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 biological medicines, and particularly relates to an indolizine chromophoric ketone compound with anti-tumor activity, and a preparation method and application thereof. The invention leads substituted o-acetylphenoxy acrylate compounds and pyridine compounds to contact and react under iodine simple substance to synthesize a new indolizine chromogen ketone compound. The indolizine chromone compound has good anti-tumor effect and can be used for screening and preparing anti-tumor drugs. The preparation method has the advantages of cheap and easily-obtained raw materials, simple operation method, mild reaction conditions, short steps and no need of using metal catalysts and toxic substances, and can be carried out by a one-pot method, thereby providing a feasible method for industrially preparing the compounds.

Description

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

Technical Field

The invention belongs to the technical field of biological medicines, and particularly relates to an indolizine chromophoric ketone compound with anti-tumor activity, and a preparation method and application thereof.

Background

Both natural and synthetic heteromultimers generally exhibit biological activity. Indolizines and chromones are important nitrogen-containing heterocycles, high in content in many natural products and bioactive compounds, which possess a wide range of biological activities, such as antibacterial, antitumor, antioxidant, anticonvulsant, anti-inflammatory, and HIV inhibitory activity.

Chromones and indolizines are considered as structurally modified dominant scaffolds for the design of new compounds with potential pharmacological activity, particularly in the areas of neurodegenerative, inflammatory and infectious diseases, as well as diabetes and cancer. In addition, the use of chromones in the treatment of asthma has also been widely explored, mainly as bronchodilators. During the drug development process, sodium keletonate (DSCG, shown in a formula I) and pranlukast (pranlukast, shown in a formula II) are finally found, and are respectively useful drugs for treating mild-moderate asthma and allergic rhinitis. The indolizine is more and more concerned by people as a key pharmacophore for discovery and research of various small molecular drugs (as shown in formulas III and IV), and shows good antitumor activity.

Since chromone and indolizine show good pharmacological activity and potential pharmaceutical value, people synthesize many compounds with chromone and indolizine frameworks, but the structures containing the two dominant frameworks are rarely reported, which attracts the attention of many scientific researchers at home and abroad. Then some indolizine chromogens are synthesized (shown as formula five and formula six).

In 2003, Deevi Basavaiah et al realized the construction of indolizine chromophoric ketone compound frameworks by Baylis-Hillman reaction, which is the first report on the synthesis of indolizine chromophoric ketone compounds, see reaction formula I:

in 2010 Yi-Chen Lee et al, using thermal and microwave-assisted cyclization to synthesize indolizine chromogens, see reaction formula II:

in conclusion, the indolizine chromocor compounds are compounds with potential medicinal value, the synthesis and pharmacological activity of the compounds are always the focus of attention of researchers, the research on the indolizine chromocor isomeric derivatives is relatively less, only one indolizine chromocor compound is reported at present, and the research on the pharmacological activity of the indolizine chromocor compounds is more rarely reported. Therefore, it is very important to synthesize a new indolizine chromogen ketone compound and research the pharmacological activity of the compound.

Disclosure of Invention

In view of the above-mentioned disadvantages of the prior art, the present invention aims to provide indolizine chromone compounds with anti-tumor activity, and a preparation method and applications thereof.

In order to achieve the above objects, one aspect of the present invention relates to an indolizine chromone compound having anti-tumor activity, wherein the structural formula of the compound is represented by formula seven:

wherein, R in the formula₁Is hydrogen, halogen, substituted alkyl or aryl;

in the formula VII, R₂Is methoxy, ethoxy, isopropoxy or substituted amino;

in the formula VII, R₃Is hydrogen, halogen, ester group, substituted alkyl or aryl.

The invention also relates to a preparation method of the indolizine chromophoric ketone compound with the anti-tumor activity, which comprises the following steps:

under the condition of an oxidant, carrying out self-organizing one-pot synthesis on a compound shown as a formula eight and a compound shown as a formula nine under the action of a catalyst iodine simple substance to obtain a compound shown as a formula seven;

wherein, R in the formula VIII₁Is hydrogen, halogen, substituted alkyl or aryl;

in the formula VIII, R₂Is methoxy, ethoxy, isopropoxy or substituted amino;

in the formula of₃Is hydrogen, halogen, ester group, substituted alkyl or aryl.

Preferably, the molar ratio of the compound shown in the formula eight to the compound shown in the formula nine is 1.0: (1.5-3.0); more preferably, the molar ratio of the compound shown in the formula eight to the compound shown in the formula nine is 1.0: (2.5-3.0).

Preferably, the molar dosage of the iodine elementary substance of the catalyst is 0.5-2.0 times of that of the compound shown in the formula VIII; further preferably, the dosage of the iodine simple substance of the catalyst is 0.8-1.2 times of the molar dosage of the compound shown in the formula VIII.

Preferably, the condition of the oxidizing agent is specifically that in the presence of the oxidizing agent, the oxidizing agent is one or more of oxygen, tert-butyl peroxybenzoate, benzoyl peroxide and methyl tert-butyl peroxide. When the oxidizing agent is one or more of tert-butyl peroxybenzoate and benzoyl peroxide, the compound of formula seven can be prepared in higher yield.

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

Preferably, the specific conditions of the self-organizing one-pot synthesis are as follows: the reaction is carried out in an organic solvent at the temperature of 80-140 ℃ for 6-15 h.

Preferably, the organic solvent is one or more of toluene, benzene, 1, 4-dioxane, dimethyl sulfoxide, 1, 2-dichloroethane, ethylene glycol, N-dimethylformamide and N-methylpyrrolidone. The dosage of the organic solvent is 15-40 mL, preferably 20-30 mL, relative to the total amount of 10mmol of the compound shown in the formula eight and the compound shown in the formula nine.

Preferably, the self-organizing 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 invention, 1, 4-Dioxane (Dioxane) is used as a solvent, tert-butyl peroxybenzoate (TBPB) is used as an oxidant, and a catalyst iodine simple substance (I)₂) At 110 ℃ for 10 hours, see reaction formula III:

furthermore, the invention also relates to application of the indolizine chromone compound with the antitumor activity in screening antitumor drugs and preparing antitumor drugs and drug carriers.

The indolizine chromone compound with the anti-tumor activity can effectively inhibit the proliferation of tumor cells, can be used for preparing anti-tumor drugs and drug carriers, and can be used for treating gastric cancer, lung cancer, cervical cancer, breast cancer or colon cancer and the like.

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

(1) the invention synthesizes a parent nucleus skeleton of

Novel indolizine chromogens;

(2) the existing technology for synthesizing indolizine chromogens is mostly multi-step reaction (see reaction formulas I and II), and raw materials are expensive and difficult to prepare; the preparation method is a metal-free catalysis one-pot total synthesis method, has mild reaction conditions, cheap and easily-obtained raw materials, shorter steps, no need of using metal catalysts and toxic substances and no influence on the environment; the target product is generated by connecting a plurality of steps in series in one pot, an intermediate does not need to be separated, the production cost is saved, the yield can reach 72 percent at most, and a feasible method is provided for industrially preparing the compound;

(3) the invention screens the anti-tumor activity of the indolizine chromocor compound for the first time, and the compound shows better anti-tumor activity, has good anti-tumor effect and can be used for screening and preparing anti-tumor drugs.

Detailed Description

The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention.

Example 1

An indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as formula ten:

preparing the compound shown in the formula ten, wherein the reaction formula is as follows:

acetyl phenoxy) acrylate, 0.6mmol of pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, wherein 4-dioxane is sealed at 110 ℃ and is magnetically stirred for reaction for 10 hours, after the reaction is finished, the reaction solution is extracted, an organic layer is washed, dried and decompressed and distilled to remove a solvent, thus obtaining a crude product, and the crude product is subjected to column chromatography separation and purification by using petroleum ether/ethyl acetate (10: 1(V/V) as eluent, thus obtaining the required product, namely a white solid, with the yield of 72%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):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).¹³C-NMR(100MHz,CDCl₃):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.

examples 2 to 4

Examples 2 to 4 indolizine chromanone compounds having antitumor activity, which have the structural formula shown in formula ten, are prepared as in example 1, except that the oxidizing agent is used, and the specific conditions and reaction yields are shown in table 1 below:

TABLE 1

Examples

Catalyst and process for preparing same

Solvent(s)

Oxidizing agent

Time (h)

Temperature of

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％

Examples 5 to 11

Examples 5 to 11 indolizine chromanone compounds having antitumor activity, the structural formula is shown in formula ten, the differences only lie in the solvents used, and the specific conditions and reaction yields are shown in table 2 below, as in example 1:

TABLE 2

Example 12

An indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown in formula ten, and the compound prepared according to the formula ten has the same reaction formula as the reaction formula IV. The preparation method of the compound shown in the formula ten comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetylphenoxy) acrylate, 0.3mmol of pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure-resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is finished, washing an organic layer, drying, and distilling under reduced pressure to remove a solvent to obtain a crude product, and performing column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate (10: 1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 30%.

Example 13

An indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown in formula ten, and the compound prepared according to the formula ten has the same reaction formula as the reaction formula IV. The preparation method of the compound shown as the formula ten comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetylphenoxy) acrylate, 0.4mmol of pyridine, 0.2mmol of elemental iodine, 0.3mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure-resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting the reaction solution after the reaction is finished, washing an organic layer, drying, and distilling under reduced pressure to remove a solvent to obtain a crude product, wherein the crude product is obtained by using petroleum ether/ethyl acetate

And (2) performing column chromatography separation and purification on the eluent with the ratio of 10:1(V/V) to obtain the required product, wherein the product is a white solid, and the yield is 46%.

Example 14

An indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown in formula ten, and the compound prepared according to the formula ten has the same reaction formula as the reaction formula IV. The preparation method of the compound shown in the formula ten comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetylphenoxy) acrylate, 0.5mmol of pyridine, 0.2mmol of elemental iodine, 0.3mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure-resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is finished, washing an organic layer, drying, and distilling under reduced pressure to remove a solvent to obtain a crude product, and performing column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate (10: 1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 59%.

Examples 15 to 19

Examples 15 to 19 indolizine chromanone compounds having antitumor activity, the structural formula is shown in formula ten, the differences only lie in the reaction time, and the specific conditions and reaction yields are shown in table 3 below, as in example 1:

TABLE 3

Examples 20 to 23

Examples 20 to 23 indolizine chromanone compounds having antitumor activity, which have the structural formula shown in formula ten, are prepared as in example 1, except that the reaction temperature is different, and the specific conditions and reaction yields are shown in table 4 below:

TABLE 4

Examples

Catalyst and process for preparing same

Solvent(s)

Oxidizing agent

Time (h)

Temperature of

Yield (%)

20

I2(1.0)

Dioxane

TBPB(3.0)

10

80

52％

21

I2(1.0)

Dioxane

TBPB(3.0)

10

100

66％

22

I2(1.0)

Dioxane

TBPB(3.0)

10

120

63％

23

I2(1.0)

Dioxane

TBPB(3.0)

10

140

59％

Examples 24 to 26

Examples 24 to 26 indolizine chromanone compounds having antitumor activity, which have the structural formula shown in formula ten, are prepared in the same manner as in example 1, except that the amount of elemental iodine is different, and the specific conditions and reaction yields are shown in table 5 below:

TABLE 5

Examples

Amount of elemental iodine

Solvent(s)

Oxidizing agent

Time (h)

Temperature of

Yield (%)

24

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

In comparative example 1, an indolizine chromophoric ketone compound with anti-tumor activity is prepared, the structural formula is shown as formula ten, the difference is that only a sealing cover is opened and magnetic stirring is carried out for reaction for 10 hours, after the reaction is finished, a reaction solution is extracted, an organic layer is washed, dried and distilled under reduced pressure to remove a solvent, a crude product is obtained, the crude product is subjected to column chromatography separation and purification by using petroleum ether/ethyl acetate (10: 1 (V/V)) as an eluent, the required product is obtained, the product is a white solid, and the yield is 15%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):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).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as formula eleven:

preparing the compound shown in the formula ten, wherein the reaction formula is as follows:

the preparation method of the compound shown as the formula eleven comprises the specific steps of adding 0.2mmol of methyl-3- (2-acetylphenoxy) acrylate, 0.6mmol of pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1 into a 15mL pressure resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is finished, washing an organic layer, drying, distilling under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate (10: 1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 68%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):δ(ppm)9.79(dt,J＝6.8,1.2Hz,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).¹³C-NMR(100MHz,CDCl₃):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

In comparative example 2 and example 27, an indolizine chromophoric ketone compound with anti-tumor activity is prepared, the structural formula is shown as formula eleven, the difference is that only a sealing cover is opened and magnetic stirring is carried out for reaction for 10 hours, after the reaction is finished, a reaction solution is extracted, an organic layer is washed, dried and distilled under reduced pressure to remove a solvent, a crude product is obtained, the crude product is subjected to column chromatography separation and purification by using petroleum ether/ethyl acetate (10: 1(V/V) as an eluent, the required product is obtained, and the yield is 36%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):δ(ppm)9.79(dt,J＝6.8,1.2Hz,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).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as a formula eleven, and the compound prepared according to the formula eleven has a reaction formula shown as a reaction formula V.

The preparation method of the compound shown as the formula eleven comprises the specific steps of adding 0.2mmol of methyl-3- (2-acetylphenoxy) acrylate, 0.6mmol of pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of methylbenzene into a 15mL pressure-resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is finished, washing an organic layer, drying, distilling under reduced pressure to remove a solvent to obtain a crude product, and performing column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate (V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 48%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):δ(ppm)9.79(dt,J＝6.8,1.2Hz,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).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as formula eleven, and the compound prepared according to the formula eleven has the following reaction formula:

the preparation method of the compound shown as the formula eleven comprises the specific steps of adding 0.2mmol of methyl-3- (2-acetylphenoxy) acrylate, 0.6mmol of pyridine, 0.2mmol of elemental iodine, 0.6mmol of methyl tert-butyl peroxide and 2mL of 1 into a 15mL pressure resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is finished, washing an organic layer, drying, distilling under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate (10: 1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 36%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):δ(ppm)9.79(dt,J＝6.8,1.2Hz,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).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as formula eleven, and the compound prepared according to the formula eleven has the following reaction formula:

the preparation method of the compound shown as the formula eleven comprises the specific steps of adding 0.2mmol of methyl-3- (2-acetylphenoxy) acrylate, 0.6mmol of pyridine, 0.4mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1 into a 15mL pressure resistant pipe, sealing at 80 ℃, magnetically stirring for reaction for 15 hours, extracting a reaction solution after the reaction is finished, washing an organic layer, drying, distilling under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate (10: 1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 41%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):δ(ppm)9.79(dt,J＝6.8,1.2Hz,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).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as formula twelve:

preparing the compound shown in the formula twelve, wherein the reaction formula is as follows:

the preparation method of the compound shown as the formula twelve comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetyl 3-chlorophenoxy) acrylate, 0.6mmol of pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure-resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is finished, washing and drying an organic layer, and distilling under reduced pressure to remove a solvent to obtain a crude product, wherein the crude product is subjected to column chromatography separation and purification by using petroleum ether/ethyl acetate 15:1(V/V) as eluent to obtain the required product, the product is a white solid, and the yield is 66%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):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＝6.8,1.2Hz,1H),4.48(q,J＝7.1Hz,2H),1.50(t,J＝7.1Hz,3H).¹³C-NMR(100MHz,CDCl₃):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

In comparative example 3 and example 31, an indolizine chromophoric ketone compound with anti-tumor activity is prepared, the structural formula is shown as formula twelve, the difference is that only a sealing cover is opened and magnetic stirring is carried out for reaction for 10 hours, after the reaction is finished, a reaction solution is extracted, an organic layer is washed, dried and distilled under reduced pressure to remove a solvent, a crude product is obtained, the crude product is subjected to column chromatography separation and purification by using petroleum ether/ethyl acetate 15:1(V/V) as an eluent, the required product is obtained, and the yield is 18%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):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＝6.8,1.2Hz,1H),4.48(q,J＝7.1Hz,2H),1.50(t,J＝7.1Hz,3H).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as formula twelve, and the compound prepared as shown in formula twelve has the following reaction formula:

the preparation method of the compound shown as the formula twelve comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetyl-3-chlorophenoxy) acrylate, 0.6mmol of pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 2-dichloroethane into a 15mL pressure-resistant pipe, sealing at 120 ℃, magnetically stirring for reaction for 12 hours, extracting a reaction solution after the reaction is finished, washing an organic layer, drying, distilling under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate 15:1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 28%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):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＝6.8,1.2Hz,1H),4.48(q,J＝7.1Hz,2H),1.50(t,J＝7.1Hz,3H).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as formula twelve, and the compound prepared as shown in formula twelve has the following reaction formula:

the preparation method of the compound shown in the formula twelve comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetyl 3-chlorophenoxy) acrylate, 0.6mmol of pyridine, 0.2mmol of elemental iodine, oxygen and 2mL of 1, 4-dioxane into a 15mL pressure resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is finished, washing an organic layer, drying, distilling under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate 15:1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 8%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):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＝6.8,1.2Hz,1H),4.48(q,J＝7.1Hz,2H),1.50(t,J＝7.1Hz,3H).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as formula twelve, and the compound prepared as shown in formula twelve has the following reaction formula:

the preparation method of the compound shown as the formula twelve comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetyl 3-chlorophenoxy) acrylate, 0.3mmol of pyridine, 0.1mmol of elemental iodine, 0.4mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure resistant pipe, sealing at 80 ℃, magnetically stirring for reaction for 6 hours, extracting a reaction solution after the reaction is completed, washing, drying and distilling an organic layer under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate 15:1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 27%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):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＝6.8,1.2Hz,1H),4.48(q,J＝7.1Hz,2H),1.50(t,J＝7.1Hz,3H).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as formula twelve, and the compound prepared as shown in formula twelve has the following reaction formula:

the preparation method of the compound shown as the formula twelve comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetyl 3-chlorophenoxy) acrylate, 0.6mmol of pyridine, 0.4mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure-resistant pipe, sealing at 140 ℃, magnetically stirring for reaction for 15 hours, extracting a reaction solution after the reaction is finished, washing, drying and distilling an organic layer under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate 15:1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 41%.

The obtained productThe result of the identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):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＝6.8,1.2Hz,1H),4.48(q,J＝7.1Hz,2H),1.50(t,J＝7.1Hz,3H).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as a formula thirteen:

preparing a compound shown as a formula thirteen, wherein the reaction formula is as follows:

the preparation method of the compound shown as the formula thirteen comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetyl 3-methoxyphenoxy) acrylate, 0.6mmol of pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is finished, washing, drying and distilling an organic layer under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate ═ 8:1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 70%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):δ(ppm)9.76(dt,J＝6.8,1.2Hz,1H),8.36(d,J＝9.1Hz,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＝7.1Hz,2H),3.94(s,3H),1.50(t,J＝7.1Hz,3H).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown in fourteen formula:

the reaction formula for preparing the compound shown in the formula fourteen is as follows:

the preparation method of the compound shown in the formula fourteen comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetyl 3-methylphenoxy) acrylate, 0.6mmol of pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is completed, washing, drying and distilling an organic layer under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate ═ 10:1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 69%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):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).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as a formula fifteen:

preparing a compound as shown in the formula fifteen, wherein the reaction formula is as follows:

the preparation method of the compound shown as the formula fifteen comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetyl 4-bromophenoxy) acrylate, 0.6mmol of pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure-resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is completed, washing, drying and distilling an organic layer under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate 15:1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 67%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):δ(ppm)9.73(dt,J＝6.8,1.2Hz,1H),8.48(d,J＝2.5Hz,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＝7.1Hz,2H),1.50(t,J＝7.1Hz,3H).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as sixteen:

preparing the compound shown in the formula sixteen by the reaction formula:

the preparation method of the compound shown as the formula sixteen comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetyl 4-fluorophenoxy) acrylate, 0.6mmol of pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is completed, washing and drying an organic layer, and distilling under reduced pressure to remove a solvent to obtain a crude product, wherein the crude product is subjected to column chromatography separation and purification by using petroleum ether/ethyl acetate ═ 10:1(V/V) as eluent to obtain the required product, the product is a white solid, and the yield is 68%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):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).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as seventeen:

preparing the compound shown in the formula seventeen, wherein the reaction formula is as follows:

the preparation method of the compound shown as the formula seventeen comprises the specific steps of adding 0.2mmol of methyl-3- (2-acetyl 3-chlorophenoxy) acrylate, 0.6mmol of pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is finished, washing and drying an organic layer, and distilling under reduced pressure to remove a solvent to obtain a crude product, wherein the crude product is subjected to column chromatography separation and purification by using petroleum ether/ethyl acetate ═ 10:1(V/V) as eluent to obtain the required product, the product is a white solid, and the yield is 66%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):δ(ppm)9.71(dt,J＝6.8,1.2Hz,1H),8.40(d,J＝9.0Hz,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).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as eighteen:

the preparation method of the compound shown in the formula eighteen comprises the following reaction formula:

the preparation method of the compound shown as the formula eighteen comprises the specific steps of adding 0.2mmol of methyl-3- (2-acetyl 4-methylphenoxy) acrylate, 0.6mmol of pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure resistant pipe, sealing at 110 ℃, magnetically stirring and reacting for 10 hours, extracting a reaction solution after the reaction is completed, washing, drying and distilling an organic layer under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate ═ 10:1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 71%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):δ(ppm)9.76(dt,J＝6.8,1.2Hz,1H),8.37(dt,J＝9.0,1.2Hz,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).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as nineteen in the formula:

the reaction formula for preparing the compound shown in the formula nineteen is as follows:

the preparation method of the compound shown as the formula nineteen comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetylnaphthyloxy) acrylate, 0.6mmol of pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1 into a 15mL pressure resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is completed, washing, drying and distilling an organic layer under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate 15:1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 50%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):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).¹³C-NMR(100MHz,CDCl₃):δ(ppm)170.8,163.1,156.8,151.5,138.0,134.8,131.6,130.5,128.9,128.8,128.7,128.3,126.9,126.1,118.9,118.3,116.1,114.1,112.3,90.9,60.1,14.6.

example 43

An indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as a formula twenty:

preparing the compound shown in the formula twenty, wherein the reaction formula is as follows:

the preparation method of the compound shown as the formula twenty comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetylphenoxy) acrylate, 0.6mmol of 4-methylpyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is completed, washing, drying and distilling an organic layer under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate ═ 12:1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 69%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):δ(ppm).9.63(dd,J＝6.6,0.9Hz,1H),8.39(dd,J＝7.6,1.4Hz,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＝6.8,1.8Hz,1H),4.56–4.38(m,2H),2.52(s,3H),1.50(t,J＝7.1Hz,3H).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as twenty-one:

the reaction formula for preparing the compound shown in the formula twenty-one is as follows:

the preparation method of the compound shown as the formula twenty one comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetylphenoxy) acrylate, 0.6mmol of 4-methoxypyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure-resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is completed, washing, drying and distilling an organic layer under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate (5: 1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 68%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):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＝7.1Hz,3H).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as twenty-two:

the reaction formula for preparing the compound as shown in the formula twenty-two is as follows:

the preparation method of the compound shown as the formula twenty-two comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetylphenoxy) acrylate, 0.6mmol of methyl isonicotinic acid, 0.2mmol of elemental iodine, 0.6mmol of benzoyl peroxide and 2mL of 1, 4-dioxane into a 15mL pressure-resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is finished, washing an organic layer, drying, distilling under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate 15:1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 67%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):δ(ppm)9.74(dd,J＝7.1,1.0Hz,1H),9.02(dd,J＝1.8,1.0Hz,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)..¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as twenty-three:

the reaction formula for preparing the compound as twenty-three is as follows:

the preparation method of the compound shown in the formula twenty-three comprises the specific steps of adding 0.2mmol of N-methyl-N-phenyl-3- (2-acetylphenoxy) acrylamide, 0.6mmol of pyridine, 0.2mmol of elementary iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is finished, washing, drying and distilling an organic layer under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate (5: 1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 67%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):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).¹³C-NMR(100MHz,CDCl₃):δ(ppm)167.5,164.0,154.9,148.6,144.7,138.0,132.5,128.5,128.4,127.2,126.1,125.9,125.6,123.9,123.1,118.7,117.3,113.6,109.7,95.6,38.1.

example 47

An indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as twenty-four:

the reaction formula for preparing the compound shown in the twenty-four formula is as follows:

the preparation method of the compound shown as the formula twenty-four comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetylphenoxy) acrylate, 0.6mmol of isoquinoline, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is completed, washing an organic layer, drying, and distilling under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate 8:1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 68%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):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).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as twenty-five:

the reaction formula for preparing the compound shown in the formula twenty five is as follows:

the preparation method of the compound shown as the formula twenty five comprises the specific steps of adding 0.2mmol of methyl-3- (2-acetyl 4-fluorophenoxy) acrylate, 0.6mmol of pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is completed, washing, drying and distilling an organic layer under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate ═ 10:1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 72%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):δ(ppm)9.73(dt,J＝6.8,1.2Hz,1H),8.39(dt,J＝9.0,1.2Hz,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＝9.2,7.6,3.2Hz,1H),7.13(td,J＝7.2,1.4Hz,1H),4.01(s,3H).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as twenty-six:

the reaction formula for preparing the compound shown in the formula twenty-six is as follows:

the preparation method of the compound shown as the formula twenty-six comprises the specific steps of adding 0.2mmol of isopropyl-3- (2-acetylphenoxy) acrylate, 0.6mmol of pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is finished, washing an organic layer, drying, and distilling under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate (10: 1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 62%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):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).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as twenty-seven:

the reaction formula for preparing the compound shown in the formula twenty-seven is as follows:

the preparation method of the compound shown as the formula twenty-seven comprises the specific steps of adding 0.2mmol (2S, 5R) -2-isopropyl-5-methylcyclohexyl-3- (2-acetylphenoxy) acrylate, 0.6mmol pyridine, 0.2mmol elementary iodine, 0.6mmol tert-butyl peroxybenzoate and 2mL1,4 dioxane into a 15mL pressure-resistant pipe, sealing at 110 ℃, carrying out magnetic stirring reaction for 10 hours, extracting a reaction solution after the reaction is finished, washing an organic layer, drying, carrying out reduced pressure distillation to remove a solvent to obtain a crude product, carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate ═ 10:1(V/V) as an eluent to obtain the required product, wherein the yield is 60%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):δ(ppm)9.79(dt,J＝6.8,1.2Hz,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).¹³C-NMR(100MHz,CDCl₃):δ(ppm)167.8,162.7,155.6,153.2,138.3,130.1,129.1,128.8,125.7,124.3,123.5,118.9,118.1,114.3,110.9,91.9,74.2,47.5,41.4,34.4,31.5,26.4,23.6,22.1,20.9,16.5.

example 51

An indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as twenty-eight:

the reaction formula for preparing the compound shown in the formula twenty-eight is as follows:

the preparation method of the compound shown as the formula twenty-eight comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetylphenoxy) acrylate, 0.6mmol of isonicotinaldehyde, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is finished, washing, drying and distilling an organic layer under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate 15:1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 67%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):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＝7.1Hz,3H).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as twenty-nine:

the reaction formula for preparing the compound shown in the formula twenty-nine is as follows:

the preparation method of the compound shown as the formula twenty-nine comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetylphenoxy) acrylate, 0.6mmol of 4-benzyl pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is completed, washing, drying and distilling an organic layer under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate 15:1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 68%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):δ(ppm)9.65(dd,J＝7.0,0.8Hz,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＝7.1Hz,3H).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as thirty:

the reaction formula for preparing the compound shown in the formula thirty is as follows:

the preparation method of the compound is characterized by comprising the specific steps of adding 0.2mmol of ethyl-3- (2-acetylphenoxy) acrylate, 0.6mmol of 7-methoxyisoquinoline, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure-resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is completed, washing, drying and distilling an organic layer under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate 15:1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 69%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):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).¹³C-NMR(100MHz,CDCl₃):δ(ppm)167.6,163.9,160.5,155.4,153.1,135.6,133.3,132.7,130.1,125.8,124.9,124.1,123.6,118.0,117.9,117.6,114.2,111.0,107.6,95.8,60.8,55.4,14.5.

example 54

An indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as thirty-one:

the reaction formula for preparing the compound shown in the formula thirty-one is as follows:

the preparation method of the compound shown as the formula thirty-one comprises the specific steps of adding 0.2mmol of ethyl-3- (2-acetylphenoxy) acrylate, 0.6mmol of 3, 5-dimethylpyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure resistant pipe, sealing at 110 ℃, magnetically stirring and reacting for 10 hours, extracting a reaction solution after the reaction is completed, washing, drying and distilling an organic layer under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate 15:1(V/V) as an eluent to obtain the required product, wherein the product is a white solid, and the yield is 70%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):δ(ppm)9.59–9.51(m,1H),8.36(dd,J＝7.9,1.6Hz,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＝7.1Hz,2H),2.69(s,3H),2.36(s,3H),1.49(t,J＝7.1Hz,3H).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as thirty-two:

the reaction formula for preparing the compound shown in the formula thirty-two is as follows:

the preparation method of the compound shown as the formula thirty-two comprises the specific steps of adding 0.2mmol of (E) -3- (2-acetylphenoxy) n-phenylacrylamide, 0.6mmol of pyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure resistant pipe, sealing at 110 ℃, magnetically stirring and reacting for 10 hours, extracting a reaction solution after the reaction is completed, washing, drying and distilling an organic layer under reduced pressure to remove a solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate 15:1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 67%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):δ(ppm)9.66(d,J＝6.8Hz,1H),8.68(d,J＝9.0Hz,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).¹³C-NMR(100MHz,CDCl₃):δ(ppm)167.1,160.6,154.7,150.0,144.5,138.2,133.1,129.1,129.0,128.3,126.2,124.8,124.0,123.5,120.1,119.5,117.3,114.7,110.0,93.8.

example 56

An indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as thirty-three:

the reaction formula for preparing the compound shown in the formula thirty-three is as follows:

the preparation method of the compound shown as thirty-three comprises the specific steps of adding 0.2mmol of (E) -3- (2-acetylphenoxyl) -1-morpholinopropyl-2-ene-1-1, 0.6mmol of pyridine, 0.2mmol of elementary iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane into a 15mL pressure-resistant pipe, sealing at 110 ℃, magnetically stirring for reaction for 10 hours, extracting a reaction solution after the reaction is finished, washing an organic layer, drying, distilling under reduced pressure to remove a solvent to obtain a crude product, and performing column chromatography separation and purification on the crude product by using petroleum ether/ethyl acetate 15:1(V/V) as eluent to obtain the required product, wherein the product is a white solid, and the yield is 67%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):δ(ppm)9.78–9.63(m,1H),8.42(dd,J＝7.9,1.7Hz,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).¹³C-NMR(100MHz,CDCl₃):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 indolizine chromogen ketone compound with anti-tumor activity has a structural formula shown as thirty-four:

the reaction formula for preparing the compound shown in the formula thirty-four is as follows:

the preparation method of the compound is as shown in formula thirty-four, and the specific steps are that 0.2mmol of methyl-3- (2-acetylphenoxy) acrylate, 0.6mmol of 3, 5-dimethylpyridine, 0.2mmol of elemental iodine, 0.6mmol of tert-butyl peroxybenzoate and 2mL of 1, 4-dioxane are added into a 15mL pressure resistant pipe, the mixture is sealed at 110 ℃ and is magnetically stirred for reaction for 10 hours, after the reaction is completed, the reaction solution is extracted, an organic layer is washed, dried and distilled under reduced pressure to remove the solvent, so that a crude product is obtained, and the crude product is subjected to column chromatography separation and purification by using petroleum ether/ethyl acetate 15:1(V/V) as eluent, so that the required product is a white solid, and the yield is 67%.

The result of the obtained identification data of the product is as follows:¹H-NMR(400MHz,CDCl₃):δ(ppm)9.58(s,1H),8.37(dd,J＝8.0,1.6Hz,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).¹³C-NMR(100MHz,CDCl₃):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

This example is intended to observe the effect of indolizinochronone derivatives of the invention in inhibiting tumor cell proliferation.

1. Instruments and devices:

superclean workbench, high-pressure steam sterilization pot, micro-pipetting gun, 96-well plate, blood counting chamber, inverted microscope, and 5% CO at 37 deg.C₂The device comprises an incubator, an enzyme-labeling instrument, an analytical balance and a micro oscillator;

2. cell lines and reagents

Oral epidermoid carcinoma cell KBV, human gastric cancer cell MKN-45, complete culture medium, pancreatin digestive juice (0.25% trypsin and 0.02% EDTA), PBS buffer solution, dimethyl sulfoxide (DMSO), tetramethyl azodicarbonyl blue (MTT) and MTT solution, wherein MTT (250mg) is added into 50mL of deionized water, the final concentration is 5mg/mL by ultrasonic dissolution in the dark, and the mixture is subpackaged and stored in the dark at 4 ℃.

3. Experimental methods

Different tumor cells in logarithmic growth phase are digested by 0.25% pancreatin to prepare single cell suspension with a certain concentration, 3000 cells/well are inoculated in a 96-well plate according to the difference of cell growth speed, and 100uL of cell suspension is added into each well. After 24h, 100uL of compound (DMSO final concentration. ltoreq.0.1%) was added to each well at a concentration of 10uM, and the control group was added to the same volume of complete medium. Each group was plated with 3 parallel wells, and after further incubation at 37 ℃ for 72h, the supernatant was discarded. Adding 20uL MTT with the concentration of 5mg/mL into each hole, continuously culturing for 2-4h, removing supernatant, adding 150uL DMSO into each hole to dissolve formazan crystals, uniformly mixing by shaking a micro oscillator, measuring an Optical Density (OD) value by an enzyme-labeling instrument under the conditions of a reference wavelength of 450nm and a detection wavelength of 570nm, taking the tumor cells treated by a culture medium control as a control group, and calculating the inhibition rate of different tumor cells under the action of each compound by using the following formula.

Cell inhibition (%) was (1-administration group mean OD value/control group mean OD value) × 100%

4. Results of the experiment

The inhibition rates of human oral epidermoid carcinoma cells KBV and human gastric carcinoma cells MKN-45 in examples 1 to 57 according to the method of the present invention are shown in Table l.

TABLE 1 inhibition of KBV and MKN-45 tumor cells by examples 1-57

As can be seen from Table 1, examples 1-57 showed some inhibition of the proliferation of both KBV and IMKN-45 tumor cells. Examples 1, 27, 41, 42, 46 and 48 have strong inhibition effects on two tumor cells, wherein examples 1 and 41 show certain selectivity, and the inhibition effect on human oral epidermoid carcinoma cells KBV is higher than that on human gastric cancer cells MKN-45; example 46 showed strong inhibition of both KBV and IMKN tumor cells. The six embodiments show stronger inhibition effect on the increment of two tumor cells, and can be used as a drug lead compound for preparing subsequent antitumor drugs; the compounds other than the above six compounds do not have strong inhibitory activity against the two cancer cells, but exhibit a certain inhibitory activity, and can provide quantitative effects on the compounds for the development of new drugs in the future.

The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.

Claims (9)

1. An indolizine chromone compound with anti-tumor activity is characterized in that the structural formula of the compound is shown as formula seven:

wherein, R in the formula₁Is hydrogen, halogen, substituted alkyl or aryl;

in the formula VII, R₂Is methoxy, ethoxy, isopropoxy or substituted amino;

in the formula VII, R₃Is hydrogen, halogen, ester group, substituted alkyl or aryl.

2. A method for producing an indolizinochronone compound having an antitumor activity according to claim 1, which comprises the steps of:

under the condition of an oxidant, carrying out self-organizing one-pot synthesis on a compound shown as a formula eight and a compound shown as a formula nine under the action of a catalyst iodine simple substance to obtain a compound shown as a formula seven;

wherein, R in the formula VIII₁Is hydrogen, halogen, substituted alkyl or aryl;

in the formula VIII, R₂Is methoxy, ethoxy, isopropoxy or substituted amino;

in the formula of₃Is hydrogen, halogen, ester group, substituted alkyl or aryl.

3. The method for preparing indolizine chromanone compounds with antitumor activity as claimed in claim 2, wherein the molar ratio of the compound represented by formula eight to the compound represented by formula nine is 1.0: (1.5-3.0).

4. The method for preparing indolizine chromone compounds with antitumor activity as claimed in claim 2, wherein the molar amount of iodine used as the catalyst is 0.5-2.0 times of that of the compound shown in formula eight.

5. The method for preparing indolizine chromanone compounds with antitumor activity as claimed in claim 2, wherein the oxidant is one or more of oxygen, tert-butyl peroxybenzoate, benzoyl peroxide and methyl tert-butyl peroxide.

6. The method for preparing an indolizinochronone compound having an antitumor activity as claimed in claim 2, wherein the molar ratio of the compound represented by formula viii to the oxidizing agent is 1: (2-3).

7. The method for preparing indolizine chromanone compounds with antitumor activity as claimed in claim 2, wherein the specific conditions for the self-organizing one-pot synthesis are as follows: the reaction is carried out in an organic solvent at the temperature of 80-140 ℃ for 6-15 h.

8. The method for producing an indolizinochronone compound having an antitumor activity as claimed in claim 7, wherein the organic solvent is one or more of toluene, benzene, 1, 4-dioxane, dimethylsulfoxide, 1, 2-dichloroethane, ethylene glycol, N-dimethylformamide, and N-methylpyrrolidone.

9. The method for producing an indolizine chromanone compound having an antitumor activity as claimed in claim 2, wherein the synthesis is performed in a closed environment.