CN112759757A - Method for purifying mono/diphosphonic acid polyethylene glycol monomethyl ether - Google Patents
Method for purifying mono/diphosphonic acid polyethylene glycol monomethyl ether Download PDFInfo
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- CN112759757A CN112759757A CN202011589828.7A CN202011589828A CN112759757A CN 112759757 A CN112759757 A CN 112759757A CN 202011589828 A CN202011589828 A CN 202011589828A CN 112759757 A CN112759757 A CN 112759757A
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- Prior art keywords
- polyethylene glycol
- glycol monomethyl
- monomethyl ether
- mono
- product
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- 239000002202 Polyethylene glycol Substances 0.000 title claims abstract description 34
- 229920001223 polyethylene glycol Polymers 0.000 title claims abstract description 34
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims abstract description 20
- XQRLCLUYWUNEEH-UHFFFAOYSA-N diphosphonic acid Chemical compound OP(=O)OP(O)=O XQRLCLUYWUNEEH-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 239000000047 product Substances 0.000 claims abstract description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000012535 impurity Substances 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 150000001336 alkenes Chemical class 0.000 claims abstract description 4
- 150000001412 amines Chemical class 0.000 claims abstract description 4
- 239000012043 crude product Substances 0.000 claims abstract description 4
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 28
- 238000003756 stirring Methods 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000012071 phase Substances 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000001177 diphosphate Substances 0.000 claims description 10
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 10
- 235000011180 diphosphates Nutrition 0.000 claims description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 239000002699 waste material Substances 0.000 claims description 6
- 239000006184 cosolvent Substances 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- -1 phospho Chemical class 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000012670 alkaline solution Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000000643 oven drying Methods 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 150000004712 monophosphates Chemical class 0.000 claims 2
- 239000002585 base Substances 0.000 claims 1
- 159000000000 sodium salts Chemical group 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical group OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
- PRFDQHCVOVMMJC-UHFFFAOYSA-N methyl phosphono hydrogen phosphate Chemical compound COP(O)(=O)OP(O)(O)=O PRFDQHCVOVMMJC-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/30—Post-polymerisation treatment, e.g. recovery, purification, drying
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for purifying mono/diphosphonic acid polyethylene glycol monomethyl ether, which is characterized in that the mono/diphosphonic acid polyethylene glycol monomethyl ether is converted into salt by alkali, and impurities in the product are extracted from the product by using an organic solvent. The invention utilizes the acidity of the diphosphate group of the product, and converts the product into a salt form by alkali, so that the water solubility of the product is better; most of the impurities in the crude product are olefin or amine derivatives, which are extracted from the product by using an organic solvent. The invention can purify mono/diphosphonic acid polyethylene glycol monomethyl ether with the purity of about 90 percent to the purity of more than 99 percent, and the required instruments and equipment, reagents are common and easy to obtain, large-scale precise expensive instruments are not needed, and the process is simple and easy to operate. Can be produced in large scale and meet the large-scale market demand.
Description
Technical Field
The invention relates to a method for purifying mono/di-phosphoric acid polyethylene glycol monomethyl ether, belonging to the technical field of biological medicines.
Background
Polyethylene glycol, as an artificially synthesized polymer material, is widely applied in the field of medicine and pharmacology at present due to good biological, blood compatibility and hydrophilicity and no toxic or side effect. At present, methoxy polyethylene glycol with one active terminal hydroxyl group is mainly studied in the aspect of drug modification, however, the activity of the terminal hydroxyl group of methoxy polyethylene glycol is weak and is difficult to meet the requirement of drug modification, and the terminal hydroxyl group is usually converted into a group with higher activity such as amino, sulfydryl, aldehyde group and the like for use. Polyethylene glycol monomethyl ether mono/diphosphate is widely used in various proteins, polypeptides and nano-drugs due to its excellent activity of terminal groups and its adsorbability. The existing synthesis method of mono/diphosphonic acid polyethylene glycol monomethyl ether can generate partial side reactions, the product is difficult to purify due to the chemical properties of polyethylene glycol, the existing purification method is mostly prepared by reversed phase high performance liquid chromatography, the method has high input cost, needs to be purified for multiple times, and is difficult to be produced and used in large scale.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a method for purifying mono/diphosphonic acid polyethylene glycol monomethyl ether, which reduces the cost required by purifying the mono/diphosphonic acid polyethylene glycol monomethyl ether and solves the problem of difficult large-scale production.
In order to solve the technical problems, the invention provides a method for purifying mono/diphosphonic acid polyethylene glycol monomethyl ether, wherein the mono/diphosphonic acid polyethylene glycol monomethyl ether is converted into a salt form by alkali, and impurities in a product are extracted from the product by using an organic solvent.
Preferably, the method specifically comprises:
dissolving the mono/diphosphonic acid polyethylene glycol monomethyl ether crude product in water, and adjusting the solution to be alkaline by using an alkaline solution;
adding a cosolvent and an organic solvent under a stirring state, stirring for 5-10 min, and standing for layering;
separating the organic phase as waste liquid, collecting water phase as product, concentrating the water phase with rotary evaporator, adding methyl tert-butyl ether, stirring, crystallizing, filtering to obtain solid, and oven drying.
Preferably, the alkali is one of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.
Preferably, the organic solvent is one or two of methanol and dichloromethane, and the methanol and the dichloromethane mainly have the function of extracting impurities from the aqueous solution of the product.
Preferably, the cosolvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran and acetonitrile. Tetrahydrofuran, 2-methyltetrahydrofuran and acetonitrile mainly act as cosolvent, so that the product can be well dissolved in a water phase under the condition of a poor solvent.
Preferably, the impurities in the product are derivatives of olefins or amines.
Preferably, the temperature when the alkali solution is adjusted to be alkaline is 20-30 ℃.
Preferably, the stirring and crystallization time is 30-40 min.
The principle of the invention is as follows:
the invention achieves the following beneficial effects: because the polyethylene glycol chain units are more and the extraction impurities are difficult to layer due to good solubility, the invention utilizes the acidity of the diphosphate group of the product and converts the product into a salt form by alkali, so that the water solubility of the product is better; most of the impurities in the crude product are olefin or amine derivatives, which are extracted from the product by using an organic solvent. The invention can purify mono/diphosphonic acid polyethylene glycol monomethyl ether with the purity of about 90 percent to the purity of more than 99 percent, and the required instruments and equipment, reagents are common and easy to obtain, large-scale precise expensive instruments are not needed, and the process is simple and easy to operate. Can be produced in large scale and meet the large-scale market demand.
Detailed Description
The present invention will be further described with reference to the following examples. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
Example 1:
2.0g of self-prepared polyethylene glycol monomethyl diphosphate (purity HPLC: 93.7 percent), 10ml of purified water is added to dissolve the mixture, the mixture is adjusted to be alkaline by 10 percent NaOH aqueous solution, the temperature is 20-30 ℃, the mixture is stirred for 5min, the pH value is not changed, MeOH, THF and DCM are added under the stirring state, the mixture is stirred for 10min at room temperature, and the mixture is kept standing for layering. Separating an organic phase as waste liquid for treatment, taking a water phase as a product, concentrating and drying the water phase by using a rotary evaporator, adding MTBE, stirring and crystallizing for 30min, filtering to obtain a product solid, drying by 1.63g, obtaining a yield of 77%, and obtaining a purity HPLC: 99.52 percent.
Example 2:
2.0g of self-prepared diphosphonic acid polyethylene glycol monomethyl ether (purity HPLC: 93.7 percent), adding 10ml of purified water for dissolving, adjusting to be alkaline by using 10 percent NaOH aqueous solution, stirring for 5min at the temperature of 20-30 ℃ without changing the pH value, adding methanol, dichloromethane and acetonitrile under the stirring state, stirring for 10min, standing and layering. Separating an organic phase as waste liquid for treatment, taking a water phase as a product, concentrating and drying a solvent by a rotary evaporator, adding MTBE, stirring and crystallizing for 30min, filtering to obtain a product solid, drying by 1.67g, obtaining a yield of 79%, and obtaining a purity HPLC: 99.67 percent.
Example 3:
2.0g of self-made polyethylene glycol monomethyl diphosphate (purity HPLC: 93.7 percent), adding 10ml of purified water for dissolving, adjusting the mixture to be alkaline by using 10 percent NaOH aqueous solution, stirring for 5min at the temperature of 20-30 ℃ without changing the pH value, adding a mixed solvent of 2-methyltetrahydrofuran, dichloromethane and methanol under the stirring state, stirring for 10min, and standing for layering. Separating an organic phase as waste liquid for treatment, taking a water phase as a product, concentrating and drying the solvent by a rotary evaporator, adding 20ml of MTBE, stirring and crystallizing for 30min, filtering to obtain a product solid, drying by 1.71g, obtaining a yield of 81%, and obtaining a purity HPLC: 99.09 percent.
Example 4:
1.0g of monophosphoric acid polyethylene glycol monomethyl ether (HPLC purity: 88.95%) is self-prepared, 5ml of purified water is added to dissolve and clear, 10% of sodium hydroxide aqueous solution is used for adjusting to be alkaline, the temperature is 20-30 ℃, stirring is carried out for 5min, the pH value is not changed, methanol, dichloromethane and acetonitrile are added under the stirring state, stirring is carried out for 10min, and standing and layering are carried out. Separating an organic phase as waste liquid for treatment, taking a water phase as a product, concentrating and drying a solvent by a rotary evaporator, adding MTBE, stirring and crystallizing for 30min, filtering to obtain a product solid, drying by 0.78g, obtaining a yield of 74%, and obtaining an HPLC purity: 99.33 percent.
Comparative example:
2.0g of self-made polyethylene glycol monomethyl diphosphate (purity HPLC: 93.7%) is prepared by reversed phase liquid chromatography, and acetonitrile and water are used as solvents. The peak time of the product is as follows: 5.84 min; time of impurity peak emergence: 6.08min, 6.42 min; and receiving the flushed product solutions in sections, detecting by using a liquid chromatography respectively, combining the qualified product phases, and freeze-drying by a freeze dryer directly. Discharging: 1.13g, 56.5% yield, purity HPLC: 98.39 percent.
Table 1 examples 1-4 and comparative example purification results
| Purification scheme | Using solvents | Product yield | Purity of the product |
| Example 1 | MeOH/DCM/THF | 77％ | 99.52％ |
| Example 2 | MeOH/DCM/2-Me-THF | 79％ | 99.67％ |
| Example 3 | MeOH/DCM/ACN | 81％ | 99.09％ |
| Example 4 | MeOH/DCM/ACN | 74％ | 99.33％ |
| Comparative example | ACN/H2O | 56.5％ | 98.39％ |
Experiments show that under the action of a mixed solvent, the efficiency of purifying the methoxypolyethylene glycol diphosphate is greatly improved, the yield is improved to more than 70 percent from about 55 percent originally, the purity is also greatly improved compared with a liquid chromatography preparation method, and the method is obviously superior to the original reverse liquid chromatography preparation method.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.
Claims (8)
1. The purification method of mono/diphosphate polyethylene glycol monomethyl ether is characterized by that it uses alkali to convert mono/diphosphate polyethylene glycol monomethyl ether into sodium salt form, and utilizes organic solvent to extract the impurity from the product.
2. The method for purifying polyethylene glycol monomethyl ether mono/diphosphate according to claim 1, characterized in that it specifically comprises:
dissolving the mono/diphosphonic acid polyethylene glycol monomethyl ether crude product in water, and adjusting the solution to be alkaline by using an alkaline solution;
adding a cosolvent and an organic solvent under the stirring state, stirring, standing and layering;
separating the organic phase as waste liquid, collecting water phase as product, concentrating the water phase with rotary evaporator, adding methyl tert-butyl ether, stirring, crystallizing, filtering to obtain solid, and oven drying.
3. The purification method of polyethylene glycol monomethyl ether mono/diphosphate according to claim 1 or 2, characterized in that the base is one of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.
4. The purification method of mono/bis (phospho) polyethylene glycol monomethyl ether according to claim 1 or 2, characterized in that the organic solvent is one or a mixture of methanol and dichloromethane.
5. The purification method of polyethylene glycol monomethyl ether mono/diphosphate according to claim 2, characterized in that the cosolvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile.
6. The method for purifying polyethylene glycol monomethyl ether mono/diphosphate according to claim 1, wherein the impurities in the product are olefin or amine derivatives.
7. The method for purifying polyethylene glycol monomethyl ether mono/diphosphate according to claim 2, wherein the temperature at which the alkali solution is adjusted to be alkaline is 20 to 30 ℃.
8. The purification method of polyethylene glycol monomethyl ether mono/diphosphate according to claim 2, wherein the time for stirring crystallization is 30 to 40 min.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113527702A (en) * | 2021-07-15 | 2021-10-22 | 东华大学 | Amphiphilic phosphorus-containing tree crown macromolecular material and preparation and application thereof |
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|---|---|---|---|---|
| US20080090991A1 (en) * | 2005-08-26 | 2008-04-17 | Id Biochem Inc. | Preparing Method Of Methoxypolyethyleneglycol And Its Derivatives |
| US20100323452A1 (en) * | 2007-02-22 | 2010-12-23 | Biovectra Inc. | Process for purification of water soluble polymers |
| CN105189606A (en) * | 2013-03-27 | 2015-12-23 | 日油株式会社 | Purification method for polyethylene glycol having single amino group |
| US20160075624A1 (en) * | 2014-09-17 | 2016-03-17 | Nanjing Carbonde Tech Co., Ltd. | Process for preparing and separating monodisperse polyethylene glycol |
| CN110325567A (en) * | 2017-01-25 | 2019-10-11 | 亨茨曼国际有限公司 | The method for producing polyether polyol |
| CN110475800A (en) * | 2017-03-30 | 2019-11-19 | 日油株式会社 | The purification process of polyethylene glycol with a carboxyl |
-
2020
- 2020-12-28 CN CN202011589828.7A patent/CN112759757B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080090991A1 (en) * | 2005-08-26 | 2008-04-17 | Id Biochem Inc. | Preparing Method Of Methoxypolyethyleneglycol And Its Derivatives |
| US20100323452A1 (en) * | 2007-02-22 | 2010-12-23 | Biovectra Inc. | Process for purification of water soluble polymers |
| CN105189606A (en) * | 2013-03-27 | 2015-12-23 | 日油株式会社 | Purification method for polyethylene glycol having single amino group |
| US20160075624A1 (en) * | 2014-09-17 | 2016-03-17 | Nanjing Carbonde Tech Co., Ltd. | Process for preparing and separating monodisperse polyethylene glycol |
| CN110325567A (en) * | 2017-01-25 | 2019-10-11 | 亨茨曼国际有限公司 | The method for producing polyether polyol |
| CN110475800A (en) * | 2017-03-30 | 2019-11-19 | 日油株式会社 | The purification process of polyethylene glycol with a carboxyl |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113527702A (en) * | 2021-07-15 | 2021-10-22 | 东华大学 | Amphiphilic phosphorus-containing tree crown macromolecular material and preparation and application thereof |
| CN113527702B (en) * | 2021-07-15 | 2023-02-03 | 东华大学 | Amphiphilic phosphorus-containing tree crown macromolecular material and preparation and application thereof |
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| CN112759757B (en) | 2023-11-24 |
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