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Method for synthesizing polyalkyl ether polymer with as propanal group as end group

Technology of a polyalkyl ether, synthesis method, applied in the field of protein chemistry

Active Publication Date: 2010-12-08
INST OF PROCESS ENG CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The polyalkyl ether polymers used are preferably dehydrated before use

Method used

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  • Method for synthesizing polyalkyl ether polymer with as propanal group as end group
  • Method for synthesizing polyalkyl ether polymer with as propanal group as end group

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] A Using dioxane as solvent to synthesize mPEG10K acetal

[0032] Take 2g (0.2mmol) of mPEG10K raw material, azeotropically remove water in 40ml of dioxane for 6h, after cooling, add 360μL (2mmol) of 1-chloro-3,3-diethoxypropional under the protection of Ar gas 160mg (4mmol) NaOH, heated at 90°C for 24h. After rotary evaporation of dioxane, a solid was obtained, dissolved in water, adjusted to neutral pH, saturated with NaCl, extracted with dichloromethane, concentrated, and then poured into cold ether for precipitation to obtain polyethylene glycol substituted with diethoxypropional group. diol.

[0033] 1 H NMR analysis result: δ=3.238, monomethoxy CH 3 O-, 3H; δ=3.5, PEG main chain, 981H; δ=1.10, acetal methyl proton CH 3 CH 2 O-, 6H; δ=1.75, acetal methylene proton OCH 2 CH 2 CH(OCH 2 CH 3 ) 2 , 2H; δ=4.5, acetal methine proton OCH 2 CH 2 CH(OCH 2 CH 3 ) 2 , 1H.

[0034] B Synthesis of mPEG10K Propionaldehyde

[0035] The acetal obtained above was diss...

Embodiment 2

[0038] A using dioxane as a solvent to synthesize mPEG20K propionaldehyde

[0039] Take 2g (0.1mmol) of mPEG20K raw material, azeotropically remove water in 40ml of dioxane for 6h, after cooling, under the protection of Ar gas, add 180μL (1mmol) of chloropropyl acetal and 80mg (2mmol) of NaOH, and heat to reflux for 24h. Heat and evaporate dioxane to dryness, dissolve in water, adjust pH to neutral, add NaCl for saturation, extract with dichloromethane, and precipitate with ether to obtain a white solid, which is dried in vacuo.

[0040] 1 H NMR analysis result: δ=3.238, monomethoxy CH 3 O-, 3H (integration basis); δ=3.5, PEG main chain, 1992H; δ=1.10, acetal methyl proton CH 3 CH 2 O-, 6H; δ=1.75, acetal methylene proton OCH 2 CH 2 CH(OCH 2 CH 3 ) 2 , 2H; δ=4.5, acetal methine proton OCH 2 CH 2 CH(OCH 2 CH 3 ) 2 , 1H.

[0041] B Synthesis of mPEG20K Propionaldehyde

[0042] The acetal obtained above was dissolved in 50 ml of PBS buffer solution with a pH of 2, ...

Embodiment 3

[0045] A Using DMF as a solvent to synthesize mPEG10K acetal

[0046] Take 2 g (0.2 mmol) of mPEG10K raw material, azeotropically remove water in 40 ml of toluene for 6 h, spin evaporate the toluene, dissolve in dry DMF, and add 288 μL (1.6 mmol) of 1-chloro-3,3 - Diethoxypropional 128mg (3.2mmol) NaH (60%), heated at 90°C for 24h. The solid was obtained after rotary evaporation of DMF, dissolved in water, adjusted to neutral pH, saturated with NaCl, extracted with dichloromethane, concentrated, then poured into cold ether for precipitation to obtain polyethylene glycol substituted with diethoxypropional group.

[0047] 1 H NMR analysis result: δ=3.238, monomethoxy CH 3 O-, 3H (integration basis); δ=3.5, PEG main chain, 991H; δ=1.10, acetal methyl proton CH 3 CH 2 O-, 6H; δ=1.75, acetal methylene proton OCH 2 CH 2 CH(OCH 2 CH 3 ) 2 , 2H; δ=4.5, acetal methine proton OCH 2 CH 2 CH(OCH 2 CH 3 ) 2 , 1H.

[0048] B Synthesis of mPEG10K Propionaldehyde

[0049] The ...

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Abstract

The invention provides a synthetic method for a propionaldehyde-terminated polyalkyl ether polymer, in particular to the synthetic method for a propionaldehyde-terminated polyethylene glycol polymer. The synthetic method comprises the following steps: (1) the polyalkyl ether polymer and good leaving group substituted dimethoxy (or ethoxy) propionaldehyde acetal carries out the reaction in organicsolvent in the presence of alkali, so as to obtain dimethoxy (or ethoxy) propionaldehyde acetal substituted polyalkyl ether polymer; (2) the propionaldehyde acetal substituted polyalkyl ether polymeris hydrolyzed in acidic aqueous solution, so as to obtain the propionaldehyde-terminated polyalkyl ether polymer. The method has the advantages of simple operation, mild condition and high conversionrate, and the propionaldehyde-terminated polyalkyl ether polymer can be directly used for the modification of a protein drug.

Description

technical field [0001] The invention belongs to the field of protein chemistry and relates to the synthesis of protein drug modifiers, more specifically to the synthesis of polyethylene glycol aldehyde protein modification reagents. Background technique [0002] With the development of bioengineering technology, many natural proteins, recombinant proteins and antibodies (or their fragments) have gradually entered the field of medicine. However, when protein is used as a drug, it has many disadvantages, such as immunogenicity, easy to be degraded by proteolytic enzymes, and poor water solubility. In the past few decades, the biopharmaceutical community has made great efforts to improve the performance of protein drugs, and one of the important aspects is the covalent linking of protein drugs to natural or synthetic polymers. Several polymer-modified protein drugs have been approved by the FDA to enter the market, and many polymer-modified protein drugs are in the clinical re...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G65/48
Inventor 马光辉赵永江苏志国雷建都
Owner INST OF PROCESS ENG CHINESE ACAD OF SCI