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Poly alkyl ether compound with strange end group and double functional groups and application thereof

A technology of hetero-difunctional compound, which is applied in the field of hetero-difunctional polyalkyl ether compounds, can solve the problem of non-reaction specificity of succinimide ester groups, non-repeatability of coupling products, and chemical coupling process. Poor controllability and other issues

Active Publication Date: 2012-08-22
INST OF PROCESS ENG CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Due to the considerable randomness of the chemical coupling process of some active functional groups currently used for proteins, polypeptides or other molecules, the controllability of the chemical coupling process is poor, and the coupling products are not reproducible, which seriously Affect their follow-up research and application, such as Drezek et al. used α-dithiopyridyl-ω-succinimide ester polyethylene glycol to couple gold nanospheres and non-specific antibody IgG-G to prepare cancer diagnostic reagents (Loo, C., Lowery, A., Halas, N., West, J., Drezek, R. Immunotargeted Nanoshells for Integrated Cancer Imaging and Therapy. Nano Letters. 2005, 5(4):709-711), J.S. Chen et al. used α-succinimide succinate-ω-succinimide ester polyethylene glycol to cross-link collagen and horseradish peroxidase to prepare long-acting sustained-release protein preparations (Chen, J.S. ,Noah,E.M.,Pallua,N.,Steffens,G.C.M.The use of bifunctional polyethyleneglycol derivatives for coupling of proteins to and cross-linking of collagen matrices.Journal of Materials Science:Materials in Medicine.2001,13(11):1029- 1035), but the succinimide ester group of their chosen polyethylene glycol cross-linking agent does not have the specificity of the reaction, which will inevitably lead to the generation of unnecessary side cross-linking products

Method used

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  • Poly alkyl ether compound with strange end group and double functional groups and application thereof
  • Poly alkyl ether compound with strange end group and double functional groups and application thereof
  • Poly alkyl ether compound with strange end group and double functional groups and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0090] Example 1 Preparation of thiobenzenesulfonate-PEG-hydrazide (~2000Da)

[0091] 350mg of polyethylene glycol (average molecular weight 2000Da) with a hydroxyl group at one end and a carboxyl group at the other end, with a chemical structure of the formula (i-A1):

[0092]

[0093] Among them, p=2, n=2, m=0, n=0, w=1, X=-O-, Y=-O-, PAG=-(CH 2 CH 2 O) h - (the average molecular weight of PAG is around 2000Da), that is, it is expressed as the following structure:

[0094]

[0095] Azeotropic removal of water with toluene, based on polyethylene glycol with one terminal hydroxyl and one terminal carboxyl group, sequentially add 1.5 times the molar amount of phosphorus tribromide and 2.5 times the molar amount of triethylamine, react at 60°C for 2 days, and then evaporate toluene to dryness , re-dissolved in brine, extracted with dichloromethane, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated, precipitated with ether, filtered, and a w...

Embodiment 2

[0107] Example 2 Preparation of thiobenzenesulfonate-PEG-hydrazide (~200Da)

[0108] 200 mg of polyethylene glycol (molecular weight: 164 Da) with a hydroxyl group at one end and a carboxyl group at the end, having the chemical structure of formula (i-A1) described in Example 1, wherein p=4, n=1, m=4, n=1, w=2, X=-O-, Y=-O-, PAG=-(CH 2 CH 2 O) h - (wherein the average molecular weight of PAG is about 200Da), azeotrope with toluene to remove water, and then add 1.5 times the molar amount of phosphorus tribromide and 2.5 times the molar amount of three Ethylamine, reacted at 60°C for 1 day, then evaporated toluene to dryness, redissolved in brine, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and evaporated to dryness to obtain a light yellow viscous liquid, which was detected by mass spectrometry as 227.1, confirmed It is polyethylene glycol with bromine at one end and carboxyl at the other end.

[0109] Use toluen...

Embodiment 3

[0112] The preparation of embodiment 3 thiobenzenesulfonate-PEG-oxoamine

[0113]500 mg of polyethylene glycol (average molecular weight 2000 Da) with a hydroxyl group at one end and bromine at one end was dissolved in DMF, and 1.5 times the molar amount of N-hydroxyphthalimide and 1.5 times the molar amount of Triethylamine, reacted at 80°C for 1 day, evaporated to dryness, redissolved with brine, filtered, extracted the filtrate with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated the filtrate, precipitated with ether, filtered to obtain a white solid powder, mass spectrometry It was detected as 2102.344±44.052n, and it was confirmed to be polyethylene glycol with a hydroxyl group at one end and a phthalimide at the other end.

[0114] Use toluene to remove water azeotropically from the polyethylene glycol with one hydroxyl at one end and phthalimide at one end obtained in the previous step, and then add 1.5 times the molar amount of tribromo Ph...

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Abstract

The invention relates to a poly alkyl ether compound with a strange end group and double functional groups, which has a formula (I), wherein A is selected from any one of electrophilic group-CONHNH2, -ONH2, or -NH2, and PAG is a poly alkyl ether chain without an end group. The poly alkyl ether compound with a strange end group and double functional groups can directly react with protein, polypeptide or free sulfhydryl and a free carbonyl group of a drug molecule under mild conditions, and is strong in reaction specificity and fast in speed. The poly alkyl ether compound can be used for chemical crosslinking between the protein, the polypeptide and other drug molecules and a carrier to prepare a combination with uniform fixed points.

Description

technical field [0001] The present invention relates to a polyalkyl ether compound with heteromeric difunctional groups, in particular to a heteromeric polyalkylene ether compound capable of covalently coupling various proteins, polypeptides, and macromolecular drugs in the fields of medicine, biochemical engineering, and chemical engineering. Bifunctional polyalkyl ether polymers and uses thereof. Background technique [0002] Polyalkylene ether polymer polyethylene glycol (polyethylene glycol) is a polymer obtained by polymerization of ethylene oxide as a raw material. Polyether compounds with good solubility in water, non-corrosive, non-irritating, non-immunogenic and antigenic, good biocompatibility, low protein and low platelet adsorption and low cell adhesion in vivo , and has been approved by the US FDA. [0003] Because polyethylene glycol has the above excellent qualities, it has been widely used as an additive in many fields, such as cosmetics, water-based coatin...

Claims

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Application Information

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IPC IPC(8): C08G65/00C08G65/334C08G65/48C07K17/08
Inventor 张竞苏志国刘强窦婧马光辉
Owner INST OF PROCESS ENG CHINESE ACAD OF SCI
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