CN110467696A - A kind of preparation method of water-soluble graft polymers photoacoustic contrast agent - Google Patents
A kind of preparation method of water-soluble graft polymers photoacoustic contrast agent Download PDFInfo
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- 239000002872 contrast media Substances 0.000 title claims abstract description 23
- 229920000578 graft copolymer Polymers 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 32
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 210000003739 neck Anatomy 0.000 claims description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 22
- 239000000741 silica gel Substances 0.000 claims description 22
- 229910002027 silica gel Inorganic materials 0.000 claims description 22
- 229960001866 silicon dioxide Drugs 0.000 claims description 22
- 239000003480 eluent Substances 0.000 claims description 20
- 230000015572 biosynthetic process Effects 0.000 claims description 19
- 238000003786 synthesis reaction Methods 0.000 claims description 19
- 239000012265 solid product Substances 0.000 claims description 16
- 239000012043 crude product Substances 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 239000012044 organic layer Substances 0.000 claims description 15
- 239000003208 petroleum Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000007789 sealing Methods 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- 238000010898 silica gel chromatography Methods 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000012074 organic phase Substances 0.000 claims description 9
- 239000011541 reaction mixture Substances 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 claims description 8
- 238000010189 synthetic method Methods 0.000 claims description 8
- -1 bromo- 1 nonyl Chemical group 0.000 claims description 7
- 238000004090 dissolution Methods 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000004587 chromatography analysis Methods 0.000 claims description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 4
- 239000005695 Ammonium acetate Substances 0.000 claims description 4
- 229940043376 ammonium acetate Drugs 0.000 claims description 4
- 235000019257 ammonium acetate Nutrition 0.000 claims description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 4
- ZWRUINPWMLAQRD-UHFFFAOYSA-N n-Nonyl alcohol Natural products CCCCCCCCCO ZWRUINPWMLAQRD-UHFFFAOYSA-N 0.000 claims description 4
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 4
- HUDYANRNMZDQGA-UHFFFAOYSA-N 1-[4-(dimethylamino)phenyl]ethanone Chemical compound CN(C)C1=CC=C(C(C)=O)C=C1 HUDYANRNMZDQGA-UHFFFAOYSA-N 0.000 claims description 3
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 3
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 3
- 229940072033 potash Drugs 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 239000012266 salt solution Substances 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 238000005292 vacuum distillation Methods 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 2
- 229960004756 ethanol Drugs 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims 1
- UYAGPULHTNCMOT-UHFFFAOYSA-N [B].FB(F)F Chemical compound [B].FB(F)F UYAGPULHTNCMOT-UHFFFAOYSA-N 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 239000011976 maleic acid Substances 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 1
- 238000003384 imaging method Methods 0.000 abstract description 8
- 239000002105 nanoparticle Substances 0.000 abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 8
- 206010028980 Neoplasm Diseases 0.000 abstract description 6
- DTKVAHYKYRDBSY-UHFFFAOYSA-N [B].[F].N1C=CC=CC=C1 Chemical compound [B].[F].N1C=CC=CC=C1 DTKVAHYKYRDBSY-UHFFFAOYSA-N 0.000 abstract description 4
- 239000007864 aqueous solution Substances 0.000 abstract description 4
- 238000007142 ring opening reaction Methods 0.000 abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 abstract description 2
- 125000000168 pyrrolyl group Chemical group 0.000 abstract description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 abstract 2
- 229920000642 polymer Polymers 0.000 abstract 2
- 201000011510 cancer Diseases 0.000 abstract 1
- 238000003745 diagnosis Methods 0.000 abstract 1
- 239000000975 dye Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 7
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 239000003292 glue Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 229910052710 silicon Inorganic materials 0.000 description 4
- 239000010703 silicon Substances 0.000 description 4
- 229910015900 BF3 Inorganic materials 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001338 self-assembly Methods 0.000 description 2
- UMLWXYJZDNNBTD-UHFFFAOYSA-N 2-(dimethylamino)-1-phenylethanone Chemical compound CN(C)CC(=O)C1=CC=CC=C1 UMLWXYJZDNNBTD-UHFFFAOYSA-N 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-N hydroperoxyl Chemical compound O[O] OUUQCZGPVNCOIJ-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
-
- 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
- C08F8/00—Chemical modification by after-treatment
- C08F8/42—Introducing metal atoms or metal-containing groups
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Physics & Mathematics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Acoustics & Sound (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Abstract
The present invention relates to a kind of preparation methods of water-soluble graft polymers photoacoustic contrast agent, belong to the technical field of new type water-solubility photoacoustic imaging contrast agent.The contrast agent is by the way that two azole polymer of oil-soluble azepine fluorine boron to be grafted on polyisobutene-alt- maleic anhydride polymer, utilize the hydroxyl of two pyrroles's end group of azepine fluorine boron and the ring-opening reaction of maleic anhydride, increase the water solubility of dyestuff, the nanoparticle of partial size 60nm or so is formed in aqueous solution when nano particle diameter is less than 200nm, it is easier to be assembled in knub position.Operation of the present invention is simple, and gained contrast agent is water-soluble good, has good advantage in easily prepared and diagnosis in cancer.
Description
Technical field
The present invention relates to a kind of preparations of water-soluble graft polymers photoacoustic contrast agent, belong to new type water-solubility photoacoustic imaging
The technical field of contrast agent.
Background technique
Photoacoustic imaging is a kind of one kind without infringement bio-imaging emerging in recent years, its principle is to utilize optoacoustic radiography
Agent is irradiated by short-pulse laser, generates the energy from laser beam, and portion of energy is converted into heat, has in local area one short
Temporary temperature rises, and the rising of sound wave is then caused by elastic dilatation.Exogenous organic photoacoustic contrast agent mainly has acyl sub-
Amine, flower cyanines class, azepine fluorine boron class, porphyrin etc..The derivative of two pyrrole structure of azepine fluorine boron has good near-infrared and inhales
Characteristic is received, its application can be extended by modifying all kinds of functional groups in side chain.The present invention relates to a kind of water-soluble graft polymers
The preparation of photoacoustic contrast agent, graft polymers can form the nano particle of partial size 60nm or so in water, be existed by EPR effect
It is enriched at tumour, to realize the photoacoustic imaging of tumour.
Summary of the invention
Technical problem solved by the present invention is the present invention relates to a kind of systems of water-soluble graft polymers photoacoustic contrast agent
It is standby, belong to the technical field of new type water-solubility photoacoustic imaging contrast agent.
In order to solve the above-mentioned technical problem, technical solution proposed by the present invention is: designing a kind of water-soluble proportional-type optoacoustic
Contrast agent, molecular structure are as follows:
A kind of water-soluble proportional-type photoacoustic contrast agent of the present invention the preparation method is as follows:
Specific step is as follows for this method:
The synthesis of B1:
The bromo- 1 nonyl alcohol of 9-, parahydroxyben-zaldehyde are added in the three neck round bottom flask with reflux condensate device and magneton
And potassium carbonate adds anhydrous DMF after vacuumizing reaction system sealing under nitrogen protection environment, it is anti-under the conditions of 110 DEG C
It should for 24 hours.After reaction mixture is cooled to room temperature, potash solid is first leached out, remaining organic phase solution is steamed by decompression
Solvent anhydrous DMF is gone in distillation, and solid crude product is mixed upper silica gel using ethyl acetate: petroleum ether=1: 6, as eluant, eluent, utilize silicon
Glue chromatography is purified, and is concentrated to get white product to organic layer drying；The synthesis of B2:
B1, sodium hydroxide and 4- dimethylamino acetophenone are added in the three neck round bottom flask with magneton, appropriate second is added
After alcohol dissolves just, reaction system is sealed and reacts 8h under the conditions of 35 DEG C.
Crude product is mixed upper silica gel using ethyl acetate: petroleum ether=1: 3, as eluant, eluent, are purified using silica gel chromatography,
Yellow solid product is concentrated to get to organic layer drying；
The synthesis of B3:
B2 is added in the flask with three necks,round bottom with condensing unit and magneton, after reaction system sealing is vacuumized, in nitrogen
Under compression ring border, anhydrous diethylamine, nitromethane and proper amount of methanol is added, is reacted for 24 hours under the conditions of 60 DEG C.Reaction mixture is cooling
To room temperature, rotate solvent, crude product is mixed upper silica gel using ethyl acetate: methylene chloride=1: 8, as eluant, eluent, utilize silicon
The purification of glue chromatography is concentrated to get white solid product to organic layer drying；
The synthesis of B4:
B3 and ammonium acetate are added in the flask with three necks,round bottom with magneton, reaction system sealing is vacuumized, in nitrogen
It protects under environment, after appropriate dehydrated alcohol dissolution is added, 80 DEG C of reactions are for 24 hours.The reactant of organic phase is rotated after reaction
Solvent is removed, crude product is mixed into upper silica gel, first rinses silicagel column with petroleum ether, after waiting a large amount of browns and fluorescence sundries to flow out,
Use methylene chloride: methanol: triethylamine: methanol=20: as eluant, eluent, using silica gel chromatography purified at 1: 1, dry to organic layer
It is concentrated to get blackish green solid product；
The synthesis of B5
B4 and anhydrous methylene chloride are added in the flask with three necks,round bottom with magneton, after B4 dissolution, under condition of ice bath
Boron trifluoride diethyl ether and triethylamine are added dropwise into three-necked flask, after being stirred to react 1h, increases reaction temperature to 30 DEG C, stirs
Mix reaction 12h.Reaction mixture is dissolved in methylene chloride, three times with the saturated salt solution rinse of ice, is quenched unreacted three
Boron fluoride diethyl ether.The methylene chloride revolving of organic phase is removed into solvent, crude product mixes silica gel, with methylene chloride: methanol: three
Ethamine=20: be used as eluant, eluent at 1: 1, is purified using silica gel chromatography, to the dry solid product for being concentrated to get purple of organic layer；
The synthesis of B6
B5 and LiH is added in the flask with three necks,round bottom with magneton, after reaction unit sealing is vacuumized, is protected in nitrogen
Under retaining ring border, anhydrous DMF is added, reacts 12h at normal temperature, then adds the Malaysia polyisobutene-alt- for being dissolved in anhydrous DMF
Acid anhydrides reacts 12h.It by being evaporated under reduced pressure away solvent DMF, is settled using petroleum ether, obtains purple solid product.
Beneficial effects of the present invention
The present invention synthesizes water-soluble good graft polymers photoacoustic contrast agent by a kind of simple preparation method, leads to
The ring-opening reaction of perhydroxyl radical and maleic anhydride, improves the water solubility of material, and material is self-assembly of partial size 60nm or so in water
Nano particle, be enriched at tumour by EPR effect, to realize the photoacoustic imaging of tumour.
Detailed description of the invention
Of the invention is described further with reference to the accompanying drawing.
Fig. 1: gained water-soluble graft polymers proportional-type contrast agent nucleus magnetic hydrogen spectrum figure.
Fig. 2: proportional-type contrast agent is self-assembly of nano particle in water, and compound concentration is 0.05mg/mL aqueous solution, uses
The pattern of transmission electron microscope observing material.
Fig. 3: compound concentration is the aqueous solution nano material of 0.3mg/mL, tests the photo-thermal of nano particle under different capacity
Energy.In 0.75W/cm-2Under power, the light thermal property of various concentration nano particle.
Fig. 4: being 200 μ g/mL aqueous solutions with concentration, and oxter kind is selected to have the nude mice of Hela, and 200 μ L of tail vein injection is used
Photoacoustic imager observes the change in signal strength of its knub position.
Specific embodiment
Embodiment 1:
The synthesis of the preparation method of above-mentioned water-soluble graft polymers contrast agent is as follows:
The synthesis of B1:
The bromo- 1 nonyl alcohol of 9-, parahydroxyben-zaldehyde are added in the three neck round bottom flask with reflux condensate device and magneton
And potassium carbonate adds anhydrous DMF after vacuumizing reaction system sealing under nitrogen protection environment, it is anti-under the conditions of 110 DEG C
It should for 24 hours.After reaction mixture is cooled to room temperature, potash solid is first leached out, remaining organic phase solution is steamed by decompression
Solvent anhydrous DMF is gone in distillation, and solid crude product is mixed upper silica gel using ethyl acetate: petroleum ether=1: 6, as eluant, eluent, utilize silicon
Glue chromatography is purified, and is concentrated to get white product to organic layer drying；
The synthesis of B2:
B1, sodium hydroxide and 4- dimethylamino acetophenone are added in the three neck round bottom flask with magneton, appropriate second is added
After alcohol dissolves just, reaction system is sealed and reacts 8h under the conditions of 35 DEG C.
Crude product is mixed upper silica gel using ethyl acetate: petroleum ether=1: 3, as eluant, eluent, are purified using silica gel chromatography,
Yellow solid product is concentrated to get to organic layer drying；
The synthesis of B3:
B2 is added in the flask with three necks,round bottom with condensing unit and magneton, after reaction system sealing is vacuumized, in nitrogen
Under compression ring border, anhydrous diethylamine, nitromethane and proper amount of methanol is added, is reacted for 24 hours under the conditions of 60 DEG C.Reaction mixture is cooling
To room temperature, rotate solvent, crude product is mixed upper silica gel using ethyl acetate: methylene chloride=1: 8, as eluant, eluent, utilize silicon
The purification of glue chromatography is concentrated to get white solid product to organic layer drying；
The synthesis of B4:
B3 and ammonium acetate are added in the flask with three necks,round bottom with magneton, reaction system sealing is vacuumized, in nitrogen
It protects under environment, after appropriate dehydrated alcohol dissolution is added, 80 DEG C of reactions are for 24 hours.The reactant of organic phase is rotated after reaction
Solvent is removed, crude product is mixed into upper silica gel, first rinses silicagel column with petroleum ether, after waiting a large amount of browns and fluorescence sundries to flow out,
Use methylene chloride: methanol: triethylamine: methanol=20: as eluant, eluent, using silica gel chromatography purified at 1: 1, dry to organic layer
It is concentrated to get blackish green solid product；
The synthesis of B5
B4 and anhydrous methylene chloride are added in the flask with three necks,round bottom with magneton, after B4 dissolution, under condition of ice bath
Boron trifluoride diethyl ether and triethylamine are added dropwise into three-necked flask, after being stirred to react 1h, increases reaction temperature to 30 DEG C, stirs
Mix reaction 12h.Reaction mixture is dissolved in methylene chloride, three times with the saturated salt solution rinse of ice, is quenched unreacted three
Boron fluoride diethyl ether.The methylene chloride revolving of organic phase is removed into solvent, crude product mixes silica gel, with methylene chloride: methanol: three
Ethamine=20: be used as eluant, eluent at 1: 1, is purified using silica gel chromatography, to the dry solid product for being concentrated to get purple of organic layer；
The synthesis of B6
B5 and LiH is added in the flask with three necks,round bottom with magneton, after reaction unit sealing is vacuumized, is protected in nitrogen
Under retaining ring border, anhydrous DMF is added, reacts 12h at normal temperature, then adds the Malaysia polyisobutene-alt- for being dissolved in anhydrous DMF
Acid anhydrides reacts 12h.It by being evaporated under reduced pressure away solvent DMF, is settled using petroleum ether, obtains purple solid product.
For a better understanding of the present invention, technical side of the invention is further illustrated below by specific embodiment
Case:
(1) synthetic method of B1:
By the bromo- 1 nonyl alcohol of 9- (10.45g, 0.05mol), parahydroxyben-zaldehyde (14.6g, 0.05mol), potassium carbonate
(13.8g, 0.1mol) is added in dry 500mL flask with three necks,round bottom, vacuumizes nitrogen protection, 200mL is added into flask
Anhydrous DMF solution, be heated to 110 DEG C stirring for 24 hours.After reaction, potassium carbonate is removed, vacuum distillation removes DMF, with acetic acid
Ethyl ester: petroleum ether=1: 6 are used as eluant, eluent, are purified with silica gel chromatographic column, obtain white solid product B1 (19g, 76.6%).
(2) synthetic method of B2:
B1 (2.64g, 0.01mol) and dimethylamino acetophenone (1.63g, 0.01mol) are dissolved in ethanol solution
(50mL), the sodium hydroxide crystal of 5g is added under condition of ice bath into reaction solution, and stirring at normal temperature reacts 8h.After reaction with
Ethyl acetate: petroleum ether=1: 3 are purified with silica gel chromatographic column as eluant, eluents, until yellow solid chemical compound B2 (5.1g,
87%).
(3) synthetic method of B3:
B2 (4.23g, 0.01mol) is added in 100mL flask with three necks,round bottom, nitrogen protection is vacuumized, nothing is then added
Water diethylamine (26mL, 0.3mol), nitromethane (35mL, 0.3mol), anhydrous methanol (10mL), 60 DEG C of reactions are for 24 hours.Reaction knot
Using ethyl acetate after beam: methylene chloride=1: 8 are purified as eluant, eluent with silica gel chromatographic column, obtain compound as white solid B3
(2.8g, 66%).
(4) synthetic method of B4:
B3 (4.68g, 0.01mol) and ammonium acetate (38.5g, 0.5mol) are added in 250mL flask with three necks,round bottom, are added
The methanol of 100mL, vacuumizes nitrogen protection.80 DEG C are stirred to react for 24 hours, use the saturation of ice after addition methylene chloride after reaction
The abundant rinse of saline solution 3 times, with methylene chloride: methanol: triethylamine=20: 1: 1 eluant, eluent separating-purifying, sufficiently after drying
To blackish green solid chemical compound B4 (2.62g, 56%).
(5) synthetic method of B5:
Compound B4 (0.86g, 0.001mol) is added in the flask with three necks,round bottom of 250mL, anhydrous the two of 50mL are added
Chloromethanes (99.99%, band molecular sieve), is added dropwise boron trifluoride and diethyl ether (60mL), is heated to 30 after reacting half an hour
DEG C reaction 12h.With methylene chloride: methanol: triethylamine=20: 1: 1 eluant, eluent separating-purifying.Obtain the solid B5 of purple
(0.4g, 46%).
(6) synthetic method of B6:
By B5 (1.0g, 0.001mol), LiH (10mg) is added in the flask with three necks,round bottom of 50mL, vacuumizes nitrogen protection,
It is added anhydrous DMF (20mL), stirring at normal temperature reacts 12h.Polyisobutene-alt- maleic anhydride (0.48g) is dissolved in anhydrous DMF
Solution is added in flask dropwise, is stirred to react 12h by (10mL).Vacuum distillation removes reaction dissolvent anhydrous DMF, and petroleum ether is heavy
Violet solid compound B-26 (0.98g, 66%) out drops.
Experimental result: the graft polymers passes through the ring-opening reaction of hydroxyl and acid anhydrides, substantially improves the water solubility of material,
Has good stability.Contrast agent forms the nano particle of 60nm in water, has good near infrared absorption characteristic, water-soluble
Property contrast agent be enriched at tumour by EPR effect, can be applied to the photoacoustic imaging of biological tissue.
Of the invention is not limited to the above embodiment the specific technical solution, all technologies formed using equivalent replacement
Scheme be the present invention claims protection scope.
Claims (3)
1. a kind of water-soluble graft polymers photoacoustic contrast agent is it is characterized by: its structural formula is as follows:
。
2. a kind of a kind of synthetic method of Watersoluble peroxygen hydrogen response type photoacoustic contrast agent as described in claim 1 is as follows:
。
3. a kind of synthetic method of water-soluble graft polymers photoacoustic contrast agent as claimed in claim 2, it is characterised in that close
At specific steps it is specific as follows:
(1) synthesis of B1:
The bromo- 1 nonyl alcohol of 9-, parahydroxyben-zaldehyde and carbon are added in the three neck round bottom flask with reflux condensate device and magneton
Sour potassium adds anhydrous DMF, reacts under the conditions of 110 DEG C after vacuumizing reaction system sealing under nitrogen protection environment
24h.After reaction mixture is cooled to room temperature, potash solid is first leached out, remaining organic phase solution passes through vacuum distillation
Solvent anhydrous DMF is removed, solid crude product is mixed upper silica gel using ethyl acetate: petroleum ether=1: 6, as eluant, eluent, utilize silica gel
Chromatography is purified, and is concentrated to get white product to organic layer drying；
(2) synthesis of B2:
B1, sodium hydroxide and 4- dimethylamino acetophenone are added in the three neck round bottom flask with magneton, it is proper that ethanol in proper amount is added
After good dissolving, reaction system is sealed and reacts 8h under the conditions of 35 DEG C.Crude product is mixed into upper silica gel with ethyl acetate: petroleum ether=
Be used as eluant, eluent at 1: 3, is purified using silica gel chromatography, is concentrated to get yellow solid product to organic layer drying；
(3) synthesis of B3:
B2 is added in the flask with three necks,round bottom with condensing unit and magneton, after reaction system sealing is vacuumized, in nitrogen ring
Under border, anhydrous diethylamine, nitromethane and proper amount of methanol is added, is reacted for 24 hours under the conditions of 60 DEG C.Reaction mixture is cooled to room
Wen Hou rotates solvent, and crude product is mixed upper silica gel using ethyl acetate: methylene chloride=1: 8, as eluant, eluent, utilize silica gel color
Chromatography is concentrated to get white solid product to organic layer drying；
(4) synthesis of B4:
B3 and ammonium acetate are added in the flask with three necks,round bottom with magneton, reaction system sealing is vacuumized, in nitrogen protection
Under environment, after appropriate dehydrated alcohol dissolution is added, 80 DEG C of reactions are for 24 hours.The reactant of organic phase is rotated after reaction and is removed
Crude product is mixed upper silica gel by solvent, first rinses silicagel column with petroleum ether, after waiting a large amount of browns and fluorescence sundries to flow out, with two
Chloromethanes: methanol: triethylamine: methanol=20: be used as eluant, eluent at 1: 1, is purified using silica gel chromatography, dry to organic layer to be concentrated
Obtain blackish green solid product；
(5) synthesis of B5
B4 and anhydrous methylene chloride are added in the flask with three necks,round bottom with magneton, after B4 dissolution, to three under condition of ice bath
Boron trifluoride diethyl ether and triethylamine is added dropwise in mouth flask, after being stirred to react 1h, increases reaction temperature to 30 DEG C, stirring is anti-
Answer 12h.Reaction mixture is dissolved in methylene chloride, three times with the saturated salt solution rinse of ice, is quenched unreacted borontrifluoride
Boron diethyl ether.The methylene chloride revolving of organic phase is removed into solvent, crude product mixes silica gel, with methylene chloride: methanol: triethylamine
Be used as eluant, eluent at=20: 1: 1, is purified using silica gel chromatography, to the dry solid product for being concentrated to get purple of organic layer；
(6) synthesis of B6
B5 and LiH is added in the flask with three necks,round bottom with magneton, after reaction unit sealing is vacuumized, in nitrogen protection ring
Under border, anhydrous DMF is added, reacts 12h at normal temperature, then adds the polyisobutene-alt- maleic acid for being dissolved in anhydrous DMF
Acid anhydride reacts 12h.It by being evaporated under reduced pressure away solvent DMF, is settled using petroleum ether, obtains purple solid product.
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