A kind of preparation method of monofunctional branched polyethylene glycol

A polyethylene glycol and functionalization technology, applied in the field of preparation of single functionalized branched polyethylene glycol, can solve the problem of end group modification rate (substitution rate, limitation of functionalization rate, difficulty in separation and purification, large steric hindrance) And other issues

Active Publication Date: 2021-03-30
XIAMEN SINOPEG BIOTECH
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

In the above preparation method, in the final step, the single reactive group succinimide active ester is obtained by modifying the terminal carboxyl group. The modification rate (substitution rate, functionalization rate) of the end group is limited due to factors such as large resistance; and because the molecular weight before and after the modification of the end group is large and close, it also brings difficulties to the separation and purification of the product

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  • A kind of preparation method of monofunctional branched polyethylene glycol
  • A kind of preparation method of monofunctional branched polyethylene glycol
  • A kind of preparation method of monofunctional branched polyethylene glycol

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preparation example Construction

[0103] The present invention provides a kind of preparation method of single functionalization branched polyethylene glycol, it is realized by following technical scheme: The structure of described single functionalization branched polyethylene glycol is as general formula (1) or general formula ( 2) as shown:

[0104]

[0105] Among them, PEG a 、PEG b Be the same or different polyethylene glycol components, each independently, all by C 1～20 The terminal oxygen atom of the hydrocarbyl-linked PEG component; L a , L b For the same or different divalent linking groups, independent of each other, respectively connected to PEG a 、PEG b the other oxygen end of the M b is an oxygen atom or a sulfur atom; L c is a carbon chain linking group; L d It is a divalent linking group containing a covalent linking group generated by a coupling reaction; the group F contains a functional end group R 01 ; 01 with L d Directly connected, or connected through a divalent linker Z;

...

Embodiment 1

[0532] Embodiment 1 branched polyethylene glycol propionaldehyde

[0533] The functionalized polyethylene glycol monomethyl ether with a molecular weight of 20kDa is used as a raw material to prepare branched polyethylene glycol propionaldehyde with a molecular weight of about 40kDa.

[0534] (1) Branched polyethylene glycol propionaldehyde with asymmetric structure (the linking group between the two PEG components and the N branching center is different)

[0535]

[0536] Corresponding to general formula (2), where, L a , L b is methylene, M b is an oxygen atom, L c is methylene, L d is an amide bond (-CONH-), F is a propionaldehyde group (-CH 2 CH 2 CHO, wherein, Z is ethylene, R 01 for -CHO). Design two mPEG (CH 3 O(CH 2 CH 2 O) n -) The molecular weight is about 20kDa.

[0537] The reaction formula is as follows:

[0538]

[0539] The preparation process is as follows:

[0540] Step a: Dissolve 10g (47.8mmol) of benzyloxycarbonyl-protected glycine (S1-...

Embodiment 2

[0554] Embodiment 2 branched polyethylene glycol propionaldehyde (one-step coupling method)

[0555]

[0556] Corresponding to general formula (1), where, L a , L b is methylene, L c is methylene, L d is an amide bond (-CONH-), F is a propionaldehyde group (-CH 2 CH 2 CHO, wherein, Z is ethylene, R 01 for -CHO). Both mPEGs were designed to have a molecular weight of approximately 10 kDa.

[0557] The preparation process is as follows:

[0558] Steps a~b: Repeat steps a~b in Example 1(1). The amino acetal intermediate S1-3 (7.3 g, yield 92%) was obtained.

[0559] Step c: Using the preparation method of Example 1 (1) step c, using 10kDa, PDI = 1.01 methoxypolyethylene glycol as a raw material to obtain about 44g of methoxypolyethylene glycol mesylate mPEG-OMs .

[0560] Using the alkylation conditions of Example 1 (1) step c, 2mmol of amino acetal intermediate S1-3 and excess methoxypolyethylene glycol methanesulfonate (8mmol) undergo alkylation reaction, membrane...

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Abstract

The invention discloses a preparation method of single-functionalized branched polyethylene glycol. A pre-modified coupling technology is adopted to introduce a functional end group to a place in front of a coupling polymer; a key intermediate IM1 having both a branched center N and a functional end F can be prepared through reaction among organic small molecules, so that pre-modified small molecules with strictly control structures are obtained, and then the single-functionalized branched polyethylene glycol containing a functional group source is obtained through step-by-step coupling or one-step coupling; therefore, the single-functionalized branched polyethylene glycol with a high replacement rate can be obtained directly or through simple chemical modification. The preparation methoddisclosed by the invention can take natural amino acid and polypeptide as branching agents. The raw materials are easy to obtain; the method is simple and convenient and favorable for large-scale production.

Description

technical field [0001] The invention relates to the field of polymer synthesis, in particular to a preparation method of monofunctional branched 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 molecule will have many excellent properties of polyethylene glycol, such as hydrophilicity, flexibility, anticoagulation, etc. 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-life in blo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G81/00C08G65/333
CPCC08G65/33324C08G65/33341C08G65/33396C08G81/00
Inventor 翁文桂刘超闫策姜琰琰周纯
Owner XIAMEN SINOPEG BIOTECH
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