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Method for synthesizing hydrosulfo-polyethylene glycol for preparing macrocyclic liposome

A technology of polyethylene glycol monomethyl ether and compounds, which is applied in the field of synthesis of mercaptolated polyethylene glycol derivatives, can solve the problem of lack of reliable identification methods for mercaptolated polyethylene glycol derivatives, lack of intermediates, and difficulties Obtaining high-purity mercaptopolyethylene glycol and other problems

Inactive Publication Date: 2012-04-04
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Use chloroform as solvent when synthesizing (II) according to literature method, 40 ℃ of reaction 4h, the result still has a large amount of unreacted raw materials; In the process of preparing (III), it is difficult to carry out according to the method of literature, can not obtain corresponding intermediate ; After synthesizing (IV) according to the method of literature, the disulfide bond of (IV) is directly broken without separation and purification, and it is difficult to obtain high-purity mercaptopolyethylene glycol through sephadex separation; and the literature lacks A Reliable Identification Method for Thiolated Polyethylene Glycol Derivatives

Method used

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  • Method for synthesizing hydrosulfo-polyethylene glycol for preparing macrocyclic liposome
  • Method for synthesizing hydrosulfo-polyethylene glycol for preparing macrocyclic liposome
  • Method for synthesizing hydrosulfo-polyethylene glycol for preparing macrocyclic liposome

Examples

Experimental program
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Effect test

Embodiment 1

[0060] Preparation of Formula I Compound A

[0061] Step 1: Add 30ml of chloroform, polyethylene glycol 2000 monomethyl ether (2.0g, 1mmol), succinic anhydride (0.603g, 6mmol) and 0.5ml of pyridine into a 100ml three-necked flask, heat and reflux in an oil bath at 60°C for 4h , washed once with 10ml of 0.5M hydrochloric acid, then washed twice with 10ml of water, removed the water layer, dried the chloroform layer with anhydrous sodium sulfate, filtered off the sodium sulfate overnight, then transferred the chloroform layer to a round-bottomed flask, and distilled off under reduced pressure The chloroform layer was recrystallized from ethyl acetate to obtain polyethylene glycol 2000-succinate (II), with a yield of 85.34%. A series of M+ sodium peaks were obtained by MALDI-TOF: 1959, 2003, 2048, 2091, 2136, 2180, 2224, 2268, 2312, 2356, etc.

[0062] The second step: in the 100ml three-necked bottle, add 25ml dioxane, polyethylene glycol 2000-succinate (II) (1.5g, 0.7mmol) (II...

Embodiment 2

[0068] Preparation of Formula I Compound B

[0069] Step 1: Add 300ml of chloroform, polyethylene glycol 2000 monomethyl ether (20.0g, 10mmol), succinic anhydride (8.1g, 80mmol) and 5ml of pyridine into a 1000ml three-neck flask, heat and reflux in an oil bath at 80°C for 4 hours, Wash once with 100ml of 0.5M hydrochloric acid, then wash twice with 100ml of water, remove the water layer, dry the chloroform layer with anhydrous sodium sulfate, filter off the sodium sulfate overnight, transfer the chloroform layer to a round bottom flask, and distill off the chloroform under reduced pressure layer, and recrystallized from ethyl acetate to obtain polyethylene glycol 2000-succinate (II), with a yield of 83.21%.

[0070] The second step: in the 500ml three-necked bottle, add 125ml dioxane, polyethylene glycol 2000-succinate (II) (8.0g, 3.79mmol) (8.0g, 3.79mmol) obtained in the first step, N-hydroxysuccinimide ( 1.54g, 18.9mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydr...

Embodiment 3

[0074] Preparation of Formula I Compound C

[0075] Step 1: Add 30ml of chloroform, polyethylene glycol 2000 monomethyl ether (2.0g, 1mmol), succinic anhydride (0.10g, 1mmol) and 0.5ml of pyridine into a 100ml three-neck flask, heat and reflux in an oil bath at 60°C for 4h , washed once with 10ml of 0.5M hydrochloric acid, then washed twice with 10ml of water, removed the water layer, dried the chloroform layer with anhydrous sodium sulfate, filtered off the sodium sulfate overnight, then transferred the chloroform layer to a round-bottomed flask, and distilled off under reduced pressure The chloroform layer was recrystallized from ethyl acetate to obtain 0.873 g of polyethylene glycol 2000-succinate (II), with a yield of 39.45%.

[0076] The second step: in the 500ml three-necked bottle, add 125ml dioxane, polyethylene glycol 2000-succinate (II) (8.0g, 3.79mmol) (8.0g, 3.79mmol) obtained in the first step, N-hydroxysuccinimide ( 0.45g, 3.80mmol), 1-ethyl-3-(3-dimethylaminopr...

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Abstract

The invention discloses a method for preparing a compound as disclosed in Formula I. The method comprises the following steps: (1) mixing methoxy polyethylene glycol and succinic anhydride with chloroform, thereby obtaining a compound as disclosed in Formula II at 60-90 DEG C; (2) mixing the compound as disclosed in Formula II, N-hydroxyl succinimide, a dehydrator and organic base to obtain a compound as disclosed in Formula III, wherein the dehydrator is selected from 1-ethyl-3-(3-dimethylin propyl)-carbonyl diimine hydrochlorate, N,N-diisopropyl carbodiimide or N,N-dicyclohexylcarbodiimide, and the organic base is selected from N-methyl morpholine, triethylamine, pyridine or dimethylamino pyridine; (3) mixing the compound as disclosed in Formula III with cysteine to obtain a compound as disclosed in Formula IV; and (4) and mixing the compound as disclosed in Formula IV with dithiothreitol to obtain the compound as disclosed in Formula I. The invention also provides a reliable method for verifying the compound as disclosed in Formula I. n is equal to 3-125.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a method for synthesizing thiolated polyethylene glycol derivatives. Background technique [0002] Liposome is a drug delivery carrier composed of a phospholipid bilayer, which has many advantages, but after entering the blood circulation, it is easily swallowed by the reticuloendothelial system, and its half-life is very short. Forms sterically stable liposomes. The most widely studied polymer is polyethylene glycol. The thiolated polyethylene glycol developed by the present invention can react with maleimidated phospholipids to generate PEGylated phospholipids, thereby preparing liposomes with long-term circulation; it can also react with proteins containing sulfhydryl groups to form Pegylated protein, thereby making it less susceptible to phagocytosis by the reticuloendothelial system. [0003] The synthetic method of thiolated polyethylene glycol has been reported in the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G65/48
Inventor 邓家欣蔡正艳陶涛
Owner SHANGHAI INST OF PHARMA IND CO LTD