A benzophenone-modified triphenylamine pyridinium organic photosensitizer, a preparation method and application thereof

Abstract

This patent application discloses a benzophenone-modified triphenylamine pyridinium salt organic photosensitizer, its preparation method, and its application. This photosensitizer is a triphenylamine-based compound, specifically synthesized into four compounds: CHO-TPAP-BP, CHO-pTPAP-BP, CHO-eTPAP-BP, and 2CN-eTPAP-BP. This organic photosensitizer combines the strong electron-withdrawing ability of pyridinium salts with the electron-donating properties of triphenylamine, resulting in greater separation of the HOMO-LUMO orbitals in the molecule. This is beneficial for reducing ΔE. ST Secondly, by utilizing the strong intersystem crossing ability of benzophenone, orbital spin coupling (SOC) can be enhanced, thereby increasing the efficiency of reactive oxygen species production and thus improving the photodynamic therapy effect; furthermore, it is hoped that anthracene and singlet oxygen ( 1 The characteristics of O2 reaction to generate internal peroxides and controllable release of oxygen under thermal conditions alleviate hypoxia during photodynamic therapy; at the same time, the multi-rotor structure and the multiple rotations and vibrations of bonds in the molecules are conducive to the construction of a photothermal conversion platform, thereby realizing multimodal synergistic therapy of tumors.

Description

TECHNICAL FIELD

[0001] The present patent application relates to the technical field of photodynamic therapy, more particularly, to a benzophenone-modified triphenylamine pyridine salt organic photosensitizer, and a preparation method and application thereof. BACKGROUND

[0002] The incidence of cancer is increasing year by year, and the mortality rate has been high all the time. Photodynamic therapy as a new cancer treatment method has become a research hotspot because of its advantages of minimally invasive, high targeting, drug resistance and visualization. The main principle of this method is that photosensitizer converts oxygen in cancer cells into active oxygen with cytotoxicity through photosensitive reaction, thereby killing cancer cells.

[0003] However, due to the strong metabolism and fast proliferation rate of cancer cells, a large amount of oxygen is needed, so the tumor microenvironment is a hypoxic environment, and the amount of oxygen is very limited, which cannot meet the amount of oxygen required for photodynamic killing of cancer cells. Therefore, if we want to kill cancer cells in a limited oxygen environment through photodynamic means, we need to overcome the problem of lack of oxygen in cancer cells.

[0004] Therefore, finding a solution to the problem of hypoxia in cancer cells to achieve tumor diagnosis and treatment integration is a problem that researchers in the field urgently need to solve.

[0005] PATENT APPLICATION CONTENT

[0006] To overcome one of the problems existing in the prior art, the primary object of the present patent application is to provide a benzophenone-modified triphenylamine pyridine salt organic photosensitizer. This kind of photosensitizer can make up for the deficiency of photodynamic therapy by improving the yield of active oxygen.

[0007] Another object of the present patent application is to provide a preparation method of the above-mentioned benzophenone-modified triphenylamine pyridine salt organic photosensitizer.

[0008] Another object of the present patent application is to provide an application of the above-mentioned benzophenone-modified triphenylamine pyridine salt organic photosensitizer.

[0009] The above-mentioned objects of the present patent application are achieved by the following technical solutions:

[0010] A benzophenone-modified triphenylamine pyridine salt organic photosensitizer, the benzophenone-modified triphenylamine pyridine salt organic photosensitizer has triphenylamine as the core, and has one of the following molecular structures:

[0011] .

[0012] The present patent application also provides a preparation method of the above-mentioned benzophenone-modified triphenylamine pyridine salt organic photosensitizer, comprising the following steps:

[0013] S11. Preparation of intermediate 4-((4-bromophenyl)(phenyl)amino)benzaldehyde (CHO-TPA-Br)

[0014] Dissolving 4-bromo triphenylamine and phosphorus oxychloride in dimethylformamide, 4-((4-bromophenyl)(phenyl)amino)benzaldehyde (CHO-TPA-Br) is obtained by oxidation reaction; N,N-

[0015] S12. Preparation of intermediate 4-(bis(4-bromophenyl)amino)benzaldehyde (CHO-TPA-2Br)

[0016] Dissolving 4,4-dibromo triphenylamine and phosphorus oxychloride in dimethylformamide, 4-(bis(4-bromophenyl)amino)benzaldehyde (CHO-TPA-2Br) is obtained by oxidation reaction; N,N

[0017] S13. Preparation of intermediates 4-([1,1'-biphenyl]-4-yl(4-bromophenyl)amino)benzaldehyde (CHO-pTPA-Br) and 4-((4-(anthracen-9-yl)phenyl)(4-bromophenyl)amino)benzaldehyde (CHO-eTPA-Br)

[0018] Dissolving the product obtained in step S12, CHO-TPA-2Br, with phenylboronic acid and 9-anthraceneboronic acid, respectively, and potassium carbonate and tetrakis triphenylphosphine palladium in a mixture of tetrahydrofuran and methanol, the reaction gives 4-([1,1'-biphenyl]-4-yl(4-bromophenyl)amino)benzaldehyde (CHO-pTPA-Br) and 4-((4-(anthracen-9-yl)phenyl)(4-bromophenyl)amino)benzaldehyde (CHO-eTPA-Br), respectively.

[0019] S14. Preparation of intermediates 4-(phenyl(4-pyridin-4-yl)phenyl)amino)benzaldehyde (CHO-TPAP), 4-([1,1'-biphenyl]-4-yl(4-(pyridin-4-yl)phenyl)amino)benzaldehyde (CHO-pTPAP) and 4-((4-(anthracen-9-yl)phenyl)(4-(pyridin-4-yl)phenyl)amino)benzaldehyde (CHO-eTPAP)

[0020] ​​The product CHO-TPA-Br obtained in step Sll, the product CHO-pTPA-Br and CHO-eTPA-Br obtained in step S13 are dissolved in a mixture of tetrahydrofuran and methanol with 4-pyridineboronic acid, potassium carbonate and tetrakis triphenylphosphine palladium to react, respectively to obtain 4-(phenyl(4-pyridin-4-yl)phenyl)amino)benzaldehyde (CHO-TPAP), 4-([l,l'-biphenyl]-4-yl(4-(pyridin-4-yl)phenyl)amino)benzaldehyde (CHO-pTPAP) and 4-((4-(anthracen-9-yl)phenyl)(4-(pyridin-4-yl)phenyl)amino)benzaldehyde (CHO-eTPAP);

[0021] S15. Preparation of intermediate 2-(4-((4-(anthracen-9-yl)phenyl)(4-(pyridin-4- yl)phenyl)amino)benzylidene)propanedinitrile (2CN-eTPAP)

[0022] The product CHO-eTPAP obtained in step S14 is dissolved in a mixture of dichloromethane and ethanol with malononitrile to react under the catalysis of anhydrous sodium acetate to obtain 2-(4-((4-(anthracen-9-yl)phenyl)(4-(pyridin-4-yl)phenyl)amino)benzylidene)propanedinitrile (2CN-eTPAP).

[0023] S16. Preparation of final products CHO-TPAP-BP, CHO-pTPAP-BP, CHO-eTPAP-BP, 2CN-eTPAP-BP

[0024] The product CHO-TPAP, CHO-pTPAP, CHO-eTPAP obtained in step S14 and the product 2CN-eTPAP obtained in step S15 are refluxed with 4-(bromomethyl)benzophenone (BP-M-Br) in tetrahydrofuran to respectively obtain 1-(4-benzoylbenzyl)-4-(4-((4-formylphenyl)(phenyl)amino)phenyl)pyridine (CHO-TPAP-BP), 4-(4-([l,l'-biphenyl]-4-yl(4-formylphenyl)amino)phenyl)-l-(4-benzoylbenzyl)pyridine (CHO-pTPAP-BP), 4-(4-((4-(anthracen-9-yl)phenyl)(4-formylphenyl)amino)phenyl)-l-(4-benzoylbenzyl)pyridine (CHO-eTPAP-BP), 4-(4-((4-(anthracen-9-yl)phenyl)(4-(2,2-dicyanovinyl)phenyl)amino)phenyl)-l-(4-benzoylbenzyl)pyridine (2CN-eTPAP-BP).

[0025] Preferably, the oxidation reaction in step Sll needs inert gas protection, the reaction time is 3 h and the temperature is 80°C.

[0026] Preferably, the oxidation reaction in step S12 requires inert gas protection, the reaction time is 5 h, and the temperature is 80℃.

[0027] Preferably, the solvent used in step S13 is tetrahydrofuran and methanol, and the volume ratio of the two is 1:1.

[0028] Preferably, the catalyst used in step S13 is Pd(PPh3)4 with a molar fraction of 4-8%, and inert gas protection is required, the reaction temperature is 80℃, and the time is 24 h.

[0029] Preferably, the solvent used in step S14 is tetrahydrofuran and methanol, and the volume ratio of the two is 1:1, the catalyst used is Pd(PPh3)4 with a molar fraction of 4-8%, and inert gas protection is required, the reaction temperature is 80℃, and the time is 24 h.

[0030] Preferably, the solvent used in step S15 is dichloromethane and ethanol, and the volume ratio of the two is 1:1, and inert gas protection is required, the reaction temperature is room temperature, and the time is 5 h.

[0031] Preferably, the molar ratio of CHO-TPAP or CHO-pTPAP or CHO-eTPAP or 2CN-eTPAP to BP-M-Br in step S16 is 1:(1.1~1.15), the reaction temperature is 80℃, and the time is 30 h.

[0032] The present patent application also provides the use of the above-mentioned benzophenone-modified triphenylamine pyridine salt organic photosensitizer in the field of photodynamic therapy.

[0033] Compared with the prior art, the present patent application has the following beneficial effects:

[0034] The benzophenone-modified triphenylamine pyridine salt organic photosensitizer of the present patent application is an AIE molecule, which has a D-A structure (TPA is an electron-donating structure, and Pys is an electron-withdrawing structure) and a benzophenone structure that can significantly enhance the active oxygen yield, has good photodynamic therapy effect, can realize diagnosis and treatment in one, can prepare fluorescent probes, or be applied in the field of anticancer drugs, etc. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 The H NMR chart of the compound CHO-TPA-Br prepared in step S11. 1 H NMR chart.

[0036] Figure 2 The H NMR chart of the compound CHO-TPA-2Br prepared in step S12. 1 H NMR chart.

[0037] Figure 3 H NMR chart of the compound CHO-pTPA-Br prepared in Step S13 1 H NMR chart.

[0038] Figure 4 H NMR chart of the compound CHO-eTPA-Br prepared in Step S13 1 H NMR chart.

[0039] Figure 5 H NMR chart of the compound CHO-TPAP prepared in Step S14 1 H NMR chart.

[0040] Figure 6 H NMR chart of the compound CHO-pTPAP prepared in Step S14 1 H NMR chart.

[0041] Figure 7 H NMR chart of the compound CHO-eTPAP prepared in Step S14 1 H NMR chart.

[0042] Figure 8 H NMR chart of the compound 2CN-eTPAP prepared in Step S15 1 H NMR chart.

[0043] Figure 9 H NMR chart of the compound CHO-TPAP-BP prepared in Step S16 1 H NMR chart.

[0044] Figure 10 H NMR chart of the compound CHO-pTPAP-BP prepared in Step S16 1 H NMR chart.

[0045] Figure 11 H NMR chart of the compound CHO-eTPAP-BP prepared in Step S16 1 H NMR chart.

[0046] Figure 12 H NMR chart of the compound 2CN-eTPAP-BP prepared in Step S16 1 H NMR chart.

[0047] Figure 13 H NMR chart of the compound CHO-TPAP-BP prepared in Step S16 13 C NMR chart.

[0048] Figure 14 C NMR chart of the compound CHO-pTPAP-BP prepared in Step S16 13 C NMR chart.

[0049] Figure 15AIE curve of the compound CHO-eTPAP-BP prepared in step S14 in dichloromethane and n-hexane mixed solvent. 13 C NMR chart.

[0050] Figure 16 AIE curve of the compound 2CN-eTPAP-BP prepared in step S16 in dichloromethane and n-hexane mixed solvent. 13 C NMR chart.

[0051] Figure 17 Normalized UV absorption spectrum of the products (A) CHO-TPAP-BP; (B) CHO-pTPAP-BP; (C) CHO-eTPAP-BP; (D) 2CN-eTPAP-BP obtained in step S16.

[0052] Figure 18 Normalized UV absorption spectrum of the products (A) CHO-TPAP-BP; (B) CHO-pTPAP-BP; (C) CHO-eTPAP-BP; (D) 2CN-eTPAP-BP obtained in step S16.

[0053] Figure 19 Solid emission fluorescence intensity of the products (A) CHO-TPAP-BP; (B) CHO-pTPAP-BP; (C) CHO-eTPAP-BP; (D) 2CN-eTPAP-BP obtained in step S16.

[0054] Figure 20 Active oxygen generation ability curve of the products (A) CHO-TPAP-BP; (B) CHO-pTPAP-BP; (C) CHO-eTPAP-BP; (D) 2CN-eTPAP-BP obtained in step S16. DETAILED DESCRIPTION

[0055] The embodiments of the present patent application will be described in detail below with reference to the examples, but those skilled in the art will understand that the following examples are only for illustration of the present patent application and should not be regarded as limiting the scope of the present patent application. The specific conditions not noted in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not noted by the manufacturer, which are all conventional products that can be obtained by commercial purchase.

[0056] It should be noted that:

[0057] In the present patent application, all the embodiments and preferred implementation methods mentioned in the present text can be combined with each other to form new technical solutions if there is no special note.

[0058] In the present patent application, unless otherwise specified, the percentage (%) or part refers to the weight percentage or weight parts of the composition.

[0059] In the present patent application, unless otherwise specified, each component or its preferred component involved can be combined with each other to form a new technical solution.

[0060] In the present patent application, unless otherwise specified, the numerical range "a~b" represents a shorthand notation for any real number combination between a and b, where a and b are both real numbers. For example, the numerical range "1~5" represents that all real numbers between "1~5" have been listed herein, and "1~5" is only a shorthand notation for these numerical combinations.

[0061] The "range" disclosed in the present patent application in the form of lower limit and upper limit can be one or more lower limits, and one or more upper limits, respectively.

[0062] In the present patent application, unless otherwise specified, each reaction or operation step can be carried out sequentially or according to the sequence. Preferably, the reaction method herein is carried out sequentially.

[0063] Unless otherwise specified, the professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any method or material similar or equivalent to that described can also be applied in the present patent application.

[0064] The present patent application provides a pyridine salt organic photosensitizer, which is a benzophenone modified triphenylamine compound and has the following molecular structure:

[0065] ;

[0066] From left to right, the first to the fourth benzophenone modified triphenylamine pyridine salt compounds are named as: 1-(4-benzoylbenzyl)-4-(4-((4-formylphenyl)(phenyl)amino)phenyl)pyridine (abbreviation: CHO-TPAP-BP), 4-(4-([1,1'-biphenyl]-4-yl(4-formylphenyl)amino)phenyl)-1-(4-benzoylbenzyl)pyridine (abbreviation: CHO-pTPAP-BP), 4-(4-((4-(anthracen-9-yl)phenyl)(4-formylphenyl)amino)phenyl)-1-(4-benzoylbenzyl)pyridine (abbreviation: CHO-eTPAP-BP), and 4-(4-((4-(anthracen-9-yl)phenyl)(4-(2,2-dicyanovinyl)phenyl)amino)phenyl)-1-(4-benzoylbenzyl)pyridine (abbreviation: 2CN-eTPAP-BP).

[0067] The benzophenone-modified triphenylamine pyridinium salt organic photosensitizer of this patent application is an AIE molecule with a DA structure (TPA is an electron-donating structure, Pys is an electron-withdrawing structure) and a benzophenone structure. The DA structure makes the HOMO-LUMO orbitals of the molecule more separated, which is beneficial for reducing Δ E ST The benzophenone structure promotes intersystem jumping and enhances orbital-spin coupling (SOC), making it easier for energy to transition from the singlet to the triplet state. Both structures contribute to the generation of reactive oxygen species (ROS), increasing ROS generation efficiency. Secondly, the multi-rotor structure and multiple rotations and vibrations of bonds in the compound of this patent application facilitate the construction of a photothermal conversion platform, thereby enabling multimodal synergistic tumor therapy. The rotor structure refers to the twisting and rotation of covalent bonds. Taking triphenylamine as an example, the covalent bond connecting the nitrogen atom to the benzene ring can twist and rotate (as shown below), which is a rotor structure. A multi-rotor structure refers to the twisting and rotation of covalent bonds within the molecule.

[0068] ;

[0069] Furthermore, the benzophenone-modified triphenylamine pyridinium salt organic photosensitizer of this patent application contains an anthracene structure, which is expected to react with singlet oxygen in the form of a peroxide formed inside the benzene ring under light conditions. 1 It combines with O2 and can controllably release oxygen under thermal conditions, which helps to solve the problem of oxygen deficiency in cancer cells; the structural formula of the peroxide is shown below:

[0070] ;

[0071] Origin of singlet oxygen: After absorbing light, the molecule reaches the triplet state. The triplet state undergoes energy conversion with oxygen in the air to form singlet oxygen.

[0072] Meanwhile, the benzophenone-modified triphenylamine organic photosensitizer of this invention is a pyridine salt, which is expected to utilize N + The hydrophilic properties of ions and their electrostatic interactions with some subcellular structures enable targeting effects, giving them high targeting specificity and achieving efficient photodynamic therapy. Therefore, the triphenylamine-based pyridine salt organic photosensitizer of this invention can improve the yield of reactive oxygen species and also has good fluorescence properties, enabling integrated diagnosis and treatment. It can be used to prepare fluorescent probes or applied in fields such as anticancer drugs.

[0073] This patent application also provides a method for preparing the above-mentioned benzophenone-modified triphenylamine pyridine salt organic photosensitizer. The method includes the following steps:

[0074] S11. Preparation of intermediate 4-((4-bromophenyl)(phenyl)amino)benzaldehyde (CHO-TPA-Br)

[0075] Dissolution of 4-bromo triphenylamine and phosphorus oxychloride in dimethylformamide, by oxidation reaction, 4-((4-bromophenyl)(phenyl)amino)benzaldehyde (CHO-TPA-Br) is obtained; N,N-

[0076] S12. Preparation of intermediate 4-(bis(4-bromophenyl)amino)benzaldehyde (CHO-TPA-2Br)

[0077] Dissolution of 4,4-dibromo triphenylamine and phosphorus oxychloride in dimethylformamide, by oxidation reaction, 4-(bis(4-bromophenyl)amino)benzaldehyde (CHO-TPA-2Br) is obtained; N,N

[0078] S13. Preparation of intermediates 4-([1,1'-biphenyl]-4-yl(4-bromophenyl)amino)benzaldehyde (CHO-pTPA-Br) and 4-((4-(anthracen-9-yl)phenyl)(4-bromophenyl)amino)benzaldehyde (CHO-eTPA-Br)

[0079] Dissolution of the product obtained in step S12, CHO-TPA-2Br, with phenylboronic acid and 9-anthraceneboronic acid, respectively, and potassium carbonate and tetrakis triphenylphosphine palladium in a mixture of tetrahydrofuran and methanol, the reaction gives 4-([1,1'-biphenyl]-4-yl(4-bromophenyl)amino)benzaldehyde (CHO-pTPA-Br) and 4-((4-(anthracen-9-yl)phenyl)(4-bromophenyl)amino)benzaldehyde (CHO-eTPA-Br), respectively.

[0080] S14. Preparation of intermediates 4-(phenyl(4-pyridin-4-yl)phenyl)amino)benzaldehyde (CHO-TPAP), 4-([1,1'-biphenyl]-4-yl(4-(pyridin-4-yl)phenyl)amino)benzaldehyde (CHO-pTPAP) and 4-((4-(anthracen-9-yl)phenyl)(4-(pyridin-4-yl)phenyl)amino)benzaldehyde (CHO-eTPAP)

[0081] Dissolution of the product obtained in step S11, CHO-TPA-Br, and the products obtained in step S13, CHO-pTPA-Br and CHO-eTPA-Br, with 4-pyridineboronic acid, and potassium carbonate and tetrakis triphenylphosphine palladium in a mixture of tetrahydrofuran and methanol, the reaction gives 4-(phenyl(4-pyridin-4-yl)phenyl)amino)benzaldehyde (CHO-TPAP), 4-([1,1'-biphenyl]-4-yl(4-(pyridin-4-yl)phenyl)amino)benzaldehyde (CHO-pTPAP) and 4-((4-(anthracen-9-yl)phenyl)(4-(pyridin-4-yl)phenyl)amino)benzaldehyde (CHO-eTPAP), respectively.​​

[0082] S15. Preparation of intermediate 2-(4-((4-(anthracen-9-yl)phenyl)(4-(pyridin-4- yl)phenyl)amino)benzylidene)propanedinitrile (2CN-eTPAP)

[0083] The product CHO-eTPAP obtained in step S14 is dissolved in a mixture of dichloromethane and ethanol, and reacted under catalysis of anhydrous sodium acetate to obtain 2-(4-((4-(anthracen-9-yl)phenyl)(4-(pyridin-4-yl)phenyl)amino)benzylidene)propanedinitrile (2CN-eTPAP).

[0084] S16. Preparation of final products CHO-TPAP-BP, CHO-pTPAP-BP, CHO-eTPAP-BP, 2CN-eTPAP-BP

[0085] The product CHO-TPAP obtained in step S14, the product CHO-pTPAP obtained in step S14, the product CHO-eTPAP obtained in step S14, and the product 2CN-eTPAP obtained in step S15 are refluxed with 4-(bromomethyl)benzophenone (BP-M-Br) in tetrahydrofuran to obtain 1-(4-benzoylbenzyl)-4-(4-((4-formylphenyl)(phenyl)amino)phenyl)pyridine (CHO-TPAP-BP), 4-(4-([1,1'-biphenyl]-4-yl(4-formylphenyl)amino)phenyl)-1-(4-benzoylbenzyl)pyridine (CHO-pTPAP-BP), 4-(4-((4-(anthracen-9-yl)phenyl)(4-formylphenyl)amino)phenyl)-1-(4-benzoylbenzyl)pyridine (CHO-eTPAP-BP), and 4-(4-((4-(anthracen-9-yl)phenyl)(4-(2,2-dicyanovinyl)phenyl)amino)phenyl)-1-(4-benzoylbenzyl)pyridine (2CN-eTPAP-BP), respectively.

[0086] In the preparation method described in the present patent application, the oxidation reaction in step S11 requires inert gas protection, the reaction time is 3 h, and the temperature is 80°C.

[0087] In the preparation method described in the present patent application, the oxidation reaction in step S12 requires inert gas protection, the reaction time is 5 h, and the temperature is 80°C.

[0088] In the preparation method described in the present patent application, the solvent used in step S13 is tetrahydrofuran and methanol, and the volume ratio of the two is 1:1.

[0089] In the preparation method of the present patent application, the catalyst used in step S13 is Pd(PPh3)4 with a molar fraction of 4-8%, and needs inert gas protection, the reaction temperature is 80°C, and the reaction time is 24 h.

[0090] In the preparation method of the present patent application, the solvent used in step S14 is tetrahydrofuran and methanol with a volume ratio of 1:1, the catalyst used is Pd(PPh3)4 with a molar fraction of 4-8%, and needs inert gas protection, the reaction temperature is 80°C, and the reaction time is 24 h.

[0091] In the preparation method of the present patent application, the solvent used in step S15 is dichloromethane and ethanol with a volume ratio of 1:1, and needs inert gas protection, the reaction temperature is room temperature, and the reaction time is 5 h.

[0092] In the preparation method of the present patent application, the molar ratio of CHO-TPAP or CHO-pTPAP or CHO-eTPAP or 2CN-eTPAP to BP-M-Br in step S16 is 1:(1.1-1.15), the reaction temperature is 80°C, and the reaction time is 30 h.

[0093] The present patent application also provides the application of the above-mentioned benzophenone-modified triphenylamine pyridinium salt organic photosensitizer in the field of photodynamic therapy.

[0094] The preparation method of the benzophenone-modified triphenylamine pyridinium salt organic photosensitizer in the present patent application will be described in detail below.

[0095] Preparation of intermediate 4-((4-bromophenyl)(phenyl)amino)benzaldehyde (CHO-TPA-Br)

[0096] The preparation method of the intermediate CHO-TPA-Br is as follows:

[0097] 4-bromotriphenylamine (20 mmol, 324.22 g / mol, 6.48 g) and N,N dimethylformamide (20 mL) were mixed for ice water bath for 15 min; phosphorus oxychloride (15 mL) was slowly added, and after stirring at room temperature for 10 min, the reaction was heated to 80°C under nitrogen protection and refluxed for 3 h. After the reaction was completed, the reaction liquid was poured into a large amount of water to precipitate the solid, which was extracted and dried, and then column chromatography was used for separation to obtain CHO-TPA-Br as a light blue solid with a yield of 85%.

[0098] The chemical reaction equation in the preparation method is as follows:

[0099] ;

[0100] AsFigure 1 The intermediate CHO-TPA-Br can be characterized by1H NMR. The1H NMR data are as follows: 1 H NMR (400MHz, Chloroform-d) δ 9.82 ( s , 1H), 7.69 ( d , J 8.8 Hz, 2H), 7.43 ( d , J 8.8 Hz, 2H),7.34 ( dd , J 8.3, 7.6 Hz, 2H), 7.18 ( t , J 7.4 Hz, 1H), 7.14 ( dd , J 8.4, 0.9 Hz, 2H),7.03 ( dd , J 8.7, 6.6 Hz, 4H).

[0101] In some preferred embodiments of the present patent application, the 4-bromo triphenylamine is dissolved in N,N dimethylformamide before the reaction of step S11, and ice bath is performed for 15 min, and then phosphorus oxychloride is added dropwise for reaction.

[0102] In some preferred embodiments of the present patent application, the reaction of step S11 is performed in N,N dimethylformamide as the reaction solvent, and dissolution is ensured as much as possible before the reaction. The conditions of the oxidation reaction are heating and refluxing under inert gas protection, and the inert atmosphere is a nitrogen atmosphere, an argon atmosphere, and a helium atmosphere. More preferably, the inert atmosphere in the step is a nitrogen (N2) atmosphere.

[0103] Preparation of intermediate 4-(bis(4-bromophenyl)amino)benzaldehyde (CHO-TPA-2Br) in Example 12

[0104] The preparation method of the intermediate CHO-TPA-2Br is as follows:

[0105] 4,4-Dibromo triphenylamine (12.4 mmol, 403.12 g / mol, 5 g) was dissolved in N,NIn dimethylformamide (20 mL), slowly drop phosphorus oxychloride (10 mL) with ice water bath for 15 min, after stirring at room temperature for 10 min, heat to 80℃ under nitrogen protection and reflux for 5 h. After the reaction is completed, pour the reaction liquid into a large amount of water to precipitate the solid, and then extract and dry column chromatography to separate CHO-TPA-2Br. The product is a yellow solid with a yield of 88%.

[0106] The chemical reaction equation in the preparation method is as follows:

[0107] ;

[0108] As shown in Figure 2 , the intermediate CHO-TPA-2Br can be obtained by nuclear magnetic hydrogen spectrum characterization. The nuclear magnetic hydrogen spectrum data of the intermediate CHO-TPA-2Br is as follows: 1 H NMR (400 MHz, Chloroform-d) δ 9.81 ( s , 1H), 7.73 – 7.65( m , 2H), 7.47 – 7.38 ( m , 4H), 7.07 – 6.97 ( m , 6H).

[0109] In some preferred embodiments of the present patent application, before the reaction of step S12, 4,4-dibromo triphenylamine is dissolved in N,N dimethylformamide for ice bath, and the ice bath time is 15 min, and then phosphorus oxychloride is added dropwise for reaction.

[0110] In some preferred embodiments of the present patent application, the reaction of step S12 is carried out in N,N dimethylformamide as the reaction solvent, and the dissolution is ensured as much as possible before the reaction. The condition of the oxidation reaction is to carry out heating reflux under inert gas protection, and the inert atmosphere is nitrogen atmosphere, argon atmosphere and helium atmosphere. More preferably, the inert atmosphere in the step is nitrogen (N2) atmosphere.

[0111] Preparation of intermediates 4-([1,1'-biphenyl]-4-yl(4-bromophenyl)amino)benzaldehyde (CHO-pTPA-Br) and 4-((4-(anthracen-9-yl)phenyl)(4-bromophenyl)amino)benzaldehyde (CHO-eTPA-Br) in step S13

[0112] The preparation method of the intermediate CHO-pTPA-Br in step S131 is as follows:

[0113] CHO-TPA-2Br (3.38 mmol, 431.13 g / mol, 1.5 g) and phenylboronic acid (6.97 mmol, 122 g / mol, 850 mg) tetrakis(triphenylphosphine)palladium (1155 g / mol, 0.17 mmol, 200 mg) and potassium carbonate (138.21 g / mol, 6.96 mmol, 961 mg) were added into a 100 mL two-necked round-bottom flask in turn, and then tetrahydrofuran and methanol were added into the round-bottom flask in a volume ratio of 1:1. The reaction was heated to 40 °C in an N2 atmosphere for 24 h. After the reaction was completed, the crude product was concentrated under reduced pressure, and then separated and purified by column chromatography. The eluent was ethyl acetate: petroleum ether = 1:50 (volume ratio). Finally, a white solid was obtained, and the yield was 80%.

[0114] The chemical reaction equation in this preparation method is as follows:

[0115] ;

[0116] As shown in Figure 3 , the compound CHO-pTPA-Br can be obtained by nuclear magnetic hydrogen spectrum characterization. The nuclear magnetic data of the compound CHO-pTPA-Br are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 9.85 ( s , 1H), 7.74 ( d, J = 8.4Hz, 2H), 7.60 ( dd, J = 8.0, 3.2 Hz, 7H), 7.46 ( t, J = 7.6 Hz, 4H), 7.35 ( t, J =7.4 Hz, 2H), 7.15 ( d, J = 8.3 Hz, 2H).

[0117] The preparation method of the intermediate CHO-eTPA-Br in step S132 is as follows:

[0118] CHO-TPA-2Br (6.96 mmol, 431.13 g / mol, 3 g) and 9-anthraceneboronic acid (15.76 mmol, 222.05 g / mol, 3.5 g), tetrakis(triphenylphosphine)palladium(0) (0.17 mmol, 1155 g / mol, 200 mg) and potassium carbonate (138.21 g / mol, 6.96 mmol, 961 mg) were added into a 100 mL two-necked round-bottom flask in turn, and then tetrahydrofuran and methanol were added into the round-bottom flask in a volume ratio of 1:1. The reaction was heated to 45 °C in an N2 atmosphere for 24 h. After the reaction was completed, the crude product was concentrated under reduced pressure, and then separated and purified by column chromatography. The eluent was ethyl acetate: petroleum ether = 1:50 (volume ratio). Finally, a yellow solid was obtained, and the yield was 85%.

[0119] The chemical reaction equation in this preparation method is as follows:

[0120] ;

[0121] As shown in Figure 4 , the compound CHO-eTPA-Br can be obtained by nuclear magnetic hydrogen spectrum characterization. The nuclear magnetic hydrogen spectrum data of the compound CHO-eTPA-Br are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 9.88 ( d, J = 6.2 Hz, 1H), 8.52 ( s , 1H), 8.06 ( d, J = 8.4 Hz, 2H), 7.83 – 7.71 ( m , 4H), 7.57 – 7.52 ( m , 2H), 7.49 ( ddd,J = 8.2, 6.5, 1.3 Hz, 2H), 7.42 ( dd, t , J = 11.1, 6.4, 3.2 Hz, 4H), 7.38 – 7.33 ( m , 2H), 7.25 – 7.18 ( m , 4H).

[0122] In some preferred embodiments of the present patent application, in step S13, the selected catalyst is palladium tetraphenylphosphine, the base used is potassium carbonate or sodium carbonate, and the molar ratio of CHO-TPA-2Br, phenylboronic acid, potassium carbonate and palladium tetraphenylphosphine is 1:2:2:(4%-8%); the molar ratio of CHO-TPA-2Br, 9-anthracene boronic acid, potassium carbonate and palladium tetraphenylphosphine is 1:2:2:(4%-8%).

[0123] In some preferred embodiments of the present patent application, the solvent used in step S13 is tetrahydrofuran (THF) and methanol (CH3OH) (volume ratio = 1:1), and tetrahydrofuran is added first, followed by methanol to ensure dissolution. The reaction is carried out under heating reflux in an inert gas atmosphere, and the inert atmosphere in the step is a nitrogen (N2) atmosphere. The reaction temperature of CHO-TPA-2Br and phenylboronic acid is set to 40°C, and the reaction time is 24 h; the reaction temperature of CHO-TPA-2Br and 9-anthracene boronic acid is set to 45°C, and the reaction time is 24 h.

[0124] In some preferred embodiments of the present patent application, after step S13, the reaction solution is cooled to room temperature, and concentrated under reduced pressure to remove the reaction solution. The crude product is then dissolved in dichloromethane and mixed with silica gel, and then purified by column chromatography using petroleum ether and ethyl acetate as the eluent (volume ratio of ethyl acetate to petroleum ether = 1:50), to obtain the intermediates: CHO-pTPA-Br and CHO-eTPA-Br.

[0125] Preparation of intermediates 4-(phenyl(4-pyridin-4-yl)phenyl)amino)benzaldehyde (CHO-TPAP), 4-([1,1'-biphenyl]-4-yl(4-(pyridin-4-yl)phenyl)amino)benzaldehyde (CHO-pTPAP) and 4-((4-(anthracen-9-yl)phenyl)(4-(pyridin-4-yl)phenyl)amino)benzaldehyde (CHO-eTPAP)

[0126] The preparation method of intermediate CHO-TPAP in step S141 is as follows:

[0127] CHO-TPA-Br (1.7 mmol, 352.23 g / mol, 600 mg) and 4-pyridineboronic acid (2.56 mmol, 122.92 g / mol, 314.08 mg), tetrakis(triphenylphosphine)palladium (0.085 mmol, 1155 g / mol, 98.18 mg) and potassium carbonate (3.4 mmol, 138.21 g / mol, 470 mg) were added into a 100 mL two-necked round-bottom flask in turn, then tetrahydrofuran and methanol were added into the round-bottom flask in a volume ratio of 1:1. The reaction was heated to 80 °C in an N2 atmosphere for 24 h. After the reaction was completed, the crude product was concentrated under reduced pressure, and then separated and purified by column chromatography. The eluent was ethyl acetate: petroleum ether = 1:200 (volume ratio). Finally, a yellow solid was obtained with a yield of 84%.

[0128] The reaction equation is as follows:

[0129] ;

[0130] As shown in Figure 5 , the compound CHO-TPAP nuclear magnetic hydrogen spectrum characterization can be obtained. The nuclear magnetic hydrogen spectrum data are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 9.87 ( s , 1H), 8.67 ( d, J = 5.0 Hz, 2H), 7.78 – 7.66( m , 3H), 7.63 ( d, J = 8.5 Hz, 2H), 7.60 – 7.47 ( m , 4H), 7.40 ( t, J = 7.7 Hz,2H), 7.32 – 7.20 ( m , 4H), 7.14 ( d, J = 8.5 Hz, 2H).

[0131] Step 142 Preparation of CHO-pTPAP

[0132] CHO-pTPA-Br (1.17 mmol, 428.33 g / mol, 500 mg) and 4-pyridineboronic acid (1.76 mmol, 122.92 g / mol, 215.72 mg), tetrakis(triphenylphosphine)palladium (0.06 mmol, 1155 g / mol, 67.56 mg) and potassium carbonate (2.34 mmol, 138.21 g / mol, 323.41 mg) were added into a 100 mL two-necked round-bottom flask in turn, then tetrahydrofuran and methanol were added into the round-bottom flask in a volume ratio of 1:1. The reaction was heated to 80 °C in an N2 atmosphere for 24 h. After the reaction was completed, the crude product was concentrated under reduced pressure, and then separated and purified by column chromatography. The eluent was ethyl acetate: petroleum ether = 1:200 (volume ratio). Finally, a yellow solid was obtained with a yield of 78%.

[0133] The reaction equation is as follows:

[0134] ;

[0135] As shown in Figure 6 , the compound CHO-pTPAP can be obtained by nuclear magnetic hydrogen spectrum characterization. The nuclear magnetic data of the compound CHO-pTPAP are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 9.78 ( s , 1H), 8.59 ( d, J = 5.5 Hz,2H), 7.68 ( d, J = 8.4 Hz, 2H), 7.54 ( dd, J = 12.0, 8.1 Hz, 6H), 7.44 ( d, J = 5.1Hz, 2H), 7.37 ( t, J = 7.5 Hz, 2H), 7.29 ( d, J = 7.3 Hz, 1H), 7.22 ( d, J = 8.4Hz, 2H), 7.20 – 7.15 ( m , 2H), 7.10 ( d, J = 8.4 Hz, 2H).

[0136] Step S143 Preparation of CHO-eTPAP

[0137] CHO-eTPA-Br (3.8 mmol, 528.45 g / mol, 2 g) and 4-pyridineboronic acid (3 mmol, 122.92 g / mol, 368.76 mg), tetrakis(triphenylphosphine)palladium (0.0475 mmol, 1155 g / mol, 54.86 mg) and potassium carbonate (1.9 mmol, 138.21 g / mol, 262.6 mg) were added into a 100 mL two-necked round-bottom flask in turn, then tetrahydrofuran and methanol were added into the flask in a 1:1 ratio. The reaction was heated to 80 °C in an N2 atmosphere for 24 h. After the reaction was completed, the crude product was concentrated under reduced pressure, and then separated and purified by column chromatography using a mixture of ethyl acetate and petroleum ether (volume ratio = 1:200) as the eluent. Finally, a yellow solid was obtained with a yield of 86%.

[0138] The reaction equation is as follows:

[0139] ;

[0140] As shown in Figure 7 , the product CHO-eTPAP characterization can be obtained. The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 9.90 ( s , 1H), 8.70 – 8.64 ( m , 2H), 8.52 ( s , 1H), 8.07 ( d, J =8.4 Hz, 2H), 7.86 – 7.80 ( m , 2H), 7.77 ( dd, J = 8.8, 1.2 Hz, 2H), 7.72 – 7.67( m , 2H), 7.59 – 7.52 ( m , 2H), 7.49 ( ddd, J = 8.3, 6.5, 1.3 Hz, 2H), 7.46 –7.37 ( m , 8H), 7.33 – 7.27 ( m , 2H).

[0141] In step S14 of some preferred embodiments of the present patent application, the selected catalyst is palladium tetraphenylphosphine, the base used is potassium carbonate or sodium carbonate, and the molar ratio of CHO-TPA-Br, 4-pyridine boronic acid, potassium carbonate and palladium tetraphenylphosphine is 1:1.5:2:(4%-8%); the molar ratio of CHO-pTPA-Br, 4-pyridine boronic acid, potassium carbonate and palladium tetraphenylphosphine is 1:1.5:2:(4%-8%); and the molar ratio of CHO-eTPA-Br, 4-pyridine boronic acid, potassium carbonate and palladium tetraphenylphosphine is 1:1.5:2:(4%-8%).

[0142] In some preferred embodiments of the present patent application, the solvent used in step S14 is tetrahydrofuran (THF) and methanol (CH3OH) (volume ratio = 1:1), and tetrahydrofuran is added first, followed by methanol to ensure dissolution. The reaction is carried out under heating reflux in an inert gas atmosphere, and the inert atmosphere in the step is a nitrogen (N2) atmosphere. The reaction temperature is set to 80°C, and the reaction time is 24 h.

[0143] In some preferred embodiments of the present patent application, after step S14, the reaction solution is cooled to room temperature, and concentrated under reduced pressure to remove the reaction solution. The crude product is then dissolved in dichloromethane and mixed with silica gel, and then purified by column chromatography using petroleum ether and ethyl acetate as the eluent (volume ratio of ethyl acetate to petroleum ether = 1:200), to obtain the intermediate: CHO-TPAP, CHO-eTPAP, CHO-pTPAP.

[0144] Preparation of intermediate 2-(4-((4-(anthracen-9-yl)phenyl)(4-(pyridin-4-yl)phenyl)amino)benzylidene)propanedinitrile (2CN-eTPAP) in step S15

[0145] The preparation method of intermediate 2CN-eTPAP is as follows:

[0146] CHO-eTPAP (1.9 mmol, 526.64 g / mol, 1 g) and malononitrile (2.42 mmol, 66.02 g / mol, 160 mg) were added into a 100 mL two-necked round-bottom flask in turn, then dichloromethane and ethanol were added into the round-bottom flask in a volume ratio of 1:1, after stirring at room temperature for 10 min, anhydrous sodium acetate (1.95 mmol, 82.05 g / mol, 160 mg) was dissolved in 5 mL of ethanol, then the anhydrous sodium acetate-ethanol mixture was added dropwise into the reaction solution, the reaction solution turned red, the reaction was carried out at room temperature for 5 h in an N2 atmosphere, after the reaction was completed, the crude product was concentrated under reduced pressure, and column chromatography was used for separation and purification, the eluent was ethyl acetate: petroleum ether = 1:200 (volume ratio), finally a red solid was obtained, and the yield was 86%.

[0147] The reaction equation is as follows:

[0148] ;

[0149] As shown in Figure 8 , compound 2CN-eTPAP can be obtained by nuclear magnetic hydrogen spectrum characterization. The nuclear magnetic data of the compound 2CN-eTPAP is as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.70 ( d, J = 5.1 Hz, 2H), 8.53 ( s ,1H), 8.08 ( d, J = 8.4 Hz, 2H), 7.87 ( d, J = 8.8 Hz, 2H), 7.73 ( dd, J = 8.7, 1.8Hz, 4H), 7.64 – 7.55 ( m , 3H), 7.54 – 7.39 ( m , 10H), 7.22 ( d, J = 8.8 Hz, 2H).

[0150] In some preferred embodiments of the present patent application, the molar ratio of CHO-eTPAP, malononitrile and anhydrous sodium acetate used in step S15 is 1:1.5:1, CHO-eTPAP is first dissolved in malononitrile in the reaction, and then anhydrous sodium acetate is added after stirring at room temperature for 10 min, and the anhydrous sodium acetate needs to be dissolved in ethanol first.

[0151] In some preferred embodiments of the present patent application, the reaction solvent in step S15 is selected to be dichloromethane (CH2Cl2) and ethanol (C2H5OH) (volume ratio = 1:1), and dichloromethane is added first and then ethanol is added to ensure dissolution during use. The reaction conditions are room temperature reflux under inert gas protection, and the inert atmosphere in the step is a nitrogen (N2) atmosphere, and the reaction time is 5 h.

[0152] In some preferred embodiments of the present patent application, after step S15, the reaction solution is removed by vacuum concentration, then the crude product is dissolved in silica gel for sample mixing, and then column chromatography is used for separation and purification, using a mixture of petroleum ether and ethyl acetate as the eluent (volume ratio of ethyl acetate to petroleum ether = 1:200), and finally the intermediate 2CN-eTPAP is obtained.

[0153] Step S16 Preparation of final products CHO-TPAP-BP, CHO-pTPAP-BP, CHO-eTPAP-BP, 2CN-eTPAP-BP

[0154] Step S161 Preparation method of final product CHO-TPAP-BP is as follows:

[0155] CHO-TPAP (0.86 mmol, 350.42 g / mol, 300 mg) was dissolved in 20 mL of tetrahydrofuran, then BP-M-Br (0.95 mmol, 275.15 g / mol, 261.39 mg) was added to the reaction solution, and the temperature was raised to 80°C for 30 h. After the reaction was completed, the precipitate in the reaction solution was filtered, and the filter residue was washed several times with a mixture of tetrahydrofuran and n-hexane to obtain a yellow solid, with a yield of 91%.

[0156] The reaction equation is as follows:

[0157] ;

[0158] As shown in the Figure 9 nuclear magnetic hydrogen spectrum and Figure 13 carbon spectrum, the characterization of compound CHO-TPAP-BP can be obtained. The nuclear magnetic data is as follows: 1 H NMR (400 MHz, Chloroform-d) δ 9.89 ( s , 1H), 9.57 ( d, J = 6.1 Hz, 2H), 8.08( d, J = 5.8 Hz, 2H), 7.88 ( d, J= 7.8 Hz, 2H), 7.80 – 7.64 ( m , 9H), 7.61 – 7.53 ( m , 1H), 7.41 ( dt, J = 20.3, 7.7 Hz, 4H), 7.22 – 7.11 ( m , 6H), 6.44 ( s , 2H). 13 CNMR (101 MHz, CDCl3) δ 195.73, 190.57, 155.15, 151.64, 150.82, 145.16, 144.83, 138.62, 137.63, 136.74, 132.94, 131.47, 131.37, 130.91, 130.27, 130.07, 129.58, 129.30, 128.47, 127.08, 126.70, 126.52, 123.58, 123.37, 122.97, 53.50.

[0159] Step 162 Preparation of the final product CHO-pTPAP-BP

[0160] CHO-pTPAP (0.71 mmol, 426.52 g / mol, 300 mg) was dissolved in 20 mL of tetrahydrofuran. Then, BP-M-Br (0.78 mmol, 275.15 g / mol, 214.62 mg) was added to the reaction solution. The mixture was then heated to 80 °C and reacted for 30 h. After the reaction was completed by thin-layer chromatography, the precipitate in the reaction solution was filtered. The filter residue was washed several times with a mixture of tetrahydrofuran and n-hexane to obtain a yellow solid with a yield of 90%.

[0161] The reaction equation is as follows:

[0162] ;

[0163] like Figure 10 The nuclear magnetic hydrogen spectrum and Figure 14 The carbon spectrum of compound CHO-pTPAP-BP was obtained. The NMR data are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 9.90 ( s , 1H), 9.57 ( d, J = 6.1 Hz, 2H), 8.10 ( d, J= 5.9 Hz, 2H), 7.88 ( d, J = 7.8 Hz, 2H), 7.79 ( d, J = 8.5 Hz, 2H),7.76 – 7.66 ( m , 6H), 7.58 (td, J = 10.9, 9.6, 6.7 Hz, 5H), 7.44 ( td, J = 7.5,4.9 Hz, 4H), 7.36 ( dd, J = 8.3, 6.2 Hz, 1H), 7.26 – 7.15 ( m , 6H), 6.45 ( s ,2H). 13 C NMR (101 MHz, CDCl3) δ 195.71, 190.53, 155.21, 151.55, 150.81, 144.79,144.33, 139.87, 139.27, 138.74, 137.49, 136.75, 132.96, 131.69, 131.42,130.95, 130.09, 129.56, 129.34, 128.95, 128.81, 128.48, 127.66, 127.13,126.95, 126.82, 123.57, 123.53, 123.21, 62.18.

[0164] Step 163 Preparation of final product CHO-eTPAP-BP

[0165] CHO-eTPAP (0.57 mmol, 528.45 g / mol, 300 mg) was dissolved in 20 mL of tetrahydrofuran, then BP-M-Br (0.63 mmol, 275.15 g / mol, 174.34 mg) was added to the reaction solution, and the temperature was raised to 80°C for 30 h. After TLC monitoring reaction completion, the precipitate in the reaction solution was filtered, and the filter residue was washed with a mixture of tetrahydrofuran and n-hexane several times to obtain an orange-red solid, with a yield of 92%.

[0166] The reaction equation is as follows:

[0167] ;

[0168] As Figure 11 the nuclear magnetic hydrogen spectrum and Figure 15The characterization of compound CHO-eTPAP-BP can be obtained as shown in the carbon spectrum. The nuclear magnetic resonance data are: 1 H NMR (400 MHz, Chloroform-d) δ 9.90 ( d, J = 21.6 Hz, 1H), 9.52 ( s , 2H),8.51 ( s , 1H), 8.15 ( d, J = 6.2 Hz, 1H), 8.07 ( dd, J = 14.0, 7.4 Hz, 3H), 7.86( d, J = 6.1 Hz, 3H), 7.81 – 7.68 ( m , 9H), 7.57 – 7.29 ( m , 14H), 7.16 ( s , 2H),6.39 ( d, J = 5.6 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 195.76, 190.59, 157.33,155.21, 151.72, 150.87, 144.77, 144.54, 137.49, 136.79, 136.75, 135.60,133.11, 132.96, 131.55, 131.37, 130.96, 130.27, 130.13, 130.08, 129.51,129.48, 128.55, 128.47, 127.08, 127.03, 126.57, 126.39, 125.73, 125.25,123.95, 123.72, 123.40, 123.36.

[0169] Step 164 Preparation of final product 2CN-eTPAP-BP

[0170] 2CN-eTPAP (0.697 mmol, 574.22 g / mol, 400 mg) was dissolved in 20 mL of tetrahydrofuran, then BP-M-Br (0.763 mmol, 275.15 g / mol, 210 mg) was added to the reaction solution, and the temperature was raised to 80°C for 30h, and thin layer chromatography was used to monitor the completion of the reaction. After the reaction was completed, the precipitate in the reaction solution was filtered, and the filter residue was washed with a mixture of tetrahydrofuran and n-hexane several times to obtain a red solid, with a yield of 90%.

[0171] The reaction equation is as follows:

[0172] ;

[0173] As Figure 12 nuclear magnetic hydrogen spectrum and Figure 16 carbon spectrum, compound 2CN-eTPAP-BP characterization can be obtained. The nuclear magnetic data are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 9.90 ( d, J = 21.6 Hz, 1H), 9.52 ( s , 2H),8.51 ( s , 1H), 8.15 ( d, J = 6.2 Hz, 1H), 8.07 ( dd, J = 14.0, 7.4 Hz, 3H), 7.86( d, J = 6.1 Hz, 3H), 7.81 – 7.68 ( m , 9H), 7.57 – 7.29 ( m , 14H), 7.16 ( s , 2H),6.39 ( d, J = 5.6 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 195.70, 157.98, 155.32,155.15, 151.88, 149.89, 144.91, 143.86, 138.79, 137.54, 137.36, 136.70,135.35, 133.29, 133.01, 132.97, 131.34, 130.98, 130.08, 129.65, 129.54,128.58, 128.49, 127.16, 126.87, 126.30, 125.83, 125.29, 125.01, 124.11,121.97, 120.28, 114.56, 113.56, 78.49.

[0174] In some preferred embodiments of the present patent application, in step S16, the selected solvent is dichloromethane, ethanol, tetrahydrofuran, more preferably, tetrahydrofuran is used as the reaction solvent, so that the raw material is completely dissolved, but the solvent is not easy to be excessive, and it is appropriate to be just dissolved. The reaction temperature is 80°C, and the reaction time is 30 h.

[0175] In some preferred embodiments of the present patent application, the ratio of CHO-TPAP, CHO-pTPAP, CHO-eTPAP and 2CN-eTPAP, BP-M-Br in step S16 is all 1:(1.1~1.15). During the reaction, solid will be precipitated, and the product adsorbed on the edge of the round-bottom flask can be scraped back into the solvent with a scraper to ensure full reaction.

[0176] In some preferred embodiments of the present patent application, after step S16, the reaction solution is cooled to precipitate the product as a solid, and then filtered, and the filter residue is collected and washed with a small amount of n-hexane several times. More preferably, a centrifuge is used to wash and remove impurities. Finally, the product is obtained by vacuum drying, and the obtained product basically meets the requirements of analytical testing.

[0177] The present patent application provides a series of preparation methods of benzophenone-modified triphenylamine pyridine salt organic photosensitizers and methods for improving the efficiency of active oxygen generation. The organic pyridine salt small molecules are prepared by using oxidation reaction, Suzuki coupling, Menshutkin and Knoevenagel classic reactions. By designing a Donor-Accept (D-A) system, the separation degree of HOMO-LUMO orbit is increased, which is beneficial to reduce Δ E ST The introduction of benzophenone further improves the intersystem crossing rate, so that more excited state energy is transferred to the triplet state, thereby promoting the efficient generation of active oxygen, which can be used for application research in the field of photodynamic therapy.

[0178] In addition, the pyridine salt organic photosensitizer provided by the present patent application can be used as a photodynamic therapy photosensitizer material, and is expected to utilize the hydrophilic characteristics of N + ions and electrostatic interactions with some subcellular structures to achieve targeting effect, so that it has high targeting property and realizes efficient photodynamic therapy; at the same time, the multi-rotor structure in the compound and the multiple rotation and vibration of the bonds in the molecule are conducive to the construction of a photothermal conversion platform, and thus realize multi-modal synergistic therapy of tumors. In summary, the photosensitizer of the present application has good application prospect.

[0179] Performance test

[0180] The compounds CHO-TPAP-BP, CHO-pTPAP-BP, CHO-eTPAP-BP and 2CN-eTPAP-BP prepared in step S16 were used as test objects, and the test results are shown in Table 1. Figures 17 to 20

[0181] Figure 17 ​The Edinburgh FLS980 was used to test the aggregation-induced emission (AIE) properties of the compounds CHO-TPAP-BP, CHO-pTPAP-BP, CHO-eTPAP-BP and 2CN-eTPAP-BP, with a test solution concentration of 1 x 10 -5 mol / L and a selected solvent system of dichloromethane and n-hexane. From Figure 17 It can be seen that the four compounds all have typical AIE characteristics. In a poor solvent environment, the intramolecular motion is restricted due to aggregation, thereby increasing the radiation transition path, and strong fluorescence emission is exhibited in the aggregated state.

[0182] Figure 18 The Shimanzi UV-2700 ultraviolet-visible spectrophotometer was used to measure the absorption spectra of the compounds CHO-TPAP-BP, CHO-pTPAP-BP, CHO-eTPAP-BP and 2CN-eTPAP-BP in solution state, with a concentration of 1 x 10 -5 mol / L. Figure 19 The Edinburgh FLS980 was used to test the fluorescence emission spectra of the compounds CHO-TPAP-BP, CHO-pTPAP-BP, CHO-eTPAP-BP and 2CN-eTPAP-BP in solid state, from Figure 17 and Figure 18 It can be seen that the organic photosensitizers CHO-TPAP-BP, CHO-pTPAP-BP, CHO-eTPAP-BP and 2CN-eTPAP-BP synthesized in the present application can achieve fluorescence emission, and thus fluorescent probes can be prepared.

[0183] Figure 20 The active oxygen generation level was tested, with 2,7-dichlorodihydrofluorescein diacetate (DCFH) being used as an active oxygen generation indicator (1 x 10 -5 mol / L). The active oxygen generation capacity of CHO-TPAP-BP, CHO-pTPAP-BP, CHO-eTPAP-BP and 2CN-eTPAP-BP (concentration: 1 x 10 -6 mol / L) was tested under different illumination times (0 s, 15 s, 30 s, 45 s, 60 s, 75 s, 90 s, 120 s, 150 s, 180 s). The principle of the test is that the non-fluorescent DCFH is oxidized (phenol is oxidized to a quinone structure) to generate strong fluorescent product 2',7'-dichlorofluorescein (DCF) under the condition of active oxygen. The fluorescence intensity at 525 nm was detected in real time by a fluorescence spectrometer to qualitatively analyze the active oxygen yield. The stronger the fluorescence intensity, the higher the active oxygen yield. From Figure 20As can be seen from the above, all four photosensitizers synthesized in this application must exhibit excellent reactive oxygen species (ROS) generation efficiency. Among them, the ROS generation efficiency of photosensitizer 2CN-eTPAP-BP is the highest, followed by CHO-eTPAP-BP, while CHO-pTPAP-BP and CHO-TPAP-BP rank last two.

[0184] Depend on Figure 20 It is evident that, due to the presence of the benzophenone structure, the reactive oxygen species (ROS) levels of CHO-TPAP-BP, CHO-pTPAP-BP, CHO-eTPAP-BP, and 2CN-eTPAP-BP are significantly increased, exceeding those of the commercially available photosensitizer Bengal Rose Red (RB), which lacks the benzophenone structure. Therefore, incorporating a benzophenone design strategy can serve as a method to enhance ROS production, providing a reference for preparing photosensitizers with high ROS yields, which can be applied in the field of photodynamic therapy.

[0185] The performance test results above show that the benzophenone-modified triphenylamine pyridine salt of the present invention is an AIE molecule, which can be used in fields such as intracellular imaging; in addition, compared with the commercially available photosensitizer Bengal Red, the molecule of the present invention has a significant improvement in reactive oxygen species generation; at the same time, the present invention aims to utilize the N in the molecule + This gives it high targeting specificity, and the multi-rotor structure and multiple rotations and vibrations of bonds in the molecule are conducive to constructing a photothermal conversion platform, thereby achieving multimodal synergistic therapy for tumors. In summary, the benzophenone-modified triphenylamine pyridine salt of the present invention is a photosensitizer with broad application prospects.

[0186] The benzophenone-modified triphenylamine pyridinium salt organic photosensitizer of this patent application is an AIE molecule with a DA structure (TPA is an electron-donating structure, Pys is an electron-withdrawing structure) and a benzophenone structure. The DA structure makes the HOMO-LUMO orbitals of the molecule more separated, which is beneficial for reducing Δ E ST The benzophenone structure can promote intersystem jumping and enhance orbital spin coupling (SOC), making it easier for energy to move from the singlet state to the triplet state. Both structures work together to promote the generation of reactive oxygen species and improve the efficiency of reactive oxygen species generation. Secondly, the multi-rotor structure in the compound of this patent application and the multiple rotations and vibrations of bonds in the molecule are conducive to the construction of a photothermal conversion platform, which in turn is conducive to the realization of multimodal synergistic treatment of tumors.

[0187] Furthermore, the benzophenone-modified triphenylamine pyridinium salt organic photosensitizer of this patent application contains an anthracene structure, which is expected to react with singlet oxygen in the form of a peroxide formed inside the benzene ring under light conditions. 1O2) and controllably release oxygen under heat conditions, solve the problem of lack of oxygen in cancer cells; at the same time, the triphenylamine-based pyridine salt organic photosensitizer based on benzophenone modification of the application is a pyridine salt, and N + The hydrophilic characteristics of the ions and the electrostatic interaction with some subcellular structures achieve the targeting effect, so that the triphenylamine-based pyridine salt organic photosensitizer has high targeting property and realizes high-efficiency photodynamic therapy, and therefore the triphenylamine-based pyridine salt organic photosensitizer solves the problem of lack of oxygen in cancer cells by improving the yield of active oxygen, and has good fluorescence characteristics, can realize diagnosis and treatment in one, can be prepared into a fluorescent probe, or be applied in the field of anticancer drugs.

[0188] In the description of the present specification, the description of the terms "one embodiment", "some embodiments", "exemplary embodiment", "example", "specific example", or "some examples" means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present patent application. In the present specification, the exemplary description of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.

[0189] Although several embodiments of the present patent application have been shown and described, those of ordinary skill in the art can understand that various changes, modifications, replacements and variations can be made to these embodiments without departing from the principles and purposes of the present patent application, and the scope of the present patent application is defined by the claims and their equivalents.

Claims

1. A benzophenone-modified triphenylamine-based pyridinium organic photosensitizer characterized by, The benzophenone-modified triphenylamine pyridine salt organic photosensitizer takes triphenylamine as the core and has the molecular structure shown in the following formula: 。 2. A process for the preparation of the benzophenone-modified triphenylamine pyridinium organic photosensitizer of claim 1, characterized in that, The method comprises the following steps: S12. Preparation of intermediate 4-(bis(4-bromophenyl)amino)benzaldehyde 4,4-dibromo triphenylamine and phosphorus oxychloride were dissolved in N,N dimethylformamide, by oxidation, to obtain 4-(bis(4-bromophenyl)amino)benzaldehyde, CHO-TPA-2Br; S13. Preparation of intermediate 4-((4-(anthracen-9-yl)phenyl)(4-bromophenyl)amino)benzaldehyde The product CHO-TPA-2Br obtained in step S12, 9-anthracene boronic acid, potassium carbonate and tetrakis(triphenylphosphine)palladium are dissolved in a mixed system of tetrahydrofuran and methanol to obtain 4-((4-(anthracen-9-yl)phenyl)(4-bromophenyl)amino)benzaldehyde, CHO-eTPA-Br. S14. Preparation of intermediate 4-((4-(anthracen-9-yl)phenyl)(4-(pyridin-4-yl)phenyl)amino)benzaldehyde The product CHO-eTPA-Br obtained in step S13, 4-pyridine boronic acid, potassium carbonate and tetrakis(triphenylphosphine)palladium are dissolved in a mixed system of tetrahydrofuran and methanol to obtain 4-((4-(anthracen-9-yl)phenyl)(4-(pyridin-4-yl)phenyl)amino)benzaldehyde, CHO-eTPAP. S15. Preparation of intermediate 2-(4-((4-(anthracen-9-yl)phenyl)(4-(pyridin-4-yl)phenyl)amino)benzylidene)malononitrile The product CHO-eTPAP obtained in step S14 and malononitrile are dissolved in a mixed system of dichloromethane and ethanol, and reacted under the catalysis of anhydrous sodium acetate to obtain 2-(4-((4-(anthracen-9-yl)phenyl)(4-(pyridin-4-yl)phenyl)amino)benzylidene)malononitrile, 2CN-eTPAP. S16. Preparation of final product 2CN-eTPAP-BP The product 2CN-eTPAP obtained in step S15 and 4-(bromomethyl)benzophenone (BP-M-Br) are refluxed in tetrahydrofuran to obtain 4-(4-((4-(anthracen-9-yl)phenyl)(4-(2,2-dicyanovinyl)phenyl)amino)phenyl)-1-(4-benzoylbenzyl)pyridine, 2CN-eTPAP-BP.

3. A process for the preparation of benzophenone-modified triphenylamine-based pyridinium salt organic photosensitizers according to claim 2, characterized by, The oxidation reaction in step S12 needs inert gas protection, the reaction time is 5 h, and the temperature is 80℃.

4. A process for the preparation of benzophenone-modified triphenylamine-based pyridinium salt organic photosensitizers according to claim 2, characterized by, The solvent used in step S13 is tetrahydrofuran and methanol, and the volume ratio of the two is 1:

1.

5. A process for the preparation of benzophenone-modified triphenylamine-based pyridinium salt organic photosensitizers according to claim 4, characterized by, The catalyst used in step S13 is Pd(PPh3)4 with a molar fraction of 4-8%, and needs inert gas protection, the reaction temperature is 80°C, and the time is 24 h 。 6. A method of preparing the benzophenone-modified triphenylamine-based pyridinium salt organic photosensitizer according to claim 2, characterized by, The solvent used in step S14 is tetrahydrofuran and methanol, and the volume ratio of the two is 1:1, the catalyst used is Pd(PPh3)4 with a molar fraction of 4-8%, and inert gas protection is needed, the reaction temperature is 80℃, and the time is 24 h.

7. A method of preparing the benzophenone-modified triphenylamine-based pyridinium salt organic photosensitizer according to claim 2, characterized by, The solvent used in step S15 is dichloromethane and ethanol, and the volume ratio of the two is 1:1, and inert gas protection is needed, the reaction temperature is room temperature, and the time is 5 h.

8. A method of preparing the benzophenone-modified triphenylamine-based pyridinium salt organic photosensitizer according to claim 2, characterized by, In step S16, the molar ratio of 2CN-eTPAP to BP-M-Br is 1:(1.1~1.15), the reaction temperature is 80℃, and the time is 30 h.

9. Use of the benzophenone-modified triphenylamine pyridine salt organic photosensitizer in claim 1 in the preparation of an active oxygen generator.

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