Preparation method of phenanthrene benzofuran compound
By reacting biphenylbenzofuran compounds with oxidants under ultraviolet light irradiation, the harsh reaction conditions and environmental pollution problems of existing synthetic methods have been solved, and the efficient synthesis and potential anti-tumor activity of phenanthrenebenzofuran compounds have been achieved.
Patent Information
- Application Number
- CN202511568208.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-10-30
- Publication Date
- 2026-01-13
AI Technical Summary
Existing methods for synthesizing phenanthrene-benzofuran compounds mostly rely on transition metal catalysts or strong acid catalytic systems, which have problems such as harsh reaction conditions, significant environmental pollution, and complex post-processing.
Phenanthene-benzofuran compounds are synthesized by reacting biphenylbenzofuran compounds with an oxidant under ultraviolet light irradiation, through photo-oxidative cyclization and photo-1,5-hydrogen migration reactions, avoiding the use of transition metal catalysts and acid catalysts, and using solvents such as dioxane and elemental iodine.
This provides a mild, safe, and efficient synthesis method that reduces catalyst costs, minimizes environmental pollution, is suitable for industrial production, and exhibits potential antitumor activity.
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Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of organic synthesis, and relates to a preparation method of a phenanthrobenzofuran compound. BACKGROUND
[0002] Phenanthrobenzofuran compounds are complex polycyclic aromatic hydrocarbon structures fused by a phenanthrene ring and a benzofuran ring, and are widely present in many natural products and drug molecules with biological activity. The compounds are found to have biological activities such as anticancer, antibacterial and antioxidant.
[0003] The prior art has developed various methods for synthesizing phenanthrobenzofuran compounds. For example, document 1: doi.10.1021 / acsomega.8b02345. Document 1 synthesizes the compounds by a ketone-catalyzed oxygen-iodine exchange method, using a cyclic diaryl iodide triflate and water as raw materials, and the specific synthesis route is as shown below:
[0004] .
[0005] Document 2: doi.10.1002 / chem.201501116. Document 2 adopts a palladium-catalyzed intramolecular oxidative C-H coupling reaction to construct phenanthrobenzofuran compounds, and the specific synthesis route is as shown below:
[0006] .
[0007] Document 3: doi.org / 10.1002 / ejoc.202200600. Document 3 realizes the synthesis of the compounds by an acid-catalyzed continuous aryl C-F bond activation, and the specific synthesis route is as shown below:
[0008] .
[0009] However, the current synthesis methods mostly rely on transition metal catalysts or strong acid catalytic systems, and have problems such as harsh reaction conditions, serious environmental pollution and complex post-processing. SUMMARY
[0010] In order to solve the technical problems that the existing synthesis methods mostly rely on transition metal catalysts or strong acid catalytic systems, and have problems such as harsh reaction conditions, serious environmental pollution and complex post-processing, the application provides a phenanthrobenzofuran compound, a preparation method and application thereof.
[0011] A first object of the application is to provide a preparation method of a phenanthrobenzofuran compound, comprising the following steps: The biphenyl benzofuran compound, the oxidizing agent and the solvent are mixed, the biphenyl benzofuran compound is subjected to photo-oxidation cyclization reaction under the action of the ultraviolet light and the oxidizing agent, and a phenanthrobenzofuran compound is obtained; the specific reaction formula is as follows: ; In the formula, R is H or -OCH3.
[0012] The specific reaction mechanism of the phenanthrobenzofuran compound is as follows: under the irradiation of ultraviolet light, the biphenyl benzofuran compound is subjected to photo-6π electrocyclization reaction to generate an intermediate A, the intermediate A is subjected to photo-1,5-hydrogen shift reaction under the action of the ultraviolet light to generate an intermediate B; the intermediate B is subjected to dehydrogenation reaction under the action of the activated iodine element under the light irradiation condition, and the phenanthrobenzofuran compound is obtained. The specific reaction process is as follows:
[0013] .
[0014] In the formula, hv represents ultraviolet light irradiation.
[0015] Preferably, the molar ratio of the biphenyl benzofuran compound and the oxidizing agent is 1:0.5-1.
[0016] Preferably, the concentration of the biphenyl benzofuran compound in the solvent is 5×10 -3 mol / L-5×10 -1 mol / L. When the concentration is too high or too low, the yield of the synthesized phenanthrobenzofuran compound is very low.
[0017] Preferably, the oxidizing agent is iodine element, hydrogen peroxide or potassium permanganate.
[0018] Preferably, the ultraviolet light irradiation is provided by a light source with a wavelength of 365 nm-450 nm, and the time of the ultraviolet light irradiation is 1 h-10 h.
[0019] Preferably, the solvent is dioxane, dichloromethane, trichloromethane, ethanol or n-hexane.
[0020] Preferably, the specific preparation method of the phenanthrobenzofuran compound is as follows: After the biphenyl benzofuran compound is dissolved in the solvent, the oxidizing agent is added, the oxidizing agent is uniformly dispersed by stirring, and then the biphenyl benzofuran compound is subjected to photo-oxidation cyclization reaction under the ultraviolet light irradiation, and the phenanthrobenzofuran compound is obtained.
[0021] The second object of the present application is to provide the use of the above-mentioned phenanthrobenzofuran compound in the preparation of an antitumor drug.
[0022] Compared with the prior art, the present application has the following technical effects: The present application provides a novel method for synthesizing phenanthrobenzofuran compounds with mild reaction conditions and high safety and efficiency. The present application uses a biphenylbenzofuran compound as a raw material, mixes the raw material, an oxidizing agent and a solvent, and under the action of the oxidizing agent and under the condition of ultraviolet light irradiation, the raw material undergoes a photo-oxidation cyclization reaction to obtain a phenanthrobenzofuran compound. The present application does not need to use a transition metal catalyst or an acid catalyst, thereby reducing the cost of the catalyst, avoiding the influence of metal ion residues on the purity of the product, and reducing the environmental pollution caused by harmful catalysts. The present application solves the technical problems of the existing synthesis methods, which are mostly dependent on transition metal catalysts or strong acid catalytic systems, and have harsh reaction conditions, serious environmental pollution and complex post-processing.
[0023] The reaction of the present application uses light as an energy source, is simple to operate, has mild reaction conditions, does not need high temperature and high pressure, is easy to control, and is suitable for industrial production. The synthesized phenanthrobenzofuran compounds of the present application show potential antitumor activity. DETAILED DESCRIPTION
[0024] In order to enable those skilled in the art to better understand the technical solutions of the present application and implement them, the present application will be further described below in combination with specific examples.
[0025] In the description of the present application, unless otherwise specified, all reagents used are commercially available, and all methods used are conventional techniques in the art.
[0026] Example 1 A method for preparing a phenanthrobenzofuran compound, comprising the following steps: Take 3-([1,1'-biphenyl]-2-yl)benzofuran as a raw material, add 1.0 mmol of the raw material and 20 mL of dioxane into a 100 mL reaction bottle in sequence, magnetically stir to completely dissolve the raw material, to obtain a solution with a concentration of 5×10 -2 mol / L; add 0.1 mmol of iodine to the above solution, continue to stir for 5 minutes to uniformly disperse the iodine; place the reaction bottle under a 365 nm ultraviolet lamp, keep the distance between the lamp and the reaction liquid surface at 10 cm, turn on the ultraviolet lamp to irradiate, and continuously stir for 2 hours; after the reaction is completed, remove the solvent by rotary evaporation to obtain a crude product; separate the crude product by silica gel column chromatography; wherein the eluent is petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 10:1, to obtain a white solid, i.e. phenanthrobenzofuran; the yield is 89%, and the synthesis route is shown below: .
[0027] Example 2 A method for preparing a phenanthrobenzofuran compound, comprising the following steps: The difference from Example 1 is: A phenanthrobenzofuran compound is prepared by using 3-(4'-methoxy-[1,1'-biphenyl]-2-yl)benzofuran as a raw material, and the synthesis route is shown as follows: .
[0028] Example 3 A method for preparing a phenanthrobenzofuran compound is basically the same as that of Example 1, and the difference is that the parameters for preparing the phenanthrobenzofuran compound are different, including the reaction solvent, the concentration of the reaction solvent, the oxidant and the reaction time, and the specific conditions are shown in Table 1: Table 1. Preparation parameters of phenanthrobenzofuran compounds This example refers to the preparation method of Example 1, and by changing the reaction solvent, the concentration of the reaction solvent, the oxidant and the reaction time, the influence of the reaction conditions on the yield of the synthesis of phenanthrobenzofuran compounds is explored.
[0029] From Table 1, it can be seen that the best reaction condition is to use dioxane as the reaction solvent, the concentration of the raw material is 5×10 -2 , the reaction time is 2 hours, the lamp of 365 nm is the radiation source, and the iodine element is the oxidant for photochemical reaction to synthesize phenanthrobenzofuran with a higher yield.
[0030] The phenanthrobenzofuran compounds prepared in Examples 1 and 2 are verified by nuclear magnetic resonance, and the nuclear magnetic resonance data are as follows: The nuclear magnetic hydrogen spectrum data of the phenanthrobenzofuran prepared in Example 1 are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.84 - 8.73 (m, 2H), 8.66 (d, J =8.0 Hz, 1H), 8.53 (m, 1H), 8.40 (m, 1H), 7.84 - 7.62 (m, 5H), 7.51 (m, 2H).
[0031] The nuclear magnetic carbon spectrum data are as follows: 13C NMR (101 MHz, Chloroform-d) δ 156.09, 151.45, 130.81, 128.81,128.42, 127.69, 127.41, 127.34, 125.84, 125.70, 125.35, 124.39, 124.01,123.67, 123.61, 122.46, 122.00, 121.94, 114.60, 112.23. The nuclear magnetic hydrogen spectrum data of the phenanthrobenzofuran prepared in Example 1 is as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.73 - 8.59 (m, 3H), 8.40 (d, J =6.7 Hz, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.78 (d, J = 7.1 Hz, 1H), 7.73 (t, J =7.4 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.51 (m, 2H), 7.34 (dd, J = 9.1, 2.5Hz, 1H), 4.08 (s, 3H). The nuclear magnetic carbon spectrum data is as follows: 13 C NMR (101 MHz, Chloroform-d) δ 159.10, 156.01, 151.13, 128.54,127.60, 126.64, 125.93, 125.71, 125.42, 125.36, 125.03, 124.32, 123.59,123.57, 123.44, 122.10, 117.95, 115.04, 112.13, 102.02, 55.85. Application experiment: The phenanthrobenzofuran compounds prepared in Example 1 to Example 2 were subjected to anti-tumor cell activity determination, and the specific method was as follows: Inoculation of cells: a single cell suspension was prepared by using culture solution (DMEM or RMPI1640) containing 10% fetal bovine serum, and was inoculated into a 96-well plate at a density of 3000 cells / well to 15000 cells / well, with a volume of 100 μL per well. The cell plate was placed in a 37°C incubator for 12 hours to 24 hours to allow the cells to adhere and recover growth.
[0032] The phenanthrobenzo-furan compound is dissolved in DMSO and added to the cell culture plate, so that the initial screening concentration is 40 μM, and the final volume of each well is 200 μL. The final volume of each well is 200 μL, and 3 replicates are set for each treatment.
[0033] Color development: after incubation at 37°C for 48 hours, the adherent cells are discarded from the culture medium in the well, then 20 μL of MTS solution and 100 μL of culture medium are added to each well; the suspended HL-60 cells are discarded from 100 μL of culture supernatant, 20 μL of MTS solution is added to each well; and 3 blank replicates without cells are set, containing only 20 μL of MTS solution and 100 μL of culture medium, and incubation is continued for 2-4 hours to allow the reaction to proceed fully before measuring the optical absorption value.
[0034] Colorimetry: select 492 nm wavelength, multifunctional enzyme label instrument (read the optical absorption value of each well, record the results, and after data processing, draw the cell inhibition rate graph with compound number as horizontal coordinate and cell inhibition rate as vertical coordinate.
[0035] Positive control compounds: two positive compounds, cisplatin (DDP) and paclitaxel (Taxol), are set for each experiment, and the cell growth curve is drawn with concentration as horizontal coordinate and cell survival rate as vertical coordinate, and the calculation results are shown in Table 2.
[0036] Table 2 Inhibition rate of antitumor activity Note: Average represents the average value; SD represents the standard deviation.
[0037] As shown in Table 2, the phenanthrobenzo-furan compound synthesized in Example 1 shows a good inhibition rate of greater than 40% on leukemia HL-60, and the phenanthrobenzo-furan compound synthesized in Example 2 shows a good inhibition rate on hepatoma SMMC-7721. It can be seen that the phenanthrobenzo-furan compound synthesized in the examples of the present application exhibits potential antitumor activity.
[0038] It should be noted that when numerical ranges are involved in the present application, both endpoints of each numerical range and any number between the two endpoints can be selected. Since the same steps and examples are used, the preferred examples are described in the present application to prevent redundancy. Although the preferred examples of the present application have been described, additional changes and modifications can be made to these examples by those skilled in the art once they know the basic inventive concept, and these changes and modifications fall within the scope of the present application.
[0039] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. If these modifications and variations fall within the scope of equivalents of this invention, then this invention also intends to include these modifications and variations.
Claims
1. A method for producing a phenanthropyrano-furan compound, characterized by, The method comprises the following steps: The biphenyl benzofuran compound, the oxidizing agent and the solvent are mixed, the biphenyl benzofuran compound is subjected to photo-oxidation cyclization reaction under the action of the ultraviolet light and the oxidizing agent, and a phenanthrobenzofuran compound is obtained; the specific reaction formula is as follows: ； In the formula, R is H or -OCH3.
2. The method for preparing phenanthrenebenzofuran compounds according to claim 1, characterized in that, The molar ratio of the biphenyl benzofuran compound and the oxidizing agent is 1:0.5-1.
3. The method of claim 1, wherein the method is represented by the following scheme: ###0001### Scheme 1 The concentration of the biphenyl benzofuran compound in the solvent is 5 x 10 -3 mol / L to 5 x 10 -1 mol / L.
4. The method of claim 1, wherein the method is represented by the following scheme: ###0001### Scheme 1 The oxidizing agent is elemental iodine, potassium permanganate or hydrogen peroxide.
5. The method of claim 1, wherein the method is represented by the following scheme: ###0001### Scheme 1 The ultraviolet light is provided by a light source with a wavelength of 365-450 nm, and the ultraviolet light irradiation time is 1-10 h.
6. The method of claim 1, wherein the method is represented by the following scheme: ###0001### Scheme 1 The solvent is dioxane, dichloromethane, trichloromethane, ethanol or n-hexane.
7. The method for preparing phenanthrenebenzofuran compounds according to claim 1, characterized in that, The specific preparation method of the phenanthrobenzofuran compound is as follows: After the biphenyl benzofuran compound is dissolved in the solvent, the oxidizing agent is added, the oxidizing agent is uniformly dispersed by stirring, then the biphenyl benzofuran compound is subjected to photo-oxidation cyclization reaction under the action of the ultraviolet light, and a phenanthrobenzofuran compound is obtained.