A flavonoid derivative, its microwave preparation method and application

Abstract

The present invention discloses a flavonoid derivative, its microwave preparation method and application, belonging to the technical field of pharmaceutical chemistry. It includes the following steps: S1. Prepare an α-diazo carbonyl compound from a 1-phenyl-2-propanone compound through a diazotization transfer reaction; S2. Heat and react the α-diazo carbonyl compound and 3-hydroxyflavone in a microwave to prepare a flavonoid derivative. The solution of the present invention is applicable to the Wolff rearrangement reaction of α-diazo compounds and alcohol compounds in a microwave, without the need to use traditional kettle reactions, catalysts and excessive substrates, and has the advantages of simple operation, rapid reaction, few by-products, high yield, less time and a wide range of substrate applicability. Moreover, the prepared flavonoid ester compound has excellent anti-cancer effects.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a flavone derivative, a microwave preparation method thereof, and an application thereof. Background Art

[0002] Cancer is one of the main threats to human life and health. As small-molecule natural plant metabolites, flavonoids have various biological activities such as anti-tumor, anti-inflammatory, and antioxidant, and have low toxicity. Therefore, they have great utilization space in terms of pharmacological properties. At present, many flavonoids have shown safety and effectiveness in the treatment of tumors. There have been relevant studies on using diazo compounds to carry out Wolff rearrangement reactions to complete related esterification reactions to obtain flavonoids. However, there are the following defects:

[0003] α-Diazo compounds are very reactive compounds. If the reaction conditions are not mild enough, the diazo group may directly undergo a substitution reaction rather than a rearrangement, thereby increasing side reactions and reducing the yield. Under pyrolysis conditions, if the temperature is not properly controlled, the substrate may degrade, resulting in impure products. For some α-diazo compounds with special spatial structures, traditional silver ion catalysts may not be able to effectively catalyze the Wolff rearrangement, leading to reaction failure, wasting raw materials and time. Moreover, silver ion catalysts are expensive, increasing the cost. The reaction of α-diazo compounds to eliminate nitrogen under heating, light, or transition metal catalysis conditions, form carbenes, and then undergo 1,2-rearrangement to obtain intermediate ketenes is explosive. If not properly handled during the reaction, it may trigger safety accidents and pose a threat to laboratory personnel and the environment.

[0004] Therefore, when carrying out the Wolff rearrangement reaction, it is necessary to strictly control the reaction conditions to ensure the safety and effectiveness of the reaction. At the same time, how to simplify the operation, reduce costs, and increase the yield is also an urgent problem to be solved at present. Summary of the Invention

[0005] The purpose of the present invention is to provide a flavone derivative, a microwave preparation method thereof, and an application thereof, to solve the problems of α-diazo compounds in Wolff in the above-mentioned background art, and can complete the transformation quickly, with few by-products and high yield, improving the safety and effectiveness of the reaction, reducing the harm to the body and the environment. At the same time, it does not require traditional autoclave reactions, catalysts, and excessive substrates, and has simple operation and reduced costs.

[0006] To achieve the above purpose, the present invention provides a flavone derivative, and the structural formula of the flavone derivative is:

[0007]

[0008] Among them, R1 is one of an unsaturated hydrocarbon group, a hydrocarbon group, a cycloaliphatic hydrocarbon, a halogen, a heterocycle or a heteroaromatic hydrocarbon; R2 is one of an unsaturated hydrocarbon group, a hydrocarbon group, a cycloaliphatic hydrocarbon, a halogen, a heterocycle or a heteroaromatic hydrocarbon.

[0009] Preferably, the R1 is one of H, F, Cl, Br, and so on.

[0010] Preferably, the R2 is: and so on.

[0011] The present invention also provides a microwave preparation method of the above flavone derivative, comprising the following steps:

[0012] S1. Prepare an α-diazo carbonyl compound from a 1-phenyl-2-propanone compound through a diazotization transfer reaction;

[0013] S2. React the α-diazo carbonyl compound and 3-hydroxyflavone by heating in a microwave to prepare a flavone derivative.

[0014] Preferably, the specific operation of step S1 is:

[0015] Add 5 ml of CH3CN to a round-bottom flask, and drop 2.6 mmol of 1,8-diazabicycloundec-7-ene into the solvent of 2 mmol of 1-phenyl-2-propanone compound and 2.4 mmol of p-acetamidobenzenesulfonyl azide at 0 °C. Restore to room temperature and stir overnight, quench with 10% NaOH, extract twice with 5 ml of methyl tert-butyl ether, and use an eluent to elute and separate to obtain a yellow solid α-diazo carbonyl compound;

[0016] The chemical reaction formula is as follows:

[0017]

[0018] Preferably, the mass fraction of the NaOH is 10%, and the eluent is a PE / EA mixed solvent with a volume ratio of 10:1.

[0019] Preferably, the specific operation of step S2 is:

[0020] Add 1 mmol of α-diazo carbonyl compound and 1 mmol of 3-hydroxyflavone to a microwave reaction tube, dissolve them in 4 mL of methyl tert-butyl ether solvent, heat to 120 °C, react for 40 min, and use an eluent to elute and separate to obtain a colorless transparent solid;

[0021] The chemical reaction formula is as follows:

[0022]

[0023] Preferably, the eluent is a mixed solvent of PE / EA with a volume ratio of 10:1.

[0024] Therefore, the present invention provides a flavonoid derivative, its microwave preparation method and application, having the following beneficial effects:

[0025] (1) Microwave heating can achieve direct energy transfer, featuring fast heating speed, high thermal energy utilization rate, and sensitive reaction.

[0026] (2) It solves the problems of complex reaction conditions and cumbersome treatment process existing in the Wolff rearrangement reaction of α-diazo compounds, can complete the conversion quickly, improves the safety and effectiveness of the reaction, and reduces the harm to the body and the environment.

[0027] (3) The solution of the present invention is applicable to the Wolff rearrangement reaction of α-diazo compounds and alcohol compounds in microwave, without the need to use traditional autoclave reactions, catalysts, and excessive substrates. It has the advantages of simple operation, rapid reaction, few by-products, high yield, short time, and wide substrate applicability, and can be applied to the synthesis of unsaturated diazoketones. The synthesized flavonoid ester compounds have excellent anti-cancer effects.

[0028] The technical solution of the present invention will be further described in detail below through the drawings and examples. Description of the Drawings

[0029] Figure 1 1H nuclear magnetic resonance spectrum of the solid compound prepared in Example 1 of the present invention obtained under the conditions of 300 MHz and CDCl3 solvent;

[0030] Figure 2 13C nuclear magnetic resonance spectrum of the solid compound prepared in Example 1 of the present invention obtained under the conditions of 75 MHz and CDCl3 solvent;

[0031] Figure 3 1H nuclear magnetic resonance spectrum of the solid compound prepared in Example 2 of the present invention obtained under the conditions of 300 MHz and CDCl3 solvent;

[0032] Figure 4 13C nuclear magnetic resonance spectrum of the solid compound prepared in Example 2 of the present invention obtained under the conditions of 75 MHz and CDCl3 solvent;

[0033] Figure 5 1H nuclear magnetic resonance spectrum of the solid compound prepared in Example 3 of the present invention obtained under the conditions of 300 MHz and CDCl3 solvent;

[0034] Figure 613C NMR spectrum of the solid compound prepared in Example 3 of the present invention obtained under the conditions of 125 MHz and CDCl3 solvent;

[0035] Figure 7 1H NMR spectrum of the solid compound prepared in Example 4 of the present invention obtained under the conditions of 300 MHz and CDCl3 solvent;

[0036] Figure 8 13C NMR spectrum of the solid compound prepared in Example 4 of the present invention obtained under the conditions of 75 MHz and CDCl3 solvent;

[0037] Figure 9 1H NMR spectrum of the solid compound prepared in Example 5 of the present invention obtained under the conditions of 300 MHz and CDCl3 solvent;

[0038] Figure 10 13C NMR spectrum of the solid compound prepared in Example 5 of the present invention obtained under the conditions of 75 MHz and CDCl3 solvent;

[0039] Figure 11 1H NMR spectrum of the solid compound prepared in Example 6 of the present invention obtained under the conditions of 300 MHz and CDCl3 solvent;

[0040] Figure 12 13C NMR spectrum of the solid compound prepared in Example 6 of the present invention obtained under the conditions of 75 MHz and CDCl3 solvent. Detailed implementation manners

[0041] The technical solutions of the present invention will be further described below with reference to the drawings and examples.

[0042] The present invention will be further described below in conjunction with specific drawings and examples. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and shall be included in the protection scope of the present invention. In addition, it should be understood that after reading the content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application and belong to the protection scope of the present invention.

[0043] Reference to "embodiments" in this document means that the specific features, structures, or characteristics described in connection with the embodiments can be included in at least one embodiment of the present application. The term "embodiment" appearing at various positions in the specification does not necessarily refer to the same embodiment, nor is it particularly limited to the independence or relevance to other embodiments. In principle, in the present application, as long as there is no technical contradiction or conflict, the various technical features mentioned in each embodiment can be combined in any way to form corresponding implementable technical solutions.

[0044] Unless otherwise defined, the meanings of the technical terms used herein are the same as those commonly understood by those skilled in the technical field to which the present application belongs; the use of the relevant terms herein is only for describing specific embodiments and is not intended to limit the present application.

[0045] Unless otherwise specified in the present invention, the reagents, instruments, equipment, etc. used in the following embodiments are all the reagents, instruments, and equipment commonly used by those skilled in the art in this field.

[0046] The biological materials used for the determination of the cancer cell inhibitory performance of the flavonoid-derived compounds prepared in the following embodiments are: human early differentiated gastric cancer cells (SGC-7019), human cervical cancer cells (Hela), human breast cancer cells (MCF-7), human colon cancer cells (SW620), human lung cancer cells (A549), human liver cancer cells (HepG2), fetal bovine serum (FBS) were all purchased from Gibco (Grand Island, NY, USA), 100 IU / mL penicillin and 100 mg / mL streptomycin (Grand Island, NY, USA). The cells were cultured in RPMI-1640 or DMEM, DMEM (1×) (1% penicillin-streptomycin and 10% FBS) at 37 °C under 5% CO2 humidified conditions.

[0047] The method for the in vitro activity test of the compounds prepared in the following embodiments is:

[0048] Dissolve the prepared compound in DMSO and dilute it to 100 mmol / L. Uniformly seed the cells in the logarithmic growth phase in a 96-well plate, ensuring that the cell density is between 30% and 40%. After overnight cell culture, dilute the 100 mmol / L compound 1000-fold with the culture medium and treat the cells, placing them in 3 replicate wells. 5-Fluorouracil is used as the positive control, and DMSO at a concentration of one-thousandth is used as the blank. After 48 h of cell incubation, dissolve 1 mL of 5 mg / mL MTT solution in 15 mL of the culture medium. Remove the original culture medium in the 96-well plate, and add 150 μL of the MTT solution diluted with the culture medium to each well under light-proof conditions. Incubate at 37 °C for 4 h. Next, remove the MTT solution and add 150 μL of dimethyl sulfoxide (DMSO). Shake on a shaker for 5 min to ensure that formazan is completely dissolved in DMSO, and measure the absorbance at 492 nm using a microplate reader. Perform at least three independent experiments. Calculate the cell proliferation inhibition rate using the following formula based on the absorbance.

[0049] Inhibition rate (%) = (1 - OD 平均值 / OD 平均对照 ) × 100

[0050] where OD 平均值 is the average absorbance value of the test compound; OD 平均对照 is the average absorbance value of the blank control group.

[0051] Example 1

[0052] This example provides a preparation method of a flavonoid derivative. The specific structure of the prepared 4-oxo-2-phenyl-4H-chromen-3-yl 2-phenylpropionate is:

[0053]

[0054] The specific preparation method is as follows:

[0055] S1. Add 5 mL of CH3CN to a 25 mL round-bottom flask. At 0 °C, drop 2.6 mmol of 1,8-diazabicycloundec-7-ene (DBU) into the solvent of 2 mmol of 1-phenyl-2-propanone and 2.4 mmol of p-acetamidobenzenesulfonyl azide (p-ABSA). Restore to room temperature and stir overnight. Quench with 10% NaOH, extract twice with 5 mL of methyl tert-butyl ether, and use PE / EA = 10:1 as the eluent to separate the yellow solid diazo compound with a yield of 70%.

[0056] S2. In a 10 mL microwave reaction tube, add 1 mmol of 1-diazo-1-phenyl-2-propanone and 1 mmol of 3-hydroxyflavone dissolved in 4 mL of methyl tert-butyl ether. React under microwave heating to 120 °C for 40 min. The eluent is PE / EA = 10:1. A colorless transparent solid of 347 mg is separated, with a yield of 93.80% and a melting point of 151.4–153.2 °C.

[0057] The 1H NMR spectrum of the prepared solid compound obtained under the conditions of 300 MHz and CDCl3 solvent is as Figure 1 shown. It can be seen from Figure 1 this that 1 H NMR (300 MHz, Chloroform-d) δ 8.16 (dd, J = 8.0, 1.7 Hz, 1H), 7.59 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 7.51–7.39 (m, 3H), 7.35–7.19 (m, 7H), 7.17–7.08 (m, 2H), 4.01 (q, J = 7.2 Hz, 1H), 1.57 (d, J = 7.2 Hz, 3H).

[0058] The 13C NMR spectrum of the prepared solid compound obtained under the conditions of 75 MHz and CDCl3 solvent is as Figure 2 shown. It can be seen from Figure 2 this that 13 C NMR (75 MHz, CDCl3) δ 172.10, 171.36, 155.98, 155.55, 139.33, 133.89, 133.73, 130.90, 129.55, 128.72, 128.38, 128.12, 127.91, 127.34, 126.08, 125.14, 123.55, 118.06, 45.33, 18.35.

[0059] The inhibition rates of the compound prepared in this example against SW620 (human colon cancer cells), MCF-7 (human breast cancer cells), SGC-7019 (human early differentiated gastric cancer cells), and A549 (human lung cancer cells) are shown in Table 1, which are 81.27%, 84.56%, 82.80%, and 60.95% respectively, superior to 5-fluorouracil in Comparative Example 1 with 8.13%, 57.44%, 33.97%, and 34.23% respectively.

[0060] Example 2

[0061] This example provides a preparation method of a flavone derivative. The specific structure of the prepared 3-(4-chlorophenyl) propionate 4-oxo-2-phenyl-4H-chromen-3-yl ester is:

[0062]

[0063] The specific preparation method is as follows:

[0064] S1. Add 5 mL of CH3CN to a 25-mL round-bottom flask. At 0 °C, add 2.6 mmol of 1,8-diazabicycloundec-7-ene (DBU) dropwise to a solution of 2 mmol of 4-chlorophenylacetone and 2.4 mmol of p-acetamidobenzenesulfonyl azide (p-ABSA). Restore to room temperature and stir overnight. Quench with 10% NaOH, extract twice with 5 mL of methyl tert-butyl ether, and use a eluent of PE / EA = 10:1 to separate and obtain a yellow solid diazo compound with a yield of 70%.

[0065] S2. Add 1 mmol of 1-(4-chlorophenyl)-1-diazopropan-2-one and 1 mmol of 3-hydroxyflavone to a 10-mL microwave reaction tube, dissolve them in 4 mL of methyl tert-butyl ether, heat to 120 °C in a microwave for reaction for 40 min, and use a eluent of PE / EA = 10:1 to separate and obtain 364 mg of a colorless transparent solid with a yield of 90.09% and a melting point of 153.5–155.6 °C.

[0066] The 1H NMR spectrum of the obtained solid compound under the conditions of 300 MHz and CDCl3 solvent is as Figure 3 shown, and it can be seen from Figure 3 that 1 H NMR (300 MHz, Chloroform-d) δ 8.19 (dd, J = 8.0, 1.6 Hz, 1H), 7.64 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 7.53–7.41 (m, 3H), 7.43–7.30 (m, 2H), 7.24–7.11 (m, 6H), 3.98 (q, J = 7.2 Hz, 1H), 1.55 (d, J = 7.2 Hz, 3H).

[0067] The 13C NMR spectrum of the obtained solid compound under the conditions of 75 MHz and CDCl3 solvent is as Figure 4 shown, and it can be seen from Figure 4 that 13 C NMR (75 MHz, CDCl3) δ 172.06, 170.96, 156.25, 155.57, 137.85, 133.97, 133.56, 133.21, 131.03, 129.46, 129.22, 128.83, 128.38, 128.10, 126.05, 125.22, 123.51, 118.09, 44.68, 18.22.

[0068] The inhibitory rates of the compound prepared in this example against SW620 (human colon cancer cells), MCF-7 (human breast cancer cells), SGC-7019 (human early differentiated gastric cancer cells), and A549 (human lung cancer cells) are shown in Table 1, which are 73.21%, 70.76%, 79.99%, and 54.82% respectively. These are superior to those of 5-fluorouracil in Comparative Example 1, which are 8.13%, 57.44%, 33.97%, and 34.23% respectively.

[0069] Example 3

[0070] This example provides a preparation method of a flavonoid derivative. The specific structure of the obtained (4-fluorophenyl) propionate 4-oxo-2-phenyl-4H-chromen-3-yl ester is as follows:

[0071]

[0072] The specific preparation method is as follows:

[0073] S1. Add 5 ml of CH3CN to a 25 mL round-bottom flask. At 0 °C, add 2.6 mmol of 1,8-diazabicycloundec-7-ene (DBU) dropwise to a solvent of 2 mmol of 4-fluorophenylacetone and 2.4 mmol of p-acetamidobenzenesulfonyl azide (p-ABSA). Restore to room temperature and stir overnight. Quench with 10% NaOH and extract twice with 5 ml of methyl tert-butyl ether. The eluent is PE / EA = 10:1 to separate the yellow solid diazo compound with a yield of 70%.

[0074] S2. Add 1 mmol of 1-diazo-1-(4-fluorophenyl)propan-2-one and 1 mmol of 3-hydroxyflavone to a 10 mL microwave reaction tube and dissolve them in 4 mL of methyl tert-butyl ether. React in the microwave and heat to 120 °C for 40 min. The eluent is PE / EA = 10:1 to separate 315 mg of a colorless transparent solid with a yield of 81.44% and a melting point of 153.5–155.6 °C.

[0075] The nuclear magnetic resonance hydrogen spectrum of the obtained solid compound under the conditions of 300 MHz and CDCl3 solvent is as Figure 5 shown. It can be seen from Figure 5 this that 11H NMR (300 MHz, Chloroform-d) δ 8.18 (dd, J = 8.0, 1.7 Hz, 1H), 7.64 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 7.51–7.45 (m, 3H), 7.36 (ddd, J = 8.2, 7.1, 1.1 Hz, 2H), 7.32–7.08 (m, 4H), 7.03–6.83 (m, 2H), 3.99 (q, J = 7.2 Hz, 1H), 1.56 (d, J = 7.2 Hz, 3H).

[0076] The carbon-13 NMR spectrum of the obtained solid compound under the conditions of 125 MHz and CDCl3 solvent is as follows Figure 6 shown, from Figure 6 it can be seen that 13 13C NMR (125 MHz, CDCl3) δ 172.08, 171.23, 162.08 (d, J = 245.6 Hz), 156.17, 155.59, 133.97, 133.63, 131.03, 129.56, 129.48, 129.42, 128.38, 128.14, 126.09, 125.22, 123.56, 118.11, 115.61, 115.44, 44.56, 18.46.

[0077] The inhibitory rates of the compound prepared in this example against SW620 (human colon cancer cells), MCF-7 (human breast cancer cells), SGC-7019 (human early differentiated gastric cancer cells), and A549 (human lung cancer cells) are shown in Table 1, which are 88.24%, 87.23%, 73.67%, and 83.08% respectively. They are superior to 5-fluorouracil in Comparative Example 1 with 8.13%, 57.44%, 33.97%, and 34.23% respectively.

[0078] Example 4

[0079] This example provides a preparation method of a flavonoid derivative. The specific structure of the obtained 4-(4-bromophenyl) propionate 4-oxo-2-phenyl-4H-chromen-3-yl ester is as follows

[0080]

[0081] The specific preparation method is as follows

[0082] S1. Add 5 mL of CH3CN to a 25-mL round-bottom flask. At 0 °C, add 2.6 mmol of 1,8-diazabicycloundec-7-ene (DBU) dropwise to a solution of 2 mmol of 4-bromophenylacetone and 2.4 mmol of p-acetamidobenzenesulfonyl azide (p-ABSA). Restore to room temperature and stir overnight. Quench with 10% NaOH, extract twice with 5 mL of methyl tert-butyl ether, and use a eluent of PE / EA = 10:1 to separate the diazo compound as a yellow solid with a yield of 70%.

[0083] S2. Add 1 mmol of 1-(4-bromophenyl)-1-diazopropan-2-one and 1 mmol of 3-hydroxyflavone to a 10-mL microwave reaction tube and dissolve them in 4 mL of methyl tert-butyl ether. React in a microwave by heating to 120 °C for 40 min. Use a eluent of PE / EA = 10:1 to separate and obtain 347 mg of a colorless transparent solid with a yield of 77.45% and a melting point of 162.1–163.6 °C.

[0084] The 1H NMR spectrum of the prepared solid compound obtained under the conditions of 300 MHz and CDCl3 solvent is as Figure 7 shown. From Figure 7 it can be seen that 1 HNMR(300MHz,Chloroform-d)δ8.18(dd,J=8.0,1.7Hz,1H),7.64(ddd,J=8.7,7.1,1.7Hz,1H),7.50–7.42(m,3H),7.41–7.29(m,4H),7.24–7.07(m,4H),3.96(q,J=7.1Hz,1H),1.54(d,J=7.2Hz,3H).

[0085] The 13C NMR spectrum of the prepared solid compound obtained under the conditions of 75 MHz and CDCl3 solvent is as Figure 8 shown. From Figure 8 it can be seen that 13 CNMR(75MHz,CDCl3)δ172.04,170.86,156.26,155.58,138.39,133.97,133.57,131.79,131.04,129.59,129.46,128.41,128.10,126.07,125.23,123.53,121.35,118.10,44.76,18.16.

[0086] The inhibitory rates of the compound prepared in this example against SW620 (human colon cancer cells), MCF-7 (human breast cancer cells), SGC-7019 (human early differentiated gastric cancer cells), and A549 (human lung cancer cells) are shown in Table 1, which are 86.55%, 81.47%, 82.80%, and 48.17% respectively, superior to 5-fluorouracil in Comparative Example 1 with 8.13%, 57.44%, 33.97%, and 34.23% respectively.

[0087] Example Five

[0088] This example provides a preparation method of a flavonoid derivative. The specific structure of the prepared 2-(2-bromophenyl) propionate 4-oxo-2-phenyl-4H-chromen-3-yl ester is as follows:

[0089] The specific preparation method is as follows:

[0090] S1. Add 5 ml of CH3CN to a 25 mL round-bottom flask. At 0 °C, drop 2.6 mmol of 1,8-diazabicycloundec-7-ene (DBU) into the solvent of 2 mmol of 2-bromophenylacetone and 2.4 mmol of p-acetamidobenzenesulfonyl azide (p-ABSA). Restore to room temperature and stir overnight. Quench with 10% NaOH and extract twice with 5 ml of methyl tert-butyl ether. The eluent is PE / EA = 10:1 to separate the yellow solid diazo compound with a yield of 70%.

[0091] S2. Add 1 mmol of 1-(2-bromophenyl)-1-diazopropan-2-one and 1 mmol of 3-hydroxyflavone to a 10 mL microwave reaction tube and dissolve them in 4 mL of methyl tert-butyl ether. React and heat to 120 °C in the microwave for 40 min. The eluent is PE / EA = 10:1 to separate 269 mg of a colorless transparent solid with a yield of 60.03% and a melting point of 152.8–154.0 °C.

[0092] The nuclear magnetic resonance hydrogen spectrum of the prepared solid compound obtained under the conditions of 300 MHz and CDCl3 solvent is as Figure 9 shown. It can be seen from Figure 9 this that 1 H NMR (300 MHz, Chloroform-d) δ8.19 (dd, J = 8.0, 1.7 Hz, 1H), 7.66–7.60 (m, 3H), 7.57–7.45 (m, 2H), 7.40–7.33 (m, 3H), 7.31–7.20 (m, 3H), 7.08 (td, J = 7.7, 1.7 Hz, 1H), 4.53 (q, J = 7.2 Hz, 1H), 1.57 (d, J = 7.2 Hz, 3H).

[0093] The carbon-13 NMR spectrum of the obtained solid compound in CDCl3 solvent at 75 MHz is as follows Figure 10 shown by Figure 10 which indicates that 13 C NMR(75MHz,CDCl3)δ172.03,170.82,156.14,155.58,139.17,133.91,133.73,132.88,131.05,129.67,128.95,128.76,128.47,128.38,127.92,126.09,125.19,124.52,123.61,118.09,44.52,17.98.

[0094] The inhibitory rates of the compound obtained in this example against SW620 (human colon cancer cells), MCF-7 (human breast cancer cells), SGC-7019 (human early differentiated gastric cancer cells), and A549 (human lung cancer cells) are shown in Table 1, which are 86.55%, 81.47%, 82.80%, and 48.17% respectively. These are superior to 5-fluorouracil in Comparative Example 1, which are 8.13%, 57.44%, 33.97%, and 34.23% respectively.

[0095] Example 6

[0096] This example provides a preparation method of a flavonoid derivative. The specific structure of the obtained 3-4-oxo-2-phenyl-4H-chromen-3-yl 4-methyl-2-phenylpentanoate is as follows

[0097] The specific preparation method is as follows

[0098] S1. Add 5 ml of CH3CN to a 25 mL round-bottom flask. At 0 °C, add 2.6 mmol of 1,8-diazabicycloundec-7-ene (DBU) dropwise to a solvent containing 2 mmol of 4-methyl-1-phenyl-2-pentanone and 2.4 mmol of p-acetamidobenzenesulfonyl azide (p-ABSA). Restore to room temperature and stir overnight. Quench with 10% NaOH and extract twice with 5 ml of methyl tert-butyl ether. The eluent is PE / EA = 10:1 to separate the yellow solid diazo compound with a yield of 70%.

[0099] S2. Add 1 mmol of 1-(2-bromophenyl)-1-diazopropan-2-one and 1 mmol of 3-hydroxyflavone to 4 mL of methyl tert-butyl ether in a 10 mL microwave reaction tube. React in the microwave by heating to 120 °C for 40 min. The eluent is PE / EA = 10:1 to separate 393 mg of a colorless transparent solid with a yield of 95.42% and a melting point of 145.7–147.5 °C.

[0100] The 1H NMR spectrum of the obtained solid compound in CDCl3 solvent at 300 MHz is as follows Figure 11 shown, and from Figure 11 it can be seen that 1 H NMR(300MHz,Chloroform-d)δ8.19(dd,J=8.0,1.7Hz,1H),7.63(ddd,J=8.7,7.1,1.7Hz,1H),7.49–7.40(m,3H),7.35(ddd,J=8.1,7.1,1.1Hz,1H),7.29–7.22(m,5H),7.19(s,1H),7.15–7.06(m,2H),3.94(dd,J=7.7,7.7Hz,1H),2.07(ddd,J=13.6,7.5,7.5Hz,1H),1.72(ddd,J=13.9,7.5,7.4Hz,1H),1.63–1.49(m,1H),0.90(d,J=6.6Hz,3H),0.88(d,J=6.6Hz,3H).

[0101] The 13C NMR spectrum of the obtained solid compound in CDCl3 solvent at 75 MHz is as follows Figure 12 shown, and from Figure 12 it can be seen that 13 C NMR(75MHz,CDCl3)δ172.11,171.00,156.02,155.54,138.10,133.85,133.66,130.81,129.51,128.70,128.36,128.32,128.07,127.36,126.11,125.11,123.58,118.05,49.22,42.00,25.50,22.65,22.29.

[0102] The inhibition rates of the compound prepared in this example against SW620 (human colon cancer cells), MCF-7 (human breast cancer cells), SGC-7019 (human early differentiated gastric cancer cells), and A549 (human lung cancer cells) are shown in Table 1, which are 75.99%, 56.55%, 59.70%, and 68.34% respectively. It is superior to 5-fluorouracil in Comparative Example 1 with 8.13%, 57.44%, 33.97%, and 34.23% respectively.

[0103] The following control test is used as a comparative example. For example, when the reaction temperature is 20 - 50 °C, test schemes corresponding to reaction temperatures outside the range of 20 - 50 can be provided.

[0104] Comparative Example 1 (control drug 5-fluorouracil)

[0105] In a 10 mL microwave reaction tube, 1 mmol of 1-diazo-1-phenyl-2-propanone and 1 mmol of 3-hydroxyflavone were dissolved in 4 mL of methyl tert-butyl ether, and the reaction was heated to 50 °C in a microwave for 40 min, but no reaction occurred.

[0106] Antitumor activity test: The inhibition rate of the raw material 3-hydroxyflavone against human lung cancer cells was 12.08%, and that of the control drug 5-fluorouracil was 34.23%.

[0107] Comparative Example 2 (blank control)

[0108] In a 10 mL microwave reaction tube, 1 mmol of 1-diazo-1-phenyl-2-propanone and 1 mmol of 3-hydroxyflavone were dissolved in 4 mL of methyl tert-butyl ether, and the reaction was heated to 120 °C in a microwave for 40 min. The eluent was PE / EA = 10:1, and 347 mg of 2-phenylpropanoic acid 4-oxo-2-phenyl-4H-chromen-3-yl ester was separated, with a yield of 93.80%.

[0109] Antitumor activity test: The inhibition rate of 2-phenylpropanoic acid 4-oxo-2-phenyl-4H-chromen-3-yl ester against human lung cancer cells was 60.95%, which was better than that of 5-fluorouracil (34.23%) in Comparative Example 1.

[0110] Table 1 Inhibition rates of the antitumor activities of compounds (%)

[0111]

[0112]

[0113] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that they can still modify or equivalently replace the technical solutions of the present invention, and these modifications or equivalent replacements cannot make the modified technical solutions deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A method for preparing a flavonoid derivative, characterized in that: The structural formula of the flavonoid derivative is: Wherein, R1 is H, F, Cl, Br, One of: R2 is One of; The preparation method of the flavonoid derivative comprises the following steps: S1. Preparing α-diazocarbonyl compounds from 1-phenyl-2-acetone compounds through diazo transfer reaction; The specific operations are: Add 5 ml of CH3CN to a round-bottom flask, add 2.6 mmol of 1,8-diazabicycloundec-7-ene dropwise to 2 mmol of 1-phenyl-2-propanone compounds and 2.4 mmol of p-acetylaminobenzenesulfonyl azide at 0°C, return to room temperature and stir overnight, quench with 10% NaOH, extract twice with 5 ml of methyl tert-butyl ether, and use an eluent to separate and obtain a yellow solid α-diazocarbonyl compound; The chemical reaction formula is as follows: S2, α-diazocarbonyl compounds and 3-hydroxyflavone are heated in a microwave to prepare flavonoid derivatives; The specific operations are: Add 1 mmol of α-diazocarbonyl compound and 1 mmol of 3-hydroxyflavone into a microwave reaction tube, dissolve in 4 mL of methyl tert-butyl ether solvent, heat to 120° C., react for 40 min, and use an eluent to elute and separate to obtain a colorless transparent solid; The chemical reaction formula is as follows:

2. The microwave preparation method of a flavonoid derivative according to claim 1, characterized in that: In step S1, the mass fraction of NaOH is 10%, and the eluent is a PE / EA mixed solvent with a volume ratio of 10:

1.

3. The microwave preparation method of a flavonoid derivative according to claim 1, characterized in that: In step S2, the eluent is a PE / EA mixed solvent with a volume ratio of 10:1.

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