Fluorine boron pyrrole compound as well as preparation method and application thereof

Abstract

The invention relates to a boron-dipyrromethene compound as well as a preparation method and application thereof, and belongs to the field of synthesis of boron-dipyrromethene compounds. The preparation method comprises the following steps: under inert gas, carrying out second reaction on a first substrate and a second substrate to obtain the BODIPY compound, wherein the first substrate is 1, 3-dimethyl-BODIPY (Boron Dipyrromethene) and / or a 1, 3-dimethyl-BODIPY substituted derivative; the second substrate is 7-methoxy-2H-methylene-3-formaldehyde or a derivative of the 7-methoxy-2H-methylene-3-formaldehyde, and the second substrate is a derivative of the 7-methoxy-2H-methylene-3-formaldehyde. The BODIPY compound is a novel-structure small-molecule compound photosensitizer which takes a series of asymmetric BODIPY as a basic framework and is used for pure type I treatment, compared with common photosensitizer molecule indocyanine green, the active oxygen yield of the BODIPY compound is about 30-40 times that of the general photosensitizer molecule indocyanine green, the BODIPY compound has better light stability, the applicability of a photodynamic reagent can be remarkably improved, and the BODIPY compound can be applied to treatment of the type I; and the preparation method is simple and high in reaction efficiency.

Description

Technical Field

[0001] The invention belongs to the field of synthesis of fluoroboryl pyrrole compounds, and specifically relates to a fluoroboryl pyrrole compound and a preparation method and application thereof. Background Art

[0002] Cancer (malignant tumor) is one of the major diseases that seriously threatens human health and life worldwide. Traditional tumor treatment methods such as surgery, chemotherapy, and radiotherapy have certain limitations, such as large toxic side effects, large secondary trauma, and easy recurrence or metastasis of tumors after surgery. Photodynamic therapy (PDT) is an emerging tumor treatment option that activates PS (photosensitizer) in tumor tissue through irradiation with a light source of a specific wavelength, producing cytotoxic ROS ( 1 O2, ·OH, superoxide anion free radical (O2 ·- ) and H2O2), causing oxidative damage to tumor cells. PDT has the advantages of being non-invasive, low in side effects, and highly spatiotemporal selectivity, which can significantly improve the efficacy and living standards of patients. According to the different types of reactive oxygen species produced, PDT can be divided into type I and type II. During the PDT process, after irradiation, PS transitions from the ground state (singlet state S0) to the excited singlet state (S1), and then to the excited triplet state (T1) through intersystem crossing. For type I PDT, triplet PS generates O2 through electron transfer. ·- , ·OH or H2O2, while the type II PDT photoreaction process transfers energy to the triplet ground state oxygen ( 3 O2) 1 O2. Traditional phototherapy materials have limited penetration depth and strong oxygen dependence, which seriously affect their overall therapeutic effect. Therefore, it is of great research significance to construct photosensitizers with near-infrared absorption and high efficiency.

[0003] Photothermal therapy (PTT) is a method of using photothermal agents to generate heat under light to treat diseases such as tumors or bacterial infections. The heat generated by non-radiative relaxation will increase the temperature of the tissue, causing the destruction of tumor cell proteins and membranes, thereby accelerating tumor cell death. In addition, hyperthermia can not only promote the ablation of cancer cells, but also induce local vascular damage, increase blood perfusion of tumor tissues, and increase the concentration of drugs in tumors. Therefore, the combination of PDT and PTT treatments may cause a synergistic anti-tumor response.

[0004] Although certain achievements have been made in the research and development of type I organic photosensitizers, there is still a lack of clear design criteria for type I photosensitizers, and the lack of commonality between different strategies has hindered its further application. Fluoroboropyrrole dyes (abbreviated as BODIPY, the full name of which is BoronDipyrromethene) are widely used in the field of PDT due to their advantages such as adjustable absorption / emission wavelengths, easy functional modification and derivatization, and good biocompatibility. Therefore, it is of great research value to construct photothermal agents with near-infrared absorption and efficient type I photosensitization mechanism based on BODIPY modification and derivatization. Summary of the invention

[0005] In view of the above problems, the present invention provides a fluoroborane pyrrole compound and a preparation method and application thereof.

[0006] The first object of the present invention is to provide a fluoroboryl pyrrole compound, the molecular structure of the fluoroboryl pyrrole compound is as shown in Formula I:

[0007]

[0008] In formula I, R1, R2, and R3 are the same or different and are independently selected from H or halogen;

[0009] R4 is methoxy or hydroxy.

[0010] Furthermore, the halogen is I or bromine.

[0011] The second object of the present invention is to provide a method for preparing the fluoroborane pyrrole compound, comprising:

[0012] Under an inert gas, the first substrate and the second substrate undergo a second reaction to obtain a fluoroboryl pyrrole compound;

[0013] Wherein, the first substrate is 1,3-dimethyl-BODIPY and / or a 1,3-dimethyl-BODIPY substituted derivative;

[0014] The second substrate is 7-methoxy-2H-methylene-3-carboxaldehyde or a 7-methoxy-2H-methylene-3-carboxaldehyde derivative, and the CAS number of the 7-methoxy-2H-methylene-3-carboxaldehyde is 57543-39-2;

[0015] The CAS number of the 1,3-dimethyl-BODIPY is 154793-49-4.

[0016] Further, the 1,3-dimethyl-BODIPY substituted derivative is a mixture of one or more of 1,3-dimethyl-BODIPY substituted derivative A and 1,3-dimethyl-BODIPY substituted derivative B;

[0017] The molecular structure of the 1,3-dimethyl-BODIPY substituted derivative A is shown in Formula II, and the molecular structure of the 1,3-dimethyl-BODIPY substituted derivative B is shown in Formula III:

[0018]

[0019] In Formula II and Formula III, X is halogen.

[0020] Furthermore, the 1,3-dimethyl-BODIPY substituted derivative is prepared by a first reaction between 1,3-dimethyl-BODIPY and a halogen-containing third substrate.

[0021] Furthermore, the 7-methoxy-2H-methylene-3-carboxaldehyde derivative is prepared by demethylating the 7-methoxy-2H-methylene-3-carboxaldehyde.

[0022] Furthermore, the third substrate is one of N-bromosuccinimide and N-iodosuccinimide.

[0023] Furthermore, in the first reaction, the molar ratio of 1,3-dimethyl-BODIPY to the third substrate is 1:1-3, and the first reaction conditions are: in the presence of a first organic solvent, the reaction temperature is 10-30° C., and the reaction time is 0.3-2 h.

[0024] Furthermore, the first organic solvent is one of dichloromethane, toluene, and acetonitrile, or a mixture of several of them.

[0025] Preferably, when the third substrate is N-bromosuccinimide, the molar ratio of the 1,3-dimethyl-BODIPY to the N-bromosuccinimide is 1:1-1.5, and the conditions of the first reaction are: the first organic solvent is dichloromethane, the reaction temperature is 10-30° C., and the reaction time is 0.3-2 h. At this time, the product obtained is a structure shown in Formula II, specifically, X is bromine;

[0026] More preferably, the molar ratio of the 1,3-dimethyl-BODIPY to the N-bromosuccinimide is 1:1.2, the reaction temperature is 20° C., and the reaction time is 0.5 h.

[0027] Preferably, when the third substrate is N-bromosuccinimide, the molar ratio of the 1,3-dimethyl-BODIPY to the N-bromosuccinimide is 1:2-3, the conditions of the first reaction are: the first organic solvent is dichloromethane, the first activating agent is a mixture of acetic acid and piperidine in any ratio, the reaction temperature is 20° C., the reaction time is 0.3-2h, and the product obtained at this time is a structure shown in Formula III, specifically, X is bromine;

[0028] More preferably, the molar ratio of the 1,3-dimethyl-BODIPY to the N-bromosuccinimide is 1:2.5, the reaction temperature is 20° C., and the reaction time is 0.5 h.

[0029] Furthermore, the second reaction condition is: in the presence of a second organic solvent and an activator, the reaction temperature is 90-150° C., and the reaction time is 5-24 h.

[0030] Furthermore, the molar ratio of the first substrate to the second substrate is 1:1-2.

[0031] Furthermore, the second organic solvent is one of toluene, acetonitrile, and N-N-dimethylformamide, or a mixture of several of them.

[0032] Furthermore, the activator is a mixture of acetic acid and piperidine in any ratio, and the added amount of the second activator is 0.1-2% of the total mass of the first substrate and the second substrate.

[0033] Preferably, when the first substrate is 1,3-dimethyl-BODIPY, the conditions of the second reaction are: the second organic solvent is toluene, the activator is a combination of acetic acid and piperidine in a volume ratio of 0.5-1.5:1, the reaction temperature is 110-120° C., and the reaction time is 6-10 hours. At this time, the molecular structure of the obtained fluoroboryl pyrrole compound is as shown in Formula IV:

[0034]

[0035] More preferably, the activating agent is a combination of acetic acid and piperidine in a ratio of 0.5:1 by volume.

[0036] Preferably, when the first substrate is 1,3-dimethyl-BODIPY substituted derivative A, the conditions of the second reaction are: the second organic solvent is toluene, the activator is a combination of acetic acid and piperidine in a volume ratio of 3-6:1, the reaction temperature is 110-120° C., and the reaction time is 6-10 hours. At this time, the molecular structure of the obtained fluoroboryl pyrrole compound is as shown in Formula V:

[0037]

[0038] More preferably, the activating agent is a combination of acetic acid and piperidine in a volume ratio of 5:1.

[0039] Preferably, when the first substrate is 1,3-dimethyl-BODIPY substituted derivative B, the conditions of the second reaction are: The conditions of the second reaction are: the second organic solvent is toluene, the activator is a combination of acetic acid and piperidine in a volume ratio of 3-6:1, the reaction temperature is 110-120°C, the reaction time is 6-10h, and the molecular structure of the obtained fluoroboryl pyrrole compound is as shown in Formula VI:

[0040]

[0041] More preferably, the activating agent is a combination of acetic acid and piperidine in a volume ratio of 5:1.

[0042] The third object of the present invention is to provide the use of the fluoroborane pyrrole compound in the preparation of photosensitizers for tumor photodynamic therapy.

[0043] The fourth object of the present invention is to provide the use of the fluoroborane pyrrole compound in the preparation of a photosensitizer in tumor photothermal therapy.

[0044] The fifth object of the present invention is to provide the use of the fluoroborane pyrrole compound as a photosensitizer in tumor photodynamic therapy.

[0045] The sixth object of the present invention is to provide the use of the fluoroborane pyrrole compounds as photosensitizers in tumor photothermal therapy.

[0046] Beneficial effects of the present invention:

[0047] The present invention discloses a fluoroborylpyrrole compound and a preparation method and application thereof. The fluoroborylpyrrole compound is a novel structural small molecule compound photosensitizer with a series of asymmetric BODIPY as the basic skeleton and used for pure type I treatment. Compared with the common photosensitizer molecule indocyanine green (ICG), the active oxygen production rate is about 30-40 times that of ICG, and the compound has better light stability, and can significantly increase the applicability of photodynamic agents. The compound has a simple preparation method, high reaction efficiency, and considerable yield, and has good industrial application prospects. The compound is expected to significantly improve the therapeutic effect of tumors.

[0048] The preparation of fluoroboryl pyrrole compounds is through the introduction of heavy atoms bromine or iodine, which can effectively promote the occurrence of excited state molecular intersystem crossing process, increase the ratio of excited state molecular triplet states, and the heavy atom effect makes it possible to be used as a photosensitizer for PDT; the present invention designs a new type of structural small molecule compound photosensitizer for pure type I treatment. Compared with type II PSs, the type I pathway has a greater advantage in that it is less dependent on oxygen.

[0049] Other features and advantages of the present invention will be described in the following description, and partly become apparent from the description, or understood by practicing the present invention. The purpose and other advantages of the present invention can be realized and obtained by the structures pointed out in the description, claims and drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0051] Figure 1 A molecular structural formula diagram of a fluoroboryl pyrrole compound according to an embodiment of the present invention is shown;

[0052] Figure 2 The normalized absorption spectrum and fluorescence spectrum of compound 1a in different solvents according to the embodiment of the present invention are shown, wherein: Figure 2 a is the normalized absorption spectrum of compound 1a in different solvents. Figure 2 b is the fluorescence spectra of compound 1a in different solvents;

[0053] Figure 3 The normalized absorption spectrum and fluorescence spectrum of compound 1b in different solvents according to the embodiment of the present invention are shown, wherein: Figure 3 a is the normalized absorption spectrum of compound 1b in different solvents. Figure 3 b is the fluorescence spectra of compound 1b in different solvents;

[0054] Figure 4 The normalized absorption spectrum and fluorescence spectrum of compound 1c in different solvents according to the embodiment of the present invention are shown, wherein: Figure 4 a is the normalized absorption spectrum of compound 1c in different solvents. Figure 4 b is the fluorescence spectra of compound 1c in different solvents;

[0055] Figure 5 The basic spectrum of the singlet oxygen generation ability of ICG in methanol according to an embodiment of the present invention is shown, Figure 5 Figure a shows the change in the DPBF absorption spectrum when ICG is irradiated in methanol. Figure 5 Middle b is the change of DPBF absorption spectrum after irradiation in methanol alone;

[0056] Figure 6The graph shows the absorbance test result of ICG after irradiation in toluene according to an embodiment of the present invention, Figure 6 Figure a shows the change in the DPBF absorption spectrum when ICG is irradiated in toluene. Figure 6 Figure b shows the change of DPBF absorption spectrum after irradiation in toluene alone;

[0057] Figure 7 According to the absorbance test result of compound 1b in toluene after irradiation in the embodiment of the present invention, Figure 7 Figure a shows the change in the DPBF absorption spectrum when compound 1b exists in toluene. Figure 7 b is a graph showing the change in absorbance of DPBF at 414 nm in toluene as a function of irradiation time;

[0058] Figure 8 The graph shows the absorbance test result of compound 1c after irradiation in toluene according to an embodiment of the present invention, Figure 8 Figure a shows the change in the DPBF absorption spectrum when compound 1c exists in toluene. Figure 8 b is a graph showing the change in absorbance of DPBF at 414 nm in toluene as a function of irradiation time;

[0059] Fig. 9 The slope change graph of compound 1b, compound 1c and ICG in the same solvent in the embodiment of the present invention is shown;

[0060] Fig.10 The photosensitizer type test diagram of compound 1b in the embodiment of the present invention is shown. Fig.10 Figure a is the absorption spectrum of ABDA at different time points in the presence of compound 1b after laser irradiation. Fig.10 Middle b is a graph showing the fluorescence intensity changes of DHE at different time points in the presence of 1b after irradiation with a laser light source;

[0061] Fig.11 One of the light and heat performance test diagrams of compound 1b in an embodiment of the present invention is shown, Fig.11 Figure a is the temperature change diagram of compound 1b with a concentration of 50 μg / mL under laser irradiation at different power densities. Fig.11 b is the different concentrations of compound 1b at 1W / cm 2 Temperature changes under laser irradiation;

[0062] Fig.12 One of the light and heat performance test diagrams of compound 1b in an embodiment of the present invention is shown, Fig.12 Where a is 20 μg / mL of compound 1b at 1 W / cm 2 The cooling curve under laser irradiation is Fig.12Where b is 20 μg / mL of compound 1b at 1 W / cm 2 Thermal stability performance diagram after four cycles of laser irradiation;

[0063] Fig.13 The spectrum obtained by the hydrogen 1 NMR spectrum test of compound 1a in the embodiment of the present invention is shown;

[0064] Fig.14 The carbon 13 NMR spectrum of compound 1a in the example of the present invention is shown. DETAILED DESCRIPTION

[0065] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0066] like Figure 1 As shown, a molecular structural formula of a fluoroboryl pyrrole compound according to an embodiment of the present invention, in which R1, R2, and R3 are the same or different and are selected from one or more of H, I and Br;

[0067] R4 is methoxy or hydroxy.

[0068] The synthesis process and performance test process of the fluoroborane pyrrole compound are shown below:

[0069] Example 1

[0070] The synthesis route of compound 1 is as follows:

[0071]

[0072] 2-Pyrrolaldehyde (300 mg, 3.15 mmol) was placed under a nitrogen atmosphere, and dichloromethane (DCM) (4 mL) was added to dissolve and cooled to -5°C. 2,4-Dimethylpyrrole (324.6 L, 3.15 mmol) was added to the reactant and mixed, stirred for 3 minutes, and then phosphorus oxychloride POCl (288.3 L, 3.15 mmol) was added dropwise, and the reactant was stirred at -5°C for 3 hours, and then moved to room temperature and stirred for 3 hours.

[0073] N,N-diisopropylethylamine DIEA (1.5 mL, 9.45 mmol) and boron trifluoride ether solution (1.2 mL, 9.45 mmol) were added under ice bath conditions. After 3 hours, the reaction mixture was washed with water and dried over sodium sulfate, and a green solid was obtained by silica gel column chromatography, which was compound 1.

[0074] (2) Synthesis of compounds 1Br and 2Br, the synthetic routes are as follows:

[0075]

[0076] 1 (220 mg, 1 mmol) and NBS (213.6 mg, 1.2 mmol) were placed in a round-bottom flask, dissolved with dichloromethane (20 mL), and stirred in air at room temperature for 1 hour. The reaction mixture was poured into dichloromethane (50 mL) and the mixture was washed with water (350 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum. Silica column chromatography was performed using petroleum ether / dichloromethane (3:1, v / v) to obtain 1Br as a purple solid in a yield of 71% (213 mg). 2Br was a purple solid and yielded 15% (57 mg).

[0077] (3) Synthesis of compounds 1I and 2I. The synthetic routes are as follows:

[0078]

[0079] 1 (220 mg, 1 mmol) and NIS (270 mg, 1.2 mmol) were placed in a round-bottom flask, dissolved with dichloromethane (20 mL), and stirred in air at room temperature for 1 hour. The reaction mixture was poured into dichloromethane (50 mL) and the mixture was washed with water (350 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum. Silica column chromatography was performed using petroleum ether / dichloromethane (3:1, v / v) to obtain 1I as a purple solid with a yield of 55% (189.7 mg). 2I was a purple solid with a yield of 35% (160 mg).

[0080] (4) Synthesis of compound 1a, the synthetic route is as follows:

[0081]

[0082] A Schlenk tube containing 1 (22 mg, 0.1 mmol), compound 2 (24.2 mg, 0.1 mmol) and a small amount of molecular sieves was pumped 3 times and filled with Ar 3 times. Toluene (5 mL), acetic acid (0.05 mL) and piperidine (0.1 mL) were then stirred in an Ar atmosphere at 110°C for 8 h. The mixture was then washed with water and extracted three times with dichloromethane. The organic layer was collected, dried over sodium sulfate, filtered and evaporated under vacuum. Chromatography (silica gel, petroleum ether / dichloromethane = 1 / 2, v / v) gave 1a as a blue solid with a yield of 20 mg (45%).

[0083] (5) Synthesis of compound 1b, the synthetic route is as follows:

[0084]

[0085] A Schlenk tube containing 1Br (30 mg, 0.1 mmol), compound 2 (25 mg, 0.1 mmol) and a small amount of molecular sieves was pumped 3 times and filled with Ar 3 times. Then, degassed toluene (3 mL), acetic acid (0.5 mL) and piperidine (0.15 mL) were stirred at 110°C under Ar atmosphere for 8 h. Then, it was washed with water and extracted three times with dichloromethane. The organic layer was collected, dried over sodium sulfate, filtered and evaporated under vacuum. Purification by chromatography (silicon dioxide, petroleum ether / ethyl acetate = 2 / 1, v / v) gave 1b as a blue-green solid with a yield of 22.7 mg (36%).

[0086] (6) Synthesis of compound 1c. The synthetic route is as follows:

[0087]

[0088] A Schlenk tube containing 2Br (38 mg, 0.1 mmol), compound 2 (25 mg, 0.1 mmol) and a small amount of molecular sieves was pumped 3 times and filled with Ar 3 times. Then, degassed toluene (3 mL), acetic acid (0.4 mL) and piperidine (0.15 mL) were stirred at 110°C under Ar atmosphere for 8 h. Then, it was washed with water and extracted three times with dichloromethane. The organic layer was collected, dried over sodium sulfate, filtered and evaporated under vacuum. Purification by chromatography (silicon dioxide, petroleum ether / ethyl acetate = 2 / 1, v / v) gave 1c as a blue-green solid with a yield of 15.7 mg (26%).

[0089] (7) Synthesis of compound 1d. The synthetic route is as follows:

[0090]

[0091] A Schlenk tube containing 1I (35 mg, 0.1 mmol), compound 2 (25 mg, 0.1 mmol) and a small amount of molecular sieves was pumped 3 times and filled with Ar 3 times. Then, degassed toluene (3 mL), acetic acid (0.5 mL) and piperidine (0.15 mL) were stirred at 110°C under Ar atmosphere for 8 h. Then, it was washed with water and extracted three times with dichloromethane. The organic layer was collected, dried over sodium sulfate, filtered and evaporated under vacuum. Purification by chromatography (silicon dioxide, petroleum ether / ethyl acetate = 2 / 1, v / v) gave 1d as a blue-green solid with a yield of 19.4 mg (34%).

[0092] (8) The synthesis of compound 3, the synthesis route is as follows:

[0093]

[0094] A Schlenk tube containing 2 (121 mg, 0.5 mmol), boron tribromide (0.48 mL, 5 mmol) and a small amount of molecular sieves was pumped 3 times and filled with Ar 3 times. Then, the degassed dichloromethane (3 mL) was stirred at 25°C under Ar atmosphere for 8 h. It was then washed with sodium bicarbonate solution and extracted three times with dichloromethane. The organic layer was collected, dried over sodium sulfate, filtered and evaporated under vacuum. Purified by chromatography (silicon dioxide, petroleum ether / ethyl acetate = 3 / 1, v / v) to obtain 3 as a yellow solid with a yield of 62.7 mg (55%).

[0095] (9) Synthesis of compound 1e. The synthetic route is as follows:

[0096]

[0097] A Schlenk tube containing 1Br (30 mg, 0.1 mmol), compound 3 (23 mg, 0.1 mmol) and a small amount of molecular sieves was pumped 3 times and filled with Ar 3 times. Then, degassed toluene (3 mL), acetic acid (0.5 mL) and piperidine (0.15 mL) were stirred at 110°C under Ar atmosphere for 8 h. Then, it was washed with water and extracted three times with dichloromethane. The organic layer was collected, dried over sodium sulfate, filtered and evaporated under vacuum. Purification by chromatography (silicon dioxide, petroleum ether / ethyl acetate = 2 / 1, v / v) gave 1e as a blue-green solid with a yield of 20.9 mg (41%).

[0098] Experimental Example 1 Basic spectrum of the compound in the embodiment of the present invention:

[0099] The absorption spectra and fluorescence spectra of compounds 1a-c in the examples of the present invention were tested in various solvents. The test results are as follows: Figure 2-4 shown.

[0100] Figure 2-Figure 4 a in the figure are the normalized absorption spectra of compounds 1a-c in different solutions, Figure 2-Figure 4 b are the fluorescence spectra of compounds 1a-c in different solutions under excitation at 650nm. Figure 2-Figure 4 It can be seen that compounds 1a-c have strong absorbance in the near-infrared region of 650-700nm and fluorescence between 750-800nm.

[0101] Experimental Example 2 Basic spectrum of singlet oxygen generation ability of the compounds in the examples of the present invention:

[0102] Specific test methods: Group 1: Changes in the absorption spectrum of DPBF (1,3-diphenylisobenzofuran) when irradiated with ICG (indocyanine green) in methanol (recorded at 2-min intervals), and changes in the absorption spectrum of DPBF after irradiation in methanol alone (recorded every 2 min). The irradiation parameters of the light source are: 10 mw / cm 2 , 755nm, the specific results are as follows Figure 5 As shown;

[0103] The second group: the change of DPBF absorption spectrum when ICG is irradiated in toluene (recorded at 2-min intervals), and the change of DPBF absorption spectrum after irradiation in toluene alone (recorded every 2 min), the light source irradiation parameters are: 10 mw / cm 2 , 755nm, the specific results are as follows Figure 6 As shown;

[0104] Group 3: Changes in the absorption spectrum of DPBF in the presence of compound 1b in toluene (recorded at 1-min intervals), and changes in the absorbance of DPBF at 414 nm with irradiation time (irr = 755 nm) in toluene. The irradiation parameters of the light source are: 10 mw / cm 2 , 755nm, the specific results are as follows Figure 7 As shown;

[0105] Group 4: Changes in the absorption spectrum of DPBF (recorded at 30s intervals) in the presence of compound 1c in toluene; and changes in the absorbance of DPBF at 414nm with irradiation time (irr = 755nm) in the presence of toluene, with the irradiation parameters of the light source being 10mw / cm 2 , 755nm, the specific results are as follows Figure 8 As shown;

[0106] Group 5: Using laser light source (755nm, 300mW / cm 2) after irradiation, in the presence of compound 1b, the absorption light of ABDA (2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline disulfonic acid disodium salt) was tested at different time points; and under the laser light source (755nm, 300mW / cm 2 ) after irradiation, the fluorescence intensity change of DHE at different time points in the presence of compound 1b, where ABDA was used as 1 O2 probe (A = 378 nm), DHE as O2 ·- Probe (A = 610nm), test results are as follows Fig.10 As shown;

[0107] from Figure 5-Figure 6 It can be seen that the blank group DPBF will not degrade in different solvents and is stable. When the common photodynamic therapy drug ICG is irradiated, the absorption spectrum of DPBF in different solutions hardly changes, indicating that the active oxygen production rate of ICG is extremely low.

[0108] from Figure 7 and Figure 8 By comparing the slopes, the slope changes of compound 1b, compound 1c and ICG in the same solvent were obtained. Fig. 9 , and the calculated comparative data of active oxygen production rate of compound 1b, compound 1c and ICG were obtained, as shown in Table 1. From the data in Table 1, it can be seen that the active oxygen production rate of compound 1b is 31.98 times that of ICG, and the active oxygen production rate of 1c is 43.91 times that of ICG.

[0109] Table 1

[0110]

[0111] Through the fifth set of tests, (ABDA) was tested as a singlet oxygen scavenger. Fig.10 It can be seen that when the ABDA solution in the presence of 1b was irradiated for 6 minutes, the absorbance change of ABDA was negligible, indicating that there was no 1 O2 is generated. When DHE solution is irradiated with laser, the fluorescence intensity near 610nm increases with time, indicating that there is O2 ·- The product is a pure type I photosensitizer.

[0112] Test Example 3 Photothermal performance test of compound 1b in the embodiment of the present invention:

[0113] This test example tests the photothermal performance of compound 1b in Example 1. Different concentrations of the compound are used and different optical powers are used for laser irradiation. The temperature is measured and recorded. 2The laser power was recorded every 10 seconds, and the photothermal heating curve and the negative natural logarithm of the cooling time and the temperature in the cooling stage were plotted. The test results are shown in Fig.11 and Fig.12 shown.

[0114] from Fig.11 It can be seen that with the increase of laser power density (from 0.15 to 1 W cm -2 , the solution temperature of the nanoparticles increased significantly. As the concentration of the compound increased (from 10 to 50 Wμg / mL), the solution temperature of the nanoparticles increased significantly.

[0115] from Fig.12 It can be seen that the compound has excellent thermal stability. After four heating and cooling cycles, the solution of the nanoparticles did not change significantly at the highest temperature during the first and fourth illumination.

[0116] Test Example 4 Structural spectrum test of compound 1a in the embodiment of the present invention:

[0117] The compound 1a in the embodiment of the present invention was subjected to NMR test, and the test results are as follows: Fig.13 (hydrogen 1 HNMR) and Fig.14 ( 13 C NMR). Wherein, the hydrogen spectrum test conditions are: 1 HNMR, 600MHz, CDCl3; Carbon spectrum test conditions: 13 CNMR, 151MHz, CDCl3.

[0118] 1 H NMR(600MHz,Chloroform-d)δ7.89(d,J=15.7Hz,1H),7.55(s,1H),7.02(d,J=15.7 Hz,1H),7.01–6.97(m,2H),6.81(s,1H),6.78(d,J=3.7Hz,1H),6.66(d,J=2.4Hz,1H ),6.59(dd,J=8.4,2.4Hz,1H),6.43(s,1H),6.39(dd,J=3.8,2.2Hz,1H),3.86(s,3H ),2.59(t,J=6.1Hz,2H),2.55–2.50(m,2H),2.30(s,3H),1.80(p,J=6.2Hz,2H), see details Fig.13 ;

[0119] 13C NMR (151 MHz, Chloroform-d)δ161.00,160.64,154.16,152.25,143.98,138.99,135.90,135.76,132.75,127.97,126.89,124.00,122.84,119.35,118.00,115.61,115.10,114.44,112.62,110.18,100.50,55.64,29.79,29.70,24.79,20.79,11.48, see for details Fig.14 .

[0120] Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent substitutions for some of the technical features therein; and these modifications or substitutions do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A fluoroborane pyrrole compound, characterized in that: The molecular structure of the fluoroborane pyrrole compound is shown in Formula I: In formula I, R1, R2, and R3 are the same or different and are independently selected from H or halogen; R4 is methoxy or hydroxy.

2. The method for preparing fluoroboryl pyrrole compounds according to claim 1, characterized in that: include: Under an inert gas, the first substrate and the second substrate undergo a second reaction to obtain a fluoroboryl pyrrole compound; Wherein, the first substrate is 1,3-dimethyl-BODIPY and / or a 1,3-dimethyl-BODIPY substituted derivative; The second substrate is 7-methoxy-2H-methylene-3-carboxaldehyde or a 7-methoxy-2H-methylene-3-carboxaldehyde derivative.

3. The method for preparing fluoroboryl pyrrole compounds according to claim 2, characterized in that: The 1,3-dimethyl-BODIPY substituted derivative is one of the compounds shown in Formula II or Formula III: In Formula II and Formula III, X is halogen.

4. The method for preparing fluoroboryl pyrrole compounds according to claim 2, characterized in that: The 1,3-dimethyl-BODIPY substituted derivative is prepared by a first reaction between 1,3-dimethyl-BODIPY and a halogen-containing third substrate; the 7-methoxy-2H-methylene-3-carboxaldehyde derivative is prepared by demethylating the 7-methoxy-2H-methylene-3-carboxaldehyde.

5. The method for preparing fluoroboryl pyrrole compounds according to claim 4, characterized in that: The third substrate is one of N-bromosuccinimide and N-iodosuccinimide.

6. The method for preparing fluoroboryl pyrrole compounds according to claim 4, characterized in that: In the first reaction, the molar ratio of 1,3-dimethyl-BODIPY to the third substrate is 1:1-3, and the first reaction conditions are: in the presence of a first organic solvent, the reaction temperature is 10-30°C, and the reaction time is 0.3-2h; the first organic solvent is one or a mixture of dichloromethane, toluene, and acetonitrile.

7. The method for preparing a fluoroboryl pyrrole compound according to any one of claims 2 to 6, characterized in that: The molar ratio of the first substrate to the second substrate is 1:1-2; the conditions of the second reaction are: in the presence of a second organic solvent and an activator, the reaction temperature is 90-150° C., and the reaction time is 5-24 hours.

8. The method for preparing fluoroboryl pyrrole compounds according to claim 7, characterized in that: The second organic solvent is one or a mixture of toluene, acetonitrile, and N-N-dimethylformamide. The activator is a mixture of acetic acid and piperidine in any ratio. The amount of the activator added is 0.1-2% of the total mass of the first substrate and the second substrate.

9. Use of the fluoroboryl pyrrole compound according to claim 1 in preparing a photosensitizer for tumor photodynamic therapy.

10. Use of the fluoroboryl pyrrole compound according to claim 1 in preparing a photosensitizer for tumor photothermal therapy.

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