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Process for the preparation of low molecular weight heparin

A technology of heparin sodium and heparin benzyl ester, which is applied in the field of preparation of enoxaparin sodium, and can solve problems such as difficulties in commercial-scale operation and separation of heparin benzyl ester sodium salt

Active Publication Date: 2020-09-15
BIOLOGICAL E LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art process, during the esterification stage, the reaction was quenched by adding sodium acetate in methanol, resulting in heparin benzyl ester as a viscous hard mass that stuck to the walls of the reactor and stirrer blades , thus causing difficulties in the separation of heparin benzyl ester sodium salt, and thus operational difficulties on a commercial scale

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Step a: 1718 g of water and 275 g of benzethonium chloride were added to a round bottom flask and stirred at room temperature until dissolved. Add 1000 g of water and 100 g of sodium heparin to another round bottom flask and stir to dissolve. The aqueous solution of benzethonium chloride was slowly added to the sodium heparin solution and maintained for 2.5 hours. Then, the reaction mass was filtered, and the obtained filter cake was repeatedly washed with water. The wet filter cake was vacuum-dried at 50° C. for 9 hours to obtain 291.6 g of heparin benzethonium salt. The benzethonium content was 71.4% as measured by HPLC.

[0054] Step b: Feed 50 g of heparin benzethonium salt (obtained in step (a)) and 189.6 g of DMF into a suitable reactor and stir at room temperature to dissolve, then add 22.0 g of benzyl chloride and stir the reaction mass 10 hours. The reaction mixture was quenched by adding 220.0 g of water at 15 to 20° C. to precipitate benzyl heparin, the r...

Embodiment 2

[0056] 50 g of heparin benzethonium salt (obtained in step (a) of Example 1) and 189.6 g of DMF were fed into a suitable reactor and stirred at room temperature to dissolve, then 22.0 g of benzyl chloride were added and stirred Reaction mass 15 hours. The reaction mixture was quenched by adding 220.0 g of water at 10 to 20° C. to precipitate benzyl heparin, the reaction mixture was left to stand and the supernatant was decanted to retain the benzyl heparin wet solid in the reactor. The wet solid was washed with 10% sodium acetate in methanol, then methanol, filtered and dried to yield 15.2 g of heparin benzyl ester sodium salt. The benzyl alcohol content of the obtained ester was 11.5% as measured by HPLC.

Embodiment 3

[0058] 10 g of heparin benzethonium salt (obtained in step (a) of Example 1) and 37.92 g of DMF were added to a suitable reactor and stirred at room temperature to dissolve, then 4.4 g of benzyl chloride were added and reaction mass 6 was stirred Hour. The heparin benzyl ester was precipitated by adding 44.0 g of water to quench the reaction mixture at 10 to 15°C, the reaction mixture was allowed to stand and the supernatant was decanted to retain the heparin benzyl ester wet solid in the reactor. The wet solid was washed with 10% sodium acetate in methanol, then methanol, filtered and dried to yield 3.19 g of heparin benzyl ester sodium salt. The benzyl alcohol content of the obtained ester was 6.6% as measured by HPLC.

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Abstract

The present invention provides an improved process for the preparation of Enoxaparin sodium. The process is simple, commercially viable and industrially advantageous.

Description

[0001] Cross References to Related Applications [0002] This application claims priority from Indian Provisional Patent Application No. 201741044415 filed on December 11, 2017, the entire contents of which are incorporated herein by reference. technical field [0003] The invention relates to a preparation method of low molecular weight heparin. More specifically, the present invention relates to an improved preparation method of enoxaparin sodium. Background technique [0004] Heparin is a bioactive agent, extracted from natural sources, that has important anticoagulant and antithrombotic properties. In particular, they are useful in the treatment of postoperative venous thrombosis. [0005] Low molecular weight heparins are prepared by chemical or enzymatic depolymerization of heparin. Low molecular weight (LMW) heparins approved and marketed in different countries include Enoxaparin, Dalteparin, Nadroparin, Parnaparin, Tinzaparin, Bemiparin and Certoparin. [0006] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/00
CPCC08B37/0078
Inventor 马诺哈尔·萨尔马·维杜拉斯里达·戈斯吉纳伦德尔·德夫·曼特纳拉特纳卡·阿雅索玛雅鲁拉
Owner BIOLOGICAL E LTD
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