CN104710625B - A kind of near-infrared response degradable water soluble copolymer and its high-efficiency synthesis method - Google Patents
A kind of near-infrared response degradable water soluble copolymer and its high-efficiency synthesis method Download PDFInfo
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 87
- 230000004044 response Effects 0.000 title claims abstract description 11
- 229920001577 copolymer Polymers 0.000 title claims abstract description 10
- 238000001308 synthesis method Methods 0.000 title claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 72
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 11
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 11
- 125000000524 functional group Chemical group 0.000 claims abstract description 5
- XDLDASNSMGOEMX-UHFFFAOYSA-N benzene benzene Chemical group C1=CC=CC=C1.C1=CC=CC=C1 XDLDASNSMGOEMX-UHFFFAOYSA-N 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 50
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 239000007787 solid Substances 0.000 claims description 28
- 238000005292 vacuum distillation Methods 0.000 claims description 25
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 230000015572 biosynthetic process Effects 0.000 claims description 22
- 238000003786 synthesis reaction Methods 0.000 claims description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 17
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- 208000035126 Facies Diseases 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 238000010992 reflux Methods 0.000 claims description 16
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 239000003480 eluent Substances 0.000 claims description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 13
- 238000002156 mixing Methods 0.000 claims description 13
- 229910002027 silica gel Inorganic materials 0.000 claims description 13
- 239000000741 silica gel Substances 0.000 claims description 13
- 229960001866 silicon dioxide Drugs 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 229960000583 acetic acid Drugs 0.000 claims description 8
- 229910000085 borane Inorganic materials 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229940125904 compound 1 Drugs 0.000 claims description 8
- 229940043279 diisopropylamine Drugs 0.000 claims description 8
- 239000012044 organic layer Substances 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 8
- 235000010265 sodium sulphite Nutrition 0.000 claims description 8
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 239000012362 glacial acetic acid Substances 0.000 claims description 7
- 239000003208 petroleum Substances 0.000 claims description 7
- 238000006116 polymerization reaction Methods 0.000 claims description 7
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- HDFQKJQEWGVKCQ-UHFFFAOYSA-N 1,3-dimethyl-2-nitrobenzene Chemical compound CC1=CC=CC(C)=C1[N+]([O-])=O HDFQKJQEWGVKCQ-UHFFFAOYSA-N 0.000 claims description 4
- RQFUZUMFPRMVDX-UHFFFAOYSA-N 3-Bromo-1-propanol Chemical compound OCCCBr RQFUZUMFPRMVDX-UHFFFAOYSA-N 0.000 claims description 4
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 claims description 4
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 claims description 4
- DENKGPBHLYFNGK-UHFFFAOYSA-N 4-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Br)C=C1 DENKGPBHLYFNGK-UHFFFAOYSA-N 0.000 claims description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 4
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 238000006392 deoxygenation reaction Methods 0.000 claims description 4
- 238000004108 freeze drying Methods 0.000 claims description 4
- 229960004337 hydroquinone Drugs 0.000 claims description 4
- 239000012286 potassium permanganate Substances 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000779 smoke Substances 0.000 claims description 4
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 claims description 4
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 claims description 3
- 239000000385 dialysis solution Substances 0.000 claims description 3
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 235000002639 sodium chloride Nutrition 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 2
- 238000004821 distillation Methods 0.000 claims 1
- 238000004062 sedimentation Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 16
- 239000000693 micelle Substances 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 8
- 229920000642 polymer Polymers 0.000 abstract description 8
- 230000005540 biological transmission Effects 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 abstract 1
- 238000010521 absorption reaction Methods 0.000 abstract 1
- 238000000862 absorption spectrum Methods 0.000 abstract 1
- 230000015556 catabolic process Effects 0.000 abstract 1
- 229920006237 degradable polymer Polymers 0.000 abstract 1
- 238000006731 degradation reaction Methods 0.000 abstract 1
- 238000002296 dynamic light scattering Methods 0.000 abstract 1
- 238000005227 gel permeation chromatography Methods 0.000 abstract 1
- 230000002209 hydrophobic effect Effects 0.000 abstract 1
- VOFUROIFQGPCGE-UHFFFAOYSA-N nile red Chemical compound C1=CC=C2C3=NC4=CC=C(N(CC)CC)C=C4OC3=CC(=O)C2=C1 VOFUROIFQGPCGE-UHFFFAOYSA-N 0.000 description 11
- 239000000463 material Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 230000005311 nuclear magnetism Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010068052 Mosaicism Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000005253 cladding Methods 0.000 description 2
- 229920000547 conjugated polymer Polymers 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 210000003765 sex chromosome Anatomy 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- GDUANFXPOZTYKS-UHFFFAOYSA-N 6-bromo-8-[(2,6-difluoro-4-methoxybenzoyl)amino]-4-oxochromene-2-carboxylic acid Chemical compound FC1=CC(OC)=CC(F)=C1C(=O)NC1=CC(Br)=CC2=C1OC(C(O)=O)=CC2=O GDUANFXPOZTYKS-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- ODJZWVFLHZHURI-UHFFFAOYSA-M [Br-].C(CCC)[P+](CCCC)(CCCC)CCCC.[NH4+].[Br-] Chemical compound [Br-].C(CCC)[P+](CCCC)(CCCC)CCCC.[NH4+].[Br-] ODJZWVFLHZHURI-UHFFFAOYSA-M 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012930 cell culture fluid Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 238000005034 decoration Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- BJXYHBKEQFQVES-NWDGAFQWSA-N enpatoran Chemical compound N[C@H]1CN(C[C@H](C1)C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N BJXYHBKEQFQVES-NWDGAFQWSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 230000003760 hair shine Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000004298 light response Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002114 nanocomposite Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The present invention is a kind of near-infrared response degradable water soluble copolymer and its high-efficiency synthesis method, synthesized by Sonogashira coupling reaction and a kind of new there is water solublity degradable polymer, micelle can be self-assembled in water, after 800nm light irradiation, in main chain, benzyne benzene structure has the effect of two-photon absorption, absorb near infrared light emitting ultraviolet light, so that absorbing the main chain ester bond functional group fracture of ultraviolet light, polymer micelle is destroyed.This new polymerss can be used as the carrier of medicament transport, for wrapping up some hydrophobic drugs, because polymer lateral chain is connected to Polyethylene Glycol (PEG), so the micelle being formed has good water solublity and biocompatibility, can be used for cell and the carrier of live body medicament transport.And this polymer micelle has been carried out with the sign such as ultra-violet absorption spectrum, gel permeation chromatography, transmission electron microscope, dynamic light scattering, have studied its molecular size range and micelle size and the light degradation property of near-infrared response.
Description
Technical field
The invention belongs to biological functional field of material technology is and in particular to one kind has polymerization under near infrared light
In owner's chain, part chemical bond ruptures, and is degraded into the synthetic method of the water solublity oligomer of small molecule.
Background technology
Medicine and carrier are exactly combined together by drug controlled release, by free diffusing or targeting combination, will
Medicament transport, to after lesions position, releases medicine out by stimulating methods such as enzyme, pH, temperature or light, reaches therapeutic effect.
Drug controlled release is conducive to improving curative effect of medication, reduces toxic and side effects, has great for improving clinical application level
Meaning.The near infrared light infringement less due to having deeper tissue penetration, can reach the therapeutic effect being administered on demand,
There are compared with ultraviolet light many merits, therefore contained based on the polymer nanocomposite medicament transport carrier of near infrared light response huge
Big clinical medicine application potential.
Content of the invention
Technical problem：It is an object of the invention to provide a kind of near-infrared response degradable water soluble copolymer and its efficient conjunction
One-tenth method, synthesizes the serial amphipathic molecule containing benzyne benzene and p-Nitrobenzyl with a kind of efficient method, and exploitation has in water
Self assembly can occur in solution, formed stably can carrying medicament polymer micelle, and there is higher targeting and biology
The new controllable drug release transport agent of the compatibility.
Technical scheme：A kind of near-infrared response degradable water soluble copolymer of the present invention has following molecular structural formula：
Wherein, n is the degree of polymerization, and n is 8-100；
Side chain is the Polyethylene Glycol that end is carboxyl, and m is the degree of polymerization, and m is 23-114.
The new near-infrared response water solublity oligomer preparation method of the present invention is as follows
1), compound 1, i.e. the synthesis of bromo- 2, the 5- Benzodiazepiness of Isosorbide-5-Nitrae-two：
1, 4-benzenediol is added in the two-mouth bottle with reflux condensing tube, adds glacial acetic acid, finish at normal temperatures by liquid
Bromine is dissolved in glacial acetic acid, then is added dropwise in reaction bulb with constant voltage low liquid funnel, reacts 24 hours after completion of dropping at 45 DEG C.Instead
Should finish, add saturation sodium sulfite to remove excessive bromine, sucking filtration is simultaneously washed repeatedly with saturation sodium sulfite, then use water
Washing repeatedly, obtains white powder.
2), the synthesis of compound 2
Two mouthfuls of round bottoms that compound 1, tetrabutyl ammonium bromide, potassium carbonate are sequentially added with reflux condensing tube and magneton burn
In bottle, reaction system is implanted sequentially acetone and 3- bromo- 1- propanol with syringe under nitrogen protection, is heated to 65 DEG C of reactions 3
My god.Reaction finishes, and filters to obtain organic faciess, vacuum distillation removes solvent and obtains crude product, then uses dichloromethane, ethyl acetate
The solid that mixing eluent purifies white by silicagel column.
3), the synthesis of compound 3
Compound 2, Hydro-Giene (Water Science)., tetra-triphenylphosphine palladium are sequentially added two mouthfuls of round bottoms with reflux condensing tube and magneton
In flask, reaction system is implanted sequentially diisopropylamine and trimethylsilyl acetylene with syringe under nitrogen protection, is heated to 65
DEG C reaction 24 hours.Reaction finishes, and filters to obtain organic faciess, and vacuum distillation removes solvent and obtains crude product, then use dichloromethane,
Ethyl acetate mixing eluent by silicagel column purify faint yellow color solid.This solid is dissolved in oxolane and methanol
In mixed solution, add a small amount of water and potassium carbonate, after being stirred at room temperature 2 hours, carry out vacuum distillation with Rotary Evaporators and take off
Remove organic solvent, residue adds water, extracted with dichloromethane, organic layer water and saturated aqueous common salt washed once respectively and then use
Anhydrous magnesium sulfate is dried, and is filtered, carry out vacuum distillation with Rotary Evaporators and slough organic solvent, obtain light after being dried
Yellow solid.
4), the synthesis of compound 4
2- nitro -1,3- dimethylbenzene, sodium hydroxide, positive tetrabutyl ammonium bromide are sequentially added with reflux condensing tube two
In mouth round-bottomed flask, it is subsequently adding water, is heated to 95 DEG C, then potassium permanganate is dividedly in some parts, react 24 hours.Reaction finishes,
Filter to obtain aqueous phase, under ice bath, dilute hydrochloric acid is slowly added dropwise to smoke filtrate, until no longer producing precipitation, sucking filtration obtains white powder.
5), the synthesis of compound 5
Compound 4 is added in two mouthfuls of round-bottomed flasks with constant pressure funnel and magneton, reaction system is protected in nitrogen
Shield is lower to add anhydrous tetrahydro furan, under ice bath, borine tetrahydrofuran solution constant pressure funnel is added dropwise over two mouthfuls of flasks
In, completion of dropping, room temperature reaction 24 hours.Reaction finishes, and methanol is added dropwise in two mouthfuls of flasks removing excessive borine, directly
To no longer producing gas, filter to obtain organic faciess, vacuum distillation removes solvent and obtains crude product, then use petroleum ether, ethyl acetate
Mixing eluent white solid is purified to obtain by silicagel column.
6), the synthesis of compound 6
Compound 5, DMAP are sequentially added in two mouthfuls of round-bottomed flasks with constant pressure funnel and magneton, reaction system
Add anhydrous tetrahydro furan under nitrogen protection, after 4- bromo-benzoyl chloride being dissolved with anhydrous tetrahydro furan under ice bath, under ice bath
It is added dropwise in two mouthfuls of flasks with constant pressure funnel, after completion of dropping, add anhydrous pyridine, room temperature reaction with syringe more again
24 hours.Filter to obtain organic faciess, vacuum distillation removes solvent, obtain residue and add water, with dichloromethane extraction, organic layer use
Saturated common salt water washing three times, is then dried with anhydrous magnesium sulfate, is filtered, subtracted with Rotary Evaporators after being dried
Pressure is distilled off organic solvent, obtains white solid.
7), the synthesis of compound 7
Compound 3 and compound 6, Hydro-Giene (Water Science)., tetra-triphenylphosphine palladium are added in polymerisation tube, reaction system is in nitrogen
Sequentially add oxolane after deoxygenation and eliminating water, diisopropylamine and Isosorbide-5-Nitrae-dioxane under gas shielded, be heated to 65 DEG C, react 48
Hour.Reaction finishes, and crosses aluminium sesquioxide neutrality post, removes catalyst, filtrate is concentrated, heavy in the mixed liquor of first alcohol and water
Fall three times, sucking filtration obtains yellow solid.
8), the synthesis of compound 8
Compound 7, end are added in two mouthfuls of round-bottomed flasks for the Polyethylene Glycol of carboxyl, DDC, DMAP, reaction system exists
Add eliminating water oxolane under nitrogen system, be heated to 25～60 DEG C, react 24～72 hours；Reaction finishes, toward reaction system
In add water, then sucking filtration, and by gained filtrate with bag filter dialyse 48～96 hours, finally by dialysis solution lyophilization, obtain
Compound 8, that is, based on benzyne benzene and the functional group's p-Nitrobenzyl that can rupture, side chain is based on water soluble functional group's Polyethylene Glycol for main chain
Water solublity degradable light-sensitive copolymer.
Described near-infrared response application in medicament slow release for the degradable conjugated polymer, concrete grammar is as follows：1), institute
Material selection is as follows, and Nile red is coated with our material, is formed and has water miscible polymer nano micelle；
Weigh a certain proportion of compound and Nile red, add Nile red to dissolve it in oxolane in sample bottle
In, then our compound dissolution in deionized water.Compound water solution is placed on ultrasonic and then fast under cell pulverization instrument
Nile red tetrahydrofuran solution is added dropwise to wherein by speed, and stirring makes oxolane volatilization clean.By transmission electron microscope TEM
Characterize and prove that this kind of material can be self-assembled into the micelle of 250nm in aqueous.
2) after polymer nano micelle is placed on being phagocytized by cells in cell culture fluid, Buddhist nun after being irradiated with 800nm light beam
Luo Hong is released.
Beneficial effect：The present invention synthesizes a kind of degradable water-soluble poly in near-infrared response by a kind of efficient method
Compound slow releasing carrier of medication, carries out synthesis condition to it on original literature method and improves, thus improving our targets
The synthetic yield of product, then by our material, Nile red cladding is made it solve the sex chromosome mosaicism that mixes of biology, so that
Nile red can be transported to intracellular and be released.It is low that this efficient synthetic method has broken synthetic yield in original document
Feature, enables us to more efficient obtain such product.The material covered in the present invention have excellent biocompatibility,
Chemical stability, heat stability.The spherical assembly having 250nm in aqueous occurs.If some functionalization are repaiied in addition
Decorations make it have specific recognition capability, then will have far-reaching application in biomedical sector.
Brief description
Fig. 1 is the nuclear-magnetism (CDCl of compound 73),
Fig. 2 is the nuclear-magnetism (CDCl of compound 83),
Fig. 3 is the nuclear-magnetism (D of compound 82O),
Fig. 4 is that the TEM of compound 8 schemes,
Fig. 5 is TEM figure after 800nm light irradiation 20 minutes for the compound 8,
Fig. 6 is TEM figure after 800nm light irradiation 40 minutes for the compound 8,
Fig. 7 is TEM figure after 800nm light irradiation 60 minutes for the compound 8,
Fig. 8 coats the spectrogram in 800nm light irradiation different time after Nile red for compound 8.
Specific embodiment
A kind of near-infrared response degradable conjugated polymer material structure of the present invention is as follows：
Wherein, n is the degree of polymerization, and n is 8-100；
Side chain is the Polyethylene Glycol that end is carboxyl, and m is the degree of polymerization, and m is 23-114.
The synthetic method of the above-claimed cpd of the present invention is as follows：
1), compound 1, i.e. the synthesis of bromo- 2, the 5- Benzodiazepiness of Isosorbide-5-Nitrae-two：
1, 4-benzenediol is added in the two-mouth bottle with reflux condensing tube, adds glacial acetic acid, finish at normal temperatures by liquid
Bromine is dissolved in glacial acetic acid, then is added dropwise in reaction bulb with constant voltage low liquid funnel, reacts 24 hours after completion of dropping at 45 DEG C.Instead
Should finish, add saturation sodium sulfite to remove excessive bromine, sucking filtration is simultaneously washed repeatedly with saturation sodium sulfite, then use water
Washing repeatedly, obtains white powder.
2), the synthesis of compound 2
Two mouthfuls of round bottoms that compound 1, tetrabutyl ammonium bromide, potassium carbonate are sequentially added with reflux condensing tube and magneton burn
In bottle, reaction system is implanted sequentially acetone and 3- bromo- 1- propanol with syringe under nitrogen protection, is heated to 65 DEG C, reacts 3
My god.Reaction finishes, and filters to obtain organic faciess, vacuum distillation removes solvent and obtains crude product, then uses dichloromethane, ethyl acetate
The solid that mixing eluent purifies white by silicagel column.
3), the synthesis of compound 3
Compound 2, Hydro-Giene (Water Science)., tetra-triphenylphosphine palladium are sequentially added two mouthfuls of round bottoms with reflux condensing tube and magneton
In flask, reaction system is implanted sequentially diisopropylamine and trimethylsilyl acetylene with syringe under nitrogen protection, is heated to 65
DEG C reaction 24 hours.Reaction finishes, and filters to obtain organic faciess, and vacuum distillation removes solvent and obtains crude product, then use dichloromethane,
The mixing eluent of ethyl acetate purifies to obtain flaxen solid by silicagel column.This solid is dissolved in oxolane and methanol mixes
Close in solution, add a small amount of water and potassium carbonate, after being stirred at room temperature 2 hours, carry out vacuum distillation with Rotary Evaporators and slough
Organic solvent, residue adds water, and is extracted with dichloromethane, and organic layer water and saturated aqueous common salt washed once and then respectively with no
Water magnesium sulfate is dried, and is filtered, carry out vacuum distillation with Rotary Evaporators and slough organic solvent, obtain yellowish after being dried
Color solid.
4), the synthesis of compound 4
2- nitro -1,3- dimethylbenzene, sodium hydroxide, positive tetrabutyl ammonium bromide are sequentially added with reflux condensing tube two
In mouth round-bottomed flask, it is subsequently adding water, is heated to 95 DEG C, then potassium permanganate is dividedly in some parts, react 24 hours.Reaction finishes,
Filter to obtain aqueous phase, under ice bath, dilute hydrochloric acid is slowly added dropwise to smoke filtrate, until not producing precipitation, sucking filtration obtains white powder.
5), the synthesis of compound 5
Compound 4 is added in the round-bottomed flask with two mouthfuls of constant pressure funnel and magneton, reaction system is in nitrogen
Protection is lower to add anhydrous tetrahydro furan, under ice bath, borine tetrahydrofuran solution constant pressure funnel is added dropwise over two mouthfuls of flasks
In, completion of dropping, room temperature reaction 24 hours.Reaction finishes, and methanol is added dropwise in two mouthfuls of flasks removing excessive borine, directly
To no longer producing gas, filter to obtain organic faciess, vacuum distillation removes solvent and obtains crude product, then use petroleum ether, ethyl acetate
Mixing eluent white solid is purified to obtain by silicagel column.
6), the synthesis of compound 6
Compound 5, DMAP are sequentially added in the round-bottomed flask with two mouthfuls of constant pressure funnel and magneton, reactant
System adds anhydrous tetrahydro furan under nitrogen protection, after 4- bromo-benzoyl chloride being dissolved with anhydrous tetrahydro furan under ice bath, ice bath
It is added dropwise in two mouthfuls of flasks with constant pressure funnel, after completion of dropping, add anhydrous pyridine, room temperature reaction with syringe more again
24 hours.Filter to obtain organic faciess, vacuum distillation removes solvent, obtain residue and add water, with dichloromethane extraction, organic layer use
Saturated common salt water washing three times, is then dried with anhydrous magnesium sulfate, is filtered, subtracted with Rotary Evaporators after being dried
Pressure is distilled off organic solvent, obtains white solid.
7), the synthesis of compound 7
Compound 3 and compound 6, Hydro-Giene (Water Science)., tetra-triphenylphosphine palladium are added in polymerisation tube, reaction system is in nitrogen
Sequentially add oxolane after deoxygenation and eliminating water, diisopropylamine and Isosorbide-5-Nitrae-dioxane under gas shielded, be heated to 65 DEG C, react 48
Hour.Reaction finishes, and crosses aluminium sesquioxide neutrality post, removes catalyst, filtrate is concentrated, heavy in the mixed liquor of first alcohol and water
Fall three times, sucking filtration obtains yellow solid.
8), the synthesis of compound 8
Compound 7, end are added in two mouthfuls of round-bottomed flasks for the Polyethylene Glycol of carboxyl, DDC, DMAP, reaction system exists
Add eliminating water oxolane under nitrogen system, be heated to 40 DEG C, react 72 hours.Reaction finishes, and adds water, so toward in reaction system
Sucking filtration afterwards, and gained filtrate is dialysed 72 hours with bag filter, finally by dialysis solution lyophilization, obtain compound 8.
For a better understanding of the present invention, the technical side of the present invention is further illustrated below by specific embodiment
Case：
1), compound 1, i.e. the synthesis of bromo- 2, the 5- Benzodiazepiness of Isosorbide-5-Nitrae-two：
1, 4-benzenediol (11g, 0.1mol) is added in the 250ml two-mouth bottle with reflux condensing tube, adds 30ml ice
Acetic acid, finishes and at normal temperatures liquid 12ml bromine is dissolved in 20ml glacial acetic acid, then is added dropwise in reaction bulb with constant voltage low liquid funnel, drips
Add and react 24 hours at 45 DEG C after finishing.Reaction finishes, and adds saturation sodium sulfite to remove excessive bromine, sucking filtration is used in combination
The washing of saturation sodium sulfite repeatedly, is washed with water and washs repeatedly, obtain white powder 24.6g.
2), the synthesis of compound 2
By compound 1 (2.65g, 0.01mol), tetrabutyl ammonium bromide (0.0096g, 0.03mmol), potassium carbonate (13.8g,
0.1mol) sequentially add in the two mouthfuls of round-bottomed flasks of 250ml with reflux condensing tube and magneton, reaction system is under nitrogen protection
It is implanted sequentially 100ml acetone and 3- bromo- 1- propanol (3.42g, 0.025mol) with syringe, is heated to 65 DEG C, react 3 days.
Reaction finishes, and filters to obtain organic faciess, and vacuum distillation removes solvent and obtains crude product, then uses dichloromethane, ethyl acetate (dichloro
Methane：Ethyl acetate=8:1) solid (3.25g, 8.5mmol) that mixing eluent purifies white by silicagel column.1H
NMR(CDCl3,400MHz):7.13(s,2H),4.11-4.16(t,4H),3.88-3.94(q,4H),2.05-2.12(m,4H),
2.01-2.04(t,2H).13C NMR(CDCl3,100MHz):150.01,118.40,111.12,68.77,60.78,
32.07.GC-MS(m/z):384(M+)
3), the synthesis of compound 3
By compound 2 (1.91g, 5mmol), Hydro-Giene (Water Science). (9.5mg, 0.05mmol), tetra-triphenylphosphine palladium (55mg,
0.05mmol) sequentially add in the two mouthfuls of round-bottomed flasks of 100ml with reflux condensing tube and magneton, reaction system is protected in nitrogen
Lower syringe is implanted sequentially 40ml diisopropylamine and trimethylsilyl acetylene (1.47g, 15mmol), is heated to 65 DEG C of reactions 24
Hour.Reaction finishes, and filters to obtain organic faciess, and vacuum distillation removes solvent and obtains crude product, then uses dichloromethane, ethyl acetate
(dichloromethane：Ethyl acetate=8:1) mixing eluent purifies to obtain flaxen solid by silicagel column.This solid is dissolved in
In 20ml oxolane and 20ml methanol, add 20ml water and potassium carbonate (3.45g, 25mmol), after being stirred at room temperature 2 hours,
Carry out vacuum distillation with Rotary Evaporators and slough organic solvent, residue adds water, with dichloromethane extraction, organic layer water and full
Washed once respectively with saline solution and then be dried with anhydrous magnesium sulfate, filtered after being dried, carried out with Rotary Evaporators
Vacuum distillation removes organic solvent, obtains faint yellow solid 1.09g.1H NMR(CDCl3,400MHz):6.99(s,2H),4,13-
4.20(t,4H),3.87-3.93(q,4H),3.39(s,2H),2.33-2.38(t,2H),2.04-2.13(m,4H).13C NMR
(CDCl3,100MHz):153.98,117.02,113.13,83.24,79.35,68.62,61.34,31.94.GC-MS(m/z):
274(M+)
4), the synthesis of compound 4
By 2- nitro -1,3- dimethylbenzene (3.02g, 20mmol), sodium hydroxide (2.00g, 50mmol), positive tetrabutyl phosphonium bromide
Ammonium (0.19g, 0.6mmol) sequentially adds in the two mouthfuls of round-bottomed flasks of 250ml with reflux condensing tube, is subsequently adding 100ml water,
It is heated to 95 DEG C, then potassium permanganate (7.90g, 50mmol) is dividedly in some parts, react 24 hours.Reaction finishes, and filters to obtain aqueous phase,
Under ice bath, dilute hydrochloric acid is slowly added dropwise to smoke filtrate, until no longer producing precipitation, sucking filtration obtains white powder 3.80g.
5), the synthesis of compound 5
The 100ml round bottom that compound 4 (2.11g, 10mmol) is added carry constant pressure funnel and magneton two mouthfuls burns
In bottle, reaction system adds 50ml anhydrous tetrahydro furan under nitrogen protection, by borine tetrahydrofuran solution constant voltage under ice bath
Dropping funnel is added dropwise in two mouthfuls of flasks, completion of dropping, room temperature reaction 24 hours.Reaction finishes, by methanol dropwise two mouthfuls of burnings
Removing excessive borine in bottle, until no longer producing gas, filtering to obtain organic faciess, vacuum distillation removes solvent and obtains crude product,
Then petroleum ether, ethyl acetate (petroleum ether are used：Ethyl acetate=8:1) mixing eluent purifies white solid by silicagel column
Body 1.68g.1H NMR(DMSO,400MHz):7.49-7.58(m,3H),5.45-5.50(t,2H),4.49-4.53(d,4H)
.13C NMR(CDCl3,100MHz):151.90,134.22,131.89,129.32,61.61.GC-MS(m/z):183(M+).
6), the synthesis of compound 6
Compound 5 (0.92g, 5mmol), DMAP (0.006g, 0.05mmol) are sequentially added with constant pressure funnel
In two mouthfuls of round-bottomed flasks of 100ml of magneton, reaction system adds anhydrous tetrahydro furan 40ml under nitrogen protection, will under ice bath
4- bromo-benzoyl chloride is added in constant pressure funnel with after the dissolving of 5ml anhydrous tetrahydro furan, dropwise plus in two mouthfuls of flasks of instillation, drips
Add Bi Houzai syringe and add anhydrous pyridine, room temperature reaction 24 hours.Filter to obtain organic faciess, vacuum distillation removes solvent,
Obtain residue and add water, with dichloromethane extraction, organic layer saturated common salt water washing three times, then entered with anhydrous magnesium sulfate
Row drying, is filtered after being dried, and carries out vacuum distillation with Rotary Evaporators and removes organic solvent, then uses petroleum ether, acetic acid
Ethyl ester (petroleum ether：Ethyl acetate=8:1) mixing eluent purifies to obtain white solid by silicagel column.1H NMR(CDCl3,
400MHz):7.85-7.89(m,4H),7.56-7.61(m,7H),5.48(s,4H).13C NMR(CDCl3,100MHz):
165.30,149.22,132.41,131.93,131.30,130.41,129.43,128.72,128.17,63.04.GC-MS(m/
z):548(M+).
7), the synthesis of compound 7
By compound 3 (0.025g, 0.1mmol) and compound 6 (0.0549g, 0.1mmol), Hydro-Giene (Water Science).
(0.00095g, 0.01mmol), tetra-triphenylphosphine palladium (0.058g, 0.01mmol) add in 100ml polymerisation tube, reactant
Tie up to and under nitrogen system, sequentially add oxolane 2ml, diisopropylamine 2ml and Isosorbide-5-Nitrae-dioxane 2ml after deoxygenation and eliminating water, plus
Heat, to 65 DEG C, is reacted 48 hours.Reaction finishes, and crosses aluminium sesquioxide neutrality post, and oxolane does eluent, removes catalyst,
Filtrate is concentrated, the mixed liquor (methanol of again with methanol and water：Water=3:1) settle three times, sucking filtration obtains yellow solid.1H NMR
(CDCl3,400MHz):7.83-8.04(m),7.48-7.68(m),6.97-7.11(br),5.42-5.55(br),4.08-
4.31(br),3.85-4.00(br),2.51-2.65(br),2.02-2.20(br).
8), the synthesis of compound 8
Compound 7 (20mg, 0.003mmol), end are the Polyethylene Glycol (12mg, 0.006mmol) of carboxyl, DDC
(1.2mg, 0.006mmol), DMAP (0.04mg, 0.0003mmol) add in two mouthfuls of round-bottomed flasks, and reaction system is protected in nitrogen
Shield is lower to add eliminating water oxolane 20ml, is heated to 40 DEG C, reacts 72 hours.Reaction finishes, and adds water, then toward in reaction system
Sucking filtration, and gained filtrate is dialysed 72 hours with bag filter (3500), finally by solution lyophilization in dialysis band, obtain chemical combination
Thing 8.1H NMR(CDCl3,400MHz):7.99-8.11(m),7.53-7.67(m),6.99-7.08(br),5.51-5.56
(br),3.81-4.09(m),3.71-3,79(br),3.59-3.68(s),2.46-2.61(m),1.79-1.98(br).
Applied research
1. method：A kind of water-soluble copolymerization that can occur under near infrared light shines and degrade is synthesized by a kind of efficient method
Thing slow releasing carrier of medication, carries out the improvement of synthesis condition with original literature method to it, thus reach our targets of raising producing
The synthetic yield of thing, then by our material, Nile red cladding is made it solve the sex chromosome mosaicism that mixes of biology, so that Buddhist nun
Luo Hongneng is transported to intracellular and is released.It is specially low that this efficient synthetic method has broken synthetic yield in original document
Point, enables us to more efficient obtain such product.The material covered in the present invention has excellent biocompatibility, change
Learn stability, heat stability.The spherical assembly having 250nm in aqueous occurs.If, some functional modifications in addition
Make it have specific recognition capability, then far-reaching application will be had in biomedical sector.
2. experimental procedure：Weigh a certain proportion of compound and Nile red, sample bottle adds a certain amount of Nile red
Dissolve it in a certain amount of oxolane, then our compound dissolution in a certain amount of deionized water.Chemical combination
Thing aqueous solution is placed on ultrasonic under cell pulverization instrument and then rapidly Nile red tetrahydrofuran solution is added dropwise to wherein, and stirring allows tetrahydrochysene
Furan volatilization is clean.Being characterized by transmission electron microscope TEM proves that this kind of material can be self-assembled into 250nm in aqueous
Micelle.
Claims (3)
1. a kind of near-infrared response degradable water soluble copolymer is it is characterised in that have following molecular structural formula：
Wherein, n is the degree of polymerization, and n is 8-100；
Side chain is the Polyethylene Glycol that end is carboxyl, and m is the degree of polymerization, and m is 23-114.
2. a kind of a kind of as claimed in claim 1 near-infrared responds the high-efficiency synthesis method of degradable water soluble copolymer, its
It is characterised by that the method synthesizing is as follows：
3. a kind of near-infrared responds the high-efficiency synthesis method of degradable water soluble copolymer, its feature as claimed in claim 2
It is that the concrete steps synthesizing are specific as follows：
1), compound 1, i.e. the synthesis of bromo- 2, the 5- Benzodiazepiness of Isosorbide-5-Nitrae-two：
1, 4-benzenediol is added in the two-mouth bottle with reflux condensing tube, adds glacial acetic acid, finish at normal temperatures that bromine is molten
In glacial acetic acid, then it is added dropwise in reaction bulb with constant voltage low liquid funnel, after completion of dropping, at 25～45 DEG C, reaction 12～48 is little
When；Reaction finishes, and adds saturation sodium sulfite to remove excessive bromine, sucking filtration simultaneously washs repeatedly with saturation sodium sulfite,
It is washed with water and washs repeatedly, after being dried, obtain white powder.
2), the synthesis of compound 2
Compound 1, tetrabutyl ammonium bromide, potassium carbonate are sequentially added two mouthfuls of round-bottomed flasks with reflux condensing tube and magneton
In, reaction system is implanted sequentially acetone and 3- bromo- 1- propanol with syringe under nitrogen protection, is heated to 45～90 DEG C, instead
Answer 24～72 hours；Reaction finishes, and filters to obtain organic faciess, and vacuum distillation removes solvent and obtains crude product, then use dichloromethane,
The solid that the mixing eluent of ethyl acetate purifies white by silicagel column.
3), the synthesis of compound 3
Compound 2, Hydro-Giene (Water Science)., tetra-triphenylphosphine palladium are sequentially added two mouthfuls of round-bottomed flasks with reflux condensing tube and magneton
In, reaction system is implanted sequentially diisopropylamine and trimethylsilyl acetylene with syringe under nitrogen protection, is heated to 45～90
DEG C reaction 12～48 hours；Reaction finishes, and filters to obtain organic faciess, and vacuum distillation removes solvent and obtains crude product, then uses dichloro
Methane, the mixing eluent of ethyl acetate purify to obtain flaxen solid by silicagel column.By this solid be dissolved in oxolane and
In methanol mixed solution, add a small amount of water and potassium carbonate, after being stirred at room temperature 2～4 hours, reduced pressure with Rotary Evaporators
Organic solvent is sloughed in distillation, and residue adds water, and is extracted with dichloromethane, and organic layer water and saturated aqueous common salt washed once respectively
Then it is dried with anhydrous magnesium sulfate, filtered after being dried, carry out vacuum distillation with Rotary Evaporators and slough organic solvent,
Obtain faint yellow solid.
4), the synthesis of compound 4
2- nitro -1,3- dimethylbenzene, sodium hydroxide, positive tetrabutyl ammonium bromide are sequentially added two mouthfuls of circles with reflux condensing tube
In the flask of bottom, it is subsequently adding water, is heated to 85～120 DEG C, then potassium permanganate is dividedly in some parts, react 12～48 hours.Reaction
Finish, filter to obtain aqueous phase, under ice bath, dilute hydrochloric acid is slowly added dropwise to smoke filtrate, until no longer producing precipitation, sucking filtration obtains white
Powder.
5), the synthesis of compound 5
Compound 4 is added in two mouthfuls of round-bottomed flasks with constant pressure funnel and magneton, reaction system is under nitrogen system
Add anhydrous tetrahydro furan, under ice bath, borine tetrahydrofuran solution constant pressure funnel is added dropwise in two mouthfuls of flasks, drip
Add complete, room temperature reaction 12～48 hours；Reaction finishes, and methanol is added dropwise in two mouthfuls of flasks removing excessive borine, directly
To not producing gas, filter to obtain organic faciess, vacuum distillation removes solvent and obtains crude product, then use petroleum ether, ethyl acetate
Mixing eluent white solid is purified to obtain by silicagel column.
6), the synthesis of compound 6
By 2- nitro -1,3- benzhydrol, DMAP sequentially add in two mouthfuls of round-bottomed flasks with constant pressure funnel and magneton,
Reaction system adds anhydrous tetrahydro furan under nitrogen protection, under ice bath dissolves 4- bromo-benzoyl chloride anhydrous tetrahydro furan
Afterwards, it is added dropwise in two mouthfuls of flasks with constant pressure funnel under ice bath, after completion of dropping, add anhydrous pyridine, room with syringe again
Temperature reaction 12～48 hours；Filter to obtain organic faciess, vacuum distillation removes solvent, obtain residue and add water, extracted with dichloromethane
Take, organic layer saturated common salt water washing three times, be then dried with anhydrous magnesium sulfate, filtered after being dried, with rotation
Evaporimeter carries out vacuum distillation and removes organic solvent, obtains white solid.
7), the synthesis of compound 7
Compound 3 and compound 6, Hydro-Giene (Water Science)., tetra-triphenylphosphine palladium are added in polymerisation tube, reaction system is in nitrogen
Sequentially add oxolane after deoxygenation eliminating water, diisopropylamine and Isosorbide-5-Nitrae-dioxane under system, be heated to 45～80 DEG C, reaction 24～
72 hours；Reaction finishes, and crosses aluminium sesquioxide neutrality post, removes catalyst, filtrate is concentrated, the mixed liquor of again with methanol and water
Sedimentation 2～4 times, sucking filtration obtains yellow solid.
8), the synthesis of compound 8
Compound 7, end are added in two mouthfuls of round-bottomed flasks for the Polyethylene Glycol of carboxyl, DDC, DMAP, reaction system is in nitrogen
Add eliminating water oxolane under system, be heated to 25～60 DEG C, react 24～72 hours；Reaction finishes, and adds toward in reaction system
Water, then sucking filtration, and gained filtrate is dialysed 48～96 hours with bag filter, finally by dialysis solution lyophilization, obtain chemical combination
Thing 8, that is, based on benzyne benzene and the functional group's p-Nitrobenzyl that can rupture, side chain is water-soluble based on water soluble functional group's Polyethylene Glycol for main chain
Property degradable light-sensitive copolymer.
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| WO2006109945A1 (en) * | 2005-04-13 | 2006-10-19 | Sungkyunkwan University Foundation For Corporate Collaboration | Temperature and ph sensitive block copolymer and polymeric hydrogles using the same |
| CN101445581A (en) * | 2008-12-26 | 2009-06-03 | 南京邮电大学 | Biology functional rigid and flexible blocking copolymer and preparation method thereof |
| CN103073730A (en) * | 2012-12-27 | 2013-05-01 | 清华大学深圳研究生院 | CA-(PLA-ran-PLC-b-PEC) periodic copolymer and preparation method and application thereof |
| CN103159959A (en) * | 2013-03-07 | 2013-06-19 | 清华大学深圳研究生院 | M-PLGA-TPGS star type amphiphilic copolymer and preparation method and application |
| WO2014058252A1 (en) * | 2012-10-10 | 2014-04-17 | 전북대학교 산학협력단 | Ph-sensitive block copolymer containing cinnamaldehyde derivatives, and method for preparing same |
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| WO2006109945A1 (en) * | 2005-04-13 | 2006-10-19 | Sungkyunkwan University Foundation For Corporate Collaboration | Temperature and ph sensitive block copolymer and polymeric hydrogles using the same |
| CN101445581A (en) * | 2008-12-26 | 2009-06-03 | 南京邮电大学 | Biology functional rigid and flexible blocking copolymer and preparation method thereof |
| WO2014058252A1 (en) * | 2012-10-10 | 2014-04-17 | 전북대학교 산학협력단 | Ph-sensitive block copolymer containing cinnamaldehyde derivatives, and method for preparing same |
| CN103073730A (en) * | 2012-12-27 | 2013-05-01 | 清华大学深圳研究生院 | CA-(PLA-ran-PLC-b-PEC) periodic copolymer and preparation method and application thereof |
| CN103159959A (en) * | 2013-03-07 | 2013-06-19 | 清华大学深圳研究生院 | M-PLGA-TPGS star type amphiphilic copolymer and preparation method and application |
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Granted publication date: 20170308 |