A boron-nitrogen chelated Aza-BODIPY based on aryl boronic acid derivative, and a preparation method and application thereof

Abstract

The application provides a boron-nitrogen chelated Aza-BODIPY based on aryl boronic acid derivatives, a preparation method and application thereof, and belongs to the technical field of near-infrared fluorescent dyes. The boron-nitrogen chelated Aza-BODIPY has excellent near-infrared optical performance, rare double absorption peaks and an emission wavelength in a near-infrared window, and low fluorescence quantum yield, which is suitable for photodynamic therapy requirements. The application also provides a preparation method of the boron-nitrogen chelated Aza-BODIPY. The method has simple procedures, simple operation, mild reaction conditions, high yield and is suitable for large-scale preparation. In addition, the boron-nitrogen chelated Aza-BODIPY has good prospects in the preparation of near-infrared fluorescent materials and photodynamic therapy drugs.

Description

Technical Field

[0001] This invention belongs to the field of near-infrared fluorescent dye technology, specifically a boron-nitrogen chelate Aza-BODIPY based on arylboronic acid, its preparation method, and its application. Background Technology

[0002] Near-infrared (NIR, 650-900 nm) fluorescent dyes have become ideal materials for bioimaging and diagnostic applications due to their significant advantages in biological tissues, including deep penetration, low autofluorescence interference, and low photodamage. Among numerous fluorophores, boron dipyrrolemethyl fluoride (BODIPY) and its derivatives are widely recognized as a highly valuable class of core fluorescent nuclei due to their excellent photophysical properties, such as high molar extinction coefficient, high fluorescence quantum yield, excellent photochemical stability, and easily modifiable chemical structure.

[0003] Current strategies for constructing near-infrared BODIPY dyes are primarily based on the systematic modulation of their electronic structure, with the core focus on expanding the dye's conjugated system and controlling its intramolecular charge transfer (ICT) intensity. Common methods include: 1) introducing strong electron-donating or electron-withdrawing groups at the α, β, or meso positions of the BODIPY core skeleton to enhance the push-pull electron effect and achieve a spectral redshift; 2) fused the BODIPY core with other aromatic ring systems to directly reduce the band gap by expanding the π-conjugated plane; 3) developing Aza-BODIPY (replacing the carbon atom at the meso position with a nitrogen atom), whose absorption and emission wavelengths can be significantly redshifted by more than 100 nm. While these strategies have made significant progress, they still face common challenges such as synthetic difficulties and fluorescence quenching (e.g., aggregation-induced quenching, ACQ).

[0004] In recent years, direct and diversified functionalization of the central boron atom has become a new direction for the modification of near-infrared BODIPY dyes. For example, BODIPY derivatives with BO and BC chelates have been reported, but BN chelated Aza-BODIPYs have been rarely studied. The unique coordination ability and steric hindrance effect of nitrogen atoms are expected to provide new means to regulate the electronic distribution, crystal stacking, and environmental interactions of dyes, thereby constructing near-infrared BODIPY dyes with deeper redshift spectra, unique photophysical properties, and stable performance.

[0005] Therefore, developing efficient and controllable synthesis methods to construct novel boron-nitrogen chelate Aza-BODIPY dyes with absorption / emission wavelengths in the near-infrared window and tunable functions is of great significance for promoting the development of the basic theory of near-infrared dye chemistry and its application in bio-diagnosis and treatment. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of existing technologies and provide an arylboronic acid-derived boron-nitrogen chelate Aza-BODIPY, its preparation method, and its applications. This boron-nitrogen chelate Aza-BODIPY exhibits excellent near-infrared optical properties, possessing rare double absorption peaks and an emission wavelength within the near-infrared window. Simultaneously, its low fluorescence quantum yield makes it suitable for photodynamic therapy. This invention also provides a method for preparing this boron-nitrogen chelate Aza-BODIPY, which is simple in procedure, easy to operate, has mild reaction conditions, and a high yield, making it suitable for large-scale preparation. The boron-nitrogen chelate Aza-BODIPY of this invention shows promising potential in the preparation of near-infrared fluorescent materials and photodynamic therapy drugs.

[0007] To achieve the above objectives, in a first aspect, the present invention provides a boron-nitrogen chelate Aza-BODIPY based on arylboronic acid, the structure of which is shown in Formula I.

[0008] ;

[0009] Wherein, R is selected from H, straight-chain alkanoyl group of C1~C6, branched-chain alkanoyl group of C4~C6, and Ar is selected from phenyl or substituted aryl group of C7~C9.

[0010] Preferably, R is selected from H, C1-C6 straight-chain alkanoyl group; Ar is selected from phenyl, C7-C9 alkoxy-substituted aryl group or C7-C9 haloalkyl-substituted aryl group.

[0011] Preferably, R is one of H, formyl, acetyl, propionyl, butyryl, valeryl, and hexanoyl; Ar is one of phenyl, 4-methoxyphenyl, 3,4,5-trimethoxyphenyl, 4-trifluoromethylphenyl, 4-trichloromethylphenyl, or 4-tribromomethylphenyl.

[0012] Preferably, the boron-nitrogen chelate Aza-BODIPY is one of the structures shown in formulas 2a, 2b, and 3a~3d:

[0013] .

[0014] Secondly, this invention provides a method for preparing boron-nitrogen chelate Aza-BODIPY, the method comprising: mixing an intermediate, ArB(OH)2, and a basic substance in the presence of a solvent, and carrying out a coordination reaction to obtain boron-nitrogen chelate Aza-BODIPY; the coordination reaction conditions are: temperature 100~120℃, time 20~30 min; the synthetic route is as follows:

[0015]

[0016] The intermediate is one of the following structures:

[0017]

[0018] R1 is one of a straight-chain alkanoyl group (C1-C6) or a branched-chain alkanoyl group (C4-C6).

[0019] Preferably, the ArB(OH)2 is selected from phenylboronic acid, 4-methoxyphenylboronic acid, 4-trifluoromethylphenylboronic acid and 3,4,5-trimethoxyphenylboronic acid.

[0020] Preferably, the solvent is selected from 1,2-dichlorobenzene, toluene, 1,2-dichloroethane, xylene, and chlorobenzene. The solvent can be any solvent conventionally used in the art, as long as it can provide a stable reaction environment.

[0021] Preferably, the alkaline substance is selected from sodium carbonate, potassium carbonate, cesium carbonate, and triethylamine.

[0022] Preferably, the molar ratio of the intermediate, ArB(OH)2, and the alkaline substance is 1:(5~8):(5~8). For example, 1:5:5, 1:6:5, 1:5:7, 1:6:8, 1:8:8, 1:7:5, or 1:8:5, etc.

[0023] Preferably, the preparation methods of intermediate 1 and intermediate 2 are as follows:

[0024] 1) Compound A1 is prepared by aldol condensation reaction of 2-aminoacetophenone, 4-tert-butylbenzaldehyde and sodium hydroxide solution in the presence of solvent. The aldol condensation reaction conditions are: reaction temperature of 25~30℃ and reaction time of 1~2 days.

[0025]

[0026] 2) Compound A2 was prepared by Michael addition reaction of compound A1 with potassium carbonate and nitromethane in the presence of solvent. The conditions for Michael addition reaction were: reaction temperature of 60~90℃ and reaction time of 5~8 h.

[0027]

[0028] 3) Compound A2 was condensed with ammonium acetate in the presence of a solvent to obtain the intermediate shown in formula V. The conditions for the condensation reaction were: reaction temperature of 60~100℃ and reaction time of 1~4 days.

[0029]

[0030] 4) In the presence of a solvent, intermediate 1 is subjected to an acylation reaction with a C1~C6 straight-chain alkyl anhydride or a C4~C6 branched alkyl anhydride to obtain intermediate 2. The conditions for the acylation reaction are: reaction temperature of 100~120℃ and reaction time of 0.5~4 h.

[0031]

[0032] Preferably, in step 1), the molar ratio of 2-aminoacetophenone, 4-tert-butylbenzaldehyde and sodium hydroxide is 1:(0.5~2):(0.5~2); more preferably, it is 1:1:1.

[0033] Preferably, in step 1), the solvent is selected from toluene, water, ethanol and chlorobenzene.

[0034] Preferably, in step 2), the molar ratio of the compound represented by formula III to potassium carbonate and nitromethane is 1:(5~6):(5~6).

[0035] Preferably, in step 2), the solvent is selected from one of ethanol, methanol, isopropanol and butanol.

[0036] Preferably, in step 3), the molar ratio of compound A2 to ammonium acetate is 1:(40~42).

[0037] Preferably, in step 3), the solvent is selected from one of ethanol, methanol, isopropanol and butanol.

[0038] Preferably, in step 4), the molar ratio of intermediate 1 to C1~C6 straight-chain alkyl anhydride or C4~C6 branched-chain alkyl anhydride is 0.2:(0.2~0.24).

[0039] Preferably, in step 4), the C1-C6 straight-chain alkyl anhydride is one of formic anhydride, acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, and hexanoic anhydride.

[0040] Preferably, in step 4), the solvent is a mixed solution of acetonitrile and tetrahydrofuran in a volume ratio of 1:1.

[0041] Thirdly, the present invention provides the application of the boron-nitrogen chelate Aza-BODIPY in the preparation of near-infrared fluorescent materials or photodynamic therapeutic drugs.

[0042] Beneficial effects:

[0043] (1) The boron-nitrogen chelated Aza-BODIPY prepared in this invention is a novel near-infrared fluorescent dye. For the first time, arylboronic acid derivatization and boron-nitrogen chelation are combined in the Aza-BODIPY framework, which significantly optimizes the optical properties. Its absorption spectrum shows a significant red shift and has rare double absorption peaks (e.g., 761 / 559 nm). The maximum emission wavelength is stably located in the 820 nm near-infrared window. It has good penetration in biological tissues and low autofluorescence interference. At the same time, the fluorescence quantum yield of this compound is extremely low (Φ<0.01), which effectively reduces the dissipation of excitation energy in the form of fluorescence and helps to enhance the intersystem crossing ability of molecules, thereby promoting the generation of reactive oxygen species (ROS). It is a multifunctional material with the potential of near-infrared fluorescence imaging and photodynamic therapy.

[0044] (2) The preparation method of boron-nitrogen chelate Aza-BODIPY of the present invention has a clear process route, simple procedures, easy operation, mild and easy-to-control reaction conditions, accurate material ratio of each step, and the coordination reaction can be completed in only 0.5~1.0h. The preparation yield of intermediate and target product is high. All raw materials used are commercially available conventional reagents, which are inexpensive and the solvent system can be recycled, making it suitable for industrial-scale production.

[0045] (3) The boron-nitrogen chelate Aza-BODIPY molecule of the present invention introduces steric hindrance groups such as tert-butyl groups, which effectively reduces molecular aggregation and improves the solubility and stability of the compound in organic solvents and physiological buffer solutions. Its boron-nitrogen chelate structure endows the molecule with good photochemical stability, making it difficult to decompose under light conditions, thus ensuring the continuous effectiveness of bioimaging and photodynamic therapy.

[0046] (4) The boron-nitrogen chelate Aza-BODIPY of the present invention can be directly applied to the preparation of near-infrared fluorescent materials. At the same time, its low fluorescence quantum yield and near-infrared light response characteristics make it a high-quality photosensitizer for photodynamic therapy drugs. It can realize the integrated design of bioimaging and photodynamic therapy, and has broad application prospects in the field of biomedical materials. It provides new ideas for the structural design and functional expansion of near-infrared BODIPY dyes. Attached Figure Description

[0047] Figure 1 This is the absorption spectrum of ADP-1 in Example 1;

[0048] Figure 2 This is the emission spectrum of ADP-1 in Example 1;

[0049] Figure 3 This is the absorption spectrum of 2a in Example 2;

[0050] Figure 4 This is the emission spectrum of 2a in Example 2;

[0051] Figure 5 This is the absorption spectrum of 3a in Example 3;

[0052] Figure 6 This is the emission spectrum of 3a in Example 3;

[0053] Figure 7 This is the absorption spectrum of 3b in Example 3;

[0054] Figure 8 This is the emission spectrum of 3b in Example 3;

[0055] Figure 9 This is the absorption spectrum of 3c in Example 3;

[0056] Figure 10 This is the emission spectrum of 3c in Example 3. Detailed Implementation

[0057] The technical solution of the present invention will be described in detail below through embodiments, but the scope of protection of the present invention is not limited to the embodiments described.

[0058] The present invention will be described in detail below through embodiments.

[0059] All reagents used in the embodiments of this invention are commercially available conventional analytical grade reagents; the room temperature is 20~30℃.

[0060] The testing instruments used are as follows:

[0061] (1) 1 HNMR and 13 CNMR: Bruker AVANCE III Spectrometers 500 MHz nuclear magnetic resonance spectrometer (Germany), solvent: CDCl3;

[0062] (2) Mass spectrometry: Ultraflextreme MALDI-TOF mass spectrometer from Bruker GmbH, Germany;

[0063] (3) Ultraviolet-visible absorption spectrum: Shimadzu UV-2450 ultraviolet / visible spectrophotometer;

[0064] (4) Fluorescence spectrum: FS5 fluorescence spectrophotometer from Hitachi, Japan;

[0065] (5) Absolute fluorescence quantum yield: Hamamatsu Photonics C11347 absolute PL quantum yield spectrometer (integrating sphere method);

[0066] (6) Tracking reaction: 0.25 mm thick fluorescent TLC plate and ZF-1 type three-purpose ultraviolet analyzer.

[0067] Example 1: Preparation of intermediates

[0068] (1) Preparation of compound A1:

[0069]

[0070] 2-Aminoacetophenone (3.7 mL, 30 mmol) and 4-tert-butylbenzaldehyde (5.0 mL, 30 mmol) were dissolved in anhydrous ethanol (80 mL) and stirred to ensure uniform dispersion. Then, an aqueous solution of NaOH (1.2 g NaOH dissolved in 6 mL H₂O) was slowly added at 0°C. The mixture was then stirred at room temperature for 2 days, and the reaction was monitored by TLC. The solution was then poured into water, extracted with DCM, dried, evaporated to dryness, and purified by column chromatography (silica gel, petroleum ether / dichloromethane = 2 / 1-1 / 1, v / v) to obtain the target product A1 (6.70 g, 75%) as a yellow solid.

[0071] The characterization data for A1 are as follows:

[0072] 1 H NMR (400 MHz, 298 K, CDCl3) δ (ppm) 7.87 (dd, J = 8.3, 1.2 Hz, 1H), 7.74 (d, J = 15.5 Hz, 1H), 7.61 - 7.57 (m, 3H), 7.44 (d, J = 8.4 Hz, 2H),7.32 - 7.28 (m, 1H), 6.73 - 6.69 (m, 2H), 1.35 (s, 9H); 13 C NMR (126 MHz, 298K, CDCl3) δ (ppm) 192.3, 154.1, 151.2, 143.4, 134.6, 132.9, 131.4, 128.5,126.3, 122.7, 119.7, 117.8, 116.4, 35.3, 31.6; HRMS (ESI) calcd. for C 19 H 22 NO + [M + H] + : 280.1696; found m / z 280.1696.

[0073] (2) Preparation of compound A2:

[0074]

[0075] Compound A1 (5.58 g, 20 mmol), potassium carbonate (14.9 g, 108 mmol), nitromethane (5.8 mL, 108 mmol), and ethanol (80 mL) were added to a 250 mL round-bottom flask. The mixture was stirred under reflux for 6 hours (TLC monitoring), followed by concentration under vacuum. The residue was then poured into water and extracted with DCM. The organic phase was collected, dried over anhydrous Na2SO4, and the organic solvent was removed under vacuum. Purification by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1, v / v) yielded the target product A2 (5.78 g, 85%) as a yellow solid.

[0076] The characterization data for A2 are as follows:

[0077] 1 H NMR (500 MHz, 298 K, DMSO-d6) δ (ppm) 7.74 (dd, J = 7.9, 0.8 Hz,1H), 7.32 - 7.28 (m, 4H), 7.24 - 7.21 (m, 1H), 7.17 (s, 2H), 6.73 (d, J = 8.4Hz, 1H), 6.51 (t, J = 7.3 Hz, 1H), 4.94 - 4.91 (m, 1H), 4.85 - 4.80 (m, 1H), 4.04 - 3.98 (m, 1H), 3.48 - 3.43 (m, 1H), 3.40 - 3.33 (m, 1H), 1.24 (s, 9H); 13 C NMR (126 MHz, 298 K, CDCl3) δ (ppm) 198.9, 150.7, 150.5, 136.5, 134.9,130.8, 127.2, 126.1, 117.7, 117.6, 116.1, 79.9, 42.3, 39.1, 34.6, 31.4; HRMS(ESI) calcd. for C 20 H 25 N2O3 + , [M + H] + : 341.1860; found 341.1861.

[0078] (3) Preparation of compound ADP-1 (intermediate 1):

[0079]

[0080] Compound A2 (5.8 g, 17 mmol) and ammonium acetate (52.4 g, 680 mmol) were placed in a 250 mL round-bottom flask, refluxed with anhydrous ethanol (60 mL) and stirred for 3 days. After returning to room temperature, the mixture was poured into water and extracted with DCM. The extract was dried, evaporated to dryness, and purified by column chromatography to obtain the black target product ADP-1 (1.11 g, 22%).

[0081] The characterization data for ADP-1 are as follows:

[0082] 1 H NMR (500 MHz, 298 K, DMSO-d6) δ (ppm) 7.98 (d, J = 8.4 Hz, 2H),7.75 (d, J = 7.7 Hz, 1H), 7.51 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.21 (t, J= 7.6 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.76 (t, J = 7.4 Hz, 1H), 6.36 (s,2H), 1.35 (s, 9H); 13 C NMR (126 MHz, 298 K, DMSO-d6) δ (ppm) 150.2, 148.3,146.9, 139.5, 130.9, 130.9, 129.4, 128.8, 124.8, 117.3, 117.1, 116.6, 116.6,115.3, 31.1, 26.4; HRMS (ESI) calcd. for C 40 H 42 N5 + , [M + H] + : 592.3435; found 592.3443.

[0083] (4) Preparation of compound ADP-2:

[0084]

[0085] Compound ADP-1 (118.3 mg, 0.2 mmol) was dissolved in 6 mL of a mixed solvent of acetonitrile / tetrahydrofuran (1 / 1, v / v). Acetic anhydride (1.2 equiv., 0.24 mmol) was added, and the reaction mixture was stirred at 100 °C until complete consumption of ADP-1 was confirmed by thin-layer chromatography (TLC). After the reaction was complete, the system was cooled to room temperature and transferred to a round-bottom flask. The organic solvent was then removed under vacuum. Purification by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 1, v / v) yielded a black solid product, compound ADP-2 (60.8 mg, 48%).

[0086] The characterization data for ADP-2 are as follows:

[0087] 1 H NMR (500 MHz, CDCl3, 298 K) δ (ppm) 11.52 (s, 1H), 9.85 (s, 1H), 8.44 (d, J = 7.7 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.3 Hz, 2H),7.78 - 7.75 (m, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.46 - 7.41 (m, 5H), 7.25 -7.20 (m, 2H), 7.16 (s, 1H), 7.09 (s, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.79 (d,J = 8.0 Hz, 1H), 4.83 (s, 2H), 1.80 (s, 3H), 1.40 (d, J = 4.7 Hz, 18H). 13 CNMR (126 MHz, CDCl3, 298 K) δ (ppm) 169.6, 154.6, 154.4, 151.4, 151.3, 148.8,147.4, 147.4, 146.2, 142.0, 141.9, 137.2, 131.5, 130.8, 130.8, 130.6, 129.5,129.3, 129.2, 129.2, 125.2, 124.3, 122.7, 122.2, 119.3, 118.0, 117.1, 116.8,116.0, 34.8, 31.4, 31.4, 24.8. HRMS (MALDI) calcd for C 42 H 44 N5O+ , [M + H] + :634.3540; found 634.3539.

[0088] Example 2: Preparation of compounds 2a and 2b

[0089] A general preparation method for boron-nitrogen chelated Aza-BODIPY when R is H:

[0090] The intermediate ADP-1 (59 mg, 0.1 mmol), arylboronic acid ArB(OH)2 (5 equiv., 0.5 mmol), and Na2CO3 (5 equiv., 0.5 mmol) were weighed and dissolved in 1,2-dichlorobenzene (4 ml). The reaction mixture was stirred at 120 °C for 30 min, and the reaction progress was monitored by thin-layer chromatography (TLC) until compound ADP-1 was completely consumed. After the reaction was completed, the system was cooled to room temperature (20~30 °C) and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 1-1 / 1, v / v) to finally obtain the target product, namely boron-nitrogen chelate Aza-BODIPY 2.

[0091]

[0092] (1) Synthesis of compound 2a:

[0093] Following the general synthetic method described above, the reaction was carried out using ADP-1 (59 mg, 0.1 mmol), phenylboronic acid (61 mg, 0.5 mmol), and Na₂CO₃ (53 mg, 0.5 mmol) as starting materials. After the reaction was completed, the system was cooled to room temperature and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, v / v) to obtain a purple-black solid product, namely boron-nitrogen chelate Aza-BODIPY 2a (64 mg, 94%).

[0094]

[0095] The characterization data for 2a are as follows:

[0096] 1¹H NMR (500 MHz, 298 K, DMSO-d₆) δ (ppm) 8.16 (d, J = 8.3 Hz, 2H), 8.09 (d, J = 8.2 Hz, 2H), 7.76 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.65 - 7.63 (m, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.39 - 7.37 (m, 1H), 7.24 - 7.17 (m, 2H), 7.00 (d, J = 3.9 Hz, 2H), 6.96 (s, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 3.7 Hz, 2H), 6.60 (t, J = 7.3 Hz, 2H), 6.50 (t, J = 7.2 Hz, 1H), 5.46 (s, 1H), 5.11 (s, 2H), 1.35 (d, J = 3.4 Hz, 18H). 13 ¹³C NMR (126 MHz, DMSO-d₆, 298 K) δ (ppm) 152.5, 151.7, 150.5, 150.4, 148.9, 146.4, 144.9, 144.2, 141.7, 135.5, 135.3, 131.1, 130.8, 130.7, 130.5, 129.4, 128.8, 128.3, 128.2, 128.1, 127.3, 126.6, 125.6, 125.3, 118.1, 116.7, 116.6, 115.8, 115.7, 115.6, 115.5, 111.2, 34.6, 34.4, 31.0, 30.9, 26.3. HRMS (ESI) calcd for C 46 H 45 BN₅ + , [M + H] + : 678.3763; found 678.3746.

[0097] (2) Synthesis of compound 2b:

[0098] Following the general synthetic method described above, the reaction was carried out using ADP-1 (59 mg, 0.1 mmol), 4-methoxyphenylboronic acid (76 mg, 0.5 mmol), and Na₂CO₃ (52 mg, 0.5 mmol) as starting materials. After the reaction was completed, the system was cooled to room temperature and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1, v / v) to obtain the target product, a purple-black solid, namely boron-nitrogen chelated Aza-BODIPY 2b (62 mg, 88%).

[0099]

[0100] The characterization data for 2b are as follows:

[0101] 1 H NMR (500 MHz, DMSO-d6, 298 K) δ (ppm) 8.19 (d, J = 8.3 Hz, 2H), 8.12 (d, J = 8.3 Hz, 2H), 7.78 (s, 1H), 7.72 - 7.67 (m, 2H), 7.58 (dd, J =16.7, 8.3 Hz, 4H), 7.43 - 7.41 (m, 1H), 7.28 - 7.21 (m, 2H), 7.01 (s, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.77 (d, J = 8.3 Hz, 2H), 6.66 - 6.59 (m, 4H), 5.40 (s, 1H), 5.14 (s, 2H), 3.61 (s, 3H), 1.38 (d, J = 4.0 Hz, 18H). 13 C NMR (126MHz, DMSO-d6, 298 K) δ (ppm) 164.3, 163.8, 163.2, 159.4, 158.9, 158.7, 158.4,151.8, 150.6, 150.5, 148.9, 146.5, 145.0, 141.8, 139.1, 135.8, 130.9, 130.8,130.7, 128.9, 128.4, 128.2, 125.8, 125.4, 122.4, 118.2, 115.7, 113.1, 110.8,54.6, 34.7, 34.5, 31.2, 31.0. HRMS (ESI) calcd for C 46 H 45 BN5 + [M + Na]+ :730.3688; found 730.3675.

[0102] Example 3: Preparation of compounds 3a-3d

[0103] The general preparation method for boron-nitrogen chelate Aza-BODIPY when R is an acetyl group is as follows: Weigh intermediate ADP-2 (63 mg, 0.1 mmol), arylboronic acid ArB(OH)2 (5 equiv., 0.5 mmol), and Na2CO3 (5 equiv., 0.5 mmol) and dissolve them in toluene (4 mL). Stir the reaction mixture at 120 °C for 25 min, monitoring the reaction progress by thin-layer chromatography (TLC) until compound ADP-2 is completely consumed. After the reaction is complete, allow the system to cool to room temperature and purify by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 1-1 / 1, v / v) to finally obtain the target product, boron-nitrogen chelate Aza-BODIPY 3.

[0104]

[0105] (1) Synthesis of compound 3a:

[0106] Following the general synthetic method described above, the reaction was carried out using ADP-2 (63 mg, 0.1 mmol), 4-trifluoromethylphenylboronic acid (95 mg, 0.5 mmol), and Na2CO3 (54 mg, 0.5 mmol) as starting materials. After column purification (eluent: petroleum ether / ethyl acetate = 3 / 1, v / v), the target product, a purplish-black solid, namely boron-nitrogen chelate Aza-BODIPY 3a (38 mg, 48%), was obtained.

[0107]

[0108] The characterization data for 3a are as follows:

[0109] 1H NMR (500 MHz, DMSO-d6, 298 K) δ (ppm) 9.24 (s, 1H), 8.19 (d, J =8.0 Hz, 2H), 8.10 (d, J = 8.0 Hz, 2H), 7.83 (s, 2H), 7.67 (d, J = 8.2 Hz,1H), 7.59 (d, J = 7.4 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H), 7.47 (t, J = 7.7 Hz,1H), 7.36 (d, J = 7.5 Hz, 2H), 7.27 (t, J = 7.5 Hz, 1H), 7.04 (s, 1H), 6.94 -6.86 (m, 4H), 6.73 (d, J = 8.6 Hz, 1H), 6.63 (t, J = 7.4 Hz, 1H), 5.17 (s,1H), 1.85 (s, 3H), 1.36 (s, 18H). 13C NMR (126 MHz, DMSO-d6, 298 K) δ (ppm)169.5, 153.0, 152.8, 151.0, 150.7, 146.9, 145.4, 143.5, 142.6, 136.4, 136.3,135.3, 130.8, 130.4, 130.1, 129.9, 128.6, 128.4, 127.6, 127.3, 126.5, 125.8,125.7, 125.5, 124.4, 124.1, 123.5, 118.8, 117.3, 116.8, 116.3, 111.2, 55.0,34.8, 34.5, 31.2, 31.0, 23.4. HRMS (ESI) calcd for C 49 H 46 BF3N5O + , [M + H] + :788.3742; found 788.3741.

[0110] (2) Synthesis of compound 3b:

[0111] Following the general synthetic method described above, the reaction was carried out using ADP-2 (63 mg, 0.1 mmol), phenylboronic acid (61 mg, 0.5 mmol), and Na2CO3 (54 mg, 0.5 mmol) as starting materials. After column purification (eluent: petroleum ether / ethyl acetate = 5 / 1, v / v), the target product, a purplish-black solid, namely boron-nitrogen chelate Aza-BODIPY 3b (36 mg, 50%), was obtained.

[0112]

[0113] The characterization data for 3b are as follows:

[0114] 1 H NMR (500 MHz, DMSO-d6, 298 K) δ (ppm) 8.17 (d, J = 8.1 Hz, 2H), 8.08 (d, J = 8.0 Hz, 2H), 7.82 - 7.79 (m, 2H), 7.65 (d, J = 8.2 Hz, 1H), 7.55(dd, J = 20.1, 8.2 Hz, 4H), 7.45 (t, J = 7.6 Hz, 1H), 7.26 - 7.21 (m, 1H), 7.03 - 7.02 (m, 4H), 6.91 (s, 2H), 6.78 (d, J = 6.3 Hz, 2H), 6.66 (d, J = 8.7Hz, 1H), 6.60 (t, J = 7.5 Hz, 1H), 5.76 (s, 1H), 5.06 (s, 1H), 1.85 (s, 3H), 1.35 (d, J = 2.8 Hz, 18H). 13 C NMR (126 MHz, DMSO-d6, 298 K) δ (ppm) 169.4,152.8, 152.8, 151.2, 151.1, 150.7, 150.6, 146.9, 145.7, 145.5, 143.8, 142.5,141.4, 140.6, 136.3, 136.0, 135.0, 130.9, 129.7, 129.5, 128.7, 128.3, 126.9,125.8, 125.5, 124.4, 118.6, 116.9, 116.6, 116.1, 111.2, 55.0, 34.7, 34.5,31.2, 31.0, 23.5. HRMS (ESI) calcd for C 48H 47 BN5O + , [M + H] + : 720.3868; found 720.3874.

[0115] (3) Synthesis of compound 3c:

[0116] Following the general synthetic method described above, the reaction was carried out using ADP-2 (63 mg, 0.1 mmol), 4-methoxyphenylboronic acid (76 mg, 0.5 mmol), and Na2CO3 (54 mg, 0.5 mmol) as starting materials. After column purification (eluent: petroleum ether / ethyl acetate = 4 / 1, v / v), the target product, a purplish-black solid, namely boron-nitrogen chelate Aza-BODIPY 3c (38 mg, 50%), was obtained.

[0117]

[0118] The characterization data for 3C are as follows:

[0119] 1 H NMR (500 MHz, DMSO-d6, 298 K) δ (ppm) 9.12 (s, 1H), 8.16 (d, J =7.6 Hz, 2H), 8.08 (d, J = 7.8 Hz, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.77 (s,1H), 7.65 (d, J = 7.3 Hz, 1H), 7.55 (dd, J = 18.5, 8.2 Hz, 4H), 7.45 (t, J =7.5 Hz, 1H), 7.24 - 7.21 (m, 1H), 7.06 - 6.99 (m, 2H), 6.90 (s, 1H), 6.71 -6.69 (m, 2H), 6.64- 6.58 (m, 4H), 5.01 (s, 1H), 3.59 (s, 3H), 1.85 (s, 3H), 1.35 (d, J = 3.7 Hz, 18H). 13C NMR (126 MHz, CDCl3, 298 K) δ (ppm) 168.4,159.0, 154.2, 153.4, 151.9, 151.6, 151.2, 146.8, 144.6, 144.5, 136.1, 136.0,131.5, 131.2, 130.7, 129.2, 128.7, 128.6, 128.3, 125.8, 125.6, 125.1, 124.0,123.2, 118.5, 117.1, 115.8, 114.8, 113.6, 113.2, 112.0, 55.0, 35.0, 34.8,31.4, 31.3, 24.1. HRMS (ESI) calcd for C 49 H 49 BN5O2 + [M + H] + : 750.3974; found 750.3980.

[0120] (4) Synthesis of compound 3d:

[0121] Following the general synthetic method described above, the reaction was carried out using ADP-2 (63 mg, 0.1 mmol), 3,4,5-trimethoxyphenylboronic acid (106 mg, 0.5 mmol), and Na2CO3 (54 mg, 0.5 mmol) as starting materials. After column purification (eluent: petroleum ether / ethyl acetate = 3 / 1-2 / 1, v / v), the target product, a purplish-black solid, namely boron-nitrogen chelated Aza-BODIPY 3d (40 mg, 51%), was obtained.

[0122]

[0123] The 3D representation data is as follows:

[0124] 1H NMR (500 MHz, CDCl3, 298 K) δ (ppm) 8.13 - 7.12 (m, 2H), 8.03 (d, J= 8.2 Hz, 2H), 7.51 (d, J = 7.9 Hz, 5H), 7.44 - 7.30 (m, 2H), 7.20 - 1.99 (s, 1H), 1.64 (s, 3H), 1.40 (d, J = 3.3 Hz, 18H). 13 C NMR (126 MHz, CDCl3, 298 K) δ (ppm) 168.4, 154.1,153.4, 153.0, 152.6, 151.4, 151.2, 146.7, 144.9, 144.6, 143.2, 137.3, 136.2,131.3, 130.7, 129.2, 129.1, 128.7, 128.6, 128.4, 125.9, 125.7, 125.4, 124.2,123.6, 118.2, 117.3, 116.0, 115.2, 112.0, 106.6, 106.2, 60.7, 55.9, 35.0,34.8, 31.4, 31.3, 23.7. HRMS (ESI) calcd for C 51 H 53 BN5O4 + [M + H] + : 810.4185; found m / z 810.4195.

[0125] Test Example 1

[0126] Weigh approximately 0.5–1.0 mg of intermediate ADP-1 and compounds 2a and 3a-c, respectively, and dissolve them in 1 mL of dichloromethane. Then dilute with n-hexane, dichloromethane, and acetonitrile to prepare a molar concentration of 10. -6 A solution of mol / L was prepared; its UV-Vis absorption spectrum and fluorescence emission spectrum were measured, and the molar absorptivity (ε), fluorescence quantum yield (Φ), and Stokes shift were calculated. The test results are as follows: Figures 1 to 10 As shown in Table 1.

[0127] Table 1

[0128]

[0129] In Table 1: Stokes-shift = 1 / λ max -1 / λ em max (cm) -1 ), where ε is the value of the maximum molar absorptivity

[10] 3 M - 1 cm -1 ]; Φ is the fluorescence quantum yield.

[0130] As shown in Table 1, the boron-nitrogen chelate Aza-BODIPY (2a, 3a-c) of the present invention exhibits a significant red shift in absorption spectrum compared to the intermediate ADP-1, and displays a rare double absorption peak (in toluene, 2a: 772 / 563 nm; 3a: 761 / 559 nm; 3b: 760 / 562 nm; 3c: 761 / 566 nm). The maximum emission wavelength is stably located in the near-infrared window above 820 nm, and it demonstrates excellent optical stability in solvents of different polarities. At the same time, the compound has an extremely low fluorescence quantum yield (Φ<0.01), which can effectively reduce fluorescence loss of light energy, making it suitable as a photosensitizer for photodynamic therapy.

[0131] In summary, the arylboronic acid-derived boron-nitrogen chelate Aza-BODIPY of this invention possesses excellent near-infrared optical properties and photochemical stability. Its low fluorescence quantum yield makes it suitable for photodynamic therapy and can be widely used in the preparation of near-infrared fluorescent materials and photodynamic therapy drugs, demonstrating significant industrial application value in the field of biomedical materials. Furthermore, its preparation method is simple, easy to operate, uses readily available raw materials, and operates under mild reaction conditions, making it suitable for large-scale industrial production and possessing promising industrialization prospects.

[0132] As described above, although the invention has been shown and described with reference to specific preferred embodiments, it should not be construed as limiting the invention itself. Various changes in form and detail may be made without departing from the spirit and scope of the invention.

Claims

1. A boron-nitrogen chelate Aza-BODIPY based on arylboronic acid, characterized in that, The structure of the boron-nitrogen chelated Aza-BODIPY is shown in Formula I. ； Wherein, R is selected from H, straight-chain alkanoyl group of C1~C6, and branched-chain alkanoyl group of C4~C6, and Ar is selected from phenyl group and substituted aryl group of C7~C9.

2. The boron-nitrogen chelate Aza-BODIPY according to claim 1, characterized in that, R is selected from H, C1~C6 straight-chain alkyl acyl groups; Ar is selected from phenyl, C7~C9 alkoxy-substituted aryl groups, or C7~C9 haloalkyl-substituted aryl groups.

3. The boron-nitrogen chelate Aza-BODIPY according to claim 1, characterized in that, R is one of H, formyl, acetyl, propionyl, butyryl, valeryl, and hexanoyl; Ar is one of phenyl, 4-methoxyphenyl, 3,4,5-trimethoxyphenyl, 4-trifluoromethylphenyl, 4-trichloromethylphenyl, or 4-tribromomethylphenyl.

4. The boron-nitrogen chelate Aza-BODIPY according to claim 1, characterized in that, The boron-nitrogen chelate Aza-BODIPY is one of the structures shown in formulas 2a~2b and 3a~3d: 。 5. The method for preparing boron-nitrogen chelated Aza-BODIPY according to claim 1, characterized in that, The preparation method is as follows: In the presence of a solvent, an intermediate, ArB(OH)₂, and a basic substance are mixed and subjected to a coordination reaction to obtain boron-nitrogen chelate Aza-BODIPY. The coordination reaction conditions are: temperature 100~120℃, time 20~30 min. The synthetic route is as follows: 。 6. The preparation method according to claim 5, characterized in that, The solvent is selected from one of 1,2-dichlorobenzene, toluene, 1,2-dichloroethane, xylene, and chlorobenzene; the alkaline substance is selected from one of sodium carbonate, potassium carbonate, cesium carbonate, and triethylamine.

7. The preparation method according to claim 5, characterized in that, The ArB(OH)2 is selected from phenylboronic acid, 4-methoxyphenylboronic acid, 4-trifluoromethylphenylboronic acid and 3,4,5-trimethoxyphenylboronic acid.

8. The preparation method according to claim 5, characterized in that, The intermediate is one of the following structures: ； R1 is one of a straight-chain alkanoyl group (C1-C6) or a branched-chain alkanoyl group (C4-C6).

9. The preparation method according to claim 8, characterized in that the preparation methods of intermediate 1 and intermediate 2 are as follows: 1) Compound A1 is prepared by aldol condensation reaction of 2-aminoacetophenone, 4-tert-butylbenzaldehyde and sodium hydroxide solution in the presence of solvent. The aldol condensation reaction conditions are: reaction temperature of 25~30℃ and reaction time of 1~2 days. ； 2) Compound A2 was prepared by Michael addition reaction of compound A1 with potassium carbonate and nitromethane in the presence of solvent. The conditions for Michael addition reaction were: reaction temperature of 60~90℃ and reaction time of 5~8 h. ； 3) In the presence of a solvent, compound A2 was condensed with ammonium acetate to prepare intermediate 1. The conditions for the condensation reaction were: reaction temperature of 60~100℃ and reaction time of 1~4 days. ； 4) In the presence of a solvent, intermediate 1 is subjected to an acylation reaction with a C1~C6 straight-chain alkyl anhydride or a C4~C6 branched alkyl anhydride to obtain intermediate 2. The conditions for the acylation reaction are: reaction temperature of 100~120℃ and reaction time of 0.5~4 h. 。 10. The use of the boron-nitrogen chelate Aza-BODIPY as described in claim 1 in the preparation of near-infrared fluorescent materials or photodynamic therapeutic drugs.

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