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Preparation method of enoxaparin sodium crude product

A technology of enoxaparin sodium and heparin sodium, which is applied in the field of preparation of crude enoxaparin sodium, can solve problems such as uneven degradation of esterified products, unstable quality, deep product color, etc., and achieve suitable molecular weight range, good decolorization effect, The effect of high product stability

Pending Publication Date: 2018-06-29
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The existing enoxaparin sodium preparation methods are mainly the processes disclosed in CN100582123C, CN102050888B and CN102585037A, all of which use heparin sodium as the starting material, and the product is obtained through salinization, esterification, and β-elimination in lye, but The existing process has problems such as uneven degradation of esterified products, dark product color, poor clarity, low yield, and unstable quality.

Method used

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  • Preparation method of enoxaparin sodium crude product
  • Preparation method of enoxaparin sodium crude product
  • Preparation method of enoxaparin sodium crude product

Examples

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Effect test

Embodiment 1

[0021] 2.5 parts by weight of benzethonium chloride are dissolved in 5 parts by weight of purified water to form a benzethonium chloride solution; 1 part by weight of heparin sodium is dissolved in 13 parts by weight of purified water to form a sodium heparin solution, and the The benzethonium chloride solution was added to the sodium heparin solution at room temperature. After the addition, the reaction was stirred at room temperature for 3 h, filtered with suction, the filter cake was washed with water for 3 times, dried in vacuum, and dried under vacuum at 50° C. to obtain a heparin quaternary ammonium salt solid.

[0022] Dissolve 1 part by weight of heparin quaternary ammonium salt in 11 parts by volume of dichloromethane, add 2 parts by weight of benzyl chloride, react at 40°C for 25 hours, cool to room temperature, add 2 parts by weight of sodium acetate under stirring The prepared 10% sodium acetate methanol solution was stirred for 40 minutes, left to settle for 3 hou...

Embodiment 2

[0029] Dissolve 2.2 parts by weight of benzethonium chloride in 4.5 parts by weight of purified water to form a benzethonium chloride solution; dissolve 1 part by weight of heparin sodium in 12 parts by weight of purified water to form a heparin sodium solution, and slowly dissolve the The benzethonium chloride solution was added to the sodium heparin solution at room temperature. After the addition, the reaction was stirred at room temperature for 2 h, filtered with suction, the filter cake was washed with water three times, dried in vacuum, and dried under vacuum at 45° C. to obtain a heparin quaternary ammonium salt solid.

[0030] Dissolve 1 part by weight of heparin quaternary ammonium salt in 9 times the volume of dichloromethane, add 2 parts by weight of benzyl chloride, react at 30°C for 21 hours, cool to room temperature, add 2 parts by weight of sodium acetate under stirring The prepared 10% sodium acetate methanol solution was stirred for 20 minutes, left to settle ...

Embodiment 3

[0037] 2.8 parts by weight of benzethonium chloride are dissolved in 5.5 parts by weight of purified water to form a benzethonium chloride solution; 1 part by weight of heparin sodium is dissolved in 14 parts by weight of purified water to form a sodium heparin solution, and the The benzethonium chloride solution was added to the sodium heparin solution at room temperature. After the addition was completed, the reaction was stirred at room temperature for 4 h, filtered with suction, the filter cake was washed with water for 3 times, dried in vacuum, and dried under vacuum at 55° C. to obtain a heparin quaternary ammonium salt solid.

[0038] Dissolve 1 part by weight of heparin quaternary ammonium salt in 13 parts by volume of dichloromethane, add 2 parts by weight of benzyl chloride, react at 35°C for 23 hours, cool to room temperature, add 2 parts by weight of sodium acetate under stirring The prepared 10% sodium acetate methanol solution was stirred for 30 minutes, left to ...

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Abstract

The invention discloses a preparation method of an enoxaparin sodium crude product. The enoxaparin sodium crude product is prepared from heparin sodium through the steps of salification, esterification and depolymerization. By the method disclosed by the invention, the problems of a large amount of solvent residues, non-ideal decoloring effect and degradation non-uniformity of heparin benzyl esterare solved, the production cost is reduced, the stability of the product is improved and the quality of the product is improved.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for preparing crude enoxaparin sodium. Background technique [0002] Enoxaparin sodium was first developed by Sanofi-Aventis, the fourth largest pharmaceutical company in the world, and was approved by the US FDA on March 29, 1993, becoming Sanofi-Aventis' best-selling product. Drug. Enoxaparin sodium is a kind of low-molecular-weight heparin sodium. It is the sodium salt of aminodextran sulfate fragments obtained by alkali degradation of heparin extracted from pig small intestinal mucosa after benzyl esterification. It is a polysaccharide mixture with a weight-average molecular weight of 4500D. Its main mechanism of action is to inhibit the activity of coagulation factors Xa, Ⅱa, Ⅸa, Ⅺa, and Ⅻa by binding to antithrombin Ⅲ and its complexes, among which the anticoagulant effect is mainly exerted by inhibiting Xa. The anti-Xa and IIa activities of low-molecular-weight he...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/10
CPCC08B37/0075C08B37/0078
Inventor 张贵民刁玉林张创立陈小印
Owner LUNAN PHARMA GROUP CORPORATION
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