CN105778116B - PEG- acrylate dendritic polymer and preparation method thereof - Google Patents
PEG- acrylate dendritic polymer and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 71
- 239000000412 dendrimer Substances 0.000 title claims abstract description 61
- 229920000736 dendritic polymer Polymers 0.000 title claims abstract description 60
- 238000006243 chemical reaction Methods 0.000 claims abstract description 143
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 30
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 30
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims abstract description 21
- 239000002994 raw material Substances 0.000 claims abstract description 15
- 238000005809 transesterification reaction Methods 0.000 claims abstract description 9
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 125000006239 protecting group Chemical group 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 351
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 135
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 98
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 96
- 239000000178 monomer Substances 0.000 claims description 82
- 238000003756 stirring Methods 0.000 claims description 80
- 239000007788 liquid Substances 0.000 claims description 70
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 52
- 239000003054 catalyst Substances 0.000 claims description 50
- 239000003480 eluent Substances 0.000 claims description 44
- 239000003208 petroleum Substances 0.000 claims description 44
- 238000010898 silica gel chromatography Methods 0.000 claims description 42
- 239000003153 chemical reaction reagent Substances 0.000 claims description 41
- 239000002904 solvent Substances 0.000 claims description 40
- 239000000243 solution Substances 0.000 claims description 38
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 claims description 34
- 238000004440 column chromatography Methods 0.000 claims description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 32
- 239000011230 binding agent Substances 0.000 claims description 32
- 238000001914 filtration Methods 0.000 claims description 32
- 239000003960 organic solvent Substances 0.000 claims description 30
- 238000002347 injection Methods 0.000 claims description 28
- 239000007924 injection Substances 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 26
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 24
- 239000012535 impurity Substances 0.000 claims description 22
- 238000004821 distillation Methods 0.000 claims description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- -1 mercapto amine compound Chemical class 0.000 claims description 15
- 229910052786 argon Inorganic materials 0.000 claims description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 10
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical group COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 239000003495 polar organic solvent Substances 0.000 claims description 10
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 10
- 238000001291 vacuum drying Methods 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- 108010084311 Novozyme 435 Proteins 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 238000012650 click reaction Methods 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- IYGAMTQMILRCCI-UHFFFAOYSA-N 3-aminopropane-1-thiol Chemical compound NCCCS IYGAMTQMILRCCI-UHFFFAOYSA-N 0.000 claims description 5
- 229960003151 mercaptamine Drugs 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 claims description 3
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 claims description 3
- LMQBGUFOFQYPJS-UHFFFAOYSA-N 4-(2-aminoethyl)benzenethiol Chemical compound NCCC1=CC=C(S)C=C1 LMQBGUFOFQYPJS-UHFFFAOYSA-N 0.000 claims description 2
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 238000013375 chromatographic separation Methods 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229920000642 polymer Polymers 0.000 abstract description 13
- 125000000524 functional group Chemical group 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 6
- 239000000654 additive Substances 0.000 abstract description 5
- 230000000996 additive effect Effects 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000000975 dye Substances 0.000 abstract description 5
- 238000006555 catalytic reaction Methods 0.000 abstract description 4
- 125000003368 amide group Chemical group 0.000 abstract 1
- 239000011203 carbon fibre reinforced carbon Chemical group 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- HRKQOINLCJTGBK-UHFFFAOYSA-N dihydroxidosulfur Chemical compound OSO HRKQOINLCJTGBK-UHFFFAOYSA-N 0.000 abstract 1
- 239000002245 particle Substances 0.000 abstract 1
- 239000002351 wastewater Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 122
- 239000000203 mixture Substances 0.000 description 17
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 description 13
- 238000004809 thin layer chromatography Methods 0.000 description 12
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 description 11
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 7
- 229920002582 Polyethylene Glycol 600 Polymers 0.000 description 7
- 229920002593 Polyethylene Glycol 800 Polymers 0.000 description 7
- 125000004185 ester group Chemical group 0.000 description 7
- 239000007789 gas Substances 0.000 description 7
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 125000006242 amine protecting group Chemical group 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000003760 magnetic stirring Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000002390 rotary evaporation Methods 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- GSJJCZSHYJNRPN-UHFFFAOYSA-N tert-butyl n-(2-sulfanylethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCS GSJJCZSHYJNRPN-UHFFFAOYSA-N 0.000 description 5
- 230000007547 defect Effects 0.000 description 4
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 4
- 229920002521 macromolecule Polymers 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 238000001223 reverse osmosis Methods 0.000 description 4
- 239000002455 scale inhibitor Substances 0.000 description 4
- GMEDUXHKSSWXSL-UHFFFAOYSA-N 3-sulfanylpropylazanium;chloride Chemical compound Cl.NCCCS GMEDUXHKSSWXSL-UHFFFAOYSA-N 0.000 description 3
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000002105 nanoparticle Substances 0.000 description 3
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000012679 convergent method Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000012678 divergent method Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000010954 inorganic particle Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000002159 nanocrystal Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000002910 structure generation Methods 0.000 description 1
- 230000002194 synthesizing 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
- C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
- C08G83/002—Dendritic macromolecules
- C08G83/003—Dendrimers
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Macromonomer-Based Addition Polymer (AREA)
- Polyethers (AREA)
Abstract
The present invention discloses PEG- acrylate dendritic polymer and preparation method thereof.The present invention is using acrylate, polyethylene glycol and primary amine thio-alcohol as raw material; by transesterification reaction; the 4.5th generation PEG- acrylate dendritic polymer is prepared in alkene-sulfydryl and the reaction of alkene-double bond click chemistry, wherein using amido protecting group, hydroxyl or carbon-carbon double bond as surface functional group.Dendritic polymer of the present invention has biggish cavity, not only serve as the coated carrier of organic dyestuff, drug and nano inoganic particle, and there is a large amount of functional group on surface, it can be used as additive and the mobile performance for improving product be blended in other polymers, and be used for anti-penetration wastewater disposal antisludging agent, Industrial Catalysis.
Description
Technical Field
The invention relates to a dendritic polymer, in particular to a PEG-acrylate dendritic polymer and a preparation method thereof.
Background
The combination of dendritic structures and linear structures in the same macromolecule brings new possibility for the self-assembly process of drug loading and nanocrystal coating, the structure has excellent geometric symmetry, and the volume and the shape of the molecule can be accurately controlled. Due to the unique structure of the dendritic polymer, the dendritic polymer has a series of unique physical and chemical characteristics such as low viscosity, high rheological property, a large number of terminal functional groups and the like, and has wide application prospects in the fields of advanced material design and the like.
However, the dendritic polymers that have been successfully prepared so far still have certain disadvantages:
(1) the synthesis conditions are complex and harsh
The existing synthesis process of the dendritic macromolecule requires strict reaction conditions and complex reaction processes, such as hydrogenation, deprotection, high temperature, long flow, multi-step treatment and the like, so that the synthesis difficulty is increased, and the possibility of molecular design of the dendritic macromolecule is limited. Therefore, the reaction conditions of these synthetic means are the main defects of the existing synthetic process.
(2) The higher the algebraic number of synthesis, the larger the space bit, the more serious the defect of branch
From the aspect of molecular design structure, the dendritic polymer with precise structure can be designed. However, with the repetition of the branching unit, steric hindrance in the molecule is increased, thereby causing some defects that the molecular structure cannot achieve accuracy.
(3) Toxicity of dendrimers containing a large number of nitrogen atoms or aromatic rings
Contains a large amount of nitrogen atoms, can form cations after entering organisms, and the interaction of the cations on the surfaces of the macromolecules and the anions on the surfaces of cell membranes destroys the biochemical environment of cells, thereby presenting certain biological toxicity. The dendritic polymer having an aromatic ring is difficult to be rapidly degraded in a living body and difficult to be completely discharged, and thus the time for which the dendritic polymer stays in the living body is long, which is disadvantageous to the health of the living body.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide the PEG-acrylate dendritic polymer which has the characteristics of mild reaction conditions, high conversion rate, environmental protection and low viscosity and high rheological property and the preparation method thereof.
The PEG-acrylate dendritic polymer is prepared by taking acrylate, polyethylene glycol (PEG) and primary amine thiol as raw materials and carrying out transesterification reaction and click chemical reaction of alkene-sulfydryl and alkene-double bond to obtain a surface functional group which takes the polyethylene glycol-acrylate as a repeating unit and contains an amino group (BOC amino protecting group). Specifically, acrylate and PEG are subjected to transesterification catalytic conversion, then alkene-thiol and alkene-double bond click reaction is carried out, and an algebraic PEG-acrylate dendritic polymer branched monomer is synthesized by combining a divergent method and a convergent method. The PEG-acrylate dendritic polymer can be used as a coating carrier of organic dyes, medicaments and inorganic nano particles, a high molecular polymer blending modified fluidity adjusting additive and a reverse osmosis water treatment scale inhibitor.
The purpose of the invention is realized by the following technical scheme:
the PEG-acrylate dendritic polymer has the following structural formula, wherein the left amplified chain segment in the formula represents one end of the bottom of the dendritic polymer, the right amplified chain segment represents the branch of the dendritic polymer, the tail end of the branch at the tail end is an amino protecting group-NHBoc, and the structures of other branches at all levels are the same as the right amplified chain segment;
R1represents a hydrogen bond or a methyl group, R2represents-CH2CH2-or-CH2CH2CH2-; the value of n is 3-20.
Preferably, the PEG-acrylate dendrimer has a molecular weight of 1.3 to 7 ten thousand.
Preferably, the PEG-acrylate dendrimer generation product Gn has a terminal group NHBoc and a terminal number Ne ofThe number of inner layer repeating units Nr isWherein,number of connecting branches NbWhere n represents the algebraic number of the synthesis, n is 1, 2, 3, 4, 5, and b represents a branch.
Preferably, the number of branched attachment branches N of said PEG-acrylate dendrimerbIs 2.
Preferably, half of the generations of said PEG-acrylate dendrimer generation GmOne end of the terminal group(s) is a hydroxyl group, the other end is an amino protecting group, and the number Ne of the terminal groups isThe number of inner layer repeating units Nr is Denotes the number of branched linking branches NbM-0.5, where m represents the algebraic number of the synthesis, m1.5, 2.5, 3.5, 4.5, b indicates branching.
The preparation method of the PEG-acrylate dendritic polymer comprises the following steps:
(1) preparing raw material polyethylene glycol methacrylate by transesterification: firstly, 1 part of polyethylene glycol is dissolved in an organic solvent according to the amount of a substance to prepare a solution of 0.3-1.5 mmol/mL, then 1-5 parts of acrylate is added, after uniform stirring, transesterification enzyme is added, 5-15 mg of transesterification is added to each milliliter of the solution, and the reaction is carried out for 24-48 hours under the stirring at the temperature of 30-70 ℃; after the reaction is finished, filtering, distilling under reduced pressure, carrying out chromatographic separation on the residual liquid, and eluting by using an eluant of petroleum ether/ethyl acetate to obtain a product of polyethylene glycol acrylate;
(2) click reaction preparation of branched monomer 1: dissolving 1 part of polyethylene glycol acrylate monoester in a polar organic solvent by mass to prepare a solution of 2-20 mmol/mL, dissolving 1-5 parts of primary mercapto amine compound in the polar organic solvent to prepare a solution of 2-20 mmol/mL, and adding 0-3 parts of an alkaline catalyst; introducing argon to remove oxygen; stirring and reacting for 2-10 h at room temperature; after the reaction is finished, carrying out reduced pressure distillation at the temperature of 30-50 ℃ to remove an organic phase, separating the residual liquid through column chromatography, eluting with an eluant of ethyl acetate/methanol, and carrying out vacuum drying to obtain a product branched monomer 1;
(3) click reaction preparation of branched monomer 2: dissolving 1 part of polyethylene glycol acrylate monoester in a polar organic solvent by mass to prepare a solution of 2-20 mmol/mL, dissolving 1-6 parts of Boc-aminothiol compound in the polar organic solvent to prepare a solution of 2-20 mmol/mL, and adding 0-3 parts of an alkaline catalyst; deoxidizing; stirring and reacting for 2-10 h at room temperature; after the reaction is finished, carrying out reduced pressure distillation at the temperature of 30-50 ℃ to remove an organic phase, separating the residual liquid by column chromatography, eluting by an eluent of ethyl acetate/methanol, and carrying out vacuum drying to obtain a product branched monomer 2;
(4) branch G0.5 for making dendrimers: dissolving 1 part of the product branched monomer 1 obtained in the step (2) in an organic solvent by mass to prepare a solution of 0.1-10 mmol/mL, and adding 0-3 parts of an acid-binding agent; then dissolving 1-5 parts of acryloyl chloride in an organic solvent to prepare a solution of 0.1-10 mmol/mL, injecting the acryloyl chloride solution into the branched monomer 2 solution under the stirring condition, reacting for 12-36 h under the stirring condition at 20-60 ℃, distilling the reaction solution under reduced pressure after the reaction is finished, and separating the residual liquid through a silica gel column to obtain a quasi-branched G0.5 (0.5 generation branched structure);
(5) preparation of branch G1.5 of dendritic Polymer: dissolving 1 part of the product branched monomer 1 obtained in the step (2) in an organic solvent by mass to prepare a solution of 0.1-10 mmol/mL, and adding 0-3 parts of an alkaline catalyst; then dissolving 0.5-5 parts of quasi-branched G0.5 obtained in the step (4) in an organic solvent to prepare a solution of 0.1-10 mmol/mL, dropwise adding a branched monomer 1 solution into the quasi-branched G0.5 solution under a stirring condition, after the reaction is finished, carrying out reduced pressure distillation on a reaction solution, and separating the residual liquid through a silica gel column to obtain a branched G1.5 (1.5 generation branched structure);
(6) preparation of branch G2.5 of dendrimer: taking 1 part of G1.5 by mass, dissolving in an organic solvent to prepare a solution of 0.1-10 mmol/mL, 0-3 parts of an acid-binding agent, injecting 1-5 parts of acryloyl chloride by using an injector, stirring at room temperature for 12-36 h after injection, filtering after reaction, distilling under reduced pressure to remove the solvent, extracting with dichloromethane and water to remove water-soluble impurities, and separating oil layer liquid by column chromatography to obtain a product; dissolving 1 part of the product in an organic solvent, dissolving 0.5-5 parts of a branched monomer 1 in the organic solvent, stirring 0-3 parts of an alkaline catalyst at 20-60 ℃ for 60-100 h, and after the reaction is finished, separating by silica gel column chromatography by using a petroleum ether/ethyl acetate mixed reagent as an eluent to obtain a branch G2.5 (2.5-generation branch structure);
(7) preparation of branch G3.5 of dendrimer: firstly, taking 1 part of G2.5 by mass, dissolving in an organic solvent to prepare a solution of 0.1-10 mmol/mL, 0-3 parts of an acid-binding agent, injecting 1-5 parts of acryloyl chloride by using an injector, stirring at room temperature for 12-36 h after injection is finished, filtering after reaction is finished, distilling under reduced pressure to remove the solvent, extracting with dichloromethane and water to remove water-soluble impurities, and separating oil layer liquid by column chromatography to obtain a product; dissolving 1 part of the product in an organic solvent, dissolving 0.5-5 parts of a branched monomer 1 in the organic solvent, stirring 0-3 parts of an alkaline catalyst at 20-60 ℃ for 60-100 h, and after the reaction is finished, separating by silica gel column chromatography by using a petroleum ether/ethyl acetate mixed reagent as an eluent to obtain a product G3.5 branched structure (3.5-substituted branched structure);
(8) preparation of branch G4.5 of dendrimer: taking 1 part of G3.5 by mass, dissolving in an organic solvent to prepare a solution of 0.1-10 mmol/mL, 0-3 parts of an acid-binding agent, injecting 1-5 parts of acryloyl chloride by using an injector, stirring at room temperature for 12-36 h after injection, filtering after reaction, distilling under reduced pressure to remove the solvent, extracting with dichloromethane and water to remove water-soluble impurities, and separating oil layer liquid by column chromatography to obtain a product; dissolving 1 part of the product in an organic solvent, dissolving 0.5-5 parts of a branched monomer 1 in the organic solvent, stirring 0-3 parts of an alkaline catalyst at 20-60 ℃ for 60-100 h, and after the reaction is finished, separating by silica gel column chromatography by using a petroleum ether/ethyl acetate mixed reagent as an eluent to obtain a branch G4.5 (4.5 th generation branch structure).
Preferably, the polyethylene glycol has an average molecular weight of 200-1000.
Preferably, the acrylate is methyl methacrylate, ethyl methacrylate, methyl acrylate or ethyl acrylate.
Preferably, the transesterase is Novozyme 435, and the organic solvent is one or more of ether, dichloromethane and tetrahydrofuran; the alkaline catalyst is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium methoxide, sodium ethoxide, triethylamine and pyridine; the polar organic solvent is one or more of methanol, ethanol, ether, dichloromethane and tetrahydrofuran; the primary mercapto amine compound includes one or more of mercaptoethylamine, p-mercaptophenylethylamine, 3-mercapto-1-propylamine and hydrochloride thereof.
Preferably, the primary mercapto amine compound is one or more of 2- (Boc-amino) ethanethiol and 3-mercapto-propyl- (Boc-amino); the acid-binding agent comprises one or more of triethylamine, pyridine, N-diisopropylethylamine and potassium carbonate.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) the PEG-acrylate dendritic polymer prepared by the invention integrates the advantages of a convergence method and a divergence method, uses transesterification reaction and alkene-sulfydryl and alkene-double bond click reaction in sequence, has mild reaction conditions, accurate molecular structure and high conversion rate, and is green and environment-friendly.
(2) Compared with the traditional polyamide-amine dendritic Polymer (PAMAM) and the like, the PEG-acrylate dendritic polymer prepared by the invention greatly reduces the content of nitrogen atoms in the molecular structure, thereby reducing the biotoxicity.
(3) The PEG-acrylate dendritic polymer prepared by the invention is a combination of a dendritic structure and a linear structure, has a series of unique physical and chemical characteristics of a dendritic polymer, such as a larger cavity, low viscosity, high rheological property, a large number of terminal functional groups and the like, can be used as a coating carrier of organic dyes, medicines and inorganic nanoparticles, can also be used as an additive and other polymers to blend and improve the flow property of a product, and has wide application prospect in the field of advanced material design such as reverse osmosis water treatment scale inhibitors, industrial catalysis and petrochemical engineering.
Drawings
FIG. 1 is a magnetic carbon spectrum of a 4.5 th generation branched core structure of example 1.
Detailed Description
The invention is further illustrated by the following examples, but the scope of the invention as claimed is not limited to the examples. In the embodiment, the volume ratio of petroleum ether to ethyl acetate in the eluent petroleum ether/ethyl acetate mixed reagent is 30-40: 1.
Example 1
(1) Preparation of PEG200 monomethacrylate monoester: 3g of PEG200 was dissolved in 15mL of tetrahydrofuran, and 2.5g of methyl methacrylate and 150mg of Novozyme 435 were added thereto, followed by stirring at 50 ℃ and reaction under magnetic stirring at a constant temperature for 25 hours. Tracking by using thin layer chromatography in the reaction process, filtering to remove transesterase after the reaction is finished, distilling the filtrate under reduced pressure by using a rotary evaporator to remove the solvent, and then separating by using a mixed reagent of petroleum ether and ethyl acetate as an eluent through silica gel column chromatography to obtain a PEG200 monomethacrylate product which is light yellow liquid and has the average molecular weight of 270 g/mol.
(2) Preparation of branched monomer 1: 2.7g of PEG200 methacrylic acid monoester was dissolved in 5mL of tetrahydrofuran, and 0.50g of catalytic sodium hydroxide and 1.3g of mercaptoethylamine hydrochloride were added thereto, followed by stirring at room temperature for 4 hours under argon. After the reaction was complete, the product was extracted with dichloromethane and water until mercaptoethylamine hydrochloride was absent from the water (confirmed by thin layer chromatography). The organic phase was dehydrated with anhydrous magnesium sulfate. And (3) carrying out rotary evaporation on the organic phase subjected to water removal at the temperature of 30 ℃, and carrying out vacuum drying to obtain a branched monomer 1 product which is a light yellow liquid and has the average molecular weight of 340 g/mol.
(3) Preparation of branched monomer 2: 2.7g of PEG200 methacrylic acid monoester was dissolved in 5mL of tetrahydrofuran, and 0.50g of catalytic sodium hydroxide and 1.8g of 2- (Boc-amino) ethanethiol were added thereto, followed by stirring and reacting at room temperature for 5 hours while introducing argon gas. After the reaction is finished, the reaction is carried out in a volume ratio of 35: 1, using petroleum ether/ethyl acetate mixed reagent as eluent, and separating by silica gel column chromatography. The branched monomer 2 product was obtained as a pale yellow liquid with an average molecular weight of 450 g/mol.
(4) Preparation of 0.5 generation branched structure: 0.45G of branched monomer 2 is dissolved in 1.5mL of dichloromethane, 0.14G of potassium carbonate is added, 0.12G of acryloyl chloride is injected by an injector, after the injection is finished, the mixture is stirred for 10 hours at room temperature, after the reaction is finished, the mixture is filtered, the solvent is removed by reduced pressure distillation, dichloromethane and water are used for extracting and removing water-soluble impurities, oil layer liquid is subjected to reduced pressure distillation and then is separated by column chromatography, and G0.5 branch (0.5 generation branch structure) is obtained, is light yellow liquid and has the average molecular weight of 500G/mol.
(5) Preparation of generation 1.5 branching structure: dissolving 0.5g G0.5.5 in dichloromethane, dissolving 0.4g of branched monomer 1 in dichloromethane, adding 0.05g of catalyst sodium hydroxide, stirring at 50 ℃ for 50h, and after the reaction is finished, mixing the mixture in a volume ratio of 35: 1, and separating by silica gel column chromatography with petroleum ether/ethyl acetate mixed reagent as eluent to obtain G1.5 branch (1.5 generation branch structure) as light yellow liquid with molecular weight of 1300G/mol.
(6) Preparation of generation 2.5 branching structure: dissolving 1.3g G1.5.5 branched structure in dichloromethane, 0.014g potassium carbonate, injecting 0.12g acryloyl chloride by using an injector, stirring at room temperature for 10h after the injection is finished, filtering after the reaction is finished, distilling under reduced pressure to remove the solvent, extracting with dichloromethane and water to remove water-soluble impurities, and separating oil layer liquid by column chromatography to obtain the product. 1.31g of the product is dissolved in 2ml of dichloromethane, 0.35g of the branched monomer 1 is dissolved in 2ml of dichloromethane, 0.05g of catalyst sodium hydroxide is stirred for 60 hours at 50 ℃, and after the reaction is finished, the volume ratio of the branched monomer 1 to the catalyst sodium hydroxide is 35: 1, and separating by silica gel column chromatography with petroleum ether/ethyl acetate mixed reagent as eluent to obtain G1.5 branch (branch structure generation 2.5) as light yellow liquid with molecular weight of 3000G/mol.
(7) Preparation of generation 3.5 branching structure: dissolving 0.3g G2.5.5 branched structure in 1ml dichloromethane, adding 0.014g potassium carbonate, injecting 0.012g acryloyl chloride with injector, stirring at room temperature for 10h after injection, filtering after reaction, distilling under reduced pressure to remove solvent, extracting with dichloromethane and water to remove water-soluble impurities, separating oil layer liquid by column chromatography to obtain the product. Dissolving 0.31g of the product in 1ml of dichloromethane, dissolving 0.04g of the branched monomer 1 in 1ml of dichloromethane, 0.005g of catalyst sodium hydroxide, stirring at 50 ℃ for 70h, and reacting, wherein the volume ratio of the mixture is 35: 1, and separating by silica gel column chromatography to obtain branch G3.5 (branch 3.5 generation) with molecular weight of 6500G/mol.
(8) Preparation of the 4.5 th generation branched structure: dissolving 0.65g G3.5.5 branch in dichloromethane, adding 0.014g potassium carbonate, injecting 0.012g acryloyl chloride with a syringe, stirring at room temperature for 10h after injection, filtering after reaction, distilling under reduced pressure to remove solvent, extracting with dichloromethane and water to remove water-soluble impurities, and separating oil layer liquid by column chromatography to obtain the product. Dissolving 0.66g of the product in dichloromethane, dissolving 0.04g of the branched monomer 1 in dichloromethane, 0.005g of catalyst sodium hydroxide, stirring for 80 hours at 50 ℃, and after the reaction is finished, mixing the mixture in a volume ratio of 35: 1 as eluent, and separating by silica gel column chromatography to obtain product G4.5 branch structure (4.5 generation branch structure, its nuclear magnetic carbon spectrum is shown in figure 1) with molecular weight of 13452G/mol. The NMR spectrum of the 4.5 th branch structure is shown in FIG. 1. As shown in fig. 1, the three characteristic peaks at 175.10ppm, 172.3ppm, and 155.75ppm were assigned to the carbonyl (C ═ O) carbons on the acrylate and on the amine protecting group, respectively; the characteristic peak at 28.38ppm is attributed to the carbon of the terminal methyl group, the characteristic peak at 16.82ppm is attributed to the carbon of the methyl group on the side chain; the characteristic peaks of the first methylene group linked to the two ester groups are 72.59ppm and 63.71 ppm; at 69.10ppm is the carbon ascribed to the second methylene group attached to the ester group, 70.28ppm to 70.68ppm are the carbons ascribed to the remaining methylene groups on the polyethylene glycol molecular chain.
The PEG-acrylate dendritic polymer prepared by the embodiment integrates the advantages of a convergence method and a divergence method, and transesterification and alkene-sulfydryl and alkene-double bond click reactions are sequentially used, because the reaction of primary amine and acrylate can be carried out at low temperature even normal temperature, the condition is mild; the product obtained by each step of reaction is subjected to column separation, and the molecular structure is controllable, so that the molecular structure is accurate; the mercapto-vinyl click reaction has strong selectivity, few side reactions in the reaction process and high conversion rate; no substances harmful to the environment are generated in the reaction process, and the method is green and environment-friendly. The PEG-acrylate dendrimer of generation 4.5 synthesized in this example has the following structural formula 2.
Branch structure right structure in the above formula 2Represents the repeating structure between N and N, the left structureRepresenting the bottom terminal portion of the dendrimer.
The branch structure of the dendritic polymerization is in a fan shape in conformation, and the dendritic polymer has a series of unique physical and chemical characteristics of large cavity, low viscosity, high rheological property, a large number of terminal functional groups and the like. The polymer with the structure can be used as a coating carrier of organic dyes, medicines and inorganic nano particles, can also be used as an additive and other polymers to blend and improve the flow property of a product, and has wide application prospect in the field of advanced material design such as reverse osmosis water treatment scale inhibitors, industrial catalysis and petrochemical industry. Compared with the traditional polyamide-amine dendritic Polymer (PAMAM) and the like, the PEG-acrylate dendritic polymer prepared by the embodiment greatly reduces the content of nitrogen atoms in the molecular structure, thereby reducing the biological toxicity.
The dendritic polymer of the embodiment has a hollow structure and can coat organic matters and inorganic matters. The product end group obtained in this example was an amino protecting group (-NHBOC). When the polymer is subjected to a reaction for removing an amino-protecting group and a reaction such as Michael addition with polyethylene glycol methacrylate, a polymer having a hydroxyl group at the terminal can be obtained.
The dendritic polymer has a large cavity, can be used as a coating carrier of organic dyes, medicines and nano inorganic particles, has a large number of functional groups on the surface, can be used as an additive and other polymers to blend and improve the flow property of a product, and can be used as a reverse osmosis water treatment scale inhibitor and industrial catalysis.
Example 2
(1) Preparation of PEG400 monomethacrylate: 6g of PEG400 was dissolved in 15mL of tetrahydrofuran, and 2.5g of methyl methacrylate and 150mg of Novozyme 435 were added thereto, followed by stirring at 50 ℃ and reaction under magnetic stirring at a constant temperature for 25 hours. Tracking by using thin layer chromatography in the reaction process, filtering to remove transesterase after the reaction is finished, distilling the filtrate under reduced pressure by using a rotary evaporator to remove the solvent, and then separating by using a mixed reagent of petroleum ether and ethyl acetate as an eluent through silica gel column chromatography to obtain the PEG200 monomethacrylate product which is light yellow liquid and has the average molecular weight of 470 g/mol.
(2) Preparation of branched monomer 1: 4.7g of PEG 400-methacrylic monoester was dissolved in 50mL of methanol, 1.0g of mercaptoethylamine was added, argon gas was introduced, and the reaction was stirred at room temperature for 3 hours. After the reaction was complete, the product was extracted with dichloromethane and water until the mercaptoethylamine salt was absent from the water (confirmed by thin layer chromatography). The organic phase was dehydrated with anhydrous magnesium sulfate. And (3) carrying out rotary evaporation on the organic phase subjected to water removal at the temperature of 30 ℃, and carrying out vacuum drying to obtain a branched monomer 1 product which is a light yellow liquid and has the average molecular weight of 547 g/mol.
(3) Preparation of branched monomer 2: 4.7g of PEG 400-methacrylic monoester was dissolved in 50mL of methanol, and 1.1g of sodium carbonate as a catalyst and 1.8g of 2- (Boc-amino) ethanethiol were added thereto, followed by stirring at room temperature for 3 hours while introducing argon gas. After the reaction is finished, the mixture is separated by silica gel column chromatography with petroleum ether/ethyl acetate mixed reagent as an eluent. The branched monomer 2 product was obtained as a pale yellow liquid with an average molecular weight of 647 g/mol.
(4) Preparation of 0.5 generation branched structure: dissolving 0.45G of branched monomer 2 in 1.5mL of dichloromethane, adding 0.12G of triethylamine as an acid-binding agent, injecting 0.12G of acryloyl chloride by using an injector, stirring at room temperature for 10 hours after injection is finished, filtering triethylamine hydrochloride generated by reaction after reaction is finished, distilling under reduced pressure to remove the solvent, extracting with dichloromethane and water to remove residual triethylamine and triethylamine salt, distilling oil layer liquid under reduced pressure, and then separating by column chromatography to obtain a product G0.5 branched structure (0.5 th generation branched structure) which is light yellow liquid with the average molecular weight of 700G/mol.
(5) Preparation of generation 1.5 branching structure: 0.5G of 0.5G G0.5.5 is dissolved in dichloromethane, 0.4G of monomer 1 is dissolved in dichloromethane, 0.1G of catalyst sodium carbonate is stirred for 50h at 50 ℃, after the reaction is finished, petroleum ether/ethyl acetate mixed reagent is used as eluent after the reaction is finished, and the product G1.5 branched structure (1.5 generation branched structure) is obtained through silica gel column chromatography separation, is light yellow liquid and has the molecular weight of 1950G/mol.
(6) Preparation of generation 2.5 branching structure: dissolving a 1.3g G1.5.5 branched structure in dichloromethane, adding 0.12g of triethylamine as an acid-binding agent, injecting 0.12g of acryloyl chloride by using an injector, stirring at room temperature for 10 hours after injection is finished, filtering triethylamine hydrochloride generated by reaction after the reaction is finished, removing the solvent by reduced pressure distillation, extracting with dichloromethane and water to remove residual triethylamine and triethylamine salt, and separating oil layer liquid by column chromatography to obtain a product. Dissolving 1.31G of the product in 2ml of dichloromethane, dissolving 0.35G of the branched monomer 1 in 2ml of dichloromethane, adding 0.1G of catalyst sodium carbonate, stirring at 50 ℃ for 60 hours, and after the reaction is finished, separating by silica gel column chromatography with a petroleum ether/ethyl acetate mixed reagent as an eluent to obtain a product G2.5 branched structure (2.5 generation branched structure) which is light yellow liquid and has the molecular weight of 4565G/mol.
(7) Preparation of generation 3.5 branching structure: dissolving 0.3g G2.5.5 branched structure in 1ml dichloromethane, adding 0.012g acid-binding agent triethylamine, injecting 0.012g acryloyl chloride by using an injector, stirring at room temperature for 12h after the injection is finished, filtering triethylamine hydrochloride generated by the reaction after the reaction is finished, removing the solvent by reduced pressure distillation, extracting with dichloromethane and water to remove the residual triethylamine and triethylamine salt, and separating oil layer liquid by column chromatography to obtain the product. Dissolving 0.31G of the product in 1ml of dichloromethane, dissolving 0.04G of the branched monomer 1 in 1ml of dichloromethane, adding 0.01G of catalyst sodium carbonate, stirring at 50 ℃ for 70h, and after the reaction is finished, separating by silica gel column chromatography with a petroleum ether/ethyl acetate mixed reagent as an eluent to obtain a product G3.5 branched structure (3.5 th generation branched structure) with the molecular weight of 9780G/mol.
(8) Preparation of the 4.5 th generation branched structure: dissolving a 0.65g G3.5.5 branched structure in dichloromethane, adding 0.012g of triethylamine as an acid-binding agent, injecting 0.012g of acryloyl chloride by using an injector, stirring at room temperature for 12h after injection is finished, filtering triethylamine hydrochloride generated by reaction after the reaction is finished, removing the solvent by reduced pressure distillation, extracting by using dichloromethane and water to remove residual triethylamine and triethylamine salt, and separating oil layer liquid by column chromatography to obtain a product. Dissolving 0.66G of the product in dichloromethane, dissolving 0.04G of the branched monomer 1 in dichloromethane, adding 0.01G of catalyst sodium carbonate, stirring at 50 ℃ for 80h, separating by silica gel column chromatography with a petroleum ether/ethyl acetate mixed reagent as an eluent after the reaction is finished to obtain a product G4.5 branched structure (a 4.5 th generation branched structure), and obtaining the product G4.5 branched structure with the molecular weight of 20230G/mol.
The product of this example differs structurally from that of example 1 in that first the monomer concentration during the synthesis of the branched monomer is different, example 2 with a monomer concentration of 2mmol/mL and example 1 with a monomer concentration of 20 mmol/mL; the molecular weight of PEG as the raw material of the second reaction is different, namely PEG400 in example 2 and PEG200 in example 1, so that the molecular weight of the polymer synthesized by the former generation is larger than that of the latter.
The product structure obtained in this example is substantially similar to that of formula 2, the main difference being that the average molecular weight of each small branched PEG segment of the branched structure is 400, and thus the relative intensities of characteristic peaks 72.59ppm and 63.71ppm of the first methylene group linked to two ester groups and the assigned methyl peak 28.38ppm of the terminal amine protecting group are relatively large compared to that of FIG. 1.
Example 3
PEG600, methyl methacrylate and 3-mercapto-1-propylamine are used as raw materials, a basic catalyst is sodium methoxide, an acid-binding agent N, N-diisopropylethylamine and tetrahydrofuran or dichloromethane are used as solvents to prepare the PEG-acrylate dendritic polymer, and the preparation method comprises the following steps:
(1) preparation of PEG600 monomethacrylate: 9g of PEG600 was dissolved in 15mL of tetrahydrofuran, and 2.5g of methyl methacrylate and 150mg of Novozyme 435 were added thereto, followed by stirring at 50 ℃ and reaction under magnetic stirring at a constant temperature for 25 hours. Tracking by using thin layer chromatography in the reaction process, filtering to remove transesterase after the reaction is finished, distilling the filtrate under reduced pressure by using a rotary evaporator to remove the solvent, and then separating by using a mixed reagent of petroleum ether and ethyl acetate as an eluent through silica gel column chromatography to obtain a PEG600 monomethacrylate product which is light yellow liquid and has the average molecular weight of 670 g/mol.
(2) Preparation of branched monomer 1: 6.7g of PEG600 monomethacrylate monoester was dissolved in 3mL of dimethyl sulfoxide, and 0.8g of sodium methoxide and 0.92g of 3-mercapto-1-propylamine as catalysts were added thereto, followed by stirring and reaction at room temperature for 3 hours while introducing argon gas. After the reaction was complete, the product was extracted with dichloromethane and water until mercaptoethylamine hydrochloride was absent from the water (confirmed by thin layer chromatography). The organic phase was dehydrated with anhydrous magnesium sulfate. And (3) carrying out rotary evaporation on the organic phase subjected to water removal at the temperature of 30 ℃, and carrying out vacuum drying to obtain a branched monomer 1 product which is a light yellow liquid and has the average molecular weight of 762 g/mol.
(3) Preparation of branched monomer 2: PEG600 monomethacrylate monoester (2 g) was dissolved in 3mL of dimethyl sulfoxide, and 0.8g of sodium methoxide and 2.0g of 3-mercapto-propyl- (Boc-amino) as catalysts were added thereto, followed by stirring and reacting at room temperature for 5 hours while introducing argon. After the reaction is finished, the mixture is separated by silica gel column chromatography with petroleum ether/ethyl acetate mixed reagent as an eluent. The branched monomer 2 product was obtained as a pale yellow liquid with an average molecular weight of 860 g/mol.
(4) Preparation of 0.5 generation branched structure: dissolving 0.85G of branched monomer 2 in 2mL of dichloromethane, adding 0.13G of acid-binding agent N, N-diisopropylethylamine, injecting 0.12G G acryloyl chloride by using an injector, stirring at room temperature for 10 hours after injection, filtering after reaction, distilling under reduced pressure to remove the solvent, extracting with dichloromethane and water to remove water-soluble impurities, distilling oil layer liquid under reduced pressure, and separating by column chromatography to obtain a product G0.5 branched structure (0.5 generation branched structure), wherein the product G0.5 branched structure is light yellow liquid, and the average molecular weight is 918G/mol.
(5) Preparation of generation 1.5 branching structure: 0.9G G0.5.5 is dissolved in dichloromethane, 0.75G of monomer 1 is dissolved in dichloromethane, 0.08G of catalyst sodium methoxide is added, the mixture is stirred for 50 hours at 50 ℃, after the reaction is finished, a petroleum ether/ethyl acetate mixed reagent is used as an eluent, and the product G1.5 branched structure (1.5 generation branched structure) is obtained through silica gel column chromatography separation, is light yellow liquid and has the molecular weight of 2600G/mol.
(6) Preparation of generation 2.5 branching structure: dissolving a 2.55g G1.5.5 branch structure in dichloromethane, adding 0.13g of acid-binding agent N, N-diisopropylethylamine, injecting 0.12g of acryloyl chloride by using an injector, stirring at room temperature for 10 hours after the injection is finished, filtering after the reaction is finished, distilling under reduced pressure to remove the solvent, extracting with dichloromethane and water to remove water-soluble impurities, and separating oil layer liquid by column chromatography to obtain the product. 2.65G of the product is dissolved in 2ml of dichloromethane, 0.8G of the branched monomer 1 is dissolved in 2ml of dichloromethane, 0.08G of catalyst sodium methoxide is added, the mixture is stirred for 58 hours at 50 ℃, after the reaction is finished, a petroleum ether/ethyl acetate mixed reagent is used as an eluent, and the product is separated by silica gel column chromatography to obtain a product G2.5 branched structure (2.5 generation branched structure) with the molecular weight of 6070G/mol.
(7) Preparation of generation 3.5 branching structure: dissolving 0.6g G2.5.5 branch structure in 4ml dichloromethane, adding 0.013g acid-binding agent N, N-diisopropylethylamine, injecting 0.012g acryloyl chloride by using an injector, stirring at room temperature for 12h after the injection is finished, filtering after the reaction is finished, removing the solvent by reduced pressure distillation, extracting water-soluble impurities by using dichloromethane and water, and separating oil layer liquid by column chromatography to obtain the product. Dissolving 4G of the product in 4ml of dichloromethane, dissolving 0.08G of the branched monomer 1 in 1ml of dichloromethane, adding 0.008G of catalyst sodium methoxide, stirring at 50 ℃ for 70h, separating by silica gel column chromatography with a petroleum ether/ethyl acetate mixed reagent as an eluent after the reaction is finished to obtain a product G3.5 branched structure (3.5 generation branched structure) with the molecular weight of 13000G/mol.
(8) Preparation of the 4.5 th generation branched structure: dissolving 1.28g G3.5.5 branch structure in dichloromethane, adding 0.13g acid-binding agent N, N-diisopropylethylamine, injecting 0.012g acryloyl chloride by using an injector, stirring at room temperature for 12h after the injection is finished, filtering after the reaction is finished, removing the solvent by reduced pressure distillation, extracting with dichloromethane and water to remove water-soluble impurities, and separating oil layer liquid by column chromatography to obtain the product. Dissolving 1.29G of the product in dichloromethane, dissolving 0.08G of the branched monomer 1 in dichloromethane, adding 0.008G of catalyst sodium methoxide, stirring at 50 ℃ for 80h, separating by silica gel column chromatography with a petroleum ether/ethyl acetate mixed reagent as an eluent after the reaction is finished to obtain a product G4.5 branched structure (4.5 th generation branched structure) with the molecular weight of 26902G/mol.
The product of this example differs in structure from example 1: firstly, different mercaptovinyl reaction raw materials are adopted, namely mercaptoethylamine hydrochloride is adopted in example 1, 3-mercapto-1-propylamine is adopted in example 3, and the synthesized branched structures are different;
the product structure obtained in this example is generally consistent with formula 2, the main difference being that the average molecular weight of each small branched PEG segment of the branched structure is 400, and the relative intensities of characteristic peaks 72.59ppm and 63.71ppm of the first methylene group linked to two ester groups and an assigned methyl peak 28.38ppm of the terminal amine protecting group are changed compared with that of fig. 1, and there is one more methylene group assigned between N and S.
The molecular weight of PEG as the raw material of the second reaction is different, namely PEG600 in example 3 and PEG200 in example 1, so that the molecular weight of the polymer synthesized by the former generation is larger than that of the latter.
Example 4
PEG800, methyl methacrylate and mercaptoethylamine (mercaptoethylamine hydrochloride) are used as raw materials, sodium ethoxide is used as an alkaline catalyst, pyridine is used as an acid-binding agent, and tetrahydrofuran or dichloromethane is used as a solvent to prepare the PEG-acrylate dendritic polymer, wherein the preparation method comprises the following steps:
(1) preparation of PEG800 monomethacrylate: 12g of PEG800 was dissolved in 15mL of tetrahydrofuran, and 2.5g of methyl methacrylate and 150mg of Novozyme 435 were added thereto, followed by stirring at 50 ℃ and magnetic stirring at a constant temperature for 25 hours. Tracking by using a thin layer chromatography in the reaction process, filtering to remove transesterase after the reaction is finished, distilling the filtrate under reduced pressure by using a rotary evaporator to remove the solvent, and then separating by using a silica gel column chromatography by using a petroleum ether/ethyl acetate mixed reagent as an eluent to obtain a PEG800 monomethacrylate product which is light yellow liquid and has the average molecular weight of 870 g/mol.
(2) Preparation of branched monomer 1: PEG800 monomethacrylate monoester (8.7 g) was dissolved in 10mL of dimethylformamide, and 0.7g of sodium ethoxide, 1.3g of mercaptoethylamine hydrochloride as a catalyst was added thereto, followed by stirring at room temperature under argon gas for reaction for 3 hours. After the reaction was complete, the product was extracted with dichloromethane and water until mercaptoethylamine hydrochloride was absent from the water (confirmed by thin layer chromatography). The organic phase was dehydrated with anhydrous magnesium sulfate. And (3) carrying out rotary evaporation on the organic phase subjected to water removal at the temperature of 30 ℃, and carrying out vacuum drying to obtain a branched monomer 1 product which is a light yellow liquid and has the average molecular weight of 947 g/mol.
(3) Preparation of branched monomer 2: PEG800 monomethacrylate monoester (2 g) was dissolved in 3mL of dimethylformamide, and 0.7g of sodium ethoxide as a catalyst and 1.8g of 2- (Boc-amino) ethanethiol were added thereto, followed by stirring at room temperature under argon for reaction for 3 hours. After the reaction is finished, the mixture is separated by silica gel column chromatography with petroleum ether/ethyl acetate mixed reagent as an eluent. The branched monomer 2 product was obtained as a pale yellow liquid with an average molecular weight of 1047 g/mol.
(4) Preparation of 0.5 generation branched structure: dissolving 1.05G of branched monomer 2 in 3mL of dichloromethane, adding 0.08G of acid-binding agent pyridine, injecting 0.12G of acryloyl chloride by using an injector, stirring at room temperature for 10 hours after injection, removing the solvent by reduced pressure distillation after the reaction is finished, extracting with dichloromethane and water to remove water-soluble impurities, distilling oil layer liquid under reduced pressure, and separating by column chromatography to obtain a product G0.5 branched structure (0.5 generation branched structure), wherein the product G is light yellow liquid and has the average molecular weight of 1103G/mol.
(5) Preparation of generation 1.5 branching structure: dissolving 1.1G G0.5.5 in dichloromethane, dissolving 1G of monomer 1 in dichloromethane, adding 0.07G of catalyst sodium ethoxide, stirring at 50 ℃ for 50h, after the reaction is finished, using petroleum ether/ethyl acetate mixed reagent as an eluent, and separating by silica gel column chromatography to obtain a product G1.5 branched structure (1.5 generation branched structure) with the molecular weight of 3153G/mol.
(6) Preparation of generation 2.5 branching structure: dissolving 3.2g G1.5.5 branch structures in dichloromethane, adding 0.08g of acid-binding agent pyridine, injecting 0.12g of acryloyl chloride by using an injector, stirring at room temperature for 10 hours after injection is finished, filtering after reaction is finished, distilling under reduced pressure to remove a solvent, extracting with dichloromethane and water to remove water-soluble impurities, and separating oil layer liquid by column chromatography to obtain a product. 3.3G of the product is dissolved in 2ml of dichloromethane, 1G of the branched monomer 1 is dissolved in 2ml of dichloromethane, 0.07G of catalyst sodium ethoxide is added, the mixture is stirred for 60 hours at 50 ℃, after the reaction is finished, a petroleum ether/ethyl acetate mixed reagent is used as an eluent, and the product G2.5 branched structure (2.5 generation branched structure) with the molecular weight of 7365G/mol is obtained by silica gel column chromatography separation.
(7) Preparation of generation 3.5 branching structure: dissolving 0.7g G2.5.5 branch structure in 1ml dichloromethane, adding 0.01g acid-binding agent pyridine, injecting 0.012g acryloyl chloride by using an injector, stirring at room temperature for 12h after the injection is finished, filtering after the reaction is finished, distilling under reduced pressure to remove the solvent, extracting with dichloromethane and water to remove water-soluble impurities, and separating oil layer liquid by column chromatography to obtain the product. Dissolving 0.71G of the product in 1ml of dichloromethane, dissolving 0.1G of the branched monomer 1 in 1ml of dichloromethane, adding 0.007G of catalyst sodium ethoxide, stirring at 50 ℃ for 70h, and after the reaction is finished, separating by silica gel column chromatography with a petroleum ether/ethyl acetate mixed reagent as an eluent to obtain a product G3.5 branched structure (3.5 generation branched structure) with the molecular weight of 15789G/mol.
(8) Preparation of the 4.5 th generation branched structure: dissolving a 1.6g G3.5.5 branched structure in dichloromethane, adding 0.01g of acid-binding agent pyridine, injecting 0.012g of acryloyl chloride by using an injector, stirring at room temperature for 12h after the injection is finished, filtering after the reaction is finished, distilling under reduced pressure to remove a solvent, extracting with dichloromethane and water to remove water-soluble impurities, and separating oil layer liquid by column chromatography to obtain a product. Dissolving 1.61G of the product in dichloromethane, dissolving 0.1G of the branched monomer 1 in dichloromethane, adding 0.007G of catalyst sodium ethoxide, stirring at 50 ℃ for 80h, separating by silica gel column chromatography with a petroleum ether/ethyl acetate mixed reagent as an eluent after the reaction is finished to obtain a product G4.5 branched structure (4.5 th generation branched structure) with the molecular weight of 32637G/mol.
The product of this example differs in structure from example 1 in that the molecular weight of the PEG as the starting material is different, that of PEG800 in example 4 and PEG200 in example 1, so that the molecular weight of the polymer synthesized in each generation in the former is larger than that in the latter. The product structure obtained in this example is generally consistent with formula 2, the main difference being that the average molecular weight of each small branched PEG segment of the branched structure is 400, and the relative intensities of characteristic peaks 72.59ppm and 63.71ppm of the first methylene group linked to two ester groups and the assigned methyl peak 28.38ppm of the terminal amine protecting group are changed compared with fig. 1.
Example 5
PEG1000, ethyl methacrylate and 3-mercapto-1-propylamine hydrochloride are used as raw materials, triethylamine is used as a catalyst, and tetrahydrofuran or dichloromethane is used as a solvent to prepare the PEG-acrylate dendritic polymer, wherein the preparation method comprises the following steps:
(1) preparation of PEG1000 acrylate: 15g of PEG1000 was dissolved in 15mL of tetrahydrofuran, and 2.5g of methyl methacrylate and 150mg of Novozyme 435 were added thereto, followed by stirring at 50 ℃ and reaction under magnetic stirring at a constant temperature for 25 hours. Tracking by using thin layer chromatography in the reaction process, filtering to remove transesterase after the reaction is finished, distilling the filtrate under reduced pressure by using a rotary evaporator to remove the solvent, and then separating by using a silica gel column chromatography by using a petroleum ether/ethyl acetate mixed reagent as an eluent to obtain a PEG1000 acrylate product which is light yellow liquid and has the average molecular weight of 1070 g/mol.
(2) Preparation of branched monomer 1: 1.07g of PEG1000 monomethacrylate monoester was dissolved in 7mL of dimethyl sulfoxide, and 0.9g of sodium ethoxide as a catalyst and 1.3g of 3-mercapto-1-propylamine hydrochloride were added thereto, followed by stirring and reaction at room temperature for 3 hours while introducing argon gas. After the reaction was complete, the product was extracted with dichloromethane and water until mercaptoethylamine hydrochloride was absent from the water (confirmed by thin layer chromatography). The organic phase was dehydrated with anhydrous magnesium sulfate. And (3) carrying out rotary evaporation on the organic phase subjected to water removal at the temperature of 30 ℃, and carrying out vacuum drying to obtain the branched monomer 1 product which is a light yellow liquid and has the average molecular weight of 1160 g/mol.
(3) Preparation of branched monomer 2: 2g of PEG1000 monomethacrylate monoester was dissolved in 3mL of dimethyl sulfoxide, and 1.2g of triethylamine as a catalyst and 1.8g of 2- (Boc-amino) ethanethiol were added thereto, followed by stirring and reacting at room temperature for 3 hours while introducing argon gas. After the reaction is finished, the mixture is separated by silica gel column chromatography with petroleum ether/ethyl acetate mixed reagent as an eluent. The branched monomer 2 product was obtained as a pale yellow liquid with an average molecular weight of 1262 g/mol.
(4) Preparation of 0.5 generation branched structure: dissolving 1.25G of branched monomer 2 in 3mL of dichloromethane, adding 0.12G of triethylamine as an acid-binding agent, injecting 0.12G of acryloyl chloride by using an injector, stirring at room temperature for 10h after injection is finished, filtering triethylamine hydrochloride generated by reaction after reaction is finished, distilling under reduced pressure to remove the solvent, extracting with dichloromethane and water to remove the residual triethylamine and triethylamine salt, distilling oil layer liquid under reduced pressure, and separating by column chromatography to obtain a product G0.5 branched structure (0.5 th generation branched structure), wherein the product G0.5 branched structure is light yellow liquid and has the average molecular weight of 1320G/mol.
(5) Preparation of generation 1.5 branching structure: dissolving 1.3G G0.5.5 in dichloromethane, dissolving 1.2G of branched monomer 1 in dichloromethane, adding 0.12G of catalyst triethylamine, stirring at 50 ℃ for 50h, after the reaction is finished, using a petroleum ether/ethyl acetate mixed reagent as an eluent, and separating by silica gel column chromatography to obtain a product G1.5 branched structure (1.5 th generation branched structure) which is light yellow liquid and has the molecular weight of 3800G/mol.
(6) Preparation of generation 2.5 branching structure: dissolving a 3.8g G1.5.5 branched structure in dichloromethane, adding 0.2g of triethylamine as an acid-binding agent, injecting 0.12g of acryloyl chloride by using an injector, stirring at room temperature for 10 hours after injection is finished, filtering triethylamine hydrochloride generated by reaction after the reaction is finished, removing the solvent by reduced pressure distillation, extracting with dichloromethane and water to remove residual triethylamine and triethylamine salt, and separating oil layer liquid by column chromatography to obtain a product. 3.9G of the product is dissolved in 2ml of dichloromethane, 1.2G of the branched monomer 1 is dissolved in 2ml of dichloromethane, 0.12G of catalyst triethylamine is added, the mixture is stirred for 60 hours at 50 ℃, after the reaction is finished, a petroleum ether/ethyl acetate mixed reagent is used as an eluent, and the product G1.5 branch structure (2.5 generation branch structure) with the molecular weight of 8870G/mol is obtained by silica gel column chromatography separation.
(7) Preparation of generation 3.5 branching structure: dissolving 0.88g G2.5.5 branched structure in 4ml of dichloromethane, adding 0.4g of triethylamine as an acid-binding agent, injecting 0.012g of acryloyl chloride by using an injector, stirring at room temperature for 12h after the injection is finished, filtering triethylamine hydrochloride generated by the reaction after the reaction is finished, removing the solvent by reduced pressure distillation, extracting by using dichloromethane and water to remove the residual triethylamine and triethylamine salt, and separating oil layer liquid by column chromatography to obtain the product. 4G of the product is dissolved in 4ml of dichloromethane, 0.012G of branched monomer 1 is dissolved in 1ml of dichloromethane, 0.012G G catalyst triethylamine is added, the mixture is stirred for 70h at 50 ℃, after the reaction is finished, petroleum ether/ethyl acetate mixed reagent is used as eluent, and the product G3.5 branched structure (3.5 generation branched structure) with the molecular weight of 19000G/mol is obtained by silica gel column chromatography separation.
(8) Preparation of the 4.5 th generation branched structure: dissolving a 1.88g G3.5.5 branched structure in dichloromethane, adding 0.012g of triethylamine as an acid-binding agent, injecting 0.012g of acryloyl chloride by using an injector, stirring at room temperature for 12h after injection, filtering triethylamine hydrochloride generated by reaction after reaction, removing the solvent by reduced pressure distillation, extracting with dichloromethane and water to remove residual triethylamine and triethylamine salt, and separating oil layer liquid by column chromatography to obtain a product. Dissolving 1.89G of the product in dichloromethane, dissolving 0.012G of the branched monomer 1 in dichloromethane, adding 0.012G of catalyst triethylamine, stirring at 50 ℃ for 80h, after the reaction is finished, using a petroleum ether/ethyl acetate mixed reagent as an eluent, and separating by silica gel column chromatography to obtain a product G4.5 branched structure, thus obtaining a product G4.5 branched structure (a 4.5 th generation branched structure) with the molecular weight of 39302G/mol.
The product of this example differs in structure from example 1: firstly, different mercaptovinyl reaction raw materials are adopted, namely mercaptoethylamine hydrochloride is adopted in example 1, 3-mercapto-1-propylamine hydrochloride is adopted in example 5, and the synthesized branched structures are different; the product structure obtained in this example is generally consistent with formula 2, the main difference being that the average molecular weight of each small branched PEG segment of the branched structure is 400, and the relative intensities of characteristic peaks 72.59ppm and 63.71ppm of the first methylene group linked to two ester groups and the peak of assigned methyl group of terminal amine protecting group of 28.38ppm are changed, and the peak of assigned methyl group between N and S is one more methylene group compared with FIG. 1. The molecular weight of PEG as the raw material of the second reaction is different, namely PEG1000 in example 5 and PEG200 in example 1, so that the molecular weight of the polymer synthesized by the former generation is larger than that of the latter generation.
Example 6
PEG2000, methyl acrylate, mercaptoethylamine and 3-mercapto-propyl- (Boc-amino) raw materials, triethylamine as a catalyst and tetrahydrofuran or dichloromethane as a solvent are used for preparing the PEG-acrylate dendritic polymer, and the preparation method comprises the following steps:
(1) preparation of PEG200 acrylate: 30g of 2000 was dissolved in 15m tetrahydrofuran, and 2.3g of methyl acrylate and 150mg of Novozyme 435 were added thereto, followed by reaction at 50 ℃ under stirring and magnetic stirring at a constant temperature for 25 hours. Tracking by using a thin layer chromatography in the reaction process, filtering to remove transesterase after the reaction is finished, distilling the filtrate under reduced pressure by using a rotary evaporator to remove the solvent, and then separating by using a silica gel column chromatography by using a petroleum ether/ethyl acetate mixed reagent as an eluent to obtain a PEG200 acrylate product which is light yellow liquid and has the average molecular weight of 2056 g/mol.
(2) Preparation of branched monomer 1: 20.6g of PEG2000 acrylate monoester were dissolved in 10mL of dichloromethane, 1.3g of mercaptoethylamine hydrochloride, and the reaction was stirred at room temperature for 9h with introduction of nitrogen. After the reaction was complete, the product was extracted with dichloromethane and water until mercaptoethylamine hydrochloride was absent from the water (confirmed by thin layer chromatography). The organic phase was dehydrated with anhydrous magnesium sulfate. And (3) carrying out rotary evaporation on the organic phase subjected to water removal at the temperature of 30 ℃, and carrying out vacuum drying to obtain a branched monomer 1 product which is a light yellow liquid and has the average molecular weight of 2133 g/mol.
(3) Preparation of branched monomer 2: 20.6g of PEG2000 acrylate monoester was dissolved in 3mL of dimethyl sulfoxide, and 2.0g of 3-mercapto-propyl- (Boc-amino) was reacted with stirring at room temperature for 10 hours under argon. After the reaction is finished, petroleum ether/ethyl acetate mixed reagent is used as an eluent, and the mixture is separated by silica gel column chromatography. The branched monomer 2 product was obtained as a pale yellow liquid with an average molecular weight of 2245 g/mol.
(4) Preparation of 0.5 generation branched structure: dissolving 2.3G of branched monomer 2 in 3mL of dichloromethane, adding 0.012G of acid-binding agent sodium carbonate, injecting 0.012G of acryloyl chloride by using an injector, stirring at room temperature for 12h after injection, removing the solvent by reduced pressure distillation after the reaction is finished, extracting water-soluble impurities by using dichloromethane and water, and separating oil layer liquid by column chromatography after reduced pressure distillation to obtain a product G0.5 branched structure (0.5 generation branched structure), wherein the product G is light yellow liquid and has the average molecular weight of 2300G/mol.
(5) Preparation of generation 1.5 branching structure: dissolving 2.3G G0.5.5 in dichloromethane, dissolving 2.3G of monomer 1 in dichloromethane, adding 0.12G of catalyst sodium carbonate, stirring at 50 ℃ for 50h, after the reaction is finished, using a petroleum ether/ethyl acetate mixed reagent as an eluent, and separating by silica gel column chromatography to obtain a product G1.5 branched structure (1.5 generation branched structure) with the molecular weight of 6735G/mol.
(6) Preparation of generation 2.5 branching structure: dissolving a 6.7g G1.5.5 branched structure in dichloromethane, adding 0.012g of acid-binding agent sodium carbonate, injecting 0.012g of acryloyl chloride by using an injector, stirring at room temperature for 12h after the injection is finished, removing the solvent by reduced pressure distillation after the reaction is finished, extracting with dichloromethane and water to remove water-soluble impurities, and separating oil layer liquid by column chromatography to obtain the product. 6.8G of the product is dissolved in 3ml of dichloromethane, 2.2G of the branched monomer 1 is dissolved in 2ml of dichloromethane, 0.2G of catalyst triethylamine is added, the mixture is stirred for 60 hours at 50 ℃, after the reaction is finished, a mixed reagent of petroleum ether and methanol is used as an eluent, and the product G1.5 is separated by silica gel column chromatography to obtain a branched structure (1.5 th generation branched structure) with the molecular weight of 15715G/mol.
(7) Preparation of generation 3.5 branching structure: dissolving 1.5g G2.5.5 branched structure in 4ml dichloromethane, adding 0.012g acid-binding agent sodium carbonate, injecting 0.012g acryloyl chloride with injector, stirring at room temperature for 12h, after reaction, distilling under reduced pressure to remove solvent, extracting with dichloromethane and water to remove water-soluble impurities, separating oil layer liquid by column chromatography to obtain the product. Dissolving 1.51G of the product in 1ml of dichloromethane, dissolving 0.23G of the branched monomer 1 in 1ml of dichloromethane, adding 0.012G G catalyst triethylamine, stirring at 50 ℃ for 70h, and after the reaction is finished, separating by silica gel column chromatography with a petroleum ether/methanol mixed reagent as an eluent to obtain a product G3.5 branched structure (3.5 th generation branched structure) with the molecular weight of 33675G/mol.
(8) Preparation of the 4.5 th generation branched structure: dissolving 3.4g G3.5.5 branched structure in dichloromethane, adding 0.012g acid-binding agent sodium carbonate, injecting 0.012g acryloyl chloride with injector, stirring at room temperature for 12h, after reaction, distilling under reduced pressure to remove solvent, extracting with dichloromethane and water to remove water-soluble impurities, separating oil layer liquid by column chromatography to obtain the product. 4G of the product is dissolved in dichloromethane, 0.23G of the branched monomer 1 is dissolved in dichloromethane, 0.012G of catalyst triethylamine is added, the mixture is stirred for 80 hours at 50 ℃, after the reaction is finished, a petroleum ether/methanol mixed reagent is used as an eluent, and the product G4.5 is separated by silica gel column chromatography to obtain a product G4.5 branched structure (a 4.5 th generation branched structure), wherein the molecular weight is 69595G/mol.
The product of this example differs in structure from example 1: firstly, the raw materials for synthesizing the acrylate monoester are different, wherein methyl acrylate is used in example 6, and methyl methacrylate is used in example 1; the product structure obtained in this example is generally consistent with formula 2, the main difference being that the average molecular weight of each small branched PEG segment of the branched structure is 400, and the relative intensities of characteristic peaks 72.59ppm and 63.71ppm of the first methylene group linked to two ester groups and the assigned methyl peak 28.38ppm of the terminal amine protecting group are changed compared with that of fig. 1, and the assigned peak of one more methylene group between N and S. The molecular weight of PEG as the raw material of the second reaction is different, namely PEG2000 in example 6 and PEG200 in example 1, so that the molecular weight of the polymer synthesized by the former generation is larger than that of the latter.
Claims (8)
- The PEG-acrylate dendritic polymer is characterized by having a structural formula as follows, wherein the left amplified chain segment in the formula represents one end of the bottom of the dendritic polymer, the right amplified chain segment represents the branch of the dendritic polymer, the tail end of the tail end branch is an amino protecting group-NHBoc, and the structures of other branches at all levels are the same as the right amplified chain segment;R1represents a hydrogen bond or a methyl group, R2represents-CH2CH2-or-CH2CH2CH2-; the value of n is 3-20.
- 2. The PEG-acrylate dendritic polymer according to claim 1, wherein said PEG-acrylate dendritic polymer has a molecular weight of 1.3 to 7 ten thousand.
- 3. The PEG-acrylate dendrimer according to claim 1, wherein said PEG-acrylate dendrimer generation product is half generation GmOne end of the terminal group(s) is a hydroxyl group, the other end is an amino protecting group, and the number Ne of the terminal groups isThe number of inner layer repeating units Nr is Denotes the number of branched linking branches NbM-0.5, where m represents the number of generations of the synthesis, m is 1.5, 2.5, 3.5, 4.5, and b represents a branch.
- 4. A method of making a PEG-acrylate dendrimer according to any one of claims 1-3, comprising the steps of:(1) preparing raw material polyethylene glycol methacrylate by transesterification: firstly, 1 part of polyethylene glycol is dissolved in an organic solvent according to the amount of a substance to prepare a solution of 0.3-1.5 mmol/mL, then 1-5 parts of acrylate is added, after uniform stirring, transesterase is added, 5-15 mg of transesterase is added to each milliliter of solution, and the reaction is carried out for 24-48 hours under the stirring at the temperature of 30-70 ℃; after the reaction is finished, filtering, distilling under reduced pressure, carrying out chromatographic separation on the residual liquid, and eluting by using an eluant of petroleum ether/ethyl acetate to obtain a product of polyethylene glycol acrylate;(2) click reaction preparation of branched monomer 1: dissolving 1 part of polyethylene glycol acrylate monoester in a polar organic solvent by mass to prepare a solution of 2-20 mmol/mL, dissolving 1-5 parts of primary mercapto amine compound in the polar organic solvent to prepare a solution of 2-20 mmol/mL, and adding 0-3 parts of an alkaline catalyst; introducing argon to remove oxygen; stirring and reacting for 2-10 h at room temperature; after the reaction is finished, carrying out reduced pressure distillation at the temperature of 30-50 ℃ to remove an organic phase, separating the residual liquid through column chromatography, eluting with an eluant of ethyl acetate/methanol, and carrying out vacuum drying to obtain a product branched monomer 1;(3) click reaction preparation of branched monomer 2: dissolving 1 part of polyethylene glycol acrylate monoester in a polar organic solvent by mass to prepare a solution of 2-20 mmol/mL, dissolving 1-6 parts of Boc-aminothiol compound in the polar organic solvent to prepare a solution of 2-20 mmol/mL, and adding 0-3 parts of an alkaline catalyst; deoxidizing; stirring and reacting for 2-10 h at room temperature; after the reaction is finished, carrying out reduced pressure distillation at the temperature of 30-50 ℃ to remove an organic phase, separating the residual liquid by column chromatography, eluting by an eluent of ethyl acetate/methanol, and carrying out vacuum drying to obtain a product branched monomer 2;(4) branch G0.5 for making dendrimers: dissolving 1 part of the product branched monomer 1 obtained in the step (2) in an organic solvent by mass to prepare a solution of 0.1-10 mmol/mL, and adding 0-3 parts of an acid-binding agent; then dissolving 1-5 parts of acryloyl chloride in an organic solvent to prepare a solution of 0.1-10 mmol/mL, injecting the acryloyl chloride solution into the branched monomer 2 solution under the stirring condition, reacting for 12-36 h under the stirring condition at 20-60 ℃, distilling the reaction solution under reduced pressure after the reaction is finished, and separating the residual liquid through a silica gel column to obtain a quasi-branch G0.5;(5) preparation of branch G1.5 of dendritic Polymer: dissolving 1 part of the product branched monomer 1 obtained in the step (2) in an organic solvent by mass to prepare a solution of 0.1-10 mmol/mL, and adding 0-3 parts of an alkaline catalyst; then dissolving 0.5-5 parts of quasi-branched G0.5 obtained in the step (4) in an organic solvent to prepare a solution of 0.1-10 mmol/mL, dropwise adding the branched monomer 1 solution into the quasi-branched G0.5 solution under the stirring condition, after the reaction is finished, carrying out reduced pressure distillation on the reaction solution, and separating the residual liquid through a silica gel column to obtain a branched G1.5;(6) preparation of branch G2.5 of dendrimer: taking 1 part of G1.5 by mass, dissolving in an organic solvent to prepare a solution of 0.1-10 mmol/mL, 0-3 parts of an acid-binding agent, injecting 1-5 parts of acryloyl chloride by using an injector, stirring at room temperature for 12-36 h after injection, filtering after reaction, distilling under reduced pressure to remove the solvent, extracting with dichloromethane and water to remove water-soluble impurities, and separating oil layer liquid by column chromatography to obtain a product; dissolving 1 part of the product in an organic solvent, dissolving 0.5-5 parts of a branched monomer 1 in the organic solvent, stirring 0-3 parts of an alkaline catalyst at 20-60 ℃ for 60-100 h, and after the reaction is finished, separating by silica gel column chromatography by using a petroleum ether/ethyl acetate mixed reagent as an eluent to obtain a branch G2.5;(7) preparation of branch G3.5 of dendrimer: firstly, taking 1 part of G2.5 by mass, dissolving in an organic solvent to prepare a solution of 0.1-10 mmol/mL, 0-3 parts of an acid-binding agent, injecting 1-5 parts of acryloyl chloride by using an injector, stirring at room temperature for 12-36 h after injection is finished, filtering after reaction is finished, distilling under reduced pressure to remove the solvent, extracting with dichloromethane and water to remove water-soluble impurities, and separating oil layer liquid by column chromatography to obtain a product; dissolving 1 part of the product in an organic solvent, dissolving 0.5-5 parts of a branched monomer 1 in the organic solvent, stirring 0-3 parts of an alkaline catalyst at 20-60 ℃ for 60-100 h, after the reaction is finished, taking a petroleum ether/ethyl acetate mixed reagent as an eluent, and separating by silica gel column chromatography to obtain a product G3.5 branched structure;(8) preparation of branch G4.5 of dendrimer: taking 1 part of G3.5 by mass, dissolving in an organic solvent to prepare a solution of 0.1-10 mmol/mL, 0-3 parts of an acid-binding agent, injecting 1-5 parts of acryloyl chloride by using an injector, stirring at room temperature for 12-36 h after injection, filtering after reaction, distilling under reduced pressure to remove the solvent, extracting with dichloromethane and water to remove water-soluble impurities, and separating oil layer liquid by column chromatography to obtain a product; dissolving 1 part of the product in an organic solvent, dissolving 0.5-5 parts of the branched monomer 1 in the organic solvent, stirring 0-3 parts of an alkaline catalyst at 20-60 ℃ for 60-100 h, and after the reaction is finished, separating by silica gel column chromatography by using a petroleum ether/ethyl acetate mixed reagent as an eluent to obtain a branch G4.5.
- 5. The method as claimed in claim 4, wherein the polyethylene glycol has an average molecular weight of 200-1000.
- 6. The process according to claim 4, wherein the acrylic ester is methyl methacrylate, ethyl methacrylate, methyl acrylate or ethyl acrylate.
- 7. The process according to claim 4, wherein the transesterase is Novozyme 435, and the organic solvent is one or more selected from ether, dichloromethane and tetrahydrofuran; the alkaline catalyst is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium methoxide, sodium ethoxide, triethylamine and pyridine; the polar organic solvent is one or more of methanol, ethanol, ether, dichloromethane and tetrahydrofuran; the primary mercapto amine compound includes one or more of mercaptoethylamine, p-mercaptophenylethylamine, 3-mercapto-1-propylamine and hydrochloride thereof.
- 8. The preparation method of claim 4, wherein the acid-binding agent is one or more of triethylamine, pyridine, N-diisopropylethylamine and potassium carbonate.
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| US5227432A (en) * | 1987-03-28 | 1993-07-13 | Basf Lacke & Farben Ag | Branched acrylate copolymer with polymerizable double bonds and methods for the production of the acrylate copolymer |
| CN1946772A (en) * | 2004-04-20 | 2007-04-11 | 德瑞迪克纳米科技公司 | Dendritic polymers with enhanced amplification and interior functionality |
| CN102604118A (en) * | 2012-02-10 | 2012-07-25 | 华南理工大学 | Polyethylene glycol dendritic polymers and preparation method thereof |
| CN103304804A (en) * | 2013-05-28 | 2013-09-18 | 中国科学院长春应用化学研究所 | Polyethylene glycol-polyamide-amine-polyamino acid linear-dendritic block polymer and preparation method thereof |
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| US5227432A (en) * | 1987-03-28 | 1993-07-13 | Basf Lacke & Farben Ag | Branched acrylate copolymer with polymerizable double bonds and methods for the production of the acrylate copolymer |
| CN1946772A (en) * | 2004-04-20 | 2007-04-11 | 德瑞迪克纳米科技公司 | Dendritic polymers with enhanced amplification and interior functionality |
| CN102604118A (en) * | 2012-02-10 | 2012-07-25 | 华南理工大学 | Polyethylene glycol dendritic polymers and preparation method thereof |
| CN103304804A (en) * | 2013-05-28 | 2013-09-18 | 中国科学院长春应用化学研究所 | Polyethylene glycol-polyamide-amine-polyamino acid linear-dendritic block polymer and preparation method thereof |
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Granted publication date: 20181211 |