CN104004008A - Fluoro aryl benzyl ether dendritic (phthalocyanino) silicon complex as well as preparation method and applications thereof - Google Patents

Abstract

The invention discloses a fluorinated aryl benzyl ether dendritic phthalocyanine silicon complex and its preparation method and application. Firstly, dichlorosilicon phthalocyanine is synthesized; , benzophenone) benzyl bromide and 2,2-bis(4-hydroxyphenyl)hexafluoropropane react to synthesize 2-(4-hydroxybenzene)-2'-(4-(4-nitro or cyano or Ester group or benzophenone-benzyloxy) hexafluoropropane. Finally dichlorosilyl phthalocyanine, respectively with 2-(4-hydroxybenzene)-2'-(4-(4-nitro or cyano or ester Base or benzophenone-benzyloxy) hexafluoropropane in toluene reflux reaction to synthesize two-(2-(4-phenoxy)-2'-(4-(4-nitro or cyano or ester group or benzophenone-benzyloxy) hexafluoropropane) axially substituted silicon(IV) phthalocyanine complexes. Make fluorodendrimeric ligand-modified phthalocyanine complexes a class of photosensitizers with good photodynamic therapeutic potential .

Description

Fluorinated aryl benzyl ether dendritic phthalocyanine silicon complex and its preparation method and application

technical field

The invention belongs to the field of complexes, in particular to a fluorinated aryl benzyl ether dendritic phthalocyanine silicon complex and its preparation method and application. The complex is used as a photosensitizer for photodynamic treatment of wet macular degeneration diseases and cancers and cell imaging.

Background technique

Photodynamic therapy (PDT) is a new approach to treat cancer, HIV and wet macular degeneration-like diseases. The key to photodynamic therapy is the photosensitizer. Phthalocyanine complexes have a similar skeleton structure to hematoporphyrin, are more stable and easy to modify, and have a maximum absorption wavelength of around 670nm. They are easy to pass through the red light region of human tissues and can be made into pure products. Potential photosensitizer. Due to the strong π-π interaction between phthalocyanine molecules, it is easy to aggregate, thereby reducing the fluorescence quantum yield of phthalocyanine molecules, shortening the quantum yield and lifetime of singlet and triplet states, thereby reducing the photosensitization efficiency. Therefore, designing and synthesizing photosensitizers with superior performance is our research goal.

In order to solve the problem of poor solubility of phthalocyanine, it is considered to introduce fluorine-containing substituents in the peripheral or axial positions of phthalocyanine. The fluorine atom isoelectronically replaces the hydrogen atom or oxygen atom in the active compound to form a fluorine-containing substituent such as: -CF ₃ , -C ₆ F ₅ -OCF ₃ , etc., which have a large steric hindrance, so they can change the compound The electron cloud density, isomer conformation and transition state of the parent molecule, thereby changing the solubility and pH of the phthalocyanine molecule. In addition, drugs with fluorinated functional groups are easily metabolized. Therefore, many lipophilic drugs have been modified by fluorinated functional groups to change their pharmacokinetics. In addition, the introduction of fluorine groups into biomacromolecules can also regulate some functions of biomacromolecules, such as the interaction with proteins and DNA molecules. On the other hand, the introduction of fluorinated dendron groups can inhibit the generation of phthalocyanine aggregates by utilizing the huge steric hindrance effect, thereby improving the photosensitive activity of phthalocyanine.

Based on the above ideas, this paper designed and synthesized a new type of fluorinated dendritic silicon (IV) phthalocyanine complexes with different end groups. The fluorine-containing substituents were introduced into the dendron structure, and a series of novel fluorinated dendrimer phthalocyanine complexes with different terminal groups were prepared for the first time, which had the synergistic effect of the dendron structure and the fluorine functional group. Not only can the steric hindrance of the dendron structure be used to inhibit the self-aggregation behavior of phthalocyanine to a certain extent, but also the solubility of phthalocyanine is improved due to the presence of fluorine functional groups, and the photophysical properties and pharmacokinetics of phthalocyanine are regulated. The chemical properties make the phthalocyanine complexes modified by fluorinated dendrimer ligands a class of photosensitizers with good potential for photodynamic therapy. There are no reports of fluorinated aryl benzyl ether dendritic phthalocyanine silicon complexes at home and abroad. the

Contents of the invention

The object of the present invention is to provide a kind of fluorinated aryl benzyl ether dendritic phthalocyanine silicon complex and its preparation method.

The invention also proposes the application of a fluorinated aryl benzyl ether dendritic phthalocyanine silicon complex as a photosensitizer.

The object of the present invention is achieved in that a kind of fluorinated aryl benzyl ether dendritic phthalocyanine silicon complex of the present invention is the compound of following structure:

In the formula: R is a cyano group, a nitro group, a benzophenone or an ester group.

The aforesaid fluorinated aryl benzyl ether dendritic phthalocyanine silicon complex of the present invention is a series of novel fluorinated dendritic phthalocyanine complexes with different terminal groups after the fluorine-containing substituent is introduced into the dendron structure. Synergy of structure and fluorine functional groups. Since the fluorine atoms replace the hydrogen atoms in the compound by isoelectronics to form the fluorine-containing substituent CF ₃ has obvious steric effects, and the dendron structure has a huge steric hindrance, which can inhibit the self-aggregation behavior of phthalocyanine to a certain extent; fluorine-containing The substituents are both hydrophilic and lipophilic, and have good phase separation properties in polar and nonpolar environments. Therefore, the introduction of fluorine-containing substituents in phthalocyanine can increase the solubility of phthalocyanine; due to the high electronegativity and chemical inertness of fluorine atoms, the carbon atoms containing fluorine-containing substituents are positively charged and have some empty orbitals, which are easy to It forms a conjugated system with the surrounding benzene ring, thus greatly sensitizing the photophysical properties of phthalocyanine. Compared with fluorine-free substituted phthalocyanine, the fluorescence spectrum intensity, lifetime, fluorescence quantum yield and singlet oxygen quantum yield are greatly enhanced. ; Due to the stability of the CF bond formed by the fluorine atom, the fluorine atom regulates the drug and has good stability, and can interact with the protein and DNA without changing the protein function, thereby modulating the therapeutic effect of the drug.

The present invention can not only suppress the self-aggregation behavior of phthalocyanine to a certain extent by utilizing the obvious steric effect of the fluorine-containing substituent _CF3 and the steric hindrance of the dendritic structure, but also improve the solubility of phthalocyanine due to the existence of the fluorine functional group , and regulate the photophysical properties and pharmacokinetic properties of phthalocyanine, 1) It can be seen from the data in Table 1 that, compared with the fluorine-free dendrimer phthalocyanine di-(2-(4-phenoxy) -2'-(4-(4-cyano-benzyloxy) propane) axially substituted silicon (IV) phthalocyanine complexes (SiPc-CN for short) and bis-(2-(4-phenoxy)- 2'-(4-(4-nitro-benzyloxy) propane) axially substituted silicon (IV) phthalocyanine complexes (SiPc-NO 2 for short ₎ , fluoroaryl benzyl ether dendritic phthalocyanine silicon complexes The intake has increased greatly, and the intake time has advanced, indicating that the fluorinated dendritic structure has significantly changed the pharmacokinetics of the photosensitizer; 2) and as can be seen from Table 2, the fluorinated aryl benzyl ether dendritic phthalocyanine silicon Compounds have obvious inhibitory effect on U251 human glioma cells. Compared with SiPc-CN and SiPc-NO ₂ without fluorinated dendritic phthalocyanine with the same dendritic structure, the silicon complex of fluorinated aryl benzyl ether dendritic phthalocyanine The inhibition rate has been improved; it can be seen that the phthalocyanine complexes modified by fluorodendrimer ligands have become a class of photosensitizers with good photodynamic therapy potential.

The preparation method of a fluorinated aryl benzyl ether phthalocyanine silicon complex of the present invention comprises the following steps: (1) Synthesizing 2-cyanobenzyl bromide and hexafluorobisphenol A in potassium carbonate and acetone solution (4-Hydroxybenzene)-2'-(4-(4-cyano-benzyloxy)hexafluoropropane; 2) 2-(4-Hydroxybenzene)-2'-(4-(4-cyano- Benzyloxy) hexafluoropropane and dichlorosilicon phthalocyanine in the presence of K ₂ CO ₃ , reflux in toluene solution to prepare bis-(2-(4-phenoxy)-2'-(4-(4- Cyano-benzyloxy) axially substituted silicon (IV) phthalocyanine complexes.

The preparation method of a fluorinated aryl benzyl ether phthalocyanine silicon complex of the present invention comprises the following steps: (1) Synthesizing 2 p-nitrobenzyl bromide and hexafluorobisphenol A in potassium carbonate and acetone solution -(4-hydroxybenzene)-2'-(4-(4-nitro-benzyloxy)hexafluoropropane; 2) 2-(4-hydroxybenzene)-2'-(4-(4-nitro -benzyloxy)hexafluoropropane and dichlorosilicon phthalocyanine in the presence of K ₂ CO ₃ by refluxing in toluene solution to prepare bis-(2-(4-phenoxy)-2'-(4-(4 -nitro-benzyloxy) axially substituted silicon(IV) phthalocyanine complexes.

The preparation method of a fluorinated aryl benzyl ether phthalocyanine silicon complex of the present invention comprises the following steps: (1) synthesis of p-benzophenone benzyl bromide and hexafluorobisphenol A in potassium carbonate and acetone solution 2-(4-Hydroxybenzene)-2'-(4-(4-benzophenone-benzyloxy)hexafluoropropane; 2) 2-(4-Hydroxybenzene)-2'-(4-(4 -Benzophenone-benzyloxy)hexafluoropropane and dichlorosilyl phthalocyanine in the presence of K ₂ CO ₃ , prepared by reflux in toluene solution to give bis-(2-(4-phenoxy)-2'- (4-(4-Benzophenone-benzyloxy) axially substituted silicon(IV) phthalocyanine complexes.

The preparation method of a fluorinated aryl benzyl ether phthalocyanine silicon complex of the present invention comprises the following steps: (1) Synthesizing 2- (4-Hydroxybenzene)-2'-(4-(4-carboxybenzyloxy)hexafluoropropane; 2) 2-(4-hydroxybenzene)-2'-(4-(4-carboxybenzyloxy) Oxy)hexafluoropropane and dichlorosilicon phthalocyanine in the presence of K ₂ CO ₃ were refluxed in toluene solution to obtain bis-(2-(4-phenoxy)-2'-(4-(4-ester Base-benzyloxy) axially substituted silicon (IV) phthalocyanine complexes.

The above-mentioned dichlorosilicon phthalocyanine of the present invention adopts 1,3-diiminoisoindoline, silicon tetrachloride and quinoline, stirs and refluxes at 200-240°C to obtain a mixed solution, and then cools the mixed solution to 70 At -90°C, pour it into methanol, filter it while it is hot, wash the filter residue with toluene, quinoline, methanol and acetone, and dry it.

The above-mentioned 2-(4-hydroxybenzene)-2'-(4-(4-cyano-benzyloxy)hexafluoropropane of the present invention preferably adopts p-cyanobenzyl bromide, anhydrous potassium carbonate, 2,2-di (4-Hydroxyphenyl)hexafluoropropane and acetone were reacted under reflux with vigorous stirring at 45-65°C, filtered, the filtrate was collected, and the solvent was evaporated under reduced pressure to obtain a white crude product, which was eluted with dichloromethane Reagent, separated and purified by silica gel chromatography column for 3 times, and obtained after drying.

The above-mentioned bis-(2-(4-phenoxy)-2'-(4-(4-cyano-benzyloxy)hexafluoropropane) axially substituted silicon (IV) phthalocyanine complex of the present invention is preferably used SiPcCl ₂ , G ₁ -F-CN-OH and anhydrous potassium carbonate and redistilled toluene were stirred and refluxed at a temperature of 110-130°C to obtain a mixture, the mixture was cooled to room temperature, the mixture was poured into water, and the aqueous layer was extracted with toluene, The organic phases were combined, and the solvent was distilled off under reduced pressure to obtain a blue-green crude product, which was separated and purified by silica gel chromatography using dichloromethane as the eluent, and dried in vacuo.

The above-mentioned 2- (4-hydroxybenzene)-2'-(4-(4-nitro-benzyloxy)hexafluoropropane of the present invention preferably adopts p-nitrobenzyl bromide, anhydrous potassium carbonate, 2,2-di (4-Hydroxyphenyl)hexafluoropropane and acetone were reacted under reflux with vigorous stirring at 45-65°C, filtered, the filtrate was collected, and the solvent was evaporated under reduced pressure to obtain a white crude product, which was eluted with dichloromethane Reagent, separated and purified by silica gel chromatography column for 3 times, and obtained after drying.

The above-mentioned bis-(2-(4-phenoxy)-2'-(4-(4-nitro-benzyloxy)hexafluoropropane) axially substituted silicon (IV) phthalocyanine complex of the present invention is preferably used SiPcCl ₂ , 2-(4-hydroxybenzene)-2'-(4-(4-nitro-benzyloxy)hexafluoropropane and anhydrous potassium carbonate and redistilled toluene, stirred and refluxed at 110-130°C The mixture was reacted, the mixture was cooled to room temperature, the mixture was poured into water, the aqueous layer was extracted with toluene, the organic phases were combined, and the solvent was evaporated under reduced pressure to obtain a blue-green crude product. The crude product used dichloromethane as the eluent, and the silica gel layer was Column separation and purification, obtained after vacuum drying.

The above-mentioned 2-(4-hydroxybenzene)-2'-(4-(4-ester-benzyloxy)hexafluoropropane of the present invention preferably adopts methyl p-bromobenzoate, anhydrous potassium carbonate, 2,2- Bis(4-hydroxyphenyl)hexafluoropropane and acetone were reacted under reflux with vigorous stirring at 45-65°C, filtered, the filtrate was collected, and the solvent was evaporated under reduced pressure to obtain a white crude product, which was washed with dichloromethane It was obtained after deagent removal, separation and purification by silica gel chromatography column for 3 times, and drying.

The above-mentioned bis-( 2-(4-phenoxy)-2'-(4-(4-ester-benzyloxy)hexafluoropropane) axially substituted silicon (IV) phthalocyanine complex of the present invention is preferably used SiPcCl ₂ , 2-(4-hydroxybenzene)-2'-(4-(4-ester-benzyloxy)hexafluoropropane and anhydrous potassium carbonate and redistilled toluene, stirred and refluxed at 110-130°C The mixture was reacted, the mixture was cooled to room temperature, the mixture was poured into water, the aqueous layer was extracted with toluene, the organic phases were combined, and the solvent was evaporated under reduced pressure to obtain a blue-green crude product. The crude product used dichloromethane as the eluent, and the silica gel layer was Column separation and purification, obtained after vacuum drying.

The above-mentioned 2-(4-hydroxybenzene)-2'-(4-(4-benzophenone-benzyloxy)hexafluoropropane of the present invention preferably adopts benzophenone benzyl bromide, anhydrous potassium carbonate, 2, 2-bis(4-hydroxyphenyl)hexafluoropropane and acetone were reacted under reflux with vigorous stirring at 45-65°C, filtered, the filtrate was collected, and the solvent was evaporated under reduced pressure to obtain a white crude product. The crude product was dichloromethane Used as eluent, separated and purified by silica gel chromatography column for 3 times, and obtained after drying.

The above-mentioned bis-(2-(4-phenoxy)-2'-(4-(4-benzophenone-benzyloxy)hexafluoropropane) axially substituted silicon (IV) phthalocyanine complex Preferably use SiPcCl ₂ , 2-(4-hydroxybenzene)-2'-(4-(4-benzophenone-benzyloxy) hexafluoropropane and anhydrous potassium carbonate and redistilled toluene at 110-130°C The mixture was stirred and refluxed at high temperature to obtain a mixture, the mixture was cooled to room temperature, the mixture was poured into water, the aqueous layer was extracted with toluene, the organic phases were combined, and the solvent was evaporated under reduced pressure to obtain a blue-green crude product, which was eluted with dichloromethane Reagent, purified by silica gel column chromatography, and obtained after vacuum drying.

The application of the aryl ether dendritic phthalocyanine complex in the preparation of photosensitizer for photodynamic therapy.

Beneficial effects of the present invention: compared with the dendritic phthalocyanine phthalocyanine complexes in previous patents, the fluorine-containing substituents are introduced into the dendritic structure, and a series of novel fluorinated dendritic phthalocyanine complexes with different terminal groups are prepared, which have a dendritic structure Synergy with fluorine functional groups. Not only can the steric hindrance of the dendron structure be used to inhibit the self-aggregation behavior of phthalocyanine to a certain extent, but also the solubility of phthalocyanine is improved due to the presence of fluorine functional groups, and the photophysical properties and pharmacokinetics of phthalocyanine are regulated. properties, making phthalocyanine complexes modified with fluorinated dendrimer ligands a class of photosensitizers with good potential for photodynamic therapy.

Detailed ways

Below in conjunction with embodiment the present invention is described in detail:

Embodiment one

1) Synthesis of dichlorosilicon phthalocyanine (SiPcCl ₂ )

Add 1,3-diiminoisoindoline (3.7 g, 25.5 mmol), silicon tetrachloride (4.2 mL) and quinoline (42 mL) into a three-necked flask respectively, stir and reflux at 220 °C for 30 min, When the mixture was cooled to 80 °C, it was poured into methanol (80 mL), filtered while hot, and the filter residue was washed with 35 mL each of toluene, quinoline, methanol and acetone. After drying, 2.2 g of a purple solid was obtained. The yield was 60%.

2) Synthesis of 2-(4-hydroxybenzene)-2'-(4-(4-cyano-benzyloxy)hexafluoropropane (abbreviation: G ₁ -F-CN-OH)

Add p-cyanobenzyl bromide (2.4 g, 12.0 mmol), anhydrous potassium carbonate (2.0 g, 14.5 mmol), 2, 2-bis(4-hydroxyphenyl) hexafluoropropane (4.9 g, 14.4 mmol), acetone (50 mL), reflux with vigorous stirring at 55 °C for 48 h, filter, collect the filtrate, and evaporate the solvent under reduced pressure to obtain a white crude product. The crude product was separated and purified three times by silica gel chromatography using dichloromethane as the eluent. After drying, 3.6 g of white powdery solid was obtained, with a yield of 71.4%.

3) Bis-(2-(4-phenoxy)-2'-(4-(4-cyano-benzyloxy)hexafluoropropane) axially substituted silicon (IV) phthalocyanine complex (abbreviation: SiPc -F-NO ₂ ) Synthesis

Add SiPcCl ₂ (0.2 g, 0.3 mmol), G ₁ -F-CN-OH (0.4 g, 1.0 mmol) and anhydrous potassium carbonate (0.2 g, 1.6 mmol) into a three-necked flask, redistill toluene (20 mL ), stirred and refluxed at 120 °C for 48 h, cooled to room temperature, poured the mixture into water, extracted the aqueous layer with toluene (50 mL′3), combined the organic phases, evaporated the solvent under reduced pressure, and obtained a blue-green crude product, which was obtained as Dichloromethane was used as the eluent, separated and purified by silica gel chromatography three times, and dried in vacuo to obtain 0.26 g of a blue-green solid with a yield of 62.0%. Elemental analysis (% of theory): 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. ¹ H NMR (400MHz, DMSO-d ₆ , 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) Synthesis of 2-(4-hydroxybenzene)-2'-(4-(4-nitro-benzyloxy)hexafluoropropane

Add p-nitrobenzyl bromide (2.7 g, 12.6 mmol), anhydrous potassium carbonate (2.0 g, 14.5 mmol), 2, 2-bis(4-hydroxyphenyl) hexafluoropropane (5.1 g , 15.1 mmol) and acetone (50 mL), stirred vigorously at 55 ℃ and refluxed for 48 h, filtered, collected the filtrate, and evaporated the organic solvent under reduced pressure to obtain a yellow crude product. The crude product was separated and purified three times by silica gel chromatography using petroleum ether:dichloromethane (volume ratio 1:10) as the eluent, and after vacuum drying, 3.8 g of light yellow powdery solid was obtained, with a yield of 65.1%.

5) Bis-(2-(4-phenoxy)-2'-(4-(4-nitro-benzyloxy)hexafluoropropane) axially substituted silicon (IV) phthalocyanine complex (abbreviation: SiPc -F-NO ₂ ) Synthesis

Add SiPcCl ₂ (0.2 g, 0.3 mmol), G ₁ -F-NO ₂ (0.5 g, 1.0 mmol) and anhydrous potassium carbonate (0.2 g, 1.6 mmol) into a three-necked flask, redistill toluene (20 mL) , 120 ℃ stirred and refluxed for 48h, cooled to room temperature, the mixture was poured into water, the aqueous layer was extracted with toluene (50 mL′3), the organic phases were combined, and the solvent was distilled off under reduced pressure to obtain a blue-green crude product. The crude product was separated and purified three times by silica gel chromatography using petroleum ether: dichloromethane (volume ratio 1:10) as the eluent. After vacuum drying, 0.29 g of a blue-green solid was obtained, with a yield of 61.2%.

Elemental analysis (% of theory): 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. ¹ H NMR (400MHz, DMSO-d ₆ , 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) Synthesis of 2-(4-hydroxybenzene)-2'-(4-(4-ester-benzyloxy)hexafluoropropane (abbreviation: G ₁ -F-CN-OH)

Add methyl p-bromobenzoate (2.8 g, 12.0 mmol), anhydrous potassium carbonate (2.0 g, 14.5 mmol), 2, 2-bis(4-hydroxyphenyl) hexafluoropropane (4.9 g , 14.4 mmol) and acetone (50 mL), stirred vigorously at 55 ℃ and refluxed for 48 h, filtered, collected the filtrate, and evaporated the organic solvent under reduced pressure to obtain a white crude product. The crude product used acetone:dichloromethane (volume ratio 1:200) as the eluent, and was separated and purified by silica gel chromatography for three times. After vacuum drying, 4.0 g of white powdery solid was obtained, with a yield of 68.5%.

7) Bis-(2-(4-phenoxy)-2'-(4-(4-ester-benzyloxy)hexafluoropropane) axially substituted silicon (IV) phthalocyanine complex (abbreviation: SiPc -F-COOCH ₃ ) Synthesis

Add SiPcCl ₂ (0.2 g, 0.3 mmol), G ₁ -F-COOCH ₃ (0.5 g, 1.0 mmol) and anhydrous potassium carbonate (0.2 g, 1.6 mmol) into a three-necked flask, redistill toluene (20 mL) , 120 ℃ stirred and refluxed for 48h, cooled to room temperature, the mixture was poured into water, the aqueous layer was extracted with toluene (50 mL′3), the organic phases were combined, and the solvent was distilled off under reduced pressure to obtain a blue crude product. The crude product was separated and purified three times by silica gel chromatography using acetone:dichloromethane (volume ratio 1:200) as the eluent. After vacuum drying, 0.3 g of blue-green solid was obtained, with a yield of 67.4%. Elemental analysis (% of theory): 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. ¹ H NMR (400MHz, DMSO-d ₆ , 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) Synthesis of 2-(4-hydroxybenzene)-2'-(4-(4-benzophenone-benzyloxy)hexafluoropropane (abbreviation: G ₁ -F-BP)

Add p-benzophenone benzyl bromide (3.2 g, 12.0 mmol), anhydrous potassium carbonate (2.0 g, 14.5 mmol), 2, 2-bis(4-hydroxyphenyl) hexafluoropropane (4.9 g, 14.4 mmol) and acetone (50 mL), stirred vigorously at 45 ℃ and refluxed for 48 h, filtered, collected the filtrate, and evaporated the organic solvent under reduced pressure to obtain a white crude product. The crude product used acetone:dichloromethane (volume ratio 1:200) as the eluent, and was separated and purified by silica gel chromatography three times. After vacuum drying, 4.3 g of white powdery solid was obtained, with a yield of 58%.

9) Bis-(2-(4-phenoxy)-2'-(4-(4-benzophenone-benzyloxy)hexafluoropropane) axially substituted silicon (IV) phthalocyanine complexes (referred to as : SiPc-F-BP) synthesis

Add SiPcCl ₂ (0.2 g, 0.3 mmol), G ₁ -F-BP (0.9 g, 1.0 mmol) and anhydrous potassium carbonate (0.2 g, 1.6 mmol) into a three-necked flask, redistill toluene (30 mL), Stir and reflux at 130°C for 48 hours, cool to room temperature, pour the mixture into water, extract the aqueous layer with toluene (50 mL'3), combine the organic phases, evaporate the solvent under reduced pressure, and obtain a blue crude product. The crude product was separated and purified three times by silica gel chromatography using acetone:dichloromethane (volume ratio 1:100) as the eluent. After vacuum drying, 0.6 g of blue-green solid was obtained, with a yield of 72.0%. Elemental analysis (% of theory): 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. ¹ H NMR (400MHz, DMSO-d ₆ , 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 two:

In Example 1, the process 2) p-cyanobenzyl bromide was changed to 4.2 g, 2,2-bis(4-hydroxyphenyl)hexafluoropropane was changed to 9.0 g, acetone was changed to 50 mL, and the reaction time was changed to 2 h , other reaction conditions were the same, and 7.5 g of white powdery solid matter was obtained, with a yield of 73%.

In Example 1, process 3) SiPcCl ₂ was changed to 0.4g, G ₁ -F-CN-OH was changed to 0.8g; the temperature was changed to 150°C and other reaction conditions were the same, the blue-green solid was 0.33g, and the yield was 70.0%.

In Example 1, the process 4) p-nitrobenzyl bromide was changed to 3.8 g, 2, 2-bis(4-hydroxyphenyl) hexafluoropropane was changed to 6.0 g, acetone was changed to 60 mL, and the reaction time was changed to 3 h , other reaction conditions were the same, and 5.5 g of white powdery solid was obtained, with a yield of 47%.

In Example 1, process 5) SiPcCl ₂ was changed to 0.5 g, G ₁ -F-CN-OH was changed to 1.0 g; the temperature was changed to 150°C, and other reaction conditions were the same, the blue-green solid was 0.30 g, and the yield was 65.0%.

In Example 1, the process 6) was changed to 4.2 g of p-esteryl benzyl bromide, 6.1 g of 2,2-bis(4-hydroxyphenyl)hexafluoropropane, 60 mL of acetone, and 3 h of reaction time , other reaction conditions were the same, and 4.7 g of white powdery solid substance was obtained with a yield of 39%.

In Example 1, process 7) SiPcCl ₂ was changed to 0.65 g, G ₁ -F-CN-OH was changed to 0.9 g; the temperature was changed to 150°C, and other reaction conditions were the same, the blue-green solid was 0.32 g, and the yield was 50.0%.

Embodiment three:

In Example 1, the process 2) p-cyanobenzyl bromide was changed to 3.2 g, 2,2-bis(4-hydroxyphenyl)hexafluoropropane was changed to 6.3 g, acetone was changed to 30 mL, and the reaction time was changed to 3 h , other reaction conditions were the same, 4.7 g of white powdery solid substance was obtained, and the yield was 46.0%.

In Example 1, process 3) SiPcCl ₂ was changed to 0.3 g, G ₁ -F-CN-OH was changed to 0.6 g; the temperature was changed to 140°C, and other reaction conditions were the same, the blue-green solid was 0.24 g, and the yield was 60.0%.

In Example 1, the process 4) p-nitrobenzyl bromide was changed to 3.6 g, 2, 2-bis(4-hydroxyphenyl) hexafluoropropane was changed to 5.8 g, acetone was changed to 50 mL, and the reaction time was changed to 4 h , other reaction conditions were the same, 5.0 g of white powdery solid substance was obtained, and the yield was 46.0%.

In Example 1, process 5) SiPcCl ₂ was changed to 0.4 g, G ₁ -F-CN-OH was changed to 0.7 g; the temperature was changed to 150°C, and other reaction conditions were the same, the blue-green solid was 0.26 g, and the yield was 60.0%.

In Example 1, the process 6) was changed to 3.0 g of p-esteryl benzyl bromide, 2.5 g of 2,2-bis(4-hydroxyphenyl)hexafluoropropane, 60 mL of acetone, and 3 h of reaction time , other reaction conditions were the same, and 3.1 g of white powdery solid substance was obtained with a yield of 27.0%.

In Example 1, the process 7) SiPcCl ₂ was changed to 0.25g, G ₁ -F-CN-OH was changed to 0.30g; the temperature was changed to 150°C, and other reaction conditions were the same, the blue-green solid was 0.10g, and the yield was 20.0%.

Embodiment four:

Uptake of Fluoroarylbenzyl Ether Dendritic Phthalocyanine Silicon Complex by 251 Glioma Cells

Prepare 1 μM fluorinated aryl benzyl ether dendritic phthalocyanine silicon complex solution prepared in the above embodiments of the present invention with PBS, scan the absorption peak of the fluoroaryl benzyl ether dendritic phthalocyanine silicon complex with an ultraviolet-visible spectrophotometer, and Concentration standard curve was made according to the peak value. U251 cells passed to the third generation were cultured in a 6-well plate, 1.5 ml per well contained 1.5×10 ⁵ cells, and after 24 hours of culture, fluorinated arylbenzyl ether dendritic phthalocyanine silicon complexes were added to make each well The final concentration was 10 uM, and incubated in a CO ₂ incubator at 37 °C, 5% CO 2 , and saturated humidity in the dark. A group of cells were collected after 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 12 h (three parallel wells were set for each group). After the cells collected at different times were washed twice with PBS solution, 1 ml of cell lysate (2.0% TritionX-100) was added, mixed with a sterile pipette, and no intact cells were detected under an optical microscope. The cell lysate was centrifuged at 12000 rpm for 30 min at 4 °C, and the supernatant was taken, and the content of fluoroarylbenzyl ether dendritic phthalocyanine silicon complex in U251 cells was detected by a UV-visible spectrophotometer. The optimal incubation time of fluorinated aryl benzyl ether dendritic phthalocyanine silicon complex acting on U251 cells was obtained.

Table 1 The amount of fluoroarylbenzyl ether dendritic phthalocyanine silicon complex uptake by U251 cells at different incubation times

As can be seen from Table 1, relative to the non-fluorinated dendrimer phthalocyanine bis-(2-(4-phenoxy)-2'-(4-(4-cyano-benzyloxy)propane ) axially substituted silicon (Ⅳ) phthalocyanine complexes (SiPc-CN for short) and bis-(2-(4-phenoxy)-2'-(4-(4-nitro-benzyloxy) propane) Axially substituted silicon (IV) phthalocyanine complexes (SiPc-NO ₂ for short), the uptake of fluorinated aryl benzyl ether dendritic phthalocyanine silicon complexes has greatly increased, and the uptake time has been advanced, indicating that the fluorinated dendritic structure is obvious Altered pharmacokinetics of the drug.

(2) Photodynamic effect evaluation

Evaluation of Photodynamic Activity of Fluoroarylbenzyl Ether Dendritic Phthalocyanine Silicon Complexes on U251 Human Glioma Cells

Inoculate a 96-well plate with 5×10 ³ cells in 100 μL per well. After culturing for 24 h, the fluoroaryl benzyl ether dendritic phthalocyanine silicon complex was added to the culture medium (DMSO). Without laser radiation, the drug was protected from light for 24 h. The cells cultured without adding fluorinated aryl benzyl ether dendritic phthalocyanine silicon complex, only adding blank solvent (physiological saline) and without laser radiation were used as negative control. Cell viability was measured by CCK-8 method.

Table 2 CCK-8 detection results of U251 cells 48 hours after PDT (n=9)

  

There was a significant difference between the two groups, p<0.01.

It can be seen from Table 2 that the fluorinated aryl benzyl ether dendritic phthalocyanine silicon complex has obvious inhibitory effect on U251 human glioma cells. Relative to the non-fluorinated dendrimer phthalocyanine bis-(2-(4-phenoxy)-2'-(4-(4-cyano-benzyloxy)propane) axially substituted silicon(IV) with the same dendritic structure Phthalocyanine complexes (SiPc-CN for short) and bis-(2-(4-phenoxy)-2'-(4-(4-nitro-benzyloxy)propane) axially substituted silicon(IV)phthalein Cyanine complex (abbreviated as SiPc-NO ₂ ), fluorinated aryl benzyl ether dendritic phthalocyanine silicon complex has increased inhibition rate.

Although the embodiment of the present invention has been disclosed as above, it is not limited to the use listed in the specification and implementation, it can be applied to various fields suitable for the present invention, and it can be easily understood by those skilled in the art Therefore, the invention is not limited to the specific details and examples shown and described herein without departing from the general concept defined by the claims and their equivalents.

Claims (10)

1. a fluorinated aryl benzyl oxide dendritic phthalocyanine silicon title complex, is characterized in that: the compound for following chemical structure:

In formula: R is cyano group, nitro, benzophenone or ester group.

2. a preparation method for fluorinated aryl benzyl oxide silicon phthalocyanine compound, comprises the steps: that (1) is to cyano group benzyl bromine and hexafluoro bisphenol-a synthetic 2-(4-hydroxybenzene in salt of wormwood and acetone soln)-2'-(4-(4-cyano group-benzyloxy) HFC-236fa; 2) 2-(4-hydroxybenzene) (4-(4-cyano group-benzyloxy) HFC-236fa and phthalocyanine silicon dichloride are at K for-2'- ₂cO ₃under existence, in toluene solution, reflux and prepare two-(2-(4-phenoxy group)-2'-(4-(4-cyano group-benzyloxy) axially replaces 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 hexafluoro bisphenol-a synthetic 2-(4-hydroxybenzene in salt of wormwood and acetone soln)-2'-(4-(4-nitro-benzyloxy) HFC-236fa; 2) 2-(4-hydroxybenzene) (4-(4-nitro-benzyloxy) HFC-236fa and phthalocyanine silicon dichloride are at K for-2'- ₂cO ₃under existence, in toluene solution, reflux and prepare two-(2-(4-phenoxy group)-2'-(4-(4-nitro-benzyloxy) axially replaces silicon (IV) phthalocyanine complex.

4. a preparation method for fluorinated aryl benzyl oxide silicon phthalocyanine compound, comprises the steps: that (1) is to benzophenone benzyl bromine and hexafluoro bisphenol-a synthetic 2-(4-hydroxybenzene in salt of wormwood and acetone soln)-2'-(4-(4-benzophenone-benzyloxy) HFC-236fa; 2) 2-(4-hydroxybenzene) (4-(4-benzophenone-benzyloxy) HFC-236fa and phthalocyanine silicon dichloride are at K for-2'- ₂cO ₃under existence, in toluene solution, reflux and prepare two-(2-(4-phenoxy group)-2'-(4-(4-benzophenone-benzyloxy) axially replaces silicon (IV) phthalocyanine complex.

5. a preparation method for fluorinated aryl benzyl oxide silicon phthalocyanine compound, comprises the steps: that (1) is to ester group benzyl bromine and hexafluoro bisphenol-a synthetic 2-(4-hydroxybenzene in salt of wormwood and acetone soln)-2'-(4-(4-ester group benzyloxy) HFC-236fa; 2) 2-(4-hydroxybenzene) (4-(4-ester group-benzyloxy) HFC-236fa and phthalocyanine silicon dichloride are at K for-2'- ₂cO ₃under existence, in toluene solution, reflux and prepare two-(2-(4-phenoxy group)-2'-(4-(4-ester group-benzyloxy) axially replaces silicon (IV) phthalocyanine complex.

6. the preparation method of fluorinated aryl benzyl oxide silicon phthalocyanine compound according to claim 2, it is characterized in that: described 2-(4-hydroxybenzene) (4-(4-cyano group-benzyloxy) HFC-236fa adopts cyano group benzyl bromine, Anhydrous potassium carbonate, 2-2'-, 2-bis-(4-hydroxyphenyl) HFC-236fa and acetone, vigorous stirring back flow reaction at 45-65 DEG C of temperature, filter, collect filtrate, pressure reducing and steaming solvent, obtain white thick product, thick product is taking methylene dichloride as eluent, silica gel column chromatography separating-purifying 3 times, obtains after being dried; Described two-(2-(4-phenoxy group)-2'-(4-(4-cyano group-benzyloxy) HFC-236fa) axially replace silicon (IV) phthalocyanine complex and adopt SiPcCl ₂, G ₁-F-CN-OH and Anhydrous potassium carbonate and heavily steam toluene, at 110-130 DEG C of temperature, stirring and refluxing is reacted to obtain mixture, mixture is cooled to room temperature, and mixture is poured into water, and water layer extracts with toluene, merge organic phase, pressure reducing and steaming solvent, obtains the thick product of blue-greenish colour, and thick product is taking methylene dichloride as eluent, 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: described 2(4-(4-nitro-benzyloxy) HFC-236fa adopts nitrobenzyl bromine, Anhydrous potassium carbonate, 2-(4-hydroxybenzene)-2'-, 2-bis-(4-hydroxyphenyl) HFC-236fa and acetone, vigorous stirring back flow reaction at 45-65 DEG C of temperature, filter, collect filtrate, pressure reducing and steaming solvent, obtain white thick product, thick product is taking methylene dichloride as eluent, and silica gel column chromatography separating-purifying 3 times, obtains after being dried; Described two-(2-(4-phenoxy group)-2'-(4-(4-nitro-benzyloxy) HFC-236fa) axially replace silicon (IV) phthalocyanine complex and adopt SiPcCl ₂2-(4-hydroxybenzene) and-2'-(4-(4-nitro-benzyloxy) HFC-236fa 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 to room temperature, mixture is poured into water, water layer extracts with toluene, merges organic phase, pressure reducing and steaming solvent, obtain the thick product of blue-greenish colour, thick product is taking methylene dichloride as eluent, and 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: described 2-(4-hydroxybenzene)-2'-(4-(4-benzophenone-benzyloxy) HFC-236faadopt 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, filter, collect filtrate, pressure reducing and steaming solvent, obtain white thick product, thick product is taking methylene dichloride as eluent, and silica gel column chromatography separating-purifying 3 times, obtains after being dried; Described two-(2-(4-phenoxy group)-2'-(4-(4-benzophenone-benzyloxy) HFC-236fa) axially replace silicon (IV) phthalocyanine complex and adopt SiPcCl ₂2-(4-hydroxybenzene) and-2'-(4-(4-benzophenone-benzyloxy) HFC-236fa 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 to room temperature, mixture is poured into water, water layer extracts with toluene, merges organic phase, pressure reducing and steaming solvent, obtain the thick product of blue-greenish colour, thick product is taking methylene dichloride as eluent, and 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, it is characterized in that: described 2-(4-hydroxybenzene) (4-(4-ester group-benzyloxy) HFC-236fa adopts parabromobenzoic acid methyl esters, Anhydrous potassium carbonate, 2 to-2'-, 2-bis-(4-hydroxyphenyl) HFC-236fa and acetone, vigorous stirring back flow reaction at 45-65 DEG C of temperature, filter, collect filtrate, pressure reducing and steaming solvent, obtain white thick product, thick product is taking methylene dichloride as eluent, silica gel column chromatography separating-purifying 3 times, obtains after being dried; Described two-(2-(4-phenoxy group)-2'-(4-(4-ester group-benzyloxy) HFC-236fa) axially replace silicon (IV) phthalocyanine complex adopt SiPcCl ₂2-(4-hydroxybenzene) and-2'-(4-(4-ester group-benzyloxy) HFC-236fa 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 to room temperature, mixture is poured into water, water layer extracts with toluene, merges organic phase, pressure reducing and steaming solvent, obtain the thick product of blue-greenish colour, thick product is taking methylene dichloride as eluent, and silica gel column chromatography separating-purifying, obtains after vacuum-drying.

10. the application of fluorinated aryl benzyl oxide dendritic phthalocyanine silicon title complex claimed in claim 1 in the photosensitizers of preparation photodynamic therapy.