CN113292573B - Indolizine chromogen ketone compound with anti-tumor activity and preparation method and application thereof - Google Patents

Abstract

The invention belongs to the technical field of biomedicine, and in particular relates to an indolizinochromone compound with antitumor activity and a preparation method and application thereof. In the present invention, a substituted o-acetphenoxy acrylate compound and a pyridine compound are contacted and reacted under the simple substance of iodine to synthesize a new indolizinochromone compound. The indolizinochromone compound of the present invention has good antitumor effect and can be used for screening and preparation of antitumor drugs. The raw materials used in the preparation method of the present invention are cheap and easily available, the operation method is simple, the reaction conditions are mild, and can be carried out by a one-pot method, the steps are short, metal catalysts and toxic substances are not required, and the industrial preparation of such compounds provides the a feasible approach.

Description

Indolizinochromone compounds with antitumor activity and preparation method and use thereof

technical field

The invention belongs to the technical field of biomedicine, and in particular relates to an indolizinochromone compound with antitumor activity and a preparation method and application thereof.

Background technique

Both natural and synthetic heteropolycycles generally exhibit biological activity. Indolizines and chromones are an important class of nitrogen-containing heterocycles, which are abundant in many natural products and bioactive compounds, and they have a wide range of biological activities, such as antibacterial, antitumor, antioxidant, anticonvulsant, antiinflammatory and HIV inhibitory activity.

Chromones and indolizines are considered advantageous scaffolds for structural modification for the design of new compounds with potential pharmacological activity, especially in the fields of neurodegenerative diseases, inflammation and infectious diseases, as well as diabetes and cancer. In addition, the use of chromones in asthma treatment has also been widely explored, mainly as bronchodilators. In the process of drug research and development, it was finally found that carloxacin (DSCG, see formula 1) and pranlukast (pranlukast, see formula 2) are useful drugs for the treatment of mild to moderate asthma and allergic rhinitis, respectively. As a key pharmacophore in various small-molecule drug discovery studies, indolizine has attracted more and more attention (as shown in formula 3 and formula 4), and exhibits good antitumor activity.

Because chromone and indolizine show good pharmacological activity and potential pharmaceutical value, many compounds with chromone and indolizine skeletons have been synthesized, but structures containing these two dominant skeletons are rarely reported. It has attracted the attention of many researchers at home and abroad. As a result, some indolizinochromone compounds have also been synthesized (as shown in formula 5 and formula 6).

In 2003, Deevi Basavaiah et al. used the Baylis–Hillman reaction to realize the construction of the skeleton of indolizinochromones, which is also the first report on the synthesis of indolizinochromones, see Reaction Formula I:

In 2010, Yi-Chen Lee et al. used thermal and microwave-assisted cyclization to synthesize indolizinochromones, see Reaction Formula II:

In summary, indolizinochromones are a class of compounds with potential medicinal value, and their synthesis and pharmacological activities have always been the focus of researchers. There are relatively few studies on the compounds, and only one indolizinochromone compound has been reported, and there are few reports on the pharmacological activity of indolizinochromones. Therefore, it is very important to synthesize a new indolizinochromone compound and study its pharmacological activity.

SUMMARY OF THE INVENTION

In view of the above deficiencies in the prior art, the object of the present invention is to provide an indolizinochromone compound with antitumor activity and a preparation method and application thereof.

In order to achieve the above object, one aspect of the present invention relates to a kind of indolizinochromone compound with antitumor activity, and the structural formula of the compound is shown in formula VII:

Wherein, R ₁ in formula seven is hydrogen, halogen, substituted alkyl or aryl;

In formula seven, R ₂ is methoxy, ethoxy, isopropoxy or substituted amino;

In formula 7, R ₃ is hydrogen, halogen, ester group, substituted alkyl group or aryl group.

Another aspect of the present invention relates to a preparation method of an indolizinochromone compound with antitumor activity, comprising the following steps:

Under the condition of oxidant, the compound shown in formula 8 and the compound shown in formula 9 are self-organized one-pot synthesis under the action of catalyst iodine to obtain the compound shown in formula 7;

Wherein, in formula eight R ₁ is hydrogen, halogen, substituted alkyl or aryl;

In formula eight, R ₂ is methoxy, ethoxy, isopropoxy or substituted amino;

In formula 9, R ₃ is hydrogen, halogen, ester group, substituted alkyl group or aryl group.

Preferably, the molar dosage ratio of the compound represented by the formula 8 and the compound represented by the formula 9 is 1.0: (1.5-3.0); further preferably, the molar dosage of the compound represented by the formula 8 and the compound represented by the formula 9 The ratio is 1.0:(2.5 to 3.0).

Preferably, the molar dosage of the catalyst iodine is 0.5-2.0 times the molar dosage of the compound shown in formula 8; further preferably, the catalyst iodine elemental dosage is 0.8-1.2 times the molar dosage of the compound shown in formula 8.

Preferably, the oxidant condition is specifically in the presence of an oxidant, and the oxidant is one or more of oxygen, tert-butyl peroxybenzoate, benzoyl peroxide and methyl tert-butyl peroxide kind. When the oxidant is one or more of t-butyl peroxybenzoate and benzoyl peroxide, the compound of formula VII can be prepared in a higher yield.

Preferably, the molar dosage ratio of the compound represented by the formula 8 to the oxidant is 1:(2-3), more preferably 1:(2.5-3).

Preferably, the specific conditions of the self-organized one-pot synthesis are as follows: carry out in an organic solvent at a temperature of 80-140° C. for 6-15 hours.

Preferably, the organic solvent is toluene, benzene, 1,4-dioxane, dimethyl sulfoxide, 1,2-dichloroethane, ethylene glycol, N,N-dimethylformamide and N - one or more of methylpyrrolidone. With respect to 10 mmol of the total amount of the compound represented by Formula 8 and the compound represented by Formula 9, the amount of the organic solvent used is 15-40 mL, preferably 20-30 mL.

Preferably, the self-organized one-pot synthesis can be carried out under stirring conditions, for example, at a stirring speed of 300-1500 rpm.

In a preferred embodiment of the present invention, 1,4-dioxane (Dioxane) is used as the solvent, tert-butyl peroxybenzoate (TBPB) is used as the oxidant, and the catalyst iodine element (I ₂ ) is used at 110° C. Reaction under conditions for 10 hours, see reaction formula III:

Further, the present invention also relates to the application of the aforementioned indolizinochromone compounds with anti-tumor activity in the screening of anti-tumor drugs, the preparation of anti-tumor drugs and drug carriers.

The indolizinochromone compounds with antitumor activity of the present invention can effectively inhibit the proliferation of tumor cells, and can be used to prepare antitumor drugs and drug carriers for the treatment of gastric cancer, lung cancer, cervical cancer, breast cancer or colon cancer. cancer etc.

Compared with the prior art, the present invention has the following advantages:

的全新的吲嗪并色原酮类化合物；(1) The present invention synthesized a kind of parent core skeleton for the first time as

The new indolizinochromones compounds;

(2) The existing technologies for synthesizing indolizinochromones are mostly multi-step reactions (refer to Reaction Formulas I and II), and the raw materials are expensive and difficult to prepare; the preparation method of the present invention is a one-pot full synthesis method without metal catalysis , the reaction conditions are mild, the raw materials are cheap and easy to obtain, the steps are short, no metal catalysts and toxic substances are required, and the environment will not be affected; the target product is generated in series in one pot and multiple steps, no intermediate separation is required, and production costs are saved, and The highest yield can reach 72%, which provides a feasible method for industrial preparation of such compounds;

(3) The present invention screened the antitumor activity of indolizinochromone compounds for the first time, and the compounds showed good antitumor activity, had good antitumor effect, and could be used for the screening of antitumor drugs and preparation.

Detailed ways

The present invention will be described in detail below with reference to specific embodiments. The following examples will help those skilled in the art to further understand the present invention, but do not limit the present invention in any form. It should be noted that, for those skilled in the art, several modifications and improvements can be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

Example 1

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula ten:

The reaction formula for preparing the compound described in formula ten is:

Acetylphenoxy) acrylate, 0.6mmol pyridine, 0.2mmol elemental iodine, 0.6mmol tert-butyl peroxybenzoate, 2mL 1,4-dioxane were sealed at 110°C and reacted with magnetic stirring for 10 hours, the reaction was completed Then, the reaction solution was extracted, the organic layer was washed, dried, and the solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=10:1 (V/V) as the eluent. The desired product was obtained, the product was a white solid, and the yield was 72%.

The identification data results of the obtained product are: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.74 (dt, J=6.8, 1.2Hz, 1H), 8.41-8.31 (m, 2H), 7.72-7.59 ( m, 2H), 7.51 (ddd, J=8.0, 6.8, 1.2Hz, 1H), 7.42 (ddd, J=8.0, 6.8, 1.2Hz, 1H), 7.09 (td, J=6.8, 1.2Hz, 1H) , 4.46 (q, J=7.1Hz, 2H), 1.49 (t, J=7.1Hz, 3H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ (ppm) 167.7, 162.9, 155.5, 153.1, 138.1, 133.0, 129.1, 128.7, 125.7, 124.3, 123.5, 118.9, 118.2, 114.3, 110.9, 91.5, 60.1, 14.5.

Example 2 to Example 4

Examples 2 to 4 are the same as in Example 1, to prepare indolizinochromone compounds with antitumor activity. Table 1 shows:

Table 1

Example catalyst solvent Oxidizer time (h) temperature ℃ Yield (%) 2 I₂ Dioxane O₂ 10 110 31% 3 I₂ Dioxane TBHP(3.0) 10 110 45% 4 I₂ Dioxane BPO(3.0) 10 110 12%

Example 5 to Example 11

Examples 5 to 11 are the same as in Example 1, to prepare indolizinochromone compounds with antitumor activity. The structural formula is shown in formula 10. The difference is only in the solvent used. The specific conditions and reaction yields are as follows Table 2 shows:

Table 2

Example 12

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula ten, and the reaction formula for preparing the compound in formula ten is the same as reaction formula IV. The preparation method of the compound as described in formula ten, the concrete steps are: add 0.2mmol ethyl-3-(2-acetphenoxy) acrylate, 0.3mmol pyridine, 0.2mmol elemental iodine, 0.6mmol to 15mL pressure-resistant tube tert-butyl peroxybenzoate, 2 mL of 1,4-dioxane, sealed at 110°C and reacted with magnetic stirring for 10 hours, after the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, and distilled under reduced pressure to remove The solvent is used to obtain the crude product, and the crude product is separated and purified by column chromatography with petroleum ether/ethyl acetate=10:1 (V/V) as the eluent to obtain the desired product. The product is a white solid with a yield of 30%.

Example 13

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula ten, and the reaction formula for preparing the compound in formula ten is the same as reaction formula IV. The preparation method of compound as described in formula ten, the concrete steps are: add 0.2mmol ethyl-3-(2-acetphenoxy) acrylate, 0.4mmol pyridine, 0.2mmol elemental iodine, 0.3mmol to 15mL pressure-resistant tube tert-butyl peroxybenzoate, 2 mL of 1,4-dioxane, sealed at 110°C and reacted with magnetic stirring for 10 hours, after the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, and distilled under reduced pressure to remove Solvent obtains crude product, crude product uses petroleum ether/ethyl acetate

=10:1 (V/V) is the eluent, and the desired product is obtained by column chromatography separation and purification. The product is a white solid with a yield of 46%.

Example 14

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula ten, and the reaction formula for preparing the compound in formula ten is the same as reaction formula IV. The preparation method of compound as described in formula ten, the concrete steps are: add 0.2mmol ethyl-3-(2-acetphenoxy) acrylate, 0.5mmol pyridine, 0.2mmol elemental iodine, 0.3mmol to 15mL pressure-resistant tube tert-butyl peroxybenzoate, 2 mL of 1,4-dioxane, sealed at 110°C and reacted with magnetic stirring for 10 hours, after the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, and distilled under reduced pressure to remove The solvent is used to obtain the crude product, and the crude product is separated and purified by column chromatography with petroleum ether/ethyl acetate=10:1 (V/V) as the eluent to obtain the desired product. The product is a white solid with a yield of 59%.

Examples 15 to 19

Example 15 to Example 19 are the same as Example 1, to prepare indolizinochromone compounds with antitumor activity. The structural formula is shown in Formula 10. The difference is only in the reaction time. The specific conditions and reaction yields are as follows 3 shows:

table 3

Examples 20 to 23

Examples 20 to 23 are the same as in Example 1, to prepare indolizinochromone compounds with anti-tumor activity. The structural formula is shown in Formula 10. The difference is only in the reaction temperature. The specific conditions and reaction yields are as follows 4 shows:

Table 4

Example catalyst solvent Oxidizer time (h) temperature ℃ Yield (%) 20 I₂(1.0) Dioxane TBPB(3.0) 10 80 52% twenty one I₂(1.0) Dioxane TBPB(3.0) 10 100 66% twenty two I₂(1.0) Dioxane TBPB(3.0) 10 120 63% twenty three I₂(1.0) Dioxane TBPB(3.0) 10 140 59%

Examples 24 to 26

Example 24 to Example 26 are the same as Example 1, to prepare indolizinochromone compounds with antitumor activity. The structural formula is shown in Formula 10. The difference is only in the amount of elemental iodine. The specific conditions and reaction yields are as follows Table 5 shows:

table 5

Example Elemental iodine dosage solvent Oxidizer time (h) temperature ℃ Yield (%) twenty four 0.1mmol Dioxane TBPB(3.0) 10 110 45% 25 0.3mmol Dioxane TBPB(3.0) 10 110 58% 26 0.4mmol Dioxane TBPB(3.0) 10 110 68%

Comparative Example 1

Comparative Example 1 is the same as Example 1 to prepare an indolizinochromone compound with antitumor activity. The structural formula is shown in Formula 10. The only difference is that the sealing cover is opened and the reaction is magnetically stirred for 10 hours. After the reaction is completed, the The reaction solution was extracted, the organic layer was washed, dried, and the solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=10:1 (V/V) as the eluent to obtain the obtained The desired product was a white solid with a yield of 15%.

The identification data results of the obtained product are: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.74 (dt, J=6.8, 1.2Hz, 1H), 8.41-8.31 (m, 2H), 7.72-7.59 ( m, 2H), 7.51 (ddd, J=8.0, 6.8, 1.2Hz, 1H), 7.42 (ddd, J=8.0, 6.8, 1.2Hz, 1H), 7.09 (td, J=6.8, 1.2Hz, 1H) , 4.46 (q, J=7.1Hz, 2H), 1.49 (t, J=7.1Hz, 3H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ (ppm) 167.7, 162.9, 155.5, 153.1, 138.1, 133.0, 129.1, 128.7, 125.7, 124.3, 123.5, 118.9, 118.2, 114.3, 110.9, 91.5, 60.1, 14.5.

Example 27

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula XI:

The reaction formula for preparing the compound described in formula ten is:

The preparation method of compound as described in formula eleven, the specific steps are: add 0.2mmol methyl-3-(2-acetphenoxy) acrylate, 0.6mmol pyridine, 0.2mmol elemental iodine, 0.6 mmol to 15mL pressure-resistant tube mmol tert-butyl peroxybenzoate and 2 mL of 1,4-dioxane were sealed at 110°C and reacted with magnetic stirring for 10 hours. After the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, and the solvent was removed by distillation under reduced pressure. The crude product was obtained, and the crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=10:1 (V/V) as the eluent to obtain the desired product. The product was a white solid with a yield of 68%.

The results of identification data of the obtained product are: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.79 (dt, J=6.8, 1.2 Hz, 1H), 8.49-8.32 (m, 2H), 7.75-7.66 ( m, 2H), 7.55 (ddd, J=8.0, 6.8, 1.2Hz, 1H), 7.45 (ddd, J=8.0, 6.0, 2.0Hz, 1H), 7.13 (td, J=7.2, 1.6Hz, 1H) , 4.02 (s, 3H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ (ppm) 160.8, 156.4, 148.6, 146.1, 131.3, 126.1, 1232, 121.8, 118.8, 117.4, 116.5, 111.9, 111.3, 107.4 ,104.0,84.3,44.3.

Comparative Example 2

Comparative Example 2 is the same as Example 27, to prepare an indolizinochromone compound with antitumor activity, the structural formula is shown in formula XI, the difference is only that the sealing cover is opened and the reaction is magnetically stirred for 10 hours. After the reaction is completed, The reaction solution was extracted, the organic layer was washed, dried, and the solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=10:1 (V/V) as an eluent to obtain a crude product. The desired product was a white solid with a yield of 36%.

The results of identification data of the obtained product are: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.79 (dt, J=6.8, 1.2 Hz, 1H), 8.49-8.32 (m, 2H), 7.75-7.66 ( m, 2H), 7.55 (ddd, J=8.0, 6.8, 1.2Hz, 1H), 7.45 (ddd, J=8.0, 6.0, 2.0Hz, 1H), 7.13 (td, J=7.2, 1.6Hz, 1H) , 4.02 (s, 3H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ (ppm) 160.8, 156.4, 148.6, 146.1, 131.3, 126.1, 1232, 121.8, 118.8, 117.4, 116.5, 111.9, 111.3, 107.4 ,104.0,84.3,44.3.

Example 28

An indolizinochromone compound with antitumor activity, the structural formula of which is shown in formula XI, and the reaction formula for preparing the compound described in formula 10 is as shown in reaction formula V.

The preparation method of compound as described in formula eleven, the specific steps are: add 0.2mmol methyl-3-(2-acetphenoxy) acrylate, 0.6mmol pyridine, 0.2mmol elemental iodine, 0.6 mmol to 15mL pressure-resistant tube mmol tert-butyl peroxybenzoate and 2 mL of toluene were sealed at 110° C. and reacted with magnetic stirring for 10 hours. After the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, and the solvent was distilled off under reduced pressure to obtain a crude product. Using petroleum ether/ethyl acetate=10:1 (V/V) as eluent to carry out column chromatography separation and purification to obtain the desired product, the product is a white solid, and the yield is 48%.

The results of identification data of the obtained product are: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.79 (dt, J=6.8, 1.2 Hz, 1H), 8.49-8.32 (m, 2H), 7.75-7.66 ( m, 2H), 7.55 (ddd, J=8.0, 6.8, 1.2Hz, 1H), 7.45 (ddd, J=8.0, 6.0, 2.0Hz, 1H), 7.13 (td, J=7.2, 1.6Hz, 1H) , 4.02 (s, 3H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ (ppm) 160.8, 156.4, 148.6, 146.1, 131.3, 126.1, 1232, 121.8, 118.8, 117.4, 116.5, 111.9, 111.3, 107.4 ,104.0,84.3,44.3.

Example 29

An indolizinochromone compound with antitumor activity, its structural formula is as shown in formula XI, and the reaction formula for preparing the compound as shown in formula XI is as follows:

The preparation method of compound as described in formula eleven, the specific steps are: add 0.2mmol methyl-3-(2-acetphenoxy) acrylate, 0.6mmol pyridine, 0.2mmol elemental iodine, 0.6 mmol to 15mL pressure-resistant tube mmol methyl tert-butyl peroxide and 2 mL of 1,4-dioxane were sealed at 110 ° C and reacted with magnetic stirring for 10 hours. After the reaction was completed, the reaction solution was extracted, and the organic layer was washed, dried, and distilled under reduced pressure to remove it. The solvent is used to obtain the crude product. The crude product is separated and purified by column chromatography with petroleum ether/ethyl acetate=10:1 (V/V) as the eluent to obtain the desired product. The product is a white solid with a yield of 36%.

The results of identification data of the obtained product are: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.79 (dt, J=6.8, 1.2 Hz, 1H), 8.49-8.32 (m, 2H), 7.75-7.66 ( m, 2H), 7.55 (ddd, J=8.0, 6.8, 1.2Hz, 1H), 7.45 (ddd, J=8.0, 6.0, 2.0Hz, 1H), 7.13 (td, J=7.2, 1.6Hz, 1H) , 4.02 (s, 3H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ (ppm) 160.8, 156.4, 148.6, 146.1, 131.3, 126.1, 1232, 121.8, 118.8, 117.4, 116.5, 111.9, 111.3, 107.4 ,104.0,84.3,44.3.

Example 30

An indolizinochromone compound with antitumor activity, its structural formula is as shown in formula XI, and the reaction formula for preparing the compound as shown in formula XI is as follows:

The preparation method of compound as described in formula eleven, the concrete steps are: add 0.2mmol methyl-3-(2-acetphenoxy) acrylate, 0.6mmol pyridine, 0.4mmol elemental iodine, 0.6 mmol to 15mL pressure-resistant tube mmol tert-butyl peroxybenzoate and 2 mL of 1,4-dioxane were sealed at 80°C and reacted with magnetic stirring for 15 hours. After the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, and the solvent was removed by distillation under reduced pressure. The crude product was obtained, and the crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=10:1 (V/V) as the eluent to obtain the desired product. The product was a white solid with a yield of 41%.

The results of identification data of the obtained product are: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.79 (dt, J=6.8, 1.2 Hz, 1H), 8.49-8.32 (m, 2H), 7.75-7.66 ( m, 2H), 7.55 (ddd, J=8.0, 6.8, 1.2Hz, 1H), 7.45 (ddd, J=8.0, 6.0, 2.0Hz, 1H), 7.13 (td, J=7.2, 1.6Hz, 1H) , 4.02 (s, 3H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ (ppm) 160.8, 156.4, 148.6, 146.1, 131.3, 126.1, 1232, 121.8, 118.8, 117.4, 116.5, 111.9, 111.3, 107.4 ,104.0,84.3,44.3.

Example 31

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula 12:

The reaction formula for preparing the compound described in formula 12 is:

The preparation method of compound as described in formula 12, the concrete steps are: add 0.2mmol ethyl-3-(2-acetyl 3-chlorophenoxy) acrylate, 0.6mmol pyridine, 0.2mmol elemental substance to 15mL pressure-resistant tube Iodine, 0.6mmol of tert-butyl peroxybenzoate, 2mL of 1,4-dioxane were sealed at 110°C and reacted with magnetic stirring for 10 hours. After the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, reduced The solvent was removed by pressure distillation to obtain the crude product, and the crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=15:1 (V/V) as the eluent to obtain the desired product. The product was a white solid, and the yield was 66%.

The result of identification data of the obtained product is: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.72 (dt, J=6.8, 1.2Hz, 1H), 8.40 (dt, J=9.0, 1.2Hz, 1H) ,8.31(d,J＝8.5Hz,1H),7.66(d,J＝1.9Hz,1H),7.59–7.50(m,1H),7.40(dd,J＝8.5,1.9Hz,1H),7.13( td, J=6.8, 1.2 Hz, 1H), 4.48 (q, J=7.1 Hz, 2H), 1.50 (t, J=7.1 Hz, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ (ppm) )166.9,162.8,155.7,153.0,139.0,138.3,129.4,128.7,127.0,125.1,122.2,119.1,118.3,114.6,110.8,91.8,60.2,14.5.

Comparative Example 3

Comparative Example 3 is the same as Example 31 to prepare an indolizinochromone compound with antitumor activity, the structural formula is as shown in formula 12, the difference is only that the sealing cover is opened and the reaction is magnetically stirred for 10 hours. After the reaction is completed, The reaction solution was extracted, the organic layer was washed, dried, and the solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=15:1 (V/V) as an eluent to obtain a crude product. The desired product was a white solid in 18% yield.

The result of identification data of the obtained product is: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.72 (dt, J=6.8, 1.2Hz, 1H), 8.40 (dt, J=9.0, 1.2Hz, 1H) ,8.31(d,J＝8.5Hz,1H),7.66(d,J＝1.9Hz,1H),7.59–7.50(m,1H),7.40(dd,J＝8.5,1.9Hz,1H),7.13( td, J=6.8, 1.2 Hz, 1H), 4.48 (q, J=7.1 Hz, 2H), 1.50 (t, J=7.1 Hz, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ (ppm) )166.9,162.8,155.7,153.0,139.0,138.3,129.4,128.7,127.0,125.1,122.2,119.1,118.3,114.6,110.8,91.8,60.2,14.5.

Example 32

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula 12, and the reaction formula for preparing the compound shown in formula 12 is as follows:

The preparation method of compound as described in formula 12, the concrete steps are: add 0.2mmol ethyl-3-(2-acetyl 3-chlorophenoxy) acrylate, 0.6mmol pyridine, 0.2mmol elemental substance to 15mL pressure-resistant tube Iodine, 0.6mmol of tert-butyl peroxybenzoate, 2mL of 1,2-dichloroethane were sealed at 120°C and reacted with magnetic stirring for 12 hours. After the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, reduced The solvent was removed by pressure distillation to obtain the crude product, and the crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=15:1 (V/V) as the eluent to obtain the desired product. The product was a white solid, and the yield was 28%.

The result of identification data of the obtained product is: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.72 (dt, J=6.8, 1.2Hz, 1H), 8.40 (dt, J=9.0, 1.2Hz, 1H) ,8.31(d,J＝8.5Hz,1H),7.66(d,J＝1.9Hz,1H),7.59–7.50(m,1H),7.40(dd,J＝8.5,1.9Hz,1H),7.13( td, J=6.8, 1.2 Hz, 1H), 4.48 (q, J=7.1 Hz, 2H), 1.50 (t, J=7.1 Hz, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ (ppm) )166.9,162.8,155.7,153.0,139.0,138.3,129.4,128.7,127.0,125.1,122.2,119.1,118.3,114.6,110.8,91.8,60.2,14.5.

Example 33

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula 12, and the reaction formula for preparing the compound shown in formula 12 is as follows:

The preparation method of compound as described in formula 12, the concrete steps are: add 0.2mmol ethyl-3-(2-acetyl 3-chlorophenoxy) acrylate, 0.6mmol pyridine, 0.2mmol elemental substance to 15mL pressure-resistant tube Iodine, oxygen, and 2 mL of 1,4-dioxane were sealed at 110° C. and reacted with magnetic stirring for 10 hours. After the reaction was completed, the reaction solution was extracted, and the organic layer was washed, dried, and distilled under reduced pressure to remove the solvent to obtain a crude product. , the crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=15:1 (V/V) as the eluent to obtain the desired product. The product was a white solid with a yield of 8%.

The result of identification data of the obtained product is: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.72 (dt, J=6.8, 1.2Hz, 1H), 8.40 (dt, J=9.0, 1.2Hz, 1H) ,8.31(d,J＝8.5Hz,1H),7.66(d,J＝1.9Hz,1H),7.59–7.50(m,1H),7.40(dd,J＝8.5,1.9Hz,1H),7.13( td, J=6.8, 1.2 Hz, 1H), 4.48 (q, J=7.1 Hz, 2H), 1.50 (t, J=7.1 Hz, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ (ppm) )166.9,162.8,155.7,153.0,139.0,138.3,129.4,128.7,127.0,125.1,122.2,119.1,118.3,114.6,110.8,91.8,60.2,14.5.

Example 34

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula 12, and the reaction formula for preparing the compound shown in formula 12 is as follows:

The preparation method of compound as described in formula twelve, the concrete steps are: add 0.2mmol ethyl-3-(2-acetyl 3-chlorophenoxy) acrylate, 0.3mmol pyridine, 0.1mmol elemental substance to 15mL pressure-resistant tube Iodine, 0.4mmol tert-butyl peroxybenzoate, 2mL 1,4-dioxane were sealed at 80°C and reacted with magnetic stirring for 6 hours. After the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, reduced The solvent was removed by pressure distillation to obtain the crude product, and the crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=15:1 (V/V) as the eluent to obtain the desired product. The product was a white solid, and the yield was 27%.

The result of identification data of the obtained product is: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.72 (dt, J=6.8, 1.2Hz, 1H), 8.40 (dt, J=9.0, 1.2Hz, 1H) ,8.31(d,J＝8.5Hz,1H),7.66(d,J＝1.9Hz,1H),7.59–7.50(m,1H),7.40(dd,J＝8.5,1.9Hz,1H),7.13( td, J=6.8, 1.2 Hz, 1H), 4.48 (q, J=7.1 Hz, 2H), 1.50 (t, J=7.1 Hz, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ (ppm) )166.9,162.8,155.7,153.0,139.0,138.3,129.4,128.7,127.0,125.1,122.2,119.1,118.3,114.6,110.8,91.8,60.2,14.5.

Example 35

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula 12, and the reaction formula for preparing the compound shown in formula 12 is as follows:

The preparation method of compound as described in formula 12, the concrete steps are: add 0.2mmol ethyl-3-(2-acetyl 3-chlorophenoxy) acrylate, 0.6mmol pyridine, 0.4mmol elemental substance to 15mL pressure-resistant tube Iodine, 0.6mmol of tert-butyl peroxybenzoate, 2mL of 1,4-dioxane were sealed at 140°C and reacted with magnetic stirring for 15 hours. After the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, reduced The solvent was removed by pressure distillation to obtain the crude product, and the crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=15:1 (V/V) as the eluent to obtain the desired product. The product was a white solid, and the yield was 41%.

The result of identification data of the obtained product is: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.72 (dt, J=6.8, 1.2Hz, 1H), 8.40 (dt, J=9.0, 1.2Hz, 1H) ,8.31(d,J＝8.5Hz,1H),7.66(d,J＝1.9Hz,1H),7.59–7.50(m,1H),7.40(dd,J＝8.5,1.9Hz,1H),7.13( td, J=6.8, 1.2 Hz, 1H), 4.48 (q, J=7.1 Hz, 2H), 1.50 (t, J=7.1 Hz, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ (ppm) )166.9,162.8,155.7,153.0,139.0,138.3,129.4,128.7,127.0,125.1,122.2,119.1,118.3,114.6,110.8,91.8,60.2,14.5.

Example 36

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula 13:

The reaction formula for preparing the compound described in formula thirteen is:

The preparation method of compound as described in formula 13, the concrete steps are: add 0.2mmol ethyl-3-(2-acetyl 3-methoxyphenoxy) acrylate, 0.6mmol pyridine, 0.2 mmol to 15mL pressure-resistant tube mmol elemental iodine, 0.6mmol tert-butyl peroxybenzoate, 2mL 1,4-dioxane were sealed at 110 ° C and magnetic stirring was reacted for 10 hours, after the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried , remove the solvent under reduced pressure to obtain the crude product, and the crude product uses petroleum ether/ethyl acetate=8:1 (V/V) as the eluent to carry out column chromatography separation and purification to obtain the desired product, the product is a white solid, and the collection is as follows: The rate is 70%.

The identification data results of the obtained product are: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.76 (dt, J=6.8, 1.2 Hz, 1H), 8.36 (d, J=9.1 Hz, 1H), 8.28 (d, J=8.8Hz, 1H), 7.59–7.44 (m, 1H), 7.14–7.05 (m, 2H), 7.00 (dd, J=8.8, 2.4Hz, 1H), 4.49 (q, J=7.1 Hz, 2H), 3.94 (s, 3H), 1.50 (t, J=7.1 Hz, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ (ppm) 167.8, 163.8, 163.0, 157.4, 153.2, 137.7 ,128.8,128.7,126.9,119.0,117.2,114.2,113.3,110.9,101.1,91.6,60.1,55.9,14.6.

Example 37

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula fourteen:

The reaction formula for preparing the compound described in formula fourteen is:

The preparation method of compound as described in formula fourteen, the concrete steps are: add 0.2mmol ethyl-3-(2-acetyl 3-methylphenoxy) acrylate, 0.6mmol pyridine, 0.2mmol to 15mL pressure-resistant tube Elemental iodine, 0.6mmol of tert-butyl peroxybenzoate, 2mL of 1,4-dioxane were sealed at 110°C and reacted with magnetic stirring for 10 hours. After the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, The solvent was removed by distillation under reduced pressure to obtain the crude product, and the crude product was separated and purified by column chromatography using petroleum ether/ethyl acetate=10:1 (V/V) as the eluent to obtain the desired product. The product was a white solid, and the yield was was 69%.

The result of identification data of the obtained product is: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.79 (dt, J=6.8, 1.2Hz, 1H), 8.40 (dt, J=9.0, 1.2Hz, 1H) ,8.28(d,J＝8.1Hz,1H),7.54(ddd,J＝8.4,7.2,1.2Hz,1H),7.49(s,1H),7.27(dd,J＝1.6,0.7Hz,1H), 7.11(td, J=6.9, 1.3Hz, 1H), 4.54-4.44(m, 2H), 2.53(s, 3H), 1.51(t, J=7.1Hz, 3H). ¹³ C-NMR (100MHz, CDCl) ₃ ): δ(ppm) 168.0, 163.1, 155.8, 153.5, 144.4, 138.2, 129.0, 128.8, 126.8, 125.5, 121.7, 119.0, 118.2, 114.3, 111.6, 91.6, 60.1, 21.8, 14.6.

Example 38

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula fifteen:

The reaction formula for preparing the compound described in formula fifteen is:

The preparation method of compound as described in formula fifteen, the concrete steps are: add 0.2mmol ethyl-3-(2-acetyl 4-bromophenoxy) acrylate, 0.6mmol pyridine, 0.2mmol elemental substance to 15mL pressure-resistant tube Iodine, 0.6mmol of tert-butyl peroxybenzoate, 2mL of 1,4-dioxane were sealed at 110°C and reacted with magnetic stirring for 10 hours. After the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, reduced The solvent was removed by pressure distillation to obtain the crude product, and the crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=15:1 (V/V) as the eluent to obtain the desired product. The product was a white solid, and the yield was 67%.

The results of identification data of the obtained product are: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.73 (dt, J=6.8, 1.2 Hz, 1H), 8.48 (d, J=2.5 Hz, 1H), 8.39 (dt, J=9.0, 1.2Hz, 1H), 7.76 (dd, J=8.8, 2.4Hz, 1H), 7.59–7.53 (m, 2H), 7.13 (td, J=6.8, 1.2Hz, 1H), 4.48 (q, J=7.1 Hz, 2H), 1.50 (t, J=7.1 Hz, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ (ppm) 166.2, 162.7, 154.4, 153.1, 138.2, 135.8 ,129.5,128.8,128.4,125.0,120.1,119.1,117.6,114.6,110.8,91.8,60.2,14.5.

Example 39

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula sixteen:

The reaction formula for preparing the compound described in formula sixteen is:

The preparation method of compound as described in formula sixteen, the specific steps are: add 0.2mmol ethyl-3-(2-acetyl 4-fluorophenoxy) acrylate, 0.6mmol pyridine, 0.2mmol elemental substance to 15mL pressure-resistant tube Iodine, 0.6mmol of tert-butyl peroxybenzoate, 2mL of 1,4-dioxane were sealed at 110°C and reacted with magnetic stirring for 10 hours. After the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, reduced The solvent was removed by pressure distillation to obtain the crude product, and the crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=10:1 (V/V) as the eluent to obtain the desired product. The product was a white solid, and the yield was 68%.

The result of identification data of the obtained product is: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.73 (dt, J=6.8, 1.2Hz, 1H), 8.38 (dt, J=9.0, 1.2Hz, 1H) ,8.01(dd,J＝8.4,3.1Hz,1H),7.65(dd,J＝9.1,4.2Hz,1H),7.55(ddd,J＝9.0,7.0,1.2Hz,1H),7.40(ddd,J =9.2,7.6,3.2Hz,1H),7.12(td,J=6.8,1.2Hz,1H),4.48(q,J=7.1Hz,2H),1.50(t,J=7.1Hz,3H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ(ppm) 166.7, 162.8, 160.3, 157.9, 153.3, 151.7, 138.4, 129.5, 128.8, 124.8, 120.9, 120.1, 119.0, 114.5, 111.0, 91.6, 60.2, 14.5.

Example 40

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula seventeen:

The reaction formula for preparing the compound described in formula seventeen is:

The preparation method of compound as described in formula seventeen, the concrete steps are: add 0.2mmol methyl-3-(2-acetyl 3-chlorophenoxy) acrylate, 0.6mmol pyridine, 0.2mmol elemental substance to 15mL pressure-resistant tube Iodine, 0.6mmol of tert-butyl peroxybenzoate, 2mL of 1,4-dioxane were sealed at 110°C and reacted with magnetic stirring for 10 hours. After the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, reduced The solvent was removed by pressure distillation to obtain the crude product, and the crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=10:1 (V/V) as the eluent to obtain the desired product. The product was a white solid, and the yield was 66%.

The results of identification data of the obtained product are: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.71 (dt, J=6.8, 1.2 Hz, 1H), 8.40 (d, J=9.0 Hz, 1H), 8.30 (d, J=8.5Hz, 1H), 7.69 (d, J=1.9Hz, 1H), 7.55 (ddd, J=8.4, 7.2, 1.2Hz, 1H), 7.40 (dd, J=8.5, 1.9Hz, 1H), 7.13 (td, J=6.8, 1.2Hz, 1H), 4.01 (s, 3H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ (ppm) 166.9, 163.2, 155.7, 152.8, 139.0, 138.4 ,129.4,128.7,126.9,125.1,122.2,119.0,118.3,114.7,110.8,91.5,51.4.

Example 41

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula eighteen:

The reaction formula for preparing the compound described in formula eighteen is:

The preparation method of compound as described in formula 18, the concrete steps are: add 0.2mmol methyl-3-(2-acetyl 4-methylphenoxy) acrylate, 0.6mmol pyridine, 0.2mmol to 15mL pressure-resistant tube Elemental iodine, 0.6mmol of tert-butyl peroxybenzoate, 2mL of 1,4-dioxane were sealed at 110°C and reacted with magnetic stirring for 10 hours. After the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, The solvent was removed by distillation under reduced pressure to obtain the crude product, and the crude product was separated and purified by column chromatography using petroleum ether/ethyl acetate=10:1 (V/V) as the eluent to obtain the desired product. The product was a white solid, and the yield was was 71%.

The result of identification data of the obtained product is: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.76 (dt, J=6.8, 1.2 Hz, 1H), 8.37 (dt, J=9.0, 1.2 Hz, 1H) ,8.14(dd,J＝1.6,0.7Hz,1H),7.59-7.45(m,3H),7.09(td,J＝6.8,1.2Hz,1H),4.00(s,3H),2.48(s,3H) ). ¹³ C-NMR (100MHz, CDCl ₃ ): δ(ppm) 167.9, 163.4, 153.8, 153.1, 138.3, 134.2, 129.2, 128.8, 125.2, 123.1, 118.9, 117.9, 114.3, 111.1, 91.2, 51.3, 20.9 .

Example 42

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula nineteen:

The reaction formula for preparing the compound described in formula nineteen is:

The preparation method of the compound as described in formula 19, the specific steps are: add 0.2mmol of ethyl-3-(2-acetnaphthyloxy)acrylate, 0.6mmol of pyridine, 0.2mmol of elemental iodine, 0.6 mmol tert-butyl peroxybenzoate and 2 mL of 1,4-dioxane were sealed at 110°C and reacted with magnetic stirring for 10 hours. After the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, and the solvent was removed by distillation under reduced pressure. The crude product was obtained, and the crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=15:1 (V/V) as the eluent to obtain the desired product. The product was a white solid with a yield of 50%.

The result of identification data of the obtained product is: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 10.27 (d, J=8.6Hz, 1H), 9.99 (dt, J=6.8, 1.2Hz, 1H), 8.43 (dt, J=9.0, 1.2Hz, 1H), 8.12 (d, J=9.0Hz, 1H), 7.93 (dd, J=8.0, 1.6Hz, 1H), 7.81–7.73 (m, 2H), 7.65– 7.51(m, 2H), 7.13(td, J=6.8, 1.4Hz, 1H), 4.51(q, J=7.1Hz, 2H), 1.53(t, J=7.1Hz, 3H). ¹³ C-NMR( 100MHz, CDCl ₃ ): δ(ppm) 170.8, 163.1, 156.8, 151.5, 138.0, 134.8, 131.6, 130.5, 128.9, 128.8, 128.7, 128.3, 126.9, 126.1, 118.9, 118.3, 116.3, 90.9, 112.1, 114.1, 1 60.1, 14.6.

Example 43

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula twentieth:

The reaction formula for preparing the compound described in formula twentieth is:

The preparation method of compound as described in formula twentieth, the concrete steps are: add 0.2mmol ethyl-3-(2-acetphenoxy) acrylate, 0.6mmol 4-picoline, 0.2mmol to 15mL pressure-resistant tube Elemental iodine, 0.6mmol of tert-butyl peroxybenzoate, 2mL of 1,4-dioxane were sealed at 110°C and reacted with magnetic stirring for 10 hours. After the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, The solvent was distilled off under reduced pressure to obtain the crude product, and the crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=12:1 (V/V) as the eluent to obtain the desired product. The product was a white solid, and the yield was was 69%.

The results of identification data of the obtained product are: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm). 9.63 (dd, J=6.6, 0.9 Hz, 1H), 8.39 (dd, J=7.6, 1.4 Hz, 1H) ), 8.18 (dt, J=2.0, 1.0Hz, 1H), 7.75–7.61 (m, 2H), 7.44 (ddd, J=8.0, 6.8, 1.2Hz, 1H), 6.95 (dd, J=6.8, 1.8 Hz, 1H), 4.56–4.38 (m, 2H), 2.52 (s, 3H), 1.50 (t, J=7.1Hz, 3H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ (ppm) 167.4, 163.2, 155.6, 153.5, 141.2, 138.7, 132.8, 128.2, 125.7, 124.3, 123.6, 118.2, 117.8, 116.8, 110.7, 90.6, 60.1, 22.1, 14.6.

Example 44

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula twenty-one:

The reaction formula for preparing the compound described in formula twenty-one is:

The preparation method of compound as described in formula twenty-one, the concrete steps are: add 0.2mmol ethyl-3-(2-acetphenoxy) acrylate, 0.6mmol 4-methoxypyridine, 0.2mmol elemental iodine, 0.6mmol tert-butyl peroxybenzoate, 2mL 1,4-dioxane were sealed at 110 ℃ and magnetic stirring was reacted for 10 hours, after the reaction was completed, the reaction solution was extracted, the organic layer was washed, Dry, remove the solvent under reduced pressure to obtain the crude product, and use petroleum ether/ethyl acetate=5:1 (V/V) as the eluent for the crude product to carry out column chromatography separation and purification to obtain the desired product. The product is a white solid, The yield was 68%.

The results of identification data of the obtained product are: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm). 9.54 (dd, J=7.5, 0.7Hz, 1H), 8.36 (dd, J=7.9, 1.2Hz, 1H) ), 7.72–7.56 (m, 3H), 7.42 (ddd, J=8.1, 6.9, 1.3Hz, 1H), 6.73 (dd, J=7.4, 2.7Hz, 1H), 4.45 (q, J=7.1Hz, 2H), 3.95 (s, 3H), 1.49 (t, J=7.1 Hz, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ (ppm) 166.75, 163.34, 160.84, 155.44, 153.76, 141.17, 132.55 ,130.07,125.58,124.23,123.74,118.07,110.23,108.10,97.29,90.40,59.94,55.77,14.52.

Example 45

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula twenty-two:

The reaction formula for preparing the compound described in formula twenty-two is:

The preparation method of compound as described in formula twenty-two, the concrete steps are: add 0.2mmol ethyl-3-(2-acetphenoxy) acrylate, 0.6mmol methylisonicotinic acid, 0.2 mmol to 15mL pressure-resistant tube mmol elemental iodine, 0.6mmol benzoyl peroxide, 2mL 1,4-dioxane were sealed at 110 ℃ and magnetic stirring was reacted for 10 hours, after the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, reduced The solvent was removed by pressure distillation to obtain the crude product, and the crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=15:1 (V/V) as the eluent to obtain the desired product. The product was a white solid, and the yield was 67%.

The result of identification data of the obtained product is: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.74 (dd, J=7.1, 1.0 Hz, 1H), 9.02 (dd, J=1.8, 1.0 Hz, 1H) ,8.36(dd,J＝7.9,1.7Hz,1H),7.71(ddd,J＝8.8,6.8,1.8Hz,1H),7.67–7.59(m,2H),7.44(ddd,J＝8.0,6.8, 1.2Hz, 1H), 4.50 (q, J=7.1Hz, 2H), 3.98 (s, 3H), 1.51 (t, J=7.1Hz, 3H).. ¹³ C-NMR (100MHz, CDCl ₃ ): δ (ppm) 168.3, 164.9, 162.5, 155.6, 152.9, 136.6, 133.5, 129.5, 128.2, 125.9, 124.5, 123.3, 121.2, 118.3, 113.3, 111.9, 94.1, 60.5, 52.8, 14.5.

Example 46

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula twenty-three:

The reaction formula for preparing the compound described in formula twenty-three is:

The preparation method of compound as described in formula twenty-three, the specific steps are: add 0.2mmol N-methyl-N-phenyl-3-(2-acetphenoxy)acrylamide, 0.6mmol pyridine into 15mL pressure-resistant tube , 0.2mmol elemental iodine, 0.6mmol tert-butyl peroxybenzoate, 2mL 1,4-dioxane were sealed at 110 ° C and magnetic stirring was reacted for 10 hours, after the reaction was completed, the reaction solution was extracted, and the organic layer was washed , drying, and distillation under reduced pressure to remove the solvent to obtain the crude product, the crude product uses petroleum ether/ethyl acetate=5:1 (V/V) as the eluent to carry out column chromatography separation and purification to obtain the desired product, and the product is a white solid , the yield is 67%.

The result of identification data of the obtained product is: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.66 (dt, J=6.8, 1.2Hz, 1H), 8.28 (dd, J=7.9, 1.7Hz, 1H) ,8.23(dt,J=9.1,1.2Hz,1H),7.57(ddd,J=8.6,7.1,1.7Hz,1H),7.50–7.42(m,1H),7.37–7.30(m,1H),7.26 –7.20(m, 3H), 7.17 – 7.11(m, 2H), 7.03(td, J=6.8, 1.3Hz, 1H), 6.99 – 6.93(m, 1H), 3.63(s, 3H). ¹³ C- NMR (100MHz, CDCl ₃ ): δ(ppm) 167.5, 164.0, 154.9, 148.6, 144.7, 138.0, 132.5, 128.5, 128.4, 127.2, 126.1, 125.9, 125.6, 123.9, 123.1, 118.7, 117.3, 113.6 95.6, 38.1.

Example 47

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula twenty-four:

The reaction formula for preparing the compound described in formula twenty-four is:

The preparation method of compound as described in formula twenty-four, the concrete steps are: add 0.2mmol ethyl-3-(2-acetphenoxy) acrylate, 0.6mmol isoquinoline, 0.2mmol elemental substance to 15mL pressure-resistant tube Iodine, 0.6mmol of tert-butyl peroxybenzoate, 2mL of 1,4-dioxane were sealed at 110°C and reacted with magnetic stirring for 10 hours. After the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, reduced The solvent was removed by pressure distillation to obtain the crude product, and the crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=8:1 (V/V) as the eluent to obtain the desired product. The product was a white solid, and the yield was 68%.

The result of identification data of the obtained product is: ¹ H-NMR (400MHz, CDCl ₃ ): δ(ppm) 1H NMR (400MHz, Chloroform-d) δ9.63(d, J=7.2Hz, 1H), 9.58-9.51( m, 1H), 8.41 (dd, J=8.0, 1.6Hz, 1H), 7.77–7.73 (m, 1H), 7.70 (ddd, J=8.7, 7.0, 1.7Hz, 1H), 7.67–7.62 (m, 2H), 7.59(dd, J＝8.5, 1.1Hz, 1H), 7.44(ddd, J＝8.0, 7.0, 1.1Hz, 1H), 7.28(d, J＝7.0Hz, 1H), 4.57(q, J =7.1Hz, 2H), 1.57 (t, J=7.1Hz, 3H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ (ppm) 168.1, 163.9, 155.5, 152.7, 135.1, 133.0, 131.0, 129.8, 128.0, 127.7, 127.2, 125.9, 124.5, 124.2, 123.8, 123.6, 118.1, 114.7, 111.5, 97.0, 60.9, 14.4.

Example 48

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula twenty-five:

The reaction formula for preparing the compound described in formula twenty-five is:

The preparation method of compound as described in formula twenty-five, the concrete steps are: add 0.2mmol methyl-3-(2-acetyl 4-fluorophenoxy) acrylate, 0.6mmol pyridine, 0.2mmol to 15mL pressure-resistant tube Elemental iodine, 0.6mmol of tert-butyl peroxybenzoate, 2mL of 1,4-dioxane were sealed at 110°C and reacted with magnetic stirring for 10 hours. After the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, The solvent was removed by distillation under reduced pressure to obtain the crude product, and the crude product was separated and purified by column chromatography using petroleum ether/ethyl acetate=10:1 (V/V) as the eluent to obtain the desired product. The product was a white solid, and the yield was was 72%.

The results of identification data of the obtained product are: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.73 (dt, J=6.8, 1.2 Hz, 1H), 8.39 (dt, J=9.0, 1.2 Hz, 1H) ,8.01(dd,J＝8.4,3.1Hz,1H),7.67(dd,J＝9.1,4.2Hz,1H),7.56(ddd,J＝8.2,6.8,1.2Hz,1H),7.41(ddd,J = 9.2, 7.6, 3.2 Hz, 1H), 7.13 (td, J=7.2, 1.4 Hz, 1H), 4.01 (s, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ (ppm) 166.8, 163.3 ,160.4,157.9,153.2,152.1,138.5,129.6,128.8,124.9,120.7,120.1,119.0,114.6,110.8,91.4,51.4.

Example 49

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula twenty-six:

The reaction formula for preparing the compound described in formula twenty-six is:

The preparation method of compound as described in formula twenty-six, the specific steps are: add 0.2mmol isopropyl-3-(2-acetphenoxy) acrylate, 0.6mmol pyridine, 0.2mmol elemental iodine to 15mL pressure-resistant tube , 0.6mmol of tert-butyl peroxybenzoate, 2mL of 1,4-dioxane were sealed at 110 ° C and magnetic stirring was reacted for 10 hours. After the reaction was completed, the reaction solution was extracted, and the organic layer was washed, dried, and reduced in pressure. The solvent was distilled off to obtain the crude product, and the crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=10:1 (V/V) as the eluent to obtain the desired product. The product was a white solid, and the yield was 62 %.

The identification data results of the obtained product are: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.77 (dt, J=6.8, 1.2Hz, 1H), 8.43-8.32 (m, 2H), 7.72-7.63 ( m, 2H), 7.53 (ddd, J=9.0, 7.0, 1.2Hz, 1H), 7.43 (ddd, J=8.1, 6.8, 1.6Hz, 1H), 7.10 (td, J=6.9, 1.3Hz, 1H) , 5.36 (p, J=6.2Hz, 1H), 1.48 (d, J=6.3Hz, 6H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ (ppm) 167.8, 162.5, 155.6, 153.3, 138.1, 132.9, 129.1, 128.7, 125.7, 124.2, 123.4, 118.9, 118.2, 114.2, 110.9, 91.9, 67.6, 22.2.

Example 50

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula twenty-seven:

The reaction formula for preparing the compound described in formula twenty-seven is:

The preparation method of compound as described in formula twenty-seven, the concrete steps are: add 0.2mmol (2S, 5R)-2-isopropyl-5-methylcyclohexyl-3-(2-acetyl to 15mL pressure-resistant tube) phenoxy) acrylate, 0.6 mmol pyridine, 0.2 mmol elemental iodine, 0.6 mmol tert-butyl peroxybenzoate, 2 mL 1,4 dioxane were sealed at 110 ° C and reacted with magnetic stirring for 10 hours, after the completion of the reaction , the reaction solution was extracted, the organic layer was washed, dried, and the solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=10:1 (V/V) as the eluent The desired product was obtained, the product was a yellow liquid, and the yield was 60%.

The results of identification data of the obtained product are: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.79 (dt, J=6.8, 1.2 Hz, 1H), 8.44-8.38 (m, 2H), 7.71 (ddd, J=8.6, 7.0, 1.7Hz, 1H), 7.64 (dd, J=8.4, 1.2Hz, 1H), 7.55 (ddd, J=9.0, 7.0, 1.3Hz, 1H), 7.47–7.43 (m, 1H) ,7.12(td,J＝6.9,1.3Hz,1H),5.01(td,J＝10.8,4.4Hz,1H),2.34-2.26(m,1H),2.22(dtd,J＝14.0,7.0,2.6Hz ,1H),1.78(ddd,J=12.6,6.4,2.7Hz,2H),1.73-1.66(m,1H),1.65-1.56(m,1H),1.27-1.14(m,3H),0.99(d , J=7.0Hz, 3H), 0.96 (d, J=6.6Hz, 3H), 0.85 (d, J=7.0Hz, 3H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ (ppm) 167.8, 162.7,155.6,153.2,138.3,130.1,129.1,128.8,125.7,124.3,123.5,118.9,118.1,114.3,110.9,91.9,74.2,47.5,41.4,34.4,31.5,26.4,23.6,2

Example 51

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula twenty-eight:

The reaction formula for preparing the compound described in formula twenty-eight is:

The preparation method of compound as described in formula twenty-eight, the concrete steps are: add 0.2mmol ethyl-3-(2-acetylphenoxy) acrylate, 0.6mmol isonicotinaldehyde, 0.2mmol elemental substance to 15mL pressure-resistant tube Iodine, 0.6mmol of tert-butyl peroxybenzoate, 2mL of 1,4-dioxane were sealed at 110°C and reacted with magnetic stirring for 10 hours. After the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried, reduced The solvent was removed by pressure distillation to obtain the crude product, and the crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=15:1 (V/V) as the eluent to obtain the desired product. The product was a white solid, and the yield was 67%.

The results of identification data of the obtained product are: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 10.10 (d, J=0.7Hz, 1H), 9.84 (dt, J=7.1, 0.8Hz, 1H), 8.91 (dd, J=1.7, 1.0Hz, 1H), 8.43 (dd, J=7.9, 1.6Hz, 1H), 7.77 (ddd, J=8.6, 7.0, 1.7Hz, 1H), 7.70 (dd, J=8.7 ,1.1Hz,1H),7.56(dd,J＝7.0,1.8Hz,1H),7.49(ddd,J＝8.1,7.0,1.2Hz,1H),4.55(q,J＝7.1Hz,2H),1.54 (t, J=7.1 Hz, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ (ppm) 189.85, 169.21, 162.58, 155.68, 152.97, 136.62, 134.58, 133.84, 128.92, 126.00, 124.71, 124.68, 123.32, 118.41, 112.30, 110.13, 95.22, 60.72, 14.53.

Example 52

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula twenty-nine:

The reaction formula for preparing the compound described in formula twenty-nine is:

The preparation method of compound as described in formula twenty-nine, the concrete steps are: add 0.2mmol ethyl-3-(2-acetphenoxy) acrylate, 0.6mmol 4-benzyl pyridine, 0.2 mmol to 15mL pressure-resistant tube mmol elemental iodine, 0.6mmol tert-butyl peroxybenzoate, 2mL 1,4-dioxane were sealed at 110 ° C and magnetic stirring was reacted for 10 hours, after the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried , Remove the solvent under reduced pressure to obtain the crude product, and the crude product uses petroleum ether/ethyl acetate=15:1 (V/V) as the eluent to carry out column chromatography separation and purification to obtain the desired product, the product is a white solid, and the collection is as follows: The rate is 68%.

The result of identification data of the obtained product is: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.65 (dd, J=7.0, 0.8 Hz, 1H), 8.43-8.35 (m, 1H), 8.21 (dd, J=1.8, 1.0Hz, 1H), 7.73–7.64 (m, 2H), 7.44 (ddd, J=8.0, 6.4, 1.6Hz, 1H), 7.39–7.32 (m, 2H), 7.30–7.26 (m, 2H), 7.25(s, 1H), 6.94(dd, J=7.0, 1.9Hz, 1H), 4.45(q, J=7.1Hz, 2H), 4.12(s, 2H), 1.45(t, J=7.1 Hz, 3H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ(ppm) 167.5, 163.1, 155.6, 153.5, 143.9, 138.5, 132.9, 129.1, 128.9, 128.5, 126.9, 125.7, 124.3, 123.6, 118.2, 117.8, 116.0, 110.8, 91.2, 60.1, 42.1, 14.5.

Example 53

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula 30:

The reaction formula for preparing the compound described in formula 30 is:

The preparation method of compound as described in formula 30, the concrete steps are: add 0.2mmol ethyl-3-(2-acetphenoxy) acrylate, 0.6mmol 7-methoxyisoquinoline to 15mL pressure-resistant tube , 0.2mmol elemental iodine, 0.6mmol tert-butyl peroxybenzoate, 2mL 1,4-dioxane were sealed at 110 ° C and magnetic stirring was reacted for 10 hours, after the reaction was completed, the reaction solution was extracted, and the organic layer was washed , drying, and distillation under reduced pressure to remove the solvent to obtain the crude product, the crude product uses petroleum ether/ethyl acetate=15:1 (V/V) as the eluent to carry out column chromatography separation and purification to obtain the desired product, and the product is a white solid , the yield is 69%.

The result of identification data of the obtained product is: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.61-9.47 (m, 2H), 8.38 (ddd, J=11.3, 8.0, 1.6Hz, 1H), 7.68 ( ddd, J=8.6, 7.0, 1.6Hz, 1H), 7.59–7.51 (m, 1H), 7.42 (ddd, J=8.0, 7.0, 1.1Hz, 1H), 7.23–7.14 (m, 2H), 7.06 ( d, J=2.7Hz, 1H), 4.55 (q, J=7.2Hz, 2H), 3.93 (d, J=13.4Hz, 3H), 1.57 (t, J=7.1Hz, 3H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ(ppm) 167.6,163.9,160.5,155.4,153.1,135.6,133.3,132.7,130.1,125.8,124.9,124.1,123.6,118.0,117.9,117.6,114.2,111.0,1 ,60.8,55.4,14.5.

Example 54

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula 31:

The reaction formula for preparing the compound described in formula 31 is:

The preparation method of compound as described in formula 31, the concrete steps are: add 0.2mmol ethyl-3-(2-acetphenoxy) acrylate, 0.6mmol 3,5-dimethyl acrylate to 15mL pressure-resistant tube Pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate, 2mL of 1,4-dioxane were sealed at 110° C. and reacted with magnetic stirring for 10 hours. After the reaction was completed, the reaction solution was extracted, and the organic layer was Washing, drying, and distillation under reduced pressure to remove the solvent to obtain the crude product. The crude product is separated and purified by column chromatography with petroleum ether/ethyl acetate=15:1 (V/V) as the eluent to obtain the desired product. The product is white solid, the yield is 70%.

The result of identification data of the obtained product is: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.59-9.51 (m, 1H), 8.36 (dd, J=7.9, 1.6 Hz, 1H), 7.66 (ddd, J=8.7,7.0,1.7Hz,1H),7.56(dd,J=8.4,1.1Hz,1H),7.40(ddd,J=8.1,7.0,1.1Hz,1H),7.07(s,1H),4.44 (q, J=7.1 Hz, 2H), 2.69 (s, 3H), 2.36 (s, 3H), 1.49 (t, J=7.1 Hz, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ( ppm) 167.4, 162.8, 155.3, 153.0, 135.5, 133.2, 132.7, 128.4, 125.7, 124.7, 123.9, 123.9, 123.5, 117.9, 110.1, 93.1, 60.4, 21.5, 17.9, 14.5.

Example 55

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula thirty-two:

The reaction formula for preparing the compound described in formula thirty-two is:

The preparation method of compound as described in formula thirty-two, the concrete steps are: add 0.2mmol (E)-3-(2-acetylphenoxy) n-phenylacrylamide, 0.6mmol pyridine, 0.2 mmol to 15mL pressure-resistant tube mmol elemental iodine, 0.6mmol tert-butyl peroxybenzoate, 2mL 1,4-dioxane were sealed at 110 ° C and magnetic stirring was reacted for 10 hours, after the reaction was completed, the reaction solution was extracted, the organic layer was washed, dried , Remove the solvent under reduced pressure to obtain the crude product, and the crude product uses petroleum ether/ethyl acetate=15:1 (V/V) as the eluent to carry out column chromatography separation and purification to obtain the desired product, the product is a white solid, and the collection is as follows: The rate was 67%.

The results of identification data of the obtained product are: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.66 (d, J=6.8 Hz, 1H), 8.68 (d, J=9.0 Hz, 1H), 8.55 (s ,1H),8.39(dd,J＝7.9,1.7Hz,1H),7.75-7.72(m,2H),7.72-7.68(m,1H),7.59(dd,J＝8.4,1.1Hz,1H), 7.54–7.49 (m, 1H), 7.49–7.43 (m, 1H), 7.43–7.38 (m, 2H), 7.20–7.13 (m, 1H), 7.10 (td, J=6.9, 1.4Hz, 1H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ(ppm) 167.1, 160.6, 154.7, 150.0, 144.5, 138.2, 133.1, 129.1, 129.0, 128.3, 126.2, 124.8, 124.0, 123.5, 120.1, 119.5, 117.3, 1 ,110.0,93.8.

Example 56

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula 33:

The reaction formula for preparing the compound described in formula 33 is:

The preparation method of compound as described in formula thirty-three, the concrete steps are: add 0.2mmol (E)-3-(2-acetylphenoloxy)-1-morpholinopropyl-2-ene to 15mL pressure-resistant tube -1-1, 0.6mmol pyridine, 0.2mmol elemental iodine, 0.6mmol tert-butyl peroxybenzoate, 2mL 1,4-dioxane were sealed at 110 ° C and magnetic stirring was reacted for 10 hours, after the reaction was completed, The reaction solution was extracted, the organic layer was washed, dried, and the solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography with petroleum ether/ethyl acetate=15:1 (V/V) as an eluent to obtain a crude product. The desired product was a white solid with a yield of 67%.

The results of identification data of the obtained product are: ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 9.78-9.63 (m, 1H), 8.42 (dd, J=7.9, 1.7 Hz, 1H), 8.06 (dd, J=9.0, 1.2Hz, 1H), 7.70 (ddd, J=8.7, 7.1, 1.8Hz, 1H), 7.56 (dd, J=8.4, 1.1Hz, 1H), 7.45 (tdd, J=7.9, 2.7, 1.2Hz, 2H), 7.07 (td, J=6.9, 1.3Hz, 1H), 3.91–3.84 (m, 4H), 3.84–3.74 (m, 4H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ (ppm) 167.4, 163.1, 155.2, 148.9, 138.0, 133.0, 128.4, 127.9, 126.1, 124.3, 123.5, 118.6, 117.4, 113.9, 109.8, 94.1, 67.2, 53.4.

Example 57

An indolizinochromone compound with antitumor activity, its structural formula is shown in formula thirty-four:

The reaction formula for preparing the compound described in formula thirty-four is:

The preparation method of compound as described in formula thirty-four, the concrete steps are: add 0.2mmol methyl-3-(2-acetphenoxy) acrylate, 0.6mmol 3,5-dimethyl acrylate to 15mL pressure-resistant tube Pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate, 2mL of 1,4-dioxane were sealed at 110° C. and reacted with magnetic stirring for 10 hours. After the reaction was completed, the reaction solution was extracted, and the organic layer was Washing, drying, and distillation under reduced pressure to remove the solvent to obtain the crude product. The crude product is separated and purified by column chromatography with petroleum ether/ethyl acetate=15:1 (V/V) as the eluent to obtain the desired product. The product is white Solid, yield 67%.

The results of identification data of the obtained product are: ¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 9.58 (s, 1H), 8.37 (dd, J=8.0, 1.6 Hz, 1H), 7.67 (ddd, J= 8.6,7.0,1.6Hz,1H),7.60(dd,J=8.4,1.2Hz,1H),7.41(ddd,J=8.0,7.0,1.2Hz,1H),7.10(s,1H),3.98(s , 3H), 2.69(s, 3H), 2.37(s, 3H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ(ppm) 167.4, 163.3, 155.4, 153.1, 135.6, 133.4, 132.8, 128.5, 125.8 ,124.8,124.1,124.0,123.5,118.0,110.2,92.7,51.5,21.5,17.9.

Example 58

The purpose of this example is to observe the effect of the indolizinochromone derivatives of the present invention in inhibiting the proliferation of tumor cells.

1. Instruments and equipment:

Ultra-clean workbench, autoclave, micropipette, 96-well plate, hemocytometer, inverted microscope, 37°C 5% _CO2 incubator, microplate reader, analytical balance and micro-shaker;

2. Cell lines and reagents

Oral epidermoid cancer cells KBV, human gastric cancer cells MKN-45, complete medium, trypsin digestion solution (0.25% trypsin + 0.02% EDTA), PBS buffer, dimethyl sulfoxide (DMSO), tetramethyl bisulfite Azole blue (MTT), MTT solution: take MTT (250 mg) and add 50 mL of deionized water, the final concentration is 5 mg/mL in the dark and ultrasonically dissolved, and store at 4°C in the dark after aliquoting.

3. Experimental method

Different tumor cells in the logarithmic growth phase were digested with 0.25% trypsin, and then prepared into a single cell suspension of a certain concentration. According to the difference in cell growth rate, 3000 cells/well were inoculated in a 96-well plate, and cells were added to each well. Suspension 100uL. After 24h, 100uL of 10uM compound (final concentration of DMSO≤0.1%) was added to each well of the experimental group, and the same volume of complete medium was added to the control group. Three parallel wells were set in each group, and the supernatant was discarded after culturing at 37℃ for 72h. Add 20uL of MTT with a concentration of 5mg/mL to each well, and continue to culture for 2-4h. After discarding the supernatant, add 150uL of DMSO to each well to dissolve the formazan crystals. The optical density (OD) was measured at a wavelength of 570 nm, and the tumor cells treated with the medium control were used as the control group, and the inhibition rates of different tumor cells under the action of each compound were calculated by the following formula.

Cell inhibition rate (%)=(1-average OD value of administration group/average OD value of control group)×100%

4. Experimental results

The inhibition rates of Examples 1-57 involved in the method of the present invention on human oral epidermoid cancer cell KBV and human gastric cancer cell MKN-45 are shown in Table 1.

Table 1 Inhibitory rate of Example 1-57 on KBV and MKN-45 tumor cells

As can be seen from Table 1, Example 1-57 showed a certain inhibitory effect on the proliferation of KBV and IMKN-45 tumor cells. Examples 1, 27, 41, 42, 46, and 48 have strong inhibitory effects on two tumor cells, among which Examples 1 and 41 show certain selectivity, and have high inhibitory effects on human oral epidermoid cancer cells KBV Inhibitory effect on human gastric cancer cell MKN-45; and Example 46 showed strong inhibitory effect on KBV and IMKN tumor cells. The above six examples show a strong inhibitory effect on the proliferation of two kinds of tumor cells, and can be used as drug lead compounds for the preparation of subsequent anti-tumor drugs; in addition to the above six compounds, the remaining compounds have strong inhibitory effects on the two kinds of cancer cells. The inhibitory activity is not strong, but it also shows a certain inhibitory activity, which can provide a quantitative effect on the number of compounds for future new drug development.

Specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the above-mentioned specific embodiments, and those skilled in the art can make various variations or modifications within the scope of the claims, which do not affect the essential content of the present invention.

Claims (9)

1. an indolizinochromone compound with antitumor activity, is characterized in that, the structural formula of described compound is as shown in formula seven:

Wherein, R ₁ in formula seven is hydrogen, halogen, substituted alkyl or aryl; In formula seven, R ₂ is methoxy, ethoxy, isopropoxy or substituted amino; In formula 7, R ₃ is hydrogen, halogen, ester group, substituted alkyl group or aryl group. 2. a preparation method of the indolizinochromone compound with antitumor activity as claimed in claim 1, is characterized in that, comprises the steps: Under the condition of oxidant, the compound shown in formula 8 and the compound shown in formula 9 are self-organized one-pot synthesis under the action of catalyst iodine to obtain the compound shown in formula 7;

Wherein, in formula eight R ₁ is hydrogen, halogen, substituted alkyl or aryl; In formula eight, R ₂ is methoxy, ethoxy, isopropoxy or substituted amino; In formula 9, R ₃ is hydrogen, halogen, ester group, substituted alkyl group or aryl group. 3. the preparation method of the indolizinochromone compound with antitumor activity according to claim 2 is characterized in that, the molar dosage ratio of the compound shown in the formula 8 and the compound shown in the formula 9 is 1.0: (1.5～3.0). 4 . The method for preparing an indolizinochromone compound with antitumor activity according to claim 2 , wherein the molar amount of the catalyst iodine is 0.5-2.0 times the molar amount of the compound represented by formula 8. 5 . 5 . The preparation method of the indolizinochromone compound with antitumor activity according to claim 2 , wherein the oxidant condition is specifically in the presence of an oxidant, and the oxidant is oxygen, peroxide One or more of tert-butyl benzoate, benzoyl peroxide and methyl tert-butyl peroxide. 6. The preparation method of the indolizinochromone compound with antitumor activity according to claim 2, wherein the molar dosage ratio of the compound represented by the formula 8 to the oxidant is 1:(2 ~3). 7 . The method for preparing indolizinochromones with antitumor activity according to claim 2 , wherein the specific conditions for the self-organized one-pot synthesis are: a temperature of 80-140° C. Carry out 6～15h in organic solvent. 8. The preparation method of the indolizinochromone compound with antitumor activity according to claim 7, wherein the organic solvent is toluene, benzene, 1,4-dioxane, dimethyl sulfoxide One or more of sulfone, 1,2-dichloroethane, ethylene glycol, N,N-dimethylformamide and N-methylpyrrolidone. 9 . The method for preparing the indolizinochromone compounds with antitumor activity according to claim 2 , wherein the synthesis is carried out in a closed environment. 10 .