. The method according to any one of claims 1 to 4, wherein the volume ratio of the organic solvent A to water is (0.2 to 50) 1; preferably, the volume ratio of the organic solvent A to water is (1-20): 1; more preferably, the volume ratio of the organic solvent A to water is (1-15): 1.
  6. 6. The method of any one of claims 1-5, wherein the alkaline conditions are provided by adding one or more alkaline reagents comprising an organic base and an inorganic base; Preferably, the organic or inorganic base is selected from triethylamine, pyridine, DIPEA, DBU, imidazole, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate; Preferably, the feeding mole ratio of the mPEG-SC to the alkaline reagent is 1 (1-10); More preferably, the feeding molar ratio of the mPEG-SC to the alkaline reagent is 1 (1-5).
  7. 7. The method according to any one of claims 1 to 6, wherein the feeding molar ratio of mPEG-SC to lysine or a salt thereof is 1 (0.4-1); preferably, the feeding mole ratio of the mPEG-SC to the lysine or the salt thereof is 1 (0.45-0.7); Preferably, the feeding mole ratio of the mPEG-SC to the lysine or the salt thereof is 1 (0.5-0.7); preferably, the feeding molar ratio of mPEG-SC to lysine or a salt thereof is 1:0.55.
  8. 8. The method of any one of claims 1-7, wherein the reaction is performed at 0-60 ℃; Preferably, the reaction is carried out at a temperature of 30-60 ℃; preferably, the reaction is carried out at 30±5 ℃.
  9. 9. The process according to any one of claims 1 to 8, wherein the process comprises the steps of 1 dissolving mPEG-SC in an organic solvent A, stirring the solution, adding an alkaline reagent, 2 dissolving lysine or a salt thereof in water, and adding an aqueous solution of lysine or a salt thereof to the reaction system of step 1.

Description

Method for preparing two-arm PEG modifier The present application claims the benefit of priority from a prior application filed by applicant at 2025, 9 and 26 to the chinese national intellectual property agency, under patent application number 202511396815.0, entitled "method for preparing two-arm PEG modifier", which is incorporated herein by reference in its entirety. Technical Field The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing a two-arm PEG modifier by using lysine or a salt thereof. Background Polyethylene glycol (PEG) is a linear high-hydrophilicity high-molecular polymer, which is nontoxic to human body, has good biocompatibility and low immunogenicity, and can endow the polymer with excellent properties to drug molecules after being connected with drugs. Polyethylene glycol modification techniques have been developed for decades and various branched PEG modifiers, such as two-arm PEG modifiers, have been developed that have a molecular weight that is multiplied compared to single-arm PEG modifiers, thereby enlarging the size of the conjugate molecule, increasing the selectivity to the modification site, in turn, extending the in vivo retention time, and reducing immunogenicity, etc. Methods for preparing two-arm PEG modifiers by using lysine have been reported in the literature and mainly comprise: 1) U.S. Pat. No. 3, 20130177961 discloses a water phase system synthesis method, which uses borax buffer solution with pH value of 8.0-8.3 as reaction solvent, after the reaction of mono-oxy polyethylene glycol succinimidyl carbonate (mPEG-SC) and lysine for 24 hours at room temperature, the corresponding mPEG 2-lysine (10 kDa) is obtained through the procedures of acidification, extraction, crystallization, DEAE column chromatography purification and the like, the final product yield is about 50%, and the reaction time is as long as 24 hours. 2) Chinese patent CN114716663A discloses a synthesis method of an organic system, which takes a mixed solvent of absolute ethyl alcohol and dichloromethane as a reaction solvent, supplements lysine in the reaction process, obtains a corresponding mPEG 2-lysine crude product through MTBE precipitation after the reaction is finished, obtains a final product mPEG 2-lysine (10 kDa) through purification steps such as DEAE column chromatography and the like, has low yield (about 71 percent), adopts a method of supplementing lysine, is difficult to accurately control the supplementing amount of a reagent, and is easy to generate monosubstituted impurities. Therefore, development of a new synthetic method of mPEG2-Lysine, which has high coupling efficiency and is suitable for industrial production, is particularly necessary. Disclosure of Invention In order to improve the technical problems, the invention provides a synthesis method of a two-arm PEG modifier, which aims to improve the reaction coupling efficiency and further improve the yield of the two-arm PEG modifier of a final product. According to an embodiment of the present invention, the two-arm PEG modifier prepared by the present invention is two-arm PEG lysine, and the preparation method thereof comprises reacting mPEG-SC represented by formula (I) with lysine or a salt thereof in a mixed system of an organic solvent A and water under alkaline conditions, Wherein n in the formula (I) and the formula (II) are the same and are integers of 4-500. According to an embodiment of the invention, wherein n is an integer between 40 and 400. According to an embodiment of the invention, wherein n is an integer between 300 and 500. According to an embodiment of the invention, wherein n is an integer of 450, i.e. the mPEG-SC molecular weight is 20KDa. According to an embodiment of the invention, the molecular weight of the two-arm PEG lysine prepared by the invention is 40kDa. According to an embodiment of the invention, wherein the lysine salt is lysine dihydrochloride. According to an embodiment of the present invention, the organic solvent a includes, but is not limited to, one or more of an alcohol solvent, a ketone solvent, an ether solvent, an ester solvent, a sulfone or sulfoxide solvent, a halogenated hydrocarbon solvent, and a nitrile solvent. The alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol. The ketone solvent includes, but is not limited to, acetone. The ether solvents include, but are not limited to, diethyl ether, tetrahydrofuran. The ester solvents include, but are not limited to, ethyl formate, ethyl acetate. The sulfone or sulfoxide solvents include, but are not limited to, dimethyl sulfoxide (DMSO). The halogenated hydrocarbon solvents include, but are not limited to, methylene chloride. The nitrile solvent includes, but is not limited to, acetonitrile (CH 3 CN). According to an embodiment of the present invention, the organic solvent a is selected from one or more of an alcohol solvent, a ketone solven