A semi-sandwich structure iridium ferrocene pyridine complex and its preparation method and application

Abstract

The invention discloses a semi-sandwich structure iridium ferrocene pyridine complex, a preparation method thereof and an anti-cancer application thereof. Its structural formula is shown in formula (I), R is methyl, phenyl or biphenyl, and the double bond is in cis and trans configurations. By testing the growth inhibition rate of the target complex on human alveolar basal epithelial cancer cells, cervical cancer cells and normal human lung epithelial cells, and comparing them, it is found that the target complex exhibits good anti-cancer activity, confirming the synergistic anti-cancer effect of ferrocene and metal iridium complexes. The substituent R is changed from methyl→phenyl→biphenyl, and the activity of the complex is effectively improved, confirming that improving the electron donation ability of the ligand is conducive to improving the anti-cancer activity of such complexes. In addition, the trans-configuration complex also shows higher activity. The target complex can accumulate in the lysosome in A549 cells and cause lysosome damage, thereby causing cancer cell death. The complex shows a certain selectivity between normal cells and cancer cells.

Description

Technical field:

[0001] The invention relates to a metal complex, in particular to a semi-sandwich structure iridium ferrocene pyridine complex and a preparation method and anti-cancer application thereof, belonging to the field of chemical pharmacy. Background technology:

[0002] Cancer, malignant tumor, is one of the diseases with the highest mortality rate in human beings. Chemotherapy (chemotherapy) is becoming increasingly important as an important means of cancer treatment. Platinum anticancer drugs represented by cisplatin are the most widely used anticancer agents, but they also show some increasingly prominent problems while being widely used, such as: a large number of normal cells damaged, high incidence of drug resistance, etc. (Coord.Chem.Rev.2015,284,286-297). Despite this, the wide application of platinum drugs has fully proved that metal complexes have great medicinal value and anticancer potential, but the problems they have have prompted people to continue to seek new metal anticancer drugs with higher efficiency, higher selectivity and clearer target (J.Med.Chem.2011,54,3-25). Semi-sandwich structure metal iridium complexes have good anticancer activity and unique anti-tumor mechanism, and have now become potential substitutes for platinum metal anticancer drugs (Acc.Chem.Res.2014,47,1174-1185). The good anti-cancer potential and structural controllability of semi-sandwich structured metal iridium complexes provide the possibility of building a new tumor treatment platform (Inorg.Chem.Commun.2021,124,108364). Ferrocene is also an active research topic in the field of cancer treatment. However, compared with other metal anticancer drugs, ferrocene drugs have weak anticancer activity and large side effects (New J.Chem.2011,35,1973-1985). Studies have found that ferrocene derivatization and combined derivatization with other metals (including gold, rhodium, platinum, etc.) usually show good synergistic effects, and its anticancer activity is further enhanced (Dalton Trans.2019,48,2840-2860). Lysosomes are acidic tissues in cells (pH:4.5~5.5) that contain a variety of hydrolases that can degrade almost all biological macromolecules. Lysosomal damage can lead to lysosomal membrane permeability (LMP), destroying the integrity of lysosomes. Extensive LMP can cause cathepsins and other hydrolases to be released from the lysosomal cavity to the cytoplasm, causing the cleavage of multiple matrices, thereby leading to apoptosis. Because lysosomes are involved in various aspects of cell death, and the content in tumor cells is significantly higher than that in normal human cells, it becomes an ideal pharmacological target for selective killing of tumor cells (Dalton Trans. 2017, 46, 16787-16791). In view of this, the present invention selects ferrocene and semi-sandwich structure iridium complexes with good anti-cancer potential, and combines them into semi-sandwich structure iridium ferrocene pyridine complexes, and enhances the anti-cancer activity of the target complex through the synergistic effect of ferrocene and iridium complexes. Regulate the stereo configuration (cis and trans isomers) of the double bond and screen for structural units with higher activity. By selecting a suitable substituent (R) to regulate the anti-cancer activity and lysosomal tissue targeting of the target drug, it is expected to become a new type of lysosomal targeted metal anticancer drug. Summary of the invention:

[0003] A ferrocene pyridine derivative, ferrocene and pyridine are connected by a double bond, and its structure is shown in formula (II):

[0004]

[0005] When connected via a trans-configuration double bond, the specific structural formula is shown in formula (L1); when connected via a cis-configuration double bond, the specific structural formula is shown in formula (L2).

[0006] An iron-iridium metal complex having anticancer activity, the structural formula of which is shown in formula (I):

[0007]

[0008] Wherein, R is selected from methyl, phenyl and biphenyl, and the double bond has two configurations, cis and trans.

[0009] Furthermore, the chemical structural formulas of all target complexes of the present invention are as follows:

[0010]

[0011] The present invention provides a method for preparing the above-mentioned compound: 4-pyridinecarboxaldehyde shown in formula (III) and ferrocenylmethyltriphenylphosphine hydrobromide shown in formula (IV) are subjected to Wittig reaction to obtain a ferrocenylpyridine compound shown in formula (II), which is then reacted with a basic iridium dimer shown in formula (V) to obtain a target complex shown in formula (I). The specific reaction route is as follows:

[0012]

[0013] Furthermore, when the compound is of formula (1), it is prepared by the following method:

[0014] (1) Add 0.25 g of hydrated iridium trichloride, 0.33 mL of 1,2,3,4,5-pentamethylcyclopentadiene and 30 mL of methanol to the inner tank of the microwave digester, dissolve by ultrasonication, evacuate and pass nitrogen, and assemble the main tank and the standard tank. Set the parameters of the microwave digester: first, heat to 395K and react for 20 minutes, then heat to 425K and continue to react for 20 minutes, with a ramp time of 5 minutes. Then filter the reaction liquid to remove unreacted iridium trichloride, and remove the solvent by vacuum distillation. Add methanol to the tank to dissolve the product, and then add ether for diffusion and purification to obtain the orange-yellow base metal iridium dimer (V, R = methyl);

[0015] (2) Add ferrocenylmethyltriphenylphosphine hydrobromide (IV, 0.49 g) to a 100 mL Schlenk bottle, evacuate and fill with nitrogen, add 20 mL of anhydrous tetrahydrofuran, and cool to 0°C. Add 20 mL of anhydrous tetrahydrofuran solution of potassium tert-butoxide (0.18 g) dropwise, stir for 30 min, add 15 mL of anhydrous tetrahydrofuran solution of 4-pyridinecarboxaldehyde (III, 0.10 g), react at low temperature for 1 h, and then warm to room temperature for reaction. After the reaction is completed (monitored by thin layer chromatography, the developing solvent is dichloromethane: methanol: triethylamine = 2 mL: 2 drops: 1 drop), add 40 mL of saturated brine to quench the reaction, and 1.0 mol L -1 The pH of the reaction solution was adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate, separated, the organic layer was combined, washed with water, dried with anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation to obtain a yellow solid crude product containing cis and trans conformations. Column chromatography was used for purification (the eluent was petroleum ether: ethyl acetate = 10:1), and the same components were combined and vacuum distilled to obtain an orange-red solid (L1);

[0016] (3) 60.0 mg of the basic iridium dimer (V, R = methyl) and 43.6 mg of the ferrocenylpyridine ligand (L1) were placed in a 100 mL Shrek bottle, evacuated and nitrogen was passed through, 30 mL of dichloromethane was injected as the reaction solvent using a syringe, stirred at room temperature for 24 h, and the solvent was removed by vacuum distillation to obtain a crude orange-red solid powder product. A small amount of dichloromethane was dissolved, and n-hexane was added to diffuse to obtain the orange-red crystalline target product (1).

[0017] Furthermore, when the compound is of formula (2), it is prepared by the following method:

[0018] (1) Add 0.25 g of hydrated iridium trichloride, 0.33 mL of 1,2,3,4,5-pentamethylcyclopentadiene and 30 mL of methanol to the inner tank of the microwave digester, dissolve by ultrasonication, evacuate and pass nitrogen, and assemble the main tank and the standard tank. Set the parameters of the microwave digester: first, heat to 395K and react for 20 minutes, then heat to 425K and continue to react for 20 minutes, with a ramp time of 5 minutes. Then filter the reaction liquid to remove unreacted iridium trichloride, and remove the solvent by vacuum distillation. Add methanol to the tank to dissolve the product, and then add ether for diffusion and purification to obtain the orange-yellow base metal iridium dimer (V, R = methyl);

[0019] (2) Add ferrocenylmethyltriphenylphosphine hydrobromide (IV, 0.49 g) to a 100 mL Schlenk bottle, evacuate and fill with nitrogen, add 20 mL of anhydrous tetrahydrofuran, and cool to 0°C. Add 20 mL of anhydrous tetrahydrofuran solution of potassium tert-butoxide (0.18 g) dropwise, stir for 30 min, add 15 mL of anhydrous tetrahydrofuran solution of 4-pyridinecarboxaldehyde (III, 0.10 g), react at low temperature for 1 h, and then warm to room temperature for reaction. After the reaction is completed (monitored by thin layer chromatography, the developing solvent is dichloromethane: methanol: triethylamine = 2 mL: 2 drops: 1 drop), add 40 mL of saturated brine to quench the reaction, and 1.0 mol L -1 The pH of the reaction solution was adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate, separated, the organic layer was combined, washed with water, dried with anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation to obtain a yellow solid crude product containing cis and trans conformations. Column chromatography was used for purification (the eluent was petroleum ether: ethyl acetate = 10:1), the same components were combined, and vacuum distillation was performed to obtain an orange-yellow solid (L2);

[0020] (3) 60.0 mg of the basic iridium dimer (V, R = methyl) and 43.6 mg of the ferrocenylpyridine ligand (L2) were placed in a 100 mL Shrek bottle, evacuated and nitrogen was passed through, 30 mL of dichloromethane was injected as the reaction solvent using a syringe, stirred at room temperature for 24 h, and the solvent was removed by vacuum distillation to obtain a crude orange-red solid powder product. A small amount of dichloromethane was dissolved, and n-hexane was added to diffuse to obtain the orange-red crystalline target product (2).

[0021] Furthermore, when the compound is of formula (3), it is prepared by the following method:

[0022] (1) Add 0.25 g of hydrated iridium trichloride, 0.44 g of 1-phenyl-2,3,4,5-tetramethylcyclopentadiene and 30 mL of methanol to the inner tank of the microwave digestion instrument, dissolve by ultrasonication, evacuate and pass nitrogen, and assemble the main tank and the standard tank. Set the parameters of the microwave digestion instrument: first raise the temperature to 395K and react for 20 minutes, then raise the temperature to 425K and continue to react for 20 minutes, and the ramp time is 5 minutes. Then filter the reaction liquid to remove the unreacted iridium trichloride, and remove the solvent by vacuum distillation. Add methanol to the tank to dissolve the product, and then add ether to diffuse and purify to obtain the orange-yellow basic metal iridium dimer (V, R = phenyl);

[0023] (2) Add ferrocenylmethyltriphenylphosphine hydrobromide (IV, 0.49 g) to a 100 mL Schlenk bottle, evacuate and fill with nitrogen, add 20 mL of anhydrous tetrahydrofuran, and cool to 0°C. Add 20 mL of anhydrous tetrahydrofuran solution of potassium tert-butoxide (0.18 g) dropwise, stir for 30 min, add 15 mL of anhydrous tetrahydrofuran solution of 4-pyridinecarboxaldehyde (III, 0.10 g), react at low temperature for 1 h, and then warm to room temperature for reaction. After the reaction is completed (monitored by thin layer chromatography, the developing solvent is dichloromethane: methanol: triethylamine = 2 mL: 2 drops: 1 drop), add 40 mL of saturated brine to quench the reaction, and 1.0 mol L -1 The pH of the reaction solution was adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate, separated, the organic layer was combined, washed with water, dried with anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation to obtain a yellow solid crude product containing cis and trans conformations. Column chromatography was used for purification (the eluent was petroleum ether: ethyl acetate = 10:1), and the same components were combined and vacuum distilled to obtain an orange-red solid (L1);

[0024] (3) 60.0 mg of the basic iridium dimer (V, R = phenyl) and 37.7 mg of the ferrocenyl bipyridine ligand (L1) were placed in a 100 mL Shrek bottle, evacuated and nitrogen was passed through, 30 mL of dichloromethane was injected as the reaction solvent using a syringe, and the mixture was stirred at room temperature for 24 h. The solvent was removed by vacuum distillation to obtain a crude orange-red powder product, which was dissolved in a small amount of dichloromethane and diffused into n-hexane to obtain the target product (3) as an orange-red crystal.

[0025] Furthermore, when the compound is of formula (4), it is prepared by the following method:

[0026] (1) Add 0.25 g of hydrated iridium trichloride, 0.44 g of 1-phenyl-2,3,4,5-tetramethylcyclopentadiene and 30 mL of methanol to the inner tank of the microwave digestion instrument, dissolve by ultrasonication, evacuate and pass nitrogen, and assemble the main tank and the standard tank. Set the parameters of the microwave digestion instrument: first raise the temperature to 395K and react for 20 minutes, then raise the temperature to 425K and continue to react for 20 minutes, and the ramp time is 5 minutes. Then filter the reaction liquid to remove the unreacted iridium trichloride, and remove the solvent by vacuum distillation. Add methanol to the tank to dissolve the product, and then add ether to diffuse and purify to obtain the orange-yellow basic metal iridium dimer (V, R = phenyl);

[0027] (2) Add ferrocenylmethyltriphenylphosphine hydrobromide (IV, 0.49 g) to a 100 mL Schlenk bottle, evacuate and fill with nitrogen, add 20 mL of anhydrous tetrahydrofuran, and cool to 0°C. Add 20 mL of anhydrous tetrahydrofuran solution of potassium tert-butoxide (0.18 g) dropwise, stir for 30 min, add 15 mL of anhydrous tetrahydrofuran solution of 4-pyridinecarboxaldehyde (III, 0.10 g), react at low temperature for 1 h, and then warm to room temperature for reaction. After the reaction is completed (monitored by thin layer chromatography, the developing solvent is dichloromethane: methanol: triethylamine = 2 mL: 2 drops: 1 drop), add 40 mL of saturated brine to quench the reaction, and 1.0 mol L -1 The pH of the reaction solution was adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate, separated, the organic layer was combined, washed with water, dried with anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation to obtain a yellow solid crude product containing cis and trans conformations. Column chromatography was used for purification (the eluent was petroleum ether: ethyl acetate = 10:1), the same components were combined, and vacuum distillation was performed to obtain an orange-yellow solid (L2);

[0028] (3) 60.0 mg of the basic iridium dimer (V, R = phenyl) and 37.7 mg of the ferrocenyl bipyridine ligand (L2) were placed in a 100 mL Shrek bottle, evacuated and nitrogen was passed through, 30 mL of dichloromethane was injected as the reaction solvent using a syringe, and the mixture was stirred at room temperature for 24 h. The solvent was removed by vacuum distillation to obtain a crude orange-red powder product, which was dissolved in a small amount of dichloromethane and diffused into n-hexane to obtain the target product (4) as orange-red crystals.

[0029] Furthermore, when the compound is of formula (5), it is prepared by the following method:

[0030] (1) Add 0.25g of hydrated iridium trichloride, 0.65g of 1-biphenyl-2,3,4,5-tetramethylcyclopentadiene and 30mL of methanol to the inner tank of the microwave digestion instrument, dissolve by ultrasonication, evacuate and pass nitrogen, and assemble the main tank and the standard tank. Set the parameters of the microwave digestion instrument: first raise the temperature to 395K and react for 20 minutes, then raise the temperature to 425K and continue to react for 20 minutes, and the ramp time is 5 minutes. Then filter the reaction liquid to remove the unreacted iridium trichloride, and distill under reduced pressure to remove the solvent. Add methanol to the tank to dissolve the product, and then add ether to diffuse and purify to obtain the orange-yellow basic metal iridium dimer (V, R = biphenyl);

[0031] (2) Add ferrocenylmethyltriphenylphosphine hydrobromide (IV, 0.49 g) to a 100 mL Schlenk bottle, evacuate and fill with nitrogen, add 20 mL of anhydrous tetrahydrofuran, and cool to 0°C. Add 20 mL of anhydrous tetrahydrofuran solution of potassium tert-butoxide (0.18 g) dropwise, stir for 30 min, add 15 mL of anhydrous tetrahydrofuran solution of 4-pyridinecarboxaldehyde (III, 0.10 g), react at low temperature for 1 h, and then warm to room temperature for reaction. After the reaction is completed (monitored by thin layer chromatography, the developing solvent is dichloromethane: methanol: triethylamine = 2 mL: 2 drops: 1 drop), add 40 mL of saturated brine to quench the reaction, and 1.0 mol L -1 The pH of the reaction solution was adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate, separated, the organic layer was combined, washed with water, dried with anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation to obtain a yellow solid crude product containing cis and trans conformations. Column chromatography was used for purification (the eluent was petroleum ether: ethyl acetate = 10:1), and the same components were combined and vacuum distilled to obtain an orange-red solid (L1);

[0032] (3) 60.0 mg of the basic iridium dimer (V, R = biphenyl) and 32.37 mg of the ferrocenylpyridine ligand (L1) were placed in a 100 mL Shrek bottle, evacuated and nitrogen was passed through, 30 mL of dichloromethane was injected as the reaction solvent using a syringe, and the mixture was stirred at room temperature for 24 h. The solvent was removed by vacuum distillation to obtain a crude orange-red powder product, which was dissolved in a small amount of dichloromethane and diffused into n-hexane to obtain the target product (5) as orange-red crystals.

[0033] Furthermore, when the compound is of formula (6), it is prepared by the following method:

[0034] (1) Add 0.25g of hydrated iridium trichloride, 0.65g of 1-biphenyl-2,3,4,5-tetramethylcyclopentadiene and 30mL of methanol to the inner tank of the microwave digestion instrument, dissolve by ultrasonication, evacuate and pass nitrogen, and assemble the main tank and the standard tank. Set the parameters of the microwave digestion instrument: first raise the temperature to 395K and react for 20 minutes, then raise the temperature to 425K and continue to react for 20 minutes, and the ramp time is 5 minutes. Then filter the reaction liquid to remove the unreacted iridium trichloride, and distill under reduced pressure to remove the solvent. Add methanol to the tank to dissolve the product, and then add ether to diffuse and purify to obtain the orange-yellow basic metal iridium dimer (V, R = biphenyl);

[0035] (2) Add ferrocenylmethyltriphenylphosphine hydrobromide (IV, 0.49 g) to a 100 mL Schlenk bottle, evacuate and fill with nitrogen, add 20 mL of anhydrous tetrahydrofuran, and cool to 0°C. Add 20 mL of anhydrous tetrahydrofuran solution of potassium tert-butoxide (0.18 g) dropwise, stir for 30 min, add 15 mL of anhydrous tetrahydrofuran solution of 4-pyridinecarboxaldehyde (III, 0.10 g), react at low temperature for 1 h, and then warm to room temperature for reaction. After the reaction is completed (monitored by thin layer chromatography, the developing solvent is dichloromethane: methanol: triethylamine = 2 mL: 2 drops: 1 drop), add 40 mL of saturated brine to quench the reaction, and 1.0 mol L -1 The pH of the reaction solution was adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate, separated, the organic layer was combined, washed with water, dried with anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation to obtain a yellow solid crude product containing cis and trans conformations. Column chromatography was used for purification (the eluent was petroleum ether: ethyl acetate = 10:1), the same components were combined, and vacuum distillation was performed to obtain an orange-yellow solid (L2);

[0036] (3) 60.0 mg of the basic iridium dimer (V, R = biphenyl) and 32.37 mg of the ferrocenylpyridine ligand (L2) were placed in a 100 mL Shrek bottle, evacuated and nitrogen was passed through, 30 mL of dichloromethane was injected as the reaction solvent using a syringe, and the mixture was stirred at room temperature for 24 h. The solvent was removed by vacuum distillation to obtain a crude orange-red powder product, which was dissolved in a small amount of dichloromethane and diffused into n-hexane to obtain the target product (6) as orange-red crystals.

[0037] The present invention provides an application of a half-sandwich structure iridium ferrocene pyridine complex prepared by the above method in the field of anticancer drugs. Both ferrocene and the half-sandwich structure iridium complex are metal anticancer complexes with good potential. The complex synthesized by the two exhibits more excellent anticancer activity, confirming their synergistic effect, which provides a structural platform for the design and development of new metal anticancer drugs.

[0038] The beneficial effects of the present invention are:

[0039] (1) The present invention proposes a synergistic anticancer effect of ferrocene and a half-sandwich structure iridium complex. Compared with a single ferrocene and iridium complex, the target complex exhibits better anticancer activity;

[0040] (2) The compounds of the present invention have suitable fluorescence, which is convenient for studying tissue targeting and provides a new idea for the design of subsequent targeted anticancer drugs.

[0041] Attached picture content:

[0042] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the ligand L1 of the present invention.

[0043] Figure 2is the hydrogen nuclear magnetic resonance spectrum of the ligand L2 of the present invention.

[0044] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of complex 1 of the present invention.

[0045] Figure 4 is the mass spectrum of complex 1 of the present invention.

[0046] Figure 5 It is the single crystal structure of complex 1 of the present invention.

[0047] Figure 6 It is the hydrogen nuclear magnetic resonance spectrum of the complex 2 of the present invention.

[0048] Figure 7 is the mass spectrum of complex 2 of the present invention.

[0049] Figure 8 This is the single crystal structure of complex 2 of the present invention.

[0050] Fig. 9 is the hydrogen nuclear magnetic resonance spectrum of complex 3 of the present invention.

[0051] Fig.10 is the mass spectrum of complex 3 of the present invention.

[0052] Fig.11 is the hydrogen nuclear magnetic resonance spectrum of complex 4 of the present invention.

[0053] Fig.12 is the mass spectrum of complex 4 of the present invention.

[0054] Fig.13 is the hydrogen nuclear magnetic resonance spectrum of complex 5 of the present invention.

[0055] Fig.14 is the mass spectrum of complex 5 of the present invention.

[0056] Fig.15 is the hydrogen nuclear magnetic resonance spectrum of complex 6 of the present invention.

[0057] Fig.16 is the mass spectrum of complex 6 of the present invention.

[0058] Fig.17 This is a cell tissue targeting test diagram of complexes 3 and 4 of the present invention.

[0059] Fig.18 This is a diagram showing that complex 3 of the present invention induces lysosomal damage.

[0060] Fig.19 Figure 4 shows the lysosomal damage induced by complex 4 of the present invention Specific implementation method:

[0061] The present invention is further illustrated with reference to the following examples of some representative compounds, but these illustrations are not intended to limit the present invention.

[0062] The starting compounds used in the synthesis of the compounds are commercial products or can be prepared from known synthetic methods, and the preparation methods of all organic compounds can be obtained from the literature, and these methods are basic and obvious to synthetic chemists. Therefore, the description of the following synthetic methods can be considered to be detailed and specific.

[0063] Example 1

[0064] Add 0.25g of hydrated iridium trichloride, 0.33mL of 1,2,3,4,5-pentamethylcyclopentadiene and 30mL of methanol to the inner tank of the microwave digestion instrument, dissolve with ultrasound, evacuate and pass nitrogen, assemble the main tank and the standard tank, set the parameters of the microwave digestion instrument: first heat to 393K, react for 20min, then continue to heat to 423K, react for 20min, and the ramp time is 5min. React with a microwave digestion instrument, filter the reaction liquid, remove the unreacted iridium trichloride, spin dry, dissolve in methanol, add ether for diffusion and purification, and obtain an orange-yellow metal iridium dimer (V, R = methyl) product with a yield of 61.0%.

[0065] Example 2

[0066] Add 0.25g of hydrated iridium trichloride, 0.44g of 1-phenyl-2,3,4,5-tetramethylcyclopentadiene and 30mL of methanol to the inner tank of the microwave digestion instrument, dissolve with ultrasound, evacuate and pass nitrogen, assemble the main tank and the standard tank, set the parameters of the microwave digestion instrument: first heat to 393K, react for 20min, then continue to heat to 423K, react for 20min, and the ramp time is 5min. React with a microwave digestion instrument, filter the reaction liquid, remove the unreacted iridium trichloride, spin dry, dissolve in methanol, add ether for diffusion and purification, and obtain an orange-yellow metal iridium dimer (V, R = phenyl) product with a yield of 51.5%.

[0067] Example 3

[0068] Add 0.25g of hydrated iridium trichloride, 0.65g of 1-biphenyl-2,3,4,5-tetramethylcyclopentadiene and 30mL of methanol to the inner tank of the microwave digestion instrument, dissolve by ultrasonication, evacuate and pass nitrogen, and assemble the main tank and the standard tank. Set the parameters of the microwave digestion instrument: first heat to 395K for 20min, then heat to 425K for 20min, and the ramp time is 5min. Then filter the reaction liquid to remove the unreacted iridium trichloride, and remove the solvent by vacuum distillation. Add methanol to the tank to dissolve the product, and then add ether for diffusion and purification to obtain the orange-yellow base metal iridium dimer (V, R = biphenyl) product with a yield of 49.5%.

[0069] Example 4

[0070] Add ferrocenylmethyltriphenylphosphine hydrobromide (Ⅳ, 0.49g) to a 100mL Schlenk bottle, evacuate and fill with nitrogen, add 20mL of anhydrous tetrahydrofuran, and cool to 0℃. Add 20mL of anhydrous tetrahydrofuran solution of potassium tert-butoxide (0.18g) dropwise, stir for 30min, add 15mL of anhydrous tetrahydrofuran solution of 4-pyridinecarboxaldehyde (Ⅲ, 0.10g) dropwise, react at low temperature for 1h, and then warm to room temperature for reaction. After the reaction is completed (monitored by thin layer chromatography, the developing solvent is dichloromethane: methanol: triethylamine = 2mL: 2 drops: 1 drop), add 40mL of saturated brine to quench the reaction, and 1.0mol L -1 The pH of the reaction solution was adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate, separated, the organic layers were combined, washed with water, dried with anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation to obtain a crude yellow solid product containing cis and trans conformations. Column chromatography was performed for purification (the eluent was petroleum ether: ethyl acetate = 10:1), the same components were combined, and vacuum distillation was performed to obtain 0.15 g of orange-red solid L1 (yield 57.3%) and 0.13 g of orange-yellow solid L2 (yield 49.7%).

[0071] The NMR spectrum of L1 is shown in Figure 1 As shown: 1 H NMR (500MHz, CDCl3) δ7.71(s,1H),7.53(s,1H),7.29(s,2H),7.13(d,J=16.1Hz,1H),6.60(d,J=16.1Hz,1H),4.50(s,2H),4.36(s,2H),4.16(s,5H).

[0072] The NMR spectrum of L2 is shown in Figure 2 As shown: 1 H NMR (500MHz, CDCl3) δ8.51(s,2H),7.24(s,2H),6.49(d,J=12.0Hz,1H),6.30(d,J=12.0Hz,1H),4.22(s,2H),4.18(s,2H),4.11(s,5H).

[0073] Example 5

[0074] 60.0 mg of iridium dimer (V, R = methyl) and 43.6 mg of ferrocenylpyridine ligand (L1) were placed in a 100 mL Schlenk bottle, evacuated and nitrogen was passed through, 30 mL of dichloromethane was added, and the mixture was stirred at room temperature for 24 h. The solvent was removed by distillation under reduced pressure, a small amount of dichloromethane was dissolved, and n-hexane was added for diffusion to obtain 121.5 mg of the target product (1) as orange-red crystals (yield 66.6%). Characterization spectrum is shown in the figure below: Figure 3 to Figure 5 As shown: 1H NMR (500MHz, CDCl3) δ8.80(d,J=6.4Hz,2H),7.29(d,J=6.9Hz,2H),7.22(d,J=16.0Hz,1H),6 .59(d,J=16.0Hz,1H),4.54(s,2H),4.43(s,2H),4.18(s,5H),1.58(s,15H).ESI-MS(m / z): C 28 H 33 NClFeIr, theoretical value 652.1045, [M-Cl] + ; The actual measured value is 652.0000.

[0075] Example 6

[0076] 60.0 mg of iridium dimer (V, R = methyl) and 43.6 mg of ferrocenylpyridine ligand (L2) were placed in a 100 mL Schlenk bottle, evacuated and nitrogen was passed through, 30 mL of dichloromethane was added, and the mixture was stirred at room temperature for 24 h. The solvent was removed by distillation under reduced pressure, a small amount of dichloromethane was dissolved, and n-hexane was added for diffusion to obtain 100.3 mg of the target product (2) as orange-yellow crystals (yield 54.9%). Characterization spectrum is shown in the figure below: Figure 6 to Figure 8 As shown: 1 H NMR (500MHz, CDCl3) δ8.76(d,J=6.1Hz,2H),7.30(d,J=6.1Hz,2H),6.61(d,J=11.9Hz,1H),6 .26(d,J=11.9Hz,1H),4.28(s,2H),4.23(s,2H),4.13(s,5H),1.53(s,15H).ESI-MS(m / z): C 28 H 33 NClFeIr, theoretical value 652.1045, [M-Cl] + ; The actual measured value is 652.1003.

[0077] Example 7

[0078] 60.0 mg of iridium dimer (V, R = phenyl) and 37.7 mg of ferrocenylpyridine ligand (L1) were placed in a 100 mL Schlenk bottle, evacuated and nitrogen was passed through, 30 mL of dichloromethane was added, and the mixture was stirred at room temperature for 24 h. The solvent was removed by distillation under reduced pressure, a small amount of dichloromethane was dissolved, and n-hexane was added for diffusion to obtain 101.5 mg of the target product (3) as orange-red crystals (yield 59.2%). Characterization spectrum is shown in the figure below: Fig. 9 and Fig.10 As shown: 1H NMR (500MHz, CDCl3) δ8.75(d,J=6.5Hz,2H),7.82–7.63(m,2H),7.40(d,J=6.7Hz,3H),7.19(d,J=6.6Hz,2H),7.14(d,J =16.0Hz,1H),6.52(d,J=16.0Hz,1H),4.49(s,2H),4.40(s,2H),4.14(s,5H),1.72(s,6H),1.52(s,6H).ESI-MS(m / z): C 34 H 38 NClFeIr, theoretical value 714.1202, [M-Cl] + ; The actual measured value is 714.1160.

[0079] Example 8

[0080] 60.0 mg of iridium dimer (V, R = phenyl) and 37.7 mg of ferrocenylpyridine ligand (L2) were placed in a 100 mL Schlenk bottle, evacuated and nitrogen was passed through, 30 mL of dichloromethane was added, and the mixture was stirred at room temperature for 24 h. The solvent was removed by distillation under reduced pressure, a small amount of dichloromethane was dissolved, and n-hexane was added for diffusion to obtain 91.2 mg of the target product (4) as orange-yellow crystals (yield 53.2%). Characterization spectrum is shown in FIG. Fig.11 and Fig.12 As shown: 1 H NMR (500MHz, CDCl3) δ8.72(d,J=6.4Hz,2H),7.70(d,J=3.9Hz,2H),7.38(d,J=3.2Hz,3H),7.21(d,J=6.1Hz,2H),6.57(d,J=12.0Hz, 1H), 6.19 (d, J = 12.0Hz, 1H), 4.26 (s, 2H), 4.19 (s, 2H), 4.11 (s, 5H), 1.71 (d, J = 13.7Hz, 6H), 1.50 (d, J = 15.1Hz, 6H). ESI-MS (m / z): C 34 H 38 NClFeIr, theoretical value 714.1202, [M-Cl] + ; The actual measured value is 714.1171.

[0081] Example 9

[0082] 60.0 mg of iridium dimer (V, R = biphenyl) and 32.37 mg of ferrocenylpyridine ligand (L1) were placed in a 100 mL Schlenk bottle, evacuated and nitrogen was passed through, 30 mL of dichloromethane was added, and the mixture was stirred at room temperature for 24 h. The solvent was removed by distillation under reduced pressure, a small amount of dichloromethane was dissolved, and n-hexane was added for diffusion to obtain 92.8 mg of the target product (5) as orange-red crystals (yield 57.4%). Characterization spectrum is shown in FIG. Fig.13 and Fig.14 As shown: 1 H NMR (500MHz, CDCl3) δ8.77(d,J=6.7Hz,2H),7.81(d,J=8.2Hz,2H),7.63(d,J=8.1Hz,4H),7.47(s,2H),7.39(s,1H),7.21(s ,2H),7.15(s,1H),6.52(d,J=16.0Hz,1H),4.49(s,2H),4.39(s,2H),4.12(s,5H),1.74(s,6H),1.57(s,6H).ESI-MS(m / z): C 40 H 42 NClFeIr, theoretical value 790.1515, [M-Cl] + ; The actual measured value is 790.1394.

[0083] Example 10

[0084] 60.0 mg of iridium dimer (V, R = biphenyl) and 32.37 mg of ferrocenylpyridine ligand (L2) were placed in a 100 mL Schlenk bottle, evacuated and nitrogen was passed through, 30 mL of dichloromethane was added, and the mixture was stirred at room temperature for 24 h. The solvent was removed by distillation under reduced pressure, a small amount of dichloromethane was dissolved, and n-hexane was added for diffusion to obtain 87.3 mg of the target product (6) as orange-red crystals (yield 54.0%). Characterization spectrum is shown in FIG. Fig.15 and Fig.16 As shown: 1 H NMR (500MHz, CDCl3) δ8.74(d,J=6.5Hz,2H),7.77(d,J=8.1Hz,2H),7.61(d,J=7.7Hz,4H),7.46(s,2H),7.38(s,1H),7.23(d,J=6.5Hz,2H ),6.57(d,J=11.9Hz,1H),6.19(d,J=11.9Hz,1H),4.25(s,2H),4.19(s,2H),4.10(s,5H),1.71(s,6H),1.57–1.49(m,6H).ESI-MS(m / z): C 40 H 42NClFeIr, theoretical value 790.1515, [M-Cl] + ; The actual measured value is 790.1453.

[0085] Embodiment 11

[0086] The experimental steps for the inhibition of proliferation of cancer cells and normal cells by the half-sandwich structure iridium ferrocene pyridine complex with anticancer activity are as follows:

[0087] (1) Solution preparation: Dissolve the complex to be tested in dimethyl sulfoxide (DMSO) to prepare a stock solution of a certain concentration, dilute it to the working concentration with cell culture medium, and incubate for 24 h;

[0088] (2) Cell growth inhibition evaluation (MTT method):

[0089] 1) Take 5000 cells to be tested, prepare a cell suspension, and inoculate it into a 96-well culture plate;

[0090] 2) Pre-culture cells with drug-free medium, incubate at 5% CO2, 310K for 24 h, add the test solution, and continue culturing for 24 h;

[0091] 3) Add 15 μL of 5 mg / mL MTT solution to each well of the culture plate, and then culture for 4 hours to form a purple crystalline substance (formazan);

[0092] 4) Terminate the culture, wash away the culture medium in the wells, add 100 μL of DMSO to dissolve the precipitate (formazan), and measure the optical density of each well using an ELISA reader (set wavelength: 570 nm);

[0093] 5) Each experiment was repeated three times, IC 50 =mean±SEM.

[0094] The inhibition rates of the target complex (Ⅰ), ferrocenylpyridine derivative (Ⅱ), basic metal iridium dimer (V) and cisplatin on the growth of human alveolar basal epithelial carcinoma cells (A549), cervical cancer cells (Hela) and normal human lung epithelial cells (BEAS-2B) are shown in Table 1.

[0095] Table 1

[0096]

[0097] It can be seen from Example 11 that under the same conditions, the ferrocenylpyridine derivative (II) and the basic metal iridium dimer (V) have almost no activity (IC 50>100μM). However, the semi-sandwich structure iridium ferrocene pyridine complexes (Ⅰ) formed by them all showed certain anticancer activity, indicating the synergistic anticancer effect of ferrocene and iridium complexes. The activity of some complexes is much higher than that of commercialized cisplatin, especially for A549 cells, the activity of the best complex 5 is 3.5 times that of cisplatin. In addition, as the substituent R changes from methyl → phenyl → biphenyl, the activity of the target complex is further improved, indicating that improving the electron donation ability of the ligand is conducive to improving the anticancer activity of such complexes. In addition, for the same ligand, compared with the cis configuration, the trans configuration complexes show higher activity, which provides a basic structural unit for the design and optimization of such complexes.

[0098] Example 12

[0099] Laser confocal microscopy was used to detect tissue targeting of the target complex in A549 cancer cells. LysoTracker Red DND-99 (LTRD) and Mito Tracker Deep Red (MTDR) were used as fluorescent probes for lysosomes and mitochondria, respectively. A549 cells were incubated with the target complex (10 μM) at 37°C for 1 hour, and then LTRD (500 nM) and MTDR (500 nM) probes were added for staining for 30 minutes. The cell plate was washed three times with phosphate buffer solution (PBS, pH: ~7.2) and then detected by confocal microscopy. The excitation wavelength of the target complex is 405 nm, and the collection wavelength is 500 ± 50 nm; the excitation wavelength of LTRD is 594 nm, and the collection wavelength is 630 ± 30 nm; MTDR is excited at 644 nm and the emission wavelength is 690 ± 30 nm. Test as Fig.17 As shown in the figure, the colocalization coefficients of complexes 3 and 4 in lysosomes were 0.77 and 0.76, respectively, while the colocalization coefficients in mitochondria were -0.05 and -0.01, respectively, confirming that the target complexes were mainly targeted to the lysosomal tissue of A549 cells. The morphological changes of lysosomes in A549 cells were detected by acridine orange (AO) staining. AO exhibits red fluorescence when accumulated in lysosomes and green fluorescence when bound to RNA in the nucleus or cytoplasm. A549 cells were colocalized with target complexes 3 and 4 (1.0×IC 50 and 3.0×IC 50 ) for 6 h, washed twice with PBS, added with AO (5 μM, 15 min), rinsed twice with PBS solution and observed under a microscope. The test data are shown in Fig.18 and Fig.19 As shown in Figure 3, AO in the control group without drug accumulation in lysosomes showed red fluorescence. 50 and 3.0×IC 50) for 6 h, the red fluorescence in the cells was significantly reduced compared with the control group, especially at 3.0×IC 50 This result shows that after treatment with the target complex, the lysosomes in A549 cells are severely damaged, leading to the death of cancer cells and achieving an anti-cancer effect.

Claims

1. A semi-sandwich structure metal iridium ferrocene pyridine complex, the structural formula of which is shown in formula (I): ； In formula (I), R is selected from methyl, phenyl or biphenyl, and the double bond contains both cis and trans conformations; When R is a methyl group and the double bonds are connected in a trans configuration, the specific structural formula is shown in formula (1); when R is a methyl group and the double bonds are connected in a cis configuration, the specific structural formula is shown in formula (2); when R is a phenyl group and the double bonds are connected in a trans configuration, the specific structural formula is shown in formula (3); when R is a phenyl group and the double bonds are connected in a cis configuration, the specific structural formula is shown in formula (4); when R is a biphenyl group and the double bonds are connected in a trans configuration, the specific structural formula is shown in formula (5); when R is a biphenyl group and the double bonds are connected in a cis configuration, the specific structural formula is shown in formula (6); 。 2. A method for preparing the half-sandwich structure iridium ferrocene pyridine complex according to claim 1, characterized in that: The following steps are involved: The 4-pyridinecarboxaldehyde shown in formula (III) and the ferrocenylmethyltriphenylphosphine hydrobromide shown in formula (IV) are reacted by Wittig reaction to obtain the ferrocenylpyridine compound shown in formula (II), which is then reacted with the basic iridium dimer shown in formula (V) to obtain the target complex shown in formula (I). The specific reaction route is as follows: 。 3. The preparation method according to claim 2, characterized in that: When the complex is of formula (1), it is prepared by the following method: (1) Add 0.25 g of hydrated iridium trichloride, 0.33 mL of 1,2,3,4,5-pentamethylcyclopentadiene and 30 mL of methanol to the inner tank of the microwave digestion instrument, dissolve by ultrasonication, evacuate and pass nitrogen, and assemble the main tank and the standard tank; set the parameters of the microwave digestion instrument: first, heat to 395 K for 20 min, then heat to 425 K for 20 min, and ramp time is 5 min; then filter the reaction liquid to remove unreacted iridium trichloride, and remove the solvent by vacuum distillation; add methanol to the tank to dissolve the product, and then add ether for diffusion and purification to obtain an orange-yellow base metal iridium dimer (V) with R as methyl; (2) Add 0.49 g of ferrocenylmethyltriphenylphosphine hydrobromide (IV) to a 100 mL Schlenk bottle, evacuate and fill with nitrogen, add 20 mL of anhydrous tetrahydrofuran, and cool to 0 °C; add dropwise 20 mL of anhydrous tetrahydrofuran solution containing 0.18 g of potassium tert-butoxide, stir for 30 min, add dropwise 15 mL of anhydrous tetrahydrofuran solution containing 0.10 g of 4-pyridinecarboxaldehyde (III), react at low temperature for 1 h, and then warm to room temperature for reaction; after the reaction is completed, monitor with thin layer chromatography, the developing solvent is dichloromethane: methanol: triethylamine = 2 mL: 2 drops: 1 drop, add 40 mL of saturated brine to quench the reaction, and 1.0 mol L -1 The pH of the reaction solution was adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate, separated, the organic layers were combined, washed with water, dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a yellow solid crude product containing cis and trans conformations; purified by column chromatography, the eluent was petroleum ether: ethyl acetate = 10:1, the same components were combined, and distilled under reduced pressure to obtain an orange-red solid (L1); (3) 60.0 mg of the base metal iridium dimer (V) with R being methyl and 43.6 mg of the ferrocenylpyridine ligand (L1) were placed in a 100 mL Shrek bottle, evacuated and nitrogen was passed through. 30 mL of dichloromethane was injected as the reaction solvent using a syringe. The mixture was stirred at room temperature for 24 h, and the solvent was removed by vacuum distillation to obtain a crude orange-red solid powder product. A small amount of dichloromethane was used to dissolve the product, and n-hexane was added to diffuse the product to obtain the target product (1) in orange-red crystals.

4. The preparation method according to claim 2, characterized in that: When the complex is of formula (2), it is prepared by the following method: (1) Add 0.25 g of hydrated iridium trichloride, 0.33 mL of 1,2,3,4,5-pentamethylcyclopentadiene and 30 mL of methanol to the inner tank of the microwave digestion instrument, dissolve by ultrasonication, evacuate and pass nitrogen, and assemble the main tank and the standard tank; set the parameters of the microwave digestion instrument: first, heat to 395 K for 20 min, then heat to 425 K for 20 min, and ramp time is 5 min; then filter the reaction liquid to remove unreacted iridium trichloride, and remove the solvent by vacuum distillation; add methanol to the tank to dissolve the product, and then add ether for diffusion and purification to obtain an orange-yellow base metal iridium dimer (V) with R as methyl; (2) Add 0.49 g of ferrocenylmethyltriphenylphosphine hydrobromide (IV) to a 100 mL Schlenk bottle, evacuate and fill with nitrogen, add 20 mL of anhydrous tetrahydrofuran, and cool to 0 °C; add dropwise 20 mL of anhydrous tetrahydrofuran solution containing 0.18 g of potassium tert-butoxide, stir for 30 min, add dropwise 15 mL of anhydrous tetrahydrofuran solution containing 0.10 g of 4-pyridinecarboxaldehyde (III), react at low temperature for 1 h, and then warm to room temperature for reaction; after the reaction is completed, monitor with thin layer chromatography, the developing solvent is dichloromethane: methanol: triethylamine = 2 mL: 2 drops: 1 drop, add 40 mL of saturated brine to quench the reaction, and 1.0 mol L -1 The pH of the reaction solution was adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate, separated, the organic layers were combined, washed with water, dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a yellow solid crude product containing cis and trans conformations; purified by column chromatography, the eluent was petroleum ether: ethyl acetate = 10:1, the same components were combined, and distilled under reduced pressure to obtain an orange-yellow solid (L2); (3) 60.0 mg of the base metal iridium dimer (V) with R being methyl and 43.6 mg of the ferrocenylpyridine ligand (L2) were placed in a 100 mL Shrek bottle, evacuated and nitrogen was passed through. 30 mL of dichloromethane was injected as the reaction solvent using a syringe. The mixture was stirred at room temperature for 24 h, and the solvent was removed by vacuum distillation to obtain a crude orange-red solid powder product. A small amount of dichloromethane was used to dissolve the product, and n-hexane was added to diffuse the product to obtain the target product (2) as orange-red crystals.

5. The preparation method according to claim 2, characterized in that: When the complex is of formula (3), it is prepared by the following method: (1) Add 0.25 g of hydrated iridium trichloride, 0.44 g of 1-phenyl-2,3,4,5-tetramethylcyclopentadiene and 30 mL of methanol to the inner tank of the microwave digestion instrument, dissolve by ultrasonication, evacuate and pass nitrogen, and assemble the main tank and the standard tank; set the parameters of the microwave digestion instrument: first, heat to 395 K for reaction for 20 min, then heat to 425 K for further reaction for 20 min, and the ramp time is 5 min; then filter the reaction liquid to remove the unreacted iridium trichloride, and remove the solvent by vacuum distillation; add methanol to the tank to dissolve the product, and then add ether for diffusion and purification to obtain an orange-yellow base metal iridium dimer (V) with R as phenyl; (2) Add 0.49 g of ferrocenylmethyltriphenylphosphine hydrobromide (IV) to a 100 mL Schlenk bottle, evacuate and fill with nitrogen, add 20 mL of anhydrous tetrahydrofuran, and cool to 0 °C; add dropwise 20 mL of anhydrous tetrahydrofuran solution containing 0.18 g of potassium tert-butoxide, stir for 30 min, add dropwise 15 mL of anhydrous tetrahydrofuran solution containing 0.10 g of 4-pyridinecarboxaldehyde (III), react at low temperature for 1 h, and then warm to room temperature for reaction; after the reaction is completed, monitor with thin layer chromatography, the developing solvent is dichloromethane: methanol: triethylamine = 2 mL: 2 drops: 1 drop, add 40 mL of saturated brine to quench the reaction, and 1.0 mol L -1 The pH of the reaction solution was adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate, separated, the organic layers were combined, washed with water, dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a yellow solid crude product containing cis and trans conformations; purified by column chromatography, the eluent was petroleum ether: ethyl acetate = 10:1, the same components were combined, and distilled under reduced pressure to obtain an orange-red solid (L1); (3) 60.0 mg of the base metal iridium dimer (V) in which R is phenyl and 37.7 mg of the ferrocenyl bipyridine ligand (L1) were placed in a 100 mL Shrek bottle, evacuated and nitrogen was passed through. 30 mL of dichloromethane was injected as the reaction solvent using a syringe. The mixture was stirred at room temperature for 24 h. The solvent was removed by vacuum distillation to obtain a crude orange-red powder product. A small amount of dichloromethane was added to dissolve the product. After diffusion with n-hexane, the target product (3) was obtained as orange-red crystals.

6. The preparation method according to claim 2, characterized in that: When the complex is of formula (4), it is prepared by the following method: (1) Add 0.25 g of hydrated iridium trichloride, 0.44 g of 1-phenyl-2,3,4,5-tetramethylcyclopentadiene and 30 mL of methanol to the inner tank of the microwave digestion instrument, dissolve by ultrasonication, evacuate and pass nitrogen, and assemble the main tank and the standard tank; set the parameters of the microwave digestion instrument: first, heat to 395 K for reaction for 20 min, then heat to 425 K for further reaction for 20 min, and the ramp time is 5 min; then filter the reaction liquid to remove the unreacted iridium trichloride, and remove the solvent by vacuum distillation; add methanol to the tank to dissolve the product, and then add ether for diffusion and purification to obtain an orange-yellow base metal iridium dimer (V) with R as phenyl; (2) Add 0.49 g of ferrocenylmethyltriphenylphosphine hydrobromide (IV) to a 100 mL Schlenk bottle, evacuate and fill with nitrogen, add 20 mL of anhydrous tetrahydrofuran, and cool to 0°C; add dropwise 20 mL of anhydrous tetrahydrofuran solution containing 0.18 g of potassium tert-butoxide, stir for 30 min, add dropwise 15 mL of anhydrous tetrahydrofuran solution containing 0.10 g of 4-pyridinecarboxaldehyde (III), react at low temperature for 1 h, and then warm to room temperature for reaction; after the reaction is completed, monitor with thin layer chromatography, the developing solvent is dichloromethane: methanol: triethylamine = 2 mL: 2 drops: 1 drop, add 40 mL of saturated brine to quench the reaction, and 1.0 mol L -1 The pH of the reaction solution was adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate, separated, the organic layers were combined, washed with water, dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a yellow solid crude product containing cis and trans conformations; purified by column chromatography, the eluent was petroleum ether: ethyl acetate = 10:1, the same components were combined, and distilled under reduced pressure to obtain an orange-yellow solid (L2); (3) 60.0 mg of the base metal iridium dimer (V) in which R is phenyl and 37.7 mg of the ferrocenyl bipyridine ligand (L2) were placed in a 100 mL Shrek bottle, evacuated and nitrogen was passed through. 30 mL of dichloromethane was injected as the reaction solvent using a syringe. The mixture was stirred at room temperature for 24 h. The solvent was removed by vacuum distillation to obtain a crude orange-red powder product. A small amount of dichloromethane was added to dissolve the product. After diffusion, n-hexane was added to obtain the target product (4) as orange-red crystals.

7. The preparation method according to claim 2, characterized in that: When the complex is of formula (5), it is prepared by the following method: (1) Add 0.25 g of hydrated iridium trichloride, 0.65 g of 1-biphenyl-2,3,4,5-tetramethylcyclopentadiene and 30 mL of methanol to the inner tank of the microwave digestion instrument, dissolve by ultrasonication, evacuate and pass nitrogen, and assemble the main tank and the standard tank; set the parameters of the microwave digestion instrument: first, heat to 395 K for reaction for 20 min, then heat to 425 K for further reaction for 20 min, and the ramp time is 5 min; then filter the reaction liquid to remove the unreacted iridium trichloride, and remove the solvent by vacuum distillation; add methanol to the tank to dissolve the product, and then add ether for diffusion and purification to obtain the orange-yellow base metal iridium dimer (V) with R as biphenyl; (2) Add 0.49 g of ferrocenylmethyltriphenylphosphine hydrobromide (IV) to a 100 mL Schlenk bottle, evacuate and fill with nitrogen, add 20 mL of anhydrous tetrahydrofuran, and cool to 0 °C; add dropwise 20 mL of anhydrous tetrahydrofuran solution containing 0.18 g of potassium tert-butoxide, stir for 30 min, add dropwise 15 mL of anhydrous tetrahydrofuran solution containing 0.10 g of 4-pyridinecarboxaldehyde (III), react at low temperature for 1 h, and then warm to room temperature for reaction; after the reaction is completed, monitor with thin layer chromatography, the developing solvent is dichloromethane: methanol: triethylamine = 2 mL: 2 drops: 1 drop, add 40 mL of saturated brine to quench the reaction, and 1.0 mol L -1 The pH of the reaction solution was adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate, separated, the organic layers were combined, washed with water, dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a yellow solid crude product containing cis and trans conformations; purified by column chromatography, the eluent was petroleum ether: ethyl acetate = 10:1, the same components were combined, and distilled under reduced pressure to obtain an orange-red solid (L1); (3) 60.0 mg of the base metal iridium dimer (V) with R = biphenyl and 32.37 mg of the ferrocenylpyridine ligand (L1) were placed in a 100 mL Shrek bottle, evacuated and nitrogen was passed through. 30 mL of dichloromethane was injected as the reaction solvent using a syringe. The mixture was stirred at room temperature for 24 h. The solvent was removed by vacuum distillation to obtain a crude orange-red powder product. A small amount of dichloromethane was added to dissolve the product. After diffusion, n-hexane was added to obtain the target product (5) as orange-red crystals.

8. The preparation method according to claim 2, characterized in that: When the complex is of formula (6), it is prepared by the following method: (1) Add 0.25 g of hydrated iridium trichloride, 0.65 g of 1-biphenyl-2,3,4,5-tetramethylcyclopentadiene and 30 mL of methanol to the inner tank of the microwave digestion instrument, dissolve by ultrasonication, evacuate and pass nitrogen, and assemble the main tank and the standard tank; set the parameters of the microwave digestion instrument: first, heat to 395 K for reaction for 20 min, then heat to 425 K for further reaction for 20 min, and the ramp time is 5 min; then filter the reaction liquid to remove the unreacted iridium trichloride, and remove the solvent by vacuum distillation; add methanol to the tank to dissolve the product, and then add ether for diffusion and purification to obtain the orange-yellow base metal iridium dimer (V) with R as biphenyl; (2) Add 0.49 g of ferrocenylmethyltriphenylphosphine hydrobromide (IV) to a 100 mL Schlenk bottle, evacuate and fill with nitrogen, add 20 mL of anhydrous tetrahydrofuran, and cool to 0 °C; add dropwise 20 mL of anhydrous tetrahydrofuran solution containing 0.18 g of potassium tert-butoxide, stir for 30 min, add dropwise 15 mL of anhydrous tetrahydrofuran solution containing 0.10 g of 4-pyridinecarboxaldehyde (III), react at low temperature for 1 h, and then warm to room temperature for reaction; after the reaction is completed, monitor with thin layer chromatography, the developing solvent is dichloromethane: methanol: triethylamine = 2 mL: 2 drops: 1 drop, add 40 mL of saturated brine to quench the reaction, and 1.0 mol L -1 The pH of the reaction solution was adjusted to neutral with dilute hydrochloric acid, extracted with ethyl acetate, separated, the organic layers were combined, washed with water, dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a yellow solid crude product containing cis and trans conformations; purified by column chromatography, the eluent was petroleum ether: ethyl acetate = 10:1, the same components were combined, and distilled under reduced pressure to obtain an orange-yellow solid (L2); (3) 60.0 mg of the base metal iridium dimer (V) with biphenyl as R and 32.37 mg of the ferrocenylpyridine ligand (L2) were placed in a 100 mL Shrek bottle, evacuated and nitrogen was passed through. 30 mL of dichloromethane was injected as the reaction solvent using a syringe. The mixture was stirred at room temperature for 24 h. The solvent was removed by vacuum distillation to obtain a crude orange-red powder product. A small amount of dichloromethane was added to dissolve the product. After diffusion with n-hexane, the target product (6) was obtained as orange-red crystals.

9. Use of a half-sandwich structure iridium ferrocene pyridine complex prepared by the preparation method according to any one of claims 2 to 8 in the preparation of anti-tumor drugs, wherein the tumor cells are epithelial cancer cells or cervical cancer cells.

Images