CN104004008B - Fluorinated aryl benzyl oxide dendritic phthalocyanine silicon complex and its preparation method and application - Google Patents
Fluorinated aryl benzyl oxide dendritic phthalocyanine silicon complex and its preparation method and application Download PDFInfo
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Abstract
The present invention discloses a kind of fluorinated aryl benzyl oxide dendritic phthalocyanine silicon complex and its preparation method and application, first synthetic phthalocyanine silicon dichloride; Then under potash exists, to (nitro or cyano group, ester group, benzophenone) benzyl bromine and the synthetic 2-(4-hydroxy benzenes of 2,2-bis-(4-hydroxyphenyl) HFC-236fa reaction)-2 ˊ-(4-(4-nitro or cyano group or ester group or benzophenone-benzyloxy) HFC-236fa. Last phthalocyanine silicon dichloride, respectively with 2-(4-hydroxy benzenes)-2 ˊ-(4-(4-nitro or cyano group or ester group or benzophenone-benzyloxy) HFC-236fa reacts synthetic two-(2-(4-phenoxy group)-2 ˊ-(4-(4-nitro or cyano group or ester group or benzophenone-benzyloxy) HFC-236fa) in reflux in toluene and axially replaces silicon (IV) phthalocyanine complex. Make the ligand modified phthalocyanine complex of fluoro branch become a class to have the sensitising agent of good optical dynamic therapy potentiality.
Description
Technical field
The invention belongs to complex field, especially belong to a kind of fluoro for aryl benzyl oxide dendritic phthalocyanine silicon complex andPreparation method and application, this complex as sensitising agent be applied to optical dynamic therapy moist macular degeneration class disease and cancer andCell imaging.
Background technology
PDT (photodynamictherapy, PDT) is that one is treated cancer, HIV and moist macular degenerationThe new method of class disease. The key of optical dynamic therapy is sensitising agent. Phthalocyanine complex is because having the skeleton knot similar to haematoporphyrinStructure, structure is more stable and easily modify, maximum absorption wavelength is positioned at about 670nm, easily see through tissue ruddiness region andCan make sterling, be considered to the very potential sensitising agent of a class. Due to π-π effect strong between Phthalocyanine, easily poly-Collection, thus the fluorescence quantum yield of reduction Phthalocyanine shortens singlet and triplet state quantum yield and life-span, thus reduce lightSensitization efficiency. Therefore, the sensitising agent of the synthetic superior performance of design is our goal in research.
In order to solve the poor problem of phthalocyanine dissolubility, people consider to introduce fluorine-containing replacement at phthalocyanine periphery or axial locationBase. Fluorine atom etc. is replaced to hydrogen atom in reactive compound or oxygen atom electronically to be formed containing fluoro substituents as-CF3、-C6F5-OCF3Deng, they have larger sterically hindered, therefore can change the cloud density of compound parent molecule, same to differentiationStructure body conformation and transition state, thereby solubility and the acid-base value of change Phthalocyanine. In addition, there is the medicine of fluoro function base easyMetabolism, therefore, has had many lipophilic medicines to modify by fluoro function base, changes their pharmacokinetics reportRoad. In addition, fluoro group is introduced in large biological molecule, also regulated and controled some functions of large biological molecule, as divided with albumen, DNASon interacts. On the other hand, introduce fluoro branch group, can utilize huge steric effect to suppress the product of phthalocyanine aggregationRaw, thus the photosensitive activity of raising phthalocyanine.
Based on above idea, fluoro branch silicon (IV) phthalocyanine complex of novel different end group has been synthesized in design herein. WillBe incorporated into dendritic structure containing fluoro substituents, prepare first the fluoro branch phthalocyanine complex of series of new different end group, its toolThere is the synergy of dendritic structure and fluorine function base. Not only can utilize the sterically hindered of dendritic structure, press down to a certain extentThe self aggregation behavior of phthalocyanine processed, and due to the existence of fluorine function base, improved the solubility of phthalocyanine, and regulated and controled phthalocyaninePhotophysical property and pharmacokinetic property, make the ligand modified phthalocyanine complex of fluoro branch become a class and there is good lightThe sensitising agent of dynamic therapy potentiality. Yet there are no the report of fluoro for aryl benzyl oxide dendritic phthalocyanine silicon complex both at home and abroad.
Summary of the invention
The object of the present invention is to provide a kind of fluorinated aryl benzyl oxide dendritic phthalocyanine silicon complex and preparation method thereof.
The present invention also proposes the application of a kind of fluorinated aryl benzyl oxide dendritic phthalocyanine silicon complex as sensitising agent.
The object of the present invention is achieved like this, and a kind of fluorinated aryl benzyl oxide dendritic phthalocyanine silicon of the present invention coordinatesThing, the compound for following structure:
In formula: R is cyano group, nitro, benzophenone or ester group.
The above-mentioned a kind of fluoro of the present invention, for aryl benzyl oxide dendritic phthalocyanine silicon complex, is to be incorporated into containing fluoro substituentsDendritic structure, the fluoro branch phthalocyanine complex of series of new different end group, it has the association of dendritic structure and fluorine function baseSame-action. Due to fluorine atom etc. electronically the hydrogen atom in substituted compound form containing fluoro substituents CF3There is obvious spaceEffect, simultaneously dendritic structure has huge sterically hinderedly, can suppress to a certain extent the self aggregation behavior of phthalocyanine; Fluorine-containingSubstituting group not only has hydrophily but also have lipophilicity, has the characteristic that is well separated in polarity and nonpolar environment. Therefore existPhthalocyanine is introduced containing the fluoro substituents solubility of phthalocyanine greatly; Due to the larger electronegativity of having of fluorine atom and chemical inertness,Make containing fluorine-containing substituent carbon atom positively charged and have part unoccupied orbital, easy and peripheral benzodiazepine ring forms conjugated system, because ofThis greatly sensitization the photophysical property of phthalocyanine, compared with floride-free substituted phthalocyanine, photoluminescence spectrum intensity, life-span, fluorescent quantum produceRate and singlet oxygen quantum yield all strengthen greatly; Because fluorine atom forms C-F key stability, therefore fluorine atom regulating medicine withThere is fine stability, can be with albumen, DNA effect and do not change protein function, thus modulation medication effect.
The present invention not only can utilize containing fluoro substituents CF3There is the space bit of obvious three-dimensional effect and dendritic structureResistance, suppresses the self aggregation behavior of phthalocyanine to a certain extent, and due to the existence of fluorine function base, has improved the dissolving of phthalocyanineSpend, and regulated and controled photophysical property and the pharmacokinetic property of phthalocyanine, 1) find out from table 1 data, with respect to identical branchThe free-floride of structure axially replaces silicon (IV) for branch phthalocyanine two-(2-(4-phenoxy group)-2'-(4-(4-cyano group-benzyloxy) propane)Phthalocyanine complex (being called for short SiPc-CN) and two-(2-(4-phenoxy group)-2'-(4-(4-nitro-benzyloxy) propane) axially replaceSilicon (IV) phthalocyanine complex (is called for short SiPc-NO2), fluorinated aryl benzyl oxide dendritic phthalocyanine silicon complex intake increases greatly, and picked-up time advance, show that fluoro dendritic structure has obviously changed the pharmacokinetics of sensitising agent; 2) and from table2 can find out, fluorinated aryl benzyl oxide dendritic phthalocyanine silicon complex has obvious inhibitory action to U251 human glioma cell. PhaseFor the free-floride of identical dendritic structure for branch phthalocyanine SiPc-CN and SiPc-NO2, fluoro is for aryl benzyl oxide dendritic phthalocyanine siliconThe inhibiting rate of complex increases; As can be seen here, the ligand modified phthalocyanine complex of fluoro branch becomes a class and has wellThe sensitising agent of optical dynamic therapy potentiality.
The preparation method of a kind of fluorinated aryl benzyl oxide silicon phthalocyanine compound of the present invention, comprises the steps: that (1) is rightCyano group benzyl bromine and hexafluoro bisphenol-a be synthetic 2-(4-hydroxy benzenes in potash and acetone soln)-2'-(4-(4-cyano group-benzyloxy)HFC-236fa; 2) 2-(4-hydroxy benzenes) (4-(4-cyano group-benzyloxy) HFC-236fa and phthalocyanine silicon dichloride are at K for-2'-2CO3ExistUnder, in toluene solution, reflux and prepare two-(2-(4-phenoxy group)-2'-(4-(4-cyano group-benzyloxy) axially replaces silicon(IV) phthalocyanine complex.
A kind of fluoro of the present invention, for the preparation method of aryl benzyl oxide silicon phthalocyanine compound, comprises the steps: (1)The synthetic 2-(4-hydroxy benzenes in potash and acetone soln to nitrobenzyl bromine and hexafluoro bisphenol-a)-2'-(4-(4-nitro-benzyloxyBase) HFC-236fa; 2) 2-(4-hydroxy benzenes) (4-(4-nitro-benzyloxy) HFC-236fa and phthalocyanine silicon dichloride are at K for-2'-2CO3DepositUnder, in toluene solution, reflux and prepare two-(2-(4-phenoxy group)-2'-(4-(4-nitro-benzyloxy) axially replaces silicon(IV) phthalocyanine complex.
The preparation method of a kind of fluorinated aryl benzyl oxide silicon phthalocyanine compound of the present invention, comprises the steps: that (1) is rightBenzophenone benzyl bromine and hexafluoro bisphenol-a be synthetic 2-(4-hydroxy benzenes in potash and acetone soln)-2'-(4-(4-hexichol firstKetone-benzyloxy) HFC-236fa; 2) 2-(4-hydroxy benzenes)-2'-(4-(4-benzophenone-benzyloxy) HFC-236fa and dichloro silicon phthaleinCyanines are at K2CO3Under existence, in toluene solution, reflux and prepare two-(2-(4-phenoxy group)-2'-(4-(4-benzophenone-benzylsOxygen base) axially replace silicon (IV) phthalocyanine complex.
The preparation method of a kind of fluorinated aryl benzyl oxide silicon phthalocyanine compound of the present invention, comprises the steps: that (1) is rightEster group benzyl bromine and hexafluoro bisphenol-a be synthetic 2-(4-hydroxy benzenes in potash and acetone soln)-2'-(4-(4-ester group benzyloxy)HFC-236fa; 2) 2-(4-hydroxy benzenes) (4-(4-ester group-benzyloxy) HFC-236fa and phthalocyanine silicon dichloride are at K for-2'-2CO3ExistUnder, in toluene solution, reflux and prepare two-(2-(4-phenoxy group)-2'-(4-(4-ester group-benzyloxy) axially replaces silicon(IV) phthalocyanine complex.
The above-mentioned phthalocyanine silicon dichloride of the present invention is to adopt 1,3-diiminoisoindole, silicon tetrachloride and quinoline,At 200-240 DEG C, stirring and refluxing obtains mixed liquor, then in the time that mixed liquor is cooled to 70-90 DEG C, by its impouring methyl alcohol, while hotFilter, filter residue with after toluene, quinoline, methyl alcohol and acetone washing, obtains after being dried respectively.
The 2-(4-hydroxy benzenes that the present invention is above-mentioned) (4-(4-cyano group-benzyloxy) HFC-236fa preferably adopts cyano group-2'-Benzyl bromine, Anhydrous potassium carbonate, 2,2-bis-(4-hydroxyphenyl) HFC-236fa and acetone, at 45-65 DEG C of temperature, vigorous stirring refluxes anti-Should, filter, collect filtrate, pressure reducing and steaming solvent, obtains white thick product, and thick product is taking carrene as eluant, eluent, silica gel column chromatographyPost separating-purifying 3 times, obtains after being dried.
Above-mentioned two-(2-(4-the phenoxy group)-2'-(4-(4-cyano group-benzyloxy) HFC-236fa) of the present invention axially replace silicon(IV) phthalocyanine complex preferably adopts SiPcCl2，G1-F-CN-OH and Anhydrous potassium carbonate and heavily steam toluene, 110-130 DEG C of temperatureLower stirring and refluxing is reacted to obtain mixture, and mixture is cooled to room temperature, and mixture is poured into water, and water layer extracts with toluene, is associated withMachine phase, pressure reducing and steaming solvent, obtains the thick product of blue-green, and thick product is taking carrene as eluant, eluent, and silica gel column chromatography separates and carriesPure, after vacuum drying, obtain.
The 2-(4-hydroxy benzenes that the present invention is above-mentioned) (4-(4-nitro-benzyloxy) HFC-236fa preferably adopts nitro-2'-Benzyl bromine, Anhydrous potassium carbonate, 2,2-bis-(4-hydroxyphenyl) HFC-236fa and acetone, at 45-65 DEG C of temperature, vigorous stirring refluxes anti-Should, filter, collect filtrate, pressure reducing and steaming solvent, obtains white thick product, and thick product is taking carrene as eluant, eluent, silica gel column chromatographyPost separating-purifying 3 times, obtains after being dried.
Above-mentioned two-(2-(4-the phenoxy group)-2'-(4-(4-nitro-benzyloxy) HFC-236fa) of the present invention axially replace silicon(IV) phthalocyanine complex preferably adopts SiPcCl2, 2-(4-hydroxy benzenes) and-2'-(4-(4-nitro-benzyloxy) HFC-236fa and nothingAqueous carbonate potassium and heavily steam toluene, at 110-130 DEG C of temperature, stirring and refluxing is reacted to obtain mixture, and mixture is cooled to room temperature, willMixture is poured into water, and water layer extracts with toluene, merges organic phase, and pressure reducing and steaming solvent, obtains the thick product of blue-green, thick productTaking carrene as eluant, eluent, silica gel column chromatography separating-purifying, obtains after vacuum drying.
The 2-(4-hydroxy benzenes that the present invention is above-mentioned) (4-(4-ester group-benzyloxy) HFC-236fa preferably adopts bromobenzene-2'-Methyl formate, Anhydrous potassium carbonate, 2,2-bis-(4-hydroxyphenyl) HFC-236fa and acetone, at 45-65 DEG C of temperature, vigorous stirring is returnedStream reaction, filters, and collects filtrate, and pressure reducing and steaming solvent, obtains white thick product, and thick product is taking carrene as eluant, eluent, silica gelChromatographic column separating-purifying 3 times, obtains after being dried.
Above-mentioned two-(2-(4-the phenoxy group)-2'-(4-(4-ester group-benzyloxy) HFC-236fa) of the present invention axially replace silicon(IV) phthalocyanine complex preferably adopts SiPcCl2, 2-(4-hydroxy benzenes) and-2'-(4-(4-ester group-benzyloxy) HFC-236fa and nothingAqueous carbonate potassium and heavily steam toluene, at 110-130 DEG C of temperature, stirring and refluxing is reacted to obtain mixture, and mixture is cooled to room temperature, willMixture is poured into water, and water layer extracts with toluene, merges organic phase, and pressure reducing and steaming solvent, obtains the thick product of blue-green, thick productTaking carrene as eluant, eluent, silica gel column chromatography separating-purifying, obtains after vacuum drying.
The 2-(4-hydroxy benzenes that the present invention is above-mentioned) (4-(4-benzophenone-benzyloxy) HFC-236fa preferably adopts two to-2'-Benzophenone benzyl bromine, Anhydrous potassium carbonate, 2,2-bis-(4-hydroxyphenyl) HFC-236fa and acetone, vigorous stirring at 45-65 DEG C of temperatureBack flow reaction, filters, and collects filtrate, and pressure reducing and steaming solvent, obtains white thick product, and thick product is taking carrene as eluant, eluent, siliconGlue chromatographic column separating-purifying 3 times, obtains after being dried.
Above-mentioned two-(2-(4-the phenoxy group)-2'-(4-(4-benzophenone-benzyloxy) HFC-236fa) of the present invention axially getPreferably adopt SiPcCl for silicon (IV) phthalocyanine complex2, 2-(4-hydroxy benzenes) and-2'-(4-(4-benzophenone-benzyloxy) hexafluoroPropane and Anhydrous potassium carbonate and heavily steam toluene, at 110-130 DEG C of temperature, stirring and refluxing is reacted to obtain mixture, and mixture is cooled toRoom temperature, is poured into water mixture, and water layer extracts with toluene, merges organic phase, and pressure reducing and steaming solvent, obtains blue-green and slightly produceProduct, thick product is taking carrene as eluant, eluent, and silica gel column chromatography separating-purifying, obtains after vacuum drying.
The application of aryl oxide dendritic phthalocyanine complex of the present invention in the sensitising agent of preparing PDT.
Beneficial effect of the present invention: compare with the branch phthalocyanine phthalocyanine complex in former patent, draw containing fluoro substituentsEnter to dendritic structure, prepare the fluoro branch phthalocyanine complex of series of new different end group, it has dendritic structure and fluorine meritThe synergy of energy base. Not only can utilize the sterically hindered of dendritic structure, the self aggregation that suppresses to a certain extent phthalocyanine is capableFor, and due to the existence of fluorine function base, improved the solubility of phthalocyanine, in regulated and controled phthalocyanine photophysical property and medicine generation, are movingMechanical property, makes the ligand modified phthalocyanine complex of fluoro branch become a class and has the photosensitive of good optical dynamic therapy potentialityAgent.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in detail:
Embodiment mono-
1) phthalocyanine silicon dichloride (SiPcCl2) synthetic
In three-neck flask, add respectively 1,3-diiminoisoindole (3.7g, 25.5mmol), silicon tetrachloride(4.2mL) and quinoline (42mL), stirring and refluxing 30min 220 DEG C time, when mixed liquor is cooled to 80 DEG C, by its impouringIn methyl alcohol (80mL), filter while hot, for filter residue, the each 35mL washing of toluene, quinoline, methyl alcohol and acetone, obtains aubergine after being driedSolid 2.2g, productive rate is 60%.
2) 2-(4-hydroxy benzenes) (4-(4-cyano group-benzyloxy) HFC-236fa (is called for short: G-2'-1-F-CN-OH) synthetic
In three-neck flask, add to cyano group benzyl bromine (2.4g, 12.0mmol) Anhydrous potassium carbonate (2.0g, 14.5Mmol), 2,2-bis-(4-hydroxyphenyl) HFC-236fa (4.9g, 14.4mmol), acetone (50mL), 55 DEG C of vigorous stirring are returnedStream reaction 48h, filters, and collects filtrate, and pressure reducing and steaming solvent, obtains white thick product. Thick product is taking carrene as eluant, eluent,Silica gel column chromatography separating-purifying 3 times, obtains white powder solid 3.6g, productive rate 71.4% after being dried.
3) two-(2-(4-phenoxy group)-2'-(4-(4-cyano group-benzyloxy) HFC-236fa) axially replace silicon (IV) phthalocyanine and joinCompound (is called for short: SiPc-F-NO2) synthetic
In three-neck flask, add SiPcCl2（0.2g,0.3mmol），G1-F-CN-OH(0.4g, 1.0mmol) andAnhydrous potassium carbonate (0.2g, 1.6mmol), heavily steams toluene (20mL), and 120 DEG C of stirring and refluxing reaction 48h, are cooled to room temperature,Mixture is poured into water, and toluene for water layer (50mL ' 3) extraction, merges organic phase, and pressure reducing and steaming solvent, obtains blue-green thickProduct, thick product is taking carrene as eluant, eluent, and silica gel column chromatography separating-purifying 3 times, obtains blue-green solid after vacuum drying0.26g, productive rate 62.0%. Elementary analysis (theoretical value %): C, 65.03 (65.00); H, 3.10 (3.08); N, 9.52 (9.72).IR（KBr/cm-1）：736，1079，1060-1160，1254-1171，1610，2228，2930-840，3438。1HNMR(400MHz,DMSO-d6,δ/ppm):9.64(d,J=8Hz,8H)；8.39(m,J=16Hz,8H)；6.62(d,J=8Hz,4H)；6.67(d,J=8Hz,4H);5.60(d,J=8Hz,4H);7.71(d,J=8Hz,4H);7.55(d,J=8Hz,4H);5.07(s,4H);MALDI-TOF-MS:m/z=1441[M+H+]。
4) 2-(4-hydroxy benzenes)-2'-(synthesizing of 4-(4-nitro-benzyloxy) HFC-236fa
In three-neck flask, add successively nitrobenzyl bromine (2.7g, 12.6mmol), Anhydrous potassium carbonate (2.0g,14.5mmol), 2,2-bis-(4-hydroxyphenyl) HFC-236fa (5.1g, 15.1mmol) and acetone (50mL), 55 DEG C are violentStirring and refluxing reaction 48h, filters, and collects filtrate, and pressure reducing and steaming organic solvent, obtains yellow thick product. Thick product is with benzinum:Carrene (volume ratio 1:10) is eluant, eluent, and silica gel column chromatography separating-purifying 3 times, obtains pale yellow powder shape after vacuum dryingSolid 3.8g, productive rate 65.1%.
5) two-(2-(4-phenoxy group)-2'-(4-(4-nitro-benzyloxy) HFC-236fa) axially replace silicon (IV) phthalocyanine and joinCompound (is called for short: SiPc-F-NO2) synthetic
In three-neck flask, add SiPcCl2（0.2g,0.3mmol），G1-F-NO2(0.5g, 1.0mmol) and nothingAqueous carbonate potassium (0.2g, 1.6mmol), heavily steams toluene (20mL), and 120 DEG C of stirring and refluxing reaction 48h, are cooled to room temperature, willMixture is poured into water, and toluene for water layer (50mL ' 3) extraction, merges organic phase, and pressure reducing and steaming solvent, obtains blue-green and slightly produceProduct. Thick product is taking benzinum: carrene (volume ratio 1:10) is as eluant, eluent, silica gel column chromatography separating-purifying 3 times, vacuum dryingAfter obtain blue-green solid 0.29g, productive rate 61.2%.
Elementary analysis (theoretical value %): C, 61.54 (61.62); H, 2.78 (2.99); N, 9.53 (9.46). IR(KBr/cm-1）：736，1079，1060-1160，1253-1170，1343，1609,2960-2840，3427。1HNMR(400MHz,DMSO-d6,δ/ppm):9.64(d,J=8Hz,8H)；8.40(m,J=16Hz,8H)；2.24(d,J=8Hz,4H),6.62(d,J=8Hz,4H)；6.70(d,J=8Hz,4H);5.60(d,J=8Hz,4H);7.77(d,J=8Hz,4H);7.50(d,J=8Hz,4H);5.12(s,4H);MALDI-TOF-MS:m/z=1481[M+1]。
6) 2-(4-hydroxy benzenes) (4-(4-ester group-benzyloxy) HFC-236fa (is called for short: G-2'-1-F-CN-OH) synthetic
In three-neck flask, add parabromobenzoic acid methyl esters (2.8g, 12.0mmol), Anhydrous potassium carbonate (2.0g,14.5mmol), 2,2-bis-(4-hydroxyphenyl) HFC-236fa (4.9g, 14.4mmol) and acetone (50mL), 55 DEG C are violentStirring and refluxing reaction 48h, filters, and collects filtrate, and pressure reducing and steaming organic solvent, obtains white thick product. Thick product acetone: twoChloromethanes (volume ratio 1:200) is eluant, eluent, and silica gel column chromatography separating-purifying 3 times obtains white powder solid after vacuum drying4.0g, productive rate 68.5%.
7) two-(2-(4-phenoxy group)-2'-(4-(4-ester group-benzyloxy) HFC-236fa) axially replace silicon (IV) phthalocyanine and joinCompound (is called for short: SiPc-F-COOCH3) synthetic
In three-neck flask, add SiPcCl2（0.2g,0.3mmol），G1-F-COOCH3（0.5g,1.0mmol）And Anhydrous potassium carbonate (0.2g, 1.6mmol), heavily steaming toluene (20mL), 120 DEG C of stirring and refluxing reaction 48h, are cooled to chamberTemperature, is poured into water mixture, and toluene for water layer (50mL ' 3) extraction, merges organic phase, and pressure reducing and steaming solvent, obtains bluenessThick product. Thick product is taking acetone: carrene (volume ratio 1:200) is as eluant, eluent, silica gel column chromatography separating-purifying 3 times, vacuumAfter dry, obtain blue-green solid 0.3g, productive rate 67.4%. Elementary analysis (theoretical value %): C, 63.49 (63.74); H, 3.21(3.34)；N，7.37(7.43)。IR（KBr/cm-1）：733，1078，1060-1160，1257-1170，1611,1726,2960-2840，3436。1HNMR(400MHz,DMSO-d6,δ/ppm):9.64(d,J=8Hz,8H)；8.38(m,J=16Hz,8H)；2.44(d,J=8Hz,4H),6.60(d,J=8Hz,4H)；6.72(d,J=8Hz,4H);5.60(d,J=8Hz,4H);7.78(d,J=8Hz,4H);7.52(d,J=8Hz,4H);5.10(s,4H;);1.28(s,6H);MALDI-TOF-MS:m/z=1507[M+1]。
8) 2-(4-hydroxy benzenes) (4-(4-benzophenone-benzyloxy) HFC-236fa (is called for short: G-2'-1-F-BP) synthetic
In three-neck flask, add benzophenone benzyl bromine (3.2g, 12.0mmol), Anhydrous potassium carbonate (2.0g,14.5mmol), 2,2-bis-(4-hydroxyphenyl) HFC-236fa (4.9g, 14.4mmol) and acetone (50mL), 45 DEG C are violentStirring and refluxing reaction 48h, filters, and collects filtrate, and pressure reducing and steaming organic solvent, obtains white thick product. Thick product acetone: twoChloromethanes (volume ratio 1:200) is eluant, eluent, and silica gel column chromatography separating-purifying 3 times obtains white powder solid after vacuum drying4.3g, productive rate 58%.
9) two-(2-(4-phenoxy group)-2'-(4-(4-benzophenone-benzyloxy) HFC-236fa) axially replace silicon (IV) phthaleinCyanines complex (is called for short: SiPc-F-BP) synthetic
In three-neck flask, add SiPcCl2（0.2g,0.3mmol），G1-F-BP(0.9g, 1.0mmol) and nothingAqueous carbonate potassium (0.2g, 1.6mmol), heavily steams toluene (30mL), and 130 DEG C of stirring and refluxing reaction 48h, are cooled to room temperature, willMixture is poured into water, and toluene for water layer (50mL ' 3) extraction, merges organic phase, and pressure reducing and steaming solvent obtains blue coarse and producesProduct. Thick product is taking acetone: carrene (volume ratio 1:100) is as eluant, eluent, silica gel column chromatography separating-purifying 3 times, vacuum dryingAfter blue-green solid 0.6g, productive rate 72.0%. Elementary analysis (theoretical value %): C, 66.49 (663.74); H, 2.75 (2.75);N，7.68(7.68)。IR（KBr/cm-1）：736，1091，1060-1160，1260-1170，1717；1726,29860-2820，3420。1HNMR(400MHz,DMSO-d6,δ/ppm):9.64(d,J=8Hz,8H)；8.38(m,J=16Hz,8H)；6.07（(d,J=8Hz,8H)；2.66(d,J=8Hz,4H),6.62(d,J=8Hz,4H)；6.70(d,J=8Hz,4H);5.62(d,J=8Hz,4H);7.80(d,J=8Hz,4H);7.54(d,J=8Hz,4H);5.10(s,4H;);1.28(s,6H);MALDI-TOF-MS:m/z=1701[M+1]。
Embodiment bis-:
In embodiment mono-, process 2) cyano group benzyl bromine is changed into 4.2g, 2,2-bis-(4-hydroxyphenyl) HFC-236fa changes into9.0g, acetone changes 50mL into, and the reaction time changes 2h into, and other reaction condition is identical, obtains white toner powder solidsMatter 7.5g, productive rate 73%.
In embodiment mono-, process 3) SiPcCl2Change 0.4g into, G1-F-CN-OH changes 0.8g into; Temperature change into 150 DEG C otherReaction condition is identical, blue-green solid 0.33g, productive rate 70.0%.
In embodiment mono-, process 4) nitrobenzyl bromine is changed into 3.8g, 2,2-bis-(4-hydroxyphenyl) HFC-236fa changes into6.0g, acetone changes 60mL into, and the reaction time changes 3h into, and other reaction condition is identical, obtains white toner powder solidsMatter 5.5g, productive rate 47%.
In embodiment mono-, process 5) SiPcCl2Change 0.5g into, G1-F-CN-OH changes 1.0g into; Temperature changes 150 DEG C into, otherReaction condition is identical, blue-green solid 0.30g, productive rate 65.0%.
In embodiment mono-, process 6) ester group benzyl bromine is changed into 4.2g, 2,2-bis-(4-hydroxyphenyl) HFC-236fa changes into6.1g, acetone changes 60mL into, and the reaction time changes 3h into, and other reaction condition is identical, obtains white toner powder solidsMatter 4.7g, productive rate 39%.
In embodiment mono-, process 7) SiPcCl2Change 0.65g into, G1-F-CN-OH changes 0.9g into; Temperature changes 150 DEG C into, itsIts reaction condition is identical, blue-green solid 0.32g, productive rate 50.0%.
Embodiment tri-:
In embodiment mono-, process 2) cyano group benzyl bromine is changed into 3.2g, 2,2-bis-(4-hydroxyphenyl) HFC-236fa changes into6.3g, acetone changes 30mL into, and the reaction time changes 3h into, and other reaction condition is identical, obtains white toner powder solidsMatter 4.7g, productive rate 46.0%.
In embodiment mono-, process 3) SiPcCl2Change 0.3g into, G1-F-CN-OH changes 0.6g into; Temperature changes 140 DEG C into, otherReaction condition is identical, blue-green solid 0.24g, productive rate 60.0%.
In embodiment mono-, process 4) nitrobenzyl bromine is changed into 3.6g, 2,2-bis-(4-hydroxyphenyl) HFC-236fa changes into5.8g, acetone changes 50mL into, and the reaction time changes 4h into, and other reaction condition is identical, obtains white look powdered solid substance5.0g, productive rate 46.0%.
In embodiment mono-, process 5) SiPcCl2Change 0.4g into, G1-F-CN-OH changes 0.7g into; Temperature changes 150 DEG C into, otherReaction condition is identical, blue-green solid 0.26g, productive rate 60.0%.
In embodiment mono-, process 6) ester group benzyl bromine is changed into 3.0g, 2,2-bis-(4-hydroxyphenyl) HFC-236fa changes into2.5g, acetone changes 60mL into, and the reaction time changes 3h into, and other reaction condition is identical, obtains white toner powder solidsMatter 3.1g, productive rate 27.0%.
In embodiment mono-, process 7) SiPcCl2Change 0.25g into, G1-F-CN-OH changes 0.30g into; Temperature changes 150 DEG C into, itsIts reaction condition is identical, blue-green solid 0.10g, productive rate 20.0%.
Embodiment tetra-:
The picked-up of 251 neuroglial cytomas to fluorinated aryl benzyl oxide dendritic phthalocyanine silicon complex
Prepare the fluorinated aryl benzyl oxide dendritic phthalocyanine silicon complex solution that 1 μ M the above embodiment of the present invention makes with PBS,Ultra-violet and visible spectrophotometer scanning fluorinated aryl benzyl oxide dendritic phthalocyanine silicon complex absorption peak, and do according to this peak valueConcentration standard curve. With the U251 cell that reaches the third generation, put 6 orifice plates and cultivate, every hole 1.5ml is containing 1.5 × 105Individual cell, trainingAfter foster 24h, adding fluoro to make every hole final concentration for aryl benzyl oxide dendritic phthalocyanine silicon complex is 10uM, is placed in 37 DEG C, 5%The CO of CO2, saturated humidity2In incubator, lucifuge is hatched. After 1h, 2h, 4h, 6h, 8h, 10h, 12h, collect respectively oneGroup cell (every group arranges 3 parallel holes). Cell that above-mentioned different time is collected is respectively with after PBS solution washing 2 times,Add cell pyrolysis liquid (2.0%TritionX-100) 1ml, blow and beat and mix with aseptic straw, under light microscope, detect notSee intact cell. Product of cell lysis, in 4 DEG C, is got to supernatant after centrifugal 30min under 12000rpm condition, and use ultraviolet canSee that spectrophotometer detects the content of fluorinated aryl benzyl oxide dendritic phthalocyanine silicon complex in U251 cell. Draw fluorinated aryl benzylEther dendritic phthalocyanine silicon complex acts on the best incubation time of U251 cell.
The amount of the different incubation time U251 of table 1 cellular uptake fluorinated aryl benzyl oxide dendritic phthalocyanine silicon complex
As can be seen from Table 1, with respect to the free-floride with identical dendritic structure for branch phthalocyanine two-(2-(4-phenoxy group)-2'-(4-(4-cyano group-benzyloxy) propane) axially replaces silicon (IV) phthalocyanine complex (being called for short SiPc-CN) and two-(2-(4-benzeneOxygen base)-2'-(4-(4-nitro-benzyloxy) propane) axially replace silicon (IV) phthalocyanine complex (be called for short SiPc-NO2), fluoroAryl benzyl oxide dendritic phthalocyanine silicon complex intake has increased greatly, and picked-up time advance, show fluoro branch knotStructure has obviously changed the pharmacokinetics of medicine.
(2) light power effect is evaluated
The photodynamic activity evaluation of fluorinated aryl benzyl oxide dendritic phthalocyanine silicon complex to U251 human glioma cell
Inoculate 96 orifice plates, every hole 100 μ L are containing 5 × 103Individual cell. Cultivate after 24h, in nutrient solution (DMSO), add fluoroAryl benzyl oxide dendritic phthalocyanine silicon complex. Without laser emission, medicine lucifuge effect 24h. Not add fluorinated aryl benzyl oxide treeDendritic silicon phthalocyanine compound, the negative contrast of cell that only adds blank solvent (physiological saline) and cultivate without laser emission. CCK-8Method is measured cell survival rate.
The CCK-8 method testing result (n=9) of 48 hours U251 cells after table 2PDT
Between two groups of groups, compare difference and have conspicuousness, p < 0.01.
As can be seen from Table 2, fluorinated aryl benzyl oxide dendritic phthalocyanine silicon complex has bright to U251 human glioma cellAobvious inhibitory action. With respect to the free-floride of identical dendritic structure for branch phthalocyanine two-(2-(4-phenoxy group)-2'-(4-(4-cyano group-Benzyloxy) propane) axially replace silicon (IV) phthalocyanine complex (be called for short SiPc-CN) and two-(2-(4-phenoxy group)-2'-(4-(4-Nitro-benzyloxy) propane) axially replace silicon (IV) phthalocyanine complex (be called for short SiPc-NO2), fluorinated aryl benzyl oxide dendroid phthaleinThe inhibiting rate of cyanines silicon complex increases.
Although embodiment of the present invention are open as above, it is not restricted in description and embodiment listedUse, it can be applied to various applicable the field of the invention completely, for those skilled in the art, and can be easilyRealize other amendment, therefore do not deviating under the universal that claim and equivalency range limit, the present invention does not limitIn specific details with illustrate here and the legend of describing.
Claims (10)
1. a fluorinated aryl benzyl oxide dendritic phthalocyanine silicon complex, is characterized in that: the compound for following chemical constitution:
In formula: R is cyano group, nitro, benzophenone or carbomethoxy.
2. a preparation method for fluorinated aryl benzyl oxide silicon phthalocyanine compound, comprises the steps: that (1) is to cyano group benzyl bromine and hexafluoroBisphenol-A is synthetic 2-(4-hydroxy benzenes in potash and acetone soln)-2'-(4-(4-cyano group-benzyloxy)) HFC-236fa; (2)2-(4-hydroxy benzenes)-2'-(4-(4-cyano group-benzyloxy)) HFC-236fa and phthalocyanine silicon dichloride be at K2CO3Under existence, molten at tolueneIn liquid, reflux and prepare two-(2-(4-phenoxy group)-2'-(4-(4-cyano group-benzyloxy)) HFC-236fa) axially replace silicon(IV) phthalocyanine complex.
3. a preparation method for fluorinated aryl benzyl oxide silicon phthalocyanine compound, comprises the steps: that (1) is to nitrobenzyl bromine and hexafluoroBisphenol-A is synthetic 2-(4-hydroxy benzenes in potash and acetone soln)-2'-(4-(4-nitro-benzyloxy)) HFC-236fa; (2)2-(4-hydroxy benzenes)-2'-(4-(4-nitro-benzyloxy)) HFC-236fa and phthalocyanine silicon dichloride be at K2CO3Under existence, molten at tolueneIn liquid, reflux and prepare two-(2-(4-phenoxy group)-2'-(4-(4-nitro-benzyloxy)) HFC-236fa) axially replace silicon(IV) phthalocyanine complex.
4. a preparation method for fluorinated aryl benzyl oxide silicon phthalocyanine compound, comprise the steps: (1) to benzophenone benzyl bromine withHexafluoro bisphenol-a is synthetic 2-(4-hydroxy benzenes in potash and acetone soln)-2'-(4-(4-benzophenone-benzyloxy)) hexafluoroPropane; (2) 2-(4-hydroxy benzenes)-2'-(4-(4-benzophenone-benzyloxy)) HFC-236fa and phthalocyanine silicon dichloride be at K2CO3ExistUnder, in toluene solution, reflux and prepare two-(2-(4-phenoxy group)-2'-(4-(4-benzophenone-benzyloxy)) hexafluoro thirdAlkane) axially replace silicon (IV) phthalocyanine complex.
5. a preparation method for fluorinated aryl benzyl oxide silicon phthalocyanine compound, comprises the steps: that (1) is to carbomethoxy benzyl bromine and sixFluorine bisphenol-A is synthetic 2-(4-hydroxy benzenes in potash and acetone soln)-2'-(4-(4-carbomethoxy benzyloxy)) HFC-236fa;(2) 2-(4-hydroxy benzenes)-2'-(4-(4-carbomethoxy-benzyloxy)) HFC-236fa and phthalocyanine silicon dichloride be at K2CO3Under existence, in firstIn benzole soln, reflux and prepare two-(2-(4-phenoxy group)-2'-(4-(4-carbomethoxy-benzyloxy)) HFC-236fa) axially getFor silicon (IV) phthalocyanine complex.
6. the preparation method of fluorinated aryl benzyl oxide silicon phthalocyanine compound according to claim 2, is characterized in that: described2-(4-hydroxy benzenes)-2'-(4-(4-cyano group-benzyloxy)) HFC-236fa adopts cyano group benzyl bromine, Anhydrous potassium carbonate, 2,2-bis-(4-hydroxyphenyl) HFC-236fa and acetone, vigorous stirring back flow reaction at 45-65 DEG C of temperature, filters, and collects filtrate, and decompression is steamedDesolventizing, obtains white thick product, and thick product is taking carrene as eluant, eluent, and silica gel column chromatography separating-purifying 3 times, obtains after being dried; Two described-(2-(4-phenoxy group)-2'-(4-(4-cyano group-benzyloxy)) HFC-236fa) axially replace silicon (IV) phthalocyanine and joinCompound adopts SiPcCl2, 2-(4-hydroxy benzenes)-2'-(4-(4-cyano group-benzyloxy)) HFC-236fa and Anhydrous potassium carbonate and heavily steamToluene, at 110-130 DEG C of temperature, stirring and refluxing is reacted to obtain mixture, and mixture is cooled to room temperature, and mixture is poured into water, waterToluene extraction for layer, merges organic phase, and pressure reducing and steaming solvent, obtains the thick product of blue-green, and thick product is taking carrene as wash-outAgent, silica gel column chromatography separating-purifying, obtains after vacuum drying.
7. the preparation method of fluorinated aryl benzyl oxide silicon phthalocyanine compound according to claim 3, is characterized in that: described2-(4-hydroxy benzenes)-2'-(4-(4-nitro-benzyloxy)) HFC-236fa adopts nitrobenzyl bromine, Anhydrous potassium carbonate, 2,2-bis-(4-hydroxyphenyl) HFC-236fa and acetone, vigorous stirring back flow reaction at 45-65 DEG C of temperature, filters, and collects filtrate, and decompression is steamedDesolventizing, obtains white thick product, and thick product is taking carrene as eluant, eluent, and silica gel column chromatography separating-purifying 3 times, obtains after being dried; Two described-(2-(4-phenoxy group)-2'-(4-(4-nitro-benzyloxy)) HFC-236fa) axially replace silicon (IV) phthalocyanine and joinCompound adopts SiPcCl2, 2-(4-hydroxy benzenes) and-2'-(4-(4-nitro-benzyloxy)) HFC-236fa and Anhydrous potassium carbonate and heavily steamingToluene, at 110-130 DEG C of temperature, stirring and refluxing is reacted to obtain mixture, and mixture is cooled to room temperature, mixture is poured into water,Water layer extracts with toluene, merges organic phase, and pressure reducing and steaming solvent, obtains the thick product of blue-green, thick product with carrene for washingDe-agent, silica gel column chromatography separating-purifying, obtains after vacuum drying.
8. the preparation method of fluorinated aryl benzyl oxide silicon phthalocyanine compound according to claim 4, is characterized in that: described2-(4-hydroxy benzenes)-2'-(4-(4-benzophenone-benzyloxy)) HFC-236fa adopts benzophenone benzyl bromine, Anhydrous potassium carbonate, 2,2-bis-(4-hydroxyphenyl) HFC-236fa and acetone, vigorous stirring back flow reaction at 45-65 DEG C of temperature, filters, and collects filtrate, subtractsPressure boils off solvent, obtains white thick product, and thick product is taking carrene as eluant, eluent, and silica gel column chromatography separating-purifying 3 times, after being driedObtain; Two described-(2-(4-phenoxy group)-2'-(4-(4-benzophenone-benzyloxy)) HFC-236fa) axially replace silicon(IV) phthalocyanine complex adopts SiPcCl2, 2-(4-hydroxy benzenes) and-2'-(4-(4-benzophenone-benzyloxy)) HFC-236fa and nothingAqueous carbonate potassium and heavily steam toluene, at 110-130 DEG C of temperature, stirring and refluxing is reacted to obtain mixture, and mixture is cooled to room temperature, willMixture is poured into water, and water layer extracts with toluene, merges organic phase, and pressure reducing and steaming solvent, obtains the thick product of blue-green, thick productTaking carrene as eluant, eluent, silica gel column chromatography separating-purifying, obtains after vacuum drying.
9. the preparation method of fluorinated aryl benzyl oxide silicon phthalocyanine compound according to claim 5, is characterized in that: described2-(4-hydroxy benzenes)-2'-(4-(4-carbomethoxy-benzyloxy)) HFC-236fa adopts parabromobenzoic acid methyl esters, Anhydrous potassium carbonate, 2,2-bis-(4-hydroxyphenyl) HFC-236fa and acetone, vigorous stirring back flow reaction at 45-65 DEG C of temperature, filters, and collects filtrate, subtractsPressure boils off solvent, obtains white thick product, and thick product is taking carrene as eluant, eluent, and silica gel column chromatography separating-purifying 3 times, after being driedObtain; Two described-(2-(4-phenoxy group)-2'-(4-(4-carbomethoxy-benzyloxy)) HFC-236fa) axially replace silicon (IV)Phthalocyanine complex adopts SiPcCl2, 2-(4-hydroxy benzenes) and-2'-(4-(4-carbomethoxy-benzyloxy)) HFC-236fa and Carbon DioxidePotassium and heavily steam toluene, at 110-130 DEG C of temperature, stirring and refluxing is reacted to obtain mixture, and mixture is cooled to room temperature, by mixtureBe poured into water, water layer extracts with toluene, merges organic phase, and pressure reducing and steaming solvent, obtains the thick product of blue-green, and thick product is with dichloroMethane is eluant, eluent, and silica gel column chromatography separating-purifying, obtains after vacuum drying.
10. fluorinated aryl benzyl oxide dendritic phthalocyanine silicon complex claimed in claim 1 is being prepared the sensitising agent of PDTIn application.
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