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Synthesis method of disulfide-coupled polyethylene glycol linker

A technology of polyethylene glycol and synthesis method, applied in the field of chemistry, can solve the problems of low tumor killing efficiency, increased cytotoxicity, etc., and achieve the effects of good economic benefits and market prospects, simple post-processing, and mild reaction conditions

Inactive Publication Date: 2021-10-22
武汉翱飞科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Although the lipophilic liposome nanoparticle formulation material modified by macromolecular polyethylene glycol (more than 2000 molecular weight) in the market can reduce the diameter of the nanoparticle and increase the tissue penetration of its drug delivery, the nanoparticle The diameter is still around 500nm, and the killing efficiency of the tumor is not high; and too many macromolecular non-degradable substances are injected into the patient, which increases the toxicity to normal cells

Method used

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  • Synthesis method of disulfide-coupled polyethylene glycol linker
  • Synthesis method of disulfide-coupled polyethylene glycol linker
  • Synthesis method of disulfide-coupled polyethylene glycol linker

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] When R is a hydroxyl group in the poly(ethylene glycol) linking agent of disulfide coupling, the synthetic method comprises the steps:

[0057]

[0058] Compound 1 is a single polyethylene glycol with THP unilateral protection.

[0059] Synthesis of Compound 2: tert-butyl acrylate with a mass of 296.1g and a concentration of 2.31mol / L was slowly added dropwise to a compound 1 with a mass of 350g and a concentration of 0.77mol / L and a mass of 4.32g with a volume fraction of 50%. Potassium hydroxide aqueous solution was stirred overnight at 25°C. After the reaction was complete as detected by TLC, the reaction solution was purified by column chromatography to obtain 240 g of a yellow oil with a yield of 53.49%.

[0060] Synthesis of Compound 3: Dissolve Compound 2 with a mass of 413 g and a concentration of 0.709 mol / L in 2 L of methanol, add 1.5 g of D001×7 cation exchange resin and a volume of 4 ml of hydrochloric acid with a concentration of 6 mol / L, at 25°C The re...

Embodiment 2

[0070] When R is a methoxy group in the polyethylene glycol linker of disulfide coupling, the synthesis steps are as follows:

[0071] Synthesis of Compound 8: Dissolve Compound 7 with a mass of 91.5 g and a concentration of 0.1 mol / L in 500 mL of methanol, slowly add 5 mL of concentrated sulfuric acid dropwise, react at 25°C for 3 h, and TLC detects that the reaction is complete, and add 200 mL of 10% saline, and then extracted with DCM, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and purified by column to obtain 89.4g of yellow liquid with a yield of 95%.

[0072] The structural formula of compound 8 is:

[0073]

Embodiment 3

[0075] In the disulfide-coupled polyethylene glycol linker, when R is , the synthesis steps are as follows:

[0076] Synthesis of compound 9: 100 g of compound 7 with a concentration of 0.11 mol / L was dissolved in 1 L of dichloromethane, and N-hydroxysuccinimide with a mass of 25 g and a concentration of 0.218 mol / L was added in batches , then add EDCI with a mass of 83.5 g and a concentration of 0.436 mol / L, stir at 25°C for 3 h, after TLC detects that the reaction is complete, the reaction solution is directly extracted twice with 600 ml of water, once with protected saline, and the organic phase is added without Water was dried over sodium sulfate, filtered, and the solvent was spin-dried to obtain 120 g of a white solid with a yield of 99%.

[0077] The structural formula of compound 9 is:

[0078]

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Abstract

The invention provides a synthesis method of a disulfide-coupled polyethylene glycol linker. The method comprises the following steps: by taking THP unilateral protected single polyethylene glycol as a raw material, carrying out addition with acrylic acid, carrying out THP deprotection, adding sulfur acetyl, and then coupling to obtain a final product. The synthesis method disclosed by the invention is simple, mild in reaction condition, less in side reaction, and suitable for industrial large-scale production, and the yield of a final product is higher than 90%, so that the synthesis method has good economic benefits and market prospects.

Description

technical field [0001] The invention relates to the field of chemistry, in particular to a synthesis method of a disulfide-coupled polyethylene glycol linker. Background technique [0002] With the development of macromolecular immune biopharmaceutical industry, monoclonal antibody-conjugated drug-directed delivery technology, liposome formulation and small polymer nanoparticle technology, the targeted delivery of biogenetic drugs is playing an important role in the development of anti-cancer toxoid drugs. The applications are gradually rising and becoming more and more prosperous. [0003] Although the lipophilic liposome nanoparticle formulation material modified by macromolecular polyethylene glycol (more than 2000 molecular weight) in the market can reduce the diameter of the nanoparticle and increase the tissue penetration of its drug delivery, the nanoparticle The diameter is still kept at about 500nm, and the killing efficiency on tumors is not high; and too many mac...

Claims

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Application Information

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IPC IPC(8): C07D207/46C07C323/12C07C319/22C08G65/334
CPCC07D207/46C07C319/22C08G65/3342C08G2650/04C07C323/12
Inventor 黄放张洋洋刘天成任伯怡
Owner 武汉翱飞科技有限公司
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