CN107629115B - Purification method of telavancin - Google Patents
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Abstract
The invention provides a purification method of telavancin, which comprises the following steps: 1) reacting mixture containing telavancin with methanol-formic acid-water solution according to the weight ratio of 1: 5 to 1: 10, mixing and dissolving; 2) purifying the filtrate by a chromatographic medium with well balanced eluent, wherein the weight ratio of the loading filtrate to the chromatographic medium is 1: 50 to 1: 100, respectively; the chromatography medium is octadecyl bonded silica gel; 3) concentrating the chromatography liquid with nanofiltration membrane to above 1/10, supplementing hydrochloric acid aqueous solution with pH of 4-5 when concentrating to 1/5 of the original volume, repeating for 3-5 times to remove buffer salt, and adding hydrochloric acid to adjust pH to 0.5-2 to obtain concentrated solution. The chromatographic medium octadecyl bonded silica gel selected by the scheme is combined with a proper acid solution or salt solvent system to have a tighter effect on the performance of the telavancin compound and the material medium in the separation process, and high-purity telavancin hydrochloride can be obtained through separation.
Description
Technical Field
The invention relates to the field of antibiotic medicines, and particularly relates to a method for purifying telavancin.
Background
Glycopeptide Antibiotics (glycoepitide Antibiotics), properties: glycopeptide antibiotics share a highly modified polypeptide backbone in structure, and act on the bacterial cell wall component D-alanyl-D-alanine by specifically binding to a peptidoglycan precursor small peptide with the end of the bacterial cell wall at D-Ala-D-Ala to inhibit the extension or/and cross-linking of peptidoglycan in the bacterial cell wall, thereby inhibiting the synthesis of the cell wall and ultimately causing bacterial cell death. The amino acids can be divided into four groups according to the difference of the contained amino acids: the vancomycin family, the ristocetin family, the avoparcin family, and the synmonicin family. The first generation glycopeptide antibiotics include vancomycin, norvancomycin, and teicoplanin, which are derived directly from the metabolites of microorganisms. Vancomycin is the glycopeptide antibiotic of the first clinical application, is also a representative drug of glycopeptide antibiotics, has 50 years of clinical application experience, and is a first-line drug for treating MRSA/MRCNS (methicillin-resistant coagulase negative staphylococcal) infection. The second generation glycopeptide antibiotics include Oritavancin (oritavacin), Dalbavancin (Dalbavancin), Telavancin (Telavancin), and ramoplanin (Ramcplanin), which are derivatives obtained by chemically modifying natural products derived from microorganisms.
The telavancin is the first semi-synthetic novel glycolipid peptide antibiotic, has unique action mechanism and good clinical treatment effect, and has very wide market prospect. The activity of telavancin on MRSA, MRSE and the like is higher than that of vancomycin and teicoplanin, the half-life period is longer than that of vancomycin, and 1-time administration can be carried out clinically. The half-life of the dalbavancin is as long as 174h, and the dalbavancin can be clinically administered 1 time a week. Oritavancin has outstanding pharmacodynamic characteristics, the half-life period of the oritavancin is 393 hours, and the oritavancin can be administrated once per treatment course.
At present, the research on the synthesis process of telavancin mainly focuses on synthesizing hydrophobic side chain N- (9-fluorenylmethoxy cluster) -decylamino technical acid by adopting different methods, and then the telavancin is obtained by the reductive amination reaction of the telavancin and vancomycin, and then the Fmoc deprotection and the Mannich reaction. Because the side reaction product and the target product telavancin in the multi-reaction of the active sites of the glycolipid peptide antibiotics are structural analogues, the purity of the target product is difficult to improve by the conventional production technical processes such as extraction, crystallization and the like to reach the pharmaceutical qualified standard.
The telavancin produced by the processes reported in some documents at present has the defects of insufficient purity, complex production process, easy product formation of Dimer (Dimer) due to long operation time and unstable product quality.
Disclosure of Invention
In order to solve the technical problem of insufficient purity in a method for preparing telavancin, the invention provides a method for purifying telavancin, which is realized by the following steps:
a method for purifying telavancin, comprising the steps of:
1) reacting mixture containing telavancin with methanol-formic acid-water solution according to the weight ratio of 1: 5 to 1: 10, mixing, dissolving the reaction mixture, and filtering to remove solid insoluble substances to obtain filtrate; the methanol-formic acid-water solution is prepared according to the volume ratio of 2:1: 1;
dimers are easily formed in the reaction mixture, so that the mass solubility is poor, and the step can achieve a good impurity removal effect.
Process route for reaction mixture containing telavancin:
the synthesis method of the novel lipopeptide antibiotic hydrochloride telavancin comprises the following steps: vancomycin hydrochloride (compound I) and N- (9-fluorenylmethoxycarbonyl) -decylaminoacetaldehyde undergo a reductive amination reaction, then 9-fluorenylmethoxycarbonyl protecting groups are removed, and a Mannich reaction is carried out on the obtained product and aminomethylphosphonic acid to synthesize a target product of a crude product of telavancin. (Compound III in the following scheme).
2) Passing the filtrate through a chromatographic medium with well-balanced eluent, wherein the weight ratio of the sample filtrate to the chromatographic medium is 1: 50 to 1: 100, respectively; the chromatography medium is octadecyl bonded silica gel; the eluent is 3-5 column volumes of solvent A-phosphate buffer solution, the phosphate buffer solution is: 0.01mol/L-0.05mol/L of sodium dihydrogen phosphate or disodium hydrogen phosphate, and a buffer solution with pH adjusted to 2.0-2.5 by phosphoric acid: the solvent A is one of acetonitrile, methanol, ethanol and acetone, gradient elution is adopted, the mass fraction of the solvent A in the eluent is changed from 10% to 50% in a gradient manner, and the elution flow rate is 1BV/h to 5 BV/h; collecting a chromatographic solution with the HPLC mass concentration of telavancin being more than 95%;
principle of selecting chromatography media:
telavancin is a hydrophobic decaaminoethyl side chain obtained by alkylating and acylating a sugar amine side chain on a 4-position ring (shown in figure 4) of vancomycin, and a hydrophilic phosphonic acid aminomethyl group is introduced at the para position of a 7-position amino acid aromatic ring, wherein the pharmacological hydrophobic group is favorable for increasing the interaction of cell membranes and the antibacterial activity to enterococci, and the hydrophilic group promotes the metabolism and clearance of tissues in vivo, reduces the renal toxicity and improves the pharmacokinetic property of the medicament in vivo. In terms of synthesis, separation and purification, due to the introduction of a new group and the large property difference of the vancomycin serving as a raw material in a spatial arrangement structure, new problems are brought to the selection of a separation medium and the operation of a purification route;
in "a method for purifying crude telavancin product CN 201510294070.7", a crude product purification method is disclosed, the process steps in the material are: acidifying and dissolving the crude telavancin product, filtering, extracting the obtained filtrate with an organic solvent, back-extracting with a hydrochloric acid solution, separating and extracting by an ion exchange method to obtain a telavancin hydrochloride solution, and then ultrafiltering, crystallizing, washing and drying the telavancin hydrochloride solution. The document states that the disclosed process realizes effective separation and purification, the effective content reaches 99 percent, the product quality is improved, and the production cost is reduced.
The extraction process and the ion exchange resin separation medium in the reference process are difficult to effectively separate the by-products in the semi-synthetic products of telavancin and the impurities introduced by raw materials of vancomycin and the like. The early-stage research and development are carried out according to the reference data, and similar effects are difficult to repeat. According to the purification and separation experience of natural products, impurities can be effectively separated by selective chromatography media, the production cost is reduced, and the product purity is improved. The combination of the later crystallization steps can obtain stable raw material of telavancin hydrochloride.
In US patent application US20050113561 synthetic preparation and isolation purification steps are reported, wherein the process comprises multi-step purification and salt formation examples, the final product yield is not high.
According to the chromatographic medium selected by the scheme, an ODS bonding material (octadecyl bonding silica gel) has a specific and selective steric hindrance effect on a telavancin compound in space, the interaction between a side chain of the telavancin bonding and ODS hydrophobic is stronger than that of a conventional ion exchange resin material, and the performance of the telavancin compound and a material medium in a separation process is more tightly influenced by combining a proper acid solution or salt solvent system.
3) Concentrating the chromatography liquid with nanofiltration membrane to above 1/10, supplementing hydrochloric acid aqueous solution with pH of 4-5 when concentrating to 1/5 of the original volume, repeating for 3-5 times to remove buffer salt, and adding hydrochloric acid to adjust pH to 0.5-2 to obtain concentrated solution.
The research in the current situation and development of vancomycin research shows that: the stability of vancomycin is poor, after the vancomycin is placed for a long time at normal temperature, the color can be observed to gradually turn red, a large number of researches show that phenolic groups and diphenol groups exist in the molecular structure of the vancomycin, and the aqueous solution of the phenolic groups is easy to hydrate or oxidize into quinone to be pink when being exposed to light. The process research of the telavancin in the scheme shows that the red phenomenon is generated after the process research lasts for a long time. Rapid purification and the formation of stable compounds are therefore required without affecting the quality of the final product. Through the whole process of the scheme, the purification is rapidly carried out, and the problems of degradation and the like caused by long time can be effectively solved.
Preferably, when the solvent a is acetonitrile in step 3), the mass fraction gradient of acetonitrile in the eluent is selected to be 15%, 18%, 20%, 50%; when the solvent A is methanol, the mass fraction gradient of the methanol in the eluent is selected to be 20%, 23%, 25% and 50%; when the solvent A is ethanol, the mass fraction gradient of the ethanol in the eluent is selected to be 15%, 18%, 20% and 50%; when the solvent A is acetone, the gradient of the mass fraction of acetone in the eluent is selected to be 15%, 18%, 20% and 50%.
Preferably, the nanofiltration membrane in the step 3) is a polyethersulfone organic solvent-resistant nanofiltration membrane, and the molecular weight cutoff is 200-1000 daltons.
The range can effectively remove degraded micromolecular impurities, simultaneously dephosphorize buffer salt, achieve the effect of low-temperature concentration of dilute sample elution solution, and avoid the thermal damage caused by overhigh freeze-drying cost or heating, decompressing and concentrating.
Preferably, the chromatography in step 3) is performed by tracking the mass concentration of telavancin in the chromatography solution by HPLC.
Preferably, the reaction mixture of telavancin in the step 1) is a crude product of telavancin synthesized by the reductive amination reaction of vancomycin hydrochloride and N- (9-fluorenylmethoxycarbonyl) -decylaminoacetaldehyde, then 9-fluorenylmethoxycarbonyl protecting group is removed, and the Mannich reaction of the crude product of telavancin and aminomethylphosphonic acid is carried out.
The invention has the beneficial effects that:
the chromatographic medium octadecyl bonded silica gel is selected, a bonding material has specific and selective steric hindrance effect on the telavancin compound in space, meanwhile, the hydrophobic interaction is stronger than that of the conventional ion exchange resin, and the chromatographic medium octadecyl bonded silica gel is combined with a proper acid solution or salt solvent system to have tighter effect on the performance of the telavancin compound and the material medium in the separation process, so that high-purity telavancin can be obtained through separation.
Drawings
FIG. 1 raw sample HPLC of the reaction;
FIG. 2 is a HPLC chart after the purification method of example 5;
FIG. 3 is a mass spectrum analysis of Telavancin;
FIG. 4 is a structural diagram of vancomycin.
Detailed Description
In order to explain technical contents, structural features, and objects and effects of the present invention in detail, the following detailed description is given with reference to the accompanying drawings in conjunction with the embodiments.
Example 1
A method for purifying telavancin, comprising the steps of:
1) reacting mixture containing telavancin with methanol-formic acid-water solution according to the weight ratio of 1: 5, mixing, dissolving the reaction mixture, and filtering to remove solid insoluble substances to obtain filtrate; the methanol-formic acid-water solution is prepared according to the volume ratio of 2:1: 1; the reaction mixture of the telavancin is a crude product of the telavancin synthesized by the reductive amination reaction of vancomycin hydrochloride and N- (9-fluorenylmethoxycarbonyl) -decylaminoacetaldehyde, then removing 9-fluorenylmethoxycarbonyl protecting group and carrying out Mannich reaction with aminomethylphosphonic acid;
2) passing the filtrate through a chromatographic medium with well-balanced eluent, wherein the weight ratio of the sample filtrate to the chromatographic medium is 1: 50; the chromatography medium is octadecyl bonded silica gel; the eluent is 3 column volumes of solvent a-phosphate buffer solution, the phosphate buffer solution is: sodium dihydrogen phosphate 0.01mol/L, buffer solution with pH adjusted to 2.0 with phosphoric acid: when the solvent A is acetonitrile, the mass fraction gradient of the acetonitrile in the eluent is selected to be 15%, 18%, 20% and 50%; the elution flow rate is 1 BV/h; collecting chromatographic solution with HPLC mass concentration of telavancin above 95% (when eluate containing telavancin with cross purity less than 95%, mixing, adsorbing with macroporous adsorbent resin HP20 for recovery, and further purifying);
3) concentrating the chromatographic solution to more than 1/10 of the original volume through a nanofiltration membrane, wherein the nanofiltration membrane is a polyethersulfone organic solvent resistant nanofiltration membrane, the cut-off molecular weight is 200 daltons, supplementing hydrochloric acid aqueous solution with pH4 when concentrating to 1/5 of the original volume in the process, repeating the process for 3 times to remove buffer salt, and adding hydrochloric acid to adjust the pH value to 0.5 to obtain concentrated solution; and (3) adopting HPLC to track the mass concentration of telavancin in the chromatographic solution for chromatography in the step 3).
Example 2
A method for purifying telavancin, comprising the steps of:
1) reacting mixture containing telavancin with methanol-formic acid-water solution according to the weight ratio of 1: 10, mixing, dissolving the reaction mixture, and filtering to remove solid insoluble substances to obtain filtrate; the methanol-formic acid-water solution is prepared according to the volume ratio of 2:1: 1; the reaction mixture of the telavancin is a crude product of the telavancin synthesized by the reductive amination reaction of vancomycin hydrochloride and N- (9-fluorenylmethoxycarbonyl) -decylaminoacetaldehyde, then removing 9-fluorenylmethoxycarbonyl protecting group and carrying out Mannich reaction with aminomethylphosphonic acid;
2) passing the filtrate through a chromatographic medium with well-balanced eluent, wherein the weight ratio of the sample filtrate to the chromatographic medium is 1: 100, respectively; the chromatography medium is octadecyl bonded silica gel; the eluent is a solvent A-phosphate buffer solution with 5 column volumes, and the phosphate buffer solution is: disodium hydrogen phosphate 0.05mol/L, buffer solution with pH adjusted to 2.5 with phosphoric acid: when the solvent A is methanol, the mass fraction gradient of the methanol in the eluent is selected to be 20%, 23%, 25% and 50%; the elution flow rate is 5 BV/h; collecting chromatographic solution with HPLC mass concentration of telavancin above 95% (when eluate containing telavancin with cross purity less than 95%, mixing, adsorbing with macroporous adsorbent resin HP20 for recovery, and further purifying);
3) concentrating the chromatographic solution to more than 1/10 of the original volume through a nanofiltration membrane, wherein the nanofiltration membrane is a polyethersulfone organic solvent resistant nanofiltration membrane, the cut-off molecular weight is 1000 daltons, supplementing hydrochloric acid aqueous solution with pH5 when concentrating to 1/5 of the original volume in the process, repeating the process for 5 times to remove buffer salt, and adding hydrochloric acid to adjust the pH value to 2 to obtain a concentrated solution; and (3) adopting HPLC to track the mass concentration of telavancin in the chromatographic solution for chromatography in the step 3).
Example 3
A method for purifying telavancin, comprising the steps of:
1) reacting mixture containing telavancin with methanol-formic acid-water solution according to the weight ratio of 1: 7, mixing, dissolving the reaction mixture, and filtering to remove solid insoluble substances to obtain filtrate; the methanol-formic acid-water solution is prepared according to the volume ratio of 2:1: 1; the reaction mixture of the telavancin is a crude product of the telavancin synthesized by the reductive amination reaction of vancomycin hydrochloride and N- (9-fluorenylmethoxycarbonyl) -decylaminoacetaldehyde, then removing 9-fluorenylmethoxycarbonyl protecting group and carrying out Mannich reaction with aminomethylphosphonic acid;
2) passing the filtrate through a chromatographic medium with well-balanced eluent, wherein the weight ratio of the sample filtrate to the chromatographic medium is 1: 70; the chromatography medium is octadecyl bonded silica gel; the eluent is a 4 column volumes of solvent a-phosphate buffer solution, the phosphate buffer solution is: sodium dihydrogen phosphate 0.02mol/L, buffer solution with pH adjusted to 2.2 with phosphoric acid: when the solvent A is ethanol, the mass fraction gradient of the ethanol in the eluent is selected to be 15%, 18%, 20% and 50%, and the elution flow rate is 2 BV/h; collecting chromatographic solution with HPLC mass concentration of telavancin above 95% (when eluate containing telavancin with cross purity less than 95%, mixing, adsorbing with macroporous adsorbent resin HP20 for recovery, and further purifying);
3) concentrating the chromatographic solution to more than 1/10 of the original volume through a nanofiltration membrane, wherein the nanofiltration membrane is a polyethersulfone organic solvent resistant nanofiltration membrane, the cut-off molecular weight is 1000 daltons, supplementing hydrochloric acid aqueous solution with pH4 when concentrating to 1/5 of the original volume in the process, repeating the process for 4 times to remove buffer salt, and adding hydrochloric acid to adjust the pH value to 1 to obtain a concentrated solution; and (3) adopting HPLC to track the mass concentration of telavancin in the chromatographic solution for chromatography in the step 3).
Example 4
A method for purifying telavancin, comprising the steps of:
1) reacting mixture containing telavancin with methanol-formic acid-water solution according to the weight ratio of 1: 8, mixing, dissolving the reaction mixture, and filtering to remove solid insoluble substances to obtain filtrate; the methanol-formic acid-water solution is prepared according to the volume ratio of 2:1: 1; the reaction mixture of the telavancin is a crude product of the telavancin synthesized by the reductive amination reaction of vancomycin hydrochloride and N- (9-fluorenylmethoxycarbonyl) -decylaminoacetaldehyde, then removing 9-fluorenylmethoxycarbonyl protecting group and carrying out Mannich reaction with aminomethylphosphonic acid;
2) passing the filtrate through a chromatographic medium with well-balanced eluent, wherein the weight ratio of the sample filtrate to the chromatographic medium is 1: 90, respectively; the chromatography medium is octadecyl bonded silica gel; the eluent is a solvent A-phosphate buffer solution with 5 column volumes, and the phosphate buffer solution is: disodium hydrogen phosphate 0.04mol/L, buffer solution with pH adjusted by phosphoric acid at 2.4: when the solvent A is acetone, the mass fraction gradient of the acetone in the eluent is selected to be 15%, 18%, 20% and 50%, and the elution flow rate is 3 BV/h; collecting chromatographic solution with HPLC mass concentration of telavancin above 95% (when eluate containing telavancin with cross purity less than 95%, mixing, adsorbing with macroporous adsorbent resin HP20 for recovery, and further purifying);
3) concentrating the chromatographic solution to more than 1/10 of the original volume through a nanofiltration membrane, wherein the nanofiltration membrane is a polyethersulfone organic solvent resistant nanofiltration membrane, the cut-off molecular weight is 200 daltons, supplementing hydrochloric acid aqueous solution with pH5 when concentrating to 1/5 of the original volume in the process, repeating the process for 3 times to remove buffer salt, and adding hydrochloric acid to adjust the pH value to 1 to obtain a concentrated solution; and (3) adopting HPLC to track the mass concentration of telavancin in the chromatographic solution for chromatography in the step 3).
Example 5
A method for purifying telavancin, comprising the steps of:
1) reacting mixture containing telavancin with methanol-formic acid-water solution according to the weight ratio of 1: 7, mixing, dissolving the reaction mixture, and filtering to remove solid insoluble substances to obtain filtrate; the methanol-formic acid-water solution is prepared according to the volume ratio of 2:1: 1; the reaction mixture of the telavancin is a crude product of the telavancin synthesized by the reductive amination reaction of vancomycin hydrochloride and N- (9-fluorenylmethoxycarbonyl) -decylaminoacetaldehyde, then removing 9-fluorenylmethoxycarbonyl protecting group and carrying out Mannich reaction with aminomethylphosphonic acid;
2) passing the filtrate through a chromatographic medium with well-balanced eluent, wherein the weight ratio of the sample filtrate to the chromatographic medium is 1: 75; the chromatography medium is octadecyl bonded silica gel; the eluent is a 4 column volumes of solvent a-phosphate buffer solution, the phosphate buffer solution is: disodium hydrogen phosphate 0.35mol/L, buffer solution with pH adjusted to 2.3 with phosphoric acid: when the solvent A is ethanol, the mass fraction gradient of the ethanol in the eluent is selected to be 15%, 18%, 20% and 50%, and the elution flow rate is 3 BV/h; collecting a chromatographic solution with the HPLC mass concentration of telavancin being more than 95%;
3) concentrating the chromatographic solution to more than 1/10 of the original volume through a nanofiltration membrane, wherein the nanofiltration membrane is a polyethersulfone organic solvent resistant nanofiltration membrane, the cut-off molecular weight is 200 daltons, supplementing hydrochloric acid aqueous solution with pH4 when concentrating to 1/5 of the original volume in the process, repeating the process for 4 times to remove buffer salt, and adding hydrochloric acid to adjust the pH value to 1.5 to obtain concentrated solution; and (3) adopting HPLC to track the mass concentration of telavancin in the chromatographic solution for chromatography in the step 3).
And (4) HPLC detection:
1. detection conditions are as follows:
mobile phase: ammonium dihydrogen phosphate water (0.05mol/L, pH2.0 adjusted with phosphoric acid): acetonitrile 80: 20,
a chromatographic column: kromasil 100-5-C184.6 × 250mm, flow rate: 1.0ml/min, column temperature: 40 ℃, detection wavelength: 210nm, telavancin Rt 19.7 min.
2. Test sample comparison test
Taking the reactant as an original sample, and detecting the purity of the reactant according to the HPLC detection conditions, wherein the details are shown in figure 1;
taking a sample of the sample obtained by the purification method of example 5, and detecting the purity of the sample according to the HPLC detection conditions, and referring to FIG. 2 in detail;
the sample obtained by the purification method of example 5 was sampled and its mass spectrum was detected, as shown in FIG. 3(HRMS (ESI) m/z: calcd C)80H106Cl2N11O27P[M+2H]2+877.8187，found 877.8249[M+2H]2+，585.5532[M+3H]3+)。
Comparing fig. 1 and fig. 2 (purity more than 95%) and fig. 3, it can be seen that the purity of telavancin can be significantly improved by the purification method of the present invention.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes, which are made by using the contents of the present specification and the accompanying drawings, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (5)
1. A purification method of telavancin is characterized by comprising the following steps:
1) performing Mannich reaction on a crude product of telavancin synthesized by using methanol-formic acid-water solution according to the weight ratio of 1: 5 to 1: 10, mixing, dissolving the crude product of the telavancin synthesized by the Mannich reaction, and filtering to remove solid insoluble substances to obtain filtrate; the methanol-formic acid-water solution is prepared according to the volume ratio of 2:1: 1;
2) passing the filtrate through a chromatographic medium with well-balanced eluent, wherein the weight ratio of the sample filtrate to the chromatographic medium is 1: 50 to 1: 100, respectively; the chromatography medium is octadecyl bonded silica gel; the eluent is 3-5 column volumes of solvent A-phosphate buffer solution, the phosphate buffer solution is: 0.01mol/L-0.05mol/L of sodium dihydrogen phosphate or disodium hydrogen phosphate, and a buffer solution with pH adjusted to 2.0-2.5 by phosphoric acid; the solvent A is one of acetonitrile, methanol, ethanol and acetone, gradient elution is adopted, the mass fraction of the solvent A in the eluent is changed from 10% to 50% in a gradient manner, and the elution flow rate is 1BV/h to 5 BV/h; collecting a chromatographic solution with the HPLC mass concentration of telavancin being more than 95%;
3) concentrating the chromatography liquid with nanofiltration membrane to above 1/10, supplementing hydrochloric acid aqueous solution with pH of 4-5 when concentrating to 1/5 of the original volume, repeating for 3-5 times to remove buffer salt, and adding hydrochloric acid to adjust pH to 0.5-2 to obtain concentrated solution.
2. The method for purifying telavancin according to claim 1, wherein when solvent a is acetonitrile in step 2), the gradient of mass fraction of acetonitrile in the eluent is selected to be 15%, 18%, 20%, 50%; when the solvent A is methanol, the mass fraction gradient of the methanol in the eluent is selected to be 20%, 23%, 25% and 50%; when the solvent A is ethanol, the mass fraction gradient of the ethanol in the eluent is selected to be 15%, 18%, 20% and 50%; when the solvent A is acetone, the gradient of the mass fraction of acetone in the eluent is selected to be 15%, 18%, 20% and 50%.
3. The method for purifying telavancin according to claim 1, wherein the nanofiltration membrane in step 3) is an organic solvent resistant polyethersulfone nanofiltration membrane with a molecular weight cutoff of 200-1000 daltons.
4. The method for purifying telavancin according to claim 1, wherein the chromatography in step 2) is performed by tracking the mass concentration of telavancin in the chromatography solution by HPLC.
5. The method for purifying telavancin as claimed in claim 1, wherein the reaction mixture of telavancin in step 1) is a crude telavancin product synthesized by the reductive amination reaction of vancomycin hydrochloride and N- (9-fluorenylmethoxycarbonyl) -decylaminoacetaldehyde, removal of the 9-fluorenylmethoxycarbonyl protecting group, and Mannich reaction of the obtained product with aminomethylphosphonic acid.
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