A porphyrone Mannich base derivative and its synthesis method and application

Abstract

The present invention discloses a Mannich base derivative of porphyrin ketone and its synthesis method and application, which belongs to the technical field of organic compound synthesis and medicine. The synthesis method of the Mannich base derivative of porphyrin ketone of the present invention comprises the following steps: under alkaline conditions provided by sodium hydroxide / potassium hydroxide / lithium hydroxide, 3,4-dihydroxybenzaldehyde reacts with acetone to generate porphyrin ketone, and then porphyrin ketone reacts with secondary amine and aldehyde in toluene / ethanol / dimethylformamide / acetonitrile / 1,4-dioxane / tetrahydrofuran to generate Mannich base. The preparation method provided by the present invention has a simple synthetic route, cheap and easy-to-obtain raw materials, has the advantages of wide application range, high yield and easy storage, can realize industrial production, and the target compound is stable in nature and easy to store. The porphyrin ketone Mannich base compound obtained by the above-mentioned preparation method can inhibit tumor cell proliferation and migration in vitro, promote tumor cell apoptosis, and also has good anti-tumor effect on the 4T1 transplanted tumor model of Balb / C mice, and exhibits biosafety.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis and medicine, and particularly relates to a porphyrone Mannich base compound, a synthesis method and application thereof. Background Art

[0002] Today, the global cancer prevention and control levels and treatment strategies are constantly improving, but the incidence of cancer, especially breast cancer, is still increasing. The latest report from the World Health Organization shows that the incidence of breast cancer ranks first among malignant tumors in the world. Chemotherapy, as the main means of clinical treatment of breast cancer, has reached a bottleneck period, and there are still many problems and challenges in dealing with breast cancer.

[0003] Although studies have shown that purpurogenol, an active monomer extracted from mulberry igniarius, has inhibitory activity against a variety of tumor cells, the application of purpurogenol has not alleviated the morbidity and mortality of malignant tumors. Purpurogenol has limitations as a tumor treatment drug in clinical practice.

[0004] There is an urgent need to develop drugs with novel structures, stronger effects in inhibiting tumor cell proliferation, and good in vitro and in vivo anti-tumor activity. Summary of the Invention

[0005] The present invention aims to address, at least to some extent, one of the technical problems existing in the prior art. To this end, the present invention provides a porphyrone Mannich base derivative, a synthesis method, and applications thereof. These compounds have simple and efficient synthesis methods, strong anti-tumor activity, and low toxicity, offering high potential for medical applications.

[0006] The present invention also provides a method for synthesizing the porphyrone Mannich base compound.

[0007] The present invention also provides an application of the porphyr ketone Mannich base compound.

[0008] According to one aspect of the present invention, a porphyrogen ketone Mannich base compound is provided, including a compound having a structure represented by formula (I) and a pharmaceutically acceptable salt thereof:

[0009]

[0010] Wherein, R1 is selected from one of O, N-CH3, N-CH(CH3)2; R2 is selected from one of H, halogen, alkyl, alkoxy and haloalkyl.

[0011] According to a preferred embodiment of the present invention, there are at least the following beneficial effects:

[0012] The porphyrin ketone Mannich base compounds provided by the present invention have anti-tumor effects in both in vivo and in vitro verification. They have inhibitory activity against various tumor cells in vitro, IC 50 The value can reach below 10 μM. In the 4T1 transplant tumor model of Balb / C mice, the tumor growth inhibition rate can reach 46% when the mice are given 40 mg / kg of the drug, and the toxicity is lower than that of the positive drug cisplatin.

[0013] In some embodiments of the present invention, in the formula (I), when R1 is selected from O, R1 is selected from one of H, halogen, alkyl, alkoxy and haloalkyl.

[0014] In some embodiments of the present invention, in the formula (I), when R1 is selected from N-CH3, R1 is selected from one of halogen and haloalkyl.

[0015] In some embodiments of the present invention, in the formula (I), when R1 is selected from N—CH(CH 3 ) 2 , R1 is selected from one of H, halogen, alkyl, alkoxy and haloalkyl.

[0016] In some embodiments of the present invention, in the formula (I), when R2 is selected from halogen, the halogen includes one of a fluorine atom, a chlorine atom and a bromine atom.

[0017] In some embodiments of the present invention, in the formula (I), when R2 is selected from an alkyl group, the alkyl group includes a methyl group.

[0018] In some embodiments of the present invention, in the formula (I), when R2 is selected from alkoxy, the alkoxy includes methoxy.

[0019] In some embodiments of the present invention, in the formula (I), when R2 is selected from a haloalkyl group, the trifluoromethyl group includes a trifluoromethyl group.

[0020] In some embodiments of the present invention, the porphyr ketone Mannich base compound includes at least one of the structural compounds represented by formula A1-14, B1-14 and C1-4:

[0021]

[0022]

[0023] In some embodiments of the present invention, the pharmaceutically acceptable salts include salts formed with inorganic acids and organic acids.

[0024] According to another aspect of the present invention, a method for synthesizing the porphyrin ketone Mannich base compound is provided, characterized in that the method comprises: performing an aldol condensation reaction of 3,4-dihydroxybenzaldehyde represented by formula (Ia) and acetone represented by formula (Ib) under the catalysis of an alkaline catalyst to produce porphyrin ketone represented by formula (Ic); then, performing a Mannich reaction of porphyrin ketone with a secondary amine compound represented by formula (Id) and a benzaldehyde compound represented by formula (Ie) in toluene / ethanol / dimethylformamide / acetonitrile / 1,4-dioxane / tetrahydrofuran to obtain the porphyrin ketone Mannich base compound represented by formula (I):

[0025]

[0026] In some embodiments of the present invention, the secondary amine compound includes morpholine, p-methylpiperazine, and p-isopropylpiperazine;

[0027] In some embodiments of the present invention, the benzaldehyde compound includes at least one of the compounds represented by the following formula:

[0028]

[0029] In some embodiments of the present invention, the molar ratio of 3,4-dihydroxybenzaldehyde, acetone and sodium hydroxide is 1:10-20:2-5.

[0030] In some embodiments of the present invention, the concentration of the aqueous solution of sodium hydroxide / potassium hydroxide / lithium hydroxide is 10 mol / L.

[0031] In some embodiments of the present invention, the molar ratio of porphyrone, secondary amine and benzaldehyde is 1:1.3:1.2.

[0032] In some embodiments of the present invention, the reaction is carried out in a solvent.

[0033] In some embodiments of the present invention, the solvent is acetone.

[0034] In some embodiments of the present invention, the solvent is toluene / ethanol / dimethylformamide / acetonitrile / 1,4-dioxane / tetrahydrofuran.

[0035] In some embodiments of the present invention, the reaction temperature is room temperature.

[0036] In some embodiments of the present invention, the reaction temperature is about 110°C.

[0037] In some embodiments of the invention, the reaction temperature is about 78°C.

[0038] In some embodiments of the present invention, the reaction temperature is about 153°C.

[0039] In some embodiments of the invention, the reaction temperature is about 82°C.

[0040] In some embodiments of the present invention, the reaction temperature is about 101°C.

[0041] In some embodiments of the invention, the reaction temperature is about 66°C.

[0042] In some embodiments of the present invention, the synthesis method further comprises purifying the obtained porphyrone derivatives after the reaction.

[0043] In some embodiments of the present invention, the purification treatment method includes extraction, column chromatography and recrystallization.

[0044] In some embodiments of the present invention, the extraction solvent used includes ethyl acetate and dichloromethane.

[0045] In some embodiments of the present invention, the object to be dried is an organic phase.

[0046] In some embodiments of the present invention, the column chromatography separation is silica gel column chromatography.

[0047] According to another aspect of the present invention, an anti-tumor drug is provided, wherein the raw materials for preparing the drug include the porphyrin ketone Mannich base compound, or the porphyrin ketone Mannich base compound synthesized by the synthesis method.

[0048] The medicine according to a preferred embodiment of the present invention has at least the following beneficial effects:

[0049] The porphyrone Mannich base compound provided by the present invention has a broad spectrum of anti-tumor activity against various tumor cells and can inhibit the growth of tumor cells.

[0050] The porphyrone Mannich base compound provided by the present invention can produce a therapeutic effect on Balb / C mice with a 4T1 transplanted tumor model through intraperitoneal injection without causing toxicity, and can be used as an active ingredient of a medicine.

[0051] In some embodiments of the present invention, the active ingredient of the drug includes the porphyrone Mannich base compound.

[0052] In some embodiments of the present invention, the active ingredient of the drug includes a compound synthesized using the porphyrone Mannich base compound as an organic synthesis intermediate.

[0053] In some embodiments of the present invention, the raw materials for preparing the drug further include pharmaceutically acceptable excipients.

[0054] In some embodiments of the present invention, the excipients include but are not limited to at least one of a solvent, a filler, a lubricant, a disintegrant, a buffer, a solubilizer, an antioxidant, an antibacterial agent, an emulsifier, a binder, and a suspending agent.

[0055] In some embodiments of the present invention, the tumor comprises at least one of breast cancer, colon cancer, ovarian cancer, and lung cancer.

[0056] In some preferred embodiments of the present invention, the tumor comprises breast cancer.

[0057] The preparation method provided by the present invention features a simple synthetic route, inexpensive and readily available raw materials, and has the advantages of wide applicability, high yield, and easy storage. This allows for industrialized production, and the target compound is stable and easy to store. The porphyrone Mannich base compounds produced by this preparation method can inhibit tumor cell proliferation and migration in vitro and promote tumor cell apoptosis. They also exhibited good anti-tumor efficacy in a 4T1 xenograft tumor model in Balb / C mice and demonstrated biosafety. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] The drawings described herein are used to provide a further understanding of the present invention and constitute a part of this application. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0059] Figure 1 This is a graph showing the number of clones formed on three tumor cells in the drug-treated group and the normal group in Application Example 2 of the present invention;

[0060] Figure 2 The migration diagram (2A) and healing area statistical diagram (2B) of triple-negative breast cancer cells in the drug-treated group and the normal group of Application Example 3 of the present invention;

[0061] Figure 3 The flow cytometry analysis graph and statistical graph of the apoptosis ratio of breast cancer cells in the drug-treated group and the normal group in Application Example 4 of the present invention are shown;

[0062] Figure 4 This is a graph showing the relationship between the tumor volume and the administration time of mice in the high-dose group, low-dose group and control group during the administration period of Application Example 5 of the present invention;

[0063] Figure 5 This is a graph showing the relationship between the tumor volume and the administration time of mice in the low-dose group, tamoxifen group, and control group during the administration period of Application Example 5 of the present invention;

[0064] Figure 6 This is a graph showing the relationship between the tumor volume and the administration time of mice in the high-dose group, cisplatin group, and control group during the administration period of Application Example 5 of the present invention;

[0065] Figure 7This is a statistical graph of tumor weight in mice after administration in Application Example 5 of the present invention;

[0066] Figure 8 This is a picture of the appearance of the tumor in the mouse after the administration of Application Example 5 of the present invention;

[0067] Figure 9 This is an H&E staining image of the tumor in the mouse after administration in Application Example 5 of the present invention;

[0068] Figure 10 This is a statistical graph of mouse weight during the drug administration period in Application Example 5 of the present invention;

[0069] Figure 11 This is a statistical graph of the weight changes of mice during the administration period of Application Example 6 of the present invention;

[0070] Figure 12 This is a statistical graph of ALT, AST, CRE, BUN, and LDH levels in mice in the drug-treated group and the control group in Application Example 6 of the present invention;

[0071] Figure 13 These are H&E staining images of the organs of mice in the drug-treated group and the control group in Application Example 6 of the present invention. DETAILED DESCRIPTION

[0072] The following examples are provided to facilitate a clearer understanding of the present invention for those skilled in the art. It should be noted that the following examples do not limit the scope of the present invention and are provided for illustrative purposes only. Unless otherwise specified, the raw materials, reagents, and devices mentioned in the following examples are commercially available or obtained by known methods.

[0073] Example 1

[0074] In this embodiment, a porphyrin ketone Mannich base compound was prepared, the specific structure of which is shown in Formula A1, and the specific process is as follows:

[0075] S1. 3,4-dihydroxybenzaldehyde 1 (138 mg, 1 mmol, CAS: 139-85-5) was dissolved in acetone 2 (870 mg, 15 mmol, CAS: 67-64-1), and an aqueous solution (10 mol / L) of sodium hydroxide (160 mg, 4 mmol, CAS: 1310-73-2) or potassium hydroxide (224 mg, 4 mmol, CAS: 1310-58-3) or lithium hydroxide (96 mg, 4 mmol, CAS: 1310-65-2) was added. After stirring at room temperature for 12 h, the reaction was stopped. The solid product in the reaction flask was extracted with water and ethyl acetate. The organic phases were combined, concentrated, and then separated by column chromatography (developing solvent: petroleum ether: ethyl acetate = 3:1) to obtain the product purpurogenol (3), a yellow solid compound. The yields of sodium hydroxide, potassium hydroxide, and lithium hydroxide as bases were 78%, 62%, and 60%, respectively. Therefore, sodium hydroxide was selected as the base in other embodiments.

[0076] S2. Toluene (5 mL, CAS: 108-88-3), ethanol (5 mL, CAS: 64-17-5), dimethylformamide (5 mL, CAS: 68-12-2), acetonitrile (5 mL, CAS: 75-05-8), 1,4-dioxane (5 mL, CAS: 123-91-1) or tetrahydrofuran (5 mL, CAS: 109-99-9) were added to purpurone (178 mg, 1 mmol), and the mixture was heated to reflux and stirred to dissolve. Subsequently, morpholine (113 mg, 1.3 mmol, CAS: 110-91-8) and benzaldehyde (127 mg, 1 .2mmol, CAS: 110-52-7) was stirred, and after 0.5 h, an aqueous solution of sodium bicarbonate (10 mL, CAS: 144-55-8) was added to quench the reaction, followed by extraction with ethyl acetate. The organic phases were combined, concentrated, and then separated by column chromatography (developing solvent: dichloromethane:methanol = 50:1) to obtain the product, porphyrone Mannich base compound A1, as a yellow solid compound. The yields using toluene / ethanol / dimethylformamide / acetonitrile / 1,4-dioxane / tetrahydrofuran as solvent were 42%, 35%, 38%, 15%, 12%, 8% and 1%, respectively. Therefore, toluene was selected as the solvent in other examples.

[0077] The reaction that occurs in this embodiment is shown below:

[0078]

[0079] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula A1 was indeed obtained in this example.

[0080] Compound 3 (Porphyrone) NMR data, 1H NMR (600 MHz, D2O-d 2 )δ2.37(s,3H),6.55(d,J=16.2Hz,1H),6.91(d,J=7.8Hz,1H),7.10(dd,J=1.8,8.4Hz,1H),7.15(d,J=1.8Hz,1H),7.54(d,J=16.8Hz,1H); 13 C NMR (600 MHz, D2O-d 2 )δ204.48,147.42,146.66,144.26,126.95,124.07,123.21,116.19,115.23,25.92.

[0081] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 10 H 10 O3(M+H) + :179.0703,found179.0698.

[0082] NMR data of compound A1, 1 H NMR (600 MHz, MeOD-d 4 )δ2.29(s,3H),2.42-2.55(m,4H),3.71-3.73(m,4H),4.58(s,1H),6.47(d,J=16.2Hz,1H),6.89(d,J=2 .4Hz,1H),6.98(d,J=2.4Hz,1H),7.23-7.26(m,1H),7.29-7.31(m,2H),7.41(s,1H),7.44-7.46(m,2H); 13 C NMR (600 MHz, MeOD-d 4 )δ200.06,147.12,145.89,145.11,139.58,128.49,128.21,127.73,126.28,126.10,123.62,121.92,112.66,74.52,66.51,52.02,25.61.

[0083] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 21 H 23 NO4(M+H) + :354.1700,found354.1716.

[0084] Example 2

[0085] In this embodiment, a porphyrin ketone Mannich base compound was prepared, the specific structure of which is shown in Formula A2. The specific process is as follows:

[0086] S1. Same as Example 1.

[0087] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Morpholine (113 mg, 1.3 mmol) and p-methylbenzaldehyde (144 mg, 1.2 mmol, CAS: 104-87-0) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound A2, a yellow solid compound.

[0088] The reaction that occurs in this embodiment is shown below:

[0089]

[0090] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula A2 was indeed obtained in this example.

[0091] NMR data of compound A2, 1 H NMR (600 MHz, MeOD-d 4 )δ2.27(s,3H),2.28(s,3H),2.42-2.54(m,4H),3.70-3.72(m,4H),4.53(s,1H),6.46(d,J=16.2Hz,1H),6.85 (d,J=1.8Hz,1H),6.97(d,J=2.4Hz,1H),7.11(d,J=8.4Hz,2H),7.30(d,J=7.8Hz,2H),7.39(d,J=16.2Hz,1H); 13 C NMR (600 MHz, MeOD-d 4 )δ200.07,147.18,145.87,145.14,137.70,136.33,128.87,128.38,128.19,126.85, 126.63,126.32,126.04,123.58,121.97,112.64,74.46,66.51,51.93,25.60,19.68.

[0092] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 22 H 25NO4(M+H) + :368.1856,found368.1887.

[0093] Example 3

[0094] In this embodiment, a porphyrone Mannich base compound was prepared, the specific structure of which is shown in Formula A3. The specific process is as follows:

[0095] S1. Same as Example 1.

[0096] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Morpholine (113 mg, 1.3 mmol) and p-anisaldehyde (163 mg, 1.2 mmol, CAS: 123-11-5) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound A3, a yellow solid compound.

[0097] The reaction that occurs in this embodiment is shown below:

[0098]

[0099] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula A3 was indeed obtained in this example.

[0100] NMR data of compound A3 1 H NMR (600 MHz, MeOD-d 4 )δ2.28(s,3H),2.41-2.53(m,4H),3.70-3.72(m,4H),3.73(s,3H),4.51(s,1H),6.47(d,J=14.4Hz ,1H),6.84(d,J=8.4Hz,3H),6.98(d,J=1.8Hz,1H),7.32(d,J=8.0Hz,2H),7.40(d,J=16.2Hz,1H); 13 C NMR (600 MHz, MeOD-d 4 )δ200.06,159.57,147.18,145.89,145.15,131.81,129.49,127.98,126.43,126.04 ,123.58,121.98,113.78,113.16,112.63,74.14,66.52,54.30,54.26,51.87,25.62.

[0101] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 22 H 25 NO5(M+H) + :384.1805,found384.1852.

[0102] Example 4

[0103] In this embodiment, a porphyrone Mannich base compound was prepared, the specific structure of which is shown in Formula A4. The specific process is as follows:

[0104] S1. Same as Example 1.

[0105] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Morpholine (113 mg, 1.3 mmol) and 3,4,5-trimethoxybenzaldehyde (235 mg, 1.2 mmol, CAS: 86-81-7) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound A4 as a yellow solid compound.

[0106] The reaction that occurs in this embodiment is shown below:

[0107]

[0108] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula A4 was indeed obtained in this example.

[0109] NMR data of compound A4 1 H NMR (600 MHz, MeOD-d 4 )δ2.30(s,3H),2.46-2.56(m,4H),3.71(s,3H),3.72-3.75(m,4H),3.80(s,3H),4.51(s,1H),6.50( d,J=16.2Hz,1H),6.80(s,2H),6.93(d,J=1.8Hz,1H),6.99(d,J=2.4Hz,1H),7.43(d,J=16.2Hz,1H); 13 C NMR (600 MHz, MeOD-d 4)δ201.49,154.79,148.48,147.35,146.51,138.87,137.20,127.76,127.62 ,125.13,123.30,114.20,106.73,75.99,67.98,61.14,56.69,53.43,27.07.

[0110] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 24 H 29 NO7(M+H) + :444.2017,found444.2065.

[0111] Example 5

[0112] In this embodiment, a porphyrin ketone Mannich base compound was prepared, the specific structure of which is shown in Formula A5. The specific process is as follows:

[0113] S1. Same as Example 1.

[0114] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Morpholine (113 mg, 1.3 mmol) and 4-fluorobenzaldehyde (149 mg, 1.2 mmol, CAS: 459-57-4) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound A5 as a yellow solid compound.

[0115] The reaction that occurs in this embodiment is shown below:

[0116]

[0117] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula A5 was indeed obtained in this example.

[0118] NMR data of compound A5 1 H NMR (600 MHz, MeOD-d 4)δ2.29(s,3H),2.41-2.55(m,4H),3.71-3.73(m,4H),4.61(s,1H),6.48(d,J=16.2Hz,1H),6.91(d, J=1.8Hz,1H),6.98(d,J=1.8Hz,1H),7.02-7.05(m,2H),7.42(d,J=16.2Hz,1H),7.46-7.49(m,2H); 13 C NMR (600 MHz, MeOD-d 4 )δ200.06,163.20,161.58,146.97,145.93,145.05,135.74,130.13,130.08,126. 29,126.20,123.69,121.71,115.18,115.04,112.68,73.20,66.50,51.98,25.62.

[0119] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 21 H 22 FNO4(M+H) + :372.1606,found372.1638.

[0120] Example 6

[0121] In this embodiment, a porphyrin ketone Mannich base compound was prepared, the specific structure of which is shown in Formula A6. The specific process is as follows:

[0122] S1. Same as Example 1.

[0123] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Morpholine (113 mg, 1.3 mmol) and 2-chlorobenzaldehyde (169 mg, 1.2 mmol, CAS: 89-98-5) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound A6 as a yellow solid compound.

[0124] The reaction that occurs in this embodiment is shown below:

[0125]

[0126] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula A6 was indeed obtained in this example.

[0127] NMR data of compound A6 1 H NMR (600MHz, CDCl3-d) δ1.60-1.62(m,2H),2.30(s,3H),2.52-2.56(m,2H),3.77(s,4H),5.36(s,1H),6.46(d,J=16.2Hz,1H), 6.74(d,J=1.8Hz,1H),7.05(d,J=1.8Hz,1H),7.22-7.24(m,2H),7.28(d,J=16.2Hz,1H),7.42-7.44(m,1H),7.50-7.52(m,1H); 13 C NMR (600MHz, CDCl3-d) δ198.37,146.37,145.54,143.47,135.57,134.13,130.14,12 9.77,129.62,127.89,126.62,125.09,124.16,121.90,112.66,69.38,66.84,27.35.

[0128] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 21 H 22 ClNO4(M+H) + :388.131,found388.1345.

[0129] Example 7

[0130] This example prepares a porphyrone Mannich base compound, the specific structure of which is shown in Formula A7. The specific process is as follows:

[0131] S1. Same as Example 1.

[0132] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Morpholine (113 mg, 1.3 mmol) and 3-chlorobenzaldehyde (169 mg, 1.2 mmol, CAS: 587-04-2) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound A7 as a yellow solid compound.

[0133] The reaction that occurs in this embodiment is shown below:

[0134]

[0135] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula A7 was indeed obtained in this example.

[0136] NMR data of compound A7 1 H NMR (600MHz, CDCl3-d) δ2.30 (s, 3H), 2.48 (d, J = 4.8Hz, 4H), 3.78 (s, 4H), 4.43 (s, 1H), 6. 47(d,J=16.2Hz,1H),6.69(s,1H),7.05(d,J=1.8Hz,1H),7.28-7.31(m,4H),7.37(s,1H); 13 C NMR (600MHz, CDCl3-d) δ198.33,171.20,145.76,145.58,143.32,140.11,134.98,130.4 8,128.86,126.78,125.15,124.03,121.86,112.88,75.65,66.69,60.42,27.40,14.20.

[0137] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 21 H 22 ClNO4(M+H) + :388.131,found388.1345.

[0138] Example 8

[0139] In this embodiment, a porphyrin ketone Mannich base compound was prepared, the specific structure of which is shown in Formula A8. The specific process is as follows:

[0140] S1. Same as Example 1.

[0141] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Morpholine (113 mg, 1.3 mmol) and 4-chlorobenzaldehyde (169 mg, 1.2 mmol, CAS: 104-88-1) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound A8 as a yellow solid compound.

[0142] The reaction that occurs in this embodiment is shown below:

[0143]

[0144] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula A8 was indeed obtained in this example.

[0145] NMR data of compound A8 1 H NMR (600 MHz, MeOD-d 4 )δ2.36(s,3H),3.19-3.23(m,2H),3.34-3.36(m,2H),3.98-3.99(m,4H),5.70(s,1H),6.63(d,J=16.2Hz,1H),7.14 (d,J=1.8Hz,1H),7.36(d,J=1.8Hz,1H),7.49(dd,J=1.8,6.6Hz,2H),7.51(d,J=16.8Hz,1H),7.76(d,J=8.4Hz,2H); 13 C NMR (600 MHz, MeOD-d 4 )δ199.72,146.34,145.75,143.68,135.47,132.64,130.31,129.28,129. 25,127.38,124.93,120.86,120.79,114.01,71.40,63.39,51.91,25.85.

[0146] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 21 H 22 ClNO4(M+H) + :388.131,found388.1339.

[0147] Example 9

[0148] This example prepares a porphyrone Mannich base compound, the specific structure of which is shown in Formula A9. The specific process is as follows:

[0149] S1. Same as Example 1.

[0150] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Morpholine (113 mg, 1.3 mmol) and 2-bromobenzaldehyde (222 mg, 1.2 mmol, CAS: 6630-33-7) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound A9 as a yellow solid compound.

[0151] The reaction that occurs in this embodiment is shown below:

[0152]

[0153] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula A9 was indeed obtained in this example.

[0154] NMR data of compound A9 1 H NMR (600 MHz, MeOD-d 4 )δ2.30(s,3H),2.50-2.53(m,2H),2.66(s,2H),3.72-3.74(m,4H),5.35(s,1H),6.46(d,J=16.2Hz,1H),6.88(d,J=1.8Hz,1H ),7.02(d,J=1.8Hz,1H),7.15-7.18(m,1H),7.32-7.35(m,1H),7.41(d,J=16.2Hz,1H),7.61-7.63(m,1H),7.68-7.69(m,1H); 13 C NMR (600 MHz, MeOD-d 4 )δ200.06,147.47,146.02,145.00,138.86,133.05,129..64,129.21,127.98, 126.12,125.51,124.51,123.76,121.75,112.71,70.55,66.59,51.56,25.56.

[0155] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 21 H 22 BrNO4(M+H) + :432.0805,found432.0842.

[0156] Example 10

[0157] In this embodiment, a porphyrone Mannich base compound was prepared, the specific structure of which is shown in Formula A10. The specific process is as follows:

[0158] S1. Same as Example 1.

[0159] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Morpholine (113 mg, 1.3 mmol) and 3-bromobenzaldehyde (222 mg, 1.2 mmol, CAS: 3132-99-8) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound A10 as a yellow solid compound.

[0160] The reaction that occurs in this embodiment is shown below:

[0161]

[0162] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula A10 was indeed obtained in this example.

[0163] NMR data of compound A10 1 H NMR (600 MHz, MeOD-d 4 )δ2.33(s,3H),2.45-2.57(m,4H),3.75-3.77(m,4H),4.63(s,1H),6.52(d,J=16.2Hz,1H),6. 98-7.03(m,2H),7.24(t,J=7.8Hz,1H),7.42(d,J=8.4Hz,1H),7.46-7.49(m,2H),7.67(s,1H); 13 C NMR (600 MHz, MeOD-d 4 )δ200.09,146.91,145.94,145.04,142.63,130.97,130.65,130.28,126.92, 126.30,126.01,123.79,122.27,121.63,112.71,72.89,66.49,52.07,25.61.

[0164] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 21 H 22 BrNO4(M+H) +:432.0805,found432.0844.

[0165] Example 11

[0166] In this embodiment, a porphyrone Mannich base compound was prepared, the specific structure of which is shown in Formula A11. The specific process is as follows:

[0167] S1. Same as Example 1.

[0168] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Morpholine (113 mg, 1.3 mmol) and 4-bromobenzaldehyde (222 mg, 1.2 mmol, CAS: 1122-91-4) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound A11 as a yellow solid compound.

[0169] The reaction that occurs in this embodiment is shown below:

[0170]

[0171] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula A11 was indeed obtained in this example.

[0172] NMR data of compound A11 1 H NMR (600 MHz, MeOD-d 4 )δ2.32(s,3H),2.42-2.55(m,4H),3.73-3.75(m,4H),4.61(s,1H),6.51(d,J=16.2Hz,1H ),6.94(d,J=1.8Hz,1H),7.01(d,J=1.8Hz,1H),7.39(d,J=9.0Hz,2H),7.44-7.48(m,3H); 13 C NMR (600 MHz, MeOD-d 4 )δ200.05,146.97,145.93,145.03,139.09,131.55,130.08,126.24,126.04,123.75,121.68,121.33,112.71,73.00,66.49,51.99,25.64.

[0173] High-resolution mass spectrometry data: HRMS (ESI) calculation for C21 H 22 BrNO4(M+H) + :432.0805,found432.0845.

[0174] Example 12

[0175] This example prepares a porphyrone Mannich base compound, the specific structure of which is shown in Formula A12. The specific process is as follows:

[0176] S1. Same as Example 1.

[0177] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Morpholine (113 mg, 1.3 mmol) and 2-trifluoromethylbenzaldehyde (206 mg, 1.2 mmol, CAS: 447-61-0) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound A12 as a yellow solid compound.

[0178] The reaction that occurs in this embodiment is shown below:

[0179]

[0180] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula A12 was indeed obtained in this example.

[0181] NMR data of compound A12 1 H NMR (600 MHz, Acetone-d 6 )δ2.23(s,3H),2.44-2.66(m,4H),3.72(s,4H),5.07(s,1H),6.44(d,J=16.2Hz,1H),6.82(d,J=1.8Hz,1H),7.08(d,J=1. 8Hz,1H),7.36(d,J=16.2Hz,1H),7.51(t,J=7.8Hz,1H),7.66-7.68(m,1H),7.78(d,J=7.8Hz,1H),8.01(d,J=7.8Hz,1H); 13 CNMR (600MHz, Acetone-d 6)δ196.76,146.84,146.48,142.95,139.08,133.37,130.00,128.54,128.09,127.90,127.71,127.52,127.27,126. 60,126.17,126.13,126.09,126.05,125.46,125.10,124,78,123.64,121.56,112.97,68.70,66.51,51.93,26.30.

[0182] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 22 H 22 F3NO4(M+H) + :422.1574,found422.1531.

[0183] Example 13

[0184] In this embodiment, a porphyrone Mannich base compound was prepared, the specific structure of which is shown in Formula A13. The specific process is as follows:

[0185] S1. Same as Example 1.

[0186] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Morpholine (113 mg, 1.3 mmol) and 3-trifluoromethylbenzaldehyde (206 mg, 1.2 mmol, CAS: 454-89-7) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound A13 as a yellow solid compound.

[0187] The reaction that occurs in this embodiment is shown below:

[0188]

[0189] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula A13 was indeed obtained in this example.

[0190] NMR data of compound A13 1 H NMR (600 MHz, MeOD-d 4)δ2.31(s,3H),2.41-2.44(m,4H),3.73-3.75(m,4H),4.75(s,1H),6.50(d,J=16.2Hz,1H),7.00(s,2H) ,7.44(d,J=16.2Hz,1H),7.49-7.52(m,1H),7.55(d,J=7.8Hz,1H),7.75(d,J=7.8Hz,1H),7.83(s,1H); 13 C NMR (600 MHz, MeOD-d 4 )δ201.52,148.35,147.40,146.45,143.06,133.28,132.19,131.98,131.77,130.77,128.27,127.80,127.53, 126.47,126.22,126.20,125.74,125.71,125.69,125.28,124.68,122.95,114.13,73.90,67.94,53.54,27.05.

[0191] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 22 H 22 F3NO4(M+H) + :422.1574,found422.1626.

[0192] Example 14

[0193] In this embodiment, a porphyrin ketone Mannich base compound was prepared, the specific structure of which is shown in Formula A14. The specific process is as follows:

[0194] S1. Same as Example 1.

[0195] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Morpholine (113 mg, 1.3 mmol) and 4-trifluoromethylbenzaldehyde (206 mg, 1.2 mmol, CAS: 444-19-6) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound A14 as a yellow solid compound.

[0196] The reaction that occurs in this embodiment is shown below:

[0197]

[0198] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula A14 was indeed obtained in this example.

[0199] NMR data of compound A14 1 H NMR (600 MHz, Acetone-d 6 )δ2.23(s,3H),2.46-2.60(m,4H),3.71-3.73(m,4H),4.80(s,1H),6.48(d,J=16.2Hz,1H),7.0 3(dd,J=2.4,21.0Hz,2H),7.37(d,J=16.2Hz,1H),7.69(d,J=8.4Hz,2H),7.76(d,J=8.4Hz,2H); 13 C NMR (600 MHz, Acetone-d 6 )δ196.75,146.35,146.09,144.56,142.98,129.54,129.33,129.10,126.76,125.75,125.72, 125.70,125.67,125.55,125.19,124.78,123.39,121.32,113.28,74.04,66.38,52.22,26.32.

[0200] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 22 H 22 F3NO4(M+H) + :422.1574,found422.1640.

[0201] Example 15

[0202] This example prepares a porphyrone Mannich base compound, the specific structure of which is shown in Formula B1. The specific process is as follows:

[0203] S1. Same as Example 1.

[0204] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Isopropylpiperazine (167 mg, 1.3 mmol, CAS: 4318-42-7) and benzaldehyde (127 mg, 1.2 mmol) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound B1, a yellow solid compound.

[0205] The reaction that occurs in this embodiment is shown below:

[0206]

[0207] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula B1 was indeed obtained in this example.

[0208] NMR data of compound B1 1 H NMR (600 MHz, MeOD-d 4 )δ1.06(d,J=6.6Hz,6H),2.29(s,3H),2.51-2.74(m,9H),4.59(s,1H),6.47(d,J=15.6Hz,1H),6.85(d,J=2.4H z,1H),6.98(d,J=2.4Hz,1H),7.24-7.27(m,1H),7.30-7.32(m,2H),7.41(d,J=16.2Hz,1H),7.44-7.45(m,2H); 13 C NMR (600 MHz, MeOD-d 4 )δ200.04,147.58,145.98,145.20,139.67,128.49,128.21,127.74,126.33,125.87,1 23.50,121.92,112.60,74.37,54.40,51.11,48,49,45.83,25.61,17.33,17.26,9.17.

[0209] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 24 H 30 N2O3(M+H) + :395.2329,found395.2375.

[0210] Example 16

[0211] In this embodiment, a porphyrin ketone Mannich base compound was prepared, the specific structure of which is shown in Formula B2. The specific process is as follows:

[0212] S1. Same as Example 1.

[0213] S2. Toluene (5 mL) was added to purpurogenol (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Isopropylpiperazine (167 mg, 1.3 mmol) and p-methylbenzaldehyde (144 mg, 1.2 mmol) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product purpurogenol Mannich base compound B2, a yellow solid compound.

[0214] The reaction that occurs in this embodiment is shown below:

[0215]

[0216] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula B2 was indeed obtained in this example.

[0217] NMR data of compound B2 1 H NMR (600 MHz, MeOD-d 4 )δ1.08(d,J=6.0Hz,6H),2.29(s,6H),2.52-2.71(m,9H),4.57(s,1H),6.47(d,J=16.2Hz,1H), 6.85(s,1H),6.98(s,1H),7.12(d,J=7.2Hz,2H),7.31(d,J=7.8Hz,2H),7.41(d,J=16.2Hz,1H); 13 C NMR (600 MHz, MeOD-d 4 )δ201.52,148.97,147.32,146.67,139.14,137.91,130.50,129.83,129.61,128.08,127.89,12 7.31,124.94,124.87,123.35,121.66,113.98,75.32,56.11,49.94,27.03,21.14,18.65,18.59.

[0218] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 25 H 32 N2O3(M+H) + :409.2486,found409.2478.

[0219] Example 17

[0220] In this embodiment, a porphyrone Mannich base compound was prepared, the specific structure of which is shown in Formula B3. The specific process is as follows:

[0221] S1. Same as Example 1.

[0222] S2. Toluene (5 mL) was added to purpurogenol (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Isopropylpiperazine (167 mg, 1.3 mmol) and p-anisaldehyde (163 mg, 1.2 mmol) were then added with stirring. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product purpurogenol Mannich base compound B3, a yellow solid compound.

[0223] The reaction that occurs in this embodiment is shown below:

[0224]

[0225] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula B3 was indeed obtained in this example.

[0226] NMR data of compound B3 1 H NMR (600 MHz, MeOD-d 4 )δ1.07(d,J=6.0Hz,6H),2.29(s,3H),2.51-2.68(m,9H),3.75(s,3H),4.5 6(s,1H),6.47(d,J=15.6Hz,1H),6.83-6.98(m,5H),7.33(d,J=8.4Hz,2H); 13 C NMR (600 MHz, MeOD-d 4 )δ201.50,161.03,149.00,147.34,146.67,132.73,131.49,130.92,129.42,127.95,127.28,12 4.92,123.26,115.54,115.20,114.60,113.97,75.07,56.03,55.75,49.94,27.04,18.68,18.62.

[0227] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 25 H 32 N2O4(M+H) + :425.2435,found425.2431.

[0228] Example 18

[0229] In this embodiment, a porphyrone Mannich base compound was prepared, the specific structure of which is shown in Formula B4. The specific process is as follows:

[0230] S1. Same as Example 1.

[0231] S2. Toluene (5 mL) was added to purpurogenol (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Isopropylpiperazine (167 mg, 1.3 mmol) and 3,4,5-trimethoxybenzaldehyde (235 mg, 1.2 mmol) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product purpurogenol Mannich base compound B4, a yellow solid compound.

[0232] The reaction that occurs in this embodiment is shown below:

[0233]

[0234] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula B4 was indeed obtained in this example.

[0235] NMR data of compound B4 1 H NMR (600 MHz, Acetone-d 6 )δ0.87(d,J=6.6Hz,6H),2.10(s,3H),2.39-2.60(m,9H),3.55(s,3H),3.65(s,6H),4.43(s,1H),6.34 (d,J=16.2Hz,1H),6.71(s,2H),6.79(d,J=1.2Hz,1H),6.91(d,J=1.8Hz,1H),7.24(d,J=16.2Hz,1H); 13 CNMR (600MHz, Acetone-d 6 )δ196.73,153.62,147.07,146.08,143.30,138.09,135.31,126.22,126.15,124.41,12 1.55,112.79,105.90,104.71,75.25,59.60,55.64,55.58,53.96,48.40,26.31,17.73.

[0236] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 27 H 36 N2O6(M+H) + :485.2646,found485.2736.

[0237] Example 19

[0238] In this example, a porphyrone Mannich base compound was prepared, the specific structure of which is shown in Formula B5. The specific process is as follows:

[0239] S1. Same as Example 1.

[0240] S2. Toluene (5 mL) was added to porphyrin ketone (178 mg, 1 mmol), and the temperature was raised to 110 ° C. and stirred to dissolve it. Then, isopropylpiperazine (167 mg, 1.3 mmol) and 4-fluorobenzaldehyde (149 mg, 1.2 mmol) were added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. Then, the mixture was extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin ketone Mannich base compound B5, a yellow solid compound.

[0241] The reaction that occurs in this embodiment is shown below:

[0242]

[0243] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula B5 was indeed obtained in this example.

[0244] NMR data of compound B5 1 H NMR (600 MHz, MeOD-d 4 )δ1.05(d,J=6.6Hz,6H),2.25-2.29(m,3H),2.50-2.67(m,9H),4.62(s,1H),6.47(d,J=16.2Hz,1H),6.8 5(d,J=1.2Hz,1H),6.99(d,J=1.8Hz,1H),7.02-7.05(m,2H),7.41(d,J=15.6Hz,1H),7.45-7.47(m,2H); 13 CNMR (600MHz, MeOD-d 4)δ200.11,200.06,200.01,163.20,161.58,147.39,146.01,145.12,145.11,135.84,135.82,130.12, 130.07,126.33,126.00,123.62,121.73,115.19,115.05,112.66,73.11,54.43,48.48,17.31,17.25.

[0245] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 24 H 29 FN2O3(M+H) + :413.2235,found413.2295.

[0246] Example 20

[0247] This example prepares a porphyrone Mannich base compound, the specific structure of which is shown in Formula B6. The specific process is as follows:

[0248] S1. Same as Example 1.

[0249] S2. Toluene (5 mL) was added to purpurogenol (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Isopropylpiperazine (167 mg, 1.3 mmol) and 2-chlorobenzaldehyde (169 mg, 1.2 mmol) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product purpurogenol Mannich base compound B6, a yellow solid compound.

[0250] The reaction that occurs in this embodiment is shown below:

[0251]

[0252] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula B6 was indeed obtained in this example.

[0253] NMR data of compound B6 1 H NMR (600 MHz, MeOD-d 4)δ1.06(d,J=6.6Hz,6H),2.29(s,3H),2.56-2.70(m,9H),5.35(s,1H),6.45(d,J=16.2Hz,1H),6.82(d, J=1.8Hz,1H),7.01(d,J=1.8Hz,1H),7.22-7.29(m,2H),7.40-7.43(m,2H),7.63(dd,J=1.8,7.8Hz,1H); 13 C NMR (600 MHz, MeOD-d 4 )δ200.04,147.98,146.21,145.10,137.17,133.76,129.63,129.50,128.98,127.37,125.93,1 25.49,123.63,121.73,112.68,67.88,54.41,50.68,48.52,45.76,25.59,17.30,17.26,9.30.

[0254] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 24 H 29 ClN2O3(M+H) + :429.1939,found429.2015.

[0255] Example 21

[0256] This example prepares a porphyrone Mannich base compound, the specific structure of which is shown in Formula B7. The specific process is as follows:

[0257] S1. Same as Example 1.

[0258] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Isopropylpiperazine (167 mg, 1.3 mmol) and 3-chlorobenzaldehyde (169 mg, 1.2 mmol) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound B7, a yellow solid compound.

[0259] The reaction that occurs in this embodiment is shown below:

[0260]

[0261] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula B7 was indeed obtained in this example.

[0262] NMR data of compound B7 1 H NMR (600 MHz, MeOD-d 4 )δ1.07(d,J=6.6Hz,6H),2.31(s,3H),2.51-2.69(m,9H),4.62(s,1H),6.49(d,J=16.2Hz,1H),6.92(d,J=1.2Hz,1 H),7.00(d,J=1.8Hz,1H),7.25-7.31(m,2H),7.40(d,J=7.2Hz,1H),7.43(d,J=16.2Hz,1H),7.49(t,J=1.8Hz,1H); 13 C NMR (600 MHz, MeOD-d 4 )δ200.07,147.32,146.03,145.10,142.47,134.23,130.01,127.97,127.66,126.48,126.10,126.06,123.67,121.63,112.69,72.94,54.56,48.48,25.60,17.32,17.25. High-resolution mass spectrometry data: HRMS (ESI) calculated for C 24 H 29 ClN2O3(M+H) + :429.1939,found 429.2007.

[0263] Example 22

[0264] In this embodiment, a porphyrone Mannich base compound was prepared, the specific structure of which is shown in Formula B8. The specific process is as follows:

[0265] S1. Same as Example 1.

[0266] S2. Toluene (5 mL) was added to porphyrin ketone (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Isopropylpiperazine (167 mg, 1.3 mmol) and 4-chlorobenzaldehyde (169 mg, 1.2 mmol) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin ketone Mannich base compound B8, a yellow solid compound.

[0267] The reaction that occurs in this embodiment is shown below:

[0268]

[0269] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula B8 was indeed obtained in this example.

[0270] NMR data of compound B8 1 H NMR(600MHz, CDCl3-d)δ0.96(s,3H),0.97(s,3H),1.17-1.19(m,1H),2.22(s,3H),2.45-2.64(m,9H),4.43(s, 3H), 6.37 (d, J = 16.2Hz, 1H), 6.57 (d, J = 1.8Hz, 1H), 6.96 (d, J = 2.4Hz, 1H), 7.19 (d, J = 1.2Hz, 1H), 7.22 (s, 2H); 13 C NMR (150MHz, CDCl3-d) δ198.37,146.71,145.57,143.62,136.54,134.39,130.08,129.20,1 28.74,128.67,126.23,124.87,124.45,121.84,112.59,74.65,54.38,48.52,27.32,18.45.

[0271] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 24 H 29 ClN2O3(M+H) + :429.1939,found429.2001.

[0272] Example 23

[0273] In this embodiment, a porphyrone Mannich base compound was prepared, the specific structure of which is shown in Formula B9. The specific process is as follows:

[0274] S1. Same as Example 1.

[0275] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), the temperature was raised to 110 ° C and stirred to dissolve it, and then isopropylpiperazine (167 mg, 1.3 mmol) and 2-bromobenzaldehyde (222 mg, 1.2 mmol) were added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction, and then extracted with ethyl acetate. The organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound B9, a yellow solid compound.

[0276] The reaction that occurs in this embodiment is shown below:

[0277]

[0278] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula B9 was indeed obtained in this example.

[0279] NMR data of compound B9 1 H NMR (600 MHz, MeOD-d 4 )δ1.07(d,J=6.6Hz,6H),2.30(s,3H),2.58-2.68(m,9H),5.36(s,1H),6.45(d,J=16.2Hz,1H),6.84(d,J=2.4H z,1H),7.02(d,J=1.8Hz,1H),7.15-7.18(m,1H),7.31-7.34(m,1H),7.41(d,J=16.2Hz,1H),7.62-7.65(m,2H); 13 C NMR (600 MHz, MeOD-d 4 )δ200.07,147.77,146.14,145.04,138.92,133.06,129.62,129.28,128.03,126.01,12 5.64,124.44,123.69,121.61,112.72,70.66,54.43,48.53,48.02,25.56,17.27,17.23.

[0280] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 24 H 29 BrN2O3(M+H) + :473.1434,found473.1527.

[0281] Example 24

[0282] In this example, a porphyrone Mannich base compound was prepared, the specific structure of which is shown in Formula B10. The specific process is as follows:

[0283] S1. Same as Example 1.

[0284] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), the temperature was raised to 110 ° C and stirred to dissolve it, and then isopropylpiperazine (167 mg, 1.3 mmol) and 3-bromobenzaldehyde (222 mg, 1.2 mmol) were added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction, and then extracted with ethyl acetate. The organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound B10, a yellow solid compound.

[0285] The reaction that occurs in this embodiment is shown below:

[0286]

[0287] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula B10 was indeed obtained in this example.

[0288] NMR data of compound B10 1 H NMR (600 MHz, MeOD-d 4 )δ1.07(d,J=6.6Hz,6H),2.30(s,3H),2.50-2.67(m,9H),4.61(s,1H),6.49(d,J=16.2Hz,1H),6.91(d,J=1.8Hz ,1H),7.00(d,J=1.8Hz,1H),7.22-7.24(m,1H),7.403-7.408(m,1H),7.41-7.46(m,2H),7.64(d,J=1.8Hz,1H); 13 C NMR (600 MHz, MeOD-d 4 )δ200.09,147.49,146.12,145.16,142.75,130.93,130.65,130.28,126.90,126.04,126.02,1 23.61,122.27,121.65,112.65,72.85,54.44,51.17,48.47,45.85,25.61,17.33,17.27,9.12.

[0289] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 24 H29 BrN2O3(M+H) + :473.1434,found473.1503.

[0290] Example 25

[0291] In this embodiment, a porphyrin ketone Mannich base compound was prepared, the specific structure of which is shown in Formula B11. The specific process is as follows:

[0292] S1. Same as Example 1.

[0293] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Isopropylpiperazine (167 mg, 1.3 mmol) and 4-bromobenzaldehyde (222 mg, 1.2 mmol) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound B11, a yellow solid compound.

[0294] The reaction that occurs in this embodiment is shown below:

[0295]

[0296] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula B11 was indeed obtained in this example.

[0297] NMR data of compound B11 1 H NMR (600 MHz, MeOD-d 4 )δ1.06(d,J=6.6Hz,6H),2.30(s,3H),2.49-2.68(m,9H),4.60(s,1H),6.48(d,J=16.2Hz,1H),6.88(d,J =1.8Hz,1H),6.99(d,J=1.8Hz,1H),7.37(d,J=8.4Hz,2H),7.42(d,J=13.2Hz,1H),7.45(d,J=9.0Hz,2H); 13 C NMR (600 MHz, MeOD-d 4)δ200.04,147.35,146.00,145.10,139.18,131.55,130.06,126.08,126.05,123.64,121. 67,121.36,112.67,72.93,54.46,51.09,48.48,25.62,22.29,21.58,17.30,17.25,13.02.

[0298] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 24 H 29 BrN2O3(M+H) + :473.1434,found473.1506.

[0299] Example 26

[0300] This example prepares a porphyrone Mannich base compound, the specific structure of which is shown in Formula B12. The specific process is as follows:

[0301] S1. Same as Example 1.

[0302] S2. Toluene (5 mL) was added to purpurogenol (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Isopropylpiperazine (167 mg, 1.3 mmol) and 2-trifluoromethylbenzaldehyde (206 mg, 1.2 mmol) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product purpurogenol Mannich base compound B12, a yellow solid compound.

[0303] The reaction that occurs in this embodiment is shown below:

[0304]

[0305] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula B12 was indeed obtained in this example.

[0306] NMR data of compound B12 1 H NMR (600 MHz, Acetone-d 6)δ0.86(d,J=6.0Hz,6H),2.10(s,3H),2.32-2.56(m,9H),4.90(s,1H),6.30(d,J=16.2Hz,1H),6.64(d,J=1.8Hz,1H),6.94( d,J=2.4Hz,1H),7.23(d,J=16.2Hz,1H),7.37-7.40(m,1H),7.52-7.54(m,1H),7.65(d,J=7.8Hz,1H),7.83(d,J=7.8Hz,1H); 13 C NMR (600 MHz, Acetone-d 6 )δ196.78,147.24,146.58,143.05,139.42,133.37,129.97,128.51,127.73,127.54,126.38,126.12,126.09 ,126.05,126.01,125.47,125.40,124.65,123.66,121.38,112.83,68.75,53.87,48.45,26.29,17.77,17.66.

[0307] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 25 H 29 F3N2O3(M+H) + :463.2203,found463.2298.

[0308] Example 27

[0309] In this embodiment, a porphyrone Mannich base compound was prepared, the specific structure of which is shown in Formula B13. The specific process is as follows:

[0310] S1. Same as Example 1.

[0311] S2. Toluene (5 mL) was added to porphyrin (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Isopropylpiperazine (167 mg, 1.3 mmol) and 3-trifluoromethylbenzaldehyde (206 mg, 1.2 mmol) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin Mannich base compound B13, a yellow solid compound.

[0312] The reaction that occurs in this embodiment is shown below:

[0313]

[0314] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula B13 was indeed obtained in this example.

[0315] NMR data of compound B13 1 H NMR (600 MHz, MeOD-d 4 )δ1.08(d,J=6.6Hz,6H),2.30(s,3H),2.50-2.72(m,9H),4.76(s,1H),6.49(d,J=16.2Hz,1H),6.96(d,J=1.8Hz, 1H),7.00(d,J=1.8Hz,1H),7.43(d,J=16.2Hz,1H),7.50-7.53(m,2H),7.56(d,J=7.8Hz,2H),7.74-7.77(m,2H); 13 C NMR (600 MHz, MeOD-d 4 )δ201.52,148.69,147.48,146.51,143.11,133.26,132.21,132.00,130.79,127.64,127.55,126.48,126.19,125.77,12 5.75,125.19,124.73,124.68,123.58,122.94,116.62,115.31,114.13,73.83,56.02,52.53,49.93,27.05,18.72,18.66.

[0316] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 25 H 29 F3N2O3(M+H) + :463.2203,found463.2332.

[0317] Example 28

[0318] In this example, a porphyrone Mannich base compound was prepared, the specific structure of which is shown in Formula B14. The specific process is as follows:

[0319] S1. Same as Example 1.

[0320] S2. Toluene (5 mL) was added to purpurogenol (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Isopropylpiperazine (167 mg, 1.3 mmol) and 4-trifluoromethylbenzaldehyde (206 mg, 1.2 mmol) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product purpurogenol Mannich base compound B14, a yellow solid compound.

[0321] The reaction that occurs in this embodiment is shown below:

[0322]

[0323] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula B14 was indeed obtained in this example.

[0324] NMR data of compound B14 1 H NMR (600 MHz, MeOD-d 4 )δ1.07(d,J=6.6Hz,6H),2.30(s,3H),2.51-2.72(m,9H),4.74(s,1H),6.49(d,J=16.2Hz,1H),6.94(d,J =1.8Hz,1H),7.00(d,J=1.8Hz,1H),7.43(d,J=16.2Hz,1H),7.60(d,J=8.4Hz,2H),7.66(d,J=8.4Hz,2H); 13 C NMR (600 MHz, MeOD-d 4 )δ201.47,192.80,131.35,131.13,130.92,130.70,130.14,128.30,127.57,127.43,126.77,126.74,12 6.72,126.50,125.14,124.70,123.03,114.10,73.95,56.15,55.96,52.56,49.92,27.05,18.72,18.68.

[0325] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 25 H 29 F3N2O3(M+H) + :463.2203,found463.2302.

[0326] Example 29

[0327] In this embodiment, a porphyrin ketone Mannich base compound was prepared, the specific structure of which is shown in Formula C1, and the specific process is as follows:

[0328] S1. Same as Example 1.

[0329] S2. Toluene (5 mL) was added to porphyrin ketone (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Methylpiperazine (130 mg, 1.3 mmol, CAS: 109-01-3) and 4-fluorobenzaldehyde (149 mg, 1.2 mmol) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin ketone Mannich base compound C1, a yellow solid compound.

[0330] The reaction that occurs in this embodiment is shown below:

[0331]

[0332] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula C1 was indeed obtained in this example.

[0333] NMR data of compound C1 1 H NMR(600MHz, CDCl3-d)δ2.22(d,J=13.8Hz,6H),2.45(s,8H),4.44(s,1H),6.38(d,J=15 .6Hz,1H),6.58(s,J=1.8Hz,1H),6.93-6.96(m,3H),7.19(d,J=4.2Hz,1H),7.26(s,2H); 13 C NMR (600MHz, CDCl3-d) δ197.32,162.43,160.79,145.42,144.52,142.53,132.90,132.88,129.38,12 8.40,128.34,125.32,123.89,123.70,120.85,115.05,114.91.111.52,73.56,53.87,44.58,26.33.

[0334] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 22 H 25 FN2O3(M+H) + :385.1922,found385.2021.

[0335] Example 30

[0336] In this embodiment, a porphyrin ketone Mannich base compound was prepared, the specific structure of which is shown in Formula C2, and the specific process is as follows:

[0337] S1. Same as Example 1.

[0338] S2. Toluene (5 mL) was added to porphyrin ketone (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Methylpiperazine (130 mg, 1.3 mmol) and 4-chlorobenzaldehyde (169 mg, 1.2 mmol) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin ketone Mannich base compound C2, a yellow solid compound.

[0339] The reaction that occurs in this embodiment is shown below:

[0340]

[0341] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula C2 was indeed obtained in this example.

[0342] NMR data of compound C2 1 H NMR (600 MHz, MeOD-d 4 )δ2.28(d,J=9.6Hz,6H),2.48-2.65(m,8H),4.62(s,1H),6.48(d,J=16.2H z,1H),6.89(s,1H),7.00(s,1H),7.29(d,J=8.4Hz,2H),7.42-7.44(m,3H); 13 C NMR (600 MHz, MeOD-d 4 )δ201.53,201.48,201.42,148.58,147.37,146.47,146.46,140.12,134.77,131.13,129.9 6,129.91,129.89,129.56,129.23,127.63,127.57,125.16,123.05,114.15,73.98,45.71.

[0343] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 22 H 25ClN2O3(M+H) + :401.1626,found401.1717.

[0344] Example 31

[0345] In this embodiment, a porphyrin ketone Mannich base compound was prepared, the specific structure of which is shown in Formula C3. The specific process is as follows:

[0346] S1. Same as Example 1.

[0347] S2. Toluene (5 mL) was added to porphyrin ketone (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Methylpiperazine (130 mg, 1.3 mmol) and 4-bromobenzaldehyde (222 mg, 1.2 mmol) were then added with stirring. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product porphyrin ketone Mannich base compound C3, a yellow solid compound.

[0348] The reaction that occurs in this embodiment is shown below:

[0349]

[0350] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula C3 was indeed obtained in this example.

[0351] NMR data of compound C3 1 H NMR (600 MHz, MeOD-d 4 )δ2.19(s,3H),2.20(s,3H),2.30-2.52(m,8H),4.52(s,1H),6.38(d,J=16.2Hz,1H),6.80(d ,J=1.8Hz,1H),6.89(d,J=2.4Hz,1H),7.27(d,J=8.4Hz,2H),7.32(s,1H),7.35-7.37(m,2H); 13 C NMR (600 MHz, MeOD-d 4 )δ200.06,147.18,145.95,145.07,139.21,131.56,130.03,126.14,123.70,121.62,121.36,112.69,72.68,54.53,44.35,25.61.

[0352] High-resolution mass spectrometry data: HRMS (ESI) calculation for C22 H 25 BrN2O3(M+H) + :445.1121,found445.1233.

[0353] Example 32

[0354] In this embodiment, a porphyrone Mannich base compound was prepared, the specific structure of which is shown in Formula C4. The specific process is as follows:

[0355] S1. Same as Example 1.

[0356] S2. Toluene (5 mL) was added to purpurogenol (178 mg, 1 mmol), and the temperature was raised to 110°C with stirring to dissolve it. Methylpiperazine (130 mg, 1.3 mmol) and 4-trifluoromethylbenzaldehyde (206 mg, 1.2 mmol) were then added and stirred. After 0.5 h, an aqueous solution of sodium bicarbonate (10 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate, and the organic phases were combined, concentrated, and separated by column chromatography (developing solvent: dichloromethane: methanol = 50:1) to obtain the product purpurogenol Mannich base compound C4, a yellow solid compound.

[0357] The reaction that occurs in this embodiment is shown below:

[0358]

[0359] The test results of the porphyrin ketone Mannich base compound obtained in this example are as follows, indicating that the porphyrin ketone Mannich base compound corresponding to Formula C4 was indeed obtained in this example.

[0360] NMR data of compound C4 1 H NMR (600 MHz, MeOD-d 4 )δ2.30(s,3H),2.54(s,3H),2.65-2.67(m,8H),4.80(s,1H),6.49(d,J=16. 2Hz,1H),6.99(d,J=4.2Hz,2H),7.44(d,J=16.2Hz,1H),7.60-7.68(m,4H); 13 C NMR (600 MHz, MeOD-d 4 )δ201.48,148.50,147.37,146.47,146.27,131.10,130.88,130.06,128.82,128.39,127.68,127 .55,126.76,126.74,126.50,125.23,124.71,122.89,114.02,72.86,55.84,51.97,45.45,27.06.

[0361] High-resolution mass spectrometry data: HRMS (ESI) calculation for C 23 H 25 F3N2O3(M+H) + :435.189,found435.1999.

[0362] Application Example 1

[0363] In this application example, cytotoxicity tests were conducted on seven tumor cell lines using the porphyrin ketone Mannich base compounds obtained in Examples 1 to 32 and the substrate porphyrin ketone.

[0364] First, seven tumor cell lines (mouse triple-negative breast cancer cells 4T1, human colon cancer cells HCT116, mouse colon cancer cells MC38, human ovarian cancer cells A2780, human non-small cell lung cancer cells A549, human triple-negative breast cancer cells MDA-MB-231 and human breast cancer cells T47D) were revived. Afterwards, when the cells were in the logarithmic growth phase, the growth inhibitory activity of the compound on tumor cells was determined using MTT (methylthiazolium tetrazolium method). The culture medium in the culture dish was aspirated, the cells were rinsed twice with 3 mL PBS, 1 mL of trypsin was added to digest the cells, and then 3 mL of DMEM complete medium was added to terminate the digestion. The cells were centrifuged at 1000 rpm for 5 minutes and then the cells were counted and the cell concentration was adjusted to 2*10 4 / mL, then seeded in a 96-well plate at 100μL / well and placed in an incubator. After 12 hours, when the cells are completely attached, the culture medium is discarded and the drug-containing culture medium is added. Set up a drug-dosing group (the Mannich base derivatives of porphyrin ketone and porphyrin ketone are prepared into a 50mM stock solution with DMSO, diluted 1000 times in the culture medium to make the final concentration of 50μM, and then diluted half and half to 25, 12.5, 6.25, 3.125, 1.5625μM), a blank group (culture medium containing 1‰ DMSO), a positive control group (cisplatin, prepared in the same way as the drug-dosing group) and a zero-adjustment group (culture medium without cells), with 3 replicates per group. After 72 hours of drug treatment, 10 μL of MTT solution (5 mg / mL) was added to each well and the cells were placed in an incubator for 4 hours. The culture medium was discarded and 100 μL of DMSO was added to each well. The cells were shaken on a shaker for 10 minutes to fully dissolve the crystals. The OD value was measured at 490 nm using a microplate reader. The cell viability was calculated according to the following formula: Viability (%) = (OD 药物组 -OD 调零组 ) / (OD 空白组 -OD 调零组 ) × 100%. After calculating the cell viability at different concentrations of each compound, GraphPad Prism 8.00 was used to fit the cell growth curve and calculate the half-maximal inhibitory concentration (IC) of the drug.50 The experiment was repeated 3 times. The experimental results are shown in Table 1.

[0365] The results in Table 1 show that the chloranthone Mannich base compounds have a broad spectrum of toxicity against tumor cells, with strong inhibitory effects on all seven tumor cell types. Compared with the substrate chloranthone, the modified derivatives showed a stronger effect in inhibiting tumor cell proliferation. Among them, compound B14 became the most promising compound in the series, with superior tumor cell toxicity to the parent compound chloranthone against all seven tumor cell lines, especially against five tumor cell lines: 4T1, MDA-MB-231, HCT116, MC38, and A2780. 50 The value is less than or equal to 10 μM, which is significantly better than the parent compound purpurogenol. As a preferred example, one of the compounds B14 is used as an example for explanation, and the embodiments of the remaining compounds can be designed by analogy.

[0366] In Table 1, >50 means that the survival rate of tumor cells is still greater than 50% when the drug concentration is 50 μM, that is, the cytotoxicity is very weak.

[0367] Table 1: Inhibitory effects of porphyrin ketone Mannich base derivatives obtained in Examples 1-32 and porphyrin ketone on seven tumor cell lines

[0368]

[0369] Application Example 2 In this application example, the anti-breast cancer cell colony-forming ability of the porphyrin ketone Mannich base compound B14 obtained in Example 28 was tested in vitro.

[0370] The experimental procedure is as follows: First, prepare a cell suspension of well-growing cells. Then, evenly plate 4T1 cells at a density of 500 / well, MDA-MB-231 cells at 2000 / well, and T47D cells at 3000 / well onto a six-well cell culture plate. After the cells have fully adhered, each well is stimulated with drugs at concentrations of 10, 5, 2.5, and 0 μM for 72 hours. The cells are then replaced with normal culture medium and cultured for 5-15 days, with the medium being changed every three days until microscopic cell colonies are formed. Cultivation is then stopped. The culture medium is discarded, the cells are washed once with PBS, and 1 mL of tissue fixative is added to each well. Fix for 50 minutes, wash once more with PBS, and then add 1 mL of 0.1% crystal violet stain. Stain for 20 minutes, then rinse twice with PBS. After the PBS in the wells has dried, the wells are photographed.

[0371] The number of cell clones formed after treatment with different concentrations of drugs is as follows Figure 1As shown, the number of colonies in the three breast cancer cell lines decreased in a dose-dependent manner with increasing drug concentration. A concentration of 2.5 μM blocked over 50% of colony formation, and at a concentration of 10 μM, virtually no colonies formed in the culture plate. The effect was particularly pronounced on 4T1 cells. Therefore, compound B14 can dose-dependently inhibit the formation of colonies in the three breast cancer cell lines, demonstrating its anti-proliferative activity.

[0372] Application Example 3

[0373] In this application example, the anti-breast cancer cell migration ability of the porphyrin ketone Mannich base compound B14 obtained in Example 28 was tested in vitro.

[0374] MDA-MB-231 cells were prepared as a cell suspension and seeded at 800,000 cells / dish in 35 mm culture dishes. After complete attachment of the cells, a scratch was made on the dish using a pipette tip. The culture medium was then prepared with serum-free medium containing the drug at concentrations of 10, 5, 2.5, and 0 μM. Microscopic photographs were taken after 0, 12, 24, and 36 hours to observe the healing of the scratch. The healing area was calculated using Image J, and the differences between the groups were statistically analyzed using GraphPad Prism 8.00.

[0375] like Figure 2 As shown, the cells in the Control group healed faster with time, while the cells in the drug group healed slower and in a dose-dependent manner. Comparing the healing areas of the cells in each group after 36 hours, it can be seen that the healing area of ​​the cells in the Control group reached more than 75%, while the healing area was 43% when the drug concentration was 5 μM, and the healing area was 22% when the drug concentration was 10 μM, which was significantly different from the Control group and was dose-dependent. Therefore, compound B14 can significantly reduce the migration ability of triple-negative breast cancer cells MDA-MB-231 ( Figure 2 **p<0.01, ***p<0.001) compared with the control group.

[0376] Application Example 4

[0377] This application example tests the ability of the porphyrin ketone Mannich base compound B14 obtained in Example 28 to promote apoptosis of breast cancer cells in vitro.

[0378] This experiment was conducted using the Annexin V-APC / PI apoptosis kit from Linktech Biopharm. Three breast cancer cells (4T1, MDA-MB-231, and T47D) were seeded at appropriate densities in 6-well cell culture plates. Twenty-four hours after administration, the cells were harvested and washed once with PBS. The supernatant was discarded, and the cells were resuspended in 500 μL of 1× Binding Buffer. Subsequently, 5 μL of Annexin V-APC and 10 μL of PI were added to each tube. After incubation in the dark for 5 minutes, the cells were analyzed using a flow cytometer. GraphPad Prism 8.00 was used to analyze the differences between the groups.

[0379] like Figure 3 As shown, the number of apoptotic cells in the three breast cancer cells increased significantly after drug treatment, and was dose-dependent. In cells 4T1 and MDA-MB-231, the number of apoptotic cells at the three doses was significantly different from that in the Control group, and there were significant differences between the high-dose group and the low-dose group, and between the high-dose group and the medium-dose group. The apoptosis rate of the high-dose group exceeded 50%. In T47D cells, the number of apoptotic cells in the medium-dose group and the high-dose group was significantly increased compared with the Control group, and there were significant differences between the low-dose group and the medium-dose group, the low-dose group and the high-dose group, and the medium-dose group and the high-dose group. Therefore, compound B14 can induce breast cancer cells, especially triple-negative breast cancer cells, to apoptosis, further inhibiting the proliferation of tumor cells ( Figure 3 *p<0.05, **p<0.01, ****p<0.0001 compared with the control group, and the medium-dose group and low-dose group & p<0.05, comparison between high-dose group and low-dose group # p<0.05, #### p<0.0001, comparison between high-dose group and medium-dose group $ p<0.05, $$ p<0.01, $$$ p<0.001).

[0380] Application Example 5

[0381] This application example tests the in vivo anti-tumor activity of the porphyrin ketone Mannich base compound B14 obtained in Example 28.

[0382] The experimental method used was to select healthy female Balb / C mice and adaptively feed them for one week while culturing 4T1 cells. After digestion and centrifugation of the 4T1 cells in the logarithmic growth phase, the cell concentration was adjusted to 1*10 7The tumor size was 90 mm / mL and the tumor volume was 100 μL per mouse. 3 Mice were randomly divided into five groups based on tumor volume. Cisplatin and tamoxifen served as positive controls: a high-dose B14 group (40 mg / kg), a low-dose B14 group (10 mg / kg), a cisplatin group (2 mg / kg), a tamoxifen group (10 mg / kg), and a control group, with nine mice in each group. Immediately after grouping, drugs were administered via intraperitoneal injection (5% DMSO + 5% Tween + 90% saline; the control group received the same volume of solvent). This marked the first day of treatment. Dosing was performed once daily, and tumor length and width, as well as mouse body weight, were measured. After 14 consecutive days of dosing, tumor length and width, as well as mouse body weight, were measured the following day. Mice were then sacrificed by cervical dislocation, and tumors and organs were removed and weighed. Tumors in each group were arranged in order of size and photographed. Tumors from three mice per group were fixed with tissue fixative for H&E staining and analysis. All organs were then stored at -80°C until further use. GraphPad Prism 8.00 was used to statistically analyze the differences between the corresponding groups and the in vivo anti-tumor effect of the target compound B14.

[0383] The formula for calculating mouse tumor volume is: volume (V / mm 3 ) = length * width * width / 2

[0384] Tumor Growth Inhibtion (TGI) formula: TGI (%) = (W c -W t ) / W c ×100%(W c is the average weight of tumors in the control group of mice, W t is the average weight of tumors in the mice in the drug-treated group)

[0385] The statistical trend of the change of mouse tumor volume during the 14-day drug administration is as follows Figure 4 , 5, 6 (Day 15 is the data of the day of sampling, no drug was given). Compared with the Control group, both the high-dose group and the low-dose group showed significant anti-tumor effects. From the second day on, the tumor volume was significantly different from that of the Control group, and there was a significant difference between the high-dose group and the low-dose group ( Figure 4 *p<0.05, ***p<0.001, ****p<0.0001 compared with the control group; *p<0.05, ***p<0.001, ****p<0.0001 compared with the control group; ## p<0.01, #### p<0.0001; comparison between high-dose group and low-dose group $ p<0.05,$$ p<0.01), there was a significant difference between the low-dose group and the tamoxifen group on day 15 ( Figure 5 Tamoxifen group compared with control group *p<0.05, ***p<0.001, ****p<0.0001; low-dose group compared with tamoxifen group $ p<0.05), there was no significant difference between the high-dose group and the cisplatin group ( Figure 6 *p<0.05, ****p<0.0001) compared with the control group.

[0386] After the last administration, the tumor and organs were weighed after sampling the next day. Figure 7 As shown, compared with the Control group, both the high-dose group and the low-dose group showed significant anti-tumor effects, among which the TGI of the high-dose group was 46%, which was equivalent to the positive control cisplatin (43%), and the TGI of the low-dose group was 33%, which was equivalent to the positive control tamoxifen (27%). In addition, there was a significant difference in TGI between the high-dose group and the low-dose group, indicating that compound B14 has a dose-dependent anti-tumor effect ( Figure 7 ***p<0.001, ****p<0.0001 compared with the control group, high-dose group compared with the low-dose group ## p<0.01). The tumor morphology of each group was as follows Figure 8 As shown. H&E staining of tumor tissue ( Figure 9 , n=3), it can be seen that the tumor tissue of the Control group showed active proliferation of breast cancer cells; the tumor tissue of the low-dose B14 group had blurred boundaries, missing cell nuclei, and necrosis; while the high-dose B14 group underwent large-area necrosis of cells, further confirming the anti-tumor effect.

[0387] The weight changes of mice in each group during the administration process were analyzed. Figure 10 As shown, the high-dose and low-dose B14 groups and the tamoxifen group showed the same trend as the control group. The weight of mice in the cisplatin group gradually decreased, and there was a significant difference compared with the control group from the 6th day. On the 15th day, the average weight of mice in the cisplatin group decreased by 16.7%, indicating that cisplatin is more toxic to Balb / C mice and has poor in vivo safety. Compound B14 had no significant effect on the weight of mice, which preliminarily illustrates the in vivo safety of purpurogenol Mannich base compounds ( Figure 10 **p<0.01, ****p<0.0001) compared with the control group.

[0388] Application Example 6

[0389] This application example further conducted an in vivo safety evaluation on the porphyrin ketone Mannich base compounds B8 and B14 obtained in Examples 22 and 28.

[0390] Healthy female Balb / C mice were acclimated for one week and randomly divided into three groups of eight: the B8 (60 mg / kg) group, the B14 (60 mg / kg) group, and the control group. The mice were then administered intraperitoneally for 14 consecutive days. On the 15th day, the mice were weighed, blood was collected from the eyeballs, and organs including the heart, liver, spleen, lungs, and kidneys were harvested and weighed. Whole blood was divided into two halves: one half was heparinized and centrifuged (3000 rpm, 4°C, 15 minutes) to obtain the plasma sample, while the other half was directly centrifuged (3000 rpm, 4°C, 15 minutes) to obtain the serum sample. The samples were aliquoted and stored at -80°C. Serum was used to measure alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CRE), and lactate dehydrogenase (LDH), and plasma was used to measure blood urea nitrogen (BUN) according to the kit instructions. Organs of three mice in each group were fixed in tissue fixative for H&E staining analysis. ALT, AST, CRE, and LDH were determined using the same kits from Nanjing Jiancheng.

[0391] The changes in body weight from administration on day 1 to sampling on day 15 were as follows: Figure 11 As shown in the table, the body weights of mice in the B8 (60 mg / kg) group, the B14 (60 mg / kg) group, and the Control group all showed an overall upward trend, indicating that compounds B8 and B14 had no significant effect on the body weight of mice. Figure 12 As shown, except for the significantly higher ALT in the serum of mice treated with compound B8 than in the control group, the other indicators showed no significant differences compared with the control group. The ALT, AST, CRE and LDH in the serum and BUN in the plasma of mice treated with compound B14 were normal compared with the control group, indicating that compound B8 has a slight toxicity to liver function, while compound B14 has no effect on the liver function, kidney function and normal cell growth of mice ( Figure 12 *p<0.05 in the comparison between group B8 and control). From the results of H&E staining of the organs of mice in each group ( Figure 13 ), no abnormalities were observed in the organs of the mice in the drug-treated group. Therefore, the porphyrin ketone Mannich base compounds provided by the present invention have good in vivo safety.

[0392] In summary, the present invention provides 32 porphyrin ketone Mannich base compounds, which have strong tumor cell toxicity against 7 tumor cell lines. Among them, the most active compound B14 can inhibit the cloning and migration of breast cancer cells in vitro and promote breast cancer cell apoptosis. It also shows a dose-dependent anti-tumor effect in the 4T1 in vivo tumor model of mice. In addition, the compound is safe in vivo at an effective dose and is expected to be further developed and studied, providing a new active organic small molecule for the research and development of new anti-breast cancer and other tumor drugs.

[0393] The above application examples, combined with the accompanying drawings, provide detailed descriptions of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Various modifications may be made within the scope of knowledge possessed by a person skilled in the art without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and the features thereof may be combined with each other unless there is a conflict.

Claims

1. A porphyrin ketone Mannich base compound, characterized in that Including compounds represented by formula (I) and pharmaceutically acceptable salts thereof: （I） in, R1 is selected from one of O, N-CH3, and N-CH(CH3)2; R2 is selected from one of H, halogen, alkyl, methoxy and trifluoromethyl.

2. The porphyrin ketone Mannich base compound according to claim 1, characterized in that The halogen includes at least one of fluorine, chlorine and bromine.

3. The porphyrin ketone Mannich base compound according to claim 1 or 2, characterized in that The porphyr ketone Mannich base compound includes at least one of the structural compounds represented by formula A1-14, B1-14 and C1-4: 。 4. A method for synthesizing the porphyrin ketone Mannich base compound according to claim 1 or 2, characterized in that: The method comprises the following steps: catalyzing a base catalyst, carrying out an aldol condensation reaction between 3,4-dihydroxybenzaldehyde represented by formula (Ia) and acetone represented by formula (Ib) to generate porphyrin ketone represented by formula (Ic); and then, carrying out a Mannich reaction between porphyrin ketone, a secondary amine compound represented by formula (Id) and a benzaldehyde compound represented by formula (Ie) to obtain a porphyrin ketone Mannich base compound represented by formula (I): 。 5. The synthesis method according to claim 4, characterized in that The base catalyst includes at least one of sodium hydroxide, potassium hydroxide and lithium hydroxide.

6. The synthesis method according to claim 4, characterized in that The molar ratio of the 3,4-dihydroxybenzaldehyde, acetone and base catalyst is 1:10-20:2-5.

7. The synthesis method according to claim 4, characterized in that The molar ratio of the 3,4-dihydroxybenzaldehyde, acetone and base catalyst is 1:15:

4.

8. The synthesis method according to claim 4, characterized in that The molar ratio of porphyrone, secondary amine compound and benzaldehyde compound is 1:1-5:1-5.

9. The synthesis method according to claim 4, characterized in that The molar ratio of porphyrone, secondary amine compound and benzaldehyde compound is 1:1.2:1.

2.

10. The method for synthesizing the porphyr ketone Mannich base compound according to claim 4, characterized in that: 3,4-dihydroxybenzaldehyde represented by formula (Ia) and acetone represented by formula (Ib) undergo aldol condensation reaction to generate porphyrin represented by formula (Ic). The reaction temperature is room temperature and the reaction time is 12 hours.

11. The method for synthesizing the porphyr ketone Mannich base compound according to claim 4, wherein: In the process of obtaining the porphyrin ketone Mannich base compound represented by formula (I) by a Mannich reaction between porphyrin ketone, a secondary amine compound represented by formula (Id) and a benzaldehyde compound represented by formula (Ie), the reaction temperature is 100° C. to 110° C., and the reaction time is 0.5 h.

12. An anti-tumor drug, characterized in that: The invention comprises the porphyrin ketone Mannich base compound according to claim 1 or 2, or the porphyrin ketone Mannich base compound synthesized by the synthesis method according to any one of claims 4 to 11.

13. The drug according to claim 12, characterized in that The raw materials for preparing the medicine also include pharmaceutically acceptable excipients.

14. The drug according to claim 12, characterized in that The tumor includes at least one of breast cancer, colon cancer, lung cancer and ovarian cancer.

Images