CN105801825A - Method for synthesizing amphiphilic polymer comprising multiple bromine functional groups and its cationizable grafted copolymer by copolymerization of catalytic cyclic lactone - Google Patents
Method for synthesizing amphiphilic polymer comprising multiple bromine functional groups and its cationizable grafted copolymer by copolymerization of catalytic cyclic lactone Download PDFInfo
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- CN105801825A CN105801825A CN201610365090.3A CN201610365090A CN105801825A CN 105801825 A CN105801825 A CN 105801825A CN 201610365090 A CN201610365090 A CN 201610365090A CN 105801825 A CN105801825 A CN 105801825A
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- functional groups
- bromo
- lactone
- peg
- toluene
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- 125000001246 bromo group Chemical group Br* 0.000 title claims abstract description 49
- 229920001577 copolymer Polymers 0.000 title claims abstract description 45
- 238000000034 method Methods 0.000 title claims abstract description 35
- 229920000642 polymer Polymers 0.000 title claims abstract description 32
- 238000007334 copolymerization reaction Methods 0.000 title claims abstract description 17
- -1 cyclic lactone Chemical class 0.000 title abstract description 11
- 230000002194 synthesizing effect Effects 0.000 title abstract description 3
- 230000003197 catalytic effect Effects 0.000 title abstract 5
- 239000000178 monomer Substances 0.000 claims abstract description 39
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 33
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 32
- 239000003054 catalyst Substances 0.000 claims abstract description 25
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000003999 initiator Substances 0.000 claims abstract description 17
- 229920002246 poly[2-(dimethylamino)ethyl methacrylate] polymer Polymers 0.000 claims abstract description 16
- UKODFQOELJFMII-UHFFFAOYSA-N pentamethyldiethylenetriamine Chemical compound CN(C)CCN(C)CCN(C)C UKODFQOELJFMII-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims abstract description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 64
- 238000006243 chemical reaction Methods 0.000 claims description 60
- 235000002597 Solanum melongena Nutrition 0.000 claims description 32
- 244000061458 Solanum melongena Species 0.000 claims description 32
- 150000002596 lactones Chemical class 0.000 claims description 28
- LFJJGHGXHXXDFT-UHFFFAOYSA-N 3-bromooxolan-2-one Chemical compound BrC1CCOC1=O LFJJGHGXHXXDFT-UHFFFAOYSA-N 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- JBFHTYHTHYHCDJ-UHFFFAOYSA-N gamma-caprolactone Chemical compound CCC1CCC(=O)O1 JBFHTYHTHYHCDJ-UHFFFAOYSA-N 0.000 claims description 22
- 150000005846 sugar alcohols Polymers 0.000 claims description 22
- 229920000578 graft copolymer Polymers 0.000 claims description 19
- 239000000047 product Substances 0.000 claims description 18
- 125000004122 cyclic group Chemical group 0.000 claims description 15
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000013019 agitation Methods 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- 238000006555 catalytic reaction Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- 238000001291 vacuum drying Methods 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- 239000012046 mixed solvent Substances 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 6
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 5
- OVPFOAFTTLOQEA-UHFFFAOYSA-N anisole;toluene Chemical compound CC1=CC=CC=C1.COC1=CC=CC=C1 OVPFOAFTTLOQEA-UHFFFAOYSA-N 0.000 claims description 5
- 238000001556 precipitation Methods 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000012265 solid product Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- 101100425892 Danio rerio tpma gene Proteins 0.000 claims description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 2
- 101150048952 TPM-1 gene Proteins 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 125000000524 functional group Chemical group 0.000 claims description 2
- 239000012982 microporous membrane Substances 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- CMQCNTNASCDNGR-UHFFFAOYSA-N toluene;hydrate Chemical compound O.CC1=CC=CC=C1 CMQCNTNASCDNGR-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 5
- QNILTEGFHQSKFF-UHFFFAOYSA-N n-propan-2-ylprop-2-enamide Chemical compound CC(C)NC(=O)C=C QNILTEGFHQSKFF-UHFFFAOYSA-N 0.000 claims 1
- 238000010560 atom transfer radical polymerization reaction Methods 0.000 abstract description 16
- 239000003814 drug Substances 0.000 abstract description 9
- 238000007151 ring opening polymerisation reaction Methods 0.000 abstract description 7
- 239000002253 acid Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 5
- 238000011068 loading method Methods 0.000 abstract description 5
- 108090000623 proteins and genes Proteins 0.000 abstract description 4
- 238000010189 synthetic method Methods 0.000 abstract description 3
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 abstract description 3
- 229920006317 cationic polymer Polymers 0.000 abstract description 2
- 238000013270 controlled release Methods 0.000 abstract description 2
- 108020004707 nucleic acids Proteins 0.000 abstract description 2
- 150000007523 nucleic acids Chemical class 0.000 abstract description 2
- 102000039446 nucleic acids Human genes 0.000 abstract description 2
- 238000012656 cationic ring opening polymerization Methods 0.000 abstract 1
- 229910052755 nonmetal Inorganic materials 0.000 abstract 1
- 150000002894 organic compounds Chemical class 0.000 abstract 1
- ASMQGLCHMVWBQR-UHFFFAOYSA-M diphenyl phosphate Chemical group C=1C=CC=CC=1OP(=O)([O-])OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-M 0.000 description 27
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 20
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 15
- 239000000376 reactant Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 10
- 238000006116 polymerization reaction Methods 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 8
- 238000007142 ring opening reaction Methods 0.000 description 8
- 238000010276 construction Methods 0.000 description 5
- 230000002209 hydrophobic effect Effects 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 229950000845 politef Drugs 0.000 description 4
- 229920001610 polycaprolactone Polymers 0.000 description 4
- 238000004062 sedimentation Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- VAJVDSVGBWFCLW-UHFFFAOYSA-N 3-Phenyl-1-propanol Chemical compound OCCCC1=CC=CC=C1 VAJVDSVGBWFCLW-UHFFFAOYSA-N 0.000 description 2
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229920003232 aliphatic polyester Polymers 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 150000001875 compounds Chemical group 0.000 description 2
- 238000012691 depolymerization reaction Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- VLCAYQIMSMPEBW-UHFFFAOYSA-N methyl 3-hydroxy-2-methylidenebutanoate Chemical compound COC(=O)C(=C)C(C)O VLCAYQIMSMPEBW-UHFFFAOYSA-N 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 230000037048 polymerization activity Effects 0.000 description 2
- 238000010526 radical polymerization reaction Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 description 2
- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 description 1
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 1
- TXBCBTDQIULDIA-UHFFFAOYSA-N 2-[[3-hydroxy-2,2-bis(hydroxymethyl)propoxy]methyl]-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(CO)(CO)COCC(CO)(CO)CO TXBCBTDQIULDIA-UHFFFAOYSA-N 0.000 description 1
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical group C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- ZJCCRDAZUWHFQH-UHFFFAOYSA-N Trimethylolpropane Chemical compound CCC(CO)(CO)CO ZJCCRDAZUWHFQH-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- OTJZCIYGRUNXTP-UHFFFAOYSA-N but-3-yn-1-ol Chemical compound OCCC#C OTJZCIYGRUNXTP-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- ACCCMOQWYVYDOT-UHFFFAOYSA-N hexane-1,1-diol Chemical compound CCCCCC(O)O ACCCMOQWYVYDOT-UHFFFAOYSA-N 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- DXYFFDHUTOBVEK-UHFFFAOYSA-N methanol;styrene Chemical compound OC.C=CC1=CC=CC=C1 DXYFFDHUTOBVEK-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229940059574 pentaerithrityl Drugs 0.000 description 1
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 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
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/66—Polyesters containing oxygen in the form of ether groups
- C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F283/00—Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G
- C08F283/02—Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G on to polycarbonates or saturated polyesters
-
- 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
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/78—Preparation processes
- C08G63/82—Preparation processes characterised by the catalyst used
- C08G63/87—Non-metals or inter-compounds thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2438/00—Living radical polymerisation
- C08F2438/01—Atom Transfer Radical Polymerization [ATRP] or reverse ATRP
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Polyesters Or Polycarbonates (AREA)
Abstract
The invention discloses a method for synthesizing amphiphilic polymer comprising multiple bromine functional groups and its cationizable grafted copolymer by copolymerization of catalytic cyclic lactone, comprising: using dihydroxy-terminated polyethylene glycol as an initiator, Epsilon-caprolactone and Alpha-bromo-Upsilon-butyrolactone as monomers and nonmetal organic compound DPP as a catalyst, further preparing an amphiphilic polymer comprising multiple bromine functional groups under mild conditions through CROP process; the synthetic method is handy and controllable; as DPP catalytic activity is high, it is possible to perform catalytic ring-opening polymerization at room temperature and synthesize PEG-P(CL-r-BL)-g-PDMAEMA amphiphilic polymer by using multiple bromine functional groups on a main chain of a copolymer as initiators, DMAEMA as a monomer and CuBr/PMDETA as a catalytic system by using ATRP (atom transfer radical polymerization) process, a cationic polymer can be formed under acid conditions, a support effectively trapping nucleic acid is formed, and this polymer is also an amphiphilic thermos-sensitive polymer and has potential application value in the field of loading, transporting and controlled release of drugs and genes.
Description
Technical field
Synthesis of polymer material technical field of the present invention, prepared by especially medical macromolecular materials, be specifically related to be catalyzed ring-type in
Ester copolymerization contains multiple bromo functional groups amphipathic nature polyalcohols and the method for cationisable's graft copolymer thereof.
Background technology
The polymer that Polyethylene Glycol (PEG) is a kind of good biocompatibility, hydrophilic is high.PEG exempts from will not causing human body
The serious antigen-reactive of epidemic disease system, and the PEG that molecular weight is less than 10000 can run through metabolism and be excreted,
Accumulate the most in vivo, there is no any toxic and side effects.Therefore, PEG is by FDA Food and Drug Administration (FDA) batch
Quasi-accreditation, is widely used in biomedicine field.PEG good hydrophilic property, chain compliance is good, and therefore, PEG is commonly used for two
The hydrophilic component of parent's property polymer, this amphipathic nature polyalcohol can be self-assembly of the micelle with PEG as shell in water.
By just can realize loading and the transport of medicine at the hydrophobic cores of micelle parcel hydrophobic drug.Polycaprolactone (PCL)
Also being the prominent polymer of a kind of biocompatibility, be the polymer of FDA certification equally, biological safety is good.And PCL
Have good drug permeability so that PCL becomes a kind of hydrophobic material conventional in polymer drug carrier.It is worth
It is noted that with PEG as initiator, the controlled ring-opening polymerisation with cyclic polyester as monomer is to prepare amphipathic biocompatibility
The effective ways of polyether-polyester copolymer, this method can control copolymer conveniently by adjusting the monomer ratio with initiator
Molecular weight, and molecular weight distribution is narrower.In addition, by with containing bromo functional groups cyclic monomer (such as α-bromo-gamma-butyrolacton)
Ring opening copolymer, bromo functional groups side base can be introduced in the polymer backbone, and the quantity of bromo functional groups side base and density can
To be regulated and controled with the ratio of 6-caprolactone by regulation α-bromo-gamma-butyrolacton.With this copolymer Han bromo functional groups as macromole
Initiator, can cause some vinyl monomer (such as methacrylic acid two by atom transfer radical polymerization (ATRP) method
Methylamino ethyl ester) polymerization obtain cationisable's graft copolymer and temperature-sensitive graft copolymers.It is noted that α-bromo-γ-
Butyrolactone is a kind of cyclic monomer being difficult to homopolymerization, therefore, when with other cyclic monomer ring opening copolymers, poly-formed
In compound chain, α-bromo-gamma-butyrolacton construction unit will not occur continuously, and this structure is follow-up ATRP method grafting effectively
Copolymerization reduces sterically hindered, is conducive to improving the monomer conversion of graft copolymerization.
But containing the rarest research of ring-opening polymerisation of bromo functional groups cyclic monomer at present, main cause is containing the ring-type list of bromo functional groups
The open loop activity of body is relatively low.Albertsson etc. were at " Polymer Chemistry " (polymer chemistry) the 5th in 2014
" Establishing α-bromo-γ-butyrolactone as a platform for synthesis of that phase 3847-3854 page delivers
Functional aliphatic polyesters-bridging the gap between ROP and SET-LRP " (based on α-bromo-γ-Ding Nei
Ester is platform complex functionality aliphatic polyester-make controlled ring-opening polymerisation effectively be combined with single electron " active " radical polymerization).
This article is with benzylalcohol as initiator, with stannous octoate [Sn (Oct)2] it is catalyst, at 110 DEG C, it is catalyzed 6-caprolactone or L-third hands over
Ester synthesizes the aliphatic polyester of main chain belt bromo functional groups with α-bromo-gamma-butyrolacton ring opening copolymer, then with multiple on this aliphatic polyester
Bromo functional groups is priming site, uses single electron transfer-" active " radical polymerization (SET-LRP) method to cause methyl-prop
The polymerization of e pioic acid methyl ester (MMA), hydroxyethyl methylacrylate (HEMA), n-butyl acrylate (nBuAc) is grafted
Copolymer.
But above-mentioned technology path yet suffers from two large problems, one be the catalyst of annular lactone ring-opening polymerisation be stannous octoate
[Sn(Oct)2], needing to be polymerized at a higher temperature, there are some side reactions, and catalyst contains metal, residual catalyst will
Affect the biological safety of polymeric articles；Two is α in polymer-bromo-gamma-butyrolacton and 6-caprolactone or L-lactide structure list
The molar ratio of unit is the highest by only 0.12, and in copolymer chain, bromo functional groups density refractory is to improve further, and this greatly limits
The grafting density of grafted chain.
Summary of the invention
For deficiencies of the prior art, the present invention provides catalysis annular lactone copolymerization containing multiple bromo functional groups two
The method of parent's property polymer, the method achieves use and catalyzes and synthesizes main chain in a mild condition without orgnometallic catalyst containing many
The amphipathic ethylene glycol of individual bromo functional groups-polycyclic shape lactone copolymers.And provide and utilize this copolymer to prepare cationisable
The method of graft copolymer, amphipathic ethylene glycol-polycyclic shape lactone copolymers that the method contains multiple bromo functional groups with main chain is
Initiator, cause dimethylaminoethyl methacrylate (DMAEMA) atom transfer radical polymerization obtain amphipathic can
Cationization graft copolymer, this amphipathic cationisable's graft copolymer material can be used for medicine and the loading of gene and fortune
Defeated, provide potential carrier material for drug controlled release and targeted therapy, gene therapy.
The synthetic method that the present invention provides, it is achieved ring opening copolymer in a mild condition, have that polymerization activity is high, polymer without
The advantages such as kish, improve biological safety.Additionally, the present invention provide method operation is simple.
To achieve these goals, the technical solution used in the present invention is as follows:
One, the catalysis annular lactone copolymerization method containing multiple bromo functional groups amphipathic nature polyalcohols, comprises the following steps:
1) Polyethylene Glycol is dry: mixed by mass volume ratio 1g:4～20mL with toluene by Polyethylene Glycol, at 120 DEG C
～160 DEG C, oil bath heating under normal pressure, to distill out toluene-water azeotropic mixture and the toluene of excess, obtain the Polyethylene Glycol being dried,
And be placed in dry protection gas, standby；
2) cyclic monomer lactone is dry: by cyclic monomer lactone and CaH2Powder puts into reactor by 10～50mL:1g,
Magnetic agitation 24～48h, so that cyclic monomer lactone is dried, then with the filtering with microporous membrane that aperture is 0.45 μm, obtains
Filtrate be dry cyclic monomer lactone, standby；
3) synthesis of copolymer: using step 1) Polyethylene Glycol that obtains is as initiator and step 2) cyclic monomer that obtains
Lactone 1:1 in mass ratio～30 mixing, and it is allowed to mix homogeneously under magnetic agitation effect；Add catalyst, by above-mentioned mixed
Compound stirs reaction 6h～29h at room temperature～100 DEG C；Dissolve product with dichloromethane again, be subsequently adding ether and obtain
Precipitation shape solid product, filters, is placed in vacuum drying oven by this precipitation shape solid product and dries to constant weight, obtain containing multiple bromines
Functional group's amphipathic nature polyalcohol.
Wherein, step 1) described in protection gas be Ar or N2。
Step 2) described in cyclic monomer lactone include 6-caprolactone and α-bromo-gamma-butyrolacton, wherein α-bromo-gamma-butyrolacton with
The mass ratio of 6-caprolactone is 1:1～10；Accordingly, step 3) obtain containing multiple bromo functional groups amphipathic nature polyalcohols be
PEG-P (CL-r-BL), this polymer is the copolymer on main chain containing multiple bromo functional groups.
Step 3) described in catalyst and Polyethylene Glycol in the mol ratio of hydroxyl be 1～5:1；Described catalyst is DPP
(diphenyl phosphate), DBU (1,8-diazabicylo [5.4.0] 11 carbon-7-alkene), TBD (1,5,7-tri-azabicyclic [4.4.0]
Decyl-5-alkene) or MSA (pyrovinic acid).
It is catalyst that the present invention uses without metallo-organic compound diphenyl phosphate (DPP), using Polyethylene Glycol as initiator,
Cause annular lactone ring opening copolymer, annular lactone monomer includes 6-caprolactone and α-bromo-gamma-butyrolacton, can by regulation ε-
Caprolactone and the α-mol ratio of bromo-gamma-butyrolacton, reaction temperature regulate the density of bromo functional groups in polymer, and this step can be square
Synthesize a kind of main chain amphipathic ethylene glycol-poly-annular lactone with multiple bromine substituents the most in a mild condition
Copolymer p EG-P (CL-r-BL), polyreaction formula is as follows:
In addition to Polyethylene Glycol, initiator can also use hexanediol, tetramethylolmethane, trimethylolpropane, Bis(pentaerythritol),
Propilolic alcohol, 3-butyne-1-ol, to vinyl benzene methanol, 6-nitrine-1-hexanol, 3-phenyl-1-propanol or hydroxyethyl methacrylate
Ethyl ester.
Two, the above-mentioned method preparing cationisable's graft copolymer containing multiple bromo functional groups amphipathic nature polyalcohols is utilized, bag
Include following steps:
(1) first eggplant shaped reaction bottle is connected vacuum/Ar biexhaust pipe operating system, repeat evacuation-logical Ar and operate three times, with
Oxygen-free environment is formed in making eggplant shaped reaction bottle；Again in the case of logical Ar, by CuBr, 1.4mmol of 0.7mmol
The methyl phenyl ethers anisole of part PMDETA (pentamethyl-diethylenetriamine) and 4mL-toluene Mixed Solvent adds in eggplant shaped reaction bottle,
And stir 15min, it is allowed to generate complex；Then in eggplant shaped reaction bottle, add monomer DMAEMA (methacrylic acid
Dimethylaminoethyl) 28mmol, and stir；Add the PEG-P (CL-r-BL) containing bromo functional groups containing 0.7mmol,
Stirring, to being completely dissolved, forms reaction solution；
Described methyl phenyl ethers anisole-toluene Mixed Solvent is mixed by the methyl phenyl ethers anisole that volume ratio is 1:0.1～10 and toluene；
(2) in the case of keeping logical Ar, eggplant shaped reaction bottle is closed, then by eggplant shaped reaction bottle oil at 40 DEG C～100 DEG C
Bath heating 5～72h, so that reaction solution generation graft reaction；
(3) allow eggplant shaped reaction bottle naturally cool to room temperature, then be added thereto to organic solvent and be diluted, then pass through alkali
Property alumina column or neutral alumina column, to remove the mantoquita in product；Redistillation obtains concentrating solution, and to concentrating solution
Middle addition precipitant, so that generating precipitation in concentrated solution；
It is filtrated to get solid polymer, then this solid polymer is placed in vacuum drying oven, dry to constant weight at 40 DEG C,
Obtain cationisable's graft copolymer, i.e. PEG-P (CL-r-BL)-g-PDMAEMA.
By using, to be catalyzed 6-caprolactone and α-bromo-gamma-butyrolacton open loop in a mild condition without metal efficient organic catalyst common
Poly-, the one-step synthesis main chain amphipathic copolymer p EG-P (CL-r-BL) containing multiple bromo functional groups.Because its main chain is with some
Individual reactive bromo functional groups, can do many modification for copolymer and modified work, because of Polyethylene Glycol based on this
The biocompatibility good with poly-annular lactone, may also be used for synthesizing some bio-medical functions high based on this copolymer
Molecule.With the upper multiple bromo functional groups of PEG-P (CL-r-BL) as initiator, with atom transfer radical polymerization (ATRP)
Method, using dimethylaminoethyl methacrylate (DMAEMA) as the monomer of grafted chain, causes its polymerization to obtain two
Parent's property cationisable's graft copolymer.Control to connect by the mol ratio of regulation monomer DMAEMA with macromole evocating agent
The length of branch chain.
Polymethylacrylic acid dimethylaminoethyl (PDMAEMA) is a kind of polymer more sensitive to temperature and pH,
At its low critical consolute temperature (LCST) below, the interaction of hydrogen bond between PDMAEMA and water is occupied an leading position,
Make it can relatively good dissolving in water；When temperature is increased to more than LCST, between PDMAEMA and water, hydrogen bond action subtracts
Weak, polymer molecule interchain hydrophobic interaction strengthens, and polymer presents hydrophobicity.By with PDMAEMA copolymerization
Method can regulate the LCST of PDMAEMA, such as, use hydrophilic polymer PEG Yu PDMAEMA to carry out copolymerization,
The LCST of copolymer can be made close to human body temperature, thus can use as Thermo-sensitive pharmaceutical carrier.It addition, utilize
The feature that PDMAEMA polymer is sensitive to pH, can regulate the hydrophilic and hydrophobic of polymer by regulation system pH value,
Especially in the environment of pH ＜ 7, PDMAEMA can be effectively increased it load and transporter gene with cationization
Ability.
PEG-P (the CL-r-BL)-g-PDMAEMA graft copolymer reaction equation of present invention synthesis is as follows:
Wherein, the monomer used by step (1) is DMAEMA.
In step (1), the mol ratio containing Br functional group with CuBr, part PMDETA in PEG-P (CL-r-BL) is
1:1:1～5；The upper mol ratio containing bromo functional groups of monomer DMAEMA Yu PEG-P (CL-r-BL) is 10～100:1.
PEG-P (CL-r-BL) and mass volume ratio 1g:2～15mL of methyl phenyl ethers anisole-toluene Mixed Solvent in step (1).
Part used in step (1) is BPY (2,2 '-bipyridyl) or TPMA (three (2-pyridylmethyl) amine).
The organic solvent added in step (3) is THF, CH2Cl2, acetone, toluene or chloroform, this organic solvent and step
Suddenly the volume ratio of the reaction solution of (1) is 3～30:1；Described precipitant is normal hexane, ether, petroleum ether or normal heptane.
The present invention is with hydroxyl carbowax as initiator, with 6-caprolactone and α-bromo-gamma-butyrolacton as monomer, with without metal
Organic compound diphenyl phosphate (DPP) is catalyst, by controlled ring-opening polymerization method (CROP), at temperate condition
Next step prepares the main chain copolymer containing multiple bromo functional groups, and synthetic method is convenient controlled, because DPP catalysis activity is higher, and can
With at room temperature catalyzed ring opening polymerization, in this synthetic system, this catalyst can improve α-bromo-gamma-butyrolacton to a certain extent
Open loop activity, suitably raise polymerization temperature and can improve the conversion ratio of α-bromo-gamma-butyrolacton.Then with many in copolymer chain
Individual bromo functional groups is initiator, uses atom transfer radical polymerization (ATRP), with dimethylaminoethyl methacrylate
(DMAEMA) be monomer, with CuBr/PMDETA as catalyst system and catalyzing, synthesize PEG-P (CL-r-BL)-g-PDMAEMA
Amphipathic graft copolymer, can form cationic polymer in acid condition, becomes effectively bag and carries the carrier of nucleic acid, simultaneously
Also it is a kind of amphipathic temperature sensing polymer, has potential application at medicine and the loading of gene, transport with controllable release field
It is worth.
Compared with prior art, there is advantages that
1, use the diphenyl phosphate (DPP) without metal as catalyst, for 6-caprolactone and α-bromo-gamma-butyrolacton
Ring opening copolymer, it is achieved ring opening copolymer in a mild condition, polymerization activity is high, polymer noresidue metal, improves biology peace
Quan Xing.
2, with Polyethylene Glycol as initiator, use diphenyl phosphate (DPP) be catalyst 6-caprolactone and α-bromo-γ-
Butyrolactone ring opening copolymer.Under relatively low polymerization temperature (room temperature), the open loop activity of α-bromo-gamma-butyrolacton is too low, and too high
Under polymerization temperature (100 DEG C), depolymerization reaction is more obvious, and both of these case all can cause α in polymer-bromo-gamma-butyrolacton
The reduction of construction unit ratio.α-bromo-gamma-butyrolacton and 6-caprolactone in the copolymer catalyzed and synthesized at 60 DEG C in the present invention
Construction unit mol ratio can reach 0.24, and the Research Literature being current was not reported.As can be seen here, present invention achieves
In broader scope, control copolymer chain by the mol ratio of regulation 6-caprolactone and α-bromo-gamma-butyrolacton cyclic monomer
The density of bromo functional groups.
3, higher because of catalyst DPP activity, polymerization parameter and technique are (as put into catalysis the most in batches
Agent is polymerized) can regulate in broader scope, thus obtain the structure main chain different from the performance amphiphilic containing bromo functional groups
Property copolymer.
4, the method using atom transfer radical polymerization (ATRP), with the brominated amphipathic nature polyalcohol of main chain as initiator,
Cause the acrylic ester monomer graft copolymerization of nitrogen atom, it is achieved amphipathic Thermo-sensitive copolymer and amphipathic cationisable
The convenient synthesis of polymer.Loading and transport for medicine and gene provide effective carrier material.
Accompanying drawing explanation
Fig. 1 is the tool by-reaction eggplant-shape bottle in various embodiments of the present invention for polyreaction；
Fig. 2 is the PEG-P (CL-r-BL) using DPP to catalyze and synthesize in the embodiment of the present invention one1H-NMR spectrum；
Fig. 3 is the PEG-P (CL-r-BL) using DPP to catalyze and synthesize in the embodiment of the present invention two1H-NMR spectrum；
Fig. 4 is the PEG-P (CL-r-BL) using DPP to catalyze and synthesize in the embodiment of the present invention three1H-NMR spectrum；
Fig. 5 is the PEG-P (CL-r-BL) using DPP to catalyze and synthesize in the embodiment of the present invention four1H-NMR spectrum；
Fig. 6 is PEG-P (the CL-r-BL)-g-PDMAEMA using ATRP method synthesis in the embodiment of the present invention five1H-NMR spectrum.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in further detail.
Embodiment one
With diphenyl phosphate as catalyst, (main chain contains multiple bromine to catalyze and synthesize the amphipathic nature polyalcohol containing multiple bromo functional groups
The amphipathic ethylene glycol of functional group-polycyclic shape lactone copolymers):
Design copolymer relative molecular weight is 12300.Weigh 1g both-end hydroxyl PEG2000 and prop up eggplant in tool as shown in Figure 1
In shaped reaction bottle, add politef magneton, be subsequently added 10mL toluene, connect distilling apparatus, by eggplant shaped reaction bottle
Being placed in 140 DEG C of oil baths, open magnetic agitation, toluene is distilled out of with azeotropic mixture and the excess toluene of water, and PEG is removed
Water is dried.Tool eggplant-shape bottle is connected vacuum/Ar biexhaust pipe operating system, successively evacuation (vacuum :-0.098MPa),
Logical argon, and when logical argon with disposable syringe respectively by α-bromo-gamma-butyrolacton 1.4mL, 6-caprolactone 2.6
ML adds eggplant shaped reaction bottle, and weighs diphenyl phosphate (DPP) 250mg (nDPP: nOH=1) eggplant shaped reaction bottle is added,
Magnetic agitation at room temperature, stopped reaction after reaction 6h, dissolves product q. s. methylene chloride, with ether sedimentation, obtains
To white powdery solid, dry in vacuum drying oven to constant weight, obtain the amphipathic nature polyalcohol containing multiple bromo functional groups
PEG-P (CL-r-BL), its1H-NMR spectrum is shown in Fig. 2.Weigh to obtain product 2.89g, productivity 46.8%.Under productivity passes through
Formula calculates:
Wherein: m1, m2, m3, m4Representative products quality, reactant Polyethylene Glycol quality, reactant α-bromo-γ-fourth respectively
Lactone quality, reactant 6-caprolactone quality.
Embodiment two
With diphenyl phosphate as catalyst, (main chain contains multiple bromine to catalyze and synthesize the amphipathic nature polyalcohol containing multiple bromo functional groups
The amphipathic ethylene glycol of functional group-polycyclic shape lactone copolymers):
Design copolymer relative molecular weight is 33400.Weigh 500mg both-end hydroxyl PEG2000 in tool as shown in Figure 1
Prop up in eggplant shaped reaction bottle, add politef magneton, be subsequently added 10mL toluene, connect distilling apparatus, by anti-for eggplant shape
Answering bottle to be placed in 140 DEG C of oil baths, open magnetic agitation, toluene is distilled out of with azeotropic mixture and the excess toluene of water, and PEG obtains
To be dried except water.Tool eggplant-shape bottle is connected vacuum/Ar biexhaust pipe operating system, successively evacuation (vacuum :-0.098MPa),
Logical argon, and when logical argon with disposable syringe respectively by dried α-bromo-gamma-butyrolacton 2.2mL, ε-
Caprolactone 3.8mL adds eggplant shaped reaction bottle, and first weighs diphenyl phosphate (DPP) 127mg addition eggplant shaped reaction bottle,
Stirring reaction 4h, adds DPP 250mg (total n subsequently at room temperatureDPP: nOH=3) in reaction system, by reaction bulb
It is placed in magnetic agitation in 60 DEG C of oil bath pans, continues stopped reaction after reaction 3.5h, product q. s. methylene chloride is dissolved,
With ether sedimentation, obtain white powdery solid, dry in vacuum drying oven to constant weight, obtain the amphiphilic containing multiple bromo functional groups
Property polymer P EG-P (CL-r-BL), its1H-NMR spectrum is shown in Fig. 3.Weigh to obtain product 3.50g, productivity 41.9%.Produce
Rate is calculated by following formula:
Wherein: m1, m2, m3, m4Representative products quality, reactant Polyethylene Glycol quality, reactant α-bromo-γ-fourth respectively
Lactone quality, reactant 6-caprolactone quality.
Under relatively low polymerization temperature (room temperature), the open loop activity of α-bromo-gamma-butyrolacton is too low, and too high polymerization temperature (100 DEG C)
Under, depolymerization reaction is more obvious, and both of these case all can cause the reduction of α in polymer-bromo-gamma-butyrolacton construction unit ratio.
In the copolymer that the present invention catalyzes and synthesizes at 60 DEG C, α-bromo-gamma-butyrolacton can reach with 6-caprolactone construction unit mol ratio
0.24, the Research Literature being current was not reported, was also that ratio is the highest, and this effect is unexpected.
Embodiment three
With diphenyl phosphate as catalyst, (main chain contains multiple bromine to catalyze and synthesize the amphipathic nature polyalcohol containing multiple bromo functional groups
The amphipathic ethylene glycol of functional group-polycyclic shape lactone copolymers):
Design copolymer relative molecular weight is 33400.Weigh 500mg both-end hydroxyl PEG2000 in tool as shown in Figure 1
Prop up in eggplant shaped reaction bottle, add politef magneton, be subsequently added 10mL toluene, connect distilling apparatus, by anti-for eggplant shape
Answering bottle to be placed in 140 DEG C of oil baths, open magnetic agitation, toluene is distilled out of with azeotropic mixture and the excess toluene of water, and PEG obtains
To be dried except water.Tool eggplant-shape bottle is connected vacuum/Ar biexhaust pipe operating system, successively evacuation (vacuum :-0.098MPa),
Logical argon, and when logical argon with disposable syringe respectively by α-bromo-gamma-butyrolacton 2.2mL, 6-caprolactone 3.8
ML adds eggplant shaped reaction bottle, and weighs diphenyl phosphate (DPP) 378mg (nDPP: nOH=3) eggplant shaped reaction bottle is added,
Reaction bulb is placed in magnetic agitation in 100 DEG C of oil bath pans, and stopped reaction after reaction 6h, by molten for product q. s. methylene chloride
Solve, with ether sedimentation, obtain white solid, dry in vacuum drying oven to constant weight, obtain the amphiphilic containing multiple bromo functional groups
Property polymer P EG-P (CL-r-BL), its1H-NMR spectrum is shown in Fig. 4.Weigh to obtain product 3.89g, productivity 46.6%.Produce
Rate is calculated by following formula:
Wherein: m1, m2, m3, m4Representative products quality, reactant Polyethylene Glycol quality, reactant α-bromo-γ-fourth respectively
Lactone quality, reactant 6-caprolactone quality.
Embodiment four
With diphenyl phosphate as catalyst, (main chain contains multiple bromine to catalyze and synthesize the amphipathic nature polyalcohol containing multiple bromo functional groups
The amphipathic ethylene glycol of functional group-polycyclic shape lactone copolymers):
Design copolymer relative molecular weight is 50000.Weigh 200mg both-end hydroxyl PEG2000 in tool as shown in Figure 1
Prop up in eggplant shaped reaction bottle, add politef magneton, be subsequently added 10mL toluene, connect distilling apparatus, by anti-for eggplant shape
Answering bottle to be placed in 140 DEG C of oil baths, open magnetic agitation, toluene is distilled out of with azeotropic mixture and the excess toluene of water, and PEG obtains
To be dried except water.Tool eggplant-shape bottle is connected vacuum/Ar biexhaust pipe operating system, successively evacuation (vacuum :-0.098MPa),
Logical argon, and when logical argon with disposable syringe respectively by α-bromo-gamma-butyrolacton 1.3mL, 6-caprolactone 2.3
ML adds eggplant shaped reaction bottle, and weighs diphenyl phosphate (DPP) 75mg (nDPP: nOH=1.5) eggplant shaped reaction bottle is added,
Reaction bulb is placed in magnetic agitation in 100 DEG C of oil bath pans, and stopped reaction after reaction 12h, by product q. s. methylene chloride
Dissolve, with ether sedimentation, obtain white powdery solid, dry in vacuum drying oven to constant weight, obtain containing multiple bromo functional groups
Amphipathic nature polyalcohol PEG-P (CL-r-BL), its1H-NMR spectrum is shown in Fig. 5.Weigh to obtain product 2.96g, productivity 59.2%.
Productivity is calculated by following formula:
Wherein: m1, m2, m3, m4Representative products quality, reactant Polyethylene Glycol quality, reactant α-bromo-γ-fourth respectively
Lactone quality, reactant 6-caprolactone quality.
Embodiment five
With containing multiple bromo functional groups amphipathic nature polyalcohols as initiator, use atom transfer radical polymerization (ATRP) method,
Cause dimethylaminoethyl methacrylate (DMAEMA) monomer graft copolymerization synthesis
PEG-P (CL-r-BL)-g-PDMAEMA copolymer:
With the copolymer p EG-P (CL-r-BL) of synthesis in embodiment two as macromole evocating agent, use ATRP method, cause
Monomer DMAEMA graft copolymerization.Tool as shown in Figure 1 is propped up eggplant shaped reaction bottle and is connected to vacuum/Ar biexhaust pipe device,
Through three evacuation-fill Ar circulation operation, it is ensured that oxygen-free environment.Afterwards in the case of being passed through Ar, successively to reaction bulb
Middle addition CuBr (0.7mmol, 100.8mg), part PMDETA (1.4mmol, 0.292mL), toluene and benzene first
The mixed solvent (v:v=1:1,4mL) of ether, stirring 15min ensures abundant complexation, and solution colour is become blackish green from light green color
Color.Adding monomer DMAEMA (28mmol, 4.4g, 4.72mL), stirring makes system mix homogeneously.It is eventually adding
PEG-P (CL-r-BL) copolymer (0.5g, containing 0.7mmol Br), stirring to copolymer is all dissolved.By eggplant shaped reaction bottle
Seal, be placed in 70 DEG C of oil bath pans, react 30h.After reaction terminates, in reaction system, add 30mL oxolane
(THF), by alkali alumina post to remove catalyst, subsequently distillation and concentration solution, precipitate with normal hexane, obtain brown
Solid, is finally placed in product in vacuum drying oven and is dried to constant weight at 40 DEG C, obtain
PEG-P (CL-r-BL)-g-PDMAEMA copolymer, its1H-NMR spectrum is shown in Fig. 6.
Weigh to obtain product 1.82g, productivity 37.1%.Productivity is calculated by following formula:
Wherein: m1, m2, m3Representative products quality, copolymer p EG-P (CL-r-BL) quality, monomer DMAEMA respectively
Quality.
The above embodiment of the present invention is only for example of the present invention is described, and is not to embodiments of the present invention
Restriction.For those of ordinary skill in the field, other not similar shapes can also be made on the basis of the above description
The change of formula and variation.Here cannot all of embodiment be given exhaustive.Every technical scheme that belongs to is drawn
What Shen went out obviously changes or changes the row still in protection scope of the present invention.
Claims (10)
1. the catalysis annular lactone copolymerization method containing multiple bromo functional groups amphipathic nature polyalcohols, it is characterised in that comprise the following steps:
1) Polyethylene Glycol is dry: mixed by mass volume ratio 1g:4 ~ 20mL with toluene by Polyethylene Glycol; 120 DEG C ~ 160 DEG C, oil bath heating under normal pressure, to distill out toluene-water azeotropic mixture and the toluene of excess, obtain the Polyethylene Glycol being dried; and be placed in dry protection gas, standby；
2) cyclic monomer lactone is dry: by cyclic monomer lactone and CaH2Powder puts into reactor, magnetic agitation 24 ~ 48h by 10 ~ 50mL:1g, so that cyclic monomer lactone is dried, then with the filtering with microporous membrane that aperture is 0.45 μm, the filtrate obtained is dry cyclic monomer lactone, standby；
3) synthesis of copolymer: Polyethylene Glycol step 1) obtained is as initiator and step 2) cyclic monomer lactone 1:1 ~ 30 in mass ratio that obtain mix, and are allowed to mix homogeneously under magnetic agitation effect；Add catalyst, said mixture is stirred at room temperature ~ 100 DEG C reaction 6 h ~ 29 h；Dissolve product with dichloromethane again, be subsequently adding ether and be precipitated shape solid product, filter, this precipitation shape solid product is placed in vacuum drying oven and dries to constant weight, obtain containing multiple bromo functional groups amphipathic nature polyalcohols.
The catalysis annular lactone copolymerization the most according to claim 1 method containing multiple bromo functional groups amphipathic nature polyalcohols, it is characterised in that the protection gas described in step 1) is Ar or N2。
The catalysis annular lactone copolymerization the most according to claim 1 method containing multiple bromo functional groups amphipathic nature polyalcohols, it is characterized in that, step 2) described in cyclic monomer lactone include 6-caprolactone and α-bromo-gamma-butyrolacton, wherein α-bromo-gamma-butyrolacton is 1:1 ~ 10 with the mass ratio of 6-caprolactone；Accordingly, what step 3) obtained is PEG-P (CL-r-BL) containing multiple bromo functional groups amphipathic nature polyalcohols.
The catalysis annular lactone copolymerization the most according to claim 1 method containing multiple bromo functional groups amphipathic nature polyalcohols, it is characterised in that the catalyst described in step 3) is 1 ~ 5:1 with the mol ratio of hydroxyl in Polyethylene Glycol；Described catalyst is DPP, DBU, TBD or MSA.
5. utilize the method preparing cationisable's graft copolymer containing multiple bromo functional groups amphipathic nature polyalcohols that claim 3 synthesizes, it is characterised in that comprise the following steps:
(1) first eggplant shaped reaction bottle is connected vacuum/Ar biexhaust pipe operating system, repeat evacuation-logical Ar and operate three times, so that forming oxygen-free environment in eggplant shaped reaction bottle；Again in the case of logical Ar, the methyl phenyl ethers anisole-toluene Mixed Solvent of the CuBr of 0.7 mmol, part PMDETA and 4mL of 1.4 mmol is added in eggplant shaped reaction bottle, and stirs 15 min, be allowed to generate complex；Then in eggplant shaped reaction bottle, add monomer DMAEMA 28 mmol, and stir；Adding the PEG-P (CL-r-BL) containing bromo functional groups containing 0.7 mmol, stirring, to being completely dissolved, forms reaction solution；
Described methyl phenyl ethers anisole-toluene Mixed Solvent is mixed by the methyl phenyl ethers anisole that volume ratio is 1:0.1 ~ 10 and toluene；
(2) in the case of keeping logical Ar, eggplant shaped reaction bottle is closed, then by eggplant shaped reaction bottle oil bath heating 5 ~ 72 h at 40 DEG C ~ 100 DEG C, so that reaction solution generation graft reaction；
(3) allow eggplant shaped reaction bottle naturally cool to room temperature, then be added thereto to organic solvent and be diluted, then by alkali alumina post or neutral alumina column, to remove the mantoquita in product；Redistillation obtains concentrating solution, and adds precipitant in solution to concentrating, so that generating precipitation in concentrated solution；
It is filtrated to get solid polymer, then this solid polymer is placed in vacuum drying oven, dry to constant weight at 40 DEG C, obtain cationisable's graft copolymer, i.e. PEG-P (CL-r-BL)-g-PDMAEMA.
The method of preparation cationisable's graft copolymer the most according to claim 5, it is characterised in that the monomer used by step (1) is NIPAM.
The method of preparation cationisable's graft copolymer the most according to claim 5, it is characterised in that be 1:1:1 ~ 5 containing Br functional group and CuBr, the mol ratio of part PMDETA in PEG-P (CL-r-BL) in step (1)；The upper mol ratio containing bromo functional groups of monomer DMAEMA Yu PEG-P (CL-r-BL) is 10 ~ 100:1.
The method of preparation cationisable's graft copolymer the most according to claim 5, it is characterised in that PEG-P (CL-r-BL) and mass volume ratio 1g: 2 ~ 15 mL of methyl phenyl ethers anisole-toluene Mixed Solvent in step (1).
The method of preparation cationisable's graft copolymer the most according to claim 5, it is characterised in that part used in step (1) is BPY or TPMA.
The method of preparation cationisable's graft copolymer the most according to claim 5, it is characterised in that the organic solvent added in step (3) is THF, CH2Cl2, acetone, toluene or chloroform, this organic solvent is 3 ~ 30:1 with the volume ratio of the reaction solution of step (1)；Described precipitant is normal hexane, ether, petroleum ether or normal heptane.
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| CN111690111A (en) * | 2020-07-30 | 2020-09-22 | 中国科学院兰州化学物理研究所 | Comb type polymer and preparation method and application thereof |
| CN113736075A (en) * | 2021-08-31 | 2021-12-03 | 深圳大学 | Preparation method of polylactone |
| CN114230738A (en) * | 2021-12-14 | 2022-03-25 | 南方海洋科学与工程广东省实验室(湛江) | Self-degradable cationic polymer and preparation method and application thereof |
| CN115124669A (en) * | 2022-05-27 | 2022-09-30 | 北京化工大学 | Preparation method and application of linear block copolymer nano-carrier with double-carrier genes and medicines |
| CN115191428A (en) * | 2022-07-25 | 2022-10-18 | 西安交通大学 | Amphiphilic star-shaped polymer loaded pesticide preparation and preparation method thereof |
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| CN111690111A (en) * | 2020-07-30 | 2020-09-22 | 中国科学院兰州化学物理研究所 | Comb type polymer and preparation method and application thereof |
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| CN113736075B (en) * | 2021-08-31 | 2022-06-24 | 深圳大学 | Preparation method of polylactone |
| CN114230738A (en) * | 2021-12-14 | 2022-03-25 | 南方海洋科学与工程广东省实验室(湛江) | Self-degradable cationic polymer and preparation method and application thereof |
| CN115124669A (en) * | 2022-05-27 | 2022-09-30 | 北京化工大学 | Preparation method and application of linear block copolymer nano-carrier with double-carrier genes and medicines |
| CN115124669B (en) * | 2022-05-27 | 2024-03-26 | 北京化工大学 | Preparation method and application of linear block copolymer nano-carrier for double-gene and medicine |
| CN115191428A (en) * | 2022-07-25 | 2022-10-18 | 西安交通大学 | Amphiphilic star-shaped polymer loaded pesticide preparation and preparation method thereof |
| CN115191428B (en) * | 2022-07-25 | 2023-08-22 | 西安交通大学 | Amphiphilic star-type polymer-loaded pesticide preparation and preparation method thereof |
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