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Preparation method of heparinoid

A heparin-like and heparin-like technology, which is applied in the field of biochemical drug heparin-like preparation, can solve the problems of high production cost, high acid consumption, and low product yield, and achieve easy control of production operations, stable molecular weight range, and simple synthesis process Effect

Active Publication Date: 2015-09-02
ZHEJIANG SANMEN HYGECON PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These methods all use a large excess of concentrated sulfuric acid, which consumes a large amount of acid, severely corrodes the production equipment, is difficult to treat the waste liquid, is not conducive to environmental protection, and is difficult to control the key points of the production process, and the molecular weight range of the obtained product is unstable. Performance indicators such as product activity are also difficult to control
[0004] European patent literature (EP1634893) has reported the method that takes chlorosulfonic acid as sulfonating agent, reacts and prepares heparinoid in formamide solvent, although most physicochemical indexes of the heparinoid prepared by this method are easy to control, but " total nitrogen " index is difficult to control. It is controlled within the standard range, and chlorosulfonic acid is a dangerous product. It will explode when it meets water, which is not conducive to transportation and storage. During the reaction process, heat will be released and a large amount of smoke will be generated. There are great safety hazards in the production operation.
In addition, when the applicant repeats the method of the above-mentioned documents, the yield of the product is low and the production cost is high, so it is not suitable for large-scale industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] (1) Dissolve 100g of chondroitin sulfate (Jiaxing Hengjie Biopharmaceutical Co., Ltd., EP7.0 standard) in 1000ml of formamide, add 150g of pyridine sulfur trioxide solid, heat up to 50°C, stir for 4 hours, and then Add 2000ml acetone to terminate the reaction, let it settle, and collect the precipitate;

[0029] (2) Dissolve the above-mentioned precipitate with 800ml of purified water, adjust the pH value of the system to 7 ± 0.5 with an aqueous solution of 30% NaOH with a mass percentage concentration, add 2 times the volume of acetone to make it precipitate; then dissolve the precipitate with 400ml Dissolve in purified water, add 2 times the volume of acetone to precipitate, and collect the precipitate;

[0030] (3) Dissolve the above precipitate with 800ml of purified water, and pass through 400ml of strongly acidic cation exchange resin (Shanghai Kaiping Resin Co., Ltd., model: 001×7) and 400ml of strongly basic anion exchange resin (Shanghai Kaiping Resin Co., Ltd....

Embodiment 2

[0034] Dissolve 100g of chondroitin sulfate in 900ml of formamide, slowly add 160ml of oleum with a mass percentage concentration of 60% dropwise, control the temperature at 20-30°C, stir and react for 6 hours, then add 1800ml of acetone to terminate the reaction, and let stand to settle, to collect sediment;

[0035] See Example 1 for post-processing, and finally freeze-dry to obtain 95 g of heparin-like products, with a total yield of 95%.

Embodiment 3

[0037] Dissolve 100g of chondroitin sulfate in 950ml of formamide, slowly introduce sulfur trioxide gas under stirring, control the temperature at 0-10°C, keep it warm for 3 hours, then add 1900ml of acetone to terminate the reaction, let it settle, and collect the precipitate ;

[0038] See Example 1 for post-processing, and finally freeze-dry to obtain 95 g of heparin-like products, with a total yield of 95%.

[0039] The main physical and chemical indicators of the heparin-like products prepared in Examples 1-3 of the present invention are as follows:

[0040] Appearance: white or slightly yellowish white powder

[0041] pH: 6.0~7.5

[0042] Specific rotation: -11.7°~-14.7°

[0043] Loss on drying: ≤6%

[0044] Residue on ignition: 38% to 48%

[0045] Electrophoresis: 1.07~1.16

[0046] Total nitrogen: 1.6%~2.0%

[0047] Intrinsic viscosity: 0.09~0.18

[0048] Organic sulfate: 25.8% to 37.3%

[0049] Free sulfur: ≤13%

[0050] D-glucuronic acid: 19% to 24%

[0051]...

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Abstract

The invention discloses a preparation method of heparinoid. The preparation method comprises the following steps : adopting chondroitin sulfate as a raw material, and treating to obtain heparinoid after sulfonation reaction. In the sulfonation reaction, the adopted solvent is formamide and the adopted sulfonating agent is free sulfur trioxide, fuming sulfuric acid or pyridine sulfur trioxide. The preparation method of heparinoid, disclosed by the invention, has the advantages that the synthesis process is simple, the production and the operation are easily controlled, no special requirement exists for production equipment, the molecular weight range of a product is stable, the physicochemical indexes of the product are controlled in the quality standard range, and simultaneously the product is high in yield and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of a biochemical drug heparinoid. Background technique [0002] Heparinoids are heparin-like substances, which are acidic mucopolysaccharides that are similar in chemical structure to heparin to a certain extent and have anticoagulant activity. It has antithrombotic, anti-inflammatory, analgesic, improved blood circulation in the affected area, absorbs exudate, cures edema and edema, and promotes tissue repair. It is clinically applicable to vascular embolism, varicose veins, superficial phlebitis, lymphadenitis, mastitis and softening scars. [0003] At present, there have been reports on the invention patent literature of heparin, such as Japanese patent literature (JP, S47-30167) adopts concentrated sulfuric acid as sulfonating agent, reacts with chondroitin sulfate in pyridine at low temperature to prepare heparin, Japanese patent literature...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/08
CPCC08B37/00C08B37/0069C07B45/02
Inventor 贾春祥
Owner ZHEJIANG SANMEN HYGECON PHARMA CO LTD
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