CN102698269A - Zinc phthalocyanine complex and preparation method thereof - Google Patents
Zinc phthalocyanine complex and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a zinc phthalocyanine complex and a preparation method thereof. The complex is (8-(7-coumarin oxygroup)-3,6-dioxoa-1-octyloxy; and the molecular formula of the zinc phthalocyanine complex is C42H32N8O6Zn. Coumarin oxygroup with a long alcoxyl chain is introduced at the periphery of the large ring of the zinc phthalocyanine, amphipathicity and biocompatibility of the zinc phthalocyanine complex are improved, and a photodynamic activity is improved. The zinc phthalocyanine complex is difficult to gather and favorable for improving cell intaking rate, and the photodynamic activity is improved; coumarin has an antitumor activity, and the coumarin is combined with photodynamic, so that the zinc phthalocyanine complex is favorable for serving as a photodynamic clinical medicine. The structure of a compound of the zinc phthalocyanine complex is single, and the compound is free from isomers, so that a product is easy to extract; and a synthetic method is simple, the side reaction is small, the yield is high, raw materials are readily available, cost is low, and industrial production is facilitated.
Description
Technical field
The invention belongs to organic and the synthetic field of metal complex, particularly is a kind of phthalocyanine Zn complex and preparation method thereof.
Background technology
Phthalocyanine is one type of macrocyclic compound with good light physics spectrochemical property; Be applied to high-tech area; With photosensitizer etc., wherein has development prospect comprising semiconductor device, photovoltaic spy and solaode, electrostatic reprography, commutator, LB film, low dimension conductor material, gas sensor, electro-catalysis, deodorizer, antibacterial, optical dynamic therapy as photosensitizer.
The multiformity of phthalocyanine compound and structural can " cutting " property, for the needed phthalocyanine compound of people's appropriate design provides possibility.The functional functional group of phthalocyanine and other is connected, and to form the new function material have complementary functions be one of important development direction of phthalocyanine compound.But, problem such as mostly there is synthetic difficulty in existing substituted phthalocyanine metal complex, and side reaction is many, and separating difficulty is big.
Summary of the invention
The object of the present invention is to provide a kind of phthalocyanine Zn complex and preparation method thereof, this coordination compound method for preparing is simple, and side reaction is few, is convenient to industrialization.
The present invention implements through following technical scheme:
The invention provides a kind of phthalocyanine Zn complex, said phthalocyanine Zn complex is (8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) Phthalocyanine Zinc, and its molecular formula is: C
42H
32N
8O
6Zn.
Said phthalocyanine Zn complex comprises α, two kinds of structures of β, and its chemical structural formula is following:
1) is α-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) Phthalocyanine Zinc;
2) be β-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) Phthalocyanine Zinc.
The present invention also provides the method for preparing of said phthalocyanine Zn complex, and said method for preparing comprises the steps:
1) be starting material with triethylamine, triethylene glycol and p-methyl benzene sulfonic chloride, synthetic 8-hydroxyl-3,6-dioxa octyl group p-toluenesulfonic esters;
2) then with 8-hydroxyl-3,6-dioxa octyl group p-toluenesulfonic esters and umbelliferone are starting material, synthetic 8-(7-coumarin oxygen base)-3,6-dioxa-1-capryl alcohol;
3) then with 8-(7-coumarin oxygen base)-3,6-dioxa-1-capryl alcohol with 3 or the 4-nitrophthalonitrile be starting material, correspondingly synthesize 3 or 4-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) phthalonitrile;
4) at last with 3 or 4-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) phthalonitrile, phthalonitrile and zinc salt be starting material, 1, the down synthetic phthalocyanine Zn complex that obtains of 8-diazabicyclo [5.4.0] 11 carbon-7-alkene catalysis.
The detailed process of said step 1) comprises: with triethylamine, triethylene glycol and p-methyl benzene sulfonic chloride is 1～4:1～4:1 in molar ratio; In the dichloromethane system, reacted 6～24 hours down in 0～25 ℃; Reaction boils off solvent after finishing, and with the thick product of dichloromethane extraction, is eluant subsequently with the petroleum ether-ethyl acetate; Use silica gel column chromatography to separate and obtain said 8-hydroxyl-3,6-dioxa octyl group p-toluenesulfonic esters.
Said step 2) detailed process comprises: with Anhydrous potassium carbonate, 8-hydroxyl-3; 6-dioxa octyl group p-toluenesulfonic esters and umbelliferone are 3～10:1～2:1 ~ 2 in molar ratio, in DMF, react 6～24 hours down in 25～60 ℃, and reaction boils off solvent after finishing; With the thick product of dichloromethane extraction; Be eluant subsequently with the petroleum ether-ethyl acetate, use silica gel column chromatography to separate and obtain said 8-(7-coumarin oxygen base)-3,6-dioxa-1-capryl alcohol.
The detailed process of said step 3) comprises: with Anhydrous potassium carbonate, 8-(7-coumarin oxygen base)-3; 6-dioxa-1-capryl alcohol and 3 or the 4-nitrophthalonitrile be 3～10:1～2:1 ~ 2 in molar ratio; In DMF, reacted 6～24 hours down in 25～60 ℃; Product is poured in the water, cooled off, leave standstill, precipitate; Getting solid behind the sucking filtration, with the thick product of dichloromethane extraction, is eluant with the petroleum ether-ethyl acetate subsequently, uses silica gel column chromatography to separate to obtain 3 or 4-(8-(7-coumarin oxygen base)-3,6-dioxa octyloxy) phthalonitrile.
The detailed process of said step 4) comprises: with 3 or 4-(8-(7-coumarin oxygen base)-3; 6-dioxa octyloxy) phthalonitrile, phthalonitrile and zinc salt are 1:3～9:1～5 in molar ratio, and with 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene is catalyst; In n-amyl alcohol, reacted 5～24 hours down in 120～150 ℃; Reaction boils off solvent after finishing, and is eluant with methanol-dichloromethane subsequently, uses silica gel column chromatography to separate and obtains phthalocyanine Zn complex.
The volume ratio of said step 3) PetroChina Company Limited. ether-ethyl acetate is 1 ~ 6:1.
The volume ratio of methanol-dichloromethane is 1:20～40 in the said step 4).
Phthalocyanine Zn complex of the present invention has the application in the photosensitizer drug that the preparation optical dynamic therapy is used.
The condensed ethandiol compounds has good water-solubility and good bioaffinity, and coumarin derivative has many-sided biological activitys such as antiviral, antitumor, antimicrobial, antiinflammatory.The present invention introduces the coumarin base that has the alcoxyl long-chain at Phthalocyanine Zinc macro ring periphery, has increased its biocompatibility, shows higher light power active anticancer.
Advantage of the present invention is:
(1) the target compound structure is single, does not have isomer, the easy purification of product.Polysubstituted Phthalocyanine Zinc is because there are a plurality of substituent groups, and each substituent group occupies different α positions and also generated different isomers because just there is the isomery of this locus in the molecular motion rotation, and 8 α positions are arranged on the phthalocyanine ring.And structural similarity makes these isomer character very similar, is difficult to separate.Just there is not such problem in mono-substituted zinc phthalocyanine.
(2) institute introduces triethylene glycol in the synthetic chemical compound, has increased the picked-up of phthalocyanine-like compound in cell, and coumarin itself just has active anticancer, with itself and light power link, helps the use as the clinical application of light power.
(3) synthetic method is simple, only needs several steps just can accomplish, and side reaction is few, and raw material is easy to get, and cost is low, helps suitability for industrialized production.
Description of drawings
Fig. 1 is 8-(7-coumarin oxygen base)-3, the infrared figure of 6-dioxa-1-capryl alcohol.
Fig. 2 is 8-(7-coumarin oxygen base)-3, the hydrogen nuclear magnetic resonance spectrogram of 6-dioxa-1-capryl alcohol.
Fig. 3 is the infared spectrum of 3-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) phthalonitrile.
Fig. 4 is 3-(8-(7-coumarin oxygen base)-3, a 6-dioxa-1-octyloxy) phthalonitrile proton nmr spectra.
Fig. 5 is 4-(8-(7-coumarin oxygen base)-3, a 6-dioxa-1-octyloxy) phthalonitrile infared spectrum.
Fig. 6 is 4-(8-(7-coumarin oxygen base)-3, a 6-dioxa-1-octyloxy) phthalonitrile proton nmr spectra.
Fig. 7 is α-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) Phthalocyanine Zinc infared spectrum.
Fig. 8 is α-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) Phthalocyanine Zinc proton nmr spectra.
Fig. 9 is β-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) Phthalocyanine Zinc infared spectrum.
Figure 10 is β-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) Phthalocyanine Zinc proton nmr spectra.
Figure 11 does
MC1, MC2Illumination and unglazed according under the condition to the curve that kills and wounds of HepG2 cell.
The specific embodiment
A kind of concrete preparation process of phthalocyanine complex comprises:
Step 1): with triethylamine, triethylene glycol and p-methyl benzene sulfonic chloride mol ratio is 1～4:1～4:1; In the dichloromethane system, reacted 6～24 hours down in 0～25 ℃, reaction boils off solvent after finishing, with the thick product of dichloromethane extraction; Be eluant subsequently with the petroleum ether-ethyl acetate; Use silica gel column chromatography to separate and obtain said 8-hydroxyl-3,6-dioxa octyl group p-toluenesulfonic esters, productive rate is 38%～45%.
Step 2): with Anhydrous potassium carbonate, 8-hydroxyl-3,6-dioxa octyl group p-toluenesulfonic esters and umbelliferone mol ratio are 3～10:1～2:1 ~ 2, in DMF, react 6～24 hours down in 25～60 ℃; Reaction boils off solvent after finishing; With the thick product of dichloromethane extraction, be eluant subsequently with the petroleum ether-ethyl acetate, use silica gel column chromatography to separate and obtain said 8-(7-coumarin oxygen base)-3; 6-dioxa-1-capryl alcohol, productive rate are 62%～87%.Infrared spectrogram is seen Fig. 1, and infrared data is as shown in table 1, and the hydrogen nuclear magnetic resonance spectrogram is seen Fig. 2, and the proton nmr spectra analytical data is following.
1H?NMR?(500?MHz,?CDCl
3):?
δ7.62?(d,?
J?=9.5?Hz,?1?H,?ArH),?7.35?(d,?
J?=8.5?Hz,?1?H,?ArH),?6.87?(dd,?
J?=2.0?Hz,?8.5?Hz,?1?H,?ArH),?6.82?(d,?
J?=2.0?Hz,?1?H,?ArH),?6.24?(d,?
J?=?9.5?Hz,?1?H,?ArH),?4.18?(t,?
J?=?4.5?Hz,?2?H,?CH
2),?3.88?(t,?
J?=?4.5?Hz,?2?H,?CH
2),?3.73-3.71?(m,?2?H,?CH
2),?3.70-3.68?(m,?2?H,?CH
2),?3.61(t,?
J?=?4.5?Hz,?2?H,?CH
2).2.23(S,?1?H,?OH).
Table 1 infrared data
Step 3): with Anhydrous potassium carbonate, 8-(7-coumarin oxygen base)-3; 6-dioxa-1-capryl alcohol and 3 or 4-nitrophthalonitrile mol ratio be 3～10:1～2:1 ~ 2; In DMF, reacted 6～24 hours down in 25～60 ℃, reaction boils off solvent after finishing, with the thick product of chloroform extraction; Be eluant with ethyl acetate-dichloromethane subsequently; Use silica gel column chromatography to separate to obtain described 3 or 4-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) phthalonitrile, productive rate is 46% ~ 62%.The infrared spectrum of 3-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) phthalonitrile is seen Fig. 3, and infrared data is as shown in table 2; Proton nmr spectra is seen Fig. 4, and the proton nmr spectra analytical data is following, 4-(8-(7-coumarin oxygen base)-3; 6-dioxa-1-octyloxy) infrared spectrum of phthalonitrile is seen Fig. 5; Infrared data such as table 3, shown in proton nmr spectra see Fig. 6, the proton nmr spectra analytical data is following.
3-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) phthalonitrile proton nmr spectra analytical data:
1H?NMR?(500?MHz,?CDCl
3):?
δ7.66?(d,?
J?=9.0?Hz,?1?H,?ArH),?7.63?(d,?
J?=9.5?Hz,?1?H,?ArH),?7.39?(d,?
J?=?9.0?Hz,?1?H,?ArH),?7.36?(d,?
J?=9.0?Hz,?1?H,?ArH),?7.32?(d,?
J?=8.5Hz,?1?H,?ArH),?6.89?(dd,
?J?=2.0?Hz,?8.5?Hz,?1?H,?ArH),?6.84?(d,?
J?=?2.0?Hz,?1?H,?ArH),?6.26?(d,?
J?=?9.5?Hz,?1?H,?ArH),?4.29?(t,?
J?=?4.5?Hz,?2?H,?CH
2),?4.18?(t,?
J?=?4.5?Hz,?2?H,?CH
2),?3.94(t,?
J?=?4.5?Hz,?2?H,?CH
2),?3.89(t,?
J?=?4.5?Hz,?2?H,?CH
2),?3.79-3.77(m,?2?H,?CH
2),?3.75-3.73(m,?2?H,?CH
2).
4-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) phthalonitrile proton nmr spectra analytical data:
1H?NMR?(500?MHz,?CDCl
3):?
δ7.70?(d,?
J?=8.5?Hz,?1?H,?ArH),?7.66?(d,?
J?=9.5?Hz,?1?H,?ArH),?7.40?(d,?
J?=?8.5?Hz,?1?H,?ArH),?7.31?(d,?
J?=2.5?Hz,?1?H,?ArH),?7.23?(dd,?
J?=2.5Hz,?9.0?Hz,?1?H,?ArH),?6.88-6.86?(m,?2?H,?ArH),?6.28?(d,?
J?=?9.5?Hz,?1?H,?ArH),?4.25?(vt,?
J?=?4.5?Hz,?2?H,?CH
2),?4.21?(vt,?
J?=?4.5?Hz,?2?H,?CH
2),?3.93-3.90(m,?4?H,?CH
2).?3.77(S,?4?H,?CH
2).
Table 2 infrared data
Table 3 infrared data
Step 4): with 3 or 4-(8-(7-coumarin oxygen base)-3; 6-dioxa octyloxy) phthalonitrile, phthalonitrile and corresponding zinc salt mol ratio are 1:3～9:1～5; 1, to react 5～24 hours down in 120～150 ℃ in 8-diazabicyclo [5.4.0] 11 carbon-7-alkene and the n-amyl alcohol, reaction boils off solvent after finishing; Be eluant with methanol-dichloromethane subsequently; Use silica gel column chromatography to separate and obtain α or β-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) Phthalocyanine Zinc, productive rate is 9.8% ~ 17%.The infrared spectrum of α-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) Phthalocyanine Zinc is seen Fig. 7, and infrared data is as shown in table 4, and proton nmr spectra is seen Fig. 8, and the proton nmr spectra analytical data is following.The infrared spectrum of β-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) Phthalocyanine Zinc is seen Fig. 9, and infrared data is as shown in table 5, and proton nmr spectra is seen Figure 10, and the proton nmr spectra analytical data is following.
α-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) Phthalocyanine Zinc proton nmr spectra analytical data is following:
1H?NMR?(500?MHz,?DMSO-d
6):?
δ9.24-9.22?(m,?3?H,?Pc-H
α),?9.18-9.15?(m,?2?H,?Pc-?H
α),?9.05?(d,
?J?=?7.0?Hz,?1?H,?Pc-?H
α),?8.69?(d,
?J?=?7.0?Hz,?1?H,?Pc-?H
α),?8.19-8.08?(m,?6?H,?Pc-H
β),?7.92?(t,
?J?=?7.5?Hz,?1?H,?Pc-H
β),?7.69?(d,?
J?=?9.5?Hz?,1?H,?ArH),?7.53?(d,?
J?=?7.5?Hz,?1?H,?Pc-H
β),?7.18?(d,?
J?=?8.5?Hz,?1?H,?ArH),?6.65?(vd,?
J?=?2.5?Hz,?1?H,?ArH),?6.52?(dd,?
J?=?2.5?Hz,?8.5?Hz?,1?H,?ArH),?6.10?(d,?
J?=?9.5?Hz,?1?H,?ArH),?4.77?(br?s,?2?H,?CH
2),?4.35(vt,?
J?=?4.5?Hz,?2?H,?CH
2),?4.07(vt,?
J?=?4.5?Hz,?2?H,?CH
2),?3.96(vt,?
J?=?4.5?Hz,?2?H,?CH
2),?3.80-3.76(m,?4?H,?CH
2).
β-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) Phthalocyanine Zinc proton nmr spectra analytical data is following:
1H?NMR?(500?MHz,?DMSO-d
6):?
δ9.21-9.17?(m,?3?H,?Pc-H
α),?9.12?(d,?
J?=?7.0?Hz,?1?H,?Pc-?H
α),?9.06?(d,
?J?=?7.0?Hz,?1?H,?Pc-?H
α),?9.03?(d,
?J?=?7.0?Hz,?1?H,?Pc-?H
α),?8.77?(d,?
J?=?7.0?Hz,?1?H,?Pc-?H
α),?8.35?(s,1?H,?Pc-?H
α),?8.19-8.05?(m,?6?H,?Pc-H
β),?7.79?(d,?
J?=?9.5?Hz,?1?H,?ArH),?7.52?(dd,?
J?=2.0Hz,?8.5?Hz,?1?H,?Pc-H
β),?7.44?(d,?
J?=?8.5?Hz,?1?H,?ArH),?6.93?(d,?
J?=?2.0?Hz,?1?H,?ArH),?6.87?(dd,?
J?=?2.0Hz,?8.5?Hz,?1?H,?ArH),?6.13?(d,?
J?=?9.5?Hz,?1?H,?CH
2),?4.60(br?s,?2?H,?CH
2),?4.23(vt,?
J?=?4.5?Hz,?2?H,?CH
2),?4.10?(vt,?
J?=?4.5?Hz,?2?H,?CH
2),?3.89-3.86(m,?4?H,?CH
2),?3.80(vt,?
J?=?4.5?Hz,?2?H,?CH
2).
Table 4 infrared data
Table 5 infrared data
We are to α-(8-(7-coumarin oxygen base)-3; 6-dioxa-1-octyloxy) Phthalocyanine Zinc (MC1) and β-(8-(7-coumarin oxygen base)-3; 6-dioxa-1-octyloxy) the stripped light power active anticancer of two kinds of phthalocyanine Zn complexes of Phthalocyanine Zinc (MC2) has carried out desk study; This can provide certain reference value to testing at body (mice) from now on, has great importance.Research contents mainly comprises the cytotoxicity (comprise light poison and dark poison) of phthalocyanine as photosensitizer.The cytotoxicity experiment of photosensitizer generally includes phototoxicity experiment and dark toxicity test two parts, adopts mtt assay (tetrazolium reducing process) to measure.(3-(4 for MTT; 5-dimethylthiazole-2)-2; 5-diphenyl tetrazole bromine salt) detection principle is that the succinate dehydrogenase in the living cells mitochondrion can make exogenous MTT be reduced to water-fast bluish violet crystallization first a ceremonial jade-ladle, used in libation (Formazan) and is deposited in the cell; And do not have succinate dehydrogenase in the dead cell, therefore can not produce the first a ceremonial jade-ladle, used in libation.With the first a ceremonial jade-ladle, used in libation that DMSO (dimethyl sulfoxide) dissolving living cells produces, measure its absorption value with ELIASA in the 570nm wavelength, can reflect living cells quantity indirectly.In certain cell number scope, the amount that MTT first a ceremonial jade-ladle, used in libation forms is directly proportional with viable count.
The attached cell that growth conditions is good is gone down to posterity with 0.25% trypsinization, with RPMI 1640 culture medium (containing 10% calf serum) preparation 2 * 10
4Cells/ ml cell suspension is inoculated in 96 well culture plates with every hole 180ml (containing 4000 tumor cells approximately), puts 37 ℃, 5% CO
2Cultivate adherent spending the night in the incubator, adherent back dosing; The blank group is established in experiment, and (blank is meant matched group except not adding the phthalocyanine, and other conditions are consistent with the given the test agent group.), (solvent control is meant that matched group does not add cell to solvent control group, and other conditions are consistent with the given the test agent group.) and the given the test agent group, phthalocyanine is formulated as DMSO (containing 5% Oleum Ricini) storing solution in advance, and all through membrane filtration (0.22 m), the phthalocyanine dilute with water is variable concentrations when using after all medicinal liquid preparations, and the content of DMSO is 1% in the final concentration.Every concentration is set 6 parallel holes, and every hole adds in the rearmounted incubator of medicine of 20 l variable concentrations hatches.The experiment of light poison: after 24 hours, discard the culture medium that contains medicinal liquid, change 100 l fresh cultures, shine with the laser instrument pair cell then, the 670nm wavelength laser, irradiation energy density is 1.5J .cm
-2Illumination finishes, and 96 orifice plates is refitted in 37 ℃, 5% CO
2Incubator in, continue to cultivate.Dark poison experiment is then directly put into incubator and is continued to cultivate after having changed fresh culture, illumination is avoided in operating process as far as possible, and behind the 24h, every hole adds the PBS solution (4mg.ml of MTT
-1) 10ml, hatched 4 hours for 37 ℃, careful supernatant discarded after 4 hours, every hole adds 200ml DMSO dissolving first a ceremonial jade-ladle, used in libation granule, after slight concussion is dissolved the first a ceremonial jade-ladle, used in libation fully, measures OD value under the 570nm wavelength with ELIASA.
We adopt mtt assay to measure the kill and wound curve of two kinds of phthalocyanines to the HepG2 human hepatoma cell, and are shown in figure 11.MC1, MC2 (Figure 11 is divided into two parts up and down, and top is represented unglazed according under the condition, and the illumination condition reason is represented in the lower part) illumination and unglazed according under the condition to the curve that kills and wounds of HepG2 cell.Illumination wavelength is 670 nm, and the illumination energy density is 1.5 Jcm
-2Data by three times independently parallel laboratory test obtain, handle with Mean ± SEM mode.Can know that by figure two kinds of phthalocyanines have no lethal effect unglazed according to pair cell under the condition, and they kill and wound the IC of HepG2 cell under certain illumination condition
50Value (half suppression ratio) is respectively 0.015,0.047 μ M.And only need the phthalocyanine of 0.5 μ M just almost can kill whole cancerous cell, so they all show very high light power active anticancer.Extremely low dark toxicity and these two kinds of phthalocyanines of higher phototoxicity explanation have all reached the requirement of desirable photosensitizer, are expected to be developed as photosensitive drug efficiently.
Following embodiment further sets forth the present invention, but the present invention is not limited only to this.
Embodiment 1
1) synthetic 8-hydroxyl-3; 6-dioxa octyl group p-toluenesulfonic esters: 32.00g (0.30mol) triethylamine, 24.00g (0.16mol) triethylene glycol and 7.60g (0.04mol) p-methyl benzene sulfonic chloride; In dichloromethane (70ml) system, reacted 10 hours down in 25 ℃, reaction finishes the back and successively extracts with hydrochloric acid solution 200ml, saturated aqueous common salt, the distilled water of 1M.(1:1 v/v) is eluant to thick product, uses silica gel column chromatography to separate and obtains product 5.48g (0.018mol), and productive rate is 45% with petroleum ether-ethyl acetate.
2) synthetic 8-(7-coumarin oxygen base)-3,6-dioxa-1-capryl alcohol: 2.76g (20mmol) Anhydrous potassium carbonate, 1.52g (5mmol) 8-hydroxyl-3,6-dioxa octyl group p-toluenesulfonic esters and 0.81 g (5 mmol) umbelliferone; At N, dinethylformamide (DMF, 15ml) in 60 ℃ of down reactions 8 hours; Reaction boils off solvent after finishing; With the thick product of dichloromethane extraction, (1:40 v/v) is eluant with methanol-dichloromethane subsequently; Use silica gel column chromatography to separate and obtain product 1.19g (4.07mmol), productive rate is 81.3%.
3) synthetic 3 or 4-(8-(7-coumarin oxygen base)-3; 6-dioxa octyloxy) phthalonitrile: 2.76 g (20mmol) Anhydrous potassium carbonate, 1.47 g (5 mmol) 8-(7-coumarin oxygen base)-3; 6-dioxa-1-capryl alcohol and 0.87 g (5 mmol) 3 or 4-nitrophthalonitrile reacted 8 hours down in 25 ℃ in 15ml DMF, after reaction finishes; Reactant mixture is poured in the 400 ml frozen water, separates out yellow mercury oxide.Sucking filtration, water washing and precipitating to filtrating is for neutral.With ethyl acetate: petroleum ether: dichloromethane=1:2:2 makes eluant, carries out silica gel column chromatography and separates, and (2.7 ~ 3.1mmol), yield is 54 ~ 62% to obtain white product 1.13 ~ 1.31g at last.
4) synthetic α or β-(8-(7-coumarin oxygen base)-3; 6-dioxa-1-octyloxy) Phthalocyanine Zinc: 0.2g (0.475mmol) 3 or 4-(8-(7-coumarin oxygen base)-3; 6-dioxa octyloxy) phthalonitrile, 0.55g (4.28mmol) phthalonitrile and 0.53g (2.38mmol) Glacial acetic acid zinc reacted 6 hours down in 150 ℃ in 1mlDBU and 15ml n-amyl alcohol, and reaction boils off solvent after finishing; Subsequently with methanol-dichloromethane (1:20; V/v) be eluant, (0.07 ~ 0.082mmol), productive rate is 11.2 ~ 17% to use the silica gel column chromatography separation to obtain product 58 ~ 71mg.
Method for preparing in (1) process, is 1:1:1 with triethylamine, triethylene glycol and p-methyl benzene sulfonic chloride mol ratio with instance 1; In the dichloromethane system, reacted 12 hours down in 0 ℃; Other operation is identical, 8-hydroxyl-3, and the productive rate of 6-dioxa octyl group p-toluenesulfonic esters is 38%.In (2) process with Anhydrous potassium carbonate, 8-hydroxyl-3; 6-dioxa octyl group p-toluenesulfonic esters and umbelliferone mol ratio are 3:1:1.2, in DMF, react 12 hours down in 25 ℃, and reaction boils off solvent after finishing; With the thick product of chloroform extraction; Be eluant with methanol-chloroform subsequently, it is said to use the silica gel column chromatography separation to obtain, and productive rate is 87%.In (3) process, with Anhydrous potassium carbonate, 8-(7-coumarin oxygen base)-3,6-dioxa-1-capryl alcohol and 3 or 4-nitrophthalonitrile mol ratio be 5:1:1.2,60 ℃ of down reactions 12 hours in DMF, other is operated with embodiment 1.Productive rate is 49% ~ 51%.In (4) process; With 3 or 4-(8-(7-coumarin oxygen base)-3; 6-dioxa octyloxy) phthalonitrile, phthalonitrile and corresponding zinc salt mol ratio are 1:3:1; 1, reacted 24 hours down in 120 ℃ in 8-diazabicyclo [5.4.0] 11 carbon-7-alkene and the n-amyl alcohol, other is operated with embodiment 1.Productive rate is 9.8% ~ 10%.
Embodiment 3
Method for preparing in (1) process, is 2:2:1 with triethylamine, triethylene glycol and p-methyl benzene sulfonic chloride mol ratio with instance 1; In the dichloromethane system, reacted 12 hours down in 0 ℃; Other operation is identical, 8-hydroxyl-3, and the productive rate of 6-dioxa octyl group p-toluenesulfonic esters is 41%.In (2) process with Anhydrous potassium carbonate, 8-hydroxyl-3; 6-dioxa octyl group p-toluenesulfonic esters and umbelliferone mol ratio are 3:1:1.5, in DMF, react 24 hours down in 60 ℃, and reaction boils off solvent after finishing; With the thick product of chloroform extraction; Be eluant with methanol-chloroform subsequently, it is said to use the silica gel column chromatography separation to obtain, and productive rate is 62%.In (3) process, with Anhydrous potassium carbonate, 8-(7-coumarin oxygen base)-3,6-dioxa-1-capryl alcohol and 3 or 4-nitrophthalonitrile mol ratio be 4:1:1.5,60 ℃ of down reactions 12 hours in DMF, other is operated with embodiment 1.Productive rate is 46% ~ 51%.In (4) process; With 3 or 4-(8-(7-coumarin oxygen base)-3; 6-dioxa octyloxy) phthalonitrile, phthalonitrile and corresponding zinc salt mol ratio are 1:6:1; 1, reacted 24 hours down in 120 ℃ in 8-diazabicyclo [5.4.0] 11 carbon-7-alkene and the n-amyl alcohol, other is operated with embodiment 1.Productive rate is 9.4% ~ 10.2%.
The above is merely preferred embodiment of the present invention, and all equalizations of doing according to claim of the present invention change and modify, and all should belong to covering scope of the present invention.
Claims (10)
1. phthalocyanine Zn complex is characterized in that: said phthalocyanine Zn complex is (8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) Phthalocyanine Zinc, and its molecular formula is: C
42H
32N
8O
6Zn.
2. phthalocyanine Zn complex according to claim 1 is characterized in that: said phthalocyanine Zn complex comprises α, two kinds of structures of β, and its chemical structural formula is following:
1）
1) is α-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) Phthalocyanine Zinc;
2) be β-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) Phthalocyanine Zinc.
3. the method for preparing of a phthalocyanine Zn complex according to claim 1 or claim 2, it is characterized in that: said method for preparing comprises the steps:
1) be starting material with triethylamine, triethylene glycol and p-methyl benzene sulfonic chloride, synthetic 8-hydroxyl-3,6-dioxa octyl group p-toluenesulfonic esters;
2) then with 8-hydroxyl-3,6-dioxa octyl group p-toluenesulfonic esters and umbelliferone are starting material, synthetic 8-(7-coumarin oxygen base)-3,6-dioxa-1-capryl alcohol;
3) then with 8-(7-coumarin oxygen base)-3,6-dioxa-1-capryl alcohol with 3 or the 4-nitrophthalonitrile be starting material, correspondingly synthesize 3 or 4-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) phthalonitrile;
4) at last with 3 or 4-(8-(7-coumarin oxygen base)-3,6-dioxa-1-octyloxy) phthalonitrile, phthalonitrile and zinc salt be starting material, 1, the down synthetic phthalocyanine Zn complex that obtains of 8-diazabicyclo [5.4.0] 11 carbon-7-alkene catalysis.
4. the method for preparing of phthalocyanine Zn complex according to claim 3; It is characterized in that: the detailed process of said step 1) comprises: with triethylamine, triethylene glycol and p-methyl benzene sulfonic chloride is 1～4:1～4:1 in molar ratio; In the dichloromethane system, reacted 6～24 hours down in 0～25 ℃; Reaction boils off solvent after finishing, and with the thick product of dichloromethane extraction, is eluant subsequently with the petroleum ether-ethyl acetate; Use silica gel column chromatography to separate and obtain said 8-hydroxyl-3,6-dioxa octyl group p-toluenesulfonic esters.
5. the method for preparing of phthalocyanine Zn complex according to claim 3; It is characterized in that: detailed process said step 2) comprises: with Anhydrous potassium carbonate, 8-hydroxyl-3; 6-dioxa octyl group p-toluenesulfonic esters and umbelliferone are 3～10:1～2:1～2 in molar ratio, in DMF, react 6～24 hours down in 25～60 ℃, and reaction boils off solvent after finishing; With the thick product of dichloromethane extraction; Be eluant subsequently with the petroleum ether-ethyl acetate, use silica gel column chromatography to separate and obtain said 8-(7-coumarin oxygen base)-3,6-dioxa-1-capryl alcohol.
6. the method for preparing of phthalocyanine Zn complex according to claim 3; It is characterized in that: the detailed process of said step 3) comprises: with Anhydrous potassium carbonate, 8-(7-coumarin oxygen base)-3; 6-dioxa-1-capryl alcohol and 3 or the 4-nitrophthalonitrile be 3～10:1～2:1 ~ 2 in molar ratio; In DMF, reacted 6～24 hours down, product is poured in the water, cool off, leave standstill, precipitate in 25～60 ℃; Getting solid behind the sucking filtration, with the thick product of dichloromethane extraction, is eluant with the petroleum ether-ethyl acetate subsequently, uses silica gel column chromatography to separate to obtain 3 or 4-(8-(7-coumarin oxygen base)-3,6-dioxa octyloxy) phthalonitrile.
7. the method for preparing of phthalocyanine Zn complex according to claim 3; It is characterized in that: the detailed process of said step 4) comprises: with 3 or 4-(8-(7-coumarin oxygen base)-3; 6-dioxa octyloxy) phthalonitrile, phthalonitrile and zinc salt are 1:3～9:1～5 in molar ratio, and with 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene is catalyst; In n-amyl alcohol, reacted 5～24 hours down in 120～150 ℃; Reaction boils off solvent after finishing, and is eluant with methanol-dichloromethane subsequently, uses silica gel column chromatography to separate and obtains phthalocyanine Zn complex.
8. the method for preparing of phthalocyanine Zn complex according to claim 6 is characterized in that: the volume ratio of said step 3) PetroChina Company Limited. ether-ethyl acetate is 1 ~ 6:1.
9. the method for preparing of phthalocyanine Zn complex according to claim 7, it is characterized in that: the volume ratio of methanol-dichloromethane is 1:20～40 in the said step 4).
10. according to claim 1 or claim 2 the application of phthalocyanine Zn complex in the photosensitizer drug used of preparation optical dynamic therapy.
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| CN103304569A (en) * | 2013-06-18 | 2013-09-18 | 福州大学 | Erlotinib-phthalocyanine conjugate and preparation method thereof |
| CN103341166A (en) * | 2013-06-18 | 2013-10-09 | 福州大学 | Erlotinib-phthalocyanine conjugate as molecule-targeting anticancer photosensitizer |
| CN103435624A (en) * | 2013-09-17 | 2013-12-11 | 福州大学 | Fluorinated coumarin-phthalocyanine conjugate and preparation method and application thereof |
| CN103554116A (en) * | 2013-11-07 | 2014-02-05 | 福州大学 | Molecularly targeted anti-cancer photosensitizer tamoxifen-phthalocyanine conjugate and preparation method thereof |
| CN104447769A (en) * | 2013-06-18 | 2015-03-25 | 福州大学 | Molecularly targeted anticancer photosensitizer erlotinib-phthalocyanine conjugate |
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| CN103288840A (en) * | 2013-06-18 | 2013-09-11 | 福州大学 | Phthalocyanine-erlotinib yoke compound and preparation and application thereof |
| CN103304569A (en) * | 2013-06-18 | 2013-09-18 | 福州大学 | Erlotinib-phthalocyanine conjugate and preparation method thereof |
| CN103341166A (en) * | 2013-06-18 | 2013-10-09 | 福州大学 | Erlotinib-phthalocyanine conjugate as molecule-targeting anticancer photosensitizer |
| CN104447769A (en) * | 2013-06-18 | 2015-03-25 | 福州大学 | Molecularly targeted anticancer photosensitizer erlotinib-phthalocyanine conjugate |
| CN103304569B (en) * | 2013-06-18 | 2016-01-27 | 福州大学 | A kind of Erlotinib-phthalocyaconjugate conjugate and preparation method thereof |
| CN104447769B (en) * | 2013-06-18 | 2016-10-26 | 福州大学 | A kind of molecular targeted anticancer photosensitizer Erlotinib-phthalocyaconjugate conjugate |
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| CN103435624B (en) * | 2013-09-17 | 2015-07-22 | 福州大学 | Fluorinated coumarin-phthalocyanine conjugate and preparation method and application thereof |
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| CN103554116B (en) * | 2013-11-07 | 2016-01-27 | 福州大学 | A kind of molecular targeted anticancer photosensitizer tamoxifen-phthalocyanine conjugates and preparation method thereof |
| WO2022032757A1 (en) * | 2020-08-11 | 2022-02-17 | Tcl华星光电技术有限公司 | Three-dimensional dye, method for preparing three-dimensional dye, and photoresist mixture |
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