CN103864862B - A kind of purification process of pentose compound - Google Patents
A kind of purification process of pentose compound Download PDFInfo
- Publication number
- CN103864862B CN103864862B CN201210540217.2A CN201210540217A CN103864862B CN 103864862 B CN103864862 B CN 103864862B CN 201210540217 A CN201210540217 A CN 201210540217A CN 103864862 B CN103864862 B CN 103864862B
- Authority
- CN
- China
- Prior art keywords
- sodium
- fondaparinux sodium
- silica gel
- stationary phase
- crude product
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
Abstract
The present invention relates to a kind of method that utilization anion-exchange column purifies pentose compound, described method is, by pentose crude product loading to bonded silica gel stationary phase, to be eluted using the aqueous solution.Described method purification efficiency is high, easy to operate.
Description
Technical field
The present invention relates to a kind of purification process of pentose, a kind of purification process of Fondaparinux sodium is more particularly related to.
Background technology
Fondaparinux sodium（Fondaparinux Sodium）It is the sodium salt of the completely artificial synthesized glycan of sulfuric acid five, has
Such as following formula（I）Shown chemical constitution：
（I）.
Fondaparinux sodium is a kind of indirect inhibitor of the Xa factor of antithrombase dependence.In France, Britain, moral
The states such as state, China and the U.S. list, clinically for treating and preventing the generations of dvt Embolic events, with good
Antithrombotic effect.
Complicated due to Fondaparinux sodium, synthetic route is long, and plurality of impurities can be formed in course of reaction, influences product
Security.And the presence of impurity can influence the stability of Fondaparinux sodium in itself, the product quality during storage is caused
Decline.
In the prior art, generally require to purify by the method for multiple column chromatography, efficiency is low.Prolonged column chromatography is crossed,
The decline of Fondaparinux sodium stability itself is also resulted in, other degradation impurities are produced.
US4818816 disclose can be produced in the method by 50 step chemical reactive synthesis Fondaparinux sodiums, this method it is many
The hydrogenation process in oligosaccharide mixture, especially final step reaction is planted, polymer impurity effect Fondaparinux sodium can be produced
Purity.The method that Fondaparinux sodium is purified by sephadex Sephadex G-25 posts is also disclosed in the patent.According to
The purity for the Fondaparinux sodium that this method is prepared is less than 90%.
US2005020536 discloses the method for first passing through activated carbon purification Fondaparinux sodium, obtains more than 99% purity.And
The Fondaparinux sodium by the purity of column chromatography more than 90% twice is disclosed, the method more than more than 99.7% purity is obtained.The party
, it is necessary to which activated carbon is fixed on the plain dish of two-dimensional fiber with resin adjuvant in method, activated carbon filtering need to circulate 2 hours, then
Also need to by filtering with microporous membrane, practical operation method is complicated, not easy to operate.
Therefore, it is badly in need of a kind of simple to operate, the method for fast and effectively purifying Fondaparinux sodium.
The content of the invention
It is an object of the invention to provide a kind of such as following formula（I）The purification process of shown compound, it is characterised in that use
Crude product of the bonded silica gel stationary phase purifying sulphur up to the salt in the liver last of the ten Heavenly stems：
（I）；
It is characterized in that, described bonded silica gel stationary phase is that, using silica gel as matrix, Bonded Phase is to contain anion exchange base
The chemical constitution of group.Preferably comprise the chemical constitution of strong alkalinity anion cation exchange groups；Strong alkalinity anion cation exchange groups are for example
With C1-C10Quaternary ammonium group functional group, more preferably with C1-C4Quaternary ammonium group functional group.
It is furthermore preferred that described Bonded Phase is the mixed chemical structure with quaternary ammonium and phenyl functional group.
Most preferably, the structure of described bonded silica gel stationary phase is as follows：
Described sulphur includes up to the salt in the liver last of the ten Heavenly stems：Sodium salt, sylvite, ammonium salt, magnesium salts etc., particular certain cancers.
The particle diameter of described bonded silica gel stationary phase is 2-50 μm, and preferable particle size is 2-10 μm.50-4000 angstroms of aperture, hole
Preferred 100-500 angstroms, more preferably 100-200 angstroms of footpath.
Further, bonded silica gel stationary phase of the present invention can be obtained by way of commercially available purchase, for example may be used
From purchased from match branch skill（http://www.sepax-tech.com.cn）HP-SAX（Silica matrix）.
Further, purification process of the present invention includes：
（1）By sulphur up to the salt in the liver last of the ten Heavenly stems crude product loading to bonded silica gel stationary phase；
（2）Eluted with sodium-chloride water solution, separate impurity, obtain the Fondaparinux sodium of purifying；
Characterized in that, described bonded silica gel stationary phase is using silica gel as matrix, Bonded Phase is to contain anion exchange
The chemical constitution of group.
Above-mentioned steps（1）In, described sulphur includes sodium salt, sylvite, ammonium salt, magnesium salts etc., particular certain cancers up to liver last of the ten Heavenly stems salt；It is described
Crude product can be prepared according to method disclosed in US4818816.Described crude product refers to that under HPLC testing conditions sulphur reaches liver
The content of last of the ten Heavenly stems sodium is less than 90% mixture：Can be Fondaparinux sodium dissolving crude product in water or acquisition solution or appoint
The reaction solution for the Fondaparinux sodium what process is obtained, or the reaction solution are dissolved in the mixture of water acquisition.
The Bonded Phase of described bonded silica gel stationary phase preferably comprises the chemical constitution of strong alkalinity anion cation exchange groups；By force
Alkali anion cation exchange groups are for example with C1-C10Quaternary ammonium group functional group, more preferably with C1-C4Quaternary ammonium group functional group.
It is furthermore preferred that described Bonded Phase is the mixed chemical structure containing quaternary ammonium and phenyl functional group.
Most preferably, the structure of described bonded silica gel stationary phase is as follows：
The particle diameter of described bonded silica gel stationary phase is 2-50 μm, and preferable particle size is 2-10 μm.50-4000 angstroms of aperture, hole
Preferred 100-500 angstroms, more preferably 100-200 angstroms of footpath.
The weight of described Fondaparinux sodium crude product loading and the weight ratio of stationary phase（w/w）For 0.001-10%, preferably
0.1-1%, more preferably 0.03-0.2%.
Described anion-exchange column length is 50-1000mm；Column internal diameter 2-500mm, described column length and post
Internal diameter ratio is 1:1-40:1, preferably 1:1-10:1.Column length is generally related to applied sample amount, when purifying on a small quantity, can select short
Small pillar；And during large-scale purification, the wide internal diameter of selection and long pillar.The ratio of column length and column internal diameter is 1:1-40:, can when 1
Effectively avoid waller effect；Especially when the ratio of column length and column internal diameter is 1:1-10:When in the range of 1, purifies and separates
Efficiency is higher, it is thus also avoided that the waste of filler.
Described loading, refers to Fondaparinux sodium being dissolved in water or 0-0.2M sodium-chloride water solution and carries out loading, its
The concentration of middle Fondaparinux sodium is 1-200mg/ml, more preferably preferably 5-100mg/ml, 20-50mg/ml.Applicant studied
Found in journey, the concentration of loading sample influences the resolution ratio of purge process, when in the range of sample concentration 5-100mg/ml, especially
When being 20-50mg/ml, the resolution ratio of separation is optimal.
Above-mentioned steps（2）In, the concentration of the aqueous solution of described sodium chloride is 0.1-2.0M, preferably 0.2-1.0M.
Described elution process, can use the eluent of various concentrations to carry out gradient elution, or use fixed concentration
Elution.It is preferred to use 0.2M-1.0M sodium-chloride water solution gradient elutions.
Described eluent flow rate is 1ml/min-1L/min, and the flow velocity of eluent is different with internal diameter according to the length of pillar
And change, it is that ordinary skill in the art means can be realized.
Further, after purifying terminates, in addition to the process of sterling desalination.Described desalination processes are that this area is normal
The technological means of rule.
The present invention is simple to operate, and operating process is short, mild condition, and the yield and purity of purifying are high, alleviate technological operation
Difficulty, reduce production cost.
Applicant is found surprisingly that, when using using silica gel as matrix, Bonded Phase is to be handed over containing anion in research process
During the bonded silica gel stationary phase for the chemical constitution for changing group, due to strong anion exchange mutually and hydrophobic phase mixed mode, make from
Subtype impurity and other kinds of impurity are obtained for preferable separation, and the purification efficiency of Fondaparinux sodium is very high,.Especially
When as follows using the structure of bonded silica gel stationary phase：
When, even when crude product purity be less than 70%, or even crude product purity below 50% when, only by once cross post purify,
Purity is very high with regard to the rate of recovery that can reach Fondaparinux sodium in more than 99.5%, and purge process.High degree is shortened
The purification process time of Fondaparinux sodium and step, are particularly conducive to stablize the purpose that final products reach quality control.Simultaneously
The problem of caused product yield of repeatedly purifying declines is reduced, the sterling yield of Fondaparinux sodium is effectively increased.
Applicant using operations technical parameter during bonded silica gel stationary phase purifying Fondaparinux sodium further to being entered
Research is gone, under the purification condition of the present invention, under conditions of it can ensure product purity, the reduction of high degree is purified into
This.
Embodiment
The present invention, but the protection domain being not intended to limit the invention will be expanded on further by specific embodiment below.
In following embodiments, unless otherwise indicated, described test method actual conditions is generally built according to normal condition or manufacturer
The condition of view is implemented；Described raw material, reagent pass through commercially available purchase and obtained；Described percentage, ratio, ratio or number etc.
Calculated according to weight.Described chromatographic column, is that the chromatographic column or purchase filler for the corresponding filler directly bought voluntarily are filled out
Dress.
Embodiment 1
By HP-SAX（Silica matrix）（5 μm of particle diameter, 120 angstroms of aperture, pore volume 1ml/g, specific surface area 300m2/ g, silica gel
Matrix is spherical, high-purity, carbon carrying capacity 16.0%, purchased from match branch skill）It is fitted into preparation chromatographic column（50×250mm）.By 1g sulphurs
Up to liver last of the ten Heavenly stems sodium（Purity about 50%）It is dissolved in 20ml water, loading.With 0.2-1.0M NaCl aqueous solution gradient elutions, flow velocity is
100ml/min.Fondaparinux sodium is collected, is merged, desalination and concentration, the Fondaparinux sodium 0.46g that purity is 99.8% is obtained.
Embodiment 2
By HP-SAX（10 μm of particle diameter, 120 angstroms of aperture, pore volume 1ml/g, specific surface area 300m2/ g, silica matrix is ball
Shape, high-purity, carbon carrying capacity 16.0%, purchased from match branch skill）It is fitted into preparation chromatographic column（50×250mm）.By 2g Fondaparinux sodiums
（Purity about 50%）It is dissolved in 20ml water, loading.With 0.2-1.0M NaCl aqueous solution gradient elutions, flow velocity is 100ml/
min.Fondaparinux sodium is collected, is merged, desalination and concentration, the Fondaparinux sodium 0.93g that purity is 99.6% is obtained.
Embodiment 3
By HP-SAX（5 μm of particle diameter, 120 angstroms of aperture, pore volume 1ml/g, specific surface area 300m2/ g, silica matrix is ball
Shape, high-purity, carbon carrying capacity 16.0%, purchased from match branch skill）It is fitted into preparation chromatographic column（100×500mm）.10g sulphurs are reached into the liver last of the ten Heavenly stems
Sodium（Purity about 50%）It is dissolved in 200ml water, loading.With 0.2-1.0M NaCl aqueous solution gradient elutions, flow velocity is 500ml/
min.Fondaparinux sodium is collected, is merged, desalination and concentration, the Fondaparinux sodium 4.47g that purity is 99.8% is obtained.
Embodiment 4
（1）According to the method for embodiment 3, sulphur is reached into liver last of the ten Heavenly stems potassium crude product 10g（Purity 50%）Loading is purified, final to obtain
99.7% Fondaparinux sodium 4.31g.
（2）According to the method for embodiment 3, sulphur is reached into liver last of the ten Heavenly stems ammonium salt crude product 10g（Purity 50%）Loading is purified, final to obtain
99.6% Fondaparinux sodium 4.25g.
（3）According to the method for embodiment 3, sulphur is reached into liver last of the ten Heavenly stems potassium crude product 10g（Purity 50%）Loading is purified, final to obtain
99.5% Fondaparinux sodium 4.10g.
（4）According to the method for embodiment 3, by Fondaparinux sodium crude product 10g（Purity is less than 50%）, loading purifying, finally obtain
99.6% Fondaparinux sodium 3.9g.
Claims (4)
1. a kind of purification process of Fondaparinux sodium, including：
(1) by the crude product loading of Fondaparinux sodium to bonded silica gel stationary phase；
(2) eluted with sodium-chloride water solution, separate impurity, obtain the Fondaparinux sodium of purifying；
Characterized in that, the Bonded Phase of described bonded silica gel stationary phase is the mixed chemical knot containing quaternary ammonium and phenyl functional group
Structure, structure is as follows：
Wherein, the crude product of step (1) described Fondaparinux sodium is that the purity of Fondaparinux sodium is 50%~90%.
2. according to the method described in claim 1, it is characterised in that the particle diameter of the bonded silica gel stationary phase described in step (1)
For 2-50 μm；50-4000 angstroms of aperture.
3. according to the method described in claim 1, it is characterised in that Fondaparinux sodium crude product loading described in step (1)
The weight ratio (w/w) of weight and stationary phase is 0.001-10%.
4. according to the method described in claim 1, it is characterised in that the concentration of the sodium-chloride water solution described in step (2) is
0.1-2.0M。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210540217.2A CN103864862B (en) | 2012-12-14 | 2012-12-14 | A kind of purification process of pentose compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210540217.2A CN103864862B (en) | 2012-12-14 | 2012-12-14 | A kind of purification process of pentose compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103864862A CN103864862A (en) | 2014-06-18 |
| CN103864862B true CN103864862B (en) | 2017-10-17 |
Family
ID=50903923
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210540217.2A Active CN103864862B (en) | 2012-12-14 | 2012-12-14 | A kind of purification process of pentose compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103864862B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109553702A (en) * | 2018-12-29 | 2019-04-02 | 博瑞生物医药（苏州）股份有限公司 | A kind of purification process for the more glucose sodium that relaxes |
| CN113461744B (en) * | 2020-03-30 | 2024-03-15 | 鲁南制药集团股份有限公司 | Purification method of fondaparinux sodium intermediate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102659859A (en) * | 2012-04-11 | 2012-09-12 | 苏州纳微生物科技有限公司 | Application of monodispersed polymethacrylate ion exchange chromatography medium in column chromatography purification of fondaparinux sodium |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2322464T3 (en) * | 2003-02-27 | 2009-06-22 | Glaxo Group Limited | COMPOSITION OF FONDAPARINUX SODICO DE ALTA PURITY. |
| CN104245718B (en) * | 2009-07-31 | 2016-11-09 | 可靠生物医药公司 | Prepare fondaparinux sodium method and synthesis in use intermediate |
| US8420790B2 (en) * | 2009-10-30 | 2013-04-16 | Reliable Biopharmaceutical Corporation | Efficient and scalable process for the manufacture of Fondaparinux sodium |
-
2012
- 2012-12-14 CN CN201210540217.2A patent/CN103864862B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102659859A (en) * | 2012-04-11 | 2012-09-12 | 苏州纳微生物科技有限公司 | Application of monodispersed polymethacrylate ion exchange chromatography medium in column chromatography purification of fondaparinux sodium |
Non-Patent Citations (2)
| Title |
|---|
| "SYNTHESIS OF HEPARIN FRAGMENTS: A METHYL CY-PENTAOSIDE WITH HIGH AFFINITY FOR ANTITHROMBIN III*";MAURICE PETITOU，et al.;《Carbohydrate Research》;19871231;第167卷;67-75 * |
| "赛分HP-SAX柱使用手册Sepax Technologies，Inc";铁达尼号;《http://www.docin.com/p-53558185.html》;20100508;1-2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103864862A (en) | 2014-06-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6438966B2 (en) | Separation and purification method for high purity vancomycin hydrochloride | |
| JP2749272B2 (en) | Purification method of anthracycline glycoside | |
| CN104892710B (en) | A kind of method for purifying reduced form β NADHs | |
| US10857483B2 (en) | Adsorbent for chromatographic separation of proteins | |
| US7897794B2 (en) | Method for purifying hydroxymethylfurfural using non-functional polymeric resins | |
| CN105131079B (en) | A kind of purification process of desmopressin acetate | |
| Kou et al. | An integrated strategy for production of four anthocyanin compounds from Ribes nigrum L. by deep eutectic solvents and flash chromatography | |
| CN108101959B (en) | Method for preparing high-purity polypeptide or analogue thereof | |
| CN103864862B (en) | A kind of purification process of pentose compound | |
| CN103570774B (en) | A kind of purification process of pentose compound | |
| CN109553702A (en) | A kind of purification process for the more glucose sodium that relaxes | |
| CN102977173A (en) | Purifying process of high-purity vitamin B12 | |
| CN101085797B (en) | Cryogel adsorption chromatography separation method for adenosine triphosphate | |
| CN102070647B (en) | Method for separating ginkgolide B from ginkgolide mixture | |
| CN108250273A (en) | Knob not Kangding high efficiency separation and purification method | |
| WO2004069371A1 (en) | Method of reducing impurity content in aqueous salt solution | |
| CN102690333B (en) | Preparation method of high-purity teicoplanin | |
| CN103910783B (en) | A kind of preparation method of high-purity echinocandin B parent nucleus | |
| Pei et al. | The selective complexation of crown ethers for lithium isotope separation: A critical review | |
| CN105555385B (en) | The preparation HPLC purified organic compound being mediated by surfactant | |
| CN102516340A (en) | Method for separating and purifying hydroxycobalamin by using D150 macroporous resin | |
| JP4143707B2 (en) | Method for producing high purity sodium chloride crystals | |
| JPH0267284A (en) | Method for recovering and purifying pyrroloquinolinequinones | |
| CN109400606B (en) | Method for refining apixaban from apixaban crude product | |
| CN114405065B (en) | Method for preparing chiral polypeptide medicine by dynamic thermodynamic equilibrium purification |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: Suzhou City, Jiangsu Province, Suzhou Industrial Park 215123 Xinghu Street No. 218 Nano Technology Park building C25 Applicant after: Borui Pharmaceutical (Suzhou) Limited by Share Ltd Address before: Xinghu Street Industrial Park of Suzhou city in Jiangsu province 215123 No. 218 BioBAY building C27 Applicant before: Borui Bio-medical Technology (Jiangsu) Co., Ltd. |
|
| COR | Change of bibliographic data | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |