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Mono-functionalized polyethylene glycol with nitrogen atom branched center and its preparation method and biologically-relevant matter

A technology of polyethylene glycol and functionalization, which is applied in the direction of medical preparations and pharmaceutical formulations of non-active ingredients, and can solve the problems of limited small molecule initiator preparation, low carbon atom reactivity, and limited branched polyethylene glycol Issues such as types and usage, to achieve the effects of enriching types, strengthening protection, and improving conditions

Active Publication Date: 2014-10-22
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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  • Mono-functionalized polyethylene glycol with nitrogen atom branched center and its preparation method and biologically-relevant matter
  • Mono-functionalized polyethylene glycol with nitrogen atom branched center and its preparation method and biologically-relevant matter
  • Mono-functionalized polyethylene glycol with nitrogen atom branched center and its preparation method and biologically-relevant matter

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Experimental program
Comparison scheme
Effect test

preparation example Construction

[0294] 1.1 Preparation of intermediate compound (3)

[0295] The intermediate compound (3) of the present invention can be produced as described below. 2 to 2000 times the molar amount of ethylene oxide and the compound (4) containing two exposed hydroxyl groups protected by terminal hydroxyl groups are polymerized, and an excess of deprotonating reagent is added to generate polyethylene glycol with two branched chains Anion intermediate (5); Hydrocarbon group X for terminal oxygen anion 1 、X 2 The intermediate compound (6) is obtained by etherification and capping; the terminal hydroxyl group of the main chain is deprotected; the newly formed terminal hydroxyl group of the main chain initiates the polymerization of ethylene oxide, and a proton source is added to obtain the intermediate compound (3). (i.e. steps a to d above).

[0296] 1.1.1 Preparation of polyethylene glycol anion intermediate (5) (step a)

[0297] The preparation of the intermediate (5) comprises two ste...

Embodiment 1

[0660] Embodiment 1: R is the preparation of monofunctional branched polyethylene glycol when class H

[0661] Preparation of Compound H1-1

[0662] 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 of the terminal hydroxyl group of the main chain of the small molecule initiator 4 =TBS. 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.

[0663]

[0664] a. In an anhydrous and oxygen-free airtight reaction kettle, add tetrahydrofuran (250mL), small molecule initiator (2.532mmol) and diphenylmethyl potassium (4.0mmol) successively;

[0665] b, adding calculated amount of ethylene oxide (50mL), gradually warming up to a temperature of 60°C, and reacting for 48 ...

Embodiment 2

[0766] The preparation of embodiment 2 active ester derivatives

[0767] Synthesis of Active Ester A1-1

[0768] The synthesis of active ester (A1-1), wherein 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.

[0769]

[0770] 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 active ester (A1-1) as a white solid.

[0771] The hydrogen spectrum data ...

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Abstract

The invention discloses a mono-functionalized polyethylene glycol with a nitrogen atom branched center and its preparation method and biologically-relevant matter. The mono-functionalized polyethylene glycol with a nitrogen atom branched center is shown in the general formula (1). The polyethylene glycol-modified biologically-relevant matter is shown in the general formula (2). X1 and X2 represent alkyl containing 1-20 carbon atoms, n1 and n2 are integers of 2-2000, n3 is an integer of 1-2000, L1, L2 and L3 represent connection groups stably existing under the conditions of light, heat, enzyme, redox, acidic or alkaline condition, R represents a functional group or is in a protected form, D represents a biologically-relevant matter, Z1 represents a connection group, and L4 represents residue formed by a reaction of R and the biologically-relevant matter. The branched polyethylene glycol with the nitrogen atom center can interact with a substrate easily so that the substrate protection based on polyethylene glycol is promoted, the state of the substrate in the human body can be effectively improved and a prospect is wide.

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 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, t...

Claims

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Application Information

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IPC IPC(8): C08G65/331C08G65/333C08G65/334C08G65/336C08G65/28C08G65/00A61K47/48
Inventor 翁文桂刘超廖金城闫策周纯袁金春
Owner XIAMEN SINOPEG BIOTECH
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