CN107586350A - The preparation method of Enoxaparin - Google Patents
The preparation method of Enoxaparin Download PDFInfo
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- CN107586350A CN107586350A CN201710655740.2A CN201710655740A CN107586350A CN 107586350 A CN107586350 A CN 107586350A CN 201710655740 A CN201710655740 A CN 201710655740A CN 107586350 A CN107586350 A CN 107586350A
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Abstract
The present invention relates to biological technical field, a kind of preparation method of Enoxaparin is disclosed, including into salt, esterification, alkaline hydrolysis, extraction, purifying and decolouring, wherein, extraction is that extraction 2 ~ 3 times is carried out to alkaline hydrolysis solution using the hydrophobic organic solvent of 1 ~ 2 times of alkaline hydrolysis amount of solution, then filters to take filtrate；Decolouring is that the activated carbon that 2 ~ 3% crude product Enoxaparin liquor capacities are added into 60 ~ 80 DEG C, the crude product Enoxaparin solution that pH is 6.0 ~ 7.0 carries out 25 ~ 40min of decolouring to it, cross and filter out activated carbon, it is cooled to room temperature, adjust pH to 6 ~ 7, the sodium chloride for adding mass fraction to be 15% is well mixed, filter to get filtrate, 3 times of methanol are added into filtrate and separate out precipitation, filter, wash, drying and described precipitate to obtain fine work Enoxaparin.Abstraction impurity removal after alkaline hydrolysis in this method, activated carbon decolorizing is carried out after removal of impurities again, good decolorizing effect, final Enoxaparin product purity is higher, on molecular weight product without influence, simple process.
Description
Technical field
The present invention relates to biological technical field, more particularly to a kind of preparation method of Enoxaparin.
Background technology
Enoxaparin Sodium（Enoxaparin Sodium）For LMWHs class（low molecular weight
Heparin, abbreviation LMWH）One of kind, there is the extremely strong a functions of anticoagulant factor Ⅹ and weak antithrombase and blood platelet knot
Close and influence the effect of platelet function.For the preventing and treating of DVT, prevent formation and the DIC of hemodialysis shunt thrombosis
Treatment.
Enoxaparin is LMWHs prepared by the heparin benzyl esters from chitling mucous membrane are carried out into alkaline bleach liquor degradation
Sodium salt, main preparation method are：Heparin sodium aqua adds benzethonium chloride, obtains the quaternary ammonium salt of heparin, the liver after vacuum drying
Plain quaternary ammonium salt is esterified in dichloromethane solution with benzyl chloride, obtains heparin benzyl ester, the β-elimination in the basic conditions of heparin benzyl ester
Obtain Enoxaparin.This method is French Sanofi-Aventis's patented method, but the purifying method of decolorizing and refining to Enoxaparin does not have
Refer to, therefore the preparation difference at home and abroad on Enoxaparin is larger, quality is also mixed secondary uneven.Purification decolorization method at present
Main active carbon decoloring, hydrophobic chromatography post, resin anion (R.A.) exchange, hydrogen peroxide oxidation decolourizes, or made combining for several method
With etc..Shortcoming is：Activated carbon decolorizing method decolorizing effect is limited, hydrophobic chromatography post and resin anion (R.A.) exchange column trivial operations,
Decolorizing effect is poor, and yield is low, and product molecular weight distribution is impacted；Although hydrogen peroxide oxidation decolorizing effect is obvious, right
Enoxaparin has degraded, influences end product quality.
The content of the invention
Goal of the invention：For problems of the prior art, the present invention provides a kind of preparation method of Enoxaparin, alkali
Abstraction impurity removal after solution, activated carbon decolorizing is then carried out again, good decolorizing effect, final Enoxaparin product purity is higher, to production
Product molecular weight is without influence, simple process.
Technical scheme：The invention provides a kind of preparation method of Enoxaparin, comprise the following steps：（1）Into salt：Use
Heparin sodium aqua and benzethonium chloride solution prepare heparin quaternary ammonium salt；（2）Esterification：The heparin quaternary ammonium salt is dissolved in dichloromethane
Afterwards, benzyl chloride stirring esterification generation heparin benzyl ester is added；（3）Alkaline hydrolysis：The heparin benzyl ester is subjected to alkaline hydrolysis in the basic conditions
Reaction, adds salt, stir to obtain alkaline hydrolysis solution thereto after reaction solution then is adjusted into neutrality；（4）Extraction：Use 1 ~ 2 times
The hydrophobic organic solvent of the alkaline hydrolysis amount of solution carries out extraction 2 ~ 3 times to the alkaline hydrolysis solution, then filters to take filtrate；（5）It is pure
Change：3 times of methanol precipitation precipitations are added into the filtrate and collect to obtain crude product Enoxaparin；（6）Decolourize：By the crude product according to promise liver
Element is dissolved in water and is prepared into crude product Enoxaparin solution, and the temperature for controlling the crude product Enoxaparin solution is in 60 ~ 80 DEG C, pH
6.0 ~ 7.0, activated carbon is added thereto 25 ~ 40min of decolouring is carried out to it, be filtered to remove the activated carbon, be cooled to room temperature, add
Enter salt to be well mixed, filter to get filtrate, 3 times of methanol are added into filtrate and separate out precipitation, filters, wash, drying described precipitate
Fine work Enoxaparin.
Preferably, described（1）In, the heparin sodium aqua is dissolved in 8 times of water by liquaemin and is formulated, the benzyl rope chlorine
Ammonium salt solution is dissolved in 4 times of water by the benzethonium chloride of 2 ~ 3 times of liquaemin weight and is formulated.
Further, described（1）In, first the heparin sodium aqua is slowly added into the benzethonium chloride solution instead
Crude product heparin quaternary ammonium salt should be generated, then the crude product heparin quaternary ammonium salt is filtered dry after 2 ~ 3 washings again, and vacuum is done at 50 DEG C
The heparin quaternary ammonium salt is obtained after dry 15 ~ 18h.
Preferably, described（2）In, the weight ratio of the volume of the dichloromethane and the heparin quaternary ammonium salt for 2.5 ~
3.5：1；The mass ratio of the volume of the benzyl chloride and the heparin quaternary ammonium salt is 1 ~ 2：1.
Preferably, described（2）In, the time for stirring esterification is 30h, and temperature is 40 DEG C.
Preferably, 1 ~ 2 times of reaction volume is additionally added in the reaction solution after the stirring esterification contains 15% anhydrous acetic acid
The methanol of sodium, collected by suction precipitation, precipitation again with methanol suction filtration cleaning is non-discolouring to washing lotion chance water, will be deposited at 50 DEG C and dries
Obtain the heparin benzyl ester.
Preferably, described（3）In, the alkalescence condition be 0.1N sodium hydrate aqueous solution, the sodium hydroxide water
The mass ratio of the volume of solution and the heparin benzyl ester is 20 ~ 30：1.
Preferably, described（3）In, the salt is sodium chloride, the mass body between the sodium chloride and the reaction solution
Product is than being 10 ~ 20%；And/or described（6）In, the salt is sodium chloride, and the sodium chloride and the crude product Enoxaparin are molten
Mass volume ratio between liquid is 10 ~ 20%；And/or described（6）In, the activated carbon and the crude product of addition are according to promise liver
Mass volume ratio between plain solution is 2 ~ 3%.
Preferably, described（3）In, the time of the Basic fluxing raction is 60min, and temperature is 60 DEG C, and reaction is dropped after terminating
To room temperature, the reaction solution is adjusted to neutrality with 1mol hydrochloric acid.
Preferably, the hydrophobic organic solvent is dichloromethane or ethyl acetate.
Beneficial effect：During being prepared in Enoxaparin, the alkaline hydrolysis that heparin benzyl ester occurs in the basic conditions is anti-
Should be the key step for producing impurity effect product color, the present invention is removed by carrying out extraction to the alkaline hydrolysis solution after Basic fluxing raction
It is miscellaneous, it can effectively remove impurity therein and obtain crude product Enoxaparin, the crude product Enoxaparin after impurity removes reuses activity
Charcoal carries out decolouring purifying, due to extracting the impurity for eliminating amount of activated charcoal and being difficult to remove, reuses activated carbon afterwards to product
Decolourized, decolorizing effect is significantly increased, and abstraction impurity removal is obtained after Basic fluxing raction and is used cooperatively with activated carbon decolorizing purifying, is made final
Obtained Enoxaparin product can reach European Pharmacopoeia requirement, and whole extraction and decolouring purge process do not influence Enoxaparin production
The molecular weight composition of product；Extraction and decolouring purge process operating procedure are easy, and extractant and active carbon for decolorization can return
Receive and recycle, cost is cheap.
Embodiment
The present invention is described in detail with reference to specific embodiment.
Embodiment 1：
Present embodiments provide for a kind of preparation method of Enoxaparin, following steps are specifically included：
1st, into salt：Liquaemin 100g is dissolved in 800ml purified waters, and 300g benzethonium chlorides are dissolved in 1200ml purified waters, under stirring
Heparin sodium aqua is slowly added into benzethonium chloride solution and stirred, reaction generation heparin quaternary salt deposit, filters to take liver
Plain quaternary salt deposit, purified water are cleaned 3 times, are filtered dry, and 50 DEG C are dried in vacuo 18 hours, obtain heparin quaternary ammonium salt 258g.
2nd, it is esterified：Heparin quaternary ammonium salt 258g is dissolved in 800ml dichloromethane, and stirring and dissolving is complete, is slowly added to funnel
320ml benzyl chlorides, 40 DEG C of reaction 30h.
Reaction terminates, and is slowly added to the methanol containing 15% anhydrous sodium acetate of 2 times of reaction solution volumes, collected by suction precipitation, sinks
Shallow lake again with methanol filters cleaning to washing lotion, and to meet water non-discolouring, will be deposited in dry heparin benzyl ester 105g at 50 DEG C.
3rd, alkaline hydrolysis：Heparin benzyl ester is dissolved in 2375ml 0.1N sodium hydrate aqueous solution, 60 DEG C of stirring reaction 60min,
Reaction is down to room temperature after terminating, with 1mol hydrochloric acid by reaction solution be adjusted to add after neutrality 356g sodium chloride stir alkaline hydrolysis is molten
Liquid.
4th, extract：Alkaline hydrolysis solution is transferred to extraction funnel, adds 2500ml dichloromethane hydrophobic organic solvent to alkaline hydrolysis solution
Extraction 2 times is carried out, filters to take filtrate.
5th, purify：3 times of methanol precipitation precipitations are added into filtrate and collect to obtain crude product Enoxaparin 60g.
6th, decolourize：Crude product Enoxaparin is dissolved in 550ml water and crude product Enoxaparin solution is made, and control crude product Enoxaparin is molten
The temperature of liquid carries out decolouring 30min in 70 DEG C, PH 6.0, thereto addition 15g activated carbons to it, is filtered to remove activated carbon, drops
Warming to room temperature, adjust PH to 7.0, add 80g sodium chloride, micro porous filtration obtains filtrate, and 3 times of methanol are added into filtrate and separate out precipitation,
Filter, wash, drying precipitates to obtain fine work Enoxaparin 56.8g.
Testing result：In fine work Enoxaparin product, 1,6- cyclization rate=16.8；Anti- FA activity is 22.5IU/mg；It is anti-
FXa activity is 106.8 IU/mg；Mean molecule quantity is 3965, wherein 2000 ~ 8000 account for 70%；Remaining indices meets Europe
Continent pharmacopoeial quality standard.
Embodiment 2：
Present embodiments provide for a kind of preparation method of Enoxaparin, following steps are specifically included：
It is wherein identical with embodiment 1 into salt, esterification and alkaline hydrolysis step.
4th, extract：Alkaline hydrolysis solution is transferred to extraction funnel, adds 3000ml dichloromethane hydrophobic organic solvent to alkaline hydrolysis solution
Extraction 3 times is carried out, filters to take filtrate.
5th, purify：3 times of methanol precipitation precipitations are added into filtrate and collect to obtain crude product Enoxaparin 62g.
6th, decolourize：Crude product Enoxaparin is dissolved in 680ml water and crude product Enoxaparin solution is made, and control crude product Enoxaparin is molten
The temperature of liquid carries out decolouring 40min in 80 DEG C, PH 6.5, thereto addition 20g activated carbons to it, is filtered to remove activated carbon, drops
Warming to room temperature, adjust PH to 6.5, add 120g sodium chloride, micro porous filtration obtains filtrate, and 3 times of methanol are added into filtrate and separate out precipitation,
Filter, wash, drying precipitates to obtain fine work Enoxaparin 58.5g.
Embodiment 3：
Present embodiments provide for a kind of preparation method of Enoxaparin, following steps are specifically included：
It is wherein identical with 2 with embodiment 1 into salt, esterification and alkaline hydrolysis step.
4th, extract：Alkaline hydrolysis solution is transferred to extraction funnel, adds 4000ml ethyl acetate hydrophobic organic solvent to alkaline hydrolysis solution
Extraction 3 times is carried out, filters to take filtrate.
5th, purify：3 times of methanol precipitation precipitations are added into filtrate and collect to obtain crude product Enoxaparin 61.5g.
6th, decolourize：Crude product Enoxaparin is dissolved in 600ml water and crude product Enoxaparin solution is made, and control crude product Enoxaparin is molten
The temperature of liquid carries out decolouring 25min in 60 DEG C, PH 7.0, thereto addition 14g activated carbons to it, is filtered to remove activated carbon, drops
Warming to room temperature, adjust PH to 6.0, add 80g sodium chloride, micro porous filtration obtains filtrate, and 3 times of methanol are added into filtrate and separate out precipitation,
Filter, wash, drying precipitates to obtain fine work Enoxaparin 58.6g.
The technical concepts and features of above-mentioned embodiment only to illustrate the invention, its object is to allow be familiar with technique
People can understand present disclosure and implement according to this, and it is not intended to limit the scope of the present invention.It is all according to the present invention
The equivalent transformation or modification that Spirit Essence is done, should all be included within the scope of the present invention.
Claims (10)
1. a kind of preparation method of Enoxaparin, it is characterised in that comprise the following steps：
（1）Into salt：Heparin quaternary ammonium salt is prepared using heparin sodium aqua and benzethonium chloride solution；
（2）Esterification：After the heparin quaternary ammonium salt is dissolved in into dichloromethane, benzyl chloride stirring esterification generation heparin benzyl ester is added；
（3）Alkaline hydrolysis：The heparin benzyl ester is subjected to Basic fluxing raction in the basic conditions, then by reaction solution be adjusted to it is neutral backward its
Middle addition salt, stir to obtain alkaline hydrolysis solution；
（4）Extraction：Extraction 2 ~ 3 times is carried out to the alkaline hydrolysis solution using the hydrophobic organic solvent of 1 ~ 2 times of alkaline hydrolysis amount of solution,
Then filtrate is filtered to take；
（5）Purifying：3 times of methanol precipitation precipitations are added into the filtrate and collect to obtain crude product Enoxaparin；
（6）Decolourize：The crude product Enoxaparin is dissolved in water and is prepared into crude product Enoxaparin solution, controls the crude product according to promise liver
The temperature of plain solution is 6.0 ~ 7.0 in 60 ~ 80 DEG C, pH, adds activated carbon thereto and 25 ~ 40min of decolouring is carried out to it, cross and filter out
The activated carbon is removed, is cooled to room temperature, adjusts pH to 6 ~ 7, salt is added and is well mixed, filter to get filtrate, 3 times of first are added into filtrate
Alcohol separates out precipitation, filters, washs, drying and described precipitate to obtain fine work Enoxaparin.
2. the preparation method of Enoxaparin according to claim 1, it is characterised in that described（1）In, the liquaemin
Solution is dissolved in 8 times of water by liquaemin and is formulated, and the benzethonium chloride solution is dissolved in by the benzethonium chloride of 2 ~ 3 times of liquaemin weight
4 times of water are formulated.
3. the preparation method of Enoxaparin according to claim 2, it is characterised in that described（1）In, first by the liver
Plain sodium solution is slowly added into reaction generation crude product heparin quaternary ammonium salt in the benzethonium chloride solution, then the crude product heparin season
Ammonium salt is filtered dry after 3 washings again, and the heparin quaternary ammonium salt is obtained after 18h is dried in vacuo at 50 DEG C.
4. the preparation method of Enoxaparin according to claim 1, it is characterised in that described（2）In, the dichloromethane
The weight ratio of the volume of alkane and the heparin quaternary ammonium salt is 2.5 ~ 3.5：1；The volume of the benzyl chloride and the heparin quaternary ammonium salt
Mass ratio be 1 ~ 2：1.
5. the preparation method of Enoxaparin according to claim 4, it is characterised in that described（2）In, stir esterification
Time is 30h, and temperature is 40 DEG C.
6. the preparation method of Enoxaparin according to claim 5, it is characterised in that anti-after the stirring esterification
The methanol containing 15% anhydrous sodium acetate that 1 ~ 2 times of reaction solution volume is additionally added in liquid is answered, collected by suction precipitation, precipitates again with methanol
Filtering cleaning to washing lotion, to meet water non-discolouring, will be deposited in dry the heparin benzyl ester at 50 DEG C.
7. the preparation method of Enoxaparin according to claim 1, it is characterised in that described（3）In, the alkaline bar
Part is 0.1N sodium hydrate aqueous solution, the mass ratio of the volume of the sodium hydrate aqueous solution and the heparin benzyl ester for 20 ~
30：1.
8. the preparation method of Enoxaparin according to claim 7, it is characterised in that described（3）In, the salt is chlorine
Change sodium, the mass volume ratio between the sodium chloride and the reaction solution is 10 ~ 20%；
And/or described（6）In, the salt is sodium chloride, the matter between the sodium chloride and the crude product Enoxaparin solution
It is 10 ~ 20% to measure volume ratio；
And/or described（6）In, the mass volume ratio between the activated carbon of addition and the crude product Enoxaparin solution
For 2 ~ 3%.
9. the preparation method of Enoxaparin according to claim 7, it is characterised in that described（3）In, the alkaline hydrolysis is anti-
The time answered is 60min, and temperature is 60 DEG C, and reaction is down to room temperature after terminating, during with 1mol hydrochloric acid, the reaction solution is adjusted to
Property.
10. the preparation method of Enoxaparin according to claim 1, it is characterised in that described（4）In, it is described hydrophobic
Organic solvent is dichloromethane or ethyl acetate.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109666086A (en) * | 2018-11-05 | 2019-04-23 | 上海宝维医药技术有限公司 | A kind of preparation method and applications of High-purity heparin quaternary ammonium salt |
| CN115043959A (en) * | 2022-05-25 | 2022-09-13 | 湖北亿诺瑞生物制药有限公司 | Preparation method of high-yield enoxaparin sodium |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850865A (en) * | 2006-05-24 | 2006-10-25 | 杭州九源基因工程有限公司 | Production method for purifying enoxaparin sodium |
-
2017
- 2017-08-03 CN CN201710655740.2A patent/CN107586350A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850865A (en) * | 2006-05-24 | 2006-10-25 | 杭州九源基因工程有限公司 | Production method for purifying enoxaparin sodium |
Non-Patent Citations (1)
| Title |
|---|
| 刘恩岐: "《粮油食品加工技术》", 30 September 2006 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109666086A (en) * | 2018-11-05 | 2019-04-23 | 上海宝维医药技术有限公司 | A kind of preparation method and applications of High-purity heparin quaternary ammonium salt |
| CN109666086B (en) * | 2018-11-05 | 2020-12-22 | 上海宝维医药技术有限公司 | Preparation method and application of high-purity heparin quaternary ammonium salt |
| CN115043959A (en) * | 2022-05-25 | 2022-09-13 | 湖北亿诺瑞生物制药有限公司 | Preparation method of high-yield enoxaparin sodium |
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Application publication date: 20180116 |