Preparation method and application of acid or active ester of polyethylene glycol with tail end connected with aminophenyl propionic acid

A technology of aminophenylpropionic acid and polyethylene glycol, which is applied in the preparation methods of peptides, chemical instruments and methods, organic chemistry, etc., can solve the problems of poor reactivity and slow reaction reaction.

Inactive Publication Date: 2013-03-13
HENAN UNIVERSITY OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Currently, many activated carboxy-PEGs used for modification have poor reactivity: either react too quickly or react too slowly
For example, the NHS ester of carboxymethylated PEG (CM-PEG) is so reactive that it hydrolyzes immediately when dissolved in water. This high reactivity is a serious drawback of the active ester of carboxymethylated PEG.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] CH with a molecular weight of 5000 Da 3 O-(CH 2 CH 2 O) n -CH 2 CO-NH-CH(C 6 h 5 )CH 2 -Synthesis of COONHS

[0035] Step 1: Preparation of CM-PEG (Carboxymethylated Polyethylene Glycol):

[0036] Dissolve 15 g (3 mmol) of monomethoxypolyethylene glycol with a molecular weight of 5000 Da in toluene, distill off part of the toluene to remove water azeotropically, then add 4 mmol of potassium tert-butoxide to reflux for 1.5 hours, and then Slowly add 4 mmol of ethyl bromoacetate to reflux reaction for 3 hours, then react at room temperature for 21 hours, remove the precipitate by filtration, evaporate the solvent under reduced pressure, dissolve the residue with a small amount of dichloromethane, precipitate the product with dry ether, dissolve the product In deionized water, add 0.1 mol / L sodium hydroxide solution until the pH value of the solution is stable at pH 10, then adjust the pH of the solution to 3 with 0.1 mol / L hydrochloric acid, extract the solution t...

Embodiment 2

[0044] CH with a molecular weight of 12000 Da 3 O-(CH 2 CH 2 O) n -CH 2 CO-NH-CH(CH 2 C 6 h 5 )-COONHS synthesis

[0045] Step 1: Preparation of CM-PEG:

[0046] Dissolve 18 g (1.5 mmol) of monomethoxypolyethylene glycol with a molecular weight of 12000 Da in an appropriate amount of toluene, distill off part of the toluene to remove water azeotropically, then add 2 mmol of potassium tert-butoxide to reflux for 2 hours , then slowly add 2 mmol of ethyl bromoacetate to reflux reaction for 4 hours, then react at room temperature for 18 hours, filter and remove the precipitate, evaporate the solvent under reduced pressure, add dichloromethane to the residue to dissolve, and precipitate the product with dry ether, and the product Dissolve in deionized water, gradually add 0.1 mol / L sodium hydroxide solution until the pH value of the solution is stable at pH 10, then adjust the pH of the solution to 3 with 0.1 mol / L hydrochloric acid, extract the solution three times with a...

Embodiment 3

[0054] Synthesis of PEG-bis-β-phenylalanine-N-hydroxysuccinimide ester with a molecular weight of 10000 Da

[0055] Step 1: Preparation of CM-PEG diacid (dicarboxymethylated polyethylene glycol):

[0056] Dissolve 10 g (1 mmol) of dihydroxypolyethylene glycol with a molecular weight of 10000 Da in toluene, distill off part of the toluene to azeotropically remove water, then add 3 mmol of potassium tert-butoxide to reflux for 1.5 hours, and then slowly add 3 mmol of ethyl bromoacetate was refluxed for 3 hours, then reacted at room temperature for 21 hours, filtered to remove the precipitate, evaporated the solvent under reduced pressure, dissolved the residue with a small amount of dichloromethane, precipitated the product with dry ether, dissolved the product in In deionized water, add 0.1 mol / L sodium hydroxide solution until the pH value of the solution is stable at pH 10, then adjust the pH of the solution to 3 with 0.1 mol / L hydrochloric acid, extract the solution three ti...

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PUM

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Abstract

The invention discloses a preparation method and application of acid or active ester of polyethylene glycol with the tail end connected with aminophenyl propionic acid, belonging to the field of medicine. In water, the polymer active ester has proper activity of reacting with the amino of bioactive substances. The structural formula is R1-(CH2CH2O)n-CH2-CO-NH-R2-CO-OR3, wherein n is equal to 43-680; the R1 can be CH3O- or -O-CH2-CO-NH-R2-CO-OR3; the R2 is the residue of the aminophenyl propionic acid except the amino and the carboxyl; aminophenyl propionic acid can be 2-amino-3-phenylpropionic acid (namely, alpha-phenylalanine) or 3-amino-3-phenylpropionic acid (namely, beta-phenylalanine); and the R3 can be H- or -N-succinimide.

Description

technical field [0001] The invention relates to a polyethylene glycol water-soluble polymer and a preparation method and application thereof, in particular to a polyethylene glycol active ester and a preparation method and application thereof. Background technique [0002] The use of chemical methods to bind the water-soluble polymer polyethylene glycol (PEG) to molecules and surfaces has significant applications in biotechnology. PEG has a wide range of applications in the field of biotechnology: some active derivatives of PEG are bound to proteins and enzyme molecules, that is, enzymes are modified. Since PEG can be dissolved in organic solvents, PEG combined with enzyme molecules can make PEG and enzyme molecules The conjugate is soluble in organic solvents; compared with unmodified protein, linking PEG to the protein can reduce the immunogenicity of the protein, reduce the rate of renal elimination, and thereby increase the half-life of the conjugate in blood circulation...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/48A61K47/34C07K1/107C12N9/96
Inventor 熊玉春罗宇李志成
Owner HENAN UNIVERSITY OF TECHNOLOGY
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