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Three-arm polyethylene glycol derivative and preparation method thereof

A technology of polyethylene glycol and derivatives, which is applied in pharmaceutical formulations, medical preparations without active ingredients, and medical preparations containing active ingredients, etc., can solve the problems of difficult separation and purification, complex product structure, etc., and achieve product structure. Simple, high modification rate, stable and repeatable effect

Active Publication Date: 2015-07-01
吕常海
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  • Claims
  • Application Information

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Problems solved by technology

The Chinese patent application number 200810225650.0 discloses a new type of multi-armed polyethylene glycol. The functional group on the surface of the protein molecule modified by this multi-armed polyethylene glycol is located at the end of the branched chain of the polyethylene glycol arm. When using this multi-armed When polyethylene glycol modifies protein drugs, one or more protein drug molecules will be connected to each polyethylene glycol arm branch, resulting in a three-dimensional network structure formed by multi-armed polyethylene glycol molecules and protein molecules. However, the complex structure of this product makes it difficult to separate and purify

Method used

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  • Three-arm polyethylene glycol derivative and preparation method thereof
  • Three-arm polyethylene glycol derivative and preparation method thereof
  • Three-arm polyethylene glycol derivative and preparation method thereof

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preparation example Construction

[0093] n in formula B1 to formula B14 2 independently selected from 7-1000. In an embodiment of the present invention, n in formulas B1-B14 2 independently selected from 10 to 800; in other embodiments, n in formulas B1 to B14 2 independently selected from 50 to 500; in another embodiment, n in formulas B1 to B14 2 independently selected from 100-300. The invention provides a preparation method of a three-arm polyethylene glycol derivative, comprising:

[0094] Under the action of an initiator and a catalyst, the ring-opening polymerization of ethylene oxide is carried out to obtain a polymerized product;

[0095] Deprotonating the polymer product to obtain a first intermediate;

[0096] subjecting the first intermediate to end-capping treatment of branched chains to obtain a second intermediate;

[0097] modifying the W functional group in the second intermediate to obtain a three-arm polyethylene glycol derivative;

[0098] Described initiator has the structure shown ...

Embodiment 1

[0163] After adding 5g of pentaerythritol, 0.2g of p-toluenesulfonic acid and 100mL of toluene respectively in the round bottom flask, the round bottom flask was heated to 80°C, and 27mL of triethyl orthoacetate was added in the round bottom flask, Carry out the reaction of 24 hours; After the reaction finishes, remove the toluene wherein, obtain the first reaction product of 5.4g;

[0164] The first reaction product was dissolved in 20 mL of DMF, and 1.8 g of KHCO was added to the first reaction product 3 Carry out the reaction with 12.3g of 3-bromopropionic acid at 25°C for 2 hours, add 50mL of ethyl acetate and 20mL of distilled water to the resulting reaction solution for precipitation, and remove the solvent by rotary evaporation to obtain 3.8 the second reaction product of g;

[0165] The second reaction product was added to 20 mL of a mixed solution of isopropanol and water at a volume ratio of 3:1, and then 1 mL of an aqueous sulfuric acid solution with a molar concen...

Embodiment 2

[0172] The initiator was prepared according to the method described in Example 1. The difference from Example 1 was that 3-bromopropene was used to replace the 3-bromopropionic acid in Example 1.

[0173] The initiator prepared by the embodiment of the present invention 2 is carried out nuclear magnetic resonance test, and test result is:

[0174] 1 H NMR (400MHz, CDCl 3 )(δppm):

[0175] 5.78-5.86(=CH-), 5.14-5.25(=CH 2 ), 3.98(-CH2O-), 3.72(-OCH 2 -C),3.48(-CCH 2 -OH);

[0176] As can be seen from the above data, the initiator prepared in Example 2 of the present invention has a structure shown in formula E2:

[0177]

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Abstract

The invention provides a three-arm polyethylene glycol derivative with a structure as shown in formula I. The three-arm polyethylene glycol derivative has a single functional group which is positioned on the center of a high polymer framework, and a product obtained by modifying a protein drug with the three-arm polyethylene glycol derivative is simple in structure, and convenient to separate and purify in the later stage. Besides, the three-arm polyethylene glycol derivative provided by the invention can perform site-specific modification on biological active molecules under a relatively gentle condition, is convenient to transform the functional group, relatively high in modification rate and capable of improving the activity of the biological drug and the in-vitro stability of the biological drug. Meanwhile, the three-arm polyethylene glycol derivative is stable in quality, and has stable repeatability on the modified biological drug. The invention further provides a preparation method of the three-arm polyethylene glycol derivative; an initiator with the structure as shown in formula II is adopted to process after performing ring opening polymerization on epoxy ethane to obtain the three-arm polyethylene glycol derivative.

Description

technical field [0001] The invention relates to the technical field of polyethylene glycol, in particular to a three-arm polyethylene glycol derivative and a preparation method thereof. Background technique [0002] There is a large amount of protease in the tissue, and the protein drug is quickly hydrolyzed and eliminated by it in the body, so that the purpose of treatment cannot be achieved; at the same time, the organs in the human body, such as the kidney, liver, etc., also have a certain filtering and metabolizing effect on the protein drug. Both also accelerate the clearance of protein drugs in the body. In order to prolong the action time of protein drugs in the body, people have done a lot of research work, such as glycosyl modified protein or protein nanosphere technology, etc. The more successful method in these technologies is to prepare PEGylated protein drugs (PEGylation), That is, polyethylene glycol (PEG) macromolecules with different molecular weights and di...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/334C08G65/333C08G65/332A61K47/48A61K45/00A61K39/395A61K39/00
Inventor 吕常海
Owner 吕常海
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