A class of amphiphilic BODIPY derivatives containing azobenzene and preparation method thereof

Abstract

The invention relates to a class of amphiphilic BODIPY derivatives containing azophenyl groups and a preparation method thereof. 4,4'-dibromoethane azobenzene and 1,7-bis(4-hydroxyphenyl)-3,5-bis(4-propynyloxy) azamethylenedipyrrole are reacted to obtain an azamethylenedipyrrole containing an azophenyl group. The azamethylenedipyrrole containing an azophenyl group is reacted under the action of boron trifluoride etherate to obtain a BODIPY mother core containing an azophenyl group. Benzamide containing a hydrophilic chain R is introduced into the BODIPY mother core structure containing an azophenyl group through a click reaction to obtain an amphiphilic Aza-BODIPY dye containing an azophenyl group, with the structural formula shown below. This series of molecules introduces a light-responsive azophenyl group for the first time, completes a self-assembly process for control, and has the characteristics of mild properties and low cost, thereby providing a new approach for achieving in vitro simulation of life systems.

Description

Technical Field

[0001] The present invention relates to the technical field of dyes, in particular to a class of amphiphilic BODIPY derivatives containing azobenzene and a preparation method thereof. Background Art

[0002] First synthesized and reported in 1968 [Liebigs.Ann.Chem.1968,718,208-223], 4,4-Difluoro-4-bora-3a,4a-diaza-dipyrromethene, difluoro-bora-dipyrromethenes (BODIPY) dyes have only been developed in the past two or three decades. These dyes have been extensively studied due to their long absorption and emission wavelengths, excellent photostability, narrow half-width, high quantum yield, and large molar extinction coefficient [Chem.Rev.2007,107,4891-4932]. The dye structure is as follows:

[0003]

[0004] Its core structure consists of two pyrrole rings on either side, with a six-membered boron-nitrogen heterocycle in the center. The three rings form a perfectly conjugated planar structure, with the two fluorine atoms attached to the boron atom flanking the BODIPY dye core plane. The parent structure has eight substitution positions, of which R1-R3 and R5-R7 are common substitution positions on the pyrroles, while R8 is derived from the aldehydes and acyl chlorides used to synthesize BODIPY. R1-R8 can be a variety of groups, with common substitutions including alkyls, alkenyls, alkynyls, aryls, and halogens. The F atom at position 4 can also be substituted with alkynyls, aryls, and other groups.

[0005] Aza-BODIPY is a derivative of BODIPY in which the carbon atom at the meso-position is replaced by a nitrogen atom, causing its UV-visible absorption spectrum to red-shift by about 100 nm, thus having higher research and application value and potential [Lu P., Polymer Chemistry, 2021, 12(3):327–348.]. Due to the reduced absorption of background light sources, light scattering, and improved sensitivity in biological sample detection, it has excellent application potential in biological detection. However, Aza-BODIPY derivatives still have some chemical defects, including poor water solubility that is not conducive to biological applications, and emission wavelengths in the near-infrared region. Therefore, in order to expand the scope of research and application, it is necessary to introduce functional groups of different properties on the basis of the parent nucleus. In recent years, researchers have introduced hydrophilic and hydrophobic substituents of different lengths or numbers at different positions of the parent nucleus to adjust the absorption and emission wavelengths of the molecule, ultimately achieving the purpose of regulating and controlling the supramolecular self-assembly process, further expanding the wide application of this dye in life sciences, fluorescent probes, ion recognition, nanomaterial preparation and other fields. Supramolecular aggregates of amphiphilic dyes have broad application prospects in biomedicine and other fields due to their certain water solubility, such as photothermal therapy of tumors, etc. Dodecyloxy groups are introduced at positions 1 and 7 on the Aza-BODIPY basic structure, and trioxygen hydrophilic chains are introduced at positions 3 and 5 to prepare amphiphilic Aza-BODIPY dyes with high photothermal conversion efficiency. Through morphological transformation modulated by near-infrared (NIR) laser, long-term blood circulation and deep tumor penetration can be achieved simultaneously [Yuan C., ACS Nano 2020, 14, 3640-3650.]. The self-assembly process of amphiphilic Aza-BODIPY dyes is mostly carried out under the control of temperature, time and other pathways. In actual application, the requirements for temperature and time are relatively strict, and the cost is high.

[0006] This invention introduces photoresponsive azophenyl groups at positions 1 and 7 of the Aza-BODIPY base structure, enabling light-field-induced supramolecular aggregation under ultraviolet light. Simultaneously, a cuprous iodide-catalyzed click reaction is used to introduce hydrophilic benzamide groups at positions 3 and 5 of Aza-BODIPY, enhancing its water solubility. This series of molecules introduces photoresponsive azophenyl groups into Aza-BODIPY dyes for the first time, and for the first time allows for the self-assembly process of Aza-BODIPY dyes to be controlled by light fields. Compared to existing Aza-BODIPY dye self-assembly pathways, this approach offers a milder, more cost-effective approach, providing a new approach for in vitro simulation of living systems. Summary of the Invention

[0007] The present invention aims to introduce photoresponsive azophenyl groups at positions 1 and 7 of the Aza-BODIPY base structure, enabling light-field-induced supramolecular aggregation under ultraviolet light. Furthermore, a benzamide group containing a hydrophilic chain is introduced at positions 3 and 5 of Aza-BODIPY using a cuprous iodide-catalyzed click reaction to enhance water solubility. This approach, along with the preparation of a series of amphiphilic Aza-BODIPY dyes containing azophenyl groups, provides an effective synthetic method for studying the self-assembly behavior and photoresponsive properties of Aza-BODIPY in vivo.

[0008] The present invention discloses a series of amphiphilic Aza-BODIPY dyes containing azophenyl groups, the structures of which are as follows:

[0009]

[0010]

[0011] The reaction formula is as follows:

[0012]

[0013] The preparation method of the amphiphilic Aza-BODIPY dye containing an azophenyl group comprises the following specific steps:

[0014] 1) reacting 4,4'-dibromoethaneazobenzene with 1,7-bis(4-hydroxyphenyl)-3,5-bis(4-propynyloxy)azamethylenedipyrrole to obtain an azomethylenedipyrrole containing an azophenyl group;

[0015] 2) Azobenzene-containing azomethylenedipyrrole reacts with boron trifluoride etherate to obtain a BODIPY core containing an azobenzene group;

[0016] 3) The BODIPY core structure containing an azophenyl group was introduced into benzamide containing different hydrophilic chains R through a click reaction to obtain the target molecule.

[0017] The preparation method of step 1) is as follows: 4,4'-dibromoethaneazobenzene and 1,7-bis(4-hydroxyphenyl)-3,5-bis(4-propynyloxy)azamethylenedipyrrole are added to a reaction flask, DMF is used as a solvent, the reaction temperature is raised to 80-85° C., and the reaction is carried out for 48-52 hours; wherein the reaction molar ratio of 4,4'-dibromoethaneazobenzene and 1,7-bis(4-hydroxyphenyl)-3,5-bis(4-propynyloxy)azamethylenedipyrrole is: 1-1.2:1-2.

[0018] The preparation method of step 2) is as follows: under nitrogen protection, azomethylenedipyrrole containing an azophenyl group, N,N-diisopropylethylamine and boron trifluoride etherate are added to a reaction flask, dry dichloromethane is added as a solvent, and the reaction is carried out at room temperature for 12 to 24 hours; wherein the reaction molar ratio of the compound obtained by the reaction, N,N-diisopropylethylamine and boron trifluoride etherate, and dry dichloromethane is: 1:5 to 8:6 to 10:100 to 500;

[0019] The preparation method of step 3) is as follows: adding an azophenyl Aza-BODIPY matrix, benzamide containing a hydrophilic chain, N,N-diisopropylethylamine, and iodinated ketone to a mixed solvent of acetonitrile and dichloromethane with a volume ratio of 1-1.2:1-1.1, and stirring at 45-50° C. for 1-2 hours; wherein the reaction molar ratio of the azophenyl Aza-BODIPY matrix, benzamide containing a hydrophilic chain, N,N-diisopropylethylamine, and iodinated ketone is: 1:2-3:2-3:0.1-0.5.

[0020] The effects of the present invention are as follows:

[0021] 1) The present invention prepares and synthesizes a series of amphiphilic Aza-BODIPYs containing azo groups, which have few synthetic steps, simple reaction conditions, high product yields and stable structures.

[0022] 2) This series of molecules has strong near-infrared absorption and fluorescence emission. In chloroform solution, the maximum absorption peak is at 688nm and the fluorescence emission peak is at 715nm. Figure 5 As shown;

[0023] 3) This series of molecules can form metastable aggregates in a mixed solvent of methanol and water, with a broad UV spectrum and a maximum absorption peak at 674nm. After irradiation with UV light, they form J aggregates, with a sharp UV spectrum and a maximum absorption peak at 714nm, as shown in the attached Figure 6 shown.

[0024] 4) This series of molecules can form metastable aggregates in a mixed solvent of methanol and water. After ultraviolet light irradiation, the metastable aggregates transform into a more stable steady state, forming J-aggregate nanofibers, thus achieving a supramolecular self-assembly process controlled by light. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 Example 1-3 (Aza-BODIPY 1) 1 H NMR spectroscopy;

[0026] Figure 2 Example 4-6 (Aza-BODIPY 2) 1 H NMR spectroscopy;

[0027] Figure 3 Examples 7-9 (Aza-BODIPY 3) 1 H NMR spectroscopy;

[0028] Figure 4 Examples 10-12 (Aza-BODIPY4) 1 H NMR spectroscopy;

[0029] Figure 5 UV absorption and fluorescence emission spectra of Aza-BODIPY in chloroform solvent;

[0030] Figure 6 Aggregation of Aza-BODIPY in a mixed solvent of methanol and water. DETAILED DESCRIPTION

[0031] Example 1. Compound Aza-BODIPY molecule 1

[0032] 1) Propynyl-substituted azamethylenedipyrrole (0.59 g, 1.0 mmol) was weighed into a reaction flask, 4,4'-dibromoethaneazobenzene (0.43 g, 1.0 mmol) was added, and DMF (50.0 ml) was added as solvent. The reaction temperature was raised to 80°C and the reaction was carried out for 52 h. After the reaction, the solvent was removed by vacuum distillation to obtain azophenyl azamethylenedipyrrole in a yield of 20%;

[0033] 2) Azophenyl azamethylenedipyrrole (0.85 g, 1.0 mmol) was weighed into a two-necked flask and maintained under nitrogen. Anhydrous dichloromethane (15.0 ml) was then added to the reaction flask via syringe, followed by DIEA (0.65 g, 5.0 mmol). After stirring at room temperature for half an hour, boron trifluoride etherate (6.0 mmol) was added to the reaction system via syringe and allowed to react at room temperature for 24 hours. The solvent was removed by rotary evaporation, and the resulting crude product was separated by column chromatography (mobile phase: DCM) to obtain the azophenyl BODIPY core in a 60% yield.

[0034] 3) Azophenyl BODIPY core (0.45 g, 0.5 mmol) was dissolved in dichloromethane (30.0 ml) and stirred. Acetonitrile (30.0 ml) was added, followed by N-(2-azidoethyl)-3,4,5-tris(2-(2-methoxyethoxy)ethoxy)benzamide (0.54 g, 1.0 mmol). CuI (9.5 mg, 0.05 mmol) and DIEA (0.13 g, 1.0 mmol) were added. The mixture was heated to 45°C and reacted for 2 hours. The reaction mixture was then dried by rotary evaporation and the crude product was separated by column chromatography (mobile phase: DCM:methanol = 30:1). The mixture was rotary evaporation again, the product flask was sealed with tin foil, and vacuum dried to obtain a purple solid compound in a 50% yield.

[0035] NMR spectrum is attached Figure 1 As shown, the chemical shifts and integrals are: δ8.07–8.04 (m, 4H), 8.03 (dd, J = 4.6, 1.8 Hz, 4H), 8.00–7.85 (m, 6H), 7.73 (d, J = 2.2 Hz, 2H), 7.47–7.38 (m, 6H), 7.27 (s, 2H), 7.09 (d, J = 1.9 Hz, 4H), 7.06 (t, J = 5.4 Hz, 4H), 7.0 2(s,2H),5.25(d,J=3.4Hz,4H),4.67–4.60(m,4H),4.22–4.15(m,12H),3.95–3.87(m,4H),3.82–3.76(m,12H),3.71–3.62(m,20H),3.55–3.50(m,12H),3.37–3.31(m,18H), all of which corresponded to the target substance. The UV absorption spectrum and fluorescence emission spectrum of the compound in chloroform solution are shown in the attached figure. Figure 5 As shown in the figure, the UV absorption peak is at 688nm and the fluorescence emission peak is at 715nm; the aggregation of the compound in a mixed polar solvent of methanol and water is shown in the figure. Figure 6 As shown, metastable aggregates exist with a UV absorption peak at 674 nm. After UV irradiation, the metastable aggregates transform into a more stable steady state, forming J-aggregate nanofibers with a UV absorption peak at 714 nm, thus achieving a supramolecular self-assembly process controlled by light pathways. This provides a reference for supramolecular self-assembly controlled by light pathways.

[0036]

[0037] Example 2. Compound Aza-BODIPY molecule 1

[0038] 1) Propynyl-substituted azamethylenedipyrrole (0.89 g, 1.5 mmol) was weighed into a reaction flask, 4,4'-dibromoethaneazobenzene (0.43 g, 1.0 mmol) was added, and DMF (60.0 ml) was added as solvent. The reaction temperature was raised to 82°C and the reaction was carried out for 50 h. After the reaction, the solvent was removed by vacuum distillation to obtain azophenyl azamethylenedipyrrole in a yield of 22%;

[0039] 2) Azophenyl azamethylenedipyrrole (0.85 g, 1.0 mmol) was weighed into a two-necked flask and maintained under nitrogen. Anhydrous dichloromethane (20.0 ml) was then added to the reaction flask via syringe, followed by DIEA (0.85 g, 6.5 mmol). After stirring at room temperature for half an hour, boron trifluoride etherate (8.0 mmol) was added to the reaction system via syringe and allowed to react at room temperature for 18 hours. The solvent was removed by rotary evaporation, and the resulting crude product was separated by column chromatography (mobile phase: DCM) to obtain the azophenyl BODIPY core in a 59% yield.

[0040] 3) Azophenyl BODIPY core (0.45 g, 0.5 mmol) was dissolved in dichloromethane (30.0 ml) and stirred. Acetonitrile (33.0 ml) was added, followed by N-(2-azidoethyl)-3,4,5-tris(2-(2-methoxyethoxy)ethoxy)benzamide (0.68 g, 1.25 mmol). CuI (34.2 mg, 0.18 mmol) and DIEA (0.16 g, 1.25 mmol) were added. The mixture was heated to 48°C and reacted for 1.5 hours. The reaction mixture was then dried by rotary evaporation and the crude product was separated by column chromatography (mobile phase: DCM:methanol = 30:1). The mixture was rotary evaporation again, the product flask was sealed with tin foil, and vacuum dried to obtain a purple solid compound in a 50% yield.

[0041] NMR spectrum is attached Figure 1 shown.

[0042]

[0043] Example 3. Compound Aza-BODIPY molecule 1

[0044] 1) Propynyl-substituted azamethylenedipyrrole (1.18 g, 2.0 mmol) was weighed into a reaction flask, 4,4'-dibromoethaneazobenzene (0.43 g, 1.0 mmol) was added, and DMF (70.0 ml) was added as solvent. The reaction temperature was raised to 85°C and the reaction was carried out for 48 h. After the reaction, the solvent was removed by vacuum distillation to obtain azophenyl azamethylenedipyrrole in a yield of 22%.

[0045] 2) Azophenyl azamethylenedipyrrole (0.85 g, 1.0 mmol) was weighed into a two-necked flask and maintained under nitrogen. Anhydrous dichloromethane (25.0 ml) was then added to the reaction flask via syringe, followed by DIEA (1.04 g, 8.0 mmol). After stirring at room temperature for half an hour, boron trifluoride etherate (10.0 mmol) was added to the reaction system via syringe and allowed to react at room temperature for 24 hours. The solvent was removed by rotary evaporation, and the resulting crude product was separated by column chromatography (mobile phase: DCM) to obtain the azophenyl BODIPY core in a 59% yield.

[0046] 3) Azophenyl BODIPY core (0.45 g, 0.5 mmol) was dissolved in dichloromethane (33.0 ml) and stirred. Acetonitrile (30.0 ml) was added, followed by N-(2-azidoethyl)-3,4,5-tris(2-(2-methoxyethoxy)ethoxy)benzamide (0.81 g, 1.5 mmol). CuI (47.5 mg, 0.25 mmol) and DIEA (0.20 g, 1.5 mmol) were added. The mixture was heated to 50°C and reacted for 1 hour. The reaction mixture was then spin-dried and the crude product was separated by column chromatography (mobile phase: DCM:methanol = 30:1). The mixture was rotary evaporated again, the product flask was sealed with tin foil, and vacuum dried to obtain a purple solid compound with a yield of 51%. The NMR spectrum is shown in the attached figure. Figure 1 shown.

[0047]

[0048] Example 4. Compound Aza-BODIPY molecule 2

[0049] 1) Propynyl-substituted azamethylenedipyrrole (0.59 g, 1.0 mmol) was weighed into a reaction flask, 4,4'-dibromoethaneazobenzene (0.43 g, 1.0 mmol) was added, and DMF (50.0 ml) was added as solvent. The reaction temperature was raised to 80°C and the reaction was carried out for 52 h. After the reaction, the solvent was removed by vacuum distillation to obtain azophenyl azamethylenedipyrrole in a yield of 20%;

[0050] 2) Azophenyl azamethylenedipyrrole (0.85 g, 1.0 mmol) was weighed into a two-necked flask and maintained under nitrogen. Anhydrous dichloromethane (15.0 ml) was then added to the reaction flask via syringe, followed by DIEA (0.65 g, 5.0 mmol). After stirring at room temperature for half an hour, boron trifluoride etherate (6.0 mmol) was added to the reaction system via syringe and allowed to react at room temperature for 24 hours. The solvent was removed by rotary evaporation, and the resulting crude product was separated by column chromatography (mobile phase: DCM) to obtain the azophenyl BODIPY core in a 60% yield.

[0051] 3) Azophenyl BODIPY core (0.45 g, 0.5 mmol) was dissolved in dichloromethane (30.0 ml) and stirred. Acetonitrile (30.0 ml) was added, followed by N-(2-azidoethyl)-3,4,5-tris(2-(2-(-2-methoxyethoxy)ethoxy)ethoxy)benzamide (0.68 g, 1.0 mmol). CuI (9.5 mg, 0.05 mmol) and DIEA (0.13 g, 1.0 mmol) were added. The mixture was heated to 45°C and reacted for 2 hours. The reaction mixture was then dried by rotary evaporation and the crude product was separated by column chromatography (mobile phase: DCM:methanol = 30:1). The mixture was rotary evaporation again, the product flask was sealed with tin foil, and vacuum dried to obtain a purple solid compound in a 50% yield.

[0052] NMR spectrum is attached Figure 2 As shown, the chemical shifts and integrals are: δ8.07–8.04 (m, 4H), 8.03 (dd, J = 4.6, 1.8 Hz, 4H), 8.00–7.85 (m, 6H), 7.73 (d, J = 2.2 Hz, 2H), 7.47–7.38 (m, 6H), 7.27 (s, 2H), 7.09 (d, J = 1.9 Hz, 4H), 7.06 (t, J = 5.4 Hz, 4H), 7.0 2(s,2H),5.25(d,J=3.4Hz,4H),4.67–4.60(m,4H),4.22–4.15(m,12H),3.95–3.87(m,4H),3.82–3.76(m,12H),3.71–3.62(m,44H),3.55–3.50(m,12H),3.37–3.31(m,18H), all corresponding to the target substances.

[0053]

[0054] Example 5. Compound Aza-BODIPY molecule 2

[0055] 1) Propynyl-substituted azamethylenedipyrrole (0.89 g, 1.5 mmol) was weighed into a reaction flask, 4,4'-dibromoethaneazobenzene (0.43 g, 1.0 mmol) was added, and DMF (60.0 ml) was added as solvent. The reaction temperature was raised to 82°C and the reaction was carried out for 50 h. After the reaction, the solvent was removed by vacuum distillation to obtain azophenyl azamethylenedipyrrole in a yield of 22%;

[0056] 2) Azophenyl azamethylenedipyrrole (0.85 g, 1.0 mmol) was weighed into a two-necked flask and maintained under nitrogen. Anhydrous dichloromethane (20.0 ml) was then added to the reaction flask via syringe, followed by DIEA (0.85 g, 6.5 mmol). After stirring at room temperature for half an hour, boron trifluoride etherate (8.0 mmol) was added to the reaction system via syringe and allowed to react at room temperature for 18 hours. The solvent was removed by rotary evaporation, and the resulting crude product was separated by column chromatography (mobile phase: DCM) to obtain the azophenyl BODIPY core in a 59% yield.

[0057] 3) Azophenyl BODIPY core (0.45 g, 0.5 mmol) was dissolved in dichloromethane (30.0 ml) and stirred. Acetonitrile (33.0 ml) was added, followed by N-(2-azidoethyl)-3,4,5-tris(2-(2-(-2-methoxyethoxy)ethoxy)ethoxy)benzamide (0.85 g, 1.25 mmol). CuI (34.2 mg, 0.18 mmol) and DIEA (0.16 g, 1.25 mmol) were added, and the mixture was heated to 48°C and reacted for 1.5 hours. The reaction mixture was dried by rotary evaporation and the crude product was separated by column chromatography (mobile phase: DCM:methanol = 30:1). The mixture was rotary evaporation again, and the product flask was sealed with tin foil for storage. The product was dried under vacuum to obtain a purple solid compound with a yield of 50%. As shown in the attached figure, Figure 2 shown.

[0058]

[0059] Example 6. Compound Aza-BODIPY molecule 2

[0060] 1) Propynyl-substituted azamethylenedipyrrole (1.18 g, 2.0 mmol) was weighed into a reaction flask, 4,4'-dibromoethaneazobenzene (0.43 g, 1.0 mmol) was added, and DMF (70.0 ml) was added as solvent. The reaction temperature was raised to 85°C and the reaction was carried out for 48 h. After the reaction, the solvent was removed by vacuum distillation to obtain azophenyl azamethylenedipyrrole in a yield of 22%.

[0061] 2) Azophenyl azamethylenedipyrrole (0.85 g, 1.0 mmol) was weighed into a two-necked flask and maintained under nitrogen. Anhydrous dichloromethane (25.0 ml) was then added to the reaction flask via syringe, followed by DIEA (1.04 g, 8.0 mmol). After stirring at room temperature for half an hour, boron trifluoride etherate (10.0 mmol) was added to the reaction system via syringe and allowed to react at room temperature for 24 hours. The solvent was removed by rotary evaporation, and the resulting crude product was separated by column chromatography (mobile phase: DCM) to obtain the azophenyl BODIPY core in a 59% yield.

[0062] 3) Azophenyl BODIPY core (0.45 g, 0.5 mmol) was dissolved in dichloromethane (33.0 ml) and stirred. Acetonitrile (30.0 ml) was added, followed by N-(2-azidoethyl)-3,4,5-tris(2-(2-(-2-methoxyethoxy)ethoxy)ethoxy)benzamide (1.02 g, 1.5 mmol). CuI (47.5 mg, 0.25 mmol) and DIEA (0.20 g, 1.5 mmol) were added. The mixture was heated to 50°C and reacted for 1 hour. The reaction mixture was dried by rotary evaporation and the crude product was separated by column chromatography (mobile phase: DCM:methanol = 30:1). The mixture was rotary evaporation again, and the product flask was sealed with tin foil for storage. The product was dried under vacuum to obtain a purple solid compound with a yield of 51%. As shown in the attached figure, the reaction mixture was dried by rotary evaporation. Figure 2 shown.

[0063]

[0064] Example 7. Compound Aza-BODIPY molecule 3

[0065] 1) Propynyl-substituted azamethylenedipyrrole (0.59 g, 1.0 mmol) was weighed into a reaction flask, 4,4'-dibromoethaneazobenzene (0.43 g, 1.0 mmol) was added, and DMF (50.0 ml) was added as solvent. The reaction temperature was raised to 80°C and the reaction was carried out for 52 h. After the reaction, the solvent was removed by vacuum distillation to obtain azophenyl azamethylenedipyrrole in a yield of 20%;

[0066] 2) Azophenyl azamethylenedipyrrole (0.85 g, 1.0 mmol) was weighed into a two-necked flask and maintained under nitrogen. Anhydrous dichloromethane (15.0 ml) was then added to the reaction flask via syringe, followed by DIEA (0.65 g, 5.0 mmol). After stirring at room temperature for half an hour, boron trifluoride etherate (6.0 mmol) was added to the reaction system via syringe and allowed to react at room temperature for 24 hours. The solvent was removed by rotary evaporation, and the resulting crude product was separated by column chromatography (mobile phase: DCM) to obtain the azophenyl BODIPY core in a 60% yield.

[0067] 3) Azophenyl BODIPY core (0.45 g, 0.5 mmol) was dissolved in dichloromethane (30.0 ml) and stirred. Acetonitrile (30.0 ml) was added, followed by N-(2-azidoethyl)-3,4,5-tris(S)-2-(2-methoxyethoxy)propoxy)benzamide (0.59 g, 1.0 mmol). CuI (9.5 mg, 0.05 mmol) and DIEA (0.13 g, 1.0 mmol) were added. The mixture was heated to 45°C and reacted for 2 hours. The reaction mixture was then dried by rotary evaporation and the crude product was separated by column chromatography (mobile phase: DCM:methanol = 30:1). The mixture was rotary evaporation again, the product flask was sealed with tin foil, and vacuum dried to obtain a purple solid compound in a 50% yield.

[0068] NMR spectrum is attached Figure 3 As shown, the chemical shifts and integrals are: δ8.07–8.04 (m, 4H), 8.03 (dd, J = 4.6, 1.8 Hz, 4H), 8.00–7.85 (m, 6H), 7.73 (d, J = 2.2 Hz, 2H), 7.47–7.38 (m, 6H), 7.27 (s, 2H), 7.09 (d, J = 1.9 Hz, 4H), 7.06 (t, J = 5.4 Hz, 4H), 7.0 2(s,2H),5.25(d,J=3.4Hz,4H),4.67–4.60(m,4H),4.22–4.15(m,12H),3.95–3.87(m,4H),3.82–3.76(m,12H),3.71–3.62(m,16H),3.55–3.50(m,10H),3.37–3.31(m,36H), all corresponding to the target substances.

[0069]

[0070] Example 8. Compound Aza-BODIPY molecule 3

[0071] 1) Propynyl-substituted azamethylenedipyrrole (0.89 g, 1.5 mmol) was weighed into a reaction flask, 4,4'-dibromoethaneazobenzene (0.43 g, 1.0 mmol) was added, and DMF (60.0 ml) was added as solvent. The reaction temperature was raised to 82°C and the reaction was carried out for 50 h. After the reaction, the solvent was removed by vacuum distillation to obtain azophenyl azamethylenedipyrrole in a yield of 22%;

[0072] 2) Azophenyl azamethylenedipyrrole (0.85 g, 1.0 mmol) was weighed into a two-necked flask and maintained under nitrogen. Anhydrous dichloromethane (20.0 ml) was then added to the reaction flask via syringe, followed by DIEA (0.85 g, 6.5 mmol). After stirring at room temperature for half an hour, boron trifluoride etherate (8.0 mmol) was added to the reaction system via syringe and allowed to react at room temperature for 18 hours. The solvent was removed by rotary evaporation, and the resulting crude product was separated by column chromatography (mobile phase: DCM) to obtain the azophenyl BODIPY core in a 59% yield.

[0073] 3) Azophenyl BODIPY core (0.45 g, 0.5 mmol) was dissolved in dichloromethane (30.0 ml) and stirred. Acetonitrile (33.0 ml) was added, followed by N-(2-azidoethyl)-3,4,5-tris(S)-2-(2-methoxyethoxy)propoxy)benzamide (0.74 g, 1.25 mmol). CuI (34.2 mg, 0.18 mmol) and DIEA (0.16 g, 1.25 mmol) were added. The mixture was heated to 48°C and reacted for 1.5 hours. The reaction mixture was then dried by rotary evaporation and the crude product was separated by column chromatography (mobile phase: DCM:methanol = 30:1). The mixture was rotary evaporation again, and the product flask was sealed with tin foil for storage. The product was then dried under vacuum to obtain a purple solid compound with a yield of 50%. The NMR spectrum is shown in the attached figure. Figure 3 shown.

[0074]

[0075] Example 9. Compound Aza-BODIPY molecule 3

[0076] 1) Propynyl-substituted azamethylenedipyrrole (1.18 g, 2.0 mmol) was weighed into a reaction flask, 4,4'-dibromoethaneazobenzene (0.43 g, 1.0 mmol) was added, and DMF (70.0 ml) was added as solvent. The reaction temperature was raised to 85°C and the reaction was carried out for 48 h. After the reaction, the solvent was removed by vacuum distillation to obtain azophenyl azamethylenedipyrrole in a yield of 22%.

[0077] 2) Azophenyl azamethylenedipyrrole (0.85 g, 1.0 mmol) was weighed into a two-necked flask and maintained under nitrogen. Anhydrous dichloromethane (25.0 ml) was then added to the reaction flask via syringe, followed by DIEA (1.04 g, 8.0 mmol). After stirring at room temperature for half an hour, boron trifluoride etherate (10.0 mmol) was added to the reaction system via syringe and allowed to react at room temperature for 24 hours. The solvent was removed by rotary evaporation, and the resulting crude product was separated by column chromatography (mobile phase: DCM) to obtain the azophenyl BODIPY core in a 59% yield.

[0078] 3) Azophenyl BODIPY core (0.45 g, 0.5 mmol) was dissolved in dichloromethane (33.0 ml) and stirred. Acetonitrile (30.0 ml) was added, followed by N-(2-azidoethyl)-3,4,5-tris(S)-2-(2-methoxyethoxy)propoxy)benzamide (0.89 g, 1.5 mmol). CuI (47.5 mg, 0.25 mmol) and DIEA (0.20 g, 1.5 mmol) were added. The mixture was heated to 50°C and reacted for 1 hour. The reaction mixture was then dried by rotary evaporation and the crude product was separated by column chromatography (mobile phase: DCM:methanol = 30:1). The mixture was rotary evaporation again, and the product flask was sealed with tin foil for storage. The product was then dried under vacuum to obtain a purple solid compound with a yield of 51%. The NMR spectrum is shown in the attached figure. Figure 3 shown.

[0079]

[0080] Example 10. Compound Aza-BODIPY molecule 4

[0081] 1) Propynyl-substituted azamethylenedipyrrole (0.59 g, 1.0 mmol) was weighed into a reaction flask, 4,4'-dibromoethaneazobenzene (0.43 g, 1.0 mmol) was added, and DMF (50.0 ml) was added as solvent. The reaction temperature was raised to 80°C and the reaction was carried out for 52 h. After the reaction, the solvent was removed by vacuum distillation to obtain azophenyl azamethylenedipyrrole in a yield of 20%;

[0082] 2) Azophenyl azamethylenedipyrrole (0.85 g, 1.0 mmol) was weighed into a two-necked flask and maintained under nitrogen. Anhydrous dichloromethane (15.0 ml) was then added to the reaction flask via syringe, followed by DIEA (0.65 g, 5.0 mmol). After stirring at room temperature for half an hour, boron trifluoride etherate (6.0 mmol) was added to the reaction system via syringe and allowed to react at room temperature for 24 hours. The solvent was removed by rotary evaporation, and the resulting crude product was separated by column chromatography (mobile phase: DCM) to obtain the azophenyl BODIPY core in a 60% yield.

[0083] 3) Azophenyl BODIPY core (0.45 g, 0.5 mmol) was dissolved in dichloromethane (30.0 ml) and stirred. Acetonitrile (30.0 ml) was added, followed by N-(2-azidoethyl)-3,4,5-tris(S)-2-(2-(2-methoxyethoxy)ethoxy)propoxy)benzamide (0.72 g, 1.0 mmol). CuI (9.5 mg, 0.05 mmol) and DIEA (0.13 g, 1.0 mmol) were added. The mixture was heated to 45°C and reacted for 2 hours. The reaction mixture was then dried by rotary evaporation and the crude product was separated by column chromatography (mobile phase: DCM:methanol = 30:1). The mixture was rotary evaporation again, the product flask was sealed with tin foil, and vacuum dried to obtain a purple solid compound in a 50% yield.

[0084] NMR spectrum is attached Figure 4 As shown, the chemical shifts and integrals are: δ8.07–8.04 (m, 4H), 8.03 (dd, J = 4.6, 1.8 Hz, 4H), 8.00–7.85 (m, 6H), 7.73 (d, J = 2.2 Hz, 2H), 7.47–7.38 (m, 6H), 7.27 (s, 2H), 7.09 (d, J = 1.9 Hz, 4H), 7.06 (t, J = 5.4 Hz, 4H), 7.0 2(s,2H),5.25(d,J=3.4Hz,4H),4.67–4.60(m,4H),4.22–4.15(m,12H),3.95–3.87(m,4H),3.82–3.76(m,12H),3.71–3.62(m,36H),3.55–3.50(m,12H),3.37–3.31(m,36H), all corresponding to the target substances.

[0085]

[0086] Example 11. Compound Aza-BODIPY molecule 4

[0087] 1) Propynyl-substituted azamethylenedipyrrole (0.89 g, 1.5 mmol) was weighed into a reaction flask, 4,4'-dibromoethaneazobenzene (0.43 g, 1.0 mmol) was added, and DMF (60.0 ml) was added as solvent. The reaction temperature was raised to 82°C and the reaction was carried out for 50 h. After the reaction, the solvent was removed by vacuum distillation to obtain azophenyl azamethylenedipyrrole in a yield of 22%;

[0088] 2) Azophenyl azamethylenedipyrrole (0.85 g, 1.0 mmol) was weighed into a two-necked flask and maintained under nitrogen. Anhydrous dichloromethane (20.0 ml) was then added to the reaction flask via syringe, followed by DIEA (0.85 g, 6.5 mmol). After stirring at room temperature for half an hour, boron trifluoride etherate (8.0 mmol) was added to the reaction system via syringe and allowed to react at room temperature for 18 hours. The solvent was removed by rotary evaporation, and the resulting crude product was separated by column chromatography (mobile phase: DCM) to obtain the azophenyl BODIPY core in a 59% yield.

[0089] 3) Azophenyl BODIPY core (0.45 g, 0.5 mmol) was dissolved in dichloromethane (30.0 ml) and stirred. Acetonitrile (33.0 ml) was added, followed by NN-(2-azidoethyl)-3,4,5-tris(S)-2-(2-(2-methoxyethoxy)ethoxy)propoxy)benzamide (0.90 g, 1.25 mmol). CuI (34.2 mg, 0.18 mmol) and DIEA (0.16 g, 1.25 mmol) were added. The mixture was heated to 48°C and reacted for 1.5 hours. The reaction mixture was then dried by rotary evaporation and the crude product was separated by column chromatography (mobile phase: DCM:methanol = 30:1). The mixture was rotary evaporation again, and the product flask was sealed with tin foil for storage. The product was then dried under vacuum to obtain a purple solid compound with a yield of 50%. The NMR spectrum is shown in the attached figure. Figure 4 shown.

[0090]

[0091] Example 12. Compound Aza-BODIPY molecule 4

[0092] 1) Propynyl-substituted azamethylenedipyrrole (1.18 g, 2.0 mmol) was weighed into a reaction flask, 4,4'-dibromoethaneazobenzene (0.43 g, 1.0 mmol) was added, and DMF (70.0 ml) was added as solvent. The reaction temperature was raised to 85°C and the reaction was carried out for 48 h. After the reaction, the solvent was removed by vacuum distillation to obtain azophenyl azamethylenedipyrrole in a yield of 22%.

[0093] 2) Azophenyl azamethylenedipyrrole (0.85 g, 1.0 mmol) was weighed into a two-necked flask and maintained under nitrogen. Anhydrous dichloromethane (25.0 ml) was then added to the reaction flask via syringe, followed by DIEA (1.04 g, 8.0 mmol). After stirring at room temperature for half an hour, boron trifluoride etherate (10.0 mmol) was added to the reaction system via syringe and allowed to react at room temperature for 24 hours. The solvent was removed by rotary evaporation, and the resulting crude product was separated by column chromatography (mobile phase: DCM) to obtain the azophenyl BODIPY core in a 59% yield.

[0094] 3) Azophenyl BODIPY core (0.45 g, 0.5 mmol) was dissolved in dichloromethane (33.0 ml) and stirred. Acetonitrile (30.0 ml) was added, followed by N-(2-azidoethyl)-3,4,5-tris(S)-2-(2-(2-methoxyethoxy)ethoxy)propoxy)benzamide (1.08 g, 1.5 mmol). CuI (47.5 mg, 0.25 mmol) and DIEA (0.20 g, 1.5 mmol) were added. The mixture was heated to 50°C and reacted for 1 hour. The reaction mixture was then dried by rotary evaporation and the crude product was separated by column chromatography (mobile phase: DCM:methanol = 30:1). The mixture was rotary evaporation again, and the product flask was sealed with tin foil for storage. The product was then dried under vacuum to obtain a purple solid compound with a yield of 51%. The NMR spectrum is shown in the attached figure. Figure 4 shown.

[0095] .

[0096] The technical solutions disclosed and proposed by the present invention can be implemented by those skilled in the art by drawing on the content of this document and appropriately changing the conditions, routes, and other aspects. Although the methods and preparation techniques of the present invention have been described through preferred embodiments, it is obvious that those skilled in the art can modify or recombine the methods and technical routes described herein without departing from the content, spirit, and scope of the present invention to achieve the ultimate preparation technology. It is particularly important to point out that all similar substitutions and modifications that are obvious to those skilled in the art are considered to be included in the spirit, scope, and content of the present invention.

Claims

1. A class of amphiphilic Aza-BODIPY dyes containing azophenyl groups, characterized in that: The structure of the dye is as follows:

2. The method for preparing the amphiphilic Aza-BODIPY dye containing an azophenyl group according to claim 1, characterized in that: The steps include: 1) reacting 4,4'-dibromoethaneazobenzene with 1,7-bis(4-hydroxyphenyl)-3,5-bis(4-propynyloxy)azamethylenedipyrrole to obtain an azomethylenedipyrrole containing an azophenyl group; 2) Azobenzene-containing azomethylenedipyrrole reacts with boron trifluoride etherate to obtain a BODIPY core containing an azobenzene group; 3) The BODIPY core structure containing an azophenyl group is introduced into a benzamide containing a hydrophilic chain R through a click reaction to obtain an amphiphilic Aza-BODIPY dye containing an azophenyl group; The reaction formula is as follows:

3. The preparation method according to claim 2, wherein: The reaction of step 1) is as follows: 4,4'-dibromoethaneazobenzene and 1,7-bis(4-hydroxyphenyl)-3,5-bis(4-propynyloxy)azamethylenedipyrrole are added to a reaction flask, DMF is used as a solvent, the reaction temperature is raised to 80-85°C, and the reaction is carried out for 48-52 hours.

4. The preparation method according to claim 3, wherein: The reaction molar ratio of 4,4'-dibromoethaneazobenzene and 1,7-bis(4-hydroxyphenyl)-3,5-bis(4-propynyloxy)azamethylenedipyrrole is 1-1.2:1-2.

5. The preparation method according to claim 2, wherein: The reaction of step 2) is as follows: under nitrogen protection, azodipyrrolidine containing an azophenyl group, N,N-diisopropylethylamine and boron trifluoride etherate are added to a reaction flask, dry dichloromethane is added as a solvent, and the reaction is carried out at room temperature for 12 to 24 hours.

6. The preparation method according to claim 2, wherein: The reaction of step 3) is as follows: adding the BODIPY core containing an azophenyl group, benzamide containing a hydrophilic chain R, N,N-diisopropylethylamine, and iodide to a mixed solvent of acetonitrile:dichloromethane with a volume ratio of 1-1.2:1-1.1, and stirring at 45-50° C. for 1-2 hours.

7. The preparation method according to claim 6, characterized in that: The reaction molar ratio of the BODIPY mother core containing an azophenyl group, benzamide containing a hydrophilic chain R, N,N-diisopropylethylamine, and iodinated ketone is 1:2-3:2-3:0.1-0.5.

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