CN103059184A - 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 be a kind ofly have tumor-targeting and Thermo-sensitive, with the macromolecular compound of large ring conjugated structure, utilize the sour environment susceptibility of Amino Porphyrins that it is enriched near the tumor tissues in working cycle in vivo, again with 405nm or 630nm wavelength laser irradiation cancer target position, porphyrin is excited and then impels active oxygen to produce, by its kill cancer cell, belong to high-molecular optical kinetics therapy techniques field.
Background technology
PDT (photodynamic therapy, photodynamic therapy) is the method for a kind of novel treatment malignant tumour that grew up in nearly 20 years.Now, PDT is also obtaining aspect the non-tumor disease paying attention to widely in treatment, can become in the near future the effective means of the persistent ailments such as treatment tetter, old blind, coronary heart disease, acquired immune deficiency syndrome (AIDS), autoimmunity systemic disease and leukemia.It is compared with three great traditions treatment tumour means such as operation, chemotherapy and radiations, have following advantage: the one, tumour there is relative selection specificity, can directionally eliminate former and recurrent tumor, seldom damage healthy tissues, toxic side effect is little, and for example general chemotherapeutics enters and need not to add condition behind the human body and just have cytotoxicity, when killing and wounding cancer cells, also can cause in various degree damage to normal organ and cell, be a kind of toxic action of general, and PDT is quite different; The 2nd, do not affect other treatment, can carry out simultaneously with chemotherapy, radiotherapy, and have certain synergy, but repetitive therapy; The 3rd, all effective in cure to various cancers, antitumor spectra is wider.
The effect basis of photodynamic therapy is the photodynamics reaction, is a kind of Photosensitive reaction of following biological effect that has oxygen molecule to participate in.Its process is: under the irradiation of specific wavelength laser, the photosensitizers such as TPP (tetraphenylporphyrin), the phthalocyanine-like compound etc. that are absorbed by tissue are excited, oxygen around the photosensitizers of excited state is given transmission ofenergy again generates active very strong singlet oxygen-O
2, the oxidation-sensitive group in singlet oxygen and the adjacent biomacromolecule is had an effect, and causes its oxidation inactivation, produces cytotoxicity and causes tumour cell impaired and even dead, and porphyrins etc. get the nod as a kind of photosensitizers for the treatment of.As seen, when adopting PDT, photosensitive drug is after injection enters human body, and very fast meeting forms different concentration distribution in different tissues, descend with different speed again afterwards, and major part excretes after a couple of days.Just photodynamic reaction can be do not caused if absorbed the irradiation that the tissue of this photosensitive drug is not subject to light, just cytotoxicity can be do not produced yet.Even be subject to the irradiation of light, as long as the drug level in light wavelength, irradiation or the tissue does not meet or do not reach requirement, cell can not be subject to large damage yet.So its effect of PDT is a kind of local controllable light toxic action.
Late 1940s Figge etc. find that haematoporphyrin (hematoporphyrin) can by lymphoglandula, tumour, embryo or wound tissue's picked-up, 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.Begin to use HpD (Hematoporphyrin Derivative the sixties in 20th century, hematoporphyrin derivative) malignant tumour is carried out the fluorescence localization diagnosis, successively reported the diagnostic result of 50 routine lung bronchogenic carcinomas and patient with esophageal carcinoma such as Lipson etc., made a definite diagnosis more than 80%, and proposed first the concept of fluorescence endoscopy method.These achievements in research are so that HpD becomes the detection photosensitizers that is used for the earliest PDT.But, comprise the TPP poorly water-soluble of HpD cytotoxicity being arranged, enter and can form general behind the human body and distribute.
The prior art of relevant PNIPAM (poly N-isopropyl acrylamide) comprises: the one, and introduce various functional groups at the end of this polymkeric substance and form block polymer, thereby change its LCST as a kind of temperature sensing polymer (lowest critical solution temperature), the 2nd, make NIPAM (NIPA) and certain monomer generation copolymerization form multipolymer, thereby change the LCST of this polymkeric substance.
ATRP (Transfer Radical Polymerization) also claims the metal catalytic radical polymerization, its initiator is Organohalogen compounds (R-X), the catalyzer of polymerization system is comprised of the transition metal complex that transition metal salt at a low price and organic ligand form, described transition metal salt such as CuCl, described organic ligand such as the electron donors such as bipyridine, polyamine.Polymerization process can form dynamic reversible balance by means of redox reaction between living radical and dormancy kind, make polymerization activity, controlled purpose thereby reach.
Prior art adopts the synthetic PNIPAM of ATRP, and the kinetic curve of polyreaction demonstrates this polyreaction and is active, controllable polymerization, and prepared 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 is so that its compound has good electricity, light, magnetic property, and especially its spectroscopic properties is so that rare earth compound becomes a kind of important luminescent material.Luminescent Material of Rare Earth Polymer is born in 1963, and Wolff etc. are with small molecules title complex Eu (TTA)
3Joined among the PMMA (polymethylmethacrylate), wherein TTA is α-thenoyltrifluoroacetone, is a kind of organic molecule part.Namely in polymkeric substance, introduce europium and organic molecule part, 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.For example, polymkeric substance respectively with europium and TTA coordination, made 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 medicine, be used for lesion detection and the treatment of photodynamic therapy, intercept simultaneously the cytotoxicity of porphyrin itself, strengthen the water-soluble and tumor-targeting of this medicine, we have invented a kind of Amino Porphyrins-poly N-isopropyl acrylamide europium complex and preparation method thereof for this reason.
The present invention's Amino Porphyrins-poly N-isopropyl acrylamide europium complex preparation method is characterized in that, with (NH
2)
n-TPP is prepared into ATRP initiator NH
2-TPP-X, X are halogen; Adopt described initiator to cause the NIPAM polymerization and obtain polymkeric substance (NH
2)
n-TPP-PNIPAM; The trivalent europium is obtained title complex (NH by organic molecule part TTA and described polymer complex
2)
n-TPP-PNIPAM-Eu (III)-TTA, n=1,2,3.
The present invention's Amino Porphyrins-poly N-isopropyl acrylamide europium complex is characterized in that its skeleton symbol is:
(NH
2)
n-TPP-PNIPAM-Eu(III)-TTA，
In the formula: TPP is tetraphenylporphyrin, is called for short porphyrin, and PNIPAM is poly N-isopropyl acrylamide, and Eu (III) is the trivalent europium, and TTA is α-thenoyltrifluoroacetone;
Its structural formula is:
The present invention takes ATRP with NH
2-TPP-X is the initiator initiated polymerization, and the temperature sensitive polymer PNIPAM that biocompatibility is good is grafted on the Porphyrin Molecule, obtains polymkeric substance (NH
2)
n-TPP-PNIPAM, polymerization activity, controlled, LCST and the body temperature of polymer product adapt, polymer product is external when being lower than LCST, PNIPAM chain and steeping in water for reconstitution are given birth to hydrogen bond action and water-soluble, when being higher than LCST in vivo, bonding force between the hydrophobic group in the PNIPAM chain strengthens, hydrogen bond action between while and the water dies down, be shrunk to nano microgel and hydrophobic Porphyrin Molecule is wrapped in the PNIPAM molecule, the cytotoxicity of porphyrin is blocked, based on good water-soluble of PNIPAM, so that porphyrin can be dissolved in the human body fluids such as blood well thereupon.Because Amino Porphyrins presents weakly alkaline, is gathered in easily in the acid tumour cell, namely specific binding shows tumor-targeting, avoids forming general and distributes.Amino Porphyrins can flip out from described nano microgel particle, is enriched near the tumor tissues, because the autofluorescence of porphyrin and the spectroscopic properties of rare earth trivalent europium, so that the present invention's title complex (NH
2)
n-TPP-PNIPAM-Eu (III)-TTA becomes a kind of Luminescent Material of Rare Earth Polymer, can launch very strong fluorescence, detects thus tumor focus, realizes lesion detection.This title complex has typical large pi-conjugated system, its electron delocalization degree is very large, increased to a certain extent the life-span of charged ion, the favourable condition that provides of photodynamic therapy is provided, with the rayed tumor focus of 405nm or 630nm wavelength, utilizes the photodynamic effect of porphyrin, the directed photodynamics that occurs is reacted, kill cancer cell is avoided the infringement of normal tissue cell, realizes targeted therapy.
The present invention's title complex is actually a kind of detection of Cancerous disease and PDT photosensitizers for the treatment of of integrating.If be not subject to the irradiation of light, even tissue has been absorbed this medicine, the photodynamics reaction can not occur yet.In addition, even be subject to the irradiation of light, as long as light wavelength is undesirable, the drug level in irradiation or the cell tissue does not reach requirement, and cell can not sustain damage yet.As seen, 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, so that this title complex becomes a kind of efficient, safe lesion detection and medicine.This medicine is after injection enters human body, and with different concentration distribution, then concentration descends with different speed again, and major part excretes after a couple of days, and is very little to the toxic side effect of health in different tissues in very fast meeting.
Embodiment
The present invention's Amino Porphyrins-poly N-isopropyl acrylamide europium complex ((NH
2)
n-TPP-PNIPAM-Eu (III)-TTA) preparation method specifically may further comprise the steps: at first, adopt the synthetic tetraphenylporphyrin TPP of Adler method, obtain amino tetraphenylporphyrin (NH through nitrated, reduction
2)
n-TPP, n=1,2,3, be called for short Amino Porphyrins; Secondly, with the 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; The 3rd, in Cu (I) X/ organic ligand catalyst system, cause NIPA monomer NIPAM polymerization by the ATRP initiator, wherein X is halogen, obtains polymkeric substance (NH
2)
n-TPP-PNIPAM, n=1,2,3; At last, polymkeric substance is cooperated with organic molecule part α-thenoyltrifluoroacetone TTA and rare-earth europium Eu, obtain 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, arrive again Thermo-sensitive Amino Porphyrins (NH
2)
n-TPP-PNIPAM, obtained at last can specificity kill tumor cell fluorescence temperature sensing polymer (NH
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 among-TPP-PNIPAM-Eu (III)-TTA is Amino Porphyrins; The basic framework that forms porphyrin compound is porphines free alkali ring, and the composition porphines is four pyrrole rings and four methynes (18 atoms, 18 electronics), their bridgings get up to consist of the aromaticity flush type porphines molecule with large pi-conjugated system, and the porphines molecular structural formula is:
Wherein the carbon between each pyrrole ring (5,10,15,20, perhaps α, β, γ, δ) is referred to as meso carbon.Therefore, porphyrin is actually the general name that is connected with the substituent class homologue of function and derivative outside porphines free alkali ring.
The present invention's title complex (NH
2)
nThe photodynamics of-TPP-PNIPAM-Eu (III)-TTA partly is exactly the aminophenyl porphyrin (abbreviation Amino Porphyrins) after porphin ring is introduced phenyl and amino group, amino can the specific recognition tumour cell in Amino Porphyrins-poly N-isopropyl acrylamide europium complex, poly N-isopropyl acrylamide has good Thermo-sensitive and water-soluble, can launch very strong fluorescence with the europium that organic molecule part α-thenoyltrifluoroacetone is connected, thereby detect tumour cell, can kill cancer cell and have the porphyrin of photodynamic effect.
The present invention's method specifically may further comprise the steps:
The first step utilizes the Adler method to synthesize tetraphenylporphyrin, described Adler method claims again the propionic acid method, utilize exactly Benzaldehyde derivatives and pyrroles to generate the porphyrin derivative under backflow (reflux) effect of propionic acid, described Benzaldehyde derivatives is phenyl aldehyde.
Concrete grammar is: on three mouthfuls of round-bottomed flasks dropping funnel, reflux condensing tube and mechanical stirrer are housed respectively, add an amount of propionic acid (propionic acid), be heated to backflow, phenyl aldehyde and pyrroles are pressed the ratio (mol ratio) of amount of substance in three mouthfuls of round-bottomed flasks of 1:1 adding.Because the pyrroles is easy to oxidized rotten, therefore, the pyrroles who uses in the experiment needs new the steaming; Too much or the very few productive rate that all can affect porphyrin of the consumption of propionic acid.The reflux temperature that temperature is controlled at propionic acid is that the reaction times is about 25 ~ 35min under 127 ~ 141 ℃ of temperature, and such 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 that refluxes, temperature of reaction is higher, cause that the generations such as a large amount of by products such as tar are arranged, need to add a small amount of DMSO (N, the N-dimethyl sulfoxide (DMSO)), can reduce oligopolymer is the generation of described by product, and having simultaneously strong absorptive DMSO is that system has been built anhydrous condition, is conducive to the generation of porphyrin.Reaction is carried out complete, and with the reaction mixture cool to room temperature, decompress filter is removed waste liquid and got filter cake, repeatedly replaces flush cake with methyl alcohol and warm deionized water, and obtaining hepatic crystal is exactly tetraphenylporphyrin.
Second step utilizes nitrosonitric acid with the nitrated one-tenth nitro of tetraphenylporphyrin porphyrin, excessive concentrated nitric acid and tetraphenylporphyrin reaction, can obtain the mixture of the different nitration product of degree of nitration, these nitration products are respectively: the itrated single nitro porphyrin TPP-NO of aromatic ring
2Two the itrated dinitrobenzene porphyrin of aromatic ring TPP-(NO
2)
2, the dinitrobenzene porphyrin has two isomer, and one is the trans-isomer trans-TPP-(NO of 5,15-, two aromatic ring nitrations
2)
2, this is a kind of to two aromatic ring nitration products, two is cis-isomer cis-TPP-(NO of 5,10-, two aromatic ring nitrations
2)
2, this is a kind of adjacent two aromatic ring nitration products; Three the itrated trinitro-porphyrin of aromatic ring TPP-(NO
2)
3Can also produce in theory four itrated products of aromatic ring.When described concentrated nitric acid adopts 98% nitrosonitric acid, can access product 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)
3With respect to tetraphenylporphyrin, along with HNO
3Equivalent (equiv) increases, namely HNO
3With the increase of tetraphenylporphyrin mol ratio, the yield of various products has different the variation, and described yield refers to that certain product accounts for the mass percent of whole products.For example, TPP-NO
2Yield descend always, be reduced to 7% by 45%, and trans-TPP-(NO
2)
2And cis-TPP-(NO
2)
2Yield first in rising trend, be elevated to 53% from 12%, drop to 6% subsequently always, see the content in the following form for details.As seen, work as HNO
3When consumption was 25equiv, two nitrated product yields reached peak value.
Concrete grammar is: tetraphenylporphyrin is dissolved in methylene dichloride CH
2Cl
2In, the nitrosonitric acid of adding 98%, its consumption is 25equiv, then reaction 3h adds in the ammoniacal liquor and excessive HNO in ice-water bath (ice bath)
3Adding water is extracted to solution and is neutral again, collect organic phase, the vacuum rotary steam desolventizing, adjacent two aromatic ring nitration products are the advantage product in the two nitrated products that obtain, and only are 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 that described various nitration products are separated, the structural formula of each nitration product is:
The 3rd step utilized reducing substances that dinitrobenzene porphyrin and trinitro-porphyrin are reduced into diamino porphyrin and triamino porphyrin, the general designation Amino Porphyrins, and described reducing substances is Na
2S, excessive Na
2S and the reaction of various nitro porphyrin can obtain 5,10-, two p-amino phenyl-s 15,20-phenylbenzene porphyrin (trans-TPP-(NH
2)
2) and 5,15-, two p-amino phenyl-s 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 among the DMF (N, N-dimethylformamide), add reductive agent Na
2S, its consumption are 20equiv, react 3h in 60 ℃ of oil bath pans, then while hot reaction soln is poured into water, and hold over night in 0 ~ 4 ℃ of refrigerator again, decompress filter obtains trans-TPP-(NH
2)
2And cis-TPP-(NH
2)
2Mixture and TPP-(NH
2)
3, utilize column chromatography to obtain pure cis-TPP-(NH
2)
2And trans-TPP-(NH
2)
2
The reaction formula in described three steps of the first step to the 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
2 R
1'=NH
2,R
2′＝H,R
3'=NH
2
R
1=NO
2,R
2=NO
2,R
3=NO
2 R
1'=NH
2,R
2'=NH
2,R
3'=NH
2
The 4th step utilized the alpha-halogen carboxylic acid halides that Amino Porphyrins is prepared into ATRP initiator NH
2-TPP-X, described alpha-halogen carboxylic acid halides reducing substances is the 2-chlorpromazine chloride, needs to add an amount of triethylamine (C
2H
5)
3N removes by product HCl.
Concrete grammar is: with cis-TPP-(NH
2)
2And trans-TPP-(NH
2)
2, TPP-(NH
2)
3Be dissolved in the methylene chloride, add again triethylamine, its consumption is 1equiv, stir 15min in ice-water bath, then add the 2-chlorpromazine chloride, its consumption is 1equiv, in ice-water bath, react 1h, vacuum rotary steam is removed the solvent in the reactant, and dry in vacuum drying oven, reactant obtains mauve ATRP initiator (NH by chromatography column
2)
n-TPP-Cl (n=1,2,3).
Below be the reaction formula of three kinds of Amino Porphyrins in each comfortable the 4th step:
1、cis-TPP-(NH
2)
2
2、trans-TPP-(NH
2)
2
3、TPP-(NH
2)
3
The 5th step was utilized the ATRP initiator (NH of back preparation
2)
n-TPP-Cl (n=1,2,3) causes NIPA monomer NIPAM polymerization in Cu (I) Cl/ organic ligand catalyst system, obtain having concurrently Thermo-sensitive, water miscible high molecular polymer (NH
2)
n-TPP-PNIPAM, described Cu (I) Cl is CuCl, the organic ligand in the described catalyst system is Me
6TREN.
Concrete grammar is: manage a side side pipe at W and add monomer NIPAM and solvent DMF, add ATRP initiator (NH in the opposite side side pipe
2)
n-TPP-Cl and DMF add CuCl and DMF in the W tube-in-tube, process liquid nitrogen freezing-after vacuumizing-thawing, inject Me in middle pipe side
6TREN, stirring reaction 20min makes it form the Cu complex compound.Again freezing, pour the liquid in two side pipes into middle pipe after vacuumizing, place thermostat water bath to react the W pipe, thermostat temperature is a certain temperature in 40 ~ 100 ℃ of scopes.After reaction is finished reaction solution is exposed to termination reaction in the air.Reaction mixture is crossed Al
2O
3Post, the rotary evaporation desolventizing, resulting polymkeric substance precipitates in normal hexane, filters to get throw out, and it is polymkeric substance (NH that vacuum-drying gets the light green solid
2)
n-TPP-PNIPAM.With cis-TPP-(NH
2)
2Be example, the reaction formula in the 5th step is:
The 6th step is with high molecular polymer (NH
2)
n-TPP-PNIPAM cooperates with organic molecule part TTA and rare-earth europium, obtains having the ligand (NH of high strength fluorescence
2)
n-TPP-PNIPAM-Eu (III)-TTA.
Concrete grammar is: rare-earth europium is with EuCl
3The ethanolic soln mode is introduced.With high molecular polymer (NH
2)
n-TPP-PNIPAM places tool plug bottle, uses respectively transfer pipet according to mass ratio Eu
3+: PNIPAM=0.07:1, mol ratio TTA:Eu
3+=2:1 gets quantitative EuCl
3Ethanolic soln and TTA ethanolic soln place tool plug bottle, add at last the dehydrated alcohol constant volume.Tool plug bottle is put into 30 ℃ of water-baths react 48h, process with DMF dialysis (MWCO, 4000), vacuum-drying 24h under 45 ° of C temperature gets title complex (NH
2)
n-TPP-PNIPAM-Eu (III)-TTA.The reaction formula in the 6th step is:
The below lifts an object lesson explanation the present invention's method again.
The first step is prepared tetraphenylporphyrin with phenyl aldehyde and pyrroles under propionic acid refluxes.5mL 0.05mol phenyl aldehyde, 6mLDMSO, the adding of 120mL propionic acid are equipped with in the there-necked flask of reflux, are heated to 135 ℃ of reflux temperatures, slowly drip the pyrroles of 3.5mL 0.05mol, dropwise rear back flow reaction 20min.Reactant is cooled to room temperature, and it is colourless that decompress filter, filter cake are washed till filtrate with methyl alcohol first, then extremely neutral with hot water wash, at 80 ℃ of vacuum-drying 12h, obtains the tetraphenylporphyrin of purple.
Second step utilizes nitrosonitric acid with the nitrated one-tenth nitro of tetraphenylporphyrin porphyrin, the tetraphenylporphyrin of getting 200mg 0.325mmol is dissolved in the 60mL methylene dichloride, add nitrosonitric acid 345mg, in ice-water bath, react 3h, then add in the ammoniacal liquor and excessive nitric acid, until solution just changes to red-purple from green, adding water is extracted to solution and is neutral again, the rotary evaporation desolventizing, drying obtains nitrating mixture in 60 ℃ of baking ovens, by chromatography column, eluant component and volume proportion are: methylene dichloride: sherwood oil=1:4, separate a nitro porphyrin and dinitrobenzene porphyrin.Because dinitrobenzene porphyrin TPP-(NO
2)
2The polarity of two isomer very approaching, trans:Rf=0.79, cis:Rf=0.77 is difficult to separate fully with column chromatography, what therefore obtain is the mixture of two kinds of dinitrobenzene porphyrins.
The 3rd step was utilized Na
2S is reduced into the diamino porphyrin with the dinitrobenzene porphyrin.Get 100mg 0.142mmol dinitrobenzene porphyrin mixture and be dissolved among the 35mL DMF, add 682mg 2.48mmol Na
2S reacts 3h in 60 ℃ of oil bath pans, then while hot reactant is poured in the water that fills 200mL, is placed on hold over night in 0 ℃ of refrigerator, and then decompress filter obtains trans-TPP-(NH
2)
2And 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)
2And cis-TPP-(NH
2)
2
The 4th step utilized the 2-chlorpromazine chloride that Amino Porphyrins is prepared into ATRP initiator (NH
2)
2-TPP-Cl.Get 50mg 0.078mmol cis-TPP-(NH
2)
2Be dissolved in the 20mL methylene dichloride, add again 10.8 μ L 0.078mmol triethylamines, in ice-water bath, stir 15min, then add the 2-chlorpromazine chloride of 7.9 μ L 0.078mmol, in ice-water bath, react 1h, the vacuum rotary steam desolventizing, dry 24h in 45 ℃ of vacuum drying ovens, reactant is by chromatography column, and eluant component and volume proportion are: methylene dichloride: ethyl acetate=100:1 obtains mauve ATRP initiator (NH
2)
2-TPP-Cl.
The 5th step was utilized ATRP initiator (NH
2)
2-TPP-Cl is at CuCl/Me
6Cause the NIPA monomer polymerization in the TREN catalyst system, obtain having concurrently Thermo-sensitive and water miscible high molecular polymer (NH
2)
2-TPP-PNIPAM.Initiator/CuCl/Me
6The mol ratio of TREN/NIPAM is 1/5/5/100.Manage a side side pipe at W and add the NIPAM of 112mg 1mmol and the DMF of 1mL, in the opposite side side pipe, add (the NH of 6.44mg 0.01mmol
2)
2The DMF of-TPP-Cl and 1mL adds the CuCl of 4.95mg 0.05mmol and the DMF of 1mL to the W tube-in-tube, under the condition of secluding air, through twice freezing-after vacuumizing-thawing, inject the Me of 12 μ l 0.1mmol to the W tube-in-tube
6TREN, afterwards stirring reaction 15min under the normal temperature; Again freezing, pour the liquid in two side pipes into middle pipe after vacuumizing, place 60 ℃ of water-baths to react airtight W pipe.After reaction is finished reaction solution is exposed to termination reaction in the air.Reaction mixture is crossed Al
2O
3Post, leacheate are THF, collect the desolventizing of color band rotary evaporation, and resulting polymkeric substance precipitates in normal hexane 3 times, dry 12h in the vacuum of 45 ℃ of temperature, and obtaining the light green solid is polymkeric substance (NH
2)
2-TPP-PNIPAM.
The 6th step is with polymkeric substance (NH
2)
2-TPP-PNIPAM cooperates with small molecules organic ligand TTA and rare-earth europium, obtains having the title complex (NH of high strength fluorescence
2)
2-TPP-PNIPAM-Eu (III)-TTA.Take by weighing 50mg EuCl
3Be dissolved in the 18mL ethanol, heated and stirred is transparent to solution in 50 ℃ of water-baths, calculates by last liquor capacity.Then, with (NH
2)
2-TPP-PNIPAM places tool plug bottle, uses respectively transfer pipet according to mass ratio Eu
3+: PNIPAM=0.07:1, mol ratio TTA:Eu
3+=2:1 gets the EuCl of calculated amount
3Ethanolic soln and TTA ethanolic soln place tool plug bottle, add at last dehydrated alcohol and are settled to 15mL.Tool plug bottle is put into 30 ℃ of water-baths react 48h, process with DMF dialysis (MWCO, 4000), vacuum-drying 24h under 45 ° of C gets 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, with (NH
2)
n-TPP is prepared into ATRP initiator NH
2-TPP-X, X are halogen; Adopt described initiator to cause the NIPAM polymerization and obtain polymkeric substance (NH
2)
n-TPP-PNIPAM; The trivalent europium is obtained title complex (NH by organic molecule part TTA and described polymer complex
2)
n-TPP-PNIPAM-Eu (III)-TTA, n=1,2,3.
2. Amino Porphyrins according to claim 1-poly N-isopropyl acrylamide europium complex preparation method is characterized in that, adopts the synthetic TPP of Adler method, obtains (NH through nitrated, reduction
2)
n-TPP, n=1,2,3, reaction formula 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
2, R
1'=NH
2,R
2'=H,R
3'=NH
2,
R
1=NO
2,R
2=NO
2,R
3=NO
2, R
1'=NH
2,R
2'=NH
2,R
3'=NH
2。
3. Amino Porphyrins according to claim 1-poly N-isopropyl acrylamide europium complex preparation method is characterized in that, uses the alpha-halogen carboxylic acid halides with (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, when n=2, and (NH
2)
n-TPP has two kinds of isomer: cis-TPP-(NH
2)
2And 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:
When 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, in Cu (I) X/ organic ligand catalyst system by (NH
2)
n-TPP-X causes the 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 causes and during the polymkeric substance that generates, produces (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 the formula: TPP is tetraphenylporphyrin, and PNIPAM is poly N-isopropyl acrylamide, and Eu (III) is the 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 that forms this porphyrin compound is porphines free alkali ring, and what form porphines is four pyrrole rings and four methynes, and their bridgings get up to consist of the aromaticity flush type porphines molecule with large pi-conjugated system, and the porphines molecular structural formula is:
The carbon between each pyrrole ring 5,10,15,20 wherein, perhaps α, β, γ, δ are referred to as meso carbon.
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