CN107629115A - A kind of purification process of Te Lawan stars - Google Patents
A kind of purification process of Te Lawan stars Download PDFInfo
- Publication number
- CN107629115A CN107629115A CN201710805483.6A CN201710805483A CN107629115A CN 107629115 A CN107629115 A CN 107629115A CN 201710805483 A CN201710805483 A CN 201710805483A CN 107629115 A CN107629115 A CN 107629115A
- Authority
- CN
- China
- Prior art keywords
- lawan
- eluent
- stars
- solution
- chromatography media
- 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.)
- Granted
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention provide a kind of purification process of Te Lawan stars its comprise the following steps：1) by the reactant mixture containing Te Lawan stars with methanol aqueous formic acid according to weight than 1：5 to 1：10 mixed dissolutions；2) chromatography media that filtrate has balanced by eluent is purified, the weight ratio of loading filtrate and chromatography media is 1：50 to 1：100；Chromatography media is octadecyl silane；3) above-mentioned chromatographic solution is crossed into NF membrane and is concentrated into more than the 1/10 of original volume, supplemented pH4 5 aqueous hydrochloric acid solution in said process when being concentrated into the 1/5 of original volume, repeat 3 to 5 times to remove buffer salt, add hydrochloric acid and adjust pH value to obtain concentrate to 0.5 2.The chromatography media octadecyl silane that this case is selected, closer, the hydrochloric acid Te Lawan stars of the isolated high-purity of energy are acted in separation process with material medium performance to Te Lawan star compounds with reference to appropriate acid solution or salt solvent system.
Description
Technical field
The present invention relates to antibiotic medicine field, more particularly to a kind of purification process of Te Lawan stars.
Background technology
Glycopeptide antibiotics (Glycopeptide Antibiotics), property：Glycopeptide antibiotics have altogether in structure
Highly modification polypeptide backbone, action target spot on bacterial cell wall components D-alanyl-D-alanine, generally by with bacterium
Peptide glycan precursor small peptide of the cell membrane using D-Ala-D-Ala as end is specifically bound, and suppresses prolonging for bacteria cell wall peptide glycan
Stretch or/and be crosslinked, so as to the synthesis of suppression of cell wall, ultimately result in bacterial cell death.Can according to amino acid contained difference
It is divided into four races：Vancomycin races, ristocetin races, avoparcin races, synmonicin races.First generation glycopeptide class resists
Raw element includes vancomycin, Norvancomycin, teicoplanin, and they are directed to the metabolite of microorganism.It is mould through the ages
Element is the glycopeptide antibiotics of first clinical practice, and the representative medicine of glycopeptide antibiotics, there is the warp of clinical practice in 50 years
Test, be the fiest-tire medication for treating MRSA/MRCNS (Meticillin Coagulase Negative Staphylococcus) infection.Second generation glycopeptide class
Antibiotic include oritavancin (Oritavancin), Dalbavancin (Dalbavancin), Te Lawan stars (Telavancin) and
Ramoplanin (Ramcplanin), it is derivative obtained from being chemically modified to microbe-derived natural products.
Te Lawan stars are first semi-synthetic new glycolipid peptide antibiotics, its unique mechanism of action and good clinic
Therapeutic effect, market prospects are boundless.Te Lawan stars are above vancomycin and teicoplanin to MRSA, MRSE isoreactivity,
Half-life period is longer than vancomycin, can clinically be administered once a day.Dalbavancin long half time reaches 174h, can clinically be administered for one week
1 time.Oritavancin has a very prominent pharmacodynamic profiles, and its half-life period is 393 hours, can each course for the treatment of be administered once.
It is concentrated mainly at present on Te Lawan star synthesising process research using different method synthesizing hydrophobic side chain N-
(9- fluorenylmethoxycarbonyl clusters base)-Decylamino skill acid, but with vancomycin reductive amination process, again by Fmoc deprotection and
Mannich reaction obtains Te Lawan stars.Side reaction product and target product in being reacted due to glycolipid peptides antibiotic activity site more
Te Lawan stars are analogues, and the purity that conventional production technology process such as extracted, crystallized more difficult raising target product reaches
To medicinal criterion of acceptability.
The Te Lawan stars that the technique of some document reports produces at present have that purity is inadequate, or production process is complicated,
Operating time length easily causes product formation dimer (Dimer), and the defects of unstable product quality.
The content of the invention
In order to solve to prepare the inadequate technical problem of the purity in Te Lawan star methods, the invention provides a kind of Te Lawan
The purification process of star, specifically the present invention be realized in：
A kind of purification process of Te Lawan stars, it comprises the following steps：
1) by the reactant mixture containing Te Lawan stars with methyl alcohol-formic acid-aqueous solution according to weight than 1：5 to 1：10 is mixed
Close, dissolve reactant mixture, cross and filter out solid insoluble, obtain filtrate；Above-mentioned methanol-formic acid-aqueous solution is according to volume ratio 2:
1:1 configuration forms；
Dimer is easily formed in reactant mixture, causes matter solubility to be deteriorated, can be played by the step and removed well
Miscellaneous effect.
The process route of reactant mixture containing Te Lawan stars：
The synthetic method of novel lipopeptide antibiotic hydrochloric acid Te Lawan stars：Vancomycin hydrochloride (chemical compounds I) and N- (9-
Fluorenylmethyloxycarbonyl) reductive amination process occurs for-decylaminoacetaldehyde, then de- 9-fluorenylmethyloxycarbonyl protection group, again with aminomethyl
Phosphonic acids carries out Mannich reaction synthesis target product Te Lawan star crude products.(following formula: compound III).
2) the weight ratio of the chromatography media for having balanced filtrate by eluent, loading filtrate and chromatography media is 1：50 to
1：100；Chromatography media is octadecyl silane；Eluent is solvent orange 2 A-phosphate buffer solution of 3-5 column volume, phosphorus
Phthalate buffer is：Sodium dihydrogen phosphate or disodium hydrogen phosphate 0.01mol/L-0.05mol/L, phosphorus acid for adjusting pH is 2.0-2.5's
Cushioning liquid：Solvent orange 2 A is acetonitrile, methanol, ethanol, one kind in acetone, using gradient elution, the quality of solvent orange 2 A in eluent
For fraction from 10% graded to 50%, elution flow rate is 1BV/h to 5BV/h；Te Lawan star HPLC mass concentrations are collected to exist
More than 95% chromatographic solution；
Select the principle of chromatography media：
Te Lawan stars be on 4 rings (such as Fig. 4) of vancomycin osamine base side chain be alkylated it is acylated hydrophobic
Last of the ten Heavenly stems aminoethyl side chain, and hydrophilic phosphonic acids aminomethyl is introduced in the contraposition of 7 amino acids aromatic rings, in pharmacologically hydrophobic group
The interaction and increase for being advantageous to increase cell membrane then promote in-vivo tissue to enterococcal antibacterial activity, hydrophilic radical
Metabolism and removing, reduce renal toxicity, improve the pharmacokinetic property of medicine in vivo.Angle is isolated and purified in synthesis, by
Have larger nature difference in introducing in new group and raw material vancomycin spatial arrangement structure, separating medium selection and
New problem is also brought in the operation of purification circuit；
《A kind of method CN201510294070.7 of purifying Te Lawan star crude products》A kind of purifying crude method is disclosed,
Processing step in its material is：Te Lawan stars crude product is acidified and dissolved, filtering, gained filtrate is extracted with organic solvent, hydrochloric acid
Solution is stripped, and extracts to obtain hydrochloric acid Te Lawan star solution afterwards using Strong acid ion-exchanger, then by hydrochloric acid Te Lawan
Star solution ultrafiltration, crystallize, wash, dry.The document says that open technique realizes and efficiently separates purifying, and effective content reaches
99%, product quality is improved, reduces production cost.
Te Lawan stars half are efficiently separated out with reference to the extraction process in technique and ion exchange resin separating medium are more difficult
The impurity of the introducings such as accessory substance and raw material vancomycin in synthetic product.Research and development early stage are carried out according to the reference, it is more difficult to
Repeat to similar effects.It is effective by selective chromatography media ability with being needed according to the purifies and separates experience of natural products
Impurity is isolated, reduces production cost, improves product purity.The hydrochloric acid Te Lawan that can be stablized with reference to crystallisation step below
Star raw material.
Synthetically prepared and purification procedures, wherein technique bag are reported in U.S. Patent US20050113561
Include the purifying of multi-step and not high into salt embodiment, final products yield.
The chromatography media that this case is selected, ODS bonding materials (octadecyl silane) are spatially to Te Lawan stars
Compound has the steric hindrance of specific selectivity, and side chain and ion of the ODS hydrophobic interactions than routine of the bonding of Te Lawan stars are handed over
Change that resin material is stronger, this case combines appropriate acid solution or salt solvent system to Te Lawan star compounds in separation process
Acted on material medium performance closer.
3) above-mentioned chromatographic solution is crossed into NF membrane and is concentrated into more than the 1/10 of original volume, original volume is being concentrated into said process
1/5 when supplement pH4-5 aqueous hydrochloric acid solution, repeat 3 to 5 times to remove buffer salt, add hydrochloric acid and adjust pH value to 0.5-2,
Obtain concentrate.
《Vancomycin present Research and development》Middle research shows：The less stable of vancomycin, puts at normal temperatures
After putting time length, you can it was observed that color gradually reddens, show by numerous studies, it may be possible in the molecular structure of vancomycin
Phenolic group and diphenylol be present, the aqueous solution of phenols meets light and is easily hydrated or is oxidized to quinone and pinkiness.In this case Te Lawan star works
Skill research process finds have red phenomenon to produce after being grown there is also the time.Therefore need to rapidly purify and formed stable chemical combination
Thing will not just have an impact to finished product quality.By this case integrated artistic, be rapidly performed by purifying, can effectively solve it is above-mentioned because
Time is grown, the problems such as caused degraded.
Preferably, in step 3) when solvent orange 2 A is acetonitrile, in eluent the mass fraction gradient selection of acetonitrile for 15%,
18%th, 20%, 50%；When solvent orange 2 A is methanol, in eluent the mass fraction gradient selection of methanol for 20%, 23%,
25%th, 50%；When solvent orange 2 A is ethanol, in eluent the mass fraction gradient selection of ethanol for 15%, 18%, 20%,
50%；When solvent orange 2 A is acetone, the mass fraction gradient selection of acetone is 15%, 18%, 20%, 50% in eluent.
Preferably, the NF membrane described in step 3) is the NF membrane of polyether sulfone organic solvent-resistant, and molecular cut off is
200-1000 dalton.
This scope can effectively remove the small molecular weight impurity of degraded, Dephosphorization acid buffering salt, and reach dilute sample
The effect of solution low temperature concentration is eluted, avoids heat damage caused by lyophilized cost is too high or heating is concentrated under reduced pressure.
Preferably, the chromatography in step 3) is using the Te Lawan star mass concentrations in HPLC tracking chromatographic solutions.
Preferably, the reactant mixture of Te Lawan stars is vancomycin hydrochloride and N- (9- fluorenyl first in described step 1)
Oxygen carbonyl) reductive amination process occurs for-decylaminoacetaldehyde, then takes off 9-fluorenylmethyloxycarbonyl protection group, enters again with AminomethylphosphoniAcid Acid
The Te Lawan star crude products of row Mannich reaction synthesis.
The beneficial effects of the present invention are：
The chromatography media octadecyl silane that this case is selected, bonding material spatially have to Te Lawan star compounds
The steric hindrance of specific selectivity, while hydrophobic interaction is more stronger than the ion exchange resin of routine, this case combines appropriate
Acid solution or salt solvent system act in separation process closer to Te Lawan star compounds with material medium performance, can divide
From obtaining the Te Lawan stars of high-purity.
Brief description of the drawings
The original loading HPLC figures of Fig. 1 reactants；
Fig. 2 is that HPLC schemes after the purification process of embodiment 5；
Fig. 3 is Te Lawan star interpretation of mass spectra figures；
Fig. 4 is vancomycin structure chart.
Embodiment
To describe the technology contents of the present invention, construction feature, the objects and the effects in detail, below in conjunction with embodiment
And accompanying drawing is coordinated to be explained in detail.
Embodiment 1
A kind of purification process of Te Lawan stars, it comprises the following steps：
1) by the reactant mixture containing Te Lawan stars with methyl alcohol-formic acid-aqueous solution according to weight than 1：5 mixing, make anti-
Answer mixture to dissolve, cross and filter out solid insoluble, obtain filtrate；Above-mentioned methyl alcohol-formic acid-aqueous solution is according to volume ratio 2:1:1 configuration
Form；The reactant mixture of described Te Lawan stars is vancomycin hydrochloride and N- (9- fluorenylmethyloxycarbonyls)-Decylamino second
Reductive amination process occurs for aldehyde, then takes off 9-fluorenylmethyloxycarbonyl protection group, carries out what Mannich reaction synthesized with AminomethylphosphoniAcid Acid again
Te Lawan star crude products；
2) the weight ratio of the chromatography media for having balanced filtrate by eluent, loading filtrate and chromatography media is 1：50；
Chromatography media is octadecyl silane；Eluent is solvent orange 2 A-phosphate buffer solution of 3 column volumes, phosphate-buffered
Liquid is：Sodium dihydrogen phosphate 0.01mol/L, cushioning liquid of the phosphorus acid for adjusting pH 2.0：When solvent orange 2 A is acetonitrile, in eluent
The mass fraction gradient selection of acetonitrile is 15%, 18%, 20%, 50%；Elution flow rate is 1BV/h；Collect Te Lawan stars HPLC
Chromatographic solution of the mass concentration more than 95% (when intersecting eluent of the purity less than 95% containing Te Lawan stars, can take conjunction
And handled with macroporous absorbent resin HP20 adsorption recovery, it is further continued for carrying out follow-up repurity)；
3) above-mentioned chromatographic solution is crossed into NF membrane and is concentrated into more than the 1/10 of original volume, described NF membrane has for polyether sulfone is resistance to
The NF membrane of solvent, molecular cut off are 200 dalton, supplement pH4's when being concentrated into the 1/5 of original volume in said process
Aqueous hydrochloric acid solution, it is repeated 3 times to remove buffer salt, adds hydrochloric acid and adjust pH value to obtain concentrate to 0.5；Chromatography in step 3)
Te Lawan star mass concentrations in chromatographic solution are tracked using HPLC.
Embodiment 2
A kind of purification process of Te Lawan stars, it comprises the following steps：
1) by the reactant mixture containing Te Lawan stars with methyl alcohol-formic acid-aqueous solution according to weight than 1：10 mixing, make
Reactant mixture dissolves, and crosses and filters out solid insoluble, obtains filtrate；Above-mentioned methyl alcohol-formic acid-aqueous solution is according to volume ratio 2:1:1 matches somebody with somebody
Put and form；The reactant mixture of described Te Lawan stars is vancomycin hydrochloride and N- (9- fluorenylmethyloxycarbonyls)-Decylamino
Reductive amination process occurs for acetaldehyde, then takes off 9-fluorenylmethyloxycarbonyl protection group, synthesized again with AminomethylphosphoniAcid Acid progress Mannich reaction
Te Lawan star crude products；
2) the weight ratio of the chromatography media for having balanced filtrate by eluent, loading filtrate and chromatography media is 1：100；
Chromatography media is octadecyl silane；Eluent is solvent orange 2 A-phosphate buffer solution of 5 column volumes, phosphate-buffered
Liquid is：Disodium hydrogen phosphate 0.05mol/L, cushioning liquid of the phosphorus acid for adjusting pH 2.5：When solvent orange 2 A is methanol, in eluent
The mass fraction gradient selection of methanol is 20%, 23%, 25%, 50%；Elution flow rate is 5BV/h；Collect Te Lawan stars HPLC
Chromatographic solution of the mass concentration more than 95% (when intersecting eluent of the purity less than 95% containing Te Lawan stars, can take conjunction
And handled with macroporous absorbent resin HP20 adsorption recovery, it is further continued for carrying out follow-up repurity)；
3) above-mentioned chromatographic solution is crossed into NF membrane and is concentrated into more than the 1/10 of original volume, described NF membrane has for polyether sulfone is resistance to
The NF membrane of solvent, molecular cut off are 1000 dalton, and pH5 is supplemented when being concentrated into the 1/5 of original volume in said process
Aqueous hydrochloric acid solution, be repeated 5 times to remove buffer salt, add hydrochloric acid adjust pH value to 2, obtain concentrate；Chromatography in step 3)
Te Lawan star mass concentrations in chromatographic solution are tracked using HPLC.
Embodiment 3
A kind of purification process of Te Lawan stars, it comprises the following steps：
1) by the reactant mixture containing Te Lawan stars with methyl alcohol-formic acid-aqueous solution according to weight than 1：7 mixing, make anti-
Answer mixture to dissolve, cross and filter out solid insoluble, obtain filtrate；Above-mentioned methyl alcohol-formic acid-aqueous solution is according to volume ratio 2:1:1 configuration
Form；The reactant mixture of described Te Lawan stars is vancomycin hydrochloride and N- (9- fluorenylmethyloxycarbonyls)-Decylamino second
Reductive amination process occurs for aldehyde, then takes off 9-fluorenylmethyloxycarbonyl protection group, carries out what Mannich reaction synthesized with AminomethylphosphoniAcid Acid again
Te Lawan star crude products；
2) the weight ratio of the chromatography media for having balanced filtrate by eluent, loading filtrate and chromatography media is 1：70；
Chromatography media is octadecyl silane；Eluent is solvent orange 2 A-phosphate buffer solution of 4 column volumes, phosphate-buffered
Liquid is：Sodium dihydrogen phosphate 0.02mol/L, cushioning liquid of the phosphorus acid for adjusting pH 2.2：When solvent orange 2 A is ethanol, in eluent
The mass fraction gradient selection of ethanol is 15%, 18%, 20%, 50%, elution flow rate 2BV/h；Collect Te Lawan stars HPLC
Chromatographic solution of the mass concentration more than 95% (when intersecting eluent of the purity less than 95% containing Te Lawan stars, can take conjunction
And handled with macroporous absorbent resin HP20 adsorption recovery, it is further continued for carrying out follow-up repurity)；
3) above-mentioned chromatographic solution is crossed into NF membrane and is concentrated into more than the 1/10 of original volume, described NF membrane has for polyether sulfone is resistance to
The NF membrane of solvent, molecular cut off are 1000 dalton, and pH4 is supplemented when being concentrated into the 1/5 of original volume in said process
Aqueous hydrochloric acid solution, be repeated 4 times to remove buffer salt, add hydrochloric acid adjust pH value to 1, obtain concentrate；Chromatography in step 3)
Te Lawan star mass concentrations in chromatographic solution are tracked using HPLC.
Embodiment 4
A kind of purification process of Te Lawan stars, it comprises the following steps：
1) by the reactant mixture containing Te Lawan stars with methyl alcohol-formic acid-aqueous solution according to weight than 1：8 mixing, make anti-
Answer mixture to dissolve, cross and filter out solid insoluble, obtain filtrate；Above-mentioned methyl alcohol-formic acid-aqueous solution is according to volume ratio 2:1:1 configuration
Form；The reactant mixture of described Te Lawan stars is vancomycin hydrochloride and N- (9- fluorenylmethyloxycarbonyls)-Decylamino second
Reductive amination process occurs for aldehyde, then takes off 9-fluorenylmethyloxycarbonyl protection group, carries out what Mannich reaction synthesized with AminomethylphosphoniAcid Acid again
Te Lawan star crude products；
2) the weight ratio of the chromatography media for having balanced filtrate by eluent, loading filtrate and chromatography media is 1：90；
Chromatography media is octadecyl silane；Eluent is solvent orange 2 A-phosphate buffer solution of 5 column volumes, phosphate-buffered
Liquid is：Disodium hydrogen phosphate 0.04mol/L, cushioning liquid of the phosphorus acid for adjusting pH 2.4：When solvent orange 2 A is acetone, in eluent
The mass fraction gradient selection of acetone is 15%, 18%, 20%, 50%, elution flow rate 3BV/h；Collect Te Lawan stars HPLC
Chromatographic solution of the mass concentration more than 95% (when intersecting eluent of the purity less than 95% containing Te Lawan stars, can take conjunction
And handled with macroporous absorbent resin HP20 adsorption recovery, it is further continued for carrying out follow-up repurity)；
3) above-mentioned chromatographic solution is crossed into NF membrane and is concentrated into more than the 1/10 of original volume, described NF membrane has for polyether sulfone is resistance to
The NF membrane of solvent, molecular cut off are 200 dalton, supplement pH5's when being concentrated into the 1/5 of original volume in said process
Aqueous hydrochloric acid solution, it is repeated 3 times to remove buffer salt, adds hydrochloric acid and adjust pH value to obtain concentrate to 1；Chromatography in step 3) is adopted
The Te Lawan star mass concentrations in chromatographic solution are tracked with HPLC.
Embodiment 5
A kind of purification process of Te Lawan stars, it comprises the following steps：
1) by the reactant mixture containing Te Lawan stars with methyl alcohol-formic acid-aqueous solution according to weight than 1：7 mixing, make anti-
Answer mixture to dissolve, cross and filter out solid insoluble, obtain filtrate；Above-mentioned methyl alcohol-formic acid-aqueous solution is according to volume ratio 2:1:1 configuration
Form；The reactant mixture of described Te Lawan stars is vancomycin hydrochloride and N- (9- fluorenylmethyloxycarbonyls)-Decylamino second
Reductive amination process occurs for aldehyde, then takes off 9-fluorenylmethyloxycarbonyl protection group, carries out what Mannich reaction synthesized with AminomethylphosphoniAcid Acid again
Te Lawan star crude products；
2) the weight ratio of the chromatography media for having balanced filtrate by eluent, loading filtrate and chromatography media is 1：75；
Chromatography media is octadecyl silane；Eluent is solvent orange 2 A-phosphate buffer solution of 4 column volumes, phosphate-buffered
Liquid is：Disodium hydrogen phosphate 0.35mol/L, cushioning liquid of the phosphorus acid for adjusting pH 2.3：When solvent orange 2 A is ethanol, in eluent
The mass fraction gradient selection of ethanol is 15%, 18%, 20%, 50%, elution flow rate 3BV/h；Collect Te Lawan stars HPLC
Chromatographic solution of the mass concentration more than 95%；
3) above-mentioned chromatographic solution is crossed into NF membrane and is concentrated into more than the 1/10 of original volume, described NF membrane has for polyether sulfone is resistance to
The NF membrane of solvent, molecular cut off are 200 dalton, supplement pH4's when being concentrated into the 1/5 of original volume in said process
Aqueous hydrochloric acid solution, it is repeated 4 times to remove buffer salt, adds hydrochloric acid and adjust pH value to obtain concentrate to 1.5；Chromatography in step 3)
Te Lawan star mass concentrations in chromatographic solution are tracked using HPLC.
HPLC is detected：
1st, testing conditions：
Mobile phase：Ammonium dihydrogen phosphate water (0.05mol/L, pH2.0 is adjusted with phosphoric acid)：Acetonitrile=80：20,
Chromatographic column：Kromasil 100-5-C18 4.6*250mm, flow velocity：1.0ml/min, column temperature：40 DEG C, detect ripple
It is long：210nm, Te Lawan star Rt=19.7min.
2nd, sample contrast test is detected
Take the original loading of reactant to detect its purity according to above-mentioned HPLC testing conditions, refer to Fig. 1；
The purification process of embodiment of learning from else's experience 5 obtains the sample of sample, detects its purity according to above-mentioned HPLC testing conditions, refers to figure
2；
The purification process of embodiment of learning from else's experience 5 obtains the sample of sample, detects its mass spectrogram, refers to Fig. 3 (HRMS (ESI) m/z：
calcd C80H106Cl2N11O27P[M+2H]2+877.8187 found 877.8249 [M+2H]2+, 585.5532 [M+3H]3+)。
Contrast accompanying drawing 1 and accompanying drawing 2 (purity more than 95%) and accompanying drawing 3, it can be seen that by the purifying side of the present invention
Method, the purity of Te Lawan stars can be significantly improved.
Embodiments of the invention are the foregoing is only, not thereby limit the scope of patent protection of the present invention, every utilization
The equivalent structure or equivalent flow conversion that description of the invention and accompanying drawing content are made, or directly or indirectly it is used in other correlations
Technical field, be included within the scope of the present invention.
Claims (5)
1. a kind of purification process of Te Lawan stars, it is characterised in that it comprises the following steps：
1) by the reactant mixture containing Te Lawan stars with methyl alcohol-formic acid-aqueous solution according to weight than 1：5 to 1：10 mixing, make
Reactant mixture dissolves, and crosses and filters out solid insoluble, obtains filtrate；Above-mentioned methyl alcohol-formic acid-aqueous solution is according to volume ratio 2:1:1 matches somebody with somebody
Put and form；
2) the weight ratio of the chromatography media for having balanced filtrate by eluent, loading filtrate and chromatography media is 1：50 to 1：
100；Chromatography media is octadecyl silane；Eluent is solvent orange 2 A-phosphate buffer solution of 3-5 column volume, phosphoric acid
Salt buffer is：Sodium dihydrogen phosphate or disodium hydrogen phosphate 0.01mol/L-0.05mol/L, phosphorus acid for adjusting pH is in the slow of 2.0-2.5
Rush solution：Solvent orange 2 A is one kind in acetonitrile, methanol, ethanol, acetone, and using gradient elution, the quality of solvent orange 2 A is divided in eluent
For number from 10% graded to 50%, elution flow rate is 1BV/h to 5BV/h；Te Lawan star HPLC mass concentrations are collected 95%
Chromatographic solution above；
3) above-mentioned chromatographic solution is crossed into NF membrane and is concentrated into more than the 1/10 of original volume, the 1/ of original volume is being concentrated into said process
PH4-5 aqueous hydrochloric acid solution is supplemented when 5, repeats 3 to 5 times to remove buffer salt, hydrochloric acid is added and adjusts pH value to be obtained dense to 0.5-2
Contracting liquid.
2. the purification process of Te Lawan stars according to claim 1, it is characterised in that when solvent orange 2 A is acetonitrile in step 3)
When, the mass fraction gradient selection of acetonitrile is 15%, 18%, 20%, 50% in eluent；When solvent orange 2 A is methanol, eluent
The mass fraction gradient selection of middle methanol is 20%, 23%, 25%, 50%；When solvent orange 2 A is ethanol, ethanol in eluent
The selection of mass fraction gradient is 15%, 18%, 20%, 50%；When solvent orange 2 A is acetone, the mass fraction of acetone in eluent
Gradient selection is 15%, 18%, 20%, 50%.
3. the purification process of Te Lawan stars according to claim 1, it is characterised in that the NF membrane described in step 3) is
The NF membrane of polyether sulfone organic solvent-resistant, molecular cut off are 200-1000 dalton.
4. the purification process of Te Lawan stars according to claim 1, it is characterised in that the chromatography in step 3) uses HPLC
Track the Te Lawan star mass concentrations in chromatographic solution.
5. the purification process of Te Lawan stars according to claim 1, it is characterised in that Te Lawan stars in described step 1)
Reactant mixture reductive amination process occurs for vancomycin hydrochloride and N- (9- fluorenylmethyloxycarbonyls)-decylaminoacetaldehyde,
9-fluorenylmethyloxycarbonyl protection group is taken off again, carries out the Te Lawan star crude products that Mannich reaction synthesizes with AminomethylphosphoniAcid Acid again.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710805483.6A CN107629115B (en) | 2017-09-08 | 2017-09-08 | Purification method of telavancin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710805483.6A CN107629115B (en) | 2017-09-08 | 2017-09-08 | Purification method of telavancin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107629115A true CN107629115A (en) | 2018-01-26 |
| CN107629115B CN107629115B (en) | 2021-05-07 |
Family
ID=61101084
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710805483.6A Active CN107629115B (en) | 2017-09-08 | 2017-09-08 | Purification method of telavancin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107629115B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110824079A (en) * | 2019-11-27 | 2020-02-21 | 苏州赛分科技有限公司 | Purification method of telavancin |
| CN112028974A (en) * | 2020-09-11 | 2020-12-04 | 福建康鸿生物科技有限公司 | Telavancin purification method |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1437611A (en) * | 2000-06-22 | 2003-08-20 | 施万制药 | Glycopeptide phosphonate derivatives |
| CN1547481A (en) * | 2001-08-24 | 2004-11-17 | ������ҩ������˾ | Process for preparing glycopeptide phosphonate derivatives |
| CN1871253A (en) * | 2003-10-22 | 2006-11-29 | 施万制药 | Hydrochloride salts of a glycopeptide phosphonate derivative |
| CN104877014A (en) * | 2015-06-02 | 2015-09-02 | 宁夏泰瑞制药股份有限公司 | Method for purifying crude Telavancin |
| CN105585617A (en) * | 2016-03-24 | 2016-05-18 | 中国医学科学院医药生物技术研究所 | Norvancomycin derivatives and preparation purifying method thereof |
| CN105646673A (en) * | 2014-11-12 | 2016-06-08 | 天津市汉康医药生物技术有限公司 | Telavancin compound |
-
2017
- 2017-09-08 CN CN201710805483.6A patent/CN107629115B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1437611A (en) * | 2000-06-22 | 2003-08-20 | 施万制药 | Glycopeptide phosphonate derivatives |
| CN1547481A (en) * | 2001-08-24 | 2004-11-17 | ������ҩ������˾ | Process for preparing glycopeptide phosphonate derivatives |
| CN1871253A (en) * | 2003-10-22 | 2006-11-29 | 施万制药 | Hydrochloride salts of a glycopeptide phosphonate derivative |
| CN105646673A (en) * | 2014-11-12 | 2016-06-08 | 天津市汉康医药生物技术有限公司 | Telavancin compound |
| CN104877014A (en) * | 2015-06-02 | 2015-09-02 | 宁夏泰瑞制药股份有限公司 | Method for purifying crude Telavancin |
| CN105585617A (en) * | 2016-03-24 | 2016-05-18 | 中国医学科学院医药生物技术研究所 | Norvancomycin derivatives and preparation purifying method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 熊伦； 管栋梁； 李剑； 黄蔚；: "特拉万星合成工艺研究", 《中国药科大学学报》 * |
| 马帅； 贾景雨； 袁红； 曹胜华；: "特拉万星的合成", 《中国新药杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110824079A (en) * | 2019-11-27 | 2020-02-21 | 苏州赛分科技有限公司 | Purification method of telavancin |
| CN112028974A (en) * | 2020-09-11 | 2020-12-04 | 福建康鸿生物科技有限公司 | Telavancin purification method |
| CN112028974B (en) * | 2020-09-11 | 2022-02-01 | 福建康鸿生物科技有限公司 | Telavancin purification method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107629115B (en) | 2021-05-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101925695B1 (en) | Separation and Purification Method for Vancomycin Hydrochloride of High Purity | |
| EP2076528B1 (en) | Purification processes of echinocandin-type compounds | |
| KR101479389B1 (en) | Purification method of azacyclohexapeptide or its salt | |
| DK2470555T3 (en) | A process for the purification of colistin and purified colistinkomponenter | |
| EP2208732B1 (en) | Deshydroxy vancomycin, the preparation, pharmaceutical composition and the use | |
| US7018814B2 (en) | Process of purifying vancomycin hydrochloride | |
| CN107629115A (en) | A kind of purification process of Te Lawan stars | |
| CN107365357A (en) | A kind of method for preparing purified of glycopeptide antibiotics Dalbavancin intermediate A 40926 | |
| CA2529124A1 (en) | Antibiotic 107891, its factors a1 and a2, pharmaceutically acceptable salts and compositions, and use thereof | |
| CN109553702A (en) | A kind of purification process for the more glucose sodium that relaxes | |
| CN107629116A (en) | A kind of purification process of Te Lawan stars | |
| JPH0363289A (en) | Factors a1, a2, a3 and h for antibiotic ge 2270 | |
| CN110655557A (en) | Separation and purification method of pneumocandin B0 serine analogue | |
| CN107163102A (en) | A kind of method of hydrophilic polypeptides purifying | |
| NO342269B1 (en) | Preparation and purification of mupirocin calcium | |
| BR112019012273A2 (en) | Process for Purification of Lipopolipeptide Antibiotics from Culture Broths and Uses of a Cation Exchange Resin | |
| CN112279895B (en) | Preparation method of chemically synthesized acidic polypeptide | |
| RU2400489C2 (en) | Vancomycin purification method | |
| US5519123A (en) | Chelating agents, their preparation from the antibiotics salmycin A,B,C, or D, and their use | |
| CN102272320B (en) | Process for purifying vancomycin wet body | |
| CN110117310A (en) | A kind of purification process of Daptomycin | |
| CN111187339B (en) | Method for extracting FR901379 from fermentation broth | |
| CN114405065B (en) | Method for preparing chiral polypeptide medicine by dynamic thermodynamic equilibrium purification | |
| CN110903346B (en) | Method for preparing vancomycin hydrochloride impurity impC | |
| CN100354301C (en) | Novel large-scale separation and preparation technology of chemically synthesized polypeptide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |