Preparation method of monofunctionalized nonlinear polyethylene glycol

A polyethylene glycol and nonlinear technology, which is applied in the field of preparation of monofunctional nonlinear polyethylene glycol, can solve the problems of end group modification rate (substitution rate, limitation of functionalization rate, difficulty of separation and purification, large molecular weight, etc.

Active Publication Date: 2019-12-20
XIAMEN SINOPEG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the above preparation method, two-arm branched polyethylene glycol carboxylic acid is first prepared, and then in the last step, a single reactive group succinimide active ester group is obtained by modifying the terminal carboxyl group; in the process, due to being The modified end group is embedded by two polymer chains, the steric hindrance and other factors lead to the limitation of the modification rate (substitution rate, functionalization rate) of the end group; and because the molecular weight of the end group before and after modification is relatively large, giving The separation and purification of products brings difficulties

Method used

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  • Preparation method of monofunctionalized nonlinear polyethylene glycol
  • Preparation method of monofunctionalized nonlinear polyethylene glycol
  • Preparation method of monofunctionalized nonlinear polyethylene glycol

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[0134] The present invention provides a kind of preparation method of monofunctional non-linear polyethylene glycol, the structural general formula (designed structure) of described monofunctional non-linear polyethylene glycol, as shown in formula (1):

[0135] Among them, F is a functional group, which contains a functional end group R 01 ; 01 with L d Directly connected, or via a divalent linker Z and L d connected;

[0136] L d is a covalent linking group containing a heteroatom; and L d Contains a covalent linker that can be formed via a coupling reaction, or L d and U form a covalent linking group that can be generated through a coupling reaction.

[0137] L d It can contain not only conventional divalent linking groups such as amide bonds, ester bonds, and urethane bonds, but also non-linear linking groups such as three-carbon bridges, such as the connections formed by the reaction of functional groups B5, B6, and E13 with disulfide bonds. Groups, such as reac...

Embodiment 1

[0285] The monofunctional non-linear polyethylene glycol derivatives of embodiment 1 and embodiment 2 can also be classified as follows: XPEG has the general formula mPEG, two L xBoth are -CH 2 CH 2 OCONH-(the number of atomic intervals is 5), U is-(-CH 2 CH 2 CH 2 CH 2 ) CH-, L in Example 1 d Contains -CONH- and -NHCO-, F is -CH 2 CH 2 -MAL (wherein MAL is a maleimide group), the L of embodiment 2 d Contains -CONH-, F is -CH 2 CH 2 -CHO. The above two embodiments can also be attributed as follows: two L x Both are -CH 2 CH 2 OCONH-(atomic interval number is 5) and -CH 2 CH 2 OCONH(CH 2 ) 4 -(the number of atomic intervals is 9), and U is >CH-. It can also be assigned in the following way: XPEGs all have the general formula mPEG-CH 2 CH 2 -, L x Both are -OCONH- (the number of atomic intervals is 3), and U is -(-CH 2 CH 2 CH 2 CH 2 )CH-; or two L x are respectively -OCONH- (the number of atomic intervals is 3) and -OCONH (CH 2 ) 4 -(the number of at...

Embodiment 7

[0287] In Example 7, two L x Both are -CH 2 CH 2 COO-.

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Abstract

The invention discloses a preparation method of monofunctionalized nonlinear polyethylene glycol. The monofunctionalized nonlinear polyethylene glycol has a nonlinear multivalent group U, one side ofthe nonlinear multivalent group is connected with a single functional end group, and the other side of the nonlinear multivalent group is connected with at least two linear polyethylene glycol chains.The preparation method includes the steps, first, a low molecular weight intermediate IM1 is obtained first, and the single functional end group or a microvariant form is introduced; and the step only refers to an organic reaction between low molecular weight reagents, the controllability is good, the structure can be precisely controlled, selectable segregation patterns are diverse, and a high-purity intermediate can be obtained; and second, then a polyethylene glycol component is introduced, and the monofunctional nonlinear polyethylene glycol with a high substitution rate can be obtained directly or by simple chemical modification of a terminal. When the monofunctionalized nonlinear polyethylene glycol continues functionalized modification or is used as a reaction raw material to construct a multistage branched nonlinear structure, the reaction steric hindrance is small, and a relatively high substitution rate or a relatively high grafting rate can also be obtained.

Description

technical field [0001] The invention relates to the field of polymer synthesis, in particular to a preparation method of monofunctional non-linear polyethylene glycol. 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. Coupling of body, cofactor, liposome and biomaterials through covalent bonds to achieve PEGylation of drugs and other biologically related substances. The modified drug molecules will have many excellent properties of polyethylene glycol, such as hydrophilicity, flexibility, anticoagulation and so on. In addition, due to the steric repulsion effect, PEG-modified drugs can avoid glomerular filtration and biological reactions such as immune responses, making them have a longer half-lif...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/336C08G65/333C08G65/334
CPCC08G65/336C08G65/33396C08G65/3348C08G2650/30C08G2650/04C08G2650/38C08G2650/50C08G2650/60
Inventor 翁文桂刘超闫策王爱兰周纯
Owner XIAMEN SINOPEG BIOTECH
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