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Eight-arm polyethylene glycol, preparation method and functionalized derivative thereof, and biologically relevant substance modified with functionalized derivative

A polyethylene glycol and functionalization technology, applied in the field of preparation of eight-arm polyethylene glycol, functionalized derivatives and modified biological-related substances, can solve the problem of the number of difficult monomer units, the low purity of the target product, and the molecular weight distribution. It can reduce the production cost, control the molecular weight and its distribution accurately, and reduce the dosage.

Active Publication Date: 2017-07-21
XIAMEN SINOPEG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Especially the eight-armed polyethylene glycol based on tripentaerythritol and hexaglycerol, taking hexaglycerol as an example, because it is difficult to accurately control the number of monomer units during its preparation, the actual number of monomer units is "6". A mixture of a series of oligomers of left and right, and it is difficult to separate them completely
This results in eight-armed polyethylene glycol and derivatives thereof prepared based on it being mixed with seven-armed and nine-armed mixtures such as pentameric and heptamerized, the target product has low purity, and causes a wide molecular weight distribution, which is difficult to control

Method used

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  • Eight-arm polyethylene glycol, preparation method and functionalized derivative thereof, and biologically relevant substance modified with functionalized derivative
  • Eight-arm polyethylene glycol, preparation method and functionalized derivative thereof, and biologically relevant substance modified with functionalized derivative
  • Eight-arm polyethylene glycol, preparation method and functionalized derivative thereof, and biologically relevant substance modified with functionalized derivative

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preparation example Construction

[0085] 2. a preparation method of eight-arm polyethylene glycol, comprising the following steps:

[0086] Step 1. Use small molecule CORE(OH) containing octahydroxyl 8 Initiator system; Octahydroxyl small molecule is used as initiator, and base forms co-initiator system; Described octahydroxyl small molecule is preferably octahydroxyl disaccharide small molecule;

[0087] Step 2, initiate ethylene oxide polymerization;

[0088] Step 3. After the reaction is completed, add a proton source to the intermediate product system having eight polyethylene glycol chains obtained in step 2 to obtain the hydroxyl-terminated eight-armed polyethylene glycol.

[0089] The above steps can be carried out in a solvent or without a solvent, and the solvent is not particularly limited, but preferably an aprotic solvent, such as toluene, benzene, xylene, acetonitrile, ethyl acetate, tetrahydrofuran, chloroform, dichloromethane, dimethyl Sulfoxide, dimethylformamide or dimethylacetamide, more pr...

Embodiment 1

[0927] Example 1: Preparation of eight-arm polyethylene glycol H1-1 with sucrose center structure

[0928] The total molecular weight is designed to be about 20kDa, wherein the molecular weight of each PEG chain is about 2500Da, corresponding to n≈56. The eight-valent central structure CORE is the residue after deoctahydroxylation of sucrose.

[0929] a. Add dimethyl sulfoxide (3L), sucrose (150mmol) and diphenylmethyl potassium (60mmol) sequentially into an anhydrous and oxygen-free airtight reaction kettle; wherein, the hydroxyl value of the sucrose raw material is determined by the phthalic anhydride-pyridine method Carry out measurement confirmation;

[0930] b. adding calculated amount of ethylene oxide (3Kg), gradually warming up to a temperature of 60°C, and reacting for 72 hours;

[0931] c. Add excess water (300mmol) to terminate the reaction, the reaction temperature is 60°C, and the reaction time is 10 minutes;

[0932] d. Open the reaction kettle, concentrate th...

Embodiment 2

[0938] Example 2: Preparation of eight-arm polyethylene glycol H1-2 with maltose center structure

[0939] The total molecular weight is designed to be about 40kDa, wherein the molecular weight of each PEG chain is about 5000Da, corresponding to n≈113. The octavalent central structure CORE is the residue after deoctahydroxylation of maltose.

[0940] a. Add toluene (3L), maltose (150mmol) and potassium tert-butoxide (120mmol) sequentially into an anhydrous and oxygen-free closed reaction kettle; wherein, the hydroxyl value of the maltose raw material is determined and confirmed by the phthalic anhydride-pyridine method;

[0941] b. Add the calculated amount of ethylene oxide (6Kg), gradually heat up to 70°C, and react for 72 hours;

[0942] c. adding excess acetic acid (240mmol) to terminate the reaction, the reaction temperature was 60°C, and the reaction time was 20 minutes;

[0943] d. Open the reaction kettle, concentrate the solvent, refine the product with isopropanol / ...

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Abstract

The present invention discloses an eight-arm polyethylene glycol (formula 1), a preparation method and a functionalized derivative thereof, and a biologically relevant substance modified with the functionalized derivative, wherein the octavalent center structure CORE contains the residue obtained after the dehydroxylation of an octahydroxy disaccharide molecule, and n is the polymerization degree of a polyethylene glycol chain, and is selected from 1-2000. According to the present invention, the eight-arm polyethylene glycol has monodispersity or polydispersity; the molecular cost of the initiator is low and the purity of the initiator is low, such that the production cost is substantially reduced, the molecular weight and the distribution control of the polymerization product and the functionalized derivative are precise, and the purity and the performance of the product can be easily improved in the biologically relevant substance modified with the functionalized derivative; and the eight-arm polyethylene glycol and the derivative thereof can further have natural chiral centers. The formula 1 is defined in the specification.

Description

technical field [0001] The invention relates to the field of polymer synthesis, in particular to an eight-armed polyethylene glycol, a preparation method, a functionalized derivative and a modified biologically related substance. 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 molecule will have many excellent properties of polyethylene glycol (such as hydrophilicity, flexibility, anticoagulation, etc.). At the same time, due to the steric repulsion effect, PEG-modified drugs avoid glomerular ...

Claims

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Application Information

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IPC IPC(8): C08G65/333C08G65/337C08G65/325C08G65/331C08G65/332C08G65/324C08G65/28C08G81/00A61K47/60
CPCC08G65/2606C08G65/3255C08G65/3322C08G65/33331C08G65/331C08G65/338C08G65/3346A61K47/60
Inventor 翁文桂刘超闫策林毅周纯
Owner XIAMEN SINOPEG BIOTECH
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