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

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Problems solved by technology

Due to the low reactivity of carbon atoms, the preparation of small molecule initiat

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

Examples

Experimental program
Comparison scheme
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Example Embodiment

[0069] 1.1 Preparation of intermediate compound (3)

[0070] The intermediate compound (3) of the present invention can be prepared as described below. After the polymerization of 2 to 2000 times molar amount of ethylene oxide with the terminal hydroxyl group-protected compound containing two exposed hydroxyl groups (4), an excessive amount of deprotonation reagent is added to produce polyethylene glycol with two branched chains Anion intermediate (5); Hydrocarbyl X for terminal oxygen anion 1 , X 2 The intermediate (6) is obtained by etherification and end-capping; the main chain terminal hydroxyl is deprotected; after the newly formed main chain terminal hydroxyl initiates the polymerization of ethylene oxide, the proton source is added to obtain the intermediate compound (3). (That is, the above steps a to d).

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

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

Example Embodiment

[0332] Example 1: Preparation of single functionalized branched polyethylene glycol when R is like H

[0333] Preparation of compound H1-1

[0334] In this example, the class H compound is selected as 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 protective group of the terminal hydroxyl group of the small molecule initiator main chain PG=TBS. The total designed molecular weight is about 20,000, of which the molecular weight of the two branches is about 2*8500=17000, which is n 1 ≈n 2 ≈193; the molecular weight of the main chain containing active functional groups is about 3000, which is n 3 ≈68.

[0335]

[0336] a. Add tetrahydrofuran (250mL), small molecule initiator (2.532mmol) and diphenylmethyl potassium (4.0mmol) to an anhydrous and oxygen-free closed reactor;

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

[0338] c. Add excess potassium diphenylmethyl (40mmol), and the...

Example Embodiment

[0435] Example 2 Preparation of 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 embodiment, the corresponding active ester is prepared directly by reacting the hydroxyl group at the end of the active functional group-containing main chain of the compound H1-1 with the carbonate ester.

[0438]

[0439] In a dry and clean 1L round bottom flask were added 40g of the branched polyethylene glycol prepared in Example 1 (H1-1, azeotropically remove water with toluene), 500mL acetonitrile, 40mL triethylamine and 10g N,N' -Disuccinimidyl carbonate, after reacting 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 active e...

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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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