CN106478780A - A kind of preparation method of oxytocin [4 Glu] - Google Patents
A kind of preparation method of oxytocin [4 Glu] Download PDFInfo
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- CN106478780A CN106478780A CN201710002006.6A CN201710002006A CN106478780A CN 106478780 A CN106478780 A CN 106478780A CN 201710002006 A CN201710002006 A CN 201710002006A CN 106478780 A CN106478780 A CN 106478780A
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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 the preparation method of a kind of oxytocin [4 Glu].The preparation method comprises the steps：Oxytocin [4 Glu] precursor crude product solution is carried out successively by anti-phase cyclisation, anti-phase purifying, anti-phase desalination using efficient liquid phase RP chromatography, you can；The filler of efficient liquid phase RP chromatography is silica gel C18；Described oxytocin [4 Glu] precursor crude product is oxytocin [4 Glu] the precursor crude product containing two free sulfhydryl groups.Novelty of the present invention has used the cyclisation of reverse phase absorption method, purifying and desalination, disposably solves the problems, such as to be cyclized, purifies and desalination, optimizes production technology, is suitable for the continuous production of industrialization.
Description
Technical field
The present invention relates to field of biological pharmacy.More particularly it relates to the preparation side of a kind of oxytocin [4-Glu]
Method.
Background technology
Oxytocin, also known as oxytocins, English entitled Oxytocin, structural formula：
Molecular formula is：C43H66N12O12S2, molecular weight is 1007.2
Oxytocin be used for induced labor, hasten parturition, postpartum and post-abortion are because of uterine atony or contracting abdomen is bad and the uterine hemorrhage that causes；
Understand placenta reserve function (oxytocins enrages test)；Collunarium can promote milk ejection.Oxytocin energy indirect stimulation uterine smooth muscle is received
Contracting, simulates the effect of eutocous uterine contractile, causes cervical dilatation, uterus to the reaction of oxytocin in During Pregnancy by
Cumulative plus, reach peak when mature.Oxytocin also can pierce mammotropic smooth muscle contraction, contribute to milk and discharge from breast, but simultaneously
The galactosis 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 validity, and the content of purity test, according to each medicine
Property and feature somewhat different, but be substantially intended to be related to respective " relevant material " and check research.Synthesis polypeptide relevant
Material is unstable essentially from the process contaminants in building-up process and due to polypeptide and the catabolite of generation, polymer etc. are miscellaneous
Matter, although the purifying process of synthesis polypeptide has had great progress at present, but 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 purifying.Research shows to close
It is deamidation product, oxidation product, hydrolysate to become modal catabolite in polypeptide.Various amino acid in composition polypeptide
In, asparagine, glutamine and peptide chain C section acid amides are easy to occur deamidation reaction (especially to raise and high temperature bar in pH value
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 in the relevant material research of synthetic polypeptide medicaments to detect these impurity.
Country's oxytocin [4-Glu] protected oxytocin resin using synthesis in solid state mostly before this at present, then dry through cracking
Dry oxytocin [4-Glu] precursor crude product (Cys-Tyr-Ile-Glu-Asn-Cys-Pro-Leu-Gly-NH2Trifluoroacetic acid
Salt), high dilution is cyclized, purifying, turns the steps such as salt, finally gives oxytocin [4-Glu].High dilution cyclisation is dense due to sample
Degree is dilute, bulky, very unfavorable for later-period purification.A kind of effective polypeptide bulk drug that prepare containing disulfide bond is also lacked now
The method of analog, therefore still in the urgent need to developing the new preparation method containing disulfide bond polypeptide.
Content of the invention
The technical problem to be solved is the preparation technology in order to overcome oxytocin in prior art [4-Glu]
The defect complicated, yield is low, sample concentration is dilute, bulky, and provide a kind of preparation method of oxytocin [4-Glu].This
The preparation method of the oxytocin [4-Glu] of invention is with polypeptide crude product oxytocin [4-Glu] containing a pair of free sulfhydryl groups (- SH)
Precursor crude product is initiation material, through the cyclisation of high pressure liquid phase reverse-phase chromatography, purifying and desalting steps, prepares highly purified oxytocin
The method of [4-Glu].The polypeptide of the present invention is 1 critical impurities in oxytocin preparation process, therefore can examine as oxytocin
The standard reference material of survey process, carries out qualitative and quantitative analysis to oxytocin and impurity, for the quality mark for improving oxytocin
Standard, control product quality are 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], which comprises the steps：Anti- using efficient liquid phase
Oxytocin [4-Glu] precursor crude product solution is carried out anti-phase cyclisation, anti-phase purifying, anti-phase desalination by phase chromatography successively, you can；High
The filler of effect liquid phase RP chromatography is silica gel C18；
Described oxytocin [4-Glu] precursor crude product is oxytocin [4-Glu] the precursor crude product containing two free sulfhydryl groups；
Described oxytocin [4-Glu] is
Wherein, described oxytocin [4-Glu] precursor crude product preferably dries system using solid-phase synthesis through cracking
Oxytocin [4-Glu] the precursor crude product for obtaining, HPLC purity are 60～90%；The knot of described oxytocin [4-Glu] precursor crude product
Structure formula is Cys-Tyr-Ile-Glu-Asn-Cys-Pro-Leu-Gly-NH2Trifluoroacetate.
Wherein, described oxytocin [4-Glu] precursor crude product solution is preferably oxytocin [4-Glu] precursor crude product and is dissolved in
Concentration of volume percent is the 5g/L solution that 5% acetonitrile solution is formed.
In the present invention, described anti-phase cyclisation, anti-phase purifying, anti-phase desalination are all complete in the anti-phase elution process of a step
Become.
Wherein, described anti-phase cyclisation, anti-phase purifying, the condition of anti-phase desalination are preferably as follows：Mobile phase A 1 is pure water, A2
H for percent by volume 0.01～0.05% (preferably 0.02～0.03%)2O2PH is 7.5～9.0 NaOH aqueous solution,
Mobile phase B is acetonitrile, and mobile phase C is described oxytocin [4-Glu] precursor crude product solution, flow velocity be 80～110mL/min (relatively
Good for 100mL/min), Detection wavelength is 220nm；
Condition according to following table carries out online loading, wash-out, and percentage 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] solution.
Wherein, the filling condition of described efficient liquid phase RP chromatography is preferably as follows：Filler is Kromasil silica gel
C18, aperture 10nm, 10 μm of particle diameter.
Oxytocin [4-Glu] is a kind of peptide material, unstable in the basic conditions, degradable, especially strong alkali environment
Under, the de- concentration of integrated survey of the present invention alkali cleaning and time, to ensure to reduce the destruction of sample and loss in desalination processes.
Innovative point of the present invention be will cyclisation, purifying and one step of desalination is anti-phase obtains polypeptide sterling, before oxytocin [4-Glu]
In body crude product contain two free sulfhydryl groups, traditional handicraft cyclisation and purifying substep carry out, and be cyclized bulky, increased pure
The difficulty of change, for cyclisation rapidly and efficiently and preparation technology, designs the more recent application of silica gel C18 filler.The present invention is innovated
Property used the cyclisation of reverse phase absorption method, purifying and desalination, disposably solves the problems, such as cyclisation, purify and desalination.
On the basis of common sense in the field is met, above-mentioned each optimum condition, can be combined, obtain final product each preferable reality of the present invention
Example.
Agents useful for same of the present invention and raw material all commercially available.
The positive effect of the present invention is：
(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 wash-out weak binding on a column, and using pH meta-alkali containing H2O2's
Mobile phase is rinsed, and is promoted two sulfydryls to become disulfide bond, is obtained target polypeptides crude product, and sample retains on a column.
(2) present invention is cyclized using online, and the sample of cyclisation avoids wash-out, can carry out gradient and wash after directly converting mobile phase
De- purifying, obtains final sterling, is suitable for continuous production.
(3) present invention has innovatively used reverse phase absorption cyclisation, purifying, desalination one-step method that polypeptide sterling is obtained, and optimizes
Production technology, is suitable for that industrialization is continuous to be produced.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but therefore do not limit the present invention to described reality
Apply among a scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product specification is selected.
In following embodiments, oxytocin [4-Glu] is
Embodiment 1 (HPLC method detection oxytocin [4-Glu] precursor crude product and purifying midbody solution purity and quantitation)
Instrument：1200 high performance liquid chromatograph of Agilent
Splitter：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 solution of pH, flow velocity is
1.0 mL/min, Detection wavelength are 220nm, and room temperature is detected, shown in gradient see the table below, percentage 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 prepares post filling)
With Load＆Lock dynamic axial compression and static locking technology, filler is silica gel C18 (Kromasil C18),
Aperture 10nm, 10 μm of particle diameter, 0.66 g/mL of column density is filled, post bed pressure 133bar is filled to, using Varian chromatogram filling system
System, 325g dry powder filler, after the stirring homogenate of 650mL isopropanol, to pour internal diameter 50mm L＆L4002 into and post is prepared, 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, make
Post is prepared used by anti-phase cyclisation, anti-phase purifying and anti-phase desalination scheme.
The anti-phase cyclisation of embodiment 3 oxytocin [4-Glu] precursor crude material, anti-phase purifying and anti-phase desalination
Instrument：Varian SD-1 high pressure liquid phase preparation system
Chromatographic column：2 self-chambering of embodiment prepare post Load＆Lock4002 10 μm of 10nm of 50 × 255 mm, C18
Oxytocin [4-Glu] precursor crude product is to dry obtained oxytocin [4-Glu] using solid-phase synthesis through cracking
Precursor crude product, structural formula are Cys-Tyr-Ile-Glu-Asn-Cys-Pro-Leu-Gly-NH2Trifluoroacetate.
It is dense that oxytocin [4-Glu] precursor crude product solution is dissolved in percent by volume for above-mentioned oxytocin [4-Glu] precursor crude product
Spend the 5g/L solution of the acetonitrile solution formation for 5%.
Mobile phase A 1 is purified water, and A2 is the H of percent by volume 0.022O2PH is the 7.5 NaOH aqueous solution, Mobile phase B
For acetonitrile, mobile phase C is described oxytocin [4-Glu] precursor crude product solution, determines its HPLC purity as described in Example 1
For 78.50%, retention time is 9.46min.
The anti-phase cyclisation of the present embodiment, anti-phase purifying and anti-phase desalination condition are as follows：Flow velocity 100mL/min, 220nm are examined
Survey, purifying gradient see the table below shown in, percentage be 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 oxytocin [4-Glu] solution is obtained, as described in Example 1
It is 99.49% to determine its HPLC purity, and retention time is 6.20min.
The anti-phase cyclisation of embodiment 4 oxytocin [4-Glu] precursor crude material, anti-phase purifying and anti-phase desalination
Instrument：Varian SD-1 high pressure liquid phase preparation system
Chromatographic column：2 self-chambering of embodiment prepare 10 μm of 10nm of post Load＆Lock4002 50 × 255mm, C18
Oxytocin [4-Glu] precursor crude product is to dry obtained oxytocin [4-Glu] using solid-phase synthesis through cracking
Precursor crude product, structural formula are Cys-Tyr-Ile-Glu-Asn-Cys-Pro-Leu-Gly-NH2Trifluoroacetate.
It is dense that oxytocin [4-Glu] precursor crude product solution is dissolved in percent by volume for above-mentioned oxytocin [4-Glu] precursor crude product
Spend the 5g/L solution of the acetonitrile solution formation for 5%.
Mobile phase A 1 is purified water, and A2 is the H of percent by volume 0.032O2PH is the 9.0 NaOH aqueous solution, Mobile phase B
For acetonitrile, mobile phase C is described oxytocin [4-Glu] precursor crude product solution, determines its HPLC purity as described in Example 1
For 78.50%, retention time is 9.46min.
The anti-phase cyclisation of the present embodiment, anti-phase purifying and anti-phase desalination condition are as follows：Flow velocity 100mL/min, 220nm are examined
Survey, purifying gradient see the table below shown in, percentage be 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 oxytocin [4-Glu] solution is obtained, as described in Example 1
It is 99.57% to determine its HPLC purity, and retention time is 6.27min.
Embodiment 5 (Mass Spectrometer Method of oxytocin [4-Glu])
Embodiment 3,4 is determined using waters micromass ZQ substance level Four bar electrospray ionization mass spectrum (ESI-MS) to obtain
Oxytocin [4-Glu] molecular mass peak [M+1]+Measured value 1009.28, leading ion fragment peak [M+2]2+Measured value
505.17, all meet theoretical value 1008.2.
Claims (9)
1. a kind of preparation method of oxytocin [4-Glu], which comprises the steps：Will contracting palace using efficient liquid phase RP chromatography
Plain [4-Glu] precursor crude product solution carries out anti-phase cyclisation, anti-phase purifying, anti-phase desalination successively, you can；Efficient liquid phase reverse-phase chromatography
The filler of method is silica gel C18；
Described oxytocin [4-Glu] precursor crude product is oxytocin [4-Glu] the precursor crude product containing two free sulfhydryl groups；
Described oxytocin [4-Glu] is
2. preparation method as claimed in claim 1, it is characterised in that described oxytocin [4-Glu] precursor crude product is employing
Solid-phase synthesis dry obtained oxytocin [4-Glu] precursor crude product through cracking, and HPLC purity is 60～90%.
3. preparation method as claimed in claim 1, it is characterised in that the structure of described oxytocin [4-Glu] precursor crude product
Formula is Cys-Tyr-Ile-Glu-Asn-Cys-Pro-Leu-Gly-NH2Trifluoroacetate.
4. preparation method as claimed in claim 1, it is characterised in that described oxytocin [4-Glu] precursor crude product solution is
Oxytocin [4-Glu] precursor crude product is dissolved in the 5g/L solution that the acetonitrile solution that concentration of volume percent is 5% is formed.
5. preparation method as claimed in claim 1, it is characterised in that described anti-phase cyclisation, anti-phase purifying, 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 purifying, 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 water-soluble
Liquid, Mobile phase B are acetonitrile, and mobile phase C is described oxytocin [4-Glu] precursor crude product solution, and flow velocity is 80～110mL/
Min, Detection wavelength are 220nm；
Condition according to following table carries out online loading, wash-out, and percentage is percent by volume；
Collect the eluent that retention time is 50～65min and obtain oxytocin [4-Glu] 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 solution.
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 RP chromatography
As follows：Filler is Kromasil silica gel C18, aperture 10nm, 10 μm of particle diameter.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN110028556A (en) * | 2019-05-07 | 2019-07-19 | 上海上药第一生化药业有限公司 | A kind of refining methd of oxytocin [- NH2] impurity |
| CN110041405A (en) * | 2019-05-07 | 2019-07-23 | 上海上药第一生化药业有限公司 | A kind of refining methd of oxytocin [5-Asp] impurity |
| 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 |
| CN110078797A (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] impurity |
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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 |
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| 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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| CN110078797B (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 ] 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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