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Mono-functional group-containing multilevel branched polyethylene glycol and its synthesis method

A polyethylene glycol and single-function technology, applied in the field of multi-level branched polyethylene glycol and its synthesis, can solve the problems of low yield, easy hydrolysis and fracture, affecting the use of reagents, etc., and achieve high yield effect

Active Publication Date: 2012-03-07
XIAMEN SINOPEG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] 1. The synthesis cycle is long, because the method is to attach linear polyethylene glycol to the two amino groups of lysine through a two-step coupling method, so it usually takes a lot of time to process linear polymers and branched polymers In the separation of the product, and the yield is often low, and the resulting product is also a mixture of the two;
[0007] 2. Since the linear polyethylene glycol coupled with the amino group at the α position generates an unstable carbamate bond, it is easily hydrolyzed and broken under alkaline conditions, thereby affecting the use of the reagent (Bioorg.Med.Chem., 2004 , 12, 5031-5037);
However, the above-mentioned most classic coupling reaction for preparing branched polyethylene glycol is difficult to meet the requirements of this fine synthesis.

Method used

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  • Mono-functional group-containing multilevel branched polyethylene glycol and its synthesis method
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  • Mono-functional group-containing multilevel branched polyethylene glycol and its synthesis method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] 1.1 Preparation of initiator

[0049] At 0°C, 82.3g of ethylene glycol, 100.4g of vinyl ether and 85mL of tetrahydrofuran as a reaction solvent were successively added to a 500mL dry and clean round-bottomed flask, and then 2.43g of p-toluenesulfonic acid was added in batches as a catalyst. After reacting for 3-5 hours and stirring overnight, a saturated sodium carbonate aqueous solution was added dropwise until pH=7. Then it was dried with anhydrous magnesium sulfate, filtered, and unreacted vinyl ethyl ether and tetrahydrofuran were removed by rotary evaporation at 75°C. The product was purified by column chromatography with diethyl ether as eluent. After the diethyl ether is removed by rotary evaporation, diol derivatives (initiators) whose two ends are respectively protected hydroxyl groups and unprotected hydroxyl groups are obtained.

[0050]

[0051] The proton spectrum data of initiator are as follows:

[0052] 1 H NMR (CDCl 3 )δ (ppm): 1.20 (CH 3 CH 2...

Embodiment 2

[0070] R is OH, X is CH 3 Preparation of Tertiary Branched Polyethylene Glycol:

[0071] In a dry and clean 50mL round-bottomed flask, add 1g of the iodomethane-terminated polymer obtained in Example 1, 20mL of tetrahydrofuran and 0.5mL of concentrated hydrochloric acid, spin dry tetrahydrofuran and concentrated hydrochloric acid after 15 minutes of reaction, and obtain R as OH, X is CH 3 branched polyethylene glycol. R is OH, X is CH 3 The hydrogen spectrum data of the branched polyethylene glycol is as follows:

[0072] 1 H NMR (CDCl 3 )δ (ppm): 3.35 (CH 3 O-), 3.40-3.80 (-CH 2 CH 2 O-, glycidol).

Embodiment 3

[0074] R is for OCH 2 CH 2 CN, X is CH 3 Preparation of Tertiary Branched Polyethylene Glycol:

[0075] In a dry and clean 50mL round-bottomed flask, add 1g of R as OH and X as CH prepared in Example 2 3 Branched polyethylene glycol, 20mL dioxane and 0.2g potassium hydroxide, slowly add 1mL acrylonitrile dropwise at 0°C. After continuing to react at room temperature for 8 hours, dioxane was removed by rotary evaporation, the product was dissolved in chloroform and washed with water three times, and the chloroform phase was dried with anhydrous magnesium sulfate, filtered, concentrated, and precipitated to obtain R as OCH 2 CH 2 CN, X is CH 3 branched polyethylene glycol. R is for OCH 2 CH 2 CN, X is CH 3 The hydrogen spectrum data of the branched polyethylene glycol is as follows:

[0076] 1 H NMR (CDCl 3 )δ (ppm): 2.40 (-CH 2 CN), 3.35 (CH 3 O-), 3.40-3.80 (-CH 2 CH 2 O-, glycidol).

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Abstract

The invention discloses mono-functional group-containing multilevel branched polyethylene glycol and its synthesis method. With a molecular weight of 2,000-1,000,000, the multilevel branched polyethylene glycol has a general structure formula as the following, wherein, R stands for OH or OCH2CH2CN or OCH2CH2CH2NH2 or Br or N3 or OCH2CHO or OCH2CH2COOH or OCH2CH2CONH2 or OCH2CH=CH2 or propargyl alcohol, or X is methyl or ethyl, z is the number of X group, n1, n2, n3... respectively expresses the polymerization degree of a 1st, 2nd, 3rd... branched chain and is an integer between 10 and 500, and the branching series can be not less than 2 and the branched chain number of each branching level is not less than 2. The mono-functional group of the mono-functional group-containing multilevel branched polyethylene glycol in the invention is disposed at an end point, so that an exact branched structure and molecular weight can be adjusted simply and accurately, and the synthesis time of branched polyethylene glycol can be saved.

Description

technical field [0001] The invention relates to a branched polyethylene glycol and a preparation method thereof, in particular to multilevel branched polyethylene glycol containing a single functional group and a synthesis method thereof. Background technique [0002] At present, in the study of biopharmaceutical carriers, the most studied is to modify the hydroxyl group of linear monohydroxypolyethylene glycol into highly reactive functional groups, such as active esters, aldehyde groups, amino groups, etc. Compared with linear polyethylene glycol with the same molecular weight, branched (two-arm and multi-arm) polyethylene glycol containing monofunctional groups has a larger molecular volume, which is more conducive to the modification and modification of small molecule drugs. At the same time, due to the special molecular shape, this branched polyethylene glycol can form an umbrella-shaped protective layer on the surface of the drug, increasing the steric hindrance around...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/338C08G65/329C08G65/331C08G65/28A61K47/48
Inventor 刘超翁文桂
Owner XIAMEN SINOPEG BIOTECH
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