Flavone derivative as well as microwave preparation method and application thereof

Abstract

The invention discloses a flavone derivative as well as a microwave preparation method and application thereof, and belongs to the technical field of medicinal chemistry. Comprising the following steps: S1, carrying out diazotization transfer reaction on a 1-phenyl-2-acetone compound to prepare an alpha-diazocarbonyl compound; and S2, heating the alpha-diazocarbonyl compound and 3-hydroxyflavone in microwaves to react to prepare the flavone derivative. The scheme provided by the invention is suitable for realizing Wolff rearrangement reaction of alpha-diazo compounds and alcohol compounds in microwaves, does not need to use the traditional kettle reaction, catalyst and excessive substrate, and has the advantages of simple operation, rapid reaction, few byproducts, high yield, short time and wide substrate application range; and the prepared flavonoid ester compound has an excellent anti-cancer effect.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemistry, and in particular to a flavonoid derivative and a microwave preparation method and application thereof. Background Art

[0002] Cancer is one of the main causes of threats to human life and health. Flavonoids, as small-molecule natural plant metabolites, have multiple biological activities such as anti-tumor, anti-inflammatory, and antioxidant, and have low toxicity. Therefore, there is a huge space for their use in pharmacological properties. At present, many flavonoids have played a role in the safety and effectiveness of the treatment of tumors. At present, there are related studies on the use of diazo compounds to carry out Wolff rearrangement reactions to complete related esterification reactions and obtain flavonoids. However, there are the following defects:

[0003] α-diazo compounds are very active compounds. If the reaction conditions are not mild enough, the diazo group may undergo a direct substitution reaction instead of 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, resulting in reaction failure, waste of raw materials and time, and silver ion catalysts are expensive, increasing costs. The reaction of α-diazo compounds eliminating nitrogen under heating, light or transition metal catalysis to form carbene and then undergoing 1,2-rearrangement to obtain the intermediate enone is explosive. If not handled properly during the reaction, it may cause safety accidents and pose a threat to laboratory personnel and the environment.

[0004] Therefore, when conducting the Wolff rearrangement reaction, the reaction conditions need to be strictly controlled to ensure the safety and effectiveness of the reaction. At the same time, how to simplify the operation, reduce costs and increase yields is also a problem that needs to be solved urgently. Summary of the invention

[0005] The purpose of the present invention is to provide a flavonoid derivative and a microwave preparation method and application thereof, which solves the problem of α-diazo compounds in Wolff mentioned in the above background technology, and can quickly complete the conversion, with less by-products and high yield, thereby improving the safety and effectiveness of the reaction and reducing harm to the body and the environment. At the same time, it does not require traditional kettle reactions, catalysts, and excess substrates, is simple to operate, and reduces costs.

[0006] To achieve the above object, the present invention provides a flavonoid derivative, the structural formula of the flavonoid derivative is:

[0007]

[0008] Wherein, R1 is one of unsaturated hydrocarbon group, hydrocarbon group, ester ring hydrocarbon, halogen, heterocycle or heterocyclic aromatic hydrocarbon; R2 is one of unsaturated hydrocarbon group, hydrocarbon group, ester ring hydrocarbon, halogen, heterocycle or heterocyclic aromatic hydrocarbon.

[0009] Preferably, R1 is H, F, Cl, Br, One of them.

[0010] Preferably, the R2 is: One of them.

[0011] The present invention also provides a microwave preparation method of the above-mentioned flavonoid derivatives, comprising the following steps:

[0012] S1. Preparing α-diazocarbonyl compounds from 1-phenyl-2-acetone compounds through diazo transfer reaction;

[0013] S2, α-diazocarbonyl compounds and 3-hydroxyflavone are heated in a microwave to prepare flavonoid derivatives.

[0014] Preferably, the specific operations of step S1 are:

[0015] 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;

[0016] The chemical reaction formula is as follows:

[0017]

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

[0019] Preferably, the specific operations of step S2 are:

[0020] 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;

[0021] The chemical reaction formula is as follows:

[0022]

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

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

[0025] (1) Microwave heating can achieve direct energy transfer and has the characteristics of fast heating speed, high thermal energy utilization rate and sensitive reaction;

[0026] (2) The complex reaction conditions and cumbersome processing process of α-diazo compounds in the Wolff rearrangement reaction are solved, and the conversion can be completed quickly, which improves the safety and effectiveness of the reaction and reduces the harm to the body and the environment;

[0027] (3) The scheme of the present invention is applicable to the Wolff rearrangement reaction of α-diazo compounds and alcohol compounds in microwaves, does not require the use of traditional kettle reactions, catalysts and excess substrates, has the advantages of simple operation, rapid reaction, few by-products, high yield, short reaction time and a wide range of substrate applications, 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 is further described in detail below through the accompanying drawings and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is a hydrogen nuclear magnetic resonance spectrum of the solid compound prepared in Example 1 of the present invention obtained at 300 MHz and CDCl3 solvent conditions;

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

[0031] Figure 3 This is a hydrogen nuclear magnetic resonance spectrum of the solid compound prepared in Example 2 of the present invention obtained at 300 MHz and CDCl3 solvent conditions;

[0032] Figure 4 This is the carbon NMR spectrum of the solid compound prepared in Example 2 of the present invention obtained at 75 MHz and CDCl3 solvent conditions;

[0033] Figure 5 This is a hydrogen nuclear magnetic resonance spectrum of the solid compound prepared in Example 3 of the present invention obtained at 300 MHz and CDCl3 solvent conditions;

[0034] Figure 6This is the carbon NMR spectrum of the solid compound prepared in Example 3 of the present invention obtained at 125 MHz and CDCl3 solvent conditions;

[0035] Figure 7 This is a hydrogen nuclear magnetic resonance spectrum of the solid compound prepared in Example 4 of the present invention obtained at 300 MHz and CDCl3 solvent conditions;

[0036] Figure 8 This is the carbon NMR spectrum of the solid compound prepared in Example 4 of the present invention obtained at 75 MHz and CDCl3 solvent conditions;

[0037] Fig. 9 This is a hydrogen nuclear magnetic resonance spectrum of the solid compound prepared in Example 5 of the present invention obtained at 300 MHz and CDCl3 solvent conditions;

[0038] Fig.10 This is the carbon nuclear magnetic resonance spectrum of the solid compound prepared in Example 5 of the present invention obtained under 75 MHz and CDCl3 solvent conditions;

[0039] Fig.11 This is a hydrogen nuclear magnetic resonance spectrum of the solid compound prepared in Example 6 of the present invention obtained at 300 MHz and CDCl3 solvent conditions;

[0040] Fig.12 This is the carbon nuclear magnetic resonance spectrum of the solid compound prepared in Example 6 of the present invention obtained under 75 MHz and CDCl3 solvent conditions. DETAILED DESCRIPTION

[0041] The technical solution of the present invention is further described below through the accompanying drawings and embodiments.

[0042] The present invention is further described below in conjunction with specific drawings and embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention. Any other changes, modifications, substitutions, combinations, simplifications made without violating the spirit and principle of the present invention should all be equivalent replacement methods and are 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 claims attached to this application, and all belong to the scope of protection of the present invention.

[0043] Reference to "embodiment" herein means that the specific features, structures or characteristics described in conjunction with the embodiment may be included in at least one embodiment of the present application. The term "embodiment" appearing in various places in the specification does not necessarily refer to the same embodiment, nor does it particularly limit its independence or association with other embodiments. In principle, in the present application, as long as there is no technical contradiction or conflict, the various technical features mentioned in the embodiments can be combined in any way to form a corresponding implementable technical solution.

[0044] Unless otherwise defined, the technical terms used in this document have the same meanings as those generally understood by those skilled in the art to which this application belongs; the use of relevant terms in this document is only for describing specific embodiments and is not intended to limit this application.

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

[0046] The biological materials used in the cancer cell inhibition test of the flavonoid-derived compounds prepared in the following examples 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) 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 and streptomycin and 10% FBS) at 37°C and 5% CO2 humidified conditions.

[0047] The method for testing the in vitro activity of the compounds prepared in the following examples is as follows:

[0048] The prepared compound was dissolved in DMSO and diluted to 100mmol / L. The cells in the logarithmic growth cycle were evenly plated in a 96-well plate to ensure that the cell density was 30%-40%. After the cells were cultured overnight, the cells were treated with 1000 times of the compound diluted 100mmol / L with culture medium and placed in 3 secondary wells. 5-Fluorouracil was used as a positive control, and 1 / 1000 concentration of DMSO was used as a blank. After the cells were incubated for 48h, 1mL of 5mg / mL MTT solution was dissolved in 15mL culture medium, the original culture medium in the 96-well plate was removed, and 150μL of MTT solution diluted with culture medium was added to each well under light-proof conditions, and incubated at 37℃ for 4h. Next, the MTT solution was removed and 150μL of dimethyl sulfoxide (DMSO) was added. Shake on a shaker for 5min to ensure that formazan was completely dissolved in dimethyl sulfoxide, and the absorbance at 492nm was measured by an enzyme reader. At least three independent experiments were performed. The cell proliferation inhibition rate was calculated using the following formula based on the absorbance.

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

[0050] Among them, OD 平均值 is the average absorbance value of the tested compound; OD 平均对照 is the average absorbance value of the blank control group.

[0051] Embodiment 1

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

[0053]

[0054] The specific preparation method is:

[0055] S1. Add 5 ml of CH3CN to a 25 mL round-bottom flask, add 2.6 mmol of 1,8-diazabicycloundec-7-ene (DBU) dropwise to a solvent of 2 mmol of 1-phenyl-2-propanone and 2.4 mmol of p-acetylaminobenzenesulfonyl azide (p-ABSA) at 0°C, return to room temperature and stir overnight, quench with 10% NaOH, extract twice with 5 ml of methyl tert-butyl ether, eluent PE / EA=10:1, and separate the diazo compound as a yellow solid 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, heat to 120 ° C in a microwave, react for 40 min, eluent PE / EA = 10:1, separate and obtain 347 mg of colorless transparent solid, yield: 93.80%, melting point: 151.4-153.2 ° C.

[0057] The obtained solid compound has a hydrogen nuclear magnetic resonance spectrum at 300 MHz and CDCl3 solvent. Figure 1 As shown by Figure 1 It can be seen that 1 H NMR(300MHz,Chloroform-d)δ8.16(dd,J=8.0,1.7Hz,1H),7.59(ddd,J=8.7,7.1,1.7Hz,1H),7.51 –7.39(m,3H),7.35–7.19(m,7H),7.17–7.08(m,2H),4.01(q,J=7.2Hz,1H),1.57(d,J=7.2Hz,3H).

[0058] The obtained solid compound has a carbon NMR spectrum obtained at 75 MHz and CDCl3 solvent conditions. Figure 2 As shown by Figure 2 It can be seen that 13 C NMR (75MHz, CDCl3) δ172.10,171.36,155.98,155.55,139.33,133.89,133.73,130.90,129. 55,128.72,128.38,128.12,127.91,127.34,126.08,125.14,123.55,118.06,45.33,18.35.

[0060] The inhibition rates of the compound prepared in this example on 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. They are better than 5-fluorouracil in Comparative Example 1 by 8.13%, 57.44%, 33.97%, and 34.23%.

[0061] Embodiment 2

[0062] This embodiment provides a method for preparing a flavonoid derivative. The specific structure of the prepared 3-(4-chlorophenyl)propionic acid 4-oxo-2-phenyl-4H-chromen-3-yl ester is:

[0063]

[0064] The specific preparation method is:

[0065] S1. Add 5 ml of CH3CN to a 25 mL round-bottom flask, add 2.6 mmol of 1,8-diazabicycloundec-7-ene (DBU) dropwise to a solvent of 2 mmol of 4-chlorophenylacetone and 2.4 mmol of p-acetylaminobenzenesulfonyl azide (p-ABSA) at 0°C, return to room temperature and stir overnight, quench with 10% NaOH, extract twice with 5 ml of methyl tert-butyl ether, eluent PE / EA=10:1, and separate the diazo compound as a yellow solid with a yield of 70%.

[0066] S2. In a 10 mL microwave reaction tube, add 1 mmol of 1-(4-chlorophenyl)-1-diazipropane-2-one and 1 mmol of 3-hydroxyflavone dissolved in 4 mL of methyl tert-butyl ether, heat to 120 ° C in a microwave, react for 40 min, eluent PE / EA = 10:1, separate and obtain 364 mg of colorless transparent solid, yield: 90.09%, melting point: 153.5-155.6 ° C.

[0067] The obtained solid compound has a hydrogen nuclear magnetic resonance spectrum at 300 MHz and CDCl3 solvent. Figure 3 As shown by Figure 3 It can be seen that 1 H NMR(300MHz,Chloroform-d)δ8.19(dd,J=8.0,1.6Hz,1H),7.64(ddd,J=8.7,7.1,1.7Hz,1H),7.53 –7.41(m,3H),7.43–7.30(m,2H),7.24–7.11(m,6H),3.98(q,J=7.2Hz,1H),1.55(d,J=7.2Hz,3H).

[0068] The obtained solid compound has a carbon NMR spectrum obtained at 75 MHz and CDCl3 solvent conditions. Figure 4 As shown by Figure 4 It can be seen that 13 C NMR (75MHz, CDCl3) δ172.06,170.96,156.25,155.57,137.85,133.97,133.56,133.21,131. 03,129.46,129.22,128.83,128.38,128.10,126.05,125.22,123.51,118.09,44.68,18.22.

[0069] The inhibition rates of the compound prepared in this example on 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. They are better than 5-fluorouracil in Comparative Example 1 by 8.13%, 57.44%, 33.97%, and 34.23%.

[0070] Embodiment 3

[0071] This example provides a method for preparing a flavonoid derivative. The specific structure of the prepared (4-fluorophenyl)propionic acid 4-oxo-2-phenyl-4H-chromen-3-yl ester is:

[0072]

[0073] The specific preparation method is:

[0074] S1. Add 5 ml of CH3CN to a 25 mL round-bottom flask, 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-acetylaminobenzenesulfonyl azide (p-ABSA) at 0°C, return to room temperature and stir overnight, quench with 10% NaOH, extract twice with 5 ml of methyl tert-butyl ether, eluent PE / EA=10:1, and separate the diazo compound as a yellow solid with a yield of 70%.

[0075] S2. In a 10 mL microwave reaction tube, add 1 mmol of 1-diazo-1-(4-fluorophenyl)propan-2-one and 1 mmol of 3-hydroxyflavone dissolved in 4 mL of methyl tert-butyl ether, heat to 120 ° C in a microwave, react for 40 min, eluent PE / EA = 10:1, separate and obtain 315 mg of colorless transparent solid, yield: 81.44%, melting point: 153.5-155.6 ° C.

[0076] The obtained solid compound has a hydrogen nuclear magnetic resonance spectrum at 300 MHz and CDCl3 solvent. Figure 5 As shown by Figure 5 It can be seen that 1H NMR(300MHz,Chloroform-d)δ8.18(dd,J=8.0,1.7Hz,1H),7.64(ddd,J=8.7,7.1,1.7Hz,1H),7.51–7.45(m,3H),7. 36(ddd,J=8.2,7.1,1.1Hz,2H),7.32–7.08(m,4H),7.03–6.83(m,2H),3.99(q,J=7.2Hz,1H),1.56(d,J=7.2Hz,3H).

[0077] The obtained solid compound has a carbon NMR spectrum obtained at 125 MHz and CDCl3 solvent conditions. Figure 6 As shown by Figure 6 It can be seen that 13 C NMR (125MHz, CDCl3) δ172.08, 171.23, 162.08 (d, J = 245.6Hz), 156.17, 155.59, 133.97, 133.63, 131.03, 1 29.56,129.48,129.42,128.38,128.14,126.09,125.22,123.56,118.11,115.61,115.44,44.56,18.46.

[0078] The inhibition rates of the compound prepared in this example on 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 better than 5-fluorouracil in Comparative Example 1 by 8.13%, 57.44%, 33.97%, and 34.23%.

[0079] Embodiment 4

[0080] This example provides a method for preparing a flavonoid derivative. The specific structure of the prepared 4-oxo-2-phenyl-4H-chromen-3-yl 4-(4-bromophenyl)propanoate is:

[0081]

[0082] The specific preparation method is:

[0083] S1. Add 5 ml of CH3CN to a 25 mL round-bottom flask, add 2.6 mmol of 1,8-diazabicycloundec-7-ene (DBU) dropwise to a solvent of 2 mmol of 4-bromophenylacetone and 2.4 mmol of p-acetylaminobenzenesulfonyl azide (p-ABSA) at 0°C, return to room temperature and stir overnight, quench with 10% NaOH, extract twice with 5 ml of methyl tert-butyl ether, eluent PE / EA=10:1, and separate the diazo compound as a yellow solid with a yield of 70%.

[0084] S2. In a 10 mL microwave reaction tube, add 1 mmol of 1-(4-bromophenyl)-1-diazipropane-2-one and 1 mmol of 3-hydroxyflavone dissolved in 4 mL of methyl tert-butyl ether, heat to 120 ° C in a microwave, react for 40 min, eluent PE / EA = 10:1, separate and obtain 347 mg of colorless transparent solid, yield: 77.45%, melting point: 162.1-163.6 ° C.

[0085] The obtained solid compound has a hydrogen nuclear magnetic resonance spectrum at 300 MHz and CDCl3 solvent. Figure 7 As shown by 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),7.5 0–7.42(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).

[0086] The obtained solid compound has a carbon NMR spectrum obtained at 75 MHz and CDCl3 solvent conditions. Figure 8 As shown by 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.

[0087] The inhibition rates of the compound prepared in this example on 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. They are better than 5-fluorouracil in Comparative Example 1 by 8.13%, 57.44%, 33.97%, and 34.23%.

[0088] Embodiment 5

[0089] This example provides a method for preparing a flavonoid derivative. The specific structure of the prepared 2-(2-bromophenyl)propionic acid 4-oxo-2-phenyl-4H-chromen-3-yl ester is:

[0090]

[0091] The specific preparation method is:

[0092] S1. Add 5 ml of CH3CN to a 25 mL round-bottom flask, add 2.6 mmol of 1,8-diazabicycloundec-7-ene (DBU) dropwise to a solvent of 2 mmol of 2-bromophenylacetone and 2.4 mmol of p-acetylaminobenzenesulfonyl azide (p-ABSA) at 0°C, return to room temperature and stir overnight, quench with 10% NaOH, extract twice with 5 ml of methyl tert-butyl ether, eluent PE / EA=10:1, and separate the diazo compound as a yellow solid with a yield of 70%.

[0093] S2. In a 10 mL microwave reaction tube, add 1 mmol of 1-(2-bromophenyl)-1-diazipropane-2-one and 1 mmol of 3-hydroxyflavone dissolved in 4 mL of methyl tert-butyl ether, heat to 120 ° C in a microwave, react for 40 min, eluent PE / EA = 10:1, separate and obtain 269 mg of colorless transparent solid, yield: 60.03%, melting point: 152.8-154.0 ° C.

[0094] The obtained solid compound has a hydrogen nuclear magnetic resonance spectrum at 300 MHz and CDCl3 solvent. Fig. 9 As shown by Fig. 9 It can be seen that 1H NMR(300MHz,Chloroform-d)δ8.19(dd,J=8.0,1.7Hz,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=7.7,1.7Hz,1H),4.53(q,J=7.2Hz,1H),1.57(d,J=7.2Hz,3H).

[0095] The obtained solid compound has a carbon NMR spectrum obtained at 75 MHz and CDCl3 solvent conditions. Fig.10 As shown by Fig.10 It can be seen 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.

[0096] The inhibition rates of the compound prepared in this example on 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. They are better than 5-fluorouracil in Comparative Example 1 by 8.13%, 57.44%, 33.97%, and 34.23%.

[0097] Embodiment 6

[0098] This embodiment provides a method for preparing a flavonoid derivative. The specific structure of the prepared 3-4-oxo-2-phenyl-4H-chromen-3-yl 4-methyl-2-phenylpentanoate is:

[0099]

[0100] The specific preparation method is:

[0101] S1. Add 5 ml of CH3CN to a 25 mL round-bottom flask, add 2.6 mmol of 1,8-diazabicycloundec-7-ene (DBU) dropwise to a solvent of 2 mmol of 4-methyl-1-phenyl-2-pentanone and 2.4 mmol of p-acetylaminobenzenesulfonyl azide (p-ABSA) at 0°C, return to room temperature and stir overnight, quench with 10% NaOH, extract twice with 5 ml of methyl tert-butyl ether, eluent PE / EA=10:1, and separate the diazo compound as a yellow solid with a yield of 70%.

[0102] S2. In a 10 mL microwave reaction tube, add 1 mmol of 1-(2-bromophenyl)-1-diazipropane-2-one and 1 mmol of 3-hydroxyflavone dissolved in 4 mL of methyl tert-butyl ether, heat to 120 ° C in a microwave, react for 40 min, eluent PE / EA = 10:1, separate and obtain 393 mg of colorless transparent solid, yield: 95.42%, melting point: 145.7-147.5 ° C.

[0103] The obtained solid compound has a hydrogen nuclear magnetic resonance spectrum at 300 MHz and CDCl3 solvent. Fig.11 As shown by Fig.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).

[0104] The obtained solid compound has a carbon NMR spectrum obtained at 75 MHz and CDCl3 solvent conditions. Fig.12 As shown by Fig.12 It can be seen that 13C 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.

[0105] The inhibition rates of the compound prepared in this example on 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. They are better than 5-fluorouracil in Comparative Example 1 by 8.13%, 57.44%, 33.97%, and 34.23%.

[0106] Taking the following control test as a comparative example, if the reaction temperature is 20-50°C, a test scheme corresponding to a reaction temperature outside the range of 20-50°C can be provided.

[0107] Comparative Example 1 (reference drug 5-fluorouracil)

[0108] In a 10 mL microwave reaction tube, 1 mmol of 1-diazo-1-phenyl-2-propanone and 1 mmol of 3-hydroxyflavone were added and dissolved in 4 mL of methyl tert-butyl ether. The mixture was heated to 50° C. in a microwave and reacted for 40 min. No reaction occurred.

[0109] Anti-tumor activity test: The inhibition rate of the raw material 3-hydroxyflavone on human lung cancer cells was 12.08%, while that of the control drug 5-fluorouracil was 34.23%.

[0110] Comparative Example 2 (blank control)

[0111] In a 10mL microwave reaction tube, add 1mmol of 1-diazo-1-phenyl-2-propanone and 1mmol of 3-hydroxyflavone dissolved in 4mL of methyl tert-butyl ether, heat to 120°C in a microwave, react for 40min, eluent PE / EA=10:1, and separate 347mg of 2-phenylpropionic acid 4-oxo-2-phenyl-4H-chromen-3-yl ester, yield: 93.80%.

[0112] Antitumor activity test: The inhibition rate of 2-phenylpropionic acid 4-oxo-2-phenyl-4H-chromen-3-yl ester on human lung cancer cells was 60.95%, which was better than 5-fluorouracil in comparative example 1 by 34.23%.

[0113] Table 1 Inhibition rate of antitumor activity of compounds (%)

[0114]

[0115] Example 1 R1 = H, R2 = CH3 81.27% 84.56% 82.80% 60.95% Example 2 R1 = 4-Cl, R2 = CH3 73.21% 70.76% 79.99% 54.82% Example 3 R1 = 4-F, R2 = CH3 88.24% 87.23% 73.67% 83.08% Example 4 R1 = 4-Br, R2 = CH3 61.29% 52.45% 39.61% 71.30% Example 5 R1 = 2-Br, R2 = CH3 86.55% 81.47% 82.80% 48.17%

[0116]

[0117] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that they can still modify or replace the technical solution of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solution to deviate from the spirit and scope of the technical solution of the present invention.

Claims

1. A flavonoid derivative, characterized in that: The structural formula of the flavonoid derivative is: Wherein, R1 is one of unsaturated hydrocarbon group, hydrocarbon group, ester ring hydrocarbon, halogen, heterocycle or heterocyclic aromatic hydrocarbon; R2 is one of unsaturated hydrocarbon group, hydrocarbon group, ester ring hydrocarbon, halogen, heterocycle or heterocyclic aromatic hydrocarbon.

2. A flavonoid derivative according to claim 1, characterized in that: R1 is H, F, Cl, Br, One of them.

3. A flavonoid derivative according to claim 1, characterized in that: The R2 is: One of them.

4. The microwave preparation method of a flavonoid derivative according to any one of claims 1 to 3, characterized in that: The following steps are involved: S1. Preparing α-diazocarbonyl compounds from 1-phenyl-2-acetone compounds through diazo transfer reaction; S2, α-diazocarbonyl compounds and 3-hydroxyflavone are heated in a microwave to prepare flavonoid derivatives.

5. The microwave preparation method of a flavonoid derivative according to claim 4, characterized in that: The specific operations of step S1 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:

6. The microwave preparation method of a flavonoid derivative according to claim 5, characterized in that: The mass fraction of the NaOH is 10%, and the eluent is a PE / EA mixed solvent with a volume ratio of 10:

1.

7. The microwave preparation method of a flavonoid derivative according to claim 4, characterized in that: The specific operations of step S2 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:

8. The microwave preparation method of a flavonoid derivative according to claim 7, characterized in that: The eluent is a PE / EA mixed solvent with a volume ratio of 10:1.

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