CN109988176B - Pyrazole structure-containing N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition derivative and preparation method and application thereof - Google Patents

Pyrazole structure-containing N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition derivative and preparation method and application thereof Download PDF

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CN109988176B
CN109988176B CN201910362657.5A CN201910362657A CN109988176B CN 109988176 B CN109988176 B CN 109988176B CN 201910362657 A CN201910362657 A CN 201910362657A CN 109988176 B CN109988176 B CN 109988176B
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bromophenyl
substituted maleimide
terpinene cycloaddition
terpinene
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CN109988176A (en
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王玮
邓莉平
杜轶君
吕峰平
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Puzhong Discovery Pharmaceutical Technology Shanghai Co ltd
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Shaoxing University Yuanpei College
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P35/02—Antineoplastic agents specific for leukemia
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses a pyrazole structure-containing N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition derivative, a preparation method and application thereof, wherein 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride and p-bromoaniline are respectively dissolved in an acetone solvent, p-bromoaniline solution is dripped into a reaction bottle containing 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride solution under stirring to prepare an N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition product, then the N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition product and 6-fluorochromone phenylhydrazone are mixed in absolute ethanol, the N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition derivative containing the pyrazole structure prepared by adding chloramine T has stronger inhibitory activity on cancer cells, and provides a foundation for the development and research of potential drugs.

Description

Pyrazole structure-containing N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition derivative containing a pyrazole structure, and a preparation method and application thereof.
Background
The chemical structural formula of the N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition derivative is shown in figure 1. The 1, 3-dipolar cycloaddition reaction is the most important method for synthesizing five-membered heterocyclic compounds with good regioselectivity and body selectivity, and is also a more active reaction in heterocyclic pharmaceutical chemistry research.
In recent years, chromones have received much attention due to a wide range of biological activities, such as anticancer, antibacterial, inhibition of platelet aggregation, and the like. Therefore, the heterocyclic compound has high synthetic value in terms of pharmacology and synthesis angle. Pyrazole derivatives have attracted considerable attention as a class of useful intermediates and as a variety of pharmaceutical activities that they themselves exhibit.
The influence of different heterocycles on the pharmacological activity caused by the aggregation of the same molecule is researched, the pyrazole N-p-bromophenylmaleimide alpha-terpinene cycloaddition derivative containing the chromone structure is synthesized through the dipolar cycloaddition reaction, and the method has important significance in the field of medicine research.
Disclosure of Invention
The invention aims to provide an N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition derivative containing a pyrazole structure, and a preparation method and application thereof.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition derivative containing a pyrazole structure has the following chemical structural formula:
Figure GDA0002850594530000021
the invention relates to a preparation method of a pyrazole structure-containing N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition derivative, which is characterized in that the preparation method of the pyrazole structure-containing N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition derivative comprises the following steps:
respectively dissolving 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride and p-bromoaniline in an acetone solvent, the p-bromoaniline solution is dripped into a reaction bottle containing 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride solution under stirring, the reaction releases heat and gradually generates light yellow precipitate, after the reaction is carried out for 1 to 2 hours at room temperature, adding manganese acetate, triethylamine and acetic anhydride into the reaction bottle in sequence, reacting, heating, gradually dissolving the precipitate, reacting for 5-8 hours at 50-60 ℃, changing the solution from orange yellow to red black, cooling to room temperature, washing and drying the precipitate in a large amount of water, and recrystallizing with acetone to obtain the product N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition product;
mixing the N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition product and 6-fluorochromone phenylhydrazone in absolute ethyl alcohol, adding chloramine T, refluxing for 12-15 hours, carrying out addition reaction, recrystallizing with methanol, and drying in vacuum to obtain the pyrazole structure-containing N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition derivative.
Further, the dissolving of 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride (compound 1) and p-bromoaniline (compound 2) in acetone solvent, respectively, comprises:
adding 2mmol of 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride into 20-30 mL of acetone solvent;
adding 2mmol of para-bromoaniline into 20-30 mL of acetone solvent.
Further, the molar ratio of the N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition product, 6-fluorochromone phenylhydrazone, and chloramine T is 1: 1: 1-1.5.
Further, the sequentially adding manganese acetate, triethylamine and acetic anhydride comprises:
adding 0.3-0.5 g of manganese acetate into 40-60 mL of acetone solvent;
adding 15-20mL of triethylamine into 40-60 mL of acetone solvent;
30-35mL of acetic anhydride is added into 40-60 mL of acetone solvent.
Further, the N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition product and 6-fluorochromone phenylhydrazone are mixed in anhydrous ethanol, wherein 1mmol of the N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition product and 1mmol of 6-fluorochromone phenylhydrazone are added in every 20-25mL of the anhydrous ethanol.
The invention also provides application of the pyrazole structure-containing N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition derivative in preparation of antitumor drugs.
The invention provides an N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition derivative containing a pyrazole structure, and a preparation method and application thereof, wherein the structure of chromone is introduced on the basis of introducing a five-membered pyrazole ring structure into an N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition product, so that the pharmacological activity can be changed, 6-fluoro-chromone phenylhydrazone substituted by formaldehyde group at the 3-position is used for substituting on the structure of pyrazole, the N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition product is subjected to structural transformation, and the prepared N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition derivative containing the pyrazole structure is used for treating Bel-7402 (human hepatoma cells), KB (oral cancer cells), SGC7901 (stomach cancer cells), HO8901 (ovarian cancer cells), HL-60 (leukemia cells) and ECA109 (intestinal cancer cells) have stronger inhibitory activity, and provide a foundation for the development and research of potential drugs.
Drawings
FIG. 1 is a chemical structural formula of N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition derivative;
FIG. 2 is a chemical structural formula of the pyrazole-containing N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition derivative of the present invention;
FIG. 3 is a chemical formula schematic diagram of a preparation method of the pyrazole structure-containing N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition derivative.
Detailed Description
The technical solutions of the present invention are further described in detail below with reference to the drawings and examples, which should not be construed as limiting the present invention.
Research shows that the pharmacological activity can be changed by introducing the structure of chromone on the basis of introducing a five-membered pyrazole ring structure into the N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition derivative. The experimental data are as follows:
Figure GDA0002850594530000041
TABLE 1
Based on the above experimental data, the structural modification of the N-p-bromophenyl substituted maleimide α -terpinene cycloaddition product was carried out using 6-fluorochromone phenylhydrazone substituted with formaldehyde group at the 3-position in the present application for substitution on the pyrazole structure.
The chemical structural formula of the pyrazole-structure-containing N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition derivative is shown in figure 2.
In one embodiment, a method for preparing an N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition derivative having a pyrazole structure comprises:
respectively dissolving 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride (compound 1) and p-bromoaniline (compound 2) in an acetone solvent, dropwise adding the p-bromoaniline solution (compound 2) into a reaction bottle containing a 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride (compound 1) solution under stirring, discharging heat and gradually generating light yellow precipitates, reacting at room temperature for 1-2 hours, sequentially adding manganese acetate, triethylamine and acetic anhydride into the reaction bottle, reacting for 1-2 hours, heating, gradually dissolving the precipitates, reacting at 50-60 ℃ for 5-8 hours, changing the solution from orange yellow to red black, cooling to room temperature, washing the precipitate with a large amount of water, drying, and recrystallizing with acetone to obtain the product N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition product (compound 3);
mixing the N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition product (compound 3) and 6-fluorochromone phenylhydrazone (compound 4) in absolute ethyl alcohol, adding chloramine T, refluxing for 12-15 hours, carrying out addition reaction, recrystallizing with methanol, and drying in vacuum to obtain the pyrazole-structure-containing N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition derivative (compound 5).
Wherein the chemistry of compound 3 is collectively referred to as: 1-isopropyl-4-methyl-bicyclo [2,2,2] -5-octene-2, 3- (N-p-bromophenyl) dicarboximide, referred to in this example as the N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition product.
While the chemistry of compound 5 is collectively referred to as: 3- (6-fluoro-chromon-3-yl) -1-phenyl-7-methyl-4-isopropyl-bicyclo [2,2,2] octa [2,3-d ]3aH,7aH pyrazole-2, 3- (N-p-bromophenyl) dicarboximide, referred to in this example as the pyrazole-containing N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition derivative.
Wherein, the synthesis of the 6-fluorochromone phenylhydrazone (compound 4) can be synthesized by a method of generating Schiff base by dehydration reaction of 6-fluorochromone with substituted formaldehyde group at the 3 position and phenylhydrazine.
Example 1, 2mmol phenylhydrazine was added to a flask containing 10mL tetrahydrofuran, and the mixture was stirred under reflux in a boiling water bath until dissolved, then 20mL absolute ethanol solution in which 2mmol of 6-fluorochromone substituted with a formaldehyde group at the 3-position was dissolved was slowly added dropwise, and the mixture was stirred under reflux in a boiling water bath for 1 hour, and 10 drops of hydrochloric acid were added dropwise, and a pale yellow precipitate appeared. And (3) refluxing and stirring in a continuous boiling water bath for 5 hours, stopping the water bath, adding 20mL of distilled water, stirring, deepening the color of a light yellow precipitate, and performing suction filtration to obtain a yellow-red needle-shaped product of 6-fluorochromone phenylhydrazone. Washing with anhydrous ether for several times, and vacuum drying to obtain the product 6-fluorochromone phenylhydrazone (compound 4).
The present invention is not limited to the method for synthesizing 6-fluorochromone phenylhydrazone (compound 4), and the chemical name of compound 4 may be expressed as: 6-fluoro-chromone-3-phenylhydrazone, which is not described in detail herein.
In one example, 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride (compound 1) and p-bromoaniline (compound 2) are each dissolved in an acetone solvent comprising:
adding 2mmol of 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride into 20-30 mL of acetone solvent;
adding 2mmol of para-bromoaniline into 20-30 mL of acetone solvent.
In one embodiment, the molar ratio of N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition product, 6-fluorochromone phenylhydrazone, and chloramine T is 1: 1: 1-1.5.
In one embodiment, manganese acetate, triethylamine and acetic anhydride are added sequentially, including:
adding 0.3-0.5 g of manganese acetate into 40-60 mL of acetone solvent;
adding 15-20mL of triethylamine into 40-60 mL of acetone solvent;
30-35mL of acetic anhydride is added into 40-60 mL of acetone solvent.
In one example, the N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition product and 6-fluorochromone phenylhydrazone are mixed in anhydrous ethanol, wherein 1mmol of the N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition product and 1mmol of 6-fluorochromone phenylhydrazone are added per 20-25mL of anhydrous ethanol.
The preparation of the N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition derivative containing the pyrazole structure (Compound 5) according to the present application is illustrated in detail by the following specific examples:
examples 2,
1) And synthesis of N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition product: respectively dissolving 2mmol of 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride (compound 1) and 2mmol of p-bromoaniline (compound 2) in 20mL of acetone solvent, dropwise adding the p-bromoaniline solution into a reaction bottle containing a 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride (compound 1) solution under stirring, reacting for 1 hour at room temperature, sequentially adding 0.3 g of manganese acetate, 15mL of triethylamine and 30mL of acetic anhydride into the reaction bottle, reacting for 1 hour at room temperature, heating, gradually dissolving the precipitate, reacting for 5 hours at 50-60 ℃, changing the solution from orange yellow to red black, cooling to room temperature, the precipitate was washed with a large amount of water, dried, and recrystallized from acetone to give the product N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition product (Compound 3).
2) Introduction of a pyrazole structure: mixing 1mmol of N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition product (compound 3) and 1mmol of 6-fluorochromone phenylhydrazone (compound 4) in 20mL of absolute ethyl alcohol, adding 1.2mmol of chloramine T, refluxing for 12 hours, performing addition reaction, recrystallizing with methanol, and drying in vacuum to obtain the pyrazole structure-containing N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition derivative (compound 5).
Examples 3,
1) And synthesis of N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition product: respectively dissolving 2mmol of 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride (compound 1) and 2mmol of p-bromoaniline (compound 2) in 30mL of acetone solvent, dropwise adding the p-bromoaniline solution into a reaction bottle containing 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride (compound 1) solution under stirring, reacting for 2 hours at room temperature while releasing heat and gradually generating light yellow precipitates, sequentially adding 0.5 g of manganese acetate, 20mL of triethylamine and 35mL of acetic anhydride into the reaction bottle, reacting for 2 hours at room temperature while heating, gradually dissolving the precipitates, reacting for 8 hours at 50-60 ℃, changing the solution from orange yellow to red black, cooling to room temperature, the precipitate was washed with a large amount of water, dried, and recrystallized from acetone to give the product N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition product (Compound 3).
2) Introduction of a pyrazole structure: mixing 1mmol of N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition product (compound 3) and 1mmol of 6-fluorochromone phenylhydrazone (compound 4) in 25mL of absolute ethyl alcohol, adding 1.5mmol of chloramine T, refluxing for 15 hours, carrying out addition reaction, recrystallizing with methanol, and carrying out vacuum drying to obtain the pyrazole structure-containing N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition derivative (compound 5).
Examples 4,
1) And synthesis of N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition product: respectively dissolving 2mmol of 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride (compound 1) and 2mmol of p-bromoaniline (compound 2) in 25mL of acetone solvent, dropwise adding the p-bromoaniline solution into a reaction bottle containing 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride (compound 1) solution under stirring, reacting for 2 hours at room temperature while releasing heat and gradually generating light yellow precipitates, sequentially adding 0.4 g of manganese acetate, 18mL of triethylamine and 33mL of acetic anhydride into the reaction bottle, reacting for 2 hours at room temperature while heating, gradually dissolving the precipitates, reacting for 6 hours at 50-60 ℃, changing the solution from orange yellow to red black, cooling to room temperature, the precipitate was washed with a large amount of water, dried, and recrystallized from acetone to give the product N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition product (Compound 3).
2) Introduction of a pyrazole structure: mixing 1mmol of N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition product (compound 3) and 1mmol of 6-fluorochromone phenylhydrazone (compound 4) in 25mL of absolute ethyl alcohol, adding 1.4mmol of chloramine T, refluxing for 13 hours, performing addition reaction, recrystallizing with methanol, and drying in vacuum to obtain the pyrazole structure-containing N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition derivative (compound 5).
Figure 3 shows the preparation of compound 5 of the present application, wherein 1 represents compound 1, 2 represents compound 2,3 represents compound 3, 4 represents compound 4, and 5 represents compound 5.
The experimental data are as follows:
the N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition derivative (compound 5) containing pyrazole structure is light yellow crystal, the yield is 63.5 percent, and the m.p.192-193 ℃.
1H NMR(DMSO)δ:7.23-7.49(m,12H,Ar-H),6.47(s,1H,C＝C-H),6.01(d,J＝8.5Hz,1H,H-5),6.09(1H,d,J＝8.5Hz,1H,H-6),3.13(1H,d,J＝8.9Hz,1H H-2),2.85(1H,d,J＝8.9Hz,1H,H-3),1.34(1H,m,H-7a),1.47(1H,m,H-7b),1.33(1H,m,H-8a),1.47(1H,m,H-8b),2.56(1H,m,H-9),1.02(3H,d,J＝7.0Hz,H-10),1.07(3H,d,J＝6.7Hz,H-11),1.50(3H,s,H-12).
IR 3457(N-C＝O),3085(ArH),1720(C＝O),1577(C＝N),1296(C-O-C)cm-1
m/e:667(100.0％)。
Anal.calcd.for C36H31BrFN3O4:C,64.67；H,4.67；N,6.29。
The result of measuring the antitumor activity of the pyrazole-containing N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition derivative (compound 5) is as follows:
MTT assay compound 5 was tested for in vitro inhibition of different tumor strains:
compound 5 was dissolved and diluted in DMSO, and tumor cells Bel-7402 (human liver cancer cells), KB (oral cancer cells), SGC7901 (gastric cancer cells), HO8901 (ovarian cancer cells), HL-60 (leukemia cells), ECA109 (intestinal cancer cells) were seeded in 4000/200. mu.L/well in 96-well plates, 2. mu.L of compound was added to each well to a final concentration of 12.0. mu.M, 6.0. mu.M, 3.0. mu.M, 1.5. mu.M, and incubated in a 37 ℃ 5% CO2 cell incubator for 72 hours with DMSO (1%) as a blank. After 72 hours, MTT was added to a final concentration of 0.25mg/mL, the mixture was placed in a 5% CO2 cell incubator at 37 ℃ for 4 hours, the solvent was then blotted, 100. mu.l DMSO was added to each well, and the absorbance (OD value) was measured at 570nm using an enzyme-linked immunosorbent assay, and the data obtained was used to calculate the IC50 value. Selecting compounds with high inhibitory activity, and determining the influence of different action times of the compounds at different concentrations on the human tumor cell cycle and apoptosis.
The test compounds at various concentrations were coarse-screened in 96-well plates and, based on the resulting inhibition, IC50 values were calculated and the results are shown in the following table:
Figure GDA0002850594530000081
Figure GDA0002850594530000091
TABLE 2
Table 2 shows that the pyrazole structure-containing N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition derivative (compound 5) has stronger inhibitory activity on Bel-7402 (human liver cancer cells), KB (oral cancer cells), SGC7901 (gastric cancer cells), HO8901 (ovarian cancer cells), HL-60 (leukemia cells) and ECA109 (intestinal cancer cells), and provides a foundation for development and research of potential drugs.
The above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and those skilled in the art can make various corresponding changes and modifications according to the present invention without departing from the spirit and the essence of the present invention, but these corresponding changes and modifications should fall within the protection scope of the appended claims.

Claims (7)

1. The pyrazole structure-containing N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition derivative is characterized in that the chemical structural formula of the pyrazole structure-containing N-p-bromophenyl-substituted maleimide alpha-terpinene cycloaddition derivative is as follows:
Figure FDA0002850594520000011
2. a method for preparing the pyrazole structure-containing N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition derivative according to claim 1, wherein the method for preparing the pyrazole structure-containing N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition derivative comprises:
respectively dissolving 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride and p-bromoaniline in an acetone solvent, the p-bromoaniline solution is dripped into a reaction bottle containing 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride solution under stirring, the reaction releases heat and gradually generates light yellow precipitate, after the reaction is carried out for 1 to 2 hours at room temperature, adding manganese acetate, triethylamine and acetic anhydride into the reaction bottle in sequence, reacting, heating, gradually dissolving the precipitate, reacting for 5-8 hours at 50-60 ℃, changing the solution from orange yellow to red black, cooling to room temperature, washing and drying the precipitate in a large amount of water, and recrystallizing with acetone to obtain the product N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition product;
mixing the N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition product and 6-fluorochromone phenylhydrazone in absolute ethyl alcohol, adding chloramine T, refluxing for 12-15 hours, carrying out addition reaction, recrystallizing with methanol, and drying in vacuum to obtain the pyrazole structure-containing N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition derivative;
wherein the chemical structural formula of the N-p-bromophenyl substituted maleimide alpha-terpinene cycloaddition product is as follows:
Figure FDA0002850594520000021
the chemical structural formula of the 6-fluorochromone phenylhydrazone is as follows:
Figure FDA0002850594520000022
3. the method for preparing the pyrazole structure-containing N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition derivative according to claim 2, wherein the dissolving of 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride and p-bromoaniline in an acetone solvent respectively comprises:
adding 2mmol of 1-isopropyl-4-methyl-bicyclo [2,2,2] oct-5-ene-2, 3-dicarboxylic anhydride into 20-30 mL of acetone solvent;
adding 2mmol of para-bromoaniline into 20-30 mL of acetone solvent.
4. The method for preparing the pyrazole structure-containing N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition derivative according to claim 2, wherein the molar ratio of the N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition product, 6-fluorochromone phenylhydrazone, and chloramine T is 1: 1: 1-1.5.
5. The method for preparing the pyrazole structure-containing N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition derivative according to claim 2, wherein the sequential addition of manganese acetate, triethylamine and acetic anhydride comprises:
adding 0.3-0.5 g of manganese acetate into 40-60 mL of acetone solvent;
adding 15-20mL of triethylamine into 40-60 mL of acetone solvent;
30-35mL of acetic anhydride is added into 40-60 mL of acetone solvent.
6. The method for preparing the pyrazole-containing N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition derivative according to claim 2, wherein the N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition product and 6-fluorochromone phenylhydrazone are mixed in anhydrous ethanol, wherein 1mmol of the N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition product and 1mmol of the 6-fluorochromone phenylhydrazone are added per 20 to 25mL of the anhydrous ethanol.
7. The use of the pyrazole structure-containing N-p-bromophenyl-substituted maleimide α -terpinene cycloaddition derivative according to claim 1 for preparing an antitumor agent.
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