Method for synthesizing heparin ester

A synthesis method and esterification technology, which are applied in the field of synthesis of heparin esterification, to achieve the effects of easy control of the reaction process, convenient operation and high yield

Inactive Publication Date: 2012-06-27
BENGBU MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The acetylation (or propionate, butyrate, valerate, hexanoate) ...

Method used

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  • Method for synthesizing heparin ester

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Embodiment 1

[0036] (1) Take 12g of low molecular weight heparin sodium and 12g of pyridine, add them into a dry reactor and mix them uniformly to obtain a mixture;

[0037] (2) Add 12 g of acetic anhydride to the above mixture, and stir for 10 hours at room temperature, normal pressure, and under the protection of an inert gas to carry out the esterification reaction;

[0038] (3) After adding 12 g of absolute ethanol to stop the reaction, filter to obtain a white powder, dissolve the white powder in deionized water, put it into a dialysis bag for dialysis for 12 hours, and freeze-dry to obtain the target compound, namely heparin ester.

[0039] The yield of the obtained heparin ester is 80%, the purity detected by high performance liquid chromatography is 98%, the average molecular weight is 12KDa, the heavy metal is ≤3ppm, and the bacterial endotoxin is ≤0.11IU / heparin unit.

[0040] The prepared heparin ester can be treated with an alkaline solution to make the pH value in the PBS buff...

Embodiment 2

[0043] (1) Take 12 g of heparin sodium and grind it into powder, 120 g of pyridine, add it into a dry reactor and mix it evenly to obtain a mixture;

[0044] (2) 120 g of propionic anhydride was added to the above mixture, and stirred for 10 hours at room temperature, normal pressure, and under the protection of an inert gas to carry out the esterification reaction;

[0045](3) After adding 120 g of absolute ethanol to stop the reaction, filter to obtain a white powder, then wash twice with absolute ethanol, dissolve the white powder in 600 ml of deionized water, put it into a dialysis bag for dialysis for 48 hours, and freeze-dry to obtain the target Compound, namely heparin ester.

[0046] The yield of the obtained heparin ester is 79%, the purity detected by high performance liquid chromatography is 98%, the average molecular weight is 8000Da, the heavy metal is ≤3ppm, and the bacterial endotoxin is ≤0.11IU / heparin unit.

[0047] The prepared heparin ester can be treated w...

Embodiment 3

[0050] (1) Take 12 g of heparin sodium and grind it into powder, and 60 g of aminopyridine, add them into a dry reactor and mix them uniformly to obtain a mixture;

[0051] (2) Add 60 g of hexanoic anhydride to the above mixture, and stir for 6 hours at 0° C. under normal pressure and under the protection of an inert gas to carry out esterification reaction;

[0052] (3) After adding 60 g of absolute ethanol to stop the reaction, filter to obtain a white powder, and freeze-dry to obtain the target compound, ie heparin ester.

[0053] The yield of the obtained heparin ester is 80%, the purity detected by high performance liquid chromatography is 98%, the average molecular weight is: 5000Da, the heavy metal is ≤3ppm, and the bacterial endotoxin is ≤0.11IU / heparin unit.

[0054] The prepared heparin ester can be treated with an alkaline solution to make the pH value in the PBS buffer solution 6.0-7.0, which meets the needs of human medicine.

[0055] The main components of the f...

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Abstract

The invention provides a method for synthesizing heparin ester. The method comprises the following steps of: performing esterification reaction on heparin in an anhydrous reactor by taking powdered sodium heparin and organic acid anhydride as raw materials and pyridine as a catalyst, objectively forming high esterification zones and low esterification zones on the surfaces of heparin molecules, and simulating charges on the surface of heparan sulfate. Surface charges of the heparin ester prepared by the method for synthesizing the heparin ester are nonuniformly distributed, which is exactly similar to charge distribution on the surface of the heparan sulfate. The in-vitro anti-tumor activity experiment and the in-vivo anti-transfer animal experiment show that the heparin ester prepared by the method for synthesizing the heparin ester has higher pharmacological effects of tumor cell proliferation resistance and tumor cell transfer activity resistance compared with Chinese herbal medicines. The method for synthesizing the heparin ester has the advantages that: 1) the yield is high and can reach about 80 percent; 2) process steps are simple, the method is convenient to operate, the reaction process is easy to control, and the control of the whole production process is the control of dryness, reaction temperature and reaction time; and 3) a filtrate obtained after reaction can be recycled, and the method is an environment-friendly green synthesis method.

Description

technical field [0001] The invention relates to a synthesis method of a compound, in particular to a synthesis method of a heparin ester. Background technique [0002] Heparin is an anticoagulant and antithrombotic drug with a molecular weight of about 30KDa, while low molecular weight heparin usually refers to the degraded fragments of heparin with an average molecular weight of less than 8000Da. Both heparins have already become commonly used clinical drugs. The anti-cell proliferation (bovine pulmonary artery smooth muscle cells, lung cancer A549 cells, MCF-7 cells, etc.) activity of heparin has also been confirmed by the academic circles (Liuyinyu, HariG. 10:229-241). However, due to side effects such as anti-platelet and hemorrhage of heparin, its anti-tumor effect has been in the research state, and it has not been applied clinically as an anti-tumor drug. [0003] In the early 1990s, Jiang Zhiwen’s research group of Bengbu Medical College discovered that hormones an...

Claims

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Application Information

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IPC IPC(8): C08B37/10A61P35/00
Inventor 梁颖蒋志文刘浩蒋琛琛吴成柱马琳艳
Owner BENGBU MEDICAL COLLEGE
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