Monofunctional branched polyethyleneglycol

A polyethylene glycol and functionalization technology, which is applied in organic chemistry, peptide preparation methods, chemical instruments and methods, etc., can solve the problems of inability to perform specific reactions, reduce the difficulty of purification, reduce steric hindrance, and improve modification rate effect

Active Publication Date: 2013-04-17
XIAMEN SINOPEG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the end groups of each arm in these multi-armed PEGs often contain the same hydroxyl functional group, which cannot react specifically

Method used

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  • Monofunctional branched polyethyleneglycol
  • Monofunctional branched polyethyleneglycol
  • Monofunctional branched polyethyleneglycol

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0073] A kind of preparation method of the branched polyethylene glycol of described single functionalization, comprises the steps:

[0074] a) A co-initiation system is composed of a small molecule initiator (4) containing a symmetrical hydroxyl group and potassium benzhydryl to initiate the polymerization of ethylene oxide, generate two branched chains, and deprotonate the ends of the branched chains to obtain an intermediate (5);

[0075] b) Capping the two branched chains of the intermediate (5) obtained in step a) to obtain the intermediate (6);

[0076] c) deprotecting the terminal hydroxyl group of the symmetry axis of the intermediate (6) obtained in step b) to obtain the intermediate (7);

[0077] d) Polymerizing ethylene oxide on the hydroxyl group of the symmetrical axis end of the intermediate (7) obtained in step c), forming a main chain of the symmetrical axis, and obtaining the intermediate (3) after protonation;

[0078] e) The intermediate (3) obtained in st...

Embodiment 1

[0270] Embodiment 1: R is the preparation of monofunctional branched polyethylene glycol when class H

[0271] Preparation of Compound H1-1

[0272] In this example, the H-like compound selected L 1 =CH 2 , L 2 =CH 2 , R 1 =H,X 1 =X 2 =CH 3 , p=1, q=0, the protecting group PG=TBS of the hydroxyl group at the end of the symmetry axis of the small molecule initiator. The total molecular weight is designed to be about 20000, and the molecular weight of the two branched chains is about 2*8500=17000, namely n 1 ≈n 2 ≈193; the molecular weight of the main chain of the symmetry axis is about 3000, that is, n 3 ≈68.

[0273]

[0274] a. Add tetrahydrofuran (250mL), small molecule initiator (2.532mmol) and diphenylmethyl potassium (4.0mmol) sequentially into an anhydrous and oxygen-free airtight reaction kettle;

[0275] b. Add the calculated amount of ethylene oxide (50mL), gradually raise the temperature to 60°C, and react for 48 hours;

[0276] c. Add excess diphenyl...

Embodiment 2

[0319] The preparation of embodiment 2 active ester derivatives

[0320] Synthesis of Active Ester A1-1

[0321] Synthesis of active ester (A1-1), where L 1 =CH2 , L 2 =CH 2 , R 1 =H,X 1 =X 2 =CH 3 , Z is OCH 2 CH 2 O, p=1, q=1, the molecular weight is about 20000, where n 1 , n 2 , n 3 The value of is the same as that of compound H1-1. In this example, the hydroxyl group at the end of the main chain of the symmetry axis of compound H1-1 is directly reacted with carbonate to prepare the corresponding active ester.

[0322]

[0323] In a dry and clean 1L round bottom flask, add 40g of branched polyethylene glycol (H1-1, dewatered by azeotropic toluene) prepared in Example 1, 500mL of acetonitrile, 40mL of triethylamine and 10g of N,N' - Disuccinimidyl carbonate, reacted at room temperature for 24 hours, concentrated, and recrystallized from isopropanol to obtain the active ester (A1-1) as a white solid.

[0324] The hydrogen spectrum data of active ester A1-1 i...

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Abstract

The invention discloses a monofunctional branched polyethyleneglycol. The general formula of the monofunctional branched polyethyleneglycol is disclosed as Formula (1), wherein X1 and X2 are respectively an alkyl group with 1-20 carbon atoms; n1 and n2 are respectively a whole number ranging from 1 to 1000; n3 is a whole number ranging from 11 to 1000; L1 and L2 are respectively a linking group capable of existing stably under illumination, enzyme, acidic or alkaline conditions; p is 0 or 1; R1 is a hydrogen atom or alkyl group with 1-20 carbon atoms; and R is a functional group. The monofunctional branched polyethyleneglycol overcomes the defects of traditional multiarm polyethyleneglycol in drug modification application, can modify biologically relevant substances under mild conditions, and has the advantages of high modification rate, fewer byproducts, high activity retentivity and the like.

Description

technical field [0001] The invention relates to the field of polymer synthesis, in particular to a monofunctional branched polyethylene glycol. Background technique [0002] PEGylation is one of the important means of drug modification. Among them, functionalized polyethylene glycol (PEG) can use its active groups to interact with drug molecules (including protein drugs and organic small molecule drugs), peptides, sugars, lipids, oligonucleotides, affinity ligands, etc. Polymers, cofactors, liposomes, and biological materials are coupled through covalent bonds to achieve polyethylene glycol modification of drugs and other biologically related substances. The modified drug molecules will have many excellent properties of polyethylene glycol (such as hydrophilicity, flexibility, anticoagulation, etc.). At the same time, due to the steric repulsion effect of PEG, PEG-modified drugs avoid glomerular filtering biological reactions such as immune responses, making them have a lo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/32C08G65/28A61K47/48C07K14/565C07K1/107C12N9/96C07H21/04C07H1/00A61K47/60
Inventor 翁文桂刘超廖金城袁金春
Owner XIAMEN SINOPEG BIOTECH
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