CN103772397A - Piperazine-modified phthalocyanine complex and preparation method thereof - Google Patents
Piperazine-modified phthalocyanine complex and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a piperazine-modified phthalocyanine complex as well as a preparation method and an application thereof. Piperazine molecules are introduced into the macrocyclic periphery of a metal phthalocyanine so as to enhance the amphipathy, the biocompatibility and the targeting of the phthalocyanine. A piperazine group contains two N atoms, so that after the synthesized phthalocyanine complex enters a tissue, if the tissue is normal, the single excitation state of the phthalocyanine can be quenched by lone pair electrons on the N atoms of the piperazine group under a light irradiation condition. Thus, the generation of singlet oxygen is avoided. If the tumor tissue is in a weak acid state, the N atoms are protonated, so that the single excitation state of the phthalocyanine cannot be quenched. Therefore, the singlet oxygen is generated so as to kill tumor cells. Based on the theory, the selectivity of the photodynamic therapy of the phthalocyanine is improved due to the introduction of the piperazine group, so that the damage of the phthalocyanine to the normal tissue is reduced. The piperazine-modified phthalocyanine complex has a single structure and does not contain isomers, and is easy to purify and low in cost, thereby being favorable for industrial production.
Description
Technical field
The invention belongs to the organic and synthetic field of metal complex, be specifically related to piperazine modified phthalocyanine complex of a class and its preparation method and application.
Technical field
The invention belongs to the organic and synthetic field of metal complex, be specifically related to piperazine modified phthalocyanine complex of a class and its preparation method and application.
Background technology
Because phthalocyanine ratio is easier to synthesize, stability is high again, makes phthalocyanine extremely extensive in industrial application.Recently, Pcs'application is become to an emerging focus in high-tech area, comprising semiconducter device, photovoltaic spy and solar cell, zerography, rectifier, LB film, low-dimensional conductor material, gas sensor, electrocatalysis, reodorant, sterilant, photosensitizers etc. for optical dynamic therapy.The application and development of phthalocyanine is just presenting rapid growth momentum.
The diversity of phthalocyanine compound and structural can " cutting " property, for the needed phthalocyanine compound of people's appropriate design provides possibility.Functional to phthalocyanine and other functional group is connected, and to form the new function material that has complementary functions be one of important development direction of phthalocyanine compound.But, the problem such as existing Substituted metallophthalocyanine mostly exists synthetic difficulty, and side reaction is many, and separating difficulty is large.
The present invention introduces the piperazine group with alkyl or alkoxyl group at the large ring periphery of Phthalocyanine Zinc, in piperazine group, contain two N atoms, when the phthalocyanine complex of synthesized enters after tissue, if healthy tissues, under illumination condition, the singlet excited of the lone-pair electron energy cancellation phthalocyanine on piperazine group N atom, thus produce without singlet oxygen; Aobvious slightly acidic in tumor tissues, N is by protonated, thereby singlet excited that can not cancellation phthalocyanine, so just can produce singlet oxygen, kills tumour cell.Based on above theory, the introducing of piperazine group can improve the selectivity of phthalocyanine optical dynamic therapy, reduce the damage of its normal tissue.This patent has mainly been reported preparation method and the Anticancer Activity in vitro thereof of such piperazine substituted phthalocyanine title complex.
Background technology
Because phthalocyanine ratio is easier to synthesize, stability is high again, makes phthalocyanine extremely extensive in industrial application.Recently, Pcs'application is become to an emerging focus in high-tech area, comprising semiconducter device, photovoltaic spy and solar cell, zerography, rectifier, LB film, low-dimensional conductor material, gas sensor, electrocatalysis, reodorant, sterilant, photosensitizers etc. for optical dynamic therapy.The application and development of phthalocyanine is just presenting rapid growth momentum.
The diversity of phthalocyanine compound and structural can " cutting " property, for the needed phthalocyanine compound of people's appropriate design provides possibility.Functional to phthalocyanine and other functional group is connected, and to form the new function material that has complementary functions be one of important development direction of phthalocyanine compound.But, the problem such as existing Substituted metallophthalocyanine mostly exists synthetic difficulty, and side reaction is many, and separating difficulty is large.
The present invention introduces the piperazine group with alkyl or alkoxyl group at the large ring periphery of Phthalocyanine Zinc, in piperazine group, contain two N atoms, when the phthalocyanine complex of synthesized enters after tissue, if healthy tissues, under illumination condition, the singlet excited of the lone-pair electron energy cancellation phthalocyanine on piperazine group N atom, thus produce without singlet oxygen; Aobvious slightly acidic in tumor tissues, N is by protonated, thereby singlet excited that can not cancellation phthalocyanine, so just can produce singlet oxygen, kills tumour cell.Based on above theory, the introducing of piperazine group can improve the selectivity of phthalocyanine optical dynamic therapy, reduce the damage of its normal tissue.This patent has mainly been reported preparation method and the Anticancer Activity in vitro thereof of such piperazine substituted phthalocyanine title complex.
Summary of the invention
The object of the present invention is to provide piperazine modified phthalocyanine complex of a class and its preparation method and application, this complex structure is single, does not have isomer, and product is easily purified; Synthetic method is fairly simple, and side reaction is few, and productive rate is higher, and raw material is easy to get, and cost is low, is conducive to suitability for industrialized production.
For achieving the above object, the present invention adopts following technical scheme:
The object of the present invention is to provide piperazine modified phthalocyanine complex of a class and its preparation method and application, this complex structure is single, does not have isomer, and product is easily purified; Synthetic method is fairly simple, and side reaction is few, and productive rate is higher, and raw material is easy to get, and cost is low, is conducive to suitability for industrialized production.
For achieving the above object, the present invention adopts following technical scheme:
The structural formula of phthalocyanine complex I is:
, wherein R is (CH
2)
ncH
3or (CH
2cH
2o)
ncH
3, n=1-3; Its preparation method can be divided into two kinds:
The first, comprises the following steps:
With compound 1:
with compound 2:
for initiator, at K
2cO
3with under acetonitrile condition, react, cross silicagel column obtain compound 3:
; Then with 3
for initiator, at LiAlH
4with under tetrahydrofuran (THF) condition, react, cross silicagel column obtain compound 4:
; By compound 4
with 3-nitrophthalonitrile at K
2cO
3with under DMF condition, react, peroxidation aluminium post obtains compound 5:
; Then with compound 5
with Pentyl alcohol, phthalonitrile be initiator, add zinc salt, under the catalysis of 1,8-diazabicyclo [5.4.0], 11 carbon-7-alkene, react, peroxidation aluminium post obtains described piperazine modified phthalocyanine complex I:
, R is (CH
2)
ncH
3, n=1-3.
Concrete steps are:
Compound 1 and compound 2, in molar ratio for 1:1 adds in acetonitrile, after both dissolving, are added to the K of 3-6 equivalent
2cO
3, under 85 ℃ of nitrogen protections, react 8-12 h; After question response finishes, be spin-dried for acetonitrile, rear with the thick product of dichloromethane extraction, subsequently take methylene chloride-methanol as eluent, cross silicagel column separation and obtain compound 3;
By compound 3 and LiAlH
4for 1:0.6 joins in dry tetrahydrofuran, under normal temperature nitrogen protection, react 8-12 h in molar ratio; After reaction finishes, the remaining LiAlH of the cancellation that adds water
4, suction filtration, with tetrahydrofuran (THF) washing, is spin-dried for tetrahydrofuran (THF), take methylene chloride-methanol as eluent, crosses silicagel column separation and obtains compound 4;
Compound 4 and 3-nitrophthalonitrile, in molar ratio for 1-2:1 joins in DMF, after both dissolve, are added to the K of 3-6 equivalent
2cO
3, under room temperature nitrogen protection, react 8-12 h; After reaction finishes, be spin-dried for DMF, rear with the thick product of dichloromethane extraction, then take methylene chloride-methanol as eluent, cross silicagel column separation and obtain compound 5;
In reaction vessel, 1:10 adds compound 5 and phthalonitrile successively in molar ratio, then add 10-20 ml Pentyl alcohol, under nitrogen protection, be warming up to 100 ℃, after question response thing dissolves, then add the required zinc salt of target product, after being stirred to dissolving, add 1 of 0.5-1 ml, 8-diazabicylo [5.4.0] 11 carbon-7-alkene, 150 ℃ of constant temperature, back flow reaction 5-12 h, after reaction finishes, vacuum rotary steam is removed Pentyl alcohol, take methylene chloride-methanol as eluent, cross silicagel column, obtain described piperazine modified phthalocyanine complex, the volume ratio of methylene chloride-methanol is 40-10:1,
Described zinc salt is zinc acetate.
The second, comprises the following steps:
With compound H O (CH
2cH
2o)
ncH
3and compound:
for initiator, under triethylamine and methylene dichloride condition, react, cross silicagel column and obtain compound: TsO (CH
2cH
2o)
ncH
3; Then with TsO (CH
2cH
2o)
ncH
3and compound
for initiator, at K
2cO
3with under acetonitrile condition, react, cross silicagel column obtain compound
; By compound
with 3-nitrophthalonitrile at K
2cO
3with under DMF condition, react, peroxidation aluminium post obtains compound:
; Then with compound
with Pentyl alcohol, phthalonitrile be initiator, add zinc salt, under the catalysis of 1,8-diazabicyclo [5.4.0], 11 carbon-7-alkene, react, peroxidation aluminium post obtains described piperazine modified phthalocyanine complex I:
, R is (CH
2cH
2o)
ncH
3, n=1-3.
Specifically comprise:
By compound H O (CH
2cH
2o)
ncH
3and compound
for 1:1.2 adds in methylene dichloride, after both dissolving, add the triethylamine of 1.5 equivalents in molar ratio, under room temperature nitrogen protection, react 8-12 h; After question response finishes, water extracts thick product, subsequently take petroleum ether-ethyl acetate as eluent, crosses silicagel column separation and obtains compound TsO (CH
2cH
2o)
ncH
3;
By compound TsO (CH
2cH
2o)
ncH
3and compound
for 1:1 adds in acetonitrile, after both dissolving, add the K of 3-6 equivalent in molar ratio
2cO
3, under 85 ℃ of nitrogen protections, react 8-12 h; After question response finishes, be spin-dried for acetonitrile, rear with the thick product of dichloromethane extraction, subsequently take methylene chloride-methanol as eluent, cross silicagel column separation and obtain compound
;
By compound
in molar ratio for 1-2:1 joins in DMF, after both dissolve, add the K of 3-6 equivalent with 3-nitrophthalonitrile
2cO
3, under room temperature nitrogen protection, react 8-12 h; After reaction finishes, be spin-dried for DMF, rear with the thick product of dichloromethane extraction, then take methylene chloride-methanol as eluent, cross silicagel column separation and obtain compound
;
In reaction vessel, 1:10 adds compound successively in molar ratio
and phthalonitrile; then add 10-20 ml Pentyl alcohol; under nitrogen protection; be warming up to 100 ℃; after question response thing dissolves; then add the required zinc salt of target product, add 1 of 0.5-1 ml, 8-diazabicylo [5.4.0] 11 carbon-7-alkene after being stirred to dissolving; 150 ℃ of constant temperature; back flow reaction 5-12 h, after reaction finishes, vacuum rotary steam is removed Pentyl alcohol; take methylene chloride-methanol as eluent; cross silicagel column, obtain described piperazine modified phthalocyanine complex, the volume ratio of methylene chloride-methanol is 40-10:1.
Described zinc salt is zinc acetate.
The structural formula of phthalocyanine complex II is:
, wherein R is (CH
2)
ncH
3or (CH
2cH
2o)
ncH
3, n=1-3; Its preparation method comprises two kinds:
The first, specifically comprises:
With compound 1:
with compound 2:
for initiator, at K
2cO
3with under acetonitrile condition, react, cross silicagel column obtain compound 3:
; Then with 3
for initiator, at LiAlH
4with under tetrahydrofuran (THF) condition, react, cross silicagel column obtain compound 4:
; With compound 4 and 4-nitrophthalonitrile at K
2cO
3with under DMF condition, react, peroxidation aluminium post obtains compound 5:
; Then take compound 5 and Pentyl alcohol, phthalonitrile as initiator, add zinc salt, under the catalysis of 1,8-diazabicyclo [5.4.0], 11 carbon-7-alkene, react, peroxidation aluminium post obtains described piperazine modified phthalocyanine complex II:
, R is (CH
2)
ncH
3, n=1-3;
Concrete steps are:
Compound 1 and compound 2, in molar ratio for 1:1 adds in acetonitrile, after both dissolving, are added to the K of 3-6 equivalent
2cO
3, under 85 ℃ of nitrogen protections, react 8-12 h; After question response finishes, be spin-dried for acetonitrile, rear with the thick product of dichloromethane extraction, subsequently take methylene chloride-methanol as eluent, cross silicagel column separation and obtain compound 3;
By compound 3 and LiAlH
4for 1:0.6 joins in dry tetrahydrofuran, under normal temperature nitrogen protection, react 8-12 h in molar ratio; After reaction finishes, the remaining LiAlH of the cancellation that adds water
4, suction filtration, with tetrahydrofuran (THF) washing, is spin-dried for tetrahydrofuran (THF), take methylene chloride-methanol as eluent, crosses silicagel column separation and obtains compound 4;
Compound 4 and 4-nitrophthalonitrile, in molar ratio for 1-2:1 joins in DMF, after waiting both to dissolve, are added to the K of 3-6 equivalent
2cO
3, under room temperature nitrogen protection, react 8-12 h; After reaction finishes, be spin-dried for DMF, rear with the thick product of dichloromethane extraction, then take methylene chloride-methanol as eluent, cross silicagel column separation and obtain compound 5;
In reaction vessel, 1:10 adds compound 5 and phthalonitrile successively in molar ratio, then add 10-20 ml Pentyl alcohol, under nitrogen protection, be warming up to 100 ℃, after question response thing dissolves, then add the required zinc salt of target product, after being stirred to dissolving, add 1 of 0.5-1 ml, 8-diazabicylo [5.4.0] 11 carbon-7-alkene, 150 ℃ of constant temperature, back flow reaction 5-12 h, after reaction finishes, vacuum rotary steam is removed Pentyl alcohol, take methylene chloride-methanol as eluent, cross silicagel column, obtain described piperazine modified phthalocyanine complex, the volume ratio of methylene chloride-methanol is 40-10:1,
Described zinc salt is zinc acetate.
The second preparation method, comprises the following steps:
With compound: HO (CH
2cH
2o)
ncH
3and compound:
for initiator, under triethylamine and methylene dichloride condition, react, cross silicagel column and obtain compound: TsO (CH
2cH
2o)
ncH
3; Then with TsO (CH
2cH
2o)
ncH
3and compound
for initiator, at K
2cO
3with under acetonitrile condition, react, cross silicagel column obtain compound
; Then by compound
with 4-nitrophthalonitrile be initiator, at K
2cO
3with under DMF condition, react, peroxidation aluminium post obtains compound:
; Then with compound
, Pentyl alcohol and phthalonitrile be initiator, adds zinc salt, under the catalysis of 1,8-diazabicyclo [5.4.0], 11 carbon-7-alkene, reacts, peroxidation aluminium post obtains described piperazine modified phthalocyanine complex II:
, R is (CH
2cH
2o)
ncH
3, n=1-3;
Specifically comprise:
By compound H O (CH
2cH
2o)
ncH
3and compound
for 1:1.2 adds in methylene dichloride, after both dissolving, add the triethylamine of 1.5 equivalents in molar ratio, under room temperature nitrogen protection, react 8-12 h; After question response finishes, water extracts thick product, subsequently take petroleum ether-ethyl acetate as eluent, crosses silicagel column separation and obtains compound TsO (CH
2cH
2o)
ncH
3;
By compound TsO (CH
2cH
2o)
ncH
3and compound
for 1:1 adds in acetonitrile, after both dissolving, add the K of 3-6 equivalent in molar ratio
2cO
3, under 85 ℃ of nitrogen protections, react 8-12 h; After question response finishes, be spin-dried for acetonitrile, rear with the thick product of dichloromethane extraction, subsequently take methylene chloride-methanol as eluent, cross silicagel column separation and obtain compound
;
By compound
in molar ratio for 1-2:1 joins in DMF, after waiting both to dissolve, add the K of 3-6 equivalent with 4-nitrophthalonitrile
2cO
3, under room temperature nitrogen protection, react 8-12 h; After reaction finishes, be spin-dried for DMF, rear with the thick product of dichloromethane extraction, then take methylene chloride-methanol as eluent, cross silicagel column separation and obtain compound
;
In reaction vessel, 1:10 adds compound successively in molar ratio
and phthalonitrile, then add 10-20 ml Pentyl alcohol, under nitrogen protection, be warming up to 100 ℃, after question response thing dissolves, then add the required zinc salt of target product, add 1 of 0.5-1 ml, 8-diazabicylo [5.4.0] 11 carbon-7-alkene after being stirred to dissolving, 150 ℃ of constant temperature, back flow reaction 5-12 h, after reaction finishes, vacuum rotary steam is removed Pentyl alcohol, take methylene chloride-methanol as eluent, cross silicagel column, obtain described piperazine modified phthalocyanine complex, the volume ratio of methylene chloride-methanol is 40-10:1;
Described zinc salt is zinc acetate.
Piperazine modified phthalocyanine complex as above application in optical dynamic therapy as anticancer photosensitizer.
Phthalocyanine-like compound is considered to the s-generation photosensitizers of tool potentiality.But because it lacks targeting, still there is in actual applications defect.The piperazine modified phthalocyanine complex designing in the present invention is to utilize the phthalocyanine can chemical tailoring and the feature of grafting, around phthalocyanine ring, key connects piperazine group, expect to utilize piperazine N atom existence form difference under different pH environment, indirectly improve the selective killing of Phthalocyanines to tumor tissues.
Remarkable advantage of the present invention is:
(1) obviously strengthen the amphipathic of photosensitizers, and kept the high photodynamic activity of photosensitizers;
(2) target compound structure is single, does not have isomer, the easy purifying of product;
(3) synthetic method is simple, and side reaction is few, and raw material is easy to get, and cost is low, is conducive to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1: the kill and wound curve of the prepared phthalocyanine compound of embodiment to HepG2 human hepatoma cell under illumination condition.
Embodiment
The concrete preparation process of the piperazine modified phthalocyanine complex of the anticancer photosensitizer of one class optical dynamic therapy comprises:
1, as R=(CH
2)
ncH
3when (n=1-3),
Step (1): compound 1 and compound 2, in molar ratio for 1:1 adds in acetonitrile, after both dissolving, are added to the K of 3-6 times of compound 1
2cO
3, under 85 ℃ of nitrogen protections, react 8-12 h.After question response finishes, be spin-dried for acetonitrile, the rear methylene dichloride dissolution sample of using, the extraction that adds water, removes salt of wormwood, subsequently take methylene chloride-methanol as eluent, crosses silicagel column separation and obtains compound 3.Productive rate is 85-90%.
Step (2): by lithium aluminum hydride (LiAlH
4) in dry tetrahydrofuran (THF), dissolve; then add the compound 3 being dissolved in tetrahydrofuran (THF); under normal temperature nitrogen protection, react 8-12 h; after reaction finishes, the remaining lithium aluminum hydride of the cancellation that adds water, suction filtration; wash with tetrahydrofuran (THF); be spin-dried for, take methylene chloride-methanol as eluent, cross silicagel column and obtain compound 4.Productive rate is 90-95%.
Step (3): compound 4 and 3-nitrophthalonitrile (4-nitrophthalonitrile), in molar ratio for 1-2:1 joins in DMF, after waiting both to dissolve, have been added to the K of 3-6 equivalent
2cO
3, under room temperature nitrogen protection, react 8-12 h.After reaction finishes, be spin-dried for DMF, the rear methylene dichloride dissolution sample of using, the extraction that adds water, removes salt of wormwood, then take methylene chloride-methanol as eluent, crosses silicagel column separation and obtains compound 5 or 6, and productive rate is 50-60%.
Step (4): add successively compound 5 or 6 in the 100 ml two neck bottles that reflux condensation mode and gas operated device are housed, phthalonitrile and Pentyl alcohol, under nitrogen protection; be warming up to 100 ℃, question response thing then adds zinc salt after dissolving; be stirred to after dissolving; add 1 of 0.5-1 ml, 8-diazabicylo [5.4.0] 11 carbon-7-alkene, 150 ℃ of constant temperature; back flow reaction 5-12 h; after reaction finishes, vacuum rotary steam is removed Pentyl alcohol, with CH
2cl
2and CH
3the volume ratio of OH be the mixing solutions of 40-20:1 as eluent, cross silicagel column, after rotary evaporation is concentrated, obtain I
or II
, productive rate is 10-20%.
2, as R=(CH
2cH
2o)
ncH
3when (n=1-3):
Step (1): by compound H O (CH
2cH
2o)
ncH
3and compound
for 1:1.2 adds in methylene dichloride, after both dissolving, add the triethylamine of 1.5 equivalents in molar ratio, under room temperature nitrogen protection, react 8-12 h.After question response finishes, water extracts thick product, and collected organic layer, subsequently take petroleum ether-ethyl acetate as eluent, is crossed silicagel column separation and obtained compound TsO (CH
2cH
2o)
ncH
3.Productive rate is 85-90%.
Step (2): by compound TsO (CH
2cH
2o)
ncH
3and compound
for 1:1 adds in acetonitrile, after both dissolving, add the K of 3-6 equivalent in molar ratio
2cO
3, under 85 ℃ of nitrogen protections, react 8-12 h.After question response finishes, be spin-dried for acetonitrile, rear with the thick product of dichloromethane extraction, subsequently take methylene chloride-methanol as eluent, cross silicagel column separation and obtain compound
.Productive rate is 80-85%.
Step (3): by compound
in molar ratio for 1-2:1 joins in DMF, after waiting both to dissolve, add the K of 3-6 equivalent with 3-nitrophthalonitrile (4-nitrophthalonitrile)
2cO
3, under room temperature nitrogen protection, react 8-12 h.After reaction finishes, be spin-dried for DMF, the rear methylene dichloride dissolution sample of using, the extraction that adds water, removes salt of wormwood, then take methylene chloride-methanol as eluent, crosses silicagel column separation and obtains compound 5 or 6, and productive rate is 50-60%.
Step (4): add successively compound in the 100 ml two neck bottles that reflux condensation mode and gas operated device are housed
or
, phthalonitrile and Pentyl alcohol, under nitrogen protection; be warming up to 100 ℃, question response thing then adds zinc salt after dissolving; be stirred to after dissolving; add 1 of 0.5-1 ml, 8-diazabicylo [5.4.0] 11 carbon-7-alkene, 150 ℃ of constant temperature; back flow reaction 5-12 h; after reaction finishes, vacuum rotary steam is removed Pentyl alcohol, with CH
2cl
2and CH
3the volume ratio of OH be the mixing solutions of 40-20:1 as eluent, cross silicagel column, after rotary evaporation is concentrated, obtain I
Or II
, productive rate is 10-20%.
The present invention has tested the in vitro light power antitumour activity of described compound to liver cancer cell HepG2, and experimental result shows that this compounds has represented very high lethal effect to HepG2 cell.
Following embodiment further sets forth the present invention, but the present invention is not limited only to this.
Embodiment 1(I a, R=C
2h
5)
1) compound 1 (3.45 g, 0.03 mol) and compound 2 (5.04 g, 0.03 mol) are added in 30ml acetonitrile, after both dissolve, add K
2cO
3(20.70 g, 0.15 mol) reacts 12 h under 85 ℃ of nitrogen protections; After question response finishes, be spin-dried for acetonitrile, add 100 ml water, the 500 ml extractions of use methylene dichloride, collected organic layer, is spin-dried for, and subsequently take methylene dichloride: methyl alcohol=30:1 is eluent, the separation of mistake glue post obtains compound 3, and (5.41 g), and productive rate is 90%.
1H?NMR?(400?MHz，CDCl
3)：δ?1.00-1.10?(m，3?H，CH
3)，1.20-1.30?(m，3?H，CH
3)，2.38-2.46?(m，2?H，CH
2)，2.46-2.66?(br?s，8?H，CH
2)，3.18-3.22?(m，2?H，CH
2)，?4.12-4.20?(m，2?H，CH
2)。HRMS (ESI): m/z C
10h
21n
2o
2[M+H]
+, calculated value 201.1598; Measured value 201.1604.
2) by lithium aluminum hydride (LiAlH
4) (0.21 g; 0.006 mol) add in the round-bottomed flask that 20 ml dry tetrahydrofuran are housed, after dropwise add the tetrahydrofuran solution of compound 3 (2.00 g, 0.01 mol); under normal temperature nitrogen protection, react 12 h; after reaction finishes, the remaining lithium aluminum hydride of the cancellation that adds water, suction filtration; wash with tetrahydrofuran (THF); be spin-dried for, take methylene dichloride: methyl alcohol=20:1 as eluent, mistake silicagel column obtains compound 4, and (1.50 g).Productive rate is 95%.
1H?NMR?(400MHz，CDCl
3)：δ?1.09?(t，
J?=?7.2?Hz，3?H，CH
3)，2.42?(q，
J?=?7.2?Hz，2?H，CH
2)，?2.47-2.66?(m，10?H，CH
2)，2.77-2.98?(br?s，1?H，OH)，3.62?(t，
J?=?5.6?Hz，2?H，CH
2)。HRMS (ESI): m/z C
8h
19n
2o[M+H]
+, calculated value 159.1492; Measured value 159.1497.
3) compound 4 (1.00 g, 0.006 mol) and 3-nitrophthalonitrile (1.60 g, 0.009 mol) are joined in 10 ml DMFs, after waiting both to dissolve, add K
2cO
3(4.36 g, 0.03 mol) reacts 12 h under room temperature nitrogen protection.After reaction finishes, be spin-dried for DMF, add 100 ml water, with methylene dichloride, 300 ml extract thick product, and then take methylene dichloride: methyl alcohol=20:1 as eluent, the separation of peroxidation aluminium post obtains compound 5a, and (1.02 g).Productive rate is 60%.
1H?NMR?(400MHz，CDCl
3)：δ?1.09?(t，
J?=?7.2?Hz，3?H，CH
3)，2.41?(q，
J?=?7.4?Hz，2?H，CH
2)，2.46-2.58?(br?s，4?H，CH
2)，2.62-2.74?(br?s，2?H，CH
2)，2.92?(t，
J?=?5.6?Hz，2?H，CH
2)，4.27?(t，
J?=?5.6?Hz，2?H，CH
2)，7.24?(d，
J?=?8.4?Hz，1?H，ArH)，?7.35?(d，
J?=?7.6?Hz，1?H，ArH)，7.63?(t，
J?=?8.2?Hz，1?H，ArH)。HRMS (ESI): m/z C
16h
21n
4o [M+H]
+, calculated value 285.171; Measured value 285.1725.
4) in the 100 ml two neck round-bottomed flasks that reflux condensation mode and gas operated device are housed, add successively compound 5a (0.25 g; 0.88 mmol) and phthalonitrile (1.01 g; 7.92 mmol) and 10 ml Pentyl alcohols; under nitrogen protection; be warming up to 100 ℃; after question response thing dissolves; then add zinc acetate (0.98 g, 4.46 mmol), add 1 of 0.5 ml after being stirred to dissolving; 8-diazabicylo [5.4.0] 11 carbon-7-alkene; 150 ℃ of constant temperature, back flow reaction 5 h, after reaction finishes; vacuum rotary steam is removed Pentyl alcohol, with CH
2cl
2and CH
3the volume ratio of OH be the mixing solutions of 10:1 as eluent, peroxidation aluminium post, after rotary evaporation is concentrated, obtains I a
, R is C
2h
5(0.09 g).Productive rate is 14%.
1H?NMR?(400?MHz，DMSO-d
6)：
δ0.96?(t，
J?=?7.2?Hz，3?H，CH
3)，2.29?(q，
J?=?7.2?Hz，2?H，CH
2)，2.53-2.60?(br?s，2?H，CH
2)，2.63-2.85?(br?s，6?H，CH
2)，3.00?(t，
J?=?5.4?Hz，2?H，CH
2)，4.58?(t，
J?=?5.4?Hz，2?H，CH
2)，7.60?(d，
J?=?8.0?Hz，1?H，Pc-H
β)，7.99?(t，
J?=?7.8?Hz，1?H，Pc-H
β)，8.09-8.25(m，6?H，Pc-H
β)，8.78(d，
J?=?6.8?Hz，1?H，Pc-H
α)，9.12-9.35(m，6?H，Pc-H
α)。HRMS (ESI): m/z C
40h
33n
10oZn [M+H]
+, calculated value 733.2125; Measured value 733.2168.
Embodiment 2(II a, R=C
2h
5)
1) compound 1 (3.45 g, 0.03 mol) and compound 2 (5.04 g, 0.03 mol) are added in 30 ml acetonitriles, after both dissolve, add K
2cO
3(20.70 g, 0.15 mol) reacts 12 h under 85 ℃ of nitrogen protections; After question response finishes, be spin-dried for acetonitrile, add 100 ml water, the 500 ml extractions of use methylene dichloride, collected organic layer, is spin-dried for, and subsequently take methylene dichloride: methyl alcohol=30:1 is eluent, the separation of mistake glue post obtains compound 3, and (5.41 g), and productive rate is 90%.
1H?NMR?(400?MHz，CDCl
3)：δ?1.00-1.10?(m，3?H，CH
3)，1.20-1.30?(m，3?H，CH
3)，2.38-2.46?(m，2?H，CH
2)，2.46-2.66?(br?s，8?H，CH
2)，3.18-3.22?(m，2?H，CH
2)，?4.12-4.20?(m，2?H，CH
2)。HRMS (ESI): m/z C
10h
21n
2o
2[M+H]
+, calculated value 201.1598; Measured value 201.1604.
2) by lithium aluminum hydride (LiAlH
4) (0.21 g; 0.006 mol) add in the round-bottomed flask that 20 ml dry tetrahydrofuran are housed, after dropwise add the tetrahydrofuran solution of compound 3 (2.00 g, 0.01 mol); under normal temperature nitrogen protection, react 12 h; after reaction finishes, the remaining lithium aluminum hydride of the cancellation that adds water, suction filtration; wash with tetrahydrofuran (THF); be spin-dried for, take methylene dichloride: methyl alcohol=20:1 as eluent, mistake silicagel column obtains compound 4, and (1.50 g).Productive rate is 95%.
1H?NMR?(400MHz，CDCl
3)：δ?1.09?(t，
J?=?7.2?Hz，3?H，CH
3)，2.42?(q，
J?=?7.2?Hz，2?H，CH
2)，?2.47-2.66?(m，10?H，CH
2)，2.77-2.98?(br?s，1?H，OH)，3.62?(t，
J?=?5.6?Hz，2?H，CH
2)。HRMS (ESI): m/z C
8h
19n
2o[M+H]
+, calculated value 159.1492; Measured value 159.1497.
3) compound 4 (1.00 g, 0.006 mol) and 4-nitrophthalonitrile (1.60 g, 0.009 mol) are joined in 10 ml DMFs, after waiting both to dissolve, add K
2cO
3(4.36 g, 0.03 mol) reacts 12 h under room temperature nitrogen protection.After reaction finishes, be spin-dried for DMF, add 100 ml water, with methylene dichloride, 300 ml extract thick product, and then take methylene dichloride: methyl alcohol=20:1 as eluent, the separation of peroxidation aluminium post obtains compound 6a, and (1.02 g).Productive rate is 60%.
1H?NMR?(400MHz，CDCl
3)：δ?1.10?(t，
J?=?7.2?Hz，3?H，CH
3)，2.44?(q，
J?=?7.2?Hz，2?H，CH
2)，2.48-2.57?(br?s，4?H，CH
2)，2.57-2.70?(br?s，4H，CH
2)，2.86?(t，?
J?=?5.8?Hz，2?H，CH
2)，4.18?(t，
J?=?5.6?Hz，2?H，CH
2)，7.20?(dd，
J?=?6.4，2.4Hz，1?H，ArH)，7.29?(d，
J?=?2.4Hz，1?H，ArH)，7.71?(d，
J?=?8.8?Hz，1?H，ArH)。HRMS (ESI): m/z C
16h
21n
4o [M+H]
+, calculated value 285.171; Measured value 285.1725.
4) in the 100 ml two neck round-bottomed flasks that reflux condensation mode and gas operated device are housed, add successively compound 6a (0.25 g; 0.88 mmol) and phthalonitrile (1.01 g; 7.92 mmol) and 10 ml Pentyl alcohols; under nitrogen protection; be warming up to 100 ℃; after question response thing dissolves; then add zinc acetate (0.98 g, 4.46 mmol), add 1 of 0.5 ml after being stirred to dissolving; 8-diazabicylo [5.4.0] 11 carbon-7-alkene; 150 ℃ of constant temperature, back flow reaction 5 h, after reaction finishes; vacuum rotary steam is removed Pentyl alcohol, with CH
2cl
2and CH
3the volume ratio of OH be the mixing solutions of 10:1 as eluent, peroxidation aluminium post, after rotary evaporation is concentrated, obtains II a
, R is C
2h
5(0.08 g).Productive rate is 12%.
1H?NMR?(400?MHz，DMSO-d
6)：
δ1.05?(t，
J?=?7.2?Hz，3?H，CH
3)，2.39?(q，
J?=?7.2?Hz，2?H，CH
2)，2.53-2.60?(br?s，2?H，CH
2)，2.63-2.85?(br?s，6?H，CH
2)，3.00?(t，
J?=?5.4?Hz，2?H，CH
2)，4.58?(t，
J?=?5.4?Hz，?2?H，CH
2)，7.56?(d，
J?=?8.0?Hz，1?H，Pc-H
β)，8.10-8.23?(m，6?H，Pc-H
β)，8.49?(s，1?H，Pc-H
β)，8.88?(d，
J?=?8.4?Hz，1?H，Pc-H
α)，9.14-9.30?(m，6?H，Pc-H
α)。HRMS (ESI): m/z C
40h
33n
10oZn [M+H]
+, calculated value 733.2125; Measured value 733.2168.
Embodiment 3(I f, R=(CH
2cH
2o)
3cH
3)
1) by compound H O (CH
2cH
2o)
3cH
3(16.41 g, 0.1 mol) and compound
(22.80 g, 0.12 mol) adds in methylene dichloride, after both dissolving, adds triethylamine (15.18 g, 0.15 mol), reacts 12 h under room temperature nitrogen protection; After question response finishes, water extracts thick product, and collected organic layer, subsequently take petroleum ether-ethyl acetate as eluent, is crossed silicagel column separation and obtained compound TsO (CH
2cH
2o)
3cH
3(27.04 g).Productive rate is 85%
[1].
2) by compound TsO (CH
2cH
2o)
3cH
3(3.19 g, 0.01 mol) and compound
(1.31 g, 0.01 mol), in molar ratio for 1:1 adds in 20 ml acetonitriles, after both dissolving, adds K
2cO
3(6.90 g, 0.05 mol) reacts 8-12 h under 85 ℃ of nitrogen protections; After question response finishes, be spin-dried for acetonitrile, add 100 ml water, with methylene dichloride, 500 ml extract thick product, and collected organic layer is spin-dried for, and subsequently take methylene dichloride: methyl alcohol=20:1 is eluent, the separation of mistake silicagel column obtains compound 4, and (2.26 g).Productive rate is 82%.
1H?NMR?(400MHz，CDCl
3)：δ?2.51-2.64?(m，12?H，CH
2)，3.38?(s，3?H，CH
3)，3.53-3.58?(m，2?H，CH
2)，3.59-3.68(m，10?H，CH
2)。HRMS (ESI): m/z C
13h
29n
2o
4[M+H]
+, calculated value 277.2049; Measured value 277.2067.
3) compound 4 (1.40 g, 0.005 mol) and 3-nitrophthalonitrile (1.05 g, 0.006 mol) are joined in DMF, after waiting both to dissolve, add K
2cO
3(3.50 g, 0.025 mol) reacts 12 h under room temperature nitrogen protection.After reaction finishes, be spin-dried for DMF, add 10 ml water, with methylene dichloride, 300 ml extract thick product, and then take methylene dichloride: methyl alcohol=20:1 as eluent, the separation of peroxidation aluminium post obtains compound 5f, and (1.21 g).Productive rate is 60%.
1H?NMR?(400MHz，CDCl
3)：δ?2.48-2.63?(m，6?H，CH
2)，2.63-2.72?(br?s，4?H，CH
2)，2.91?(t，
J?=?5.6?Hz，2?H，CH
2)，3.38?(s，3?H，CH
3)，3.50-3.58?(m，2?H，?CH
2)，3.58-3.68?(m，8?H，CH
2)，4.26?(t，
J?=?5.6?Hz，2?H，CH
2)，7.24?(d，
J?=?8.8?Hz，1?H，?ArH)，7.36?(d，
J?=?7.6Hz，1?H，?ArH)，7.63?(t，
J?=?8.2?Hz，1?H，ArH)。HRMS (ESI): m/z C
21h
31n
4o
4[M+H]
+, calculated value 403.2267; Measured value 403.2286.
4) in the 100 ml two neck round-bottomed flasks that reflux condensation mode and gas operated device are housed, add successively compound 5f (0.24 g; 0.59 mmol) and phthalonitrile (0.68 g; 5.31 mmol) and 10 ml Pentyl alcohols; under nitrogen protection; be warming up to 100 ℃; after question response thing dissolves; then add zinc acetate (0.65 g, 2.97 mmol), add 1 of 0.5 ml after being stirred to dissolving; 8-diazabicylo [5.4.0] 11 carbon-7-alkene; 150 ℃ of constant temperature, back flow reaction 5 h, after reaction finishes; vacuum rotary steam is removed Pentyl alcohol, with CH
2cl
2and CH
3the volume ratio of OH be the mixing solutions of 10:1 as eluent, peroxidation aluminium post, after rotary evaporation is concentrated, obtains I f
, R is (CH
2cH
2o)
3cH
3, (0.07 g).Productive rate is 13%.
1H?NMR?(400?MHz，CDCl
3)：
δ2.97-3.04?(br?s，4?H，CH
2)，3.09?(q，
J?=?7.2?Hz，4?H，CH
2)，3.23?(s，3?H，CH
3)，?3.34-3.38?(m，2?H，CH
2)，3.43-3.45?(m，2?H，CH
2)，3.45-3.48(m，2?H，CH
2)，3.49-3.53?(m，?4?H，CH
2?)，3.54-3.59?(br?s，2?H，CH
2)，3.81-3.86?(br?s，2?H，CH
2)，4.76-4.82?(br?s，2H，CH
2)，7.21?(d，
J?=?8.0Hz，1?H，Pc-H
β)，7.23?(t，
J?=?7.4Hz，1H，Pc-H
β)，8.05-8.15?(m，6?H，?Pc-H
β)，8.66?(d，
J?=?7.6?Hz，1?H，Pc-H
α)，8.95?(s，1?H，Pc-H
α)，9.17-9.23?(m，1?H，Pc-H
α)，9.24-9.34?(m，4?H，Pc-H
α)。HRMS (ESI): m/z C
45h
43n
10o
4zn [M+H]
+, calculated value 851.2682; Measured value 851.2697.
Embodiment 4(II f, R=(CH
2cH
2o)
3cH
3)
1) by compound H O (CH
2cH
2o)
3cH
3(16.41 g, 0.1 mol) and compound
(22.80 g, 0.12 mol) adds in methylene dichloride, after both dissolving, adds triethylamine (15.18 g, 0.15 mol), reacts 12 h under room temperature nitrogen protection; After question response finishes, water extracts thick product, and collected organic layer, subsequently take petroleum ether-ethyl acetate as eluent, is crossed silicagel column separation and obtained compound TsO (CH
2cH
2o)
3cH
3(27.04 g).Productive rate is 85%
[1].
2) by compound TsO (CH
2cH
2o)
3cH
3(3.19 g, 0.01 mol) and compound
(1.31 g, 0.01 mol), in molar ratio for 1:1 adds in 20 ml acetonitriles, after both dissolving, adds K
2cO
3(6.90 g, 0.05 mol) reacts 8-12 h under 85 ℃ of nitrogen protections; After question response finishes, be spin-dried for acetonitrile, add 100 ml water, with methylene dichloride, 500 ml extract thick product, and collected organic layer is spin-dried for, and subsequently take methylene dichloride: methyl alcohol=20:1 is eluent, the separation of mistake silicagel column obtains compound 4, and (2.26 g).Productive rate is 82%.
1H?NMR?(400MHz，CDCl
3)：δ?2.51-2.64?(m，12?H，CH
2)，3.38?(s，3?H，CH
3)，3.53-3.58?(m，2?H，CH
2)，3.59-3.68(m，10?H，CH
2)。HRMS (ESI): m/z C
13h
29n
2o
4[M+H]
+, calculated value 277.2049; Measured value 277.2067.
3) compound 4 (1.40 g, 0.005 mol) and 4-nitrophthalonitrile (1.05 g, 0.006 mol) are joined in DMF, after waiting both to dissolve, add K
2cO
3(3.50 g, 0.025 mol) reacts 12 h under room temperature nitrogen protection.After reaction finishes, be spin-dried for DMF, add 10 ml water, with methylene dichloride, 300 ml extract thick product, and then take methylene dichloride: methyl alcohol=20:1 as eluent, the separation of peroxidation aluminium post obtains compound 6f, and (1.21 g).Productive rate is 60%.
1H?NMR?(400MHz，CDCl
3)：δ?2.49-2.69?(m，10?H，CH
2)，2.84?(t，
J?=?5.8?Hz，2?H，CH
2)，3.38?(s，3?H，CH
3)，3.53-3.57?(m，2?H，CH
2)，3.60-3.68?(m，8?H，?CH
2)，4.17?(t，
J?=?5.6Hz，2?H，CH
2)，7.20?(dd，
J?=?6.0，2.8Hz，1?H，ArH)，7.29?(d，
J?=?2.8?Hz，?1?H，ArH)，7.71?(d，
J?=?8.8Hz，1?H，ArH)。HRMS (ESI): m/z C
21h
31n
4o
4[M+H]
+, calculated value 403.2267; Measured value 403.2286.
4) in the 100 ml two neck round-bottomed flasks that reflux condensation mode and gas operated device are housed, add successively compound 6f (0.24 g; 0.59 mmol) and phthalonitrile (0.68 g; 5.31 mmol) and 10 ml Pentyl alcohols; under nitrogen protection; be warming up to 100 ℃; after question response thing dissolves; then add zinc acetate (0.65 g, 2.97 mmol), add 1 of 0.5 ml after being stirred to dissolving; 8-diazabicylo [5.4.0] 11 carbon-7-alkene; 150 ℃ of constant temperature, back flow reaction 5 h, after reaction finishes; vacuum rotary steam is removed Pentyl alcohol, with CH
2cl
2and CH
3the volume ratio of OH be the mixing solutions of 10:1 as eluent, peroxidation aluminium post, after rotary evaporation is concentrated, obtains II f
, R is (CH
2cH
2o)
3cH
3, (0.08 g).Productive rate is 16%.
1H?NMR?(400?MHz，CDCl
3)：
δ2.94?(t，
J?=?5.0?Hz，2?H，CH
2)，3.04-3.16(m，8?H，CH
2)，3.23?(t，
J?=?5.2?Hz，2?H，?CH
2)，3.38(s，3?H，CH
3)，3.54-3.58?(m，2?H，CH
2)，3.63-3.69?(m，6?H，CH
2)，3.84?(t，
J?=?5.2?Hz，2?H，CH
2?)，4.54?(t，
J?=?5.2?Hz，2?H，CH
2)，7.30?(dd，
J?=?6.0，2.0Hz，1?H，Pc-H
β)，7.93-8.08?(m，6?H，Pc-H
β)，8.16?(d，
J?=?2.0Hz，1?H，Pc-?H
α)，8.66?(d，
J?=?8.0?Hz，1?H，Pc-H
α)，8.99?(d，?
J?=?7.2?Hz，1?H，Pc-H
α)，9.02-9.06?(m，1?H，Pc-H
α)，9.11-9.21?(m，4?H，Pc-H
α)。HRMS (ESI): m/z C
45h
43n
10o
4zn [M+H]
+, calculated value 851.2682; Measured value 851.2697.
Above-mentioned 4 products that embodiment makes of application example 1()
In vitro light power antitumour activity to ZnPcS2P2 (above-mentioned 4 products that embodiment makes) has carried out desk study, can be for providing certain reference value in body experiment from now on.Main research comprises the cell phototoxicity of the phthalocyanine in the present invention.The cell phototoxicity of photosensitizers adopts mtt assay (tetrazolium reduction method) to measure, and measuring method is as follows:
The attached cell that growth conditions is good, RPMI 1640 substratum (containing 10% calf serum) preparation 4 × 10 is used in trysinization after going down to posterity
4cells/ml cell suspension, approximately contains 8000 tumour cells by every hole 180 μ l() be inoculated in 96 well culture plates, put 37 ℃, 5% CO
2in incubator, cultivate adherent spending the night, adherent rear dosing; Blank group is established in experiment, and (blank refers to control group except not adding phthalocyanine, other conditions are consistent with given the test agent group), (solvent control refers to that control group does not add cell to solvent control group, other conditions are consistent with given the test agent group) and given the test agent group, phthalocyanine is formulated as DMSO(in advance containing 5% Viscotrol C) storing solution, after all liquid preparations, all through organic membrane filter, (0.22 μ m), when use, phthalocyanine dilute with water is different concns, and in final concentration, the content of DMSO is 1%.Every concentration is set 6 parallel holes, and every hole adds the medicine of 20 μ l different concns to be placed in incubator to hatch.After 24 hours, remove the substratum containing liquid, change 100 μ l fresh cultures, then with laser apparatus, cell is irradiated, 670 nm wavelength lasers, irradiation energy density is 1.5 J/cm
2.Illumination is complete, 96 orifice plates is refitted in to 37 ℃, 5% CO
2incubator in, continue cultivate.After 24 h, every hole adds PBS solution (4 mg/ml) the 10 μ l of MTT, hatches 4 hours for 37 ℃, careful supernatant discarded after 4 hours, every hole adds 200 μ l DMSO to dissolve first a ceremonial jade-ladle, used in libation particles, after slight concussion is dissolved first a ceremonial jade-ladle, used in libation completely, measures OD value under 570 nm wavelength by microplate reader.
Adopt mtt assay to measure phthalocyanine I a, II a, I f, II f is the situation of killing and wounding to human hepatoma cell HepG2 under illumination condition.Illumination wavelength is 670 nm, and illumination energy density is 1.5 J/cm
2.Data by three times independently parallel laboratory test obtain, with Mean ± SEM mode processing (seeing Fig. 1).I a as seen from the figure, II a, I f, under certain illumination condition, (illumination energy density is 1.5 J/cm to II f
2) kill and wound the IC of HepG2 cell
50value (half-inhibition concentration) is respectively 0.0063 μ M, 0.0085 μ M, 0.0114 μ M, 0.0029 μ M.Four kinds of phthalocyanine complexes all show very high light power antitumour activity, are expected to be developed as efficient photosensitive drug.
The foregoing is only preferred embodiment of the present invention, all equalizations of doing according to the present patent application the scope of the claims change and modify, and all should belong to covering scope of the present invention.
Reference
[1]?Shigeo?Kohmoto,?Emiko?Mori,?Keiki?Kishikawa.?Room-Temperature?Discotic?Nematic?Liquid?Crystals?over?a?Wide?Temperature?Range:?Alkali-Metal-Ion-Induced?Phase?Transition?from?Discotic?Nematic?to?Columnar?Phases.?J.?Am.?Chem.?Soc?2007;?129:?13364-13365。
Claims (7)
1. the piperazine modified phthalocyanine complex of a class, is characterized in that: described phthalocyanine complex structural formula is as follows:
(I), wherein R is (CH
2)
ncH
3or (CH
2cH
2o)
ncH
3, n=1-3.
2. the piperazine modified phthalocyanine complex of a class, is characterized in that: described phthalocyanine complex structural formula is as follows:
3. a method of preparing piperazine modified phthalocyanine complex as claimed in claim 1, is characterized in that: comprise the following steps:
With compound:
and compound:
for initiator, at K
2cO
3with under acetonitrile condition, react, cross silicagel column obtain compound:
; Then with
for initiator, at LiAlH
4with under tetrahydrofuran (THF) condition, react, cross silicagel column obtain compound:
; By compound
with 3-nitrophthalonitrile at K
2cO
3with under DMF condition, react, peroxidation aluminium post obtains compound:
; Then with compound
with Pentyl alcohol, phthalonitrile be initiator, add zinc salt, under the catalysis of 1,8-diazabicyclo [5.4.0], 11 carbon-7-alkene, react, peroxidation aluminium post obtains described piperazine modified phthalocyanine complex:
, R is (CH
2)
ncH
3, n=1-3.
4. a method of preparing piperazine modified phthalocyanine complex as claimed in claim 1, is characterized in that: comprise the following steps:
With compound H O (CH
2cH
2o)
ncH
3and compound:
for initiator, under triethylamine and methylene dichloride condition, react, cross silicagel column and obtain compound: TsO (CH
2cH
2o)
ncH
3; Then with TsO (CH
2cH
2o)
ncH
3and compound
for initiator, at K
2cO
3with under acetonitrile condition, react, cross silicagel column obtain compound
; By compound
with 3-nitrophthalonitrile at K
2cO
3with under DMF condition, react, peroxidation aluminium post obtains compound:
; Then with compound
with Pentyl alcohol, phthalonitrile be initiator, add zinc salt, under the catalysis of 1,8-diazabicyclo [5.4.0], 11 carbon-7-alkene, react, peroxidation aluminium post obtains described piperazine modified phthalocyanine complex:
, R is (CH
2cH
2o)
ncH
3, n=1-3.
5. a method of preparing piperazine modified phthalocyanine complex as claimed in claim 2, is characterized in that: comprise the following steps:
With compound:
and compound:
for initiator, at K
2cO
3with under acetonitrile condition, react, cross silicagel column obtain compound:
; Then with
for initiator, at LiAlH
4with under tetrahydrofuran (THF) condition, react, cross silicagel column obtain compound:
; With compound
with 4-nitrophthalonitrile at K
2cO
3with under DMF condition, react, peroxidation aluminium post obtains compound:
; Then with compound
with Pentyl alcohol, phthalonitrile be initiator, add zinc salt, under the catalysis of 1,8-diazabicyclo [5.4.0], 11 carbon-7-alkene, react, peroxidation aluminium post obtains described piperazine modified phthalocyanine complex:
, R is (CH
2)
ncH
3, n=1-3.
6. a method of preparing piperazine modified phthalocyanine complex as claimed in claim 2, is characterized in that: comprise the following steps:
With compound: HO (CH
2cH
2o)
ncH
3and compound:
for initiator, under triethylamine and methylene dichloride condition, react, cross silicagel column and obtain compound: TsO (CH
2cH
2o)
ncH
3; Then with TsO (CH
2cH
2o)
ncH
3and compound
for initiator, at K
2cO
3with under acetonitrile condition, react, cross silicagel column obtain compound
; Then by compound
with 4-nitrophthalonitrile be initiator, at K
2cO
3with under DMF condition, react, peroxidation aluminium post obtains compound:
; Then with compound
, Pentyl alcohol and phthalonitrile be initiator, adds zinc salt, under the catalysis of 1,8-diazabicyclo [5.4.0], 11 carbon-7-alkene, reacts, peroxidation aluminium post obtains described piperazine modified phthalocyanine complex:
, R is (CH
2cH
2o)
ncH
3, n=1-3.
7. a class piperazine modified phthalocyanine complex as claimed in claim 1 or 2 application in optical dynamic therapy as anticancer photosensitizer.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104311566A (en) * | 2014-09-22 | 2015-01-28 | 福州大学 | Preparation method and application of water soluble cationic zinc phthalocyanine photosensitizer |
| CN105418643A (en) * | 2015-12-22 | 2016-03-23 | 福州大学 | Bilateral biotin-phthalocyanine zinc conjugate as well as preparation and application thereof |
| CN111303167A (en) * | 2020-03-30 | 2020-06-19 | Tcl华星光电技术有限公司 | Color development material, optical filter and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0906758A1 (en) * | 1997-08-14 | 1999-04-07 | MOLTENI L. & C. dei Fratelli Alitti Società di Esercizio S.P.A. | Zinc-phthalocyanines and corresponding conjugates, their preparation and use in photodynamic therapy and as diagnostic agents |
| CN1249307A (en) * | 1999-08-19 | 2000-04-05 | 北京工业大学 | Metallic phthalocyanine carboxylic acid derivatives and its preparing process and application |
| CN102702210A (en) * | 2012-06-01 | 2012-10-03 | 福州大学 | Application of phthalocyanine metal complex containing piperazine ethyoxyl modified groups |
-
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- 2014-01-25 CN CN201410034749.8A patent/CN103772397B/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0906758A1 (en) * | 1997-08-14 | 1999-04-07 | MOLTENI L. & C. dei Fratelli Alitti Società di Esercizio S.P.A. | Zinc-phthalocyanines and corresponding conjugates, their preparation and use in photodynamic therapy and as diagnostic agents |
| CN1249307A (en) * | 1999-08-19 | 2000-04-05 | 北京工业大学 | Metallic phthalocyanine carboxylic acid derivatives and its preparing process and application |
| CN102702210A (en) * | 2012-06-01 | 2012-10-03 | 福州大学 | Application of phthalocyanine metal complex containing piperazine ethyoxyl modified groups |
Non-Patent Citations (1)
| Title |
|---|
| 黄金陵等: "酞菁配合物的结构与其光动力抗癌活性", 《物理化学学报》, vol. 17, no. 7, 31 July 2001 (2001-07-31), pages 662 - 671 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104311566A (en) * | 2014-09-22 | 2015-01-28 | 福州大学 | Preparation method and application of water soluble cationic zinc phthalocyanine photosensitizer |
| CN104311566B (en) * | 2014-09-22 | 2016-05-04 | 福州大学 | Preparation and the application of water-soluble cationic Phthalocyanine Zinc sensitising agent |
| CN105418643A (en) * | 2015-12-22 | 2016-03-23 | 福州大学 | Bilateral biotin-phthalocyanine zinc conjugate as well as preparation and application thereof |
| CN111303167A (en) * | 2020-03-30 | 2020-06-19 | Tcl华星光电技术有限公司 | Color development material, optical filter and preparation method thereof |
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