CN101165071A - Clexane and preparation method thereof - Google Patents
Clexane and preparation method thereof Download PDFInfo
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- CN101165071A CN101165071A CNA2006100969557A CN200610096955A CN101165071A CN 101165071 A CN101165071 A CN 101165071A CN A2006100969557 A CNA2006100969557 A CN A2006100969557A CN 200610096955 A CN200610096955 A CN 200610096955A CN 101165071 A CN101165071 A CN 101165071A
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Abstract
The present invention is enoxaparin and its preparation process, and features that the preparation process includes the following steps: dissolving sodium heparin in water, dissolving benzethonium chloride in water, mixing these two kinds of solution to react, vacuum suction filtering, washing the solid with water and stoving to obtain quaternary ammonium salt of heparin; dissolving the salt in dichloromethane, adding benzyl chloride to react, adding methanol solution of sodium acetate to produce precipitate, suction filtering, washing the solid with methanol and stoving to obtain heparin benzyl ester; dissolving heparin benzyl ester in 0.1N water solution of sodium hydroxide, adding sodium chloride, membrane filtering after dissolving, adding methanol to separate out precipitate, suction filtering, washing and stoving solid to obtain coarse enoxaparin sodium product; and purifying to obtain refined enoxaparin sodium product. The present invention has low production cost and high product quality.
Description
Technical field:
The invention discloses biochemical product of a kind of enoxaparin by name and preparation method thereof.This preparation method belongs to a kind of preparation method of biochemical drug.
Technical background: enoxaparin is a kind of anti-freezing and antithrombotic reagent, is the derivative of low molecular weight heparin sodium.Enoxaparin is a raw material with chitterlings mucous membrane heparin, by quaternized, the esterification of heparin, finally obtains by β-elimination in alkaline solution.The preparation method of enoxaparin is more, but preparation method commonly used at present has following two kinds:
Method one: in the acidic aqueous solution of heparin, add the benzethonium chloride aqueous solution, the dry quaternary ammonium salt that gets heparin of the precipitation that obtains washing final vacuum.At N, the normal temperature esterification obtains heparin 4-benzyl chloride ester in the dinethylformamide (DMF) after 48 hours with heparin quaternary ammonium salt, 4-chlorobenzyl chloride, and the β-elimination under alkaline condition of heparin 4-benzyl chloride ester generates enoxaparin.
Method two: use the acidic aqueous solution and benzethonium chloride reaction generation heparin quaternary ammonium salt of dermatan sulfate less than 2% heparin, with this heparin quaternary ammonium salt, Benzyl Chloride in methylene dichloride under the certain temperature esterification 12～48 hours heparin benzyl ester, heparin benzyl ester is β-eliminations generation enoxaparin under alkaline condition.
Method one uses unfractionated heparin as raw material, has used toxicity, 4-chlorobenzyl chloride, organic solvent N that pungency is bigger in preparation process, dinethylformamide, and the process time of esterification simultaneously is long.Method two has been avoided the bigger reagent of toxicity to choosing specific heparin as raw material in preparation process, the organic solvent usage quantity is less, and the relative method one of esterification time reduces to some extent.But also exist defectives such as unstable product quality, tooling cost height, yield be lower.
Summary of the invention:
The objective of the invention is to disclose a kind of enoxaparin and preparation method thereof, it can overcome the defective that above complete processing is brought effectively, reduces production costs, and improves the quality of products.The object of the present invention is achieved like this.Enoxaparin and preparation method thereof is under the normal temperature heparin sodium to be dissolved in 7～11 times of water, transfers pH to 7.0～9.0; Be dissolved in the benzethonium chloride of 2～3 times of heparin sodium amounts in 3～7 times of water and stir, after the heparin sodium aqueous solution is added in the benzethonium chloride aqueous solution fully reaction, vacuum filtration, vacuum tightness 〉=0.08MPa, solid is blunged and is washed the back suction filtration, repeats twice, and solid is in 45～60 ℃, with oven dry in 20～30 hours, get the heparin quaternary ammonium salt of sodium-salt form.The heparin quaternary ammonium salt is dissolved in 3～7 times the methylene dichloride, add 1～4 times of Benzyl Chloride, reaction solution is placed 20～45 ℃ of aqueous solution, react after 20～30 hours and take out, add 10% sodium-acetate methanol solution of 1 times of total reaction volume, suction filtration, suction filtration behind the solid usefulness methyl alcohol agitator treating, solid is washed till suction filtration liquid and meets the water nondiscoloration, and solid gets the heparin benzyl ester of sodium-salt form in 45～60 ℃ of oven dry.Heparin benzyl ester is dissolved in the aqueous solution of 55～70 ℃ in sodium hydroxide of 15～25 times of 0.1N, stirring reaction 15～60 minutes, be cooled to room temperature, dilute hydrochloric acid transfers pH to neutral, adds 15% sodium-chlor, dissolving back membrane filtration, methyl alcohol with 2 times of amounts is separated out precipitation, suction filtration, washing, solid gets the enoxaparin crude product in 45～60 ℃ of oven dry.Above-mentioned enoxaparin crude product is dissolved in 7～11 times of water, transfers pH to 8.0～11.0, be heated to 30～55 ℃, the amount that adds hydrogen peroxide is 1%～2% of the aqueous solution, transfer pH to 8.0～11.0, reacted 0.5～3 hour, transfer pH to 7.0～8.0, add 10% sodium-chlor, dissolving back membrane filtration is separated out precipitation with the methyl alcohol of 2 times of amounts, suction filtration, the oven dry of washing back gets the enoxaparin elaboration.The present invention meets the European Pharmacopoeia quality standard, and yield is with external quite specific mass is good mutually for the import like product of the quality of the pharmaceutical preparations and existing market sale, and price is low.
Description of drawings:
Fig. 1 is a process flow sheet of the present invention;
Embodiment:
Enoxaparin of the present invention and preparation method thereof is under the normal temperature heparin sodium to be dissolved in 7～11 times of water, transfers pH to 7.0～9.0; The benzethonium chloride of 2～3 times of heparin sodium amounts is dissolved in 3～7 times of water and stirs, after the heparin sodium aqueous solution is added in the benzethonium chloride aqueous solution fully reaction, vacuum filtration, vacuum tightness 〉=0.08MPa, solid is blunged and is washed the back suction filtration, repeats twice, and solid is in 45～60 ℃, with oven dry in 20～30 hours, get the heparin quaternary ammonium salt of sodium-salt form.The heparin quaternary ammonium salt is dissolved in 3～7 times the methylene dichloride, add 1～4 times of Benzyl Chloride, reaction solution is placed 20～45 ℃ of aqueous solution, react after 20～30 hours and take out, add 10% sodium-acetate methanol solution of 1 times of total reaction volume, suction filtration, solid is used suction filtration behind the methyl alcohol agitator treating again, solid is washed till suction filtration liquid and meets the water nondiscoloration, and solid gets the heparin benzyl ester of sodium-salt form in 45～60 ℃ of oven dry.Heparin benzyl ester is dissolved in the aqueous solution of 55～70 ℃ in sodium hydroxide of 15～25 times of 0.1N, stirring reaction 15～60 minutes, be cooled to room temperature, dilute hydrochloric acid transfers pH to neutral, adds 15% sodium-chlor, dissolving back membrane filtration, methyl alcohol with 2 times of amounts is separated out precipitation, suction filtration, washing, solid gets the enoxaparin crude product in 45～60 ℃ of oven dry.Crude product is dissolved in 7～11 times of water, transfers pH to 8.0～11.0, be heated to 30～55 ℃, the amount that adds hydrogen peroxide is 1%～2% of the aqueous solution, transfer pH to 8.0～11.0, reacted 0.5～3 hour, transfer pH to 7.0～8.0, add 10% sodium-chlor, dissolving back membrane filtration is separated out precipitation with the methyl alcohol of 2 times of amounts, suction filtration, the oven dry of washing back gets the enoxaparin elaboration.
During concrete enforcement, example one: under the normal temperature 60g heparin sodium is dissolved in the 600ml water, transfer pH to 8.0, after the above-mentioned heparin sodium aqueous solution being joined in the 15%1000ml benzethonium chloride aqueous solution that has prepared fully reaction, have precipitation to separate out, vacuum filtration is behind the water agitator treating, 50 ℃ of oven dry of solid, the heparin quaternary ammonium salt 162.4g of sodium-salt form.Above-mentioned solid is dissolved in the 800ml methylene dichloride, adds Benzyl Chloride 162.4ml, room temperature condition was placed 24 hours down, added 1 times of amount 10% sodium-acetate methanol solution, suction filtration, and behind the methyl alcohol agitator treating, 50 ℃ of oven dry of solid get solid 50g, are heparin benzyl ester.Heparin benzyl ester is dissolved in the sodium hydroxide solution of 750ml 0.1N, is heated to 60 ℃, stirring reaction 60 minutes is cooled to room temperature, dilute hydrochloric acid transfers to neutrality, adds the sodium-chlor of 112.5g, separates out precipitation with the methyl alcohol of 2 times of amounts, suction filtration, washing, solid get enoxaparin crude product 26g in 50 ℃ of oven dry.The enoxaparin crude product is dissolved in the 200ml water, transfers pH to 9.0, be heated to 30 ℃, the amount that adds hydrogen peroxide is 1.5% of the aqueous solution, transfer pH to 9.0, react after 1 hour, transfer pH to 7.5, add 10% sodium-chlor, methyl alcohol with 2 times of amounts is separated out precipitation, suction filtration, washing, solid gets enoxaparin elaboration 25g in 50 ℃ of oven dry.
Detected result A
231Nm=15.6, anti-XaIU:105.6, IIa:25.1.Anti-XaIU/IIa:4.2.Molecular weight: average 4148,2000～8000:77.1%,＜2000:16.5%.All the other every indexs meet the European Pharmacopoeia quality standard.
Example two: under the normal temperature 60g heparin sodium is dissolved in the 480ml water, transfer pH to 8.0, after the above-mentioned heparin sodium aqueous solution being joined in the 25%480ml benzethonium chloride aqueous solution that has prepared fully reaction, there is precipitation to separate out, vacuum filtration, behind the water agitator treating, 50 ℃ of oven dry of solid, the heparin quaternary ammonium salt 155g of sodium-salt form.Above-mentioned solid is dissolved in the 465ml methylene dichloride, adds Benzyl Chloride 310ml, placed 24 hours under 45 ℃ of conditions, add 1 times of amount 10% sodium-acetate methanol solution, suction filtration, behind the methyl alcohol agitator treating, 50 ℃ of oven dry of solid get solid 58g, are heparin benzyl ester.Heparin benzyl ester is dissolved in the sodium hydroxide solution of 1450ml0.1N, is heated to 70 ℃, stirring reaction 15 minutes is chilled to room temperature, dilute hydrochloric acid transfers to neutrality, adds the sodium-chlor of 217.5g, separates out precipitation with the methyl alcohol of 2 times of amounts, suction filtration, washing, solid get enoxaparin crude product 30g in 50 ℃ of oven dry.The enoxaparin crude product is dissolved in the 330ml water, transfers pH to 9.0, be preheated to 30 ℃, the amount that adds hydrogen peroxide is 1.5% of the aqueous solution, transfer pH to 9.0, react after 1 hour, transfer pH to 7.5, add 10% sodium-chlor, methyl alcohol with 2 times of amounts is separated out precipitation, suction filtration, washing, 50 ℃ of oven dry get enoxaparin elaboration 27.2g.
Detected result: A
231Nm=16.8, anti-XaIU:101.4, IIa:22.3.Anti-XaIU/IIa:4.5.Molecular weight: average 4076,2000～8000:75.1%,＜2000:14.0%.All the other every indexs meet the European Pharmacopoeia quality standard.
Claims (1)
1. the preparation method of an enoxaparin, comprise that with heparin sodium be raw material,, obtain enoxaparin by β in the alkaline solution-elimination back membrane filtration, drying again by quaternized, esterification, it is characterized in that: under the normal temperature heparin sodium is dissolved in 7～11 times of water, transfers pH to 7.0～9.0; Be dissolved in the benzethonium chloride of 2～3 times of heparin sodium amounts in 3～7 times of water and stir, after the heparin sodium aqueous solution is added in the benzethonium chloride aqueous solution fully reaction, vacuum filtration, vacuum tightness 〉=0.08MPa, solid is blunged and is washed the back suction filtration, repeats twice, and solid is in 45～60 ℃, with oven dry in 20～30 hours, get the heparin quaternary ammonium salt of sodium-salt form; The heparin quaternary ammonium salt is dissolved in 3～7 times the methylene dichloride, add 1～4 times of Benzyl Chloride, reaction solution is placed 20～45 ℃ of aqueous solution, react after 20～30 hours and take out, add 10% sodium-acetate methanol solution of 1 times of total reaction volume, suction filtration, suction filtration behind the solid usefulness methyl alcohol agitator treating, solid is washed till suction filtration liquid and meets the water nondiscoloration, and solid gets the heparin benzyl ester of sodium-salt form in 45～60 ℃ of oven dry; Heparin benzyl ester is dissolved in the aqueous solution of 55～70 ℃ in sodium hydroxide of 15～25 times of 0.1N, stirring reaction 15～60 minutes, be cooled to room temperature, dilute hydrochloric acid transfers pH to neutral, adds 15% sodium-chlor, dissolving back membrane filtration, methyl alcohol with 2 times of amounts is separated out precipitation, suction filtration, washing, solid gets the enoxaparin crude product in 45～60 ℃ of oven dry; Above-mentioned enoxaparin crude product is dissolved in 7～11 times of water, transfers pH to 8.0～11.0, be heated to 30～55 ℃, the amount that adds hydrogen peroxide is 1%～2% of the aqueous solution, transfer pH to 8.0～11.0, reacted 0.5～3 hour, transfer pH to 7.0～8.0, add 10% sodium-chlor, dissolving back membrane filtration is separated out precipitation with the methyl alcohol of 2 times of amounts, suction filtration, the oven dry of washing back gets the enoxaparin elaboration.
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Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101974107A (en) * | 2010-09-16 | 2011-02-16 | 山东海科化工集团有限公司 | Method for separating ester |
| CN102040672A (en) * | 2010-10-11 | 2011-05-04 | 山东郁茏生物科技有限公司 | Low-heat solid-phase synthesis method of heparin quaternary ammonium salt |
| CN102040673A (en) * | 2010-10-11 | 2011-05-04 | 山东郁茏生物科技有限公司 | Refining and purification method of enoxaparin |
| CN102050888A (en) * | 2010-12-13 | 2011-05-11 | 河北常山生化药业股份有限公司 | Method for preparing enoxaparin sodium |
| CN102516416A (en) * | 2011-12-28 | 2012-06-27 | 蚌埠医学院 | Method for synthesizing heparin ester |
| CN102558392A (en) * | 2010-12-14 | 2012-07-11 | 王芃 | Preparation method of high-FXa-resistant low-FIIa-resistant low-molecular heparin sodium |
| CN102585038A (en) * | 2012-03-13 | 2012-07-18 | 麦科罗夫（南通）生物制药有限公司 | Islamic enoxaparin sodium and method for producing and purifying same |
| CN102585037A (en) * | 2012-02-10 | 2012-07-18 | 麦科罗夫（南通）生物制药有限公司 | Enoxaparin sodium and production purification method thereof |
| CN102633908A (en) * | 2012-05-02 | 2012-08-15 | 雷晓刚 | Method for preparing high-quality LMW (low molecular weight) heparins |
| CN102924629A (en) * | 2012-12-03 | 2013-02-13 | 苏州二叶制药有限公司 | Enoxaparin sodium compound and preparation method thereof |
| WO2013044793A1 (en) * | 2011-09-26 | 2013-04-04 | Xu Meiying | High-purity heparin benzyl ester salt, preparation method therefor and application thereof |
| CN103342761A (en) * | 2013-07-15 | 2013-10-09 | 河北常山生化药业股份有限公司 | Technology for preparing enoxaparin sodium by membrane separation |
| CN103554305A (en) * | 2013-10-14 | 2014-02-05 | 南昌市浩然生物医药有限公司 | Synthetic method of affinity precipitation medium and application thereof to preparation of enoxaparin sodium |
| CN106243246A (en) * | 2015-08-21 | 2016-12-21 | 苏州融析生物科技有限公司 | A kind of sheep Enoxaparin Sodium and preparation method and application |
| CN108219030A (en) * | 2016-12-21 | 2018-06-29 | 鲁南制药集团股份有限公司 | A kind of preparation method of Enoxaparin Sodium crude product |
| CN109485749A (en) * | 2018-10-31 | 2019-03-19 | 江西浩然生物医药有限公司 | A method of chromatography and Ultrafiltration Membrane prepare Enoxaparin Sodium |
| US11299558B2 (en) | 2017-12-11 | 2022-04-12 | Biological E Limited | Process for the preparation of low molecular weight heparin |
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2006
- 2006-10-20 CN CN 200610096955 patent/CN100582123C/en active Active
Cited By (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101974107A (en) * | 2010-09-16 | 2011-02-16 | 山东海科化工集团有限公司 | Method for separating ester |
| CN101974107B (en) * | 2010-09-16 | 2012-07-04 | 山东海科化工集团有限公司 | Method for separating ester |
| CN102040672B (en) * | 2010-10-11 | 2012-09-05 | 山东郁茏生物科技有限公司 | Low-heat solid-phase synthesis method of heparin quaternary ammonium salt |
| CN102040672A (en) * | 2010-10-11 | 2011-05-04 | 山东郁茏生物科技有限公司 | Low-heat solid-phase synthesis method of heparin quaternary ammonium salt |
| CN102040673A (en) * | 2010-10-11 | 2011-05-04 | 山东郁茏生物科技有限公司 | Refining and purification method of enoxaparin |
| CN102050888A (en) * | 2010-12-13 | 2011-05-11 | 河北常山生化药业股份有限公司 | Method for preparing enoxaparin sodium |
| CN102558392A (en) * | 2010-12-14 | 2012-07-11 | 王芃 | Preparation method of high-FXa-resistant low-FIIa-resistant low-molecular heparin sodium |
| WO2013044793A1 (en) * | 2011-09-26 | 2013-04-04 | Xu Meiying | High-purity heparin benzyl ester salt, preparation method therefor and application thereof |
| CN102516416A (en) * | 2011-12-28 | 2012-06-27 | 蚌埠医学院 | Method for synthesizing heparin ester |
| CN102585037A (en) * | 2012-02-10 | 2012-07-18 | 麦科罗夫（南通）生物制药有限公司 | Enoxaparin sodium and production purification method thereof |
| CN102585038A (en) * | 2012-03-13 | 2012-07-18 | 麦科罗夫（南通）生物制药有限公司 | Islamic enoxaparin sodium and method for producing and purifying same |
| CN102633908A (en) * | 2012-05-02 | 2012-08-15 | 雷晓刚 | Method for preparing high-quality LMW (low molecular weight) heparins |
| CN102924629B (en) * | 2012-12-03 | 2013-11-13 | 苏州二叶制药有限公司 | Enoxaparin sodium compound and preparation method thereof |
| CN102924629A (en) * | 2012-12-03 | 2013-02-13 | 苏州二叶制药有限公司 | Enoxaparin sodium compound and preparation method thereof |
| CN103342761B (en) * | 2013-07-15 | 2016-01-06 | 河北常山生化药业股份有限公司 | A kind of membrane sepn prepares Enoxaparin Sodium technique |
| CN103342761A (en) * | 2013-07-15 | 2013-10-09 | 河北常山生化药业股份有限公司 | Technology for preparing enoxaparin sodium by membrane separation |
| CN103554305A (en) * | 2013-10-14 | 2014-02-05 | 南昌市浩然生物医药有限公司 | Synthetic method of affinity precipitation medium and application thereof to preparation of enoxaparin sodium |
| CN106243246A (en) * | 2015-08-21 | 2016-12-21 | 苏州融析生物科技有限公司 | A kind of sheep Enoxaparin Sodium and preparation method and application |
| CN106467577A (en) * | 2015-08-21 | 2017-03-01 | 苏州融析生物科技有限公司 | A kind of pulmonis Bovis seu Bubali Enoxaparin Sodium and preparation method and application |
| CN106467578A (en) * | 2015-08-21 | 2017-03-01 | 苏州融析生物科技有限公司 | A kind of Intestinum Bovis seu Bubali mucosa Enoxaparin Sodium and preparation method and application |
| CN106243246B (en) * | 2015-08-21 | 2019-05-24 | 苏州融析生物科技有限公司 | A kind of sheep Enoxaparin Sodium and the preparation method and application thereof |
| CN108219030A (en) * | 2016-12-21 | 2018-06-29 | 鲁南制药集团股份有限公司 | A kind of preparation method of Enoxaparin Sodium crude product |
| US11299558B2 (en) | 2017-12-11 | 2022-04-12 | Biological E Limited | Process for the preparation of low molecular weight heparin |
| CN109485749A (en) * | 2018-10-31 | 2019-03-19 | 江西浩然生物医药有限公司 | A method of chromatography and Ultrafiltration Membrane prepare Enoxaparin Sodium |
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Application publication date: 20080423 Assignee: Huai'an Maidesen Pharmaceutical Co., Ltd. Assignor: Jiangsu Aland Nourishment Co.,Ltd. Contract record no.: 2015320000086 Denomination of invention: Clexane and preparation method thereof Granted publication date: 20100120 License type: Common License Record date: 20150320 |
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