CN103059184B - Amino porphyrin- poly (N-isopropylacrylamide) europium coordination compound and preparation method thereof - Google Patents
Amino porphyrin- poly (N-isopropylacrylamide) europium coordination compound and preparation method thereof Download PDFInfo
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Abstract
The invention discloses amino porphyrin-poly (N-isopropylacrylamide) europium coordination compound and a preparation method of the amino porphyrin-poly (N-isopropylacrylamide) europium coordination compound. The preparation method of the amino porphyrin- poly (N-isopropylacrylamide) europium coordination compound is characterized in that (NH2)n-TPP is prepared into an ATRP initiator which is NH2-TPP-X, wherein the X is halogen. The NH2-TPP-X is adopted to initiate NIPAM to be polymerized to obtain polymer which is (NH2)n-TPP-PNIPAM. The europium with tervalence is coordinated with the polymer (NH2)n-TPP-PNIPAM to obtain coordination compound which is (NH2)n-TPP-PNIPAM-Eu(III)-TTA through the TTA, wherein the n meets an equation that is n=1,2,3. The amino porphyrin- poly (N-isopropylacrylamide) europium coordination compound is characterized in that a short form of the amino porphyrin- poly (N-isopropylacrylamide) europium coordination compound is (NH2)n-TPP-PNIPAM-Eu(III)-TTA, wherein the TPP is tetraphenylporphyrin, wherein the shortened form of the tetraphenylporphyrin is porphyrin, the PNIPAM is the poly (N-isopropylacrylamide), the Eu(III) is the europium with the tervalence, and the TTA is alpha- thenoyltrifluoroacetone.
Description
Technical field
The present invention relates to a kind of Amino Porphyrins-poly N-isopropyl acrylamide europium complex and preparation method thereof, described title complex a kind ofly has tumor-targeting and Thermo-sensitive, macromolecular compound with large ring conjugated structure, the sour environment susceptibility of Amino Porphyrins is utilized to make it be enriched near tumor tissues in working cycle in vivo, cancer target position is irradiated again with 405nm or 630nm wavelength laser, porphyrin is excited and then impels active oxygen to produce, kill cancer cells by it, belong to high-molecular optical photodynamic therapy technical field.
Background technology
PDT (photodynamic therapy, photodynamic therapy) is the method for a kind of novel treatment malignant tumour grown up for nearly 20 years.Now, PDT have also been obtained and payes attention to widely in the non-tumor disease for the treatment of, can become the effective means of the persistent ailment such as treatment tetter, old blind, coronary heart disease, acquired immune deficiency syndrome (AIDS), autoimmune system disease and leukemia in the near future.Compared with it treats tumour means with three great traditions such as operation, chemotherapy and radiations, tool has the following advantages: one is have relative selection specificity to tumour, can directionally eliminate former and recurrent tumor, little damaging normal tissue, toxic side effect is little, such as, just has cytotoxicity without the need to additional condition after general chemotherapeutics enters human body, while killing and wounding cancer cells, also can cause damage in various degree to normal organ and cell, be a kind of toxic action of general, and PDT is quite different; Two is do not affect other treatment, can carry out simultaneously, and have certain synergy with chemotherapy, radiotherapy, can repetitive therapy; Three is all effective in cure to various cancer, and antitumor spectra is wider.
The exposure basis of photodynamic therapy is photodynamics reaction, is a kind of Photosensitive reaction of the adjoint biological effect having oxygen molecule to participate in.Its process is: under the irradiation of specific wavelength laser, excited by photosensitizers such as TPP (tetraphenylporphyrin), phthalocyanine-like compound etc. that tissue absorbs, the photosensitizers of excited state again transmission ofenergy to the oxygen of surrounding, generate active very strong singlet oxygen-O
2, the oxidation-sensitive group in singlet oxygen and adjacent biomacromolecule is had an effect, and causes its Oxidative inactivation, and produce cytotoxicity and cause tumour cell impaired and even dead, porphyrin etc. are treated photosensitizers as one and got the nod.Visible, when adopting PDT, photosensitive drug, after injection enters human body, can form different concentration distribution very soon in different tissues, decline again afterwards, and major part excretes after a couple of days with different speed.If the irradiation that the tissue that intake of this photosensitive drug is not subject to light would not cause photodynamic reaction, also cytotoxicity would not be produced.Even if receive the irradiation of light, as long as the drug level in the wavelength of light, irradiation or tissue does not meet or do not reach requirement, cell also can not be subject to large damage.So its effect of PDT is a kind of local controllable light toxic action.
Late 1940s Figge etc. find that haematoporphyrin (hematoporphyrin) can be absorbed by lymphoglandula, tumour, embryo or wound tissue, after by uviolizing, can produce a kind of bright orange fluorescence.Nineteen fifty-five Rasmussen-Taxdal etc. give the haematoporphyrin of 10 routine malignant tumor patient intravenous injection 500 ~ 1000mg, find that there is fluorescence at 8 routine patient tumors positions.Start the sixties in 20th century to apply HpD (Hematoporphyrin Derivative, hematoporphyrin derivative) fluorescence localization diagnosis is carried out to malignant tumour, as Lipson etc. successively reports the diagnostic result of 50 routine lung bronchogenic carcinomas and patient with esophageal carcinoma, more than 80% is made a definite diagnosis, and proposes the concept of fluorescence endoscopy method first.These achievements in research make HpD become the earliest for the detection photosensitizers of PDT.But, comprise the TPP poorly water-soluble of HpD, have cytotoxicity, general distribution after entering human body, can be formed.
About the prior art of PNIPAM (poly N-isopropyl acrylamide) comprising: one is introduce various functional groups at the end of this polymkeric substance to form block polymer, thus change its LCST as a kind of temperature sensing polymer (lowest critical solution temperature), two is make NIPAM (NIPA) and certain monomer generation copolymerization form multipolymer, thus changes the LCST of this polymkeric substance.
ATRP (Transfer Radical Polymerization) also claims metal catalytic radical polymerization, its initiator is Organohalogen compounds (R-X), the transition metal complex that the catalyzer of polymerization system is formed by transition metal salt at a low price and organic ligand forms, described transition metal salt is as CuCl, and described organic ligand is as the electron donor such as bipyridine, polyamine.Polymerization process by means of redox reaction, can between living radical and dormancy kind the reversible balance of formative dynamics, thus reach and make polymerization activity, controlled object.
Prior art adopts ATRP to synthesize PNIPAM, and the kinetic curve of polyreaction demonstrates this polyreaction for active, controllable polymerization, and obtained molecular weight distribution is very narrow, and polydispersity coefficient is in 1.06 ~ 1.08 scopes.
The 4f electronic configuration of rare earth element uniqueness makes its compound have excellent electricity, light, magnetic property, and especially its spectroscopic properties makes rare earth compound become a kind of important luminescent material.Luminescent Material of Rare Earth Polymer is born in 1963, and Wolff etc. are by small molecule partner Eu (TTA)
3joined in PMMA (polymethylmethacrylate), wherein TTA is α-thenoyltrifluoroacetone, is a kind of organic micromolecule ligand.Namely introduce europium and organic micromolecule ligand in the polymer, obtain binary and ternary ligand polymer, become a kind of Luminescent Material of Rare Earth Polymer that can be used in biomarker and fluorescent molecular probe field.Such as, polymkeric substance respectively with europium and TTA coordination, obtained binary complex Ar-PNIPAM/Eu (III) and ternary complex PNIPAM/Eu (III)/TTA.
Summary of the invention
The object of the invention is to, obtain a kind of porphyrin drugs, for the lesion detection in photodynamic therapy and treatment, intercept the cytotoxicity of porphyrin itself simultaneously, strengthen the water-soluble of this medicine and tumor-targeting, we have invented a kind of Amino Porphyrins-poly N-isopropyl acrylamide europium complex and preparation method thereof for this reason.
Amino Porphyrins-poly N-isopropyl acrylamide europium complex the preparation method of the present invention is characterized in that, by (NH
2)
n-TPP is prepared into ATRP initiator NH
2-TPP-X, X are halogen; Adopt described initiator to cause NIPAM polymerization and obtain polymkeric substance (NH
2)
n-TPP-PNIPAM; Trivalent europium is obtained title complex (NH by organic micromolecule ligand TTA and described polymer complex
2)
n-TPP-PNIPAM-Eu (III)-TTA, n=1,2,3.
Amino Porphyrins-poly N-isopropyl acrylamide the europium complex of the present invention is characterized in that, its skeleton symbol is:
(NH
2)
n-TPP-PNIPAM-Eu(III)-TTA，
In formula: TPP is tetraphenylporphyrin, be called for short porphyrin, PNIPAM is poly N-isopropyl acrylamide, and Eu (III) is trivalent europium, and TTA is α-thenoyltrifluoroacetone;
Its structural formula is:
The present invention takes ATRP with NH
2-TPP-X is initiator initiated polymerization, is grafted on Porphyrin Molecule, obtains polymkeric substance (NH by temperature sensitive polymer PNIPAM good for biocompatibility
2)
n-TPP-PNIPAM, polymerization activity, controlled, LCST and the body temperature of polymer product adapt, when polymer product is in vitro lower than LCST, PNIPAM chain and water generation hydrogen bond action and water-soluble, time in vivo higher than LCST, bonding force between hydrophobic group in PNIPAM chain strengthens, hydrogen bond action simultaneously and between water dies down, be shrunk to nano microgel and hydrophobic Porphyrin Molecule is wrapped in PNIPAM molecule, the cytotoxicity of porphyrin is blocked, based on good water-soluble of PNIPAM, make porphyrin to be dissolved in the human body fluids such as blood well thereupon.Because Amino Porphyrins presents weakly alkaline, be easily gathered in acid tumour cell, i.e. specific binding, shows tumor-targeting, avoids the formation of general distribution.Amino Porphyrins can flip out from described nano microgel particle, is enriched near tumor tissues, due to the autofluorescence of porphyrin and the spectroscopic properties of rare earth trivalent europium, makes the title complex (NH of the present invention
2)
n-TPP-PNIPAM-Eu (III)-TTA becomes a kind of Luminescent Material of Rare Earth Polymer, can launch very strong fluorescence, detect tumor focus thus, realize lesion detection.This title complex has typical large pi-conjugated system, its electron delocalization degree is very large, add the life-span of charged ion to a certain extent, for the carrying out of photodynamic therapy provides favourable condition, with the rayed tumor focus of 405nm or 630nm wavelength, utilize the photodynamic effect of porphyrin, the directed photodynamics that occurs is reacted, kill cancer cells, avoid the infringement of normal tissue cell, realize targeted therapy.
The title complex of the present invention is actually a kind of detection integrating Cancerous disease and the PDT photosensitizers for the treatment of.If be not subject to the irradiation of light, even if tissue intake of this medicine, photodynamics reaction also can not be there is.In addition, even if be subject to the irradiation of light, as long as the wavelength of light is undesirable, the drug level in irradiation or cell tissue does not reach requirement, and cell also can not sustain damage.Visible, it (NH of the present invention
2)
n-TPP-PNIPAM-Eu (III)-TTA title complex has fluorescence, targeting, Thermo-sensitive, water-soluble and photodynamic effect, makes this title complex become a kind of efficient, safe lesion detection and medicine.This medicine, very soon can with different concentration distribution in different tissues after injection enters human body, and then concentration declines with different speed again, and major part excretes after a couple of days, very little to the toxic side effect of health.
Embodiment
Amino Porphyrins-poly N-isopropyl acrylamide the europium complex ((NH of the present invention
2)
n-TPP-PNIPAM-Eu (III)-TTA) preparation method specifically comprises the following steps: first, adopts Adler method synthesis tetraphenylporphyrin TPP, obtains amino tetraphenylporphyrin (NH through nitrated, reduction
2)
n-TPP, n=1,2,3, be called for short Amino Porphyrins; Secondly, with alpha-halogen carboxylic acid halides, Amino Porphyrins is prepared into ATRP initiator (NH
2)
n-TPP-X, n=1,2,3, wherein X is halogen; 3rd, in Cu (I) X/ organic ligand catalyst system, cause NIPA monomer NIPAM by ATRP initiator be polymerized, wherein X is halogen, obtains polymkeric substance (NH
2)
n-TPP-PNIPAM, n=1,2,3; Finally, polymkeric substance is coordinated with organic micromolecule ligand α-thenoyltrifluoroacetone TTA and rare-earth europium Eu, obtains title complex (NH
2)
n-TPP-PNIPAM-Eu (III)-TTA.
Its technique effect of each step of the method is, from tetraphenylporphyrin TPP to the aminophenyl porphyrin cis-TPP-(NH that can be combined with tumor cell specific
2)
2, trans-TPP-(NH
2)
2, TPP-(NH
2)
3, then to Thermo-sensitive Amino Porphyrins (NH
2)
n-TPP-PNIPAM, finally obtains and specificity can kill the fluorescence temperature sensing polymer (NH of tumour cell
2)
n-TPP-PNIPAM-Eu (III)-TTA.
It (NH of the present invention
2)
n-TPP-PNIPAM-Eu (III)-TTA is a kind of porphyrin compound, and molecular weight is within 4000 ~ 20000 scopes; At (NH
2)
nthe core that can produce photodynamic effect in-TPP-PNIPAM-Eu (III)-TTA is Amino Porphyrins; The basic framework of composition porphyrin compound is porphines free alkali ring, and what form porphines is four pyrrole rings and four methynes (18 atoms, 18 electronics), their bridgings formation one of getting up has the aromaticity flush type porphines molecule of large pi-conjugated system, and porphines molecular structural formula is:
Carbon wherein between each pyrrole ring (5,10,15,20, or α, β, γ, δ) be referred to as meso carbon.Therefore, porphyrin is actually the general name being connected with the substituent class homologue of function and derivative outside porphines free alkali ring.
Title complex (the NH of the present invention
2)
nthe photodynamics part of-TPP-PNIPAM-Eu (III)-TTA is exactly the aminophenyl porphyrin (abbreviation Amino Porphyrins) introduce phenyl and amino group on porphin ring after, in Amino Porphyrins-poly N-isopropyl acrylamide europium complex, amino can specific recognition tumour cell, poly N-isopropyl acrylamide has good Thermo-sensitive and water-soluble, the europium be connected with organic micromolecule ligand α-thenoyltrifluoroacetone can launch very strong fluorescence, thus detect tumour cell, and the porphyrin with photodynamic effect can kill cancer cells.
The method of the present invention specifically comprises the following steps:
The first step utilizes Adler method to synthesize tetraphenylporphyrin, described Adler method is also known as propionic acid method, utilize Benzaldehyde derivatives and pyrroles to generate porphyrin derivative exactly under backflow (reflux) effect of propionic acid, described Benzaldehyde derivatives is phenyl aldehyde.
Concrete grammar is: three mouthfuls of round-bottomed flasks are equipped with dropping funnel, reflux condensing tube and mechanical stirrer respectively, add appropriate propionic acid (propionic acid), be heated to backflow, phenyl aldehyde and pyrroles are added in three mouthfuls of round-bottomed flasks for 1:1 by the ratio (mol ratio) of amount of substance.Because pyrroles is easy to oxidized rotten, therefore, the pyrroles used in experiment needs new steaming; Too much or the very few productive rate that all can affect porphyrin of the consumption of propionic acid.Temperature controls at reflux temperature i.e. 127 ~ 141 DEG C of temperature of propionic acid, and the reaction times is about 25 ~ 35min, and as 30min, the reaction times is long, and by product is too much, brings difficulty to separating-purifying; Reaction times is too short, reacts insufficient, greatly reduces the productive rate of resultant.In view of the requirement of backflow, temperature of reaction is higher, cause there is a large amount of by products as generations such as tar, need to add a small amount of DMSO (N, N-dimethyl sulfoxide (DMSO)), can reduce the generation of oligopolymer and described by product, have strong absorptive DMSO is that system has built anhydrous condition simultaneously, is conducive to the generation of porphyrin.Reaction is carried out complete, and by reaction mixture cool to room temperature, decompress filter removing waste liquid obtains filter cake, and repeatedly replace flush cake with methyl alcohol and warm deionized water, obtaining hepatic crystal is exactly tetraphenylporphyrin.
Second step utilizes nitrosonitric acid by nitrated for tetraphenylporphyrin one-tenth nitro porphyrin, excessive concentrated nitric acid and tetraphenylporphyrin react, the mixture of the different nitration product of degree of nitration can be obtained, these nitration products respectively: an itrated single nitro porphyrin TPP-NO of aromatic ring
2; Two aromatic ring itrated dinitrobenzene porphyrin TPP-(NO
2)
2, dinitrobenzene porphyrin has two isomer, and one is the trans-isomer trans-TPP-(NO of 5,15-bis-aromatic ring nitration
2)
2, this is a kind of to two aromatic ring nitration products, and two is cis-isomer cis-TPP-(NO of 5,10-bis-aromatic ring nitration
2)
2, this is a kind of adjacent two aromatic ring nitration products; Three aromatic ring itrated trinitro-porphyrin TPP-(NO
2)
3; Four itrated products of aromatic ring can also be produced in theory.When described concentrated nitric acid adopts the nitrosonitric acid of 98%, product can be obtained as nitrating agent and comprise TPP-NO
2, trans-TPP-(NO
2)
2, cis-TPP-(NO
2)
2with a small amount of TPP-(NO
2)
3.Relative to tetraphenylporphyrin, along with HNO
3equivalent (equiv) increases, namely HNO
3with the increase of tetraphenylporphyrin mol ratio, the yield of various product has different change, and described yield refers to that certain product accounts for the mass percent of whole product.Such as, TPP-NO
2yield decline always, be reduced to 7% by 45%, and trans-TPP-(NO
2)
2with cis-TPP-(NO
2)
2yield first in rising trend, be elevated to 53% from 12%, drop to 6% subsequently always, refer to the content in form below.Visible, work as HNO
3when consumption is 25equiv, di-nitrated product yield reaches peak value.
Concrete grammar is: tetraphenylporphyrin is dissolved in methylene dichloride CH
2cl
2in, add the nitrosonitric acid of 98%, its consumption is 25equiv, and in ice-water bath (ice bath), reaction 3h, then adds the HNO that ammonia neutralization is excessive
3add water again and be extracted to solution in neutral, collect organic phase, vacuum rotary steam is except desolventizing, in the di-nitrated product obtained, adjacent two aromatic ring nitration products are predominant product, and are only tracer level to two aromatic ring nitration products, and drying obtains single nitro porphyrin, two kinds of dinitrobenzene porphyrins and trinitro-porphyrin mixture, utilize column chromatography to be separated by described various nitration product, the structural formula of each nitration product is:
3rd step utilizes reducing substances that dinitrobenzene porphyrin and trinitro-porphyrin are reduced into diamino porphyrin and triamino porphyrin, and be referred to as Amino Porphyrins, described reducing substances is Na
2s, excessive Na
2s and various nitro porphyrin react, and can obtain 5,10-bis-p-amino phenyl-15,20-phenylbenzene porphyrin (trans-TPP-(NH
2)
2) and 5,15-bis-p-amino phenyl-10,20-phenylbenzene porphyrin (cis-TPP-(NH
2)
2) mixture and 5,10,15-triamino phenyl-20-phenyl porphyrin (TPP-(NH
2)
3).
Concrete grammar is: described two kinds of dinitrobenzene porphyrins and trinitro-porphyrin are dissolved in DMF (N, N-dimethylformamide), add reductive agent Na
2s, its consumption is 20equiv, reacts 3h, be then poured into water by reaction soln while hot in 60 DEG C of oil bath pans, then in 0 ~ 4 DEG C of refrigerator hold over night, decompress filter obtains trans-TPP-(NH
2)
2with cis-TPP-(NH
2)
2mixture and TPP-(NH
2)
3, utilize column chromatography to obtain pure cis-TPP-(NH
2)
2with trans-TPP-(NH
2)
2.
The described the first step to the reaction formula of the 3rd step is:
R
1=NO
2,R
2=H,R
3=H R
1'=NH
2,R
2′＝H,R
3′＝H
R
1=NO
2,R
2=NO
2,R
3=H R
1'=NH
2,R
2'=NH
2,R
3'=H
R
1=NO
2,R
2=H,R
3=NO
2R
1'=NH
2,R
2′＝H,R
3'=NH
2
R
1=NO
2,R
2=NO
2,R
3=NO
2R
1'=NH
2,R
2'=NH
2,R
3'=NH
2
4th step utilizes alpha-halogen carboxylic acid halides Amino Porphyrins to be prepared into ATRP initiator NH
2-TPP-X, described alpha-halogen carboxylic acid halides reducing substances is 2-chlorpromazine chloride, need add appropriate triethylamine (C
2h
5)
3n removes by product HCl.
Concrete grammar is: by cis-TPP-(NH
2)
2with trans-TPP-(NH
2)
2, TPP-(NH
2)
3be dissolved in methylene chloride, add triethylamine again, its consumption is 1equiv, in ice-water bath, stir 15min, then add 2-chlorpromazine chloride, its consumption is 1equiv, 1h is reacted in ice-water bath, solvent in vacuum rotary steam removing reactant, dry in vacuum drying oven, reactant obtains mauve ATRP initiator (NH by chromatography column
2)
n-TPP-Cl (n=1,2,3).
Below the reaction formula in three kinds of each comfortable 4th steps of Amino Porphyrins:
1、cis-TPP-(NH
2)
2
2、trans-TPP-(NH
2)
2
3、TPP-(NH
2)
3
ATRP initiator (the NH that 5th step utilizes back to prepare
2)
n-TPP-Cl (n=1,2,3) causes NIPA monomer NIPAM in Cu (I) Cl/ organic ligand catalyst system to be polymerized, and obtains having Thermo-sensitive, water miscible high molecular polymer (NH concurrently
2)
n-TPP-PNIPAM, described Cu (I) Cl is CuCl, and the organic ligand in described catalyst system is Me
6tREN.
Concrete grammar is: in W pipe side, side pipe adds monomer NIPAM and solvent DMF, adds ATRP initiator (NH in opposite side side pipe
2)
n-TPP-Cl and DMF, adds CuCl and DMF in W tube-in-tube, after liquid nitrogen freezing-vacuumize-thaw, injects Me in middle pipe side
6tREN, stirring reaction 20min, make it form Cu complex compound.Again freezing, vacuumize after pour the liquid in two side pipes into middle pipe, W pipe is placed in thermostat water bath and reacts, thermostat temperature is a certain temperature within the scope of 40 ~ 100 DEG C.After having reacted, reaction solution is exposed to termination reaction in air.Reaction mixture is crossed Al
2o
3post, rotary evaporation is except desolventizing, and the polymkeric substance obtained precipitates in normal hexane, filters to obtain throw out, and vacuum-drying obtains light green solid and polymkeric substance (NH
2)
n-TPP-PNIPAM.With cis-TPP-(NH
2)
2for example, the reaction formula of the 5th step is:
6th step is by high molecular polymer (NH
2)
n-TPP-PNIPAM coordinates with organic micromolecule ligand TTA and rare-earth europium, obtains the ligand (NH with high strength fluorescence
2)
n-TPP-PNIPAM-Eu (III)-TTA.
Concrete grammar is: rare-earth europium is with EuCl
3ethanolic soln mode is introduced.By high molecular polymer (NH
2)
n-TPP-PNIPAM is placed in tool plug bottle, uses transfer pipet according to mass ratio Eu respectively
3+: PNIPAM=0.07:1, mol ratio TTA:Eu
3+=2:1 gets quantitative EuCl
3ethanolic soln and TTA ethanolic soln, be placed in tool plug bottle, finally add dehydrated alcohol constant volume.Tool plug bottle is put into 30 DEG C of water-baths and reacts 48h, with DMF dialysis (MWCO, 4000) process, vacuum-drying 24h at 45 ° of C temperature, obtains title complex (NH
2)
n-TPP-PNIPAM-Eu (III)-TTA.The reaction formula of the 6th step is:
Lift the method that an object lesson illustrates the present invention below again.
The first step phenyl aldehyde and pyrroles prepare tetraphenylporphyrin under propionic acid backflow.5mL 0.05mol phenyl aldehyde, 6mLDMSO, 120mL propionic acid being added is equipped with in the there-necked flask of reflux, is heated to 135 DEG C of reflux temperatures, slowly drips the pyrroles of 3.5mL 0.05mol, dropwises rear back flow reaction 20min.Reactant is cooled to room temperature, decompress filter, filter cake is first colourless to filtrate with methanol wash column, then extremely neutral by hot water wash, at 80 DEG C of vacuum-drying 12h, obtains the tetraphenylporphyrin of purple.
Second step utilizes nitrosonitric acid by nitrated for tetraphenylporphyrin one-tenth nitro porphyrin, the tetraphenylporphyrin getting 200mg 0.325mmol is dissolved in 60mL methylene dichloride, add nitrosonitric acid 345mg, 3h is reacted in ice-water bath, then the nitric acid that ammonia neutralization is excessive is added, until solution just changes to red-purple from green, add water again and be extracted to solution in neutral, rotary evaporation is except desolventizing, in 60 DEG C of baking ovens, drying obtains nitrating mixture, by chromatography column, eluant component and volume proportion are: methylene dichloride: sherwood oil=1:4, a nitro porphyrin and dinitrobenzene porphyrin are separated.Due to dinitrobenzene porphyrin TPP-(NO
2)
2two isomer polarity closely, trans:Rf=0.79, cis:Rf=0.77, be difficult to be separated completely with column chromatography, and what therefore obtain is the mixture of two kinds of dinitrobenzene porphyrins.
3rd step utilizes Na
2dinitrobenzene porphyrin is reduced into diamino porphyrin by S.Get 100mg 0.142mmol dinitrobenzene porphyrin mixture to be dissolved in 35mL DMF, add 682mg 2.48mmol Na
2s, reacts 3h in 60 DEG C of oil bath pans, and then poured into by reactant while hot and fill in the water of 200mL, be placed on hold over night in 0 DEG C of refrigerator, then decompress filter obtains trans-TPP-(NH
2)
2with cis-TPP-(NH
2)
2mixture, makes this mixture by chromatography column, and eluant component and volume proportion are: methylene dichloride: ethyl acetate=40:1, obtains mauve Amino Porphyrins trans-TPP-(NH
2)
2with cis-TPP-(NH
2)
2.
4th step utilizes 2-chlorpromazine chloride Amino Porphyrins to be prepared into ATRP initiator (NH
2)
2-TPP-Cl.Get 50mg 0.078mmol cis-TPP-(NH
2)
2be dissolved in 20mL methylene dichloride, add 10.8 μ L 0.078mmol triethylamines again, 15min is stirred in ice-water bath, then add the 2-chlorpromazine chloride of 7.9 μ L 0.078mmol, in ice-water bath, react 1h, vacuum rotary steam is except desolventizing, dry 24h in 45 DEG C of vacuum drying ovens, reactant is by chromatography column, and eluant component and volume proportion are: methylene dichloride: ethyl acetate=100:1, obtain mauve ATRP initiator (NH
2)
2-TPP-Cl.
5th step utilizes ATRP initiator (NH
2)
2-TPP-Cl is at CuCl/Me
6cause NIPA monomer polymerization in TREN catalyst system, obtain having Thermo-sensitive and water miscible high molecular polymer (NH concurrently
2)
2-TPP-PNIPAM.Initiator/CuCl/Me
6the mol ratio of TREN/NIPAM is 1/5/5/100.Add the DMF of NIPAM and 1mL of 112mg 1mmol at W pipe side side pipe, in opposite side side pipe, add (the NH of 6.44mg 0.01mmol
2)
2the DMF of-TPP-Cl and 1mL, adds the DMF of CuCl and 1mL of 4.95mg 0.05mmol to W tube-in-tube, under the condition of isolated air, through twice freezing-vacuumize-thaw after, inject the Me of 12 μ l 0.1mmol to W tube-in-tube
6tREN, afterwards stirring reaction 15min under normal temperature; Again freezing, vacuumize after pour the liquid in two side pipes into middle pipe, airtight W pipe is placed in 60 DEG C of water-baths and reacts.After having reacted, reaction solution is exposed to termination reaction in air.Reaction mixture is crossed Al
2o
3post, leacheate is THF, and collect color band rotary evaporation except desolventizing, the polymkeric substance obtained precipitates 3 times in normal hexane, and dry 12h in the vacuum of 45 DEG C of temperature, obtains light green solid and polymkeric substance (NH
2)
2-TPP-PNIPAM.
6th step is by polymkeric substance (NH
2)
2-TPP-PNIPAM coordinates with small molecules organic ligand TTA and rare-earth europium, obtains the title complex (NH with high strength fluorescence
2)
2-TPP-PNIPAM-Eu (III)-TTA.Take 50mg EuCl
3be dissolved in 18mL ethanol, in 50 DEG C of water-baths, heated and stirred is transparent to solution, calculates by last liquor capacity.Then, by (NH
2)
2-TPP-PNIPAM is placed in tool plug bottle, uses transfer pipet according to mass ratio Eu respectively
3+: PNIPAM=0.07:1, mol ratio TTA:Eu
3+=2:1 gets the EuCl of calculated amount
3ethanolic soln and TTA ethanolic soln, be placed in tool plug bottle, finally adds dehydrated alcohol and be settled to 15mL.Tool plug bottle is put into 30 DEG C of water-baths and reacts 48h, with DMF dialysis (MWCO, 4000) process, vacuum-drying 24h under 45 ° of C, obtains final product (NH
2)
2-TPP-PNIPAM-Eu (III)-TTA.
Claims (9)
1. Amino Porphyrins-poly N-isopropyl acrylamide europium complex preparation method, is characterized in that, by (NH
2)
n-TPP is prepared into ATRP initiator NH
2-TPP-X, TPP are tetraphenylporphyrin, and X is halogen; Adopt described initiator to cause NIPAM polymerization and obtain polymkeric substance (NH
2)
n-TPP-PNIPAM; Trivalent europium is obtained title complex (NH by organic micromolecule ligand TTA and described polymer complex
2)
n-TPP-PNIPAM-Eu (III)-TTA, n=1,2,3, TTA is α-thenoyltrifluoroacetone, and the structural formula of described title complex is:
2. Amino Porphyrins according to claim 1-poly N-isopropyl acrylamide europium complex preparation method, is characterized in that, adopts Adler method synthesis TPP, obtains (NH through nitrated, reduction
2)
n-TPP, n=1,2,3, reaction formula is:
3. Amino Porphyrins according to claim 1-poly N-isopropyl acrylamide europium complex preparation method, is characterized in that, with alpha-halogen carboxylic acid halides by (NH
2)
n-TPP is prepared into (NH
2)
n-TPP-X, n=1,2,3, wherein X is halogen.
4. Amino Porphyrins according to claim 3-poly N-isopropyl acrylamide europium complex preparation method, is characterized in that, as n=2, and (NH
2)
n-TPP has two kinds of isomer: cis-TPP-(NH
2)
2with trans-TPP-(NH
2)
2, cis-TPP-(NH
2)
2be prepared to (NH
2)
2the reaction formula of-TPP-Cl is:
Trans-TPP-(NH
2)
2be prepared to (NH
2)
2the reaction formula of-TPP-Cl is:
As n=3, TPP-(NH
2)
3be prepared to (NH
2)
3the reaction formula of-TPP-Cl is:
5. Amino Porphyrins according to claim 1-poly N-isopropyl acrylamide europium complex preparation method, is characterized in that, by (NH in Cu (I) X/ organic ligand catalyst system
2)
n-TPP-X causes NIPAM polymerization, obtains (NH
2)
n-TPP-PNIPAM, n=1,2,3.
6. Amino Porphyrins according to claim 5-poly N-isopropyl acrylamide europium complex preparation method, is characterized in that, as (NH
2)
n-TPP-X is by cis-TPP-(NH
2)
2(the NH of preparation
2)
2during-TPP-Cl, the polyreaction formula of initiation is:
7. Amino Porphyrins according to claim 1-poly N-isopropyl acrylamide europium complex preparation method, is characterized in that, as (NH
2)
n-TPP-PNIPAM is by cis-TPP-(NH
2)
2(the NH of preparation
2)
2-TPP-Cl cause and generate polymkeric substance time, produce (NH
2)
2the reaction formula of-TPP-PNIPAM-Eu (III)-TTA is:
8. Amino Porphyrins-poly N-isopropyl acrylamide europium complex, is characterized in that:
A. its skeleton symbol is: (NH
2)
n-TPP-PNIPAM-Eu (III)-TTA, in formula: TPP is tetraphenylporphyrin, PNIPAM is poly N-isopropyl acrylamide, and Eu (III) is trivalent europium, and TTA is α-thenoyltrifluoroacetone;
B. its structural formula is:
9. Amino Porphyrins according to claim 8-poly N-isopropyl acrylamide europium complex, is characterized in that, (NH
2)
n-TPP-PNIPAM-Eu (III)-TTA is a kind of porphyrin compound, and molecular weight is within 4000 ~ 20000 scopes; The basic framework forming this porphyrin compound is porphines free alkali ring, and what form porphines is four pyrrole rings and four methynes, and their bridgings formation one of getting up has the aromaticity flush type porphines molecule of large pi-conjugated system, and porphines molecular structural formula is:
Carbon 5,10,15,20 wherein between each pyrrole ring, or α, β, γ, δ are meso carbon.
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