Amphipathic near-infrared two-region aza-BODIPY dye and preparation method thereof

Abstract

The invention relates to an amphiphilic near-infrared two-region aza-BODIPY dye and a preparation method thereof, the dye has the following general formula structure: aza-BODIPY 3 and 5 sites are respectively connected with a benzene ring; substituent groups R1, R2 and R3 are independently connected to the para-position and two meta-positions of each benzene ring respectively; r1, R2 and R3 are independently selected from hydrogen, propargyl connected through an oxygen atom or bis (propargyl) amino connected through a nitrogen atom; wherein at least one of R1, R2 and R3 on each benzene ring is propargyl or bis (propargyl) amino; moreover, the terminal alkynyl in the propargyl group or the bis (propargyl) amino group is optionally connected with a diethylene glycol monomethyl ether chain through a click chemical reaction, and the structure of the diethylene glycol monomethyl ether chain is-(OCHCH) 2-OCH. The invention relates to aza-BODIPY (aza-BODIPY) fluorescent dye with strong absorption and emission in a near-infrared second region and an efficient preparation method of the aza-BODIPY fluorescent dye.

Description

Technical Field

[0001] This invention relates to the field of organic functional dye synthesis technology, specifically to a class of aza-BODIPY fluorescent dyes exhibiting strong absorption and emission in the near-infrared II region (NIR-II, 900-1700 nm) and their efficient preparation method. These dyes achieve excellent amphiphilicity and biocompatibility by introducing modifiable alkynyl groups into their benzene ring side chains and further linking them with hydrophilic polyethylene glycol chains, making them suitable for applications in biomedical imaging, photothermal therapy (PTT), and other fields. Background Technology

[0002] Near-infrared II (NIR-II, 1000-1700 nm) fluorescence imaging has attracted much attention in the biomedical field due to its deeper tissue penetration and lower autofluorescence background. The development of this technology urgently requires high-performance small-molecule fluorescent dyes with emission wavelengths located in this window. Aza-BODIPY is a classic fluorophore with a high molar extinction coefficient and good photostability, but its intrinsic absorption and emission are usually located in the visible light or near-infrared I (NIR-I) region. To effectively redshift the spectrum of dyes into the NIR-II region, common molecular engineering strategies include extending π-conjugated systems (J. Wang, C. Yu, E. Hao, L. Jiao, Coord. Chem. Rev. 2022, 470, 214709.) and constructing strong push-pull structures (J. Su, X. Zhang, Z. Dong, H. Pan, F. Zhang, X. Li, S. Wang, Z. Chen, ACS Appl. Mater. Interfaces 2024, 16, 51241-51252.). However, while pursuing redshift, these strategies often face challenges such as complex synthesis, increased molecular hydrophobicity, or intensified nonradiative decay, which limits the practical application performance of the dyes (X. Li, Y. Yang, R. Zhang, W. Huang, Chem. Soc. Rev. 2025, 54, 11184-11225.). In recent years, julonidine with a rigid planar structure (9-aldehyde julonidine (CAS: 33985-71-6)) is a molecular formula C 13 H 15Heterocyclic aldehydes of NO are mainly used in dye-sensitized solar cells (DSSCs) and as intermediates in organic synthesis. The chemical name of 9-aldehyde julonidine is 2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinazine-9-carboxaldehyde. Its structure uses a tricyclic fused system as the parent nucleus, with an aldehyde group attached at position 9 to form an α,β-unsaturated conjugated system. With a molecular weight of 201.26, an exact mass of 201.115, and a LogP value of 2.74 (indicating moderate lipophilicity), it is introduced as a strong electron donor into the aza-BODIPY system, providing a new approach to promote intramolecular charge transfer and achieve efficient spectral redshift. For example, Bai et al. reported that julonidine-modified dyes successfully pushed the emission wavelength to 1060 nm, verifying the effectiveness of this group (L. Bai, P. Sun, Y. Liu, H. Zhang, W. Hu, W. Zhang, Z. Liu, Q. Fan, L. Li, W. Huang, Chem. Commun. 2019, 55, 10920-10923.). Despite preliminary explorations, how to further and stably push the emission of aza-BODIPY into the NIR-II long-wavelength region (>1100 nm) through systematic molecular design remains a key focus and challenge in current research. Summary of the Invention

[0003] The purpose of this invention is to provide a novel class of functionalizable aza-BODIPY fluorescent dyes with NIR-II optical properties and a simple and efficient preparation method. This invention introduces strong electron-donating julonidin groups at positions 1 and 7 of the aza-BODIPY core, designs and synthesizes a series of novel derivatives, and explores the enhancing effect of this structural unit on the spectral redshift. Results show that this strategy effectively promotes intramolecular charge transfer, enabling the emission of all target dyes to cover the NIR-II window. The optimal dye achieves a maximum emission wavelength of 1109 nm in polar solvents, significantly expanding the NIR-II emission capability of this type of dye. Simultaneously, at least one propargyloxy or bis(propargyl)amino group is introduced as an intermediate on the benzene ring at positions 3 and 5, and can be further linked to a diethylene glycol monomethyl ether chain via click chemistry. This approach maintains the excellent optical properties of the dye core while endowing it with good water solubility and amphiphilicity, providing a new material basis for constructing high-performance NIR-II biological probes.

[0004] The technical solution of the present invention is as follows:

[0005] Amphiphilic near-infrared II region azirfluoroboron dipyrrole dyes have the following general formula:

[0006]

[0007] In aza-BODIPY, a benzene ring is attached to each of the 3 and 5 positions; each benzene ring has a substituent R1, R2, and R3 independently attached to the para and two meta positions; R1, R2, and R3 are each independently selected from: hydrogen, propargyloxy group connected by an oxygen atom, or bis(propargyl)amino group connected by a nitrogen atom; at least one of R1, R2, and R3 on each benzene ring is propargyloxy or bis(propargyl)amino; and, optionally, a diethylene glycol monomethyl ether chain with the structure -(OCH2CH2)2-OCH3 is attached to the terminal alkynyl group of the propargyloxy or bis(propargyl)amino group via a click chemistry reaction.

[0008] The amphiphilic near-infrared II-region azirfluoroboron dipyrrole dye of the present invention comprises substances with the following structure

[0009] Both R3 groups on the two benzene rings are bis(propynyl)amino groups, and both R1 and R2 are hydrogens, with a -(OCH2CH2)2-OCH3 chain attached to the terminal alkynyl group; the compound is named BF2-ADP-982;

[0010] Both R3 groups on the two benzene rings are propargyloxy groups, and both R1 and R2 are hydrogen atoms, with a -(OCH2CH2)2-OCH3 chain attached to the terminal alkynyl group; the compound is named BF2-ADP-1005;

[0011] R1 and R2 on both benzene rings are propargyloxy groups, R3 is hydrogen, and a -(OCH2CH2)2-OCH3 chain is attached to the terminal alkynyl group; the compound is named BF2-ADP-1050;

[0012] R1, R2, and R3 on both benzene rings are all propargyloxy groups, and a -(OCH2CH2)2-OCH3 chain is attached to the terminal alkynyl group; the compound is named BF2-ADP-1035.

[0013] The preparation method of the amphiphilic near-infrared II region azirconium fluoride boron dipyrrole dye of the present invention is shown in the following equation:

[0014]

[0015] In this case, each of the benzene rings 5a-d has a substituent R1, R2, R3 independently attached to the para and two meta positions; R1, R2, R3 are each independently selected from: hydrogen, propargyloxy, or bis(propargyl)amino; and at least one of R1, R2, R3 on each benzene ring is propargyloxy or bis(propargyl)amino.

[0016] The preparation method of the amphiphilic near-infrared II region azirconium fluoride boron dipyrrole dye includes the following steps:

[0017] 1) An aromatic ketone with known substituents R1, R2, and R3 undergoes an aldol condensation reaction with 9-aldehyde juulonidine to yield a chalcone intermediate:

[0018] 2) The chalcone intermediate is subjected to a Michael addition reaction with nitromethane to obtain a nitromethane intermediate;

[0019] 3) The nitroalkane intermediate is refluxed with ammonium acetate in n-butanol to undergo cyclization condensation, yielding the aziridinemethylene ligand;

[0020] 4) Complex the aza-dipyrrolemethane ligand with boron trifluoride diethyl ether to obtain the aza-BODIPY intermediate;

[0021] 5) The azido-alkynyl cycloaddition reaction catalyzed by cuprous iodide is used to attach the azido-polyethylene glycol monomethyl ether chain to the alkynyl group of the aza-BODIPY intermediate in step 4) to obtain the target dye.

[0022] In step 1), the aromatic ketones with the determined substituents R1, R2, and R3 and 9-aldehyde juulonidine are added to a round-bottom flask, ethanol is added as a solvent, and then a 20%~25% (w / w) sodium hydroxide aqueous solution is prepared and added to the system. After stirring at room temperature for 20~24 h, an orange solid is precipitated. After filtration and washing, a chalcone intermediate is obtained, which is an orange solid. The molar ratio of aromatic ketone, 9-aldehyde juulonidine, and sodium hydroxide is 1.0:1.0~1.1:5.0~5.5.

[0023] In step 2), the chalcone intermediate and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added to a round-bottom flask, ethanol is added as a solvent, the temperature is raised to 80~85 ℃ and stirred for 0.5~1.0 h, nitromethane is added, and the reaction continues for 20~24 h. After the reaction is completed, the solvent is removed by rotary evaporation, the mixture is extracted with dichloromethane, dried with anhydrous magnesium sulfate, filtered, the solvent is removed by rotary evaporation, and column chromatography is performed. The mobile phase is dichloromethane:petroleum ether = 5.0~6.0:1.0 (v:v) to obtain the nitromethane intermediate, which is a yellow oily substance. The molar ratio of chalcone intermediate, DBU and nitromethane is 1.0:5.0~6.0:20.0~25.0.

[0024] In step 3), the nitroalkane intermediate is dissolved in n-butanol, ammonium acetate is added, and the mixture is heated to 115-120 °C and refluxed for 12-15 h. After the reaction is completed, the mixture is cooled to room temperature, the solvent is removed by rotary evaporation, the mixture is extracted with dichloromethane, dried with anhydrous magnesium sulfate, filtered, and the solvent is removed by rotary evaporation to obtain the aziridine dipyrrolemethane ligand, which is a dark blue solid. The molar ratio of the nitroalkane intermediate to ammonium acetate is 1.0:20.0-25.0.

[0025] In step 4), the aza-dipyrrolemethane ligand is added to a two-necked round-bottom flask under nitrogen protection, dissolved in anhydrous dichloromethane, and then N,N-diisopropylethylamine is added. The mixture is stirred at room temperature for 30-50 min, followed by the addition of boron trifluoride ethyl ether. The reaction continues at room temperature for 20-24 h. After the reaction is complete, water is added to quench the reaction, and the mixture is extracted with dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and the solvent is removed by rotary evaporation. The mixture is then purified by column chromatography with a mobile phase of dichloromethane:methanol = 100-120:1 (v:v) to obtain the aza-BODIPY intermediate, which is a green solid. The molar ratio of the aza-dipyrrolemethane ligand, N,N-diisopropylethylamine, and boron trifluoride ethyl ether is 1.0:10.0-15.0:15.0-20.0.

[0026] In step 5), the aza-BODIPY intermediate, azido-modified polyethylene glycol monomethyl ether chain, cuprous iodide, and N,N-diisopropylethylamine are added to a mixed solvent, which is a mixture of dichloromethane and acetonitrile with a volume ratio of 1:1~1.2. The mixture is heated to 55~60℃ and reacted for 8~8.5 h. After the reaction, the solvent is removed by rotary evaporation, and the mixture is extracted with dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and the solvent is removed by rotary evaporation. The mixture is then purified by column chromatography with a mobile phase of DCM:MeOH = 30~40:1 (v:v) to obtain the target dye, which is a deep blue solid. The molar ratio of the aza-BODIPY intermediate, azido-modified polyethylene glycol monomethyl ether chain, cuprous iodide, and N,N-diisopropylethylamine is 1.0:6.0~8.0:0.1~0.2:5.0~6.0.

[0027] Structural characterization methods and results

[0028] 1. Nuclear magnetic resonance spectroscopy analysis

[0029] The target compound was analyzed at room temperature using a Bruker AVANCE III HD 500 MHz or a JEOL JNM ECZ600R nuclear magnetic resonance spectrometer. 1 H NMR and 13 C10 NMR determination. Samples were dissolved in deuterated chloroform (CDCl3) at a moderate concentration to ensure clear signals and prevent aggregation. Chemical shifts (δ) are reported in ppm.1 The H NMR spectrum used the residual solvent peak in tetramethylsilane (TMS, δ = 0.00 ppm) or CDCl3 (δ = 7.26 ppm) as internal standards; 13 The C10 NMR spectra used the central triplet of CDCl3 (δ = 77.0 ppm) as an internal standard. Acquisition parameters included sufficient spectral width, acquisition time, and number of accumulations to ensure adequate signal resolution and signal-to-noise ratio. All spectra clearly showed the hydrogen and carbon atom signals corresponding to the target molecular structure. The chemical shifts, integral area ratios, and coupling splitting modes (such as singlets, doublets, and multiplets) of each signal peak were reasonably assigned, thus confirming the correctness of the molecular structure at the atomic connection level.

[0030] 2. High-resolution mass spectrometry analysis

[0031] The precise molecular weights of the compounds were determined using a MicroTOF-Q II high-resolution mass spectrometer, employing an electrospray ionization source and acquiring data in positive ion mode. Samples were dissolved in a suitable volatile solvent (dichloromethane) and injected directly. In the resulting mass spectra, the measured mass-to-charge ratio (m / z) of the molecular ion peaks of the target compounds (e.g., [M+H]⁺ or [M+Na]⁺) was compared with the theoretical values ​​calculated based on their molecular formulas. The deviations between the measured and theoretical values ​​for all target dyes met the criteria for high-resolution confirmation, thus confirming the composition of the synthesized products at the molecular formula level.

[0032] Absorption and emission spectroscopy test methods and results

[0033] 1. Ultraviolet-Visible-Near Infrared Absorption Spectroscopy

[0034] Absorption spectra were acquired using a Shimadzu UV-3600 UV-Vis-NIR spectrophotometer. Tests were conducted at a constant temperature of 25°C using paired quartz cuvettes (10 mm path length). Each target dye was precisely prepared to a concentration of 1.0 × 10⁻⁶. -5 A dichloromethane solution of M was used to ensure the absorbance fell within the instrument's linear response range. Using the pure solvent as a reference, scans were performed within a set wavelength range (e.g., 350-1200 nm) at a moderate scan rate. The complete absorption curve was recorded, and its maximum absorption wavelength (λ) was determined. max According to the Lambert-Beer law (A = εcl), the molar absorptivity (ε) corresponding to each major absorption band is calculated from the measured absorbance (A), known concentration (c), and optical path (l). For example... Figure 13 As shown, this series of dyes all exhibit strong near-infrared absorption in dichloromethane, with maximum absorption wavelengths between 827 nm and 900 nm, and the molar absorptivity of the main absorption bands are all above 10. 4 M-1 ·cm -1 The magnitude of the sample confirms its absorption capacity as a near-infrared dye.

[0035] 2. Fluorescence spectrum

[0036] Steady-state fluorescence spectra were measured using an Edinburgh FLS 1000 fluorescence spectrometer. A xenon lamp was used as the excitation source, equipped with a monochromator to select the excitation wavelength. Tests were conducted at room temperature using four-sided transparent quartz fluorescence cuvettes (10 mm × 10 mm). Samples were also prepared in 1.0 × 10⁻⁻⁻⁶ mm configurations. 5 M is a dichloromethane solution. The excitation wavelength is set to 720 nm. The emission signal is dispersed by an emission monochromator and then acquired by a near-infrared detector. The emission spectrum is corrected for wavelength and intensity response using the calibration file provided with the instrument to obtain the true emission spectrum shape. Figure 14 As shown, all dyes exhibit significant near-infrared emission, with a maximum emission wavelength (λ). em The emission values ​​are located between 982 nm and 1050 nm, with the maximum emission values ​​of BF2-ADP-1005, BF2-ADP-1050, and BF2-ADP-1035 clearly falling within the second near-infrared window of 1000-1700 nm. The spectral shape shows a certain mirror relationship with the absorption spectrum, further confirming that the emission originates from the observed absorption transition.

[0037] The superior effects of this invention are as follows:

[0038] 1) Excellent NIR-II optical performance: A series of aza-BODIPY dyes prepared all exhibited strong near-infrared absorption and emission in dichloromethane. Among them, BF2-ADP-1005, BF2-ADP-1050, and BF2-ADP-1035 had maximum emission wavelengths of 1005 nm, 1050 nm, and 1035 nm, respectively, clearly entering the NIR-II window; the emission of BF2-ADP-982 was also located at 982 nm, close to the NIR-II boundary. The optimal dye, BF2-ADP-1050, further red-shifted its maximum absorption wavelength to 1109 nm in the polar solvent DMSO, providing a crucial optical basis for deep tissue imaging.

[0039] 2) Flexible structural modification: Nitrogen / oxygen linking atoms and terminal alkynyl groups are pre-introduced onto the 3,5-benzene ring of the dye, providing universal sites for subsequent modular derivatization. The introduction of the diethylene glycol monomethyl ether chain into the molecule results in mild reaction conditions and high yields. This design allows for the flexible replacement of the dye's hydrophilic segments, targeting groups, or other functional modules in the final step, greatly enhancing the versatility and customizability of the molecular platform and laying the foundation for constructing multifunctional biological probes.

[0040] 3) Good amphiphilicity and biocompatibility: By linking the diethylene glycol monomethyl ether chain, the water solubility and dispersibility of the dye in physiological environments are significantly improved, which is beneficial for subsequent biological applications. Attached Figure Description

[0041] Figure 1 It is the dye of compound BF2-ADP-982. 1 H NMR spectrum;

[0042] Figure 2 It is the dye of compound BF2-ADP-982. 13 C NMR spectrum;

[0043] Figure 3 This is a high-resolution mass spectrometry of the dye BF2-ADP-982.

[0044] Figure 4 It is the dye of compound BF2-ADP-1005. 1 H NMR spectrum;

[0045] Figure 5 It is the dye of compound BF2-ADP-1005. 13 C NMR spectrum;

[0046] Figure 6 This is a high-resolution mass spectrometry of the dye BF2-ADP-1005.

[0047] Figure 7 It is the dye of compound BF2-ADP-1050. 1 H NMR spectrum;

[0048] Figure 8 It is the dye of compound BF2-ADP-1050. 13 C NMR spectrum;

[0049] Figure 9 This is a high-resolution mass spectrometry of the dye BF2-ADP-1050.

[0050] Figure 10 It is the dye of compound BF2-ADP-1035. 1 H NMR spectrum;

[0051] Figure 11 It is the dye of compound BF2-ADP-1035. 13 C NMR spectrum;

[0052] Figure 12 This is a high-resolution mass spectrometry of the dye BF2-ADP-1035.

[0053] Figure 13These are the UV-Vis-NIR absorption and emission spectra of four compounds;

[0054] Figure 14 These are the emission spectra of BF2-ADP-1050 in different polar solvents. Detailed Implementation

[0055] For ease of description, the four compounds are named BF2-ADP-982, BF2-ADP-1005, BF2-ADP-1050, and BF2-ADP-1035, respectively, based on their maximum emission wavelength.

[0056] Compound BF2-ADP-982: In this compound, R3 on both benzene rings is bis(propynyl)amino (-N-(CH2-C≡CH)2), R1 and R2 are both hydrogen (H), and a -(OCH2CH2)2-OCH3 chain is attached to the terminal alkynyl group.

[0057] Compound BF2-ADP-1005: In this compound, R3 on both benzene rings is propoxyl (-O-CH2-C≡CH), R1 and R2 are both hydrogen (H), and a -(OCH2CH2)2-OCH3 chain is attached to the terminal alkynyl group.

[0058] Compound BF2-ADP-1050: In this compound, R1 and R2 on both benzene rings are propoxy groups (-O-CH2-C≡CH), R3 is hydrogen (H), and a -(OCH2CH2)2-OCH3 chain is attached to the terminal alkynyl group.

[0059] Compound BF2-ADP-1035: In this compound, R1, R2, and R3 on both benzene rings are propargyloxy groups (-O-CH2-C≡CH), and a -(OCH2CH2)2-OCH3 chain is attached to the terminal alkynyl group.

[0060] The preparation method includes the following steps:

[0061] 1) Aromatic ketones with known substituents R1, R2, and R3 undergo aldol condensation with 9-aldehyde julonidine to yield chalcone intermediates;

[0062] 2) The chalcone intermediate is subjected to a Michael addition reaction with nitromethane to obtain a nitromethane intermediate;

[0063] 3) The nitroalkane intermediate is refluxed with ammonium acetate in n-butanol to undergo cyclization condensation, yielding the aziridinemethylene ligand;

[0064] 4) Complex the aza-dipyrrolemethane ligand with boron trifluoride diethyl ether to obtain the aza-BODIPY intermediate;

[0065] 5) The azido-alkynyl cycloaddition reaction catalyzed by cuprous iodide is used to attach the azido-polyethylene glycol monomethyl ether chain to the alkynyl group of the aza-BODIPY intermediate in step 4) to obtain the target dye.

[0066] In step 1), the aromatic ketones with the determined substituents R1, R2, and R3 and 9-aldehyde juulonidine are added to a round-bottom flask, ethanol is added as a solvent, and then a 20%~25% (w / w) sodium hydroxide aqueous solution is prepared and slowly added to the system. After stirring at room temperature for 20~24 h, an orange solid is precipitated. After filtration and washing, a chalcone intermediate is obtained, which is an orange solid. The molar ratio of aromatic ketone, 9-aldehyde juulonidine, and sodium hydroxide is 1.0:1.0~1.1:5.0~5.5.

[0067] In step 2), the chalcone intermediate and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added to a round-bottom flask, ethanol is added as a solvent, the temperature is raised to 80-85 °C and stirred for 0.5-1.0 h, nitromethane is added, and the reaction continues for 20-24 h. After the reaction is completed, the solvent is removed by rotary evaporation, and the mixture is extracted with dichloromethane (DCM), dried with anhydrous magnesium sulfate, filtered, and the solvent is removed by rotary evaporation. Column chromatography is then performed (mobile phase volume ratio: DCM: petroleum ether = 5.0-6.0:1.0) to obtain a nitromethane intermediate, which is a yellow oil. The molar ratio of chalcone intermediate, DBU, and nitromethane is 1.0:5.0-6.0:20.0-25.0.

[0068] In step 3), the nitroalkane intermediate is dissolved in n-butanol, ammonium acetate is added, and the mixture is heated to 115-120 °C and refluxed for 12-15 h. After the reaction is complete, the mixture is cooled to room temperature, the solvent is removed by rotary evaporation, extracted with DCM, dried over anhydrous magnesium sulfate, filtered, and the solvent is removed by rotary evaporation to obtain the aziridine dipyrrolemethane ligand, which is a dark blue solid. The molar ratio of the nitroalkane intermediate to ammonium acetate is 1.0:20.0-25.0.

[0069] In step 4), the aza-dipyrrolemethane ligand is added to a two-necked round-bottom flask under nitrogen protection, dissolved in anhydrous dichloromethane, and then N,N-diisopropylethylamine is added. The mixture is stirred at room temperature for 30-50 min, followed by the addition of boron trifluoride diethyl ether. The reaction continues at room temperature for 20-24 h. After the reaction is complete, water is added to quench the reaction, followed by extraction with dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and the solvent is removed by rotary evaporation. The mixture is then purified by column chromatography (mobile phase volume ratio: DCM:methanol (MeOH) = 100.0-120.0:1) to obtain the aza-BODIPY intermediate, which is a green solid. The molar ratio of the aza-dipyrrolemethane ligand, N,N-diisopropylethylamine, and boron trifluoride diethyl ether is 1.0:10.0-15.0:15.0-20.0.

[0070] In step 5), the aza-BODIPY intermediate, azido-modified polyethylene glycol monomethyl ether chain, cuprous iodide, and N,N-diisopropylethylamine are added to a mixed solvent, which is a mixture of dichloromethane and acetonitrile with a volume ratio of 1:1 to 1.2. The mixture is heated to 55 to 60°C and reacted for 8 to 8.5 h. After the reaction, the solvent is removed by rotary evaporation, and the mixture is extracted with dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and the solvent is removed by rotary evaporation. The mixture is then purified by column chromatography (mobile phase volume ratio: DCM:MeOH = 30 to 40:1) to obtain the target dye, which is a deep blue solid. The molar ratio of the aza-BODIPY intermediate, azido-modified polyethylene glycol monomethyl ether chain, cuprous iodide, and N,N-diisopropylethylamine is 1.0:6.0 to 8.0:0.1 to 0.2:5.0 to 6.0.

[0071] Example 1. Compound BF2-ADP-982

[0072]

[0073] 1) Weigh 2.0 g of compound 5a, i.e., 4-[bis(propynyl)amino]acetophenone, and dissolve 2.0 g of 9-aldehyde juulonidin in 20 mL of ethanol. Add 10.0 mL of 20% (w / w) sodium hydroxide (NaOH) aqueous solution dropwise. Stir the reaction at room temperature for 20 hours. After the reaction is complete, filter the solution, wash the solid with ethanol, and then wash with cold water until neutral to give 3.5 g of orange solid chalcone intermediate 4a, with a yield of 94%.

[0074] 2) Weigh 2.0 g of the chalcone intermediate 4a obtained in the previous step and dissolve it in 20 mL of ethanol along with 4.0 mL of 1,8-diazabicycloundec-7-ene (DBU). Heat the mixture to 80 °C and stir for 0.5 hours. Then, add 6.2 mL of nitromethane to the reaction system and continue stirring at 80 °C for 20 hours. After the reaction is complete, remove most of the solvent by rotary evaporation under reduced pressure. Extract the residue with dichloromethane, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate. Purify the crude product by column chromatography (eluent: dichloromethane / petroleum ether = 5:1, v / v) to give 1.5 g of yellow oily nitromethane intermediate 3a, in 65% yield.

[0075] 3) Weigh 2.0 g of the nitroalkane intermediate 3a obtained in the previous step and dissolve it in 10 mL of n-butanol. Add 7.7 g of ammonium acetate to the solution. Heat the reaction mixture to 115 °C and reflux with stirring for 12 hours. After the reaction is complete, cool to room temperature and concentrate under reduced pressure to remove most of the n-butanol. Extract the residue with dichloromethane, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate to obtain a dark blue, thin-film-like aziridine methane ligand, which can be used directly in the next step of the reaction.

[0076] 4) Place the aza-dipyrrolemethane ligand obtained in the previous step (approximately 1.8 g theoretical amount) in a dry two-necked flask and purge it with nitrogen for protection. Add 30 mL of anhydrous dichloromethane to dissolve it. While stirring, add 3.6 mL of N,N-diisopropylethylamine (DIEA) and stir at room temperature for 30 minutes. Then, slowly add 4.2 mL of boron trifluoride diethyl ether (BF3·Et2O). After the addition is complete, continue stirring at room temperature for 20 hours under nitrogen protection. After the reaction is complete, add 20 mL of water to quench the reaction. Separate the organic phase, extract the aqueous phase with dichloromethane, combine the organic phases, dry with anhydrous magnesium sulfate, filter, and concentrate. The crude product obtained is purified by column chromatography (eluent: dichloromethane / methanol = 100:1, v / v) to give 0.4 g of green solid aza-BODIPY intermediate 2a (i.e., the precursor of BF2-ADP-982), with a yield of 21%.

[0077] 5) Weigh 0.5 g of the aza-BODIPY intermediate 2a obtained in the previous step, and add it together with 0.5 g of diethylene glycol monomethyl ether azide (compound 7), 0.02 g of cuprous iodide (CuI), and 0.40 mL of N,N-diisopropylethylamine (DIEA) into 20 mL of mixed solvent (dichloromethane:acetonitrile = 1:1, v / v). Heat the reaction mixture to 55 °C and stir under reflux for 8 hours. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. Dissolve and extract the residue with dichloromethane, combine the organic phases, dry with anhydrous magnesium sulfate, filter, and concentrate. The crude product is purified by column chromatography (eluent: dichloromethane / methanol = 30:1, v / v) to give 0.4 g of deep blue solid target dye BF2-ADP-982 (1a), with a yield of 48%. The 1H NMR spectrum is attached. Figure 1 As shown, the chemical shift and integral are: 1 H NMR (500 MHz, CDCl3) δ 8.01 (d, J = 9.1 Hz, 4H), 7.63 (s, 4H), 7.57 (s, 4H), 6.90 (d, J = 9.1 Hz, 4H), 4.79 (s, 8H), 4.51 (t, J = 5.1 Hz,8H), 3.83 (t, J = 5.1 Hz, 8H), 3.56 - 3.49 (m, 8H), 3.42 - 3.38 (m, 8H), 3.27(s, 12H), 3.25 (t, J = 5.8 Hz, 8H), 2.77 (t, J = 6.4 Hz, 8H), 1.99 (p, J =6.3 Hz, 8H). The carbon NMR spectrum is attached. Figure 2 As shown, the chemical shift and integral are: 13 C NMR (126 MHz, CDCl3) δ 154.94, 148.92, 144.75, 143.58, 141.91, 131.11, 128.26, 123.18, 121.34, 121.05, 114.12, 112.50, 77.32, 77.06, 76.81, 71.69, 70.53, 69.42, 58.99, 50.21, 46.68, 31.58, 27.99, 22.65, 21.83, 14.13, 0.00. All values ​​correspond one-to-one with the target substance. The mass spectrum is shown below. Figure 3 As shown, calculate C 76 H 95 BF2N 19 O8, molecular weight 1450.7602; experimentally determined [M+H]+ The molecular weight is 1450.7679. Confirmed by both mass spectrometry and NMR, it can be considered the target compound.

[0078] Example 2. Compound BF2-ADP-1005

[0079]

[0080] 1) Weigh 2.0 g of compound 5b, i.e., 4-propyneoxyacetophenone, and dissolve it with 2.4 g of 9-aldehyde juulonidin in 20 mL of ethanol. Add 12.0 mL of 22% (w / w) NaOH aqueous solution dropwise. Stir the reaction at room temperature for 22 hours. After the reaction is complete, filter the solution, wash the solid with ethanol, and then wash with cold water until neutral to give 3.5 g of orange solid chalcone intermediate 4b, with a yield of 85%.

[0081] 2) Weigh 2.5 g of the chalcone intermediate 4b obtained in the previous step and dissolve it in 20 mL of ethanol along with 5.4 g of 1,8-diazabicycloundec-7-ene (DBU). Heat the mixture to 82 °C and stir for 0.7 h. Then, add 4.3 mL of nitromethane to the reaction system and continue stirring at 82 °C for 22 h. After the reaction is complete, remove most of the solvent by rotary evaporation under reduced pressure. Extract the residue with dichloromethane, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate. The crude product is purified by column chromatography (eluent: dichloromethane / petroleum ether = 5.5:1, v / v) to give 1.8 g of a yellow oily nitromane intermediate 3b, in 62% yield.

[0082] 3) Weigh 2.5 g of the nitroalkane intermediate 3b obtained in the previous step and dissolve it in 10 mL of n-butanol. Add 9.6 g of ammonium acetate to the solution. Heat the reaction mixture to 117 °C and reflux with stirring for 12 hours. After the reaction is complete, cool to room temperature and concentrate under reduced pressure to remove most of the n-butanol. Extract the residue with dichloromethane, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate to obtain a dark blue, thin-film-like aziridine methane ligand, which can be used directly in the next step of the reaction.

[0083] 4) Place the aza-dipyrrolemethane ligand obtained in the previous step (approximately 2.0 g theoretical amount) in a dry two-necked flask and purge it with nitrogen. Add 30 mL of anhydrous dichloromethane to dissolve it. While stirring, add 4.5 mL of N,N-diisopropylethylamine (DIEA) and stir at room temperature for 40 minutes. Then, slowly add 5.4 mL of boron trifluoride diethyl ether (BF3·Et2O). After the addition is complete, continue stirring at room temperature for 22 hours under nitrogen protection. After the reaction is complete, add 20 mL of water to quench the reaction. Separate the organic phase, extract the aqueous phase with dichloromethane, combine the organic phases, dry with anhydrous magnesium sulfate, filter, and concentrate. The crude product obtained is purified by column chromatography (eluent: dichloromethane / methanol = 110:1, v / v) to give 0.9 g of green solid aza-BODIPY intermediate 2b (i.e., the precursor of BF2-ADP-1005), with a yield of 38%.

[0084] 5) Weigh 0.5 g of the aza-BODIPY intermediate 2b obtained in the previous step, and add it together with 0.5 g of diethylene glycol monomethyl ether azide, 0.02 g of cuprous iodide (CuI), and 0.38 mL of N,N-diisopropylethylamine (DIEA) into 20 mL of mixed solvent (dichloromethane:acetonitrile = 1:1.1, v / v). Heat the reaction mixture to 57 °C and reflux with stirring for 8.2 hours. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. Dissolve and extract the residue with dichloromethane, combine the organic phases, dry with anhydrous magnesium sulfate, filter, and concentrate. The crude product is purified by column chromatography (eluent: dichloromethane / methanol = 35:1, v / v) to give 0.3 g of deep blue solid target dye BF2-ADP-1005 (1b), with a yield of 44%. The 1H NMR spectrum is attached. Figure 4 As shown, the chemical shift and integral are: 1 H NMR (500 MHz, CDCl3) δ 7.99 (d, J = 8.5 Hz, 4H), 7.84 (s, 2H), 7.57(s, 4H), 7.03 (d, J = 8.5 Hz, 4H), 6.70 (s, 2H), 5.25 (s, 4H), 4.56 (t, J =5.1 Hz, 4H), 3.87 (t, J = 5.1 Hz, 4H), 3.60 - 3.54 (m, 4H), 3.50 - 3.45 (m,4H), 3.34 (s, 6H), 3.26 (t, J = 5.8 Hz, 8H), 2.75 (t, J = 6.3 Hz, 8H), 1.97(p, J = (6.1 Hz, 8H). The carbon NMR spectrum is attached. Figure 5 As shown, the chemical shift and integral are:13 C NMR (126 MHz, CDCl3) δ 159.63, 155.58, 145.05, 143.95, 143.68, 142.95, 131.05, 131.01, 128.52, 125.65, 124.13, 121.15, 120.56, 114.60, 77.31, 77.06, 76.80, 71.70, 70.53, 69.41, 62.01, 59.04, 50.30, 50.09, 28.00, 21.73, 0.00. All values ​​correspond one-to-one with the target substance. The mass spectrum is shown below. Figure 6 As shown, calculate C 60 H 67 BF2N 11 O6, molecular weight 1086.5267; experimentally determined [M+H] + With a molecular weight of 1086.5346, confirmed by both mass spectrometry and NMR, it can be considered the target compound.

[0085] Example 3. Compound BF2-ADP-1050

[0086]

[0087] 1) Weigh 1.0 g of compound 5c, i.e., 3,5-bis(propoxy)acetophenone, and dissolve it in 20 mL of ethanol with 1.0 g of 9-aldehyde juulonidin. Add 4.8 mL of 25% (w / w) NaOH aqueous solution dropwise. Stir the reaction at room temperature for 24 hours. After the reaction is complete, filter the solution, wash the solid with ethanol, and then wash with cold water until neutral to give 1.6 g of orange solid chalcone intermediate 4c, with a yield of 89%.

[0088] 2) Weigh 2.0 g of the chalcone intermediate 4c obtained in the previous step and dissolve it in 20 mL of ethanol along with 4.4 g of 1,8-diazabicycloundec-7-ene (DBU). Heat the mixture to 85 °C and stir for 1 hour. Then, add 6.5 mL of nitromethane to the reaction system and continue stirring at 85 °C for 24 hours. After the reaction is complete, remove most of the solvent by rotary evaporation under reduced pressure. Extract the residue with dichloromethane, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate. The crude product is purified by column chromatography (eluent: dichloromethane / petroleum ether = 6:1, v / v) to give 1.5 g of a yellow oily nitromane intermediate 3c, in 65% yield.

[0089] 3) Weigh 0.8 g of the nitroalkane intermediate 3c obtained in the previous step and dissolve it in 10 mL of n-butanol. Add 3.2 g of ammonium acetate to the solution. Heat the reaction mixture to 120°C and reflux with stirring for 15 hours. After the reaction is complete, cool to room temperature and concentrate under reduced pressure to remove most of the n-butanol. Extract the residue with dichloromethane, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate to obtain a dark blue, thin-film-like aziridine methane ligand, which can be used directly in the next step of the reaction.

[0090] 4) Place the azadipyrrolemethane ligand obtained in the previous step (approximately 0.5 g theoretical amount) in a dry two-necked flask and purge it with nitrogen for protection. Add 30 mL of anhydrous dichloromethane to dissolve it. While stirring, add 1.4 mL of N,N-diisopropylethylamine (DIEA) and stir at room temperature for 50 minutes. Then, slowly add 1.5 mL of boron trifluoride diethyl ether (BF3·Et2O). After the addition is complete, continue stirring at room temperature for 24 hours under nitrogen protection. After the reaction is complete, add 20 mL of water to quench the reaction. Separate the organic phase, extract the aqueous phase with dichloromethane, combine the organic phases, dry with anhydrous magnesium sulfate, filter, and concentrate. The crude product obtained is purified by column chromatography (eluent: dichloromethane / methanol = 120:1, v / v) to give 0.3 g of green solid aza-BODIPY intermediate 2c (i.e., the precursor of BF2-ADP-1050), with a yield of 35%.

[0091] 5) Weigh 0.5 g of the aza-BODIPY intermediate 2c obtained in the previous step, and add it together with 0.6 g of diethylene glycol monomethyl ether azide, 0.02 g of cuprous iodide (CuI), and 0.36 mL of N,N-diisopropylethylamine (DIEA) to 20 mL of mixed solvent (dichloromethane:acetonitrile = 1:1.2, v / v). Heat the reaction mixture to 60 °C and reflux for 8.5 hours. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. Dissolve and extract the residue with dichloromethane, combine the organic phases, dry with anhydrous magnesium sulfate, filter, and concentrate. The crude product is purified by column chromatography (eluent: dichloromethane / methanol = 40:1, v / v) to give 0.3 g of deep blue solid target dye BF2-ADP-1050 (1c), with a yield of 36%. The 1H NMR spectrum is attached. Figure 7 As shown, the chemical shift and integral are: 1H NMR (500 MHz, CDCl3) δ 7.83 (s, 4H), 7.60 (s, 4H), 7.32 (d, J = 2.3Hz, 4H), 6.72 (s, 2H), 6.67 (t, J = 2.3 Hz, 2H), 5.17 (s, 8H), 4.51 (t, J =5.2 Hz, 8H), 3.83 (t, J = 5.2 Hz, 8H), 3.54 (dd, J = 5.6, 3.3 Hz, 8H), 3.45(dd, J = 5.7, 3.2 Hz, 8H), 3.30 (s, 20H), 2.76 (t, J = 6.3 Hz, 8H), 1.99 (p,J = 5.6 (Hz, 8H). The hydrogen NMR spectrum is attached. Figure 8 As shown, the chemical shift and integral are: 13 C NMR (126 MHz, CDCl3) δ 159.02, 155.72, 145.36, 144.27, 143.41, 134.54, 128.76, 124.27, 121.28, 120.53, 114.32, 108.53, 104.18, 77.37, 77.12, 76.86, 71.68, 70.47, 69.32, 61.96, 58.97, 50.15, 45.86, 27.99, 21.65, 8.59, -0.00. All values ​​correspond one-to-one with the target substance. The mass spectrum is shown below. Figure 9 As shown, calculate C 76 H 92 BF2N 17 O 12 The molecular weight of Na is 1506.7070; the molecular weight of [M+Na]+ was experimentally determined to be 1506.7071, which was confirmed by both mass spectrometry and NMR, and can be considered as the target compound.

[0092] Example 4. Compound BF2-ADP-1035

[0093]

[0094] 1) Weigh 3.0 g of compound 5d, i.e., 3,4,5-tris(propynyl)acetophenone, and dissolve it in 20 mL of ethanol with 2.2 g of 9-aldehyde juulonidin. Add 12.0 mL of 20% (w / w) NaOH aqueous solution dropwise. Stir the reaction at room temperature for 24 hours. After the reaction is complete, filter the solution, wash the solid with ethanol, and then wash with cold water until neutral to give 4.4 g of orange solid chalcone intermediate 4d, with a yield of 89%.

[0095] 2) Weigh 5.0 g of the chalcone intermediate 4d obtained in the previous step and dissolve it in 20 mL of ethanol along with 8.2 g of 1,8-diazabicycloundec-7-ene (DBU). Heat the mixture to 80 °C and stir for 0.5 hours. Then, add 5.8 mL of nitromethane to the reaction system and continue stirring at 80 °C for 24 hours. After the reaction is complete, remove most of the solvent by rotary evaporation under reduced pressure. Extract the residue with dichloromethane, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate. Purify the crude product by column chromatography (eluent: dichloromethane / petroleum ether = 5:1, v / v) to give 2.5 g of yellow oily nitromethane intermediate 3d, with a yield of 44%.

[0096] 3) Weigh 2.5 g of the nitroalkane intermediate 3d obtained in the previous step and dissolve it in 10 mL of n-butanol. Add 7.6 g of ammonium acetate to the solution. Heat the reaction mixture to 115 °C and reflux with stirring for 12 hours. After the reaction is complete, cool to room temperature and concentrate under reduced pressure to remove most of the n-butanol. Extract the residue with dichloromethane, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate to obtain a dark blue, thin-film-like aziridinemethylene ligand, which can be used directly in the next step of the reaction.

[0097] 4) Place the aza-dipyrrolemethane ligand obtained in the previous step (approximately 2.0 g theoretical amount) in a dry two-necked flask and purge it with nitrogen for protection. Add 30 mL of anhydrous dichloromethane to dissolve it. While stirring, add 3.5 mL of N,N-diisopropylethylamine (DIEA) and stir at room temperature for 30 minutes. Then, slowly add 4.0 mL of boron trifluoride diethyl ether (BF3·Et2O). After the addition is complete, continue stirring at room temperature for 24 hours under nitrogen protection. After the reaction is complete, add 20 mL of water to quench the reaction. Separate the organic phase, extract the aqueous phase with dichloromethane, combine the organic phases, dry with anhydrous magnesium sulfate, filter, and concentrate. The crude product obtained is purified by column chromatography (eluent: dichloromethane / methanol = 100:1, v / v) to give 0.5 g of green solid aza-BODIPY intermediate 2d (i.e., the precursor of BF2-ADP-1035), with a yield of 21%.

[0098] 5) Weigh 0.1 g of the aza-BODIPY intermediate 2d obtained in the previous step, and add it together with 0.1 g of diethylene glycol monomethyl ether azide, 0.02 g of cuprous iodide (CuI), and 0.14 mL of N,N-diisopropylethylamine (DIEA) into 20 mL of mixed solvent (dichloromethane:acetonitrile = 1:1, v / v). Heat the reaction mixture to 55 °C and stir under reflux for 8 hours. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure. Dissolve and extract the residue with dichloromethane, combine the organic phases, dry with anhydrous magnesium sulfate, filter, and concentrate. The crude product is purified by column chromatography (eluent: dichloromethane / methanol = 30:1, v / v) to give 0.1 g of deep blue solid target dye BF2-ADP-1035 (1d), with a yield of 56%. The 1H NMR spectrum is attached. Figure 10 As shown, the chemical shift and integral are: 1 H NMR (500 MHz, CDCl3) δ 7.96 (s, 4H), 7.91 (s, 2H), 7.64 (s, 4H), 7.45(s, 4H), 6.72 (s, 2H), 5.25 (s, 12H), 4.52 (q, J = 7.1, 6.3 Hz, 12H), 3.85(dt, J = 8.4, 5.3 Hz, 12H), 3.55 (dd, J = 5.6, 3.4 Hz, 12H), 3.46 - 3.39 (m,12H), 3.29 (d, J = 12.4 Hz, 26H), 2.79 (t, J = 6.3 Hz, 8H), 2.01 (q, J = (6.0 Hz, 8H). The carbon NMR spectrum is attached. Figure 11 As shown, the chemical shift and integral are: 13 C NMR (126 MHz, CDCl3) δ155.23, 151.80, 145.29, 144.34, 144.22, 143.29, 139.28, 128.78, 128.45,124.96, 124.85, 124.57, 121.34, 120.44, 114.29, 109.28, 77.36, 77.11, 76.85,71.70, 70.45, 70.39, 69.43, 69.27, 66.45, 63.23, 63.03, 58.93, 52.93, 50.13,49.98, 28.02, 21.68, 7.94, 0.00. All correspond one-to-one with the target substance. The mass spectrum is shown below. Figure 12 As shown, calculate C 92 H119 BF2N 23 O 18 The molecular weight is 1882.9094; the experimentally determined [M+H]... + With a molecular weight of 1882.9197, confirmed by both mass spectrometry and nuclear magnetic resonance, it can be considered the target compound.

[0099] Based on the precise spectral data obtained, the series of aza-BODIPY dyes of this invention exhibit excellent fluorescence emission performance in the near-infrared II (NIR-II) window, thus clarifying their application value as NIR-II fluorescent probes. Specifically, as Figure 13 The image shows the UV-Vis-NIR absorption (black) and emission (red) spectra of four compounds in dichloromethane, where c = 1 × 10⁻⁶. -5 The concentrations (mol / L) for (a)-(d) are BF2-ADP-982, BF2-ADP-1005, BF2-ADP-1050, and BF2-ADP-1035, respectively. In dichloromethane, the maximum emission wavelengths (λ) of dyes BF2-ADP-1005, BF2-ADP-1050, and BF2-ADP-1035 are... em The maximum emission wavelengths reached 1005 nm, 1050 nm, and 1035 nm, respectively, all clearly covering the NIR-II spectral region (1000-1700 nm). Among them, for the dye BF2-ADP-1050, which had the longest maximum emission wavelength, its emission spectra in different solvents were studied, such as... Figure 14 As shown, where c = 1×10 -5 mol / L, λ ex = 720 nm, with the legend showing TOL: toluene; CHCl3: chloroform; DCM: dichloromethane; Acetone: acetone; ACN: acetonitrile; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide. With increasing solvent polarity, the emission peak of BF2-ADP-1050 exhibits a redshift, reaching 1109 nm in the polar solvent DMSO, extending into the near-infrared region beyond 1100 nm. This series of data directly demonstrates that the design of introducing julonidin as a strong electron donor into the molecule, as described in this invention, effectively overcomes the limitation of the short core emission wavelength of classic aza-BODIPY dyes, successfully obtaining a fluorescent dye with an emission wavelength extending into the NIR-II window. This provides a new solution with clear optical performance evidence to address the scarcity of high-performance NIR-II organic small molecule dyes suitable for deep tissue imaging in existing technologies.

[0100] The technical solutions disclosed and proposed in this invention can be implemented by those skilled in the art by appropriately modifying the conditions and routes, etc. Although the methods and preparation techniques of this invention have been described through preferred embodiments, those skilled in the art can obviously modify or recombine the methods and technical routes described herein without departing from the content, spirit, and scope of this invention to achieve the final preparation technique. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the spirit, scope, and content of this invention.

Claims

1. Amphiphilic near-infrared II region azirconium-fluorinated boron dipyrrole dyes, characterized by: It has the following general formula structure: In aza-BODIPY, a benzene ring is attached to each of the 3 and 5 positions; each benzene ring has a substituent R1, R2, and R3 independently attached to the para and two meta positions; R1, R2, and R3 are each independently selected from: hydrogen, propargyloxy group connected by an oxygen atom, or bis(propargyl)amino group connected by a nitrogen atom; at least one of R1, R2, and R3 on each benzene ring is propargyloxy or bis(propargyl)amino; and, optionally, a diethylene glycol monomethyl ether chain with the structure -(OCH2CH2)2-OCH3 is attached to the terminal alkynyl group of the propargyloxy or bis(propargyl)amino group via a click chemistry reaction.

2. The amphiphilic near-infrared II-region azirconium fluoroboron dipyrrole dye of claim 1, characterized in that, Substances including the following structures Both R3 groups on the two benzene rings are bis(propynyl)amino groups, and both R1 and R2 are hydrogens, with a -(OCH2CH2)2-OCH3 chain attached to the terminal alkynyl group; the compound is named BF2-ADP-982; Both R3 groups on the two benzene rings are propargyloxy groups, and both R1 and R2 are hydrogen atoms, with a -(OCH2CH2)2-OCH3 chain attached to the terminal alkynyl group; the compound is named BF2-ADP-1005; R1 and R2 on both benzene rings are propargyloxy groups, R3 is hydrogen, and a -(OCH2CH2)2-OCH3 chain is attached to the terminal alkynyl group; the compound is named BF2-ADP-1050; R1, R2, and R3 on both benzene rings are all propargyloxy groups, and a -(OCH2CH2)2-OCH3 chain is attached to the terminal alkynyl group; the compound is named BF2-ADP-1035.

3. The method for preparing the amphiphilic near-infrared II-region azirconium-fluorinated boron dipyrrole dye of claim 1, characterized in that the equation... as follows:

4. The method for preparing the amphiphilic near-infrared II-region azirconium-fluorinated boron dipyrrole dye as described in claim 3, characterized in that, Includes the following steps: 1) An aromatic ketone with known substituents R1, R2, and R3 undergoes an aldol condensation reaction with 9-aldehyde juulonidine to yield a chalcone intermediate: 2) The chalcone intermediate is subjected to a Michael addition reaction with nitromethane to obtain a nitromethane intermediate; 3) The nitroalkane intermediate is refluxed with ammonium acetate in n-butanol to undergo cyclization condensation, yielding the aziridinemethylene ligand; 4) Complex the aza-dipyrrolemethane ligand with boron trifluoride diethyl ether to obtain the aza-BODIPY intermediate; 5) The azido-alkynyl cycloaddition reaction catalyzed by cuprous iodide is used to attach the azido-polyethylene glycol monomethyl ether chain to the alkynyl group of the aza-BODIPY intermediate in step 4) to obtain the target dye.

5. The method for preparing the amphiphilic near-infrared II-region azirconium-fluorinated boron dipyrrole dye as described in claim 4, characterized in that, In step 1), the aromatic ketones with the determined substituents R1, R2, and R3 and 9-aldehyde juulonidine are added to a round-bottom flask, and ethanol is added as a solvent. Then, a 20%~25% (w / w) sodium hydroxide aqueous solution is prepared and added to the system. After stirring at room temperature for 20~24 h, an orange solid is precipitated. After filtration and washing, a chalcone intermediate is obtained, which is an orange solid. The molar ratio of aromatic ketone, 9-aldehyde juulonidine, and sodium hydroxide is 1.0:1.0~1.1:5.0~5.

5.

6. The method for preparing the amphiphilic near-infrared II-region azafluoroboron dipyrrole dye as described in claim 4, characterized in that, In step 2), the chalcone intermediate and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were added to a round-bottom flask, ethanol was added as a solvent, the temperature was raised to 80~85 ℃ and stirred for 0.5~1.0 h, nitromethane was added, and the reaction continued for 20~24 h. After the reaction was completed, the solvent was removed by rotary evaporation, the mixture was extracted with dichloromethane, dried with anhydrous magnesium sulfate, filtered, the solvent was removed by rotary evaporation, and column chromatography was performed. The mobile phase was dichloromethane:petroleum ether in a volume ratio of 5.0~6.0:1.0 to obtain a nitromethane intermediate, which was a yellow oily substance. The molar ratio of chalcone intermediate, DBU and nitromethane was 1.0:5.0~6.0:20.0~25.

0.

7. The method for preparing the amphiphilic near-infrared II-region azirconium-fluorinated boron dipyrrole dye as described in claim 4, characterized in that, In step 3), the nitroalkane intermediate is dissolved in n-butanol, ammonium acetate is added, and the mixture is heated to 115-120 °C and refluxed for 12-15 h. After the reaction is completed, the mixture is cooled to room temperature, the solvent is removed by rotary evaporation, the mixture is extracted with dichloromethane, dried with anhydrous magnesium sulfate, filtered, and the solvent is removed by rotary evaporation to obtain the aziridine dipyrrolemethane ligand, which is a dark blue solid. The molar ratio of the nitroalkane intermediate to ammonium acetate is 1.0:20.0-25.

0.

8. The method for preparing the amphiphilic near-infrared II-region azafluoroboron dipyrrole dye as described in claim 4, characterized in that, In step 4), the aza-dipyrrolemethane ligand was added to a two-necked round-bottom flask under nitrogen protection, dissolved in anhydrous dichloromethane, and then N,N-diisopropylethylamine was added. The mixture was stirred at room temperature for 30-50 min, followed by the addition of boron trifluoride diethyl ether. The reaction was continued at room temperature for 20-24 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by rotary evaporation. The mixture was then purified by column chromatography with a mobile phase of dichloromethane and methanol in a volume ratio of 100-120:1 to obtain the aza-BODIPY intermediate, which is a green solid. The molar ratio of aziridine methane ligand, N,N-diisopropylethylamine, and boron trifluoride diethyl ether is 1.0:10.0~15.0:15.0~20.

0.

9. The method for preparing the amphiphilic near-infrared II-region azafluoroboron dipyrrole dye as described in claim 4, characterized in that, In step 5), the aza-BODIPY intermediate, azido-modified polyethylene glycol monomethyl ether chain, cuprous iodide, and N,N-diisopropylethylamine are added to a mixed solvent, which is a mixture of dichloromethane and acetonitrile with a volume ratio of 1:1 to 1.

2. The mixture is heated to 55 to 60 °C and reacted for 8 to 8.5 h. After the reaction is complete, the solvent is removed by rotary evaporation, and the mixture is extracted with dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and the solvent is removed by rotary evaporation. The mixture is then purified by column chromatography with a mobile phase of DCM:MeOH in a volume ratio of 30 to 40:1 to obtain the target dye, which is a deep blue solid. The molar ratio of the aza-BODIPY intermediate, azido-modified polyethylene glycol monomethyl ether chain, cuprous iodide, and N,N-diisopropylethylamine is 1.0:6.0 to 8.0:0.1 to 0.2:5.0 to 6.0.

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