CN106518976A - Preparation method of oxytocin [4-Glu, 5-Asp] - Google Patents
Preparation method of oxytocin [4-Glu, 5-Asp] Download PDFInfo
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- CN106518976A CN106518976A CN201710002007.0A CN201710002007A CN106518976A CN 106518976 A CN106518976 A CN 106518976A CN 201710002007 A CN201710002007 A CN 201710002007A CN 106518976 A CN106518976 A CN 106518976A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/16—Oxytocins; Vasopressins; Related peptides
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Abstract
The invention discloses a preparation method of oxytocin [4-Glu, 5-Asp]. The preparation method includes following steps: adopting high-performance liquid reversed phase chromatography to sequentially perform reversed phase cyclizing, reversed phase purifying and reversed phase desalting on an oxytocin [4-Glu, 5-Asp] precursor crude product solution, wherein a filler of the high-performance liquid reversed phase chromatography is silica gel C18, and an oxytocin [4-Glu, 5-Asp] precursor crude product contains two free sulfhydryl groups. A reversed phase adsorption method is creatively applied for cyclizing, purifying and desalting, so that the problems of cyclizing, purifying and desalting are solved once for all, production process is optimized, and the preparation method is suitable for industrial continuous production.
Description
Technical field
The present invention relates to field of biological pharmacy.More particularly it relates to the system of a kind of oxytocin [4-Glu, 5-Asp]
Preparation Method.
Background technology
Oxytocin, also known as oxytocin, English entitled Oxytocin, structural formula：
Molecular formula is：C43H66N12O12S2, molecular weight is 1007.2
Oxytocin be used for induced labor, hasten parturition, puerperal and post-abortion are because of uterine atony or contracting abdomen is bad and the metrorrhagia that causes；
Understand Placenta Hominiss reserve function (oxytocin enrages test)；Collunarium can promote milk ejection.Oxytocin energy indirect stimulation uterine smooth muscle is received
Contracting, simulates the effect of eutocous uterine contraction, causes cervical dilatation, uterus to the reaction of oxytocin in During Pregnancy by
It is cumulative to add, peak is reached when mature.Mammotropic smooth muscle contraction can be also pierced in oxytocin, contributed to milk and discharged from breast, but and
The galactopoiesiss amount of mammary gland is not increased.
For a medicine, a small amount of impurity contained therein is to cause the most important reason of medicine side effect, therefore right
The inspection of its purity is to ensure one of important foundation of drug safety effectiveness, and the content of purity test, according to each medicine
Property and feature it is somewhat different, but be substantially intended to be related to respective " relevant material " and check research.Synthesis polypeptide it is relevant
Material is essentially from process contaminants in building-up process and unstable due to polypeptide and the catabolite that produces, polymer etc. are miscellaneous
Matter, although the purifying process of synthesis polypeptide has had great progress at present, process contaminants are still the relevant material of synthesis polypeptide
Important sources, this mainly due to synthesis polypeptide some process contaminants (such as disappearance peptide, fracture peptide, oxidation peptide, disulfide bond hand over
Product for changing etc.) may be very approximate with the property of medicine itself, so as to cause certain difficulty to purification.Research shows to close
Into in polypeptide, modal catabolite is deamidation product, oxidation product, hydrolyzate.In the various aminoacid of composition polypeptide
In, agedoite, glutamine and peptide chain C section amide are easy to deamidation reaction (especially in pH value rising and high temperature bar
Under part).
As in synthesis polypeptide, the property of some impurity with target product closely, hence sets up suitable method abundant
It is the great difficulty faced during the relevant material of synthetic polypeptide medicaments is studied to detect these impurity.
Country's oxytocin [4-Glu, 5-Asp] protected oxytocin resin using solid phase synthesis mostly before this at present, then passed through
Dry oxytocin [4-Glu, the 5-Asp] precursor crude product (Cys-Tyr-Ile-Glu-Asp-Cys-Pro-Leu-Gly-NH of cracking2
Trifluoroacetate), high dilution cyclisation, purification turns the steps such as salt, finally gives oxytocin [4-Glu, 5-Asp].It is highly dilute
Cyclisation is released as sample concentration is dilute, it is bulky, it is very unfavorable for later-period purification.Also lack now a kind of effectively to prepare containing two
The method of the polypeptide crude drug analog of sulfide linkage, therefore still in the urgent need to developing the new preparation method containing disulfide bond polypeptide.
The content of the invention
The technical problem to be solved is for the system for overcoming oxytocin in prior art [4-Glu, 5-Asp]
For complex process, yield is low, sample concentration is dilute, bulky defect, and provides a kind of oxytocin [4-Glu, 5-Asp]
Preparation method.The preparation method of the oxytocin [4-Glu, 5-Asp] of the present invention is thick with the polypeptide containing a pair of free sulfhydryl groups (- SH)
Product oxytocin [4-Glu, 5-Asp] precursor crude product is initiation material, through the cyclisation of high-pressure liquid phase reversed phase chromatography, purification and de-
Salt step, the method for preparing highly purified oxytocin [4-Glu, 5-Asp].During the polypeptide of the present invention is oxytocin preparation process
1 critical impurities, therefore oxytocin and impurity can be carried out qualitative and fixed as the standard reference material of oxytocin detection process
Amount analysis, for the quality standard for improving oxytocin, control product quality is significant.
The present invention is to solve above-mentioned technical problem by the following technical programs：
The invention provides the preparation method of a kind of oxytocin [4-Glu, 5-Asp], which comprises the steps：Using efficient
Oxytocin [4-Glu, 5-Asp] precursor crude product solution is carried out anti-phase cyclisation, anti-phase purification, anti-phase by liquid phase reverse-phase chromatography successively
Desalination, you can；The filler of efficient liquid phase reverse-phase chromatography is silica gel C18；
Described oxytocin [4-Glu, 5-Asp] precursor crude product is the oxytocin containing two free sulfhydryl groups [4-Glu, 5-Asp]
Precursor crude product；
Described oxytocin [4-Glu, 5-Asp] is
Wherein, described oxytocin [4-Glu, 5-Asp] precursor crude product preferably passes through cracking using solid-phase synthesis
Oxytocin [4-Glu, 5-Asp] precursor crude product obtained in being dried, HPLC purity are 60～90%；Described oxytocin [4-Glu,
5-Asp] precursor crude product structural formula be Cys-Tyr-Ile-Glu-Asp-Cys-Pro-Leu-Gly-NH2Trifluoroacetate.
Wherein, described oxytocin [4-Glu, 5-Asp] precursor crude product solution is preferably oxytocin [4-Glu, 5-Asp]
Precursor crude product is dissolved in the 5g/L solution that the acetonitrile solution that concentration of volume percent is 5% is formed.
In the present invention, described anti-phase cyclisation, anti-phase purification, anti-phase desalination are complete in the anti-phase elution process of a step
Into.
Wherein, described anti-phase cyclisation, anti-phase purification, the condition of anti-phase desalination are preferably as follows：Mobile phase A 1 be pure water, A2
For the H of percent by volume 0.01～0.05% (preferably 0.02～0.03%)2O2PH is 7.5～9.0 NaOH aqueous solutions,
Mobile phase B is acetonitrile, and mobile phase C is described oxytocin [4-Glu, 5-Asp] precursor crude product solution, and flow velocity is 80～110mL/
Min (preferably 100mL/min), Detection wavelength is 220nm；
Condition according to following table carries out online loading, eluting, and percentage ratio is percent by volume；
| Elution step | Elution time | Eluent |
| 1 | 0～10min | 100%C |
| 2 | 10～25min | 95%A1+5%B |
| 3 | 25.1～30min | 95%A2+5%B |
| 4 | 30.1～35 | 95%A1+5%B |
| 5 | 35～50min | 95%A1+5%B → 80%A1+20%B |
| 6 | 50～65min | 80%A1+20%B → 73%A1+27%B |
| 7 | 65～75min | 50%A1+50%B |
| 8 | 75～80min | 95%A1+5%B |
Collect the eluent that retention time is 50～65min and obtain oxytocin [4-Glu, 5-Asp] solution.
Wherein, the filling condition of described efficient liquid phase reverse-phase chromatography is preferably as follows：Filler is Kromasil silica gel
C18, aperture 10nm, 10 μm of particle diameter.
Oxytocin [4-Glu, 5-Asp] is a kind of peptide material, unstable in the basic conditions, degradable, especially by force
Under alkali environment, the de- concentration of integrated survey of the present invention alkali cleaning and time, with ensure to reduce in desalination processes the destruction of sample and
Loss.
Innovative point of the present invention is will cyclisation, purification and one step of desalination is anti-phase obtains polypeptide sterling, oxytocin [4-Glu, 5-
Asp] contain two free sulfhydryl groups in precursor crude product, traditional handicraft cyclisation and purification substep are carried out, and be cyclized it is bulky, increase
Add the difficulty of purification, for cyclisation rapidly and efficiently and preparation technology, design the more recent application of silica gel C18 fillers.This
Bright novelty has used the cyclisation of reverse phase absorption method, purification and desalination, disposably solves the problems, such as cyclisation, purification and desalination.
On the basis of common sense in the field is met, above-mentioned each optimum condition, can combination in any, obtain final product each preferable reality of the present invention
Example.
Agents useful for same of the present invention and raw material are commercially available.
The present invention positive effect be：
(1) present invention is first adsorbed onto reduced form polypeptide crude product in fixing phase, using polypeptide using the method for online cyclisation
With the hydrophobic binding of reverse phase filler, the acid ion of neutral eluting weak binding on a column, and using pH meta-alkalis containing H2O2's
Mobile phase is rinsed, and promotes two sulfydryls into disulfide bond, obtains target polypeptides crude product, and sample retains on a column.
(2) using online cyclisation, the sample of cyclisation avoids eluting, can carry out gradient and wash after directly converting mobile phase the present invention
De- purification, obtains final sterling, is adapted to continuous production.
(3) present invention has innovatively used reverse phase absorption cyclisation, purification, desalination one-step method that polypeptide sterling, optimization is obtained
Production technology, suitable industrialization are continuously produced.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Among applying a scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product description is selected.
In following embodiments, oxytocin [4-Glu, 5-Asp] is
(HPLC methods detect oxytocin [4-Glu, 5-Asp] precursor crude product and purification midbody solution purity and determine embodiment 1
Amount)
Instrument：1200 high performance liquid chromatographs of Agilent
Detached dowel：Waters XBridge-C18,4.6 × 150 mm, 5 μm
Mobile phase：A is 50% acetonitrile solution of percent by volume, and B is 0.02M KH2PO43.0 aqueous solutions of pH, flow velocity is
1.0 mL/min, Detection wavelength is 220nm, room temperature detection, and shown in gradient see the table below, percentage ratio is percent by volume.
| Elution step | Elution time | Eluent |
| 1 | 0～15min | 35%A+65%B |
| 2 | 15～25min | 35%A+65%B → 100%A |
| 3 | 25～28min | 100%A |
| 4 | 28.0～28.1min | 100%A → 35%A+65%B |
| 5 | 28.1～32min | 35%A+65%B |
Embodiment 2 (50mm internal diameter L＆L4002 prepare post filling)
With Load＆Lock dynamic axial compressions and static locking technology, filler is silica gel C18 (Kromasil C18),
Aperture 10nm, 10 μm of particle diameter fill 0.66 g/mL of column density, are filled to post bed pressure 133bar, using the filling of Varian chromatographs are
System, 325g dry powder fillers, after the stirring homogenate of 650mL isopropanols, are poured internal diameter 50mm L＆L4002 into and prepare post, and compression ratio is 1.5:
1, carrier gas is N2, adjust nebulizer gas pressure oil pressure meter pressure is caused for 200bar, dynamic axial compression to post bed height 25.5cm, work
Post is prepared used by anti-phase cyclisation, anti-phase purification and anti-phase desalination scheme.
The anti-phase cyclisation of embodiment 3 oxytocin [4-Glu, 5-Asp] precursor crude material, anti-phase purification and anti-phase desalination
Instrument：Varian SD-1 high-pressure liquid phase preparation systems
Chromatographic column：2 self-chambering of embodiment prepares 50 × 255 mm of post Load＆Lock4002,10 μm of 10nm of C18
Oxytocin [4-Glu, 5-Asp] precursor crude product is to be dried obtained oxytocin using solid-phase synthesis through cracking
[4-Glu, 5-Asp] precursor crude product, structural formula is Cys-Tyr-Ile-Glu-Asp-Cys-Pro-Leu-Gly-NH2Trifluoro second
Hydrochlorate.
Oxytocin [4-Glu, 5-Asp] precursor crude product solution is dissolved in for above-mentioned oxytocin [4-Glu, 5-Asp] precursor crude product
Concentration of volume percent is the 5g/L solution that 5% acetonitrile solution is formed.
Mobile phase A 1 is purified water, and A2 is the H of percent by volume 0.022O2PH is 7.5 NaOH aqueous solutions, Mobile phase B
For acetonitrile, mobile phase C is described oxytocin [4-Glu, 5-Asp] precursor crude product solution, determines which as described in Example 1
HPLC purity is 79.25%, and retention time is 9.33min.
The anti-phase cyclisation of the present embodiment, anti-phase purification and anti-phase desalination condition are as follows：Flow velocity 100mL/min, 220nm are examined
Survey, shown in purification gradient see the table below, percentage ratio is percent by volume.
| Elution step | Elution time | Eluent |
| 1 | 0～10min | 100%C |
| 2 | 10～25min | 95%A1+5%B |
| 3 | 25.1～30min | 95%A2+5%B |
| 4 | 30.1～35 | 95%A1+5%B |
| 5 | 35～50min | 95%A1+5%B → 80%A1+20%B |
| 6 | 50～65min | 80%A1+20%B → 73%A1+27%B |
| 7 | 65～75min | 50%A1+50%B |
| 8 | 75～80min | 95%A1+5%B |
Collect the eluent that retention time is 50～65min and obtain oxytocin [4-Glu, 5-Asp] solution, by embodiment 1
Method determine its HPLC purity for 99.63%, retention time is 6.46min.
The anti-phase cyclisation of embodiment 4 oxytocin [4-Glu, 5-Asp] precursor crude material, anti-phase purification and anti-phase desalination
Instrument：Varian SD-1 high-pressure liquid phase preparation systems
Chromatographic column：2 self-chambering of embodiment prepares post 50 × 255mm of Load＆Lock4002,10 μm of 10nm of C18
Oxytocin [4-Glu, 5-Asp] precursor crude product is to be dried obtained oxytocin using solid-phase synthesis through cracking
[4-Glu, 5-Asp] precursor crude product, structural formula is Cys-Tyr-Ile-Glu-Asp-Cys-Pro-Leu-Gly-NH2Trifluoro second
Hydrochlorate.
Oxytocin [4-Glu, 5-Asp] precursor crude product solution is dissolved in for above-mentioned oxytocin [4-Glu, 5-Asp] precursor crude product
Concentration of volume percent is the 5g/L solution that 5% acetonitrile solution is formed.
Mobile phase A 1 is purified water, and A2 is the H of percent by volume 0.032O2PH is 9.0 NaOH aqueous solutions, Mobile phase B
For acetonitrile, mobile phase C is described oxytocin [4-Glu, 5-Asp] precursor crude product solution, determines which as described in Example 1
HPLC purity is 79.25%, and retention time is 9.33min.
The anti-phase cyclisation of the present embodiment, anti-phase purification and anti-phase desalination condition are as follows：Flow velocity 100mL/min, 220nm are examined
Survey, shown in purification gradient see the table below, percentage ratio is percent by volume.
| Elution step | Elution time | Eluent |
| 1 | 0～10min | 100%C |
| 2 | 10～25min | 95%A1+5%B |
| 3 | 25.1～30min | 95%A2+5%B |
| 4 | 30.1～35 | 95%A1+5%B |
| 5 | 35～50min | 95%A1+5%B → 80%A1+20%B |
| 6 | 50～65min | 80%A1+20%B → 73%A1+27%B |
| 7 | 65～75min | 50%A1+50%B |
| 8 | 75～80min | 95%A1+5%B |
Collect the eluent that retention time is 50～65min and obtain oxytocin [4-Glu, 5-Asp] solution, by embodiment 1
Method determine its HPLC purity for 99.50%, retention time is 6.45min.
Embodiment 5 (Mass Spectrometer Method of oxytocin [4-Glu, 5-Asp])
Embodiment 3,4 is determined using waters micromass ZQ substances level Four bar Electrospray Mass Spectrometry (ESI-MS) to obtain
Oxytocin [4-Glu, 5-Asp] molecular mass peak [M+1]+Measured value 1010.31, leading ion fragment peak [M+2]2+Determine
Value 505.68, all meets theoretical value 1009.2.
Claims (9)
1. a kind of preparation method of oxytocin [4-Glu, 5-Asp], which comprises the steps：Using efficient liquid phase reverse-phase chromatography
Oxytocin [4-Glu, 5-Asp] precursor crude product solution is carried out into anti-phase cyclisation, anti-phase purification, anti-phase desalination successively, you can；Efficiently
The filler of liquid phase reverse-phase chromatography is silica gel C18；
Described oxytocin [4-Glu, 5-Asp] precursor crude product is the oxytocin containing two free sulfhydryl groups [4-Glu, 5-Asp] precursor
Crude product；
Described oxytocin [4-Glu, 5-Asp] is
2. preparation method as claimed in claim 1, it is characterised in that described oxytocin [4-Glu, 5-Asp] precursor crude product
Be using solid-phase synthesis through cracking be dried obtained in oxytocin [4-Glu, 5-Asp] precursor crude product, HPLC purity be 60～
90%.
3. preparation method as claimed in claim 1, it is characterised in that described oxytocin [4-Glu, 5-Asp] precursor crude product
Structural formula be Cys-Tyr-Ile-Glu-Asp-Cys-Pro-Leu-Gly-NH2Trifluoroacetate.
4. preparation method as claimed in claim 1, it is characterised in that described oxytocin [4-Glu, 5-Asp] precursor crude product
Solution is the 5g/ that oxytocin [4-Glu, 5-Asp] precursor crude product is dissolved in that the acetonitrile solution that concentration of volume percent is 5% is formed
L solution.
5. preparation method as claimed in claim 1, it is characterised in that described anti-phase cyclisation, anti-phase purification, anti-phase desalination are equal
It is to complete in the anti-phase elution process of a step.
6. preparation method as claimed in claim 1, it is characterised in that described anti-phase cyclisation, anti-phase purification, anti-phase desalination
Condition is as follows：Mobile phase A 1 is pure water, and A2 is the H of percent by volume 0.01～0.05%2O2PH be 7.5～9.0 NaOH it is water-soluble
Liquid, Mobile phase B is acetonitrile, and mobile phase C is described oxytocin [4-Glu, 5-Asp] precursor crude product solution, flow velocity is 80～
110mL/min, Detection wavelength are 220nm；
Condition according to following table carries out online loading, eluting, and percentage ratio is percent by volume；
Collect the eluent that retention time is 50～65min and obtain oxytocin [4-Glu, 5-Asp] solution.
7. preparation method as claimed in claim 6, it is characterised in that described A2 is percent by volume 0.02～0.03%
H2O2PH is 7.5～9.0 NaOH aqueous solutions.
8. preparation method as claimed in claim 6, it is characterised in that described flow velocity is 100mL/min.
9. preparation method as claimed in claim 1, it is characterised in that the filling condition of described efficient liquid phase reverse-phase chromatography
It is as follows：Filler be Kromasil silica gel C18, aperture 10nm, 10 μm of particle diameter.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110016072A (en) * | 2019-05-07 | 2019-07-16 | 上海上药第一生化药业有限公司 | A kind of refining methd of oxytocin |
| CN110078796A (en) * | 2019-05-07 | 2019-08-02 | 上海上药第一生化药业有限公司 | A kind of refining methd of oxytocin [4-Glu, 5-Asp] impurity |
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| CN103374054A (en) * | 2012-04-28 | 2013-10-30 | 上海第一生化药业有限公司 | One-step method based solid-phase polypeptide synthesis method |
| CN103980351A (en) * | 2014-05-27 | 2014-08-13 | 上海第一生化药业有限公司 | Method for preparing vasopressin and vasopressin tannate |
| CN104672308A (en) * | 2014-12-23 | 2015-06-03 | 青岛康原药业有限公司 | Method for preparing vasopressin tannate |
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| CN103374054A (en) * | 2012-04-28 | 2013-10-30 | 上海第一生化药业有限公司 | One-step method based solid-phase polypeptide synthesis method |
| CN102850441A (en) * | 2012-07-23 | 2013-01-02 | 无锡市凯利药业有限公司 | Solid-phase synthetic method of oxytocin |
| CN103980351A (en) * | 2014-05-27 | 2014-08-13 | 上海第一生化药业有限公司 | Method for preparing vasopressin and vasopressin tannate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110016072A (en) * | 2019-05-07 | 2019-07-16 | 上海上药第一生化药业有限公司 | A kind of refining methd of oxytocin |
| CN110078796A (en) * | 2019-05-07 | 2019-08-02 | 上海上药第一生化药业有限公司 | A kind of refining methd of oxytocin [4-Glu, 5-Asp] impurity |
| CN110078796B (en) * | 2019-05-07 | 2021-04-13 | 上海上药第一生化药业有限公司 | Method for refining oxytocin [4-Glu,5-Asp ] impurity |
| CN110016072B (en) * | 2019-05-07 | 2022-03-15 | 上海上药第一生化药业有限公司 | Method for refining oxytocin |
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