A fluoroborane pyrrole compound and its preparation method and application

Abstract

The present invention relates to a fluoroborane pyrrole compound and its preparation method and application, and belongs to the field of synthesis of fluoroborane pyrrole compounds. The preparation method includes a first substrate and a second substrate performing a second reaction under an inert gas to obtain a fluoroborane 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-formaldehyde or a 7-methoxy-2H-methylene-3-formaldehyde derivative. The fluoroborane pyrrole compound of the present invention is a novel structure small molecule compound photosensitizer based on a series of asymmetric BODIPY as a basic skeleton and for pure type I treatment. Compared with the common photosensitizer molecule indocyanine green, its active oxygen yield is about 30-40 times that of it, has better photostability, can significantly increase the applicability of photodynamic agents, and the preparation method is simple and the reaction efficiency is high.

Description

Technical Field

[0001] The invention belongs to the field of synthesis of fluoroborane pyrrole compounds, and particularly relates to a fluoroborane 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, generating cytotoxic ROS ( 1 O2, ·OH, superoxide anion radical (O2 ·- ) and H2O2), causing oxidative damage to tumor cells. PDT has the advantages of being non-invasive, having few side effects, and having high 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 Traditional phototherapy materials have limited penetration depth and strong oxygen dependence, which seriously affect their overall therapeutic effect. Therefore, the construction of high-efficiency photosensitizers with near-infrared absorption is of great research significance.

[0003] Photothermal therapy (PTT) is a method that uses photothermal agents to generate heat under illumination to treat diseases such as tumors and bacterial infections. Heat generated by non-radiative relaxation elevates tissue temperature, disrupting tumor cell proteins and membranes, thereby accelerating tumor cell death. Furthermore, hyperthermia not only promotes cancer cell ablation but also induces local vascular damage, increasing tumor tissue blood perfusion and boosting intratumoral drug concentrations. Therefore, combining PDT and PTT treatments may result in a synergistic anti-tumor response.

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

[0005] In order to solve 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 fluoroborane pyrrole compound, the molecular structure of which is 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 fluoroborane 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] Furthermore, 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-carbaldehyde derivative is prepared by demethylating the 7-methoxy-2H-methylene-3-carbaldehyde.

[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 or a mixture of dichloromethane, toluene, and acetonitrile.

[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 has 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, and 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., and the reaction time is 0.3-2 h. At this time, the product obtained has 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 conditions 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 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-dimethylformamide, or a mixture of several thereof.

[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 h. At this time, the molecular structure of the obtained fluoroborane 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 a 1,3-dimethyl-BODIPY substituted derivative A, the conditions for the second reaction are: the second organic solvent is toluene, the activating agent 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 h. At this time, the molecular structure of the obtained fluoroborane 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 a 1,3-dimethyl-BODIPY substituted derivative B, the conditions for 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 h. At this time, the molecular structure of the obtained fluoroborane 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 a photosensitizer 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 for 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 compound as a photosensitizer in tumor photothermal therapy.

[0046] Beneficial effects of the present invention:

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

[0048] The preparation of fluoroborane pyrrole compounds is achieved by introducing heavy atoms bromine or iodine, which can effectively promote the occurrence of intersystem crossing processes in excited-state molecules and increase the ratio of excited-state triplet states. The heavy atom effect makes them suitable as photosensitizers 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 in part will become apparent from the description, or will be 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 following briefly introduces the drawings required for use in the embodiments or the description of the prior art. 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 any creative work.

[0051] Figure 1 shows a molecular structural formula diagram of a fluoroborane pyrrole compound according to an embodiment of the present invention;

[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 and fluorescence spectra 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 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 results of ICG after irradiation in toluene according to an embodiment of the present invention, Figure 6 Figure a shows the change in DPBF absorption spectrum when ICG is irradiated in toluene. Figure 6 Figure b shows the change in the absorption spectrum of DPBF 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 DPBF absorption spectrum when compound 1b exists in toluene. Figure 7 Figure b shows the change of absorbance of DPBF at 414 nm in toluene as a function of irradiation time;

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

[0059] Figure 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] Figure 10 The photosensitizer type test diagram of compound 1b in the embodiment of the present invention is shown. Figure 10 Figure a is the absorption spectrum of ABDA at different time points in the presence of compound 1b after laser irradiation. Figure 10 Middle b is the fluorescence intensity change diagram of DHE at different time points in the presence of 1b after laser light irradiation;

[0061] Figure 11 One of the photothermal performance test diagrams of compound 1b in an embodiment of the present invention is shown. Figure 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. Figure 11 b in the figure represents different concentrations of compound 1b at 1W / cm 2 Temperature changes under laser irradiation;

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

[0063] Figure 13 The figure shows the spectrum obtained from the hydrogen 1 NMR spectrum test of compound 1a in the embodiment of the present invention;

[0064] Figure 14 The figure shows the spectrum obtained by carbon 13 nuclear magnetic resonance testing of compound 1a in the embodiment of the present invention. DETAILED DESCRIPTION

[0065] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only 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 making creative efforts shall fall within the scope of protection of the present invention.

[0066] like Figure 1 As shown, according to an embodiment of the present invention, a molecular structural formula of a fluoroborane pyrrole compound, 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 the mixture and cooled to -5°C. 2,4-Dimethylpyrrole (324.6 L, 3.15 mmol) was added to the reaction mixture, mixed, and stirred for 3 minutes. Phosphorus oxychloride (POCl) (288.3 L, 3.15 mmol) was then added dropwise. The reaction mixture 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 etherate (1.2 mL, 9.45 mmol) were added under ice-cooling conditions. After 3 hours, the reaction mixture was washed with water, dried over sodium sulfate, and purified by silica gel column chromatography to obtain a green solid, 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 in 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 obtained as a purple solid in a yield of 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 in 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. Purification by silica column chromatography using petroleum ether / dichloromethane (3:1, v / v) afforded 1I as a purple-red solid in a 55% yield (189.7 mg). 2I was obtained as a purple solid in a 35% yield (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 three times and then filled with Ar three times. Toluene (5 mL), acetic acid (0.05 mL) and piperidine (0.1 mL) were then stirred at 110°C in an Ar atmosphere 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 in 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 three times and then filled with Ar three 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. The mixture was then washed with water and extracted three times with dichloromethane. The organic layer was collected, dried over sodium sulfate under vacuum, filtered, and evaporated. Purification by chromatography (silica, petroleum ether / ethyl acetate = 2 / 1, v / v) gave 1b as a blue-green solid in 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 three times and then filled with Ar three 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. The mixture was then washed with water and extracted three times with dichloromethane. The organic layer was collected, dried over sodium sulfate under vacuum, filtered, and evaporated. Purification by chromatography (silica, petroleum ether / ethyl acetate = 2 / 1, v / v) gave 1c as a blue-green solid in 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 three times and then filled with Ar three 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. The mixture was then washed with water and extracted three times with dichloromethane. The organic layer was collected, dried over sodium sulfate under vacuum, filtered, and evaporated. Purification by chromatography (silica, petroleum ether / ethyl acetate = 2 / 1, v / v) gave 1d as a blue-green solid in a yield of 19.4 mg (34%).

[0092] (8) Synthesis of compound 3, the synthetic 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 three times and refilled with Ar three times. Then, degassed dichloromethane (3 mL) was stirred at 25°C under an 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 under vacuum, filtered, and evaporated. Purification by chromatography (silica, petroleum ether / ethyl acetate = 3 / 1, v / v) gave 3 as a yellow solid in 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 three times and then filled with Ar three 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. The mixture was then washed with water and extracted three times with dichloromethane. The organic layer was collected, dried over sodium sulfate under vacuum, filtered, and evaporated. Purification by chromatography (silica, petroleum ether / ethyl acetate = 2 / 1, v / v) gave 1e as a blue-green solid in 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 and fluorescence spectra of compounds 1a-c in various solvents were tested. 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 method: Group 1: Changes in the absorption spectrum of DPBF (1,3-diphenylisobenzofuran) when irradiated with ICG (indocyanine green) in methanol (recorded at 2-minute intervals), and changes in the absorption spectrum of DPBF after irradiation in methanol alone (recorded every 2 minutes). The light source irradiation parameters are: 10mw / cm 2 , 755nm, the specific results are as follows Figure 5 As shown;

[0103] The second group: the changes in the DPBF absorption spectrum when irradiated in the presence of ICG in toluene (recorded at 2-min intervals), and the changes in the DPBF absorption spectrum after irradiation in toluene alone (recorded every 2-min). The light source irradiation parameters are: 10mw / 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 a light source of 10mw / cm 2 , 755nm, the specific results are as follows Figure 8 As shown;

[0106] The fifth group: laser light source (755nm, 300mW / cm 2) after irradiation, in the presence of compound 1b, ABDA (2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline disulfonic acid disodium salt) absorption light test 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 was tested in the presence of compound 1b, wherein ABDA was used as 1 O2 probe (A = 378 nm), DHE as O2 ·- Probe (A = 610nm), test results are as follows Figure 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 The slope comparison calculation shows the slope changes of compound 1b, compound 1c and ICG in the same solvent. Figure 9 , and the calculated comparative data of active oxygen production rates 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 compound 1c is 43.91 times that of ICG.

[0109] Table 1

[0110]

[0111] The fifth set of tests used (ABDA) as a singlet oxygen scavenger. Figure 10 It can be seen that when the ABDA solution in the presence of 1b is irradiated for 6 minutes, the absorbance change of ABDA is negligible, indicating that there is 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 and different optical powers of the laser are used to measure and record the temperature. 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 Figure 11 and Figure 12 shown.

[0114] from Figure 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 μg / mL), the solution temperature of the nanoparticles increased significantly.

[0115] from Figure 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: Figure 13 (hydrogen 1 HNMR) and Figure 14 ( 13 C NMR). The hydrogen spectrum test conditions are: 1 HNMR, 600 MHz, CDCl3; C-spectrometry 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 Figure 13 ;

[0119] 13C NMR (151 MHz, Chloroform-d) δ 161.00, 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 Figure 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 replacements for some of the technical features therein; and these modifications or replacements do not cause the essence of the corresponding technical solutions to 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 fluoroborane pyrrole compounds according to claim 1, wherein include: Under an inert gas, the first substrate and the second substrate undergo a second reaction to obtain a fluoroborane 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-carbaldehyde or a 7-methoxy-2H-methylene-3-carbaldehyde derivative.

3. The method for preparing fluoroborane pyrrole compounds according to claim 2, wherein: 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 fluoroborane pyrrole compounds according to claim 2, wherein: 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 fluoroborane pyrrole compounds according to claim 4, wherein: The third substrate is one of N-bromosuccinimide and N-iodosuccinimide.

6. The method for preparing fluoroborane pyrrole compounds according to claim 4, wherein: 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 fluoroborane pyrrole compound according to any one of claims 2 to 6, wherein: 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 fluoroborane pyrrole compounds according to claim 7, wherein: 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 fluoroborane pyrrole compound according to claim 1 in preparing a photosensitizer for tumor photodynamic therapy.

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

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