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Single functionalized polyethylene glycol with nitrogen-atom branching center, preparation method and biologically-relevant substance thereof

A technology of polyethylene glycol and functionalization, which is applied in the field of preparation methods and biologically related substances, monofunctionalized polyethylene glycol, and can solve the problem of limiting the type and use of branched polyethylene glycol, and the low reactivity of carbon atoms , limit the preparation of small molecule initiators, etc., to achieve the effect of enriching types, strengthening protection, and improving the state

Active Publication Date: 2015-03-04
XIAMEN SINOPEG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the low reactivity of carbon atoms, the preparation of small molecule initiators is limited, thereby limiting the types and uses of branched polyethylene glycols

Method used

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  • Single functionalized polyethylene glycol with nitrogen-atom branching center, preparation method and biologically-relevant substance thereof
  • Single functionalized polyethylene glycol with nitrogen-atom branching center, preparation method and biologically-relevant substance thereof
  • Single functionalized polyethylene glycol with nitrogen-atom branching center, preparation method and biologically-relevant substance thereof

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Experimental program
Comparison scheme
Effect test

preparation example Construction

[0069] 1.1 Preparation of intermediate compound (3)

[0070] The intermediate compound (3) of the present invention can be produced as follows. 2 to 2000 times the molar amount of ethylene oxide is polymerized with the terminal hydroxyl-protected compound (4) containing two exposed hydroxyl groups, and an excess of deprotonating reagent is added to generate polyethylene glycol with two branched chains Anion intermediate (5); Hydrocarbyl X for terminal oxyanions 1 、X 2 The intermediate compound (6) is obtained by etherification and capping; the hydroxyl group at the end of the main chain is deprotected; after the newly formed hydroxyl group at the end of the main chain initiates the polymerization of ethylene oxide, the intermediate compound (3) can be obtained by adding a proton source. (i.e. steps a~d above).

[0071] 1.1.1 Preparation of polyethylene glycol anion intermediate (5) (step a)

[0072] The preparation of intermediate (5) includes two steps: the polymerization...

Embodiment 1

[0332] Embodiment 1: R is the preparation of monofunctional branched polyethylene glycol when class H

[0333] Preparation of Compound H1-1

[0334] In this example, the H-like compound selected L 1 =CH 2 CH 2 , L 2 =CH 2 CH 2 , L 3 =CH 2 CH 2 ,X 1 =X 2 =CH 3 , q=0, the protecting group PG=TBS of the terminal hydroxyl group of the main chain 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 containing active functional groups is about 3000, that is, n 3 ≈68.

[0335]

[0336] a. Add tetrahydrofuran (250mL), small molecule initiator (2.532mmol) and diphenylmethyl potassium (4.0mmol) sequentially into an anhydrous and oxygen-free airtight reaction kettle;

[0337] b. Add the calculated amount of ethylene oxide (50mL), gradually raise the temperature to 60°C, and react for 48 hours;

[...

Embodiment 2

[0435] The preparation of embodiment 2 active ester derivatives

[0436] Synthesis of Active Ester A1-1

[0437] Synthesis of active ester (A1-1), where L 1 =CH 2 CH 2 , L 2 =CH 2 CH 2 , L 3 =CH 2 CH 2 ,X 1 =X 2 =CH 3 , q=0, 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 corresponding active ester was directly prepared by reacting the hydroxyl group at the end of the main chain containing the active functional group of compound H1-1 with carbonate.

[0438]

[0439] 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.

[0440] The hydrogen spectrum data of...

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Abstract

The invention discloses single functionalized polyethylene glycol with a nitrogen-atom branching center, a preparation method and a biologically-relevant substance thereof. General formula of the single functionalized polyethylene glycol with the nitrogen-atom branching center is as shown in the formula (1), and general formula of the polyethylene glycol-modified biologically-relevant substance is as shown in the formula (2), wherein X1 and X2 are an alkyl group having 1-20 carbon atoms; n1, n2 and n3 are an integer of 1-1000; L1, L2 and L3 are a linking group which stably exists under the illumination, enzyme, acidic or alkaline condition; R is a functional group; D is the biologically-relevant substance; Z is a linking group; and L4 is residue obtained after a reaction between a functional group and the biologically-relevant substance. The branched polyethylene glycol with the nitrogen-atom center enriches varieties of branched polyethylene glycol, is easy to interact with a substrate, is more beneficial to protection of the substrate by polyethylene glycol, improves in vivo status of the substrate more effectively, and has a wider prospect.

Description

[0001] Technical Field The present invention relates to the field of polymer synthesis chemistry, and specifically relates to a monofunctional polyethylene glycol with a nitrogen atom branching center, a preparation method and biologically related substances thereof. 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, ...

Claims

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Application Information

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IPC IPC(8): C08G65/32C08G65/28A61K47/48C07K1/107C07K14/565C12N9/96C12N9/36C12N15/10C12N15/113C12N5/00C12N7/00
CPCY02P20/55
Inventor 翁文桂刘超廖金城袁金春
Owner XIAMEN SINOPEG BIOTECH
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