CN108690028B - L-valine substituted maleimide derivative and preparation method and application thereof - Google Patents

L-valine substituted maleimide derivative and preparation method and application thereof Download PDF

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CN108690028B
CN108690028B CN201810638019.7A CN201810638019A CN108690028B CN 108690028 B CN108690028 B CN 108690028B CN 201810638019 A CN201810638019 A CN 201810638019A CN 108690028 B CN108690028 B CN 108690028B
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substituted maleimide
valine
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ethanol
maleimide derivative
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王玮
邓莉平
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Hunan Xuxiang Biotechnology Co.,Ltd.
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Shaoxing University Yuanpei College
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
    • C07D207/452—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention discloses an L-valine substituted maleimide derivative and a preparation method thereof, which comprises the steps of firstly synthesizing 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde, then preparing L-valine substituted maleimide by adopting a method of dehydrating 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde and 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate to generate Schiff base hydrazone, introducing a pyrazole ring into an L-valine substituted maleimide structure by using a1, 3-dipolar cycloaddition method so as to synthesize a derivative simultaneously containing 5- (1-phenyl-3-methyl-4-1, 2, 4-triazolyl) structure and pyridazinone structure. The L-valine substituted maleimide derivative prepared by the invention has stronger tumor cell inhibition effect and provides a basis for further application in the medical field.

Description

L-valine substituted maleimide derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an L-valine substituted maleimide derivative, and a preparation method and application thereof.
Background
L-valine substituted maleimide has the following chemical structural formula:
Figure GDA0002191969300000011
R＝(S)-CH(CH3)2
at present, 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 the chemical research of heterocyclic drugs. The triazole has aromaticity and abundant electrons in a molecular structure, can interact with enzymes and receptors in organisms by forming hydrogen bonds, and has various biological activities. In recent years, pyridazinone compounds become hot spots of research in the pharmaceutical field due to the unique physiological activity of pyridazinone compounds, and have strong effects of inhibiting cancer cell diffusion, resisting bacteria and viruses, reducing blood fat, reducing blood sugar, promoting metabolism and the like. Therefore, the heterocyclic compound has high synthetic value in terms of pharmacology and synthesis angle.
Pyrazole derivatives are widely concerned as a class of useful intermediates and various pharmaceutical activities shown by the intermediates, and in order to better research the influence of different heterocycles on pharmacological activity caused by aggregation in the same molecule, the synthesis of pyrazole derivatives modified by different groups is still an intense research topic of researchers.
Disclosure of Invention
The invention aims to provide an L-valine substituted maleimide derivative and a preparation method thereof, and the L-valine substituted maleimide derivative is prepared.
In order to achieve the purpose, the technical scheme of the invention is as follows:
an L-valine substituted maleimide derivative, wherein the chemical structural formula of the L-valine substituted maleimide derivative is as follows:
Figure GDA0002191969300000021
wherein:
R＝(S)-CH(CH3)2。
the invention also provides a preparation method of the L-valine substituted maleimide derivative, which comprises the following steps:
step 1, dissolving 1,2, 4-triazole in an ethanol solvent, adding potassium hydroxide, performing ultrasonic treatment at normal temperature for 0.5-1 hour, performing reduced pressure distillation to remove ethanol, adding DMSO (dimethyl sulfoxide), adding 5-chloro-3-methyl-1-phenyl-4-pyrazole formaldehyde in batches, performing ultrasonic treatment at 50-60 ℃ for 2-3 hours, performing TLC (thin layer chromatography) detection, pouring the mixture into ice water after the raw materials are reacted, precipitating a light yellow solid, performing suction filtration, drying the solid matter, and performing ethanol-water recrystallization to obtain a first compound 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde;
step 2, adding 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate into a flask containing ethanol, refluxing and stirring in a boiling water bath until the mixture is dissolved, slowly dropwise adding an anhydrous ethanol solution in which 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazolecarboxaldehyde is dissolved, continuing refluxing and stirring in the boiling water bath for 1-2 hours, dropwise adding hydrochloric acid until a yellowish precipitate appears, continuously refluxing and stirring in the boiling water bath for 5-7 hours, stopping the water bath, adding distilled water, stirring, deepening the yellowish precipitate, performing suction filtration to obtain a yellowish red needle-shaped product, washing with anhydrous ether for multiple times, recrystallizing with ethanol, and performing vacuum drying to obtain a second compound;
step 3, adding maleic anhydride and L-valine into a DMF solvent dried by a molecular sieve, stirring and refluxing for 8-10 hours, cooling to room temperature, adding ethyl acetate for dilution, washing with a saturated ammonium chloride solution, drying an organic phase with anhydrous magnesium sulfate, filtering, performing vacuum distillation and spin drying on the filtered organic phase, and recrystallizing with ethyl acetate to obtain L-valine substituted maleimide;
and 4, dissolving the L-valine substituted maleimide and the second compound in ethanol, adding chloramine T, refluxing for 7-8 hours, obtaining a light yellow precipitate after TLC detection reaction is finished, filtering the precipitate under reduced pressure, recrystallizing the precipitate with methanol, and drying in vacuum to obtain the L-valine substituted maleimide derivative containing 5- (1-phenyl-3-methyl-4-1, 2, 4-triazolyl) substitution.
Further, the mass ratio of the 1,2, 4-triazole to the 5-chloro-3-methyl-1-phenyl-4-pyrazole formaldehyde substance is 7: 5.
Further, the ratio of the 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde to the 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate substance is 2: 3.
Further, the mass ratio of the maleic anhydride to the L-valine is 1: 1.
Further, the amount ratio of the second compound, the L-valine substituted maleimide and the chloramine T substance is 10:11: 12.
The invention also provides application of the L-valine substituted maleimide derivative in the aspect of antitumor drugs, and the L-valine substituted maleimide derivative has a strong tumor cell inhibition effect.
The invention provides an L-valine substituted maleimide derivative and a preparation method thereof, which comprises the steps of firstly synthesizing 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde, then preparing L-valine substituted maleimide by adopting a method of dehydrating 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde and 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate to generate Schiff base hydrazone, introducing a pyrazole ring into an L-valine substituted maleimide structure by using a1, 3-dipolar cycloaddition method, thereby synthesizing the L-valine substituted maleimide derivative simultaneously containing 5- (1-phenyl-3-methyl-4-1, 2, 4-triazolyl) structure and pyridazinone structure. The L-valine substituted maleimide derivative containing 5- (1-phenyl-3-methyl-4-1, 2, 4-triazolyl) substitution prepared by the invention has stronger tumor cell inhibition effect and provides a foundation for further application in the medical field.
Drawings
FIG. 1 is a flow chart of the preparation method of the present invention;
FIG. 2 is a schematic diagram of the preparation of a first compound and a second compound according to the present invention;
FIG. 3 is a schematic diagram showing the chemical structure of the preparation of L-valine substituted maleimide according to the present invention;
FIG. 4 is a schematic diagram of the chemical structural formula of the preparation of the 5- (1-phenyl-3-methyl-4-1, 2, 4-triazolyl substituted L-valine substituted maleimide derivative of the present invention.
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.
Pyrazole derivatives have attracted considerable attention as a class of useful intermediates and as a variety of pharmaceutical activities that they themselves exhibit. In order to better study the influence of different heterocycles on the pharmacological activity caused by aggregation in the same molecule, the invention synthesizes a pyrazole-type L-valine-substituted maleimide derivative containing a 5- (1-phenyl-3-methyl-4-1, 2, 4-triazolyl) structure and a pyridazinone structure, which has biological activity, also called a 5- (1-phenyl-3-methyl-4-1, 2, 4-triazolyl) -substituted L-valine-substituted maleimide derivative, also referred to as an L-valine-substituted maleimide derivative in the embodiment simply by a dipolar cycloaddition reaction.
The invention provides an L-valine substituted maleimide derivative, which has the following chemical structural formula:
Figure GDA0002191969300000041
wherein:
R＝(S)-CH(CH3)2。
as shown in fig. 1, the method for preparing the L-valine substituted maleimide derivative of the present invention comprises the following steps:
step S1, dissolving 1,2, 4-triazole in an ethanol solvent, adding potassium hydroxide, performing ultrasonic treatment for 0.5-1 hour at normal temperature, performing reduced pressure distillation to remove ethanol, adding DMSO, adding 5-chloro-3-methyl-1-phenyl-4-pyrazolecarboxaldehyde in batches, performing ultrasonic treatment for 2-3 hours at 50-60 ℃, performing TLC detection to obtain a mixture, pouring the mixture into ice water after the raw materials are reacted, precipitating a light yellow solid, performing suction filtration, drying the solid matter, and performing ethanol-water recrystallization to obtain a first compound 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazolecarboxaldehyde;
step S2, adding 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate into a flask containing ethanol, refluxing and stirring in a boiling water bath until the mixture is dissolved, slowly dropwise adding an anhydrous ethanol solution in which 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazolecarboxaldehyde is dissolved, continuing refluxing and stirring in the boiling water bath for 1-2 hours, dropwise adding hydrochloric acid until a yellowish precipitate appears, continuously refluxing and stirring in the boiling water bath for 5-7 hours, stopping the water bath, adding distilled water, stirring, deepening the yellowish precipitate, performing suction filtration to obtain a yellowish red needle product, washing with anhydrous ether for multiple times, recrystallizing with ethanol, and performing vacuum drying to obtain a second compound;
step S3, adding maleic anhydride and L-valine into a DMF solvent dried by a molecular sieve, stirring and refluxing for 8-10 hours, cooling to room temperature, adding ethyl acetate for dilution, washing with a saturated ammonium chloride solution, drying an organic phase with anhydrous magnesium sulfate, filtering, performing vacuum distillation and spin drying on the filtered organic phase, and recrystallizing with ethyl acetate to obtain L-valine substituted maleimide;
and S4, dissolving the L-valine substituted maleimide and the second compound in ethanol, adding chloramine T, refluxing for 7-8 hours, obtaining a light yellow precipitate after TLC detection reaction is finished, filtering the precipitate under reduced pressure, recrystallizing the precipitate with methanol, and drying in vacuum to obtain the L-valine substituted maleimide derivative containing 5- (1-phenyl-3-methyl-4-1, 2, 4-triazolyl) substitution.
The preparation is illustrated in detail below by means of specific examples:
examples 1,
Dissolving 21mmol of 1,2, 4-triazole in 50mL of ethanol solvent, adding 25mmol of potassium hydroxide, performing ultrasonic treatment at normal temperature of 25 ℃ for half an hour, performing reduced pressure distillation to remove ethanol, adding 40mL of DMSO (dimethyl sulfoxide), adding 15mmol of 5-chloro-3-methyl-1-phenyl-4-pyrazolecarboxaldehyde in batches, performing ultrasonic treatment at 50 ℃ for 2 hours, performing TLC detection, pouring the mixture into 200mL of ice water after the raw materials are reacted, separating out light yellow solid, and performing suction filtration; and after drying the solid matter, recrystallizing the solid matter by using ethanol-water to obtain a first compound 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde.
Wherein, the ultrasonic refers to the reaction under the condition of ultrasonic wave, and the application of the ultrasonic is mature in the technical field of chemical industry, and is not described herein again.
The method for generating the second compound by dehydrating and reacting 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde with 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate comprises the following steps:
the method comprises the following specific operations: adding 3mmol of 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate into a flask containing 20mL of ethanol, refluxing and stirring in a boiling water bath until the mixture is dissolved, slowly dropwise adding 15mL of absolute ethanol solution in which 2mmol of 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde is dissolved, continuing refluxing and stirring in the boiling water bath for 1 hour, and dropwise adding 10 drops of hydrochloric acid until a light yellow precipitate appears. 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 the light yellow precipitate, and performing suction filtration to obtain a yellowish red needle-shaped product. Washing with anhydrous ether for several times, recrystallizing with ethanol, and vacuum drying to obtain the second compound.
The preparation processes of the first compound and the second compound are shown as a figure 2, wherein 1 represents the chemical structural formula of the first compound, and 2 represents the chemical structural formula of the second compound, wherein the amount ratio of the 1,2, 4-triazole to the 5-chloro-3-methyl-1-phenyl-4-pyrazole formaldehyde substance is 7:5, and the amount ratio of the 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde to the 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate substance is 2: 3.
Adding 2.45 g (25mmol) of maleic anhydride and 3.28 g (25mmol) of L-valine into 15ml of DMF solvent (N, N-dimethylformamide) dried by a molecular sieve, stirring and refluxing for 8 hours, cooling to room temperature, adding 50ml of ethyl acetate for dilution, washing with saturated ammonium chloride solution for 6 times (30 ml each time), drying an organic phase by anhydrous magnesium sulfate, distilling and spinning the filtered organic phase by vacuum distillation, and recrystallizing by ethyl acetate to obtain a white solid compound, namely L-valine substituted maleimide.
FIG. 3 shows the preparation of L-valine substituted maleimide, and 3 shows the chemical formula of L-valine substituted maleimide, wherein R ═ R-CH2CH(CH3)2The mass ratio of the maleic anhydride to the L-valine is 1: 1.
1mmol of white solid compound L-valine substituted maleimide and 1.1mmol of compound 2 are added into 30mL of 95% ethanol, 1.2mmol of chloramine T is added, reflux is carried out for 7 hours, after TLC detection reaction is finished, light yellow precipitate is obtained, the precipitate is filtered under reduced pressure, and is recrystallized by methanol, and vacuum drying is carried out, so that the L-valine substituted maleimide derivative containing 5- (1-phenyl-3-methyl-4-1, 2, 4-triazolyl) substitution is obtained.
FIG. 4 shows a production process of a 5- (1-phenyl-3-methyl-4-1, 2, 4-triazolyl) -substituted L-valine-substituted maleimide derivative, and 4 represents a chemical structural formula of the 5- (1-phenyl-3-methyl-4-1, 2, 4-triazolyl) -substituted L-valine-substituted maleimide derivative, wherein:
R＝(R)-CH(CH3)2。
the ratio of the second compound to the L-valine substituted maleimide to the chloramine T substance is 10:11: 12.
It should be noted that the present invention provides the ratio of the amount of each substance participating in the preparation in each step, and provides an example, and those skilled in the art can prepare the product by using different amounts of each substance according to the method of the present technical solution, and the present invention is not limited thereto.
The present example also provides the following experimental data:
l-valine substituted maleimide derivative as pale yellow powder, yield 21.6%, melting point: the nuclear magnetic hydrogen spectrum data and the element analysis data are as follows at 134-135 ℃:
1H NMR(CD3OD)δ:10.08(s,1H,NHN),8.02(s,2H，N＝C-H),7.32-7.19(m,5H,Ar-H),6.49(s,1H,C＝C-H),5.82(d,J＝10.2Hz,1H),5.34(d,J＝10.2Hz,1H),4.47(CH,1H,HC-N-C＝O)，2.63-2.75(m,1H,CH),2.38(s,3H,CH3)2.00-2.07(m,1H,CH),0.76-0.80(dd,6H,J＝2.4Hz,6.8Hz,2CH3)。
IR(KBr)v/cm-13457(N-C＝O),3086(ArH),1774(C＝O,pyridazinone),1720(C＝O),1575(C＝N),1298(C-O-C)cm-1,1693(C＝O)cm-1
m/e:584(100.0％)
Anal.calcd.for C27H24N10O6：C,55.46；H,4.17；N,23.93。
in this example, MTT method was used to determine the in vitro inhibitory effect of a 5- (1-phenyl-3-methyl-4-1, 2, 4-triazolyl) -substituted L-valine-substituted maleimide derivative (hereinafter referred to as Compound 4) on various tumor strains, and the results of the determination of the antitumor activity of the L-valine-substituted maleimide derivative were as follows:
dissolving compound 4 in DMSO, diluting, and collecting tumor cells Bel-7402 (human liver cancer cell), KB (oral cancer cell), SGC7901 (gastric cancer cell), HO8901 (ovarian cancer cell), HL-60 (leukemia cell),ECA109 (intestinal cancer cells) was seeded into 4000/200. mu.L/well of 96-well plates, and 2. mu.L of the 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, together at 37 ℃ with 5% CO2The cells were incubated in an incubator for 72 hours, with DMSO (1%) as a blank control. After 72 hours, MTT was added to a final concentration of 0.25mg/mL and the mixture was left at 37 ℃ with 5% CO2After 4 hours in the cell incubator, the solvent was blotted, 100. mu.l DMSO was added to each well, absorbance (OD value) was measured at 570nm with an enzyme-linked immunosorbent assay, and the data obtained was used to calculate IC50The value is obtained. 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 of different concentrations were coarse-screened in 96-well plates and IC was calculated from the resulting inhibition50Values, results are given in the table below.
Figure GDA0002191969300000081
TABLE 1
In Table 1, the IC of the 5- (1-phenyl-3-methyl-4-1, 2, 4-triazolyl) -substituted L-valine-substituted maleimide derivative (Compound 4) for six tumor cell lines is shown50The values show that the compound has stronger tumor cell inhibition effects on SGC7901 (gastric cancer cells), HL-60 (leukemia cells) and Bel-7402 (human liver cancer cells), and provides a foundation for further application in the field of medicines.
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. An L-valine substituted maleimide derivative, wherein the chemical structural formula of the L-valine substituted maleimide derivative is as follows:
Figure FDA0002191969290000011
wherein: r ═ S) -CH (CH)3)2。
2. A process for producing an L-valine-substituted maleimide derivative according to claim 1, which comprises:
step 1, dissolving 1,2, 4-triazole in an ethanol solvent, adding potassium hydroxide, performing ultrasonic treatment at normal temperature for 0.5-1 hour, performing reduced pressure distillation to remove ethanol, adding DMSO (dimethyl sulfoxide), adding 5-chloro-3-methyl-1-phenyl-4-pyrazolecarboxaldehyde in batches, performing ultrasonic treatment at 50-60 ℃ for 2-3 hours, performing TLC (thin layer chromatography) detection, pouring the mixture into ice water after the raw materials are reacted, precipitating a light yellow solid, performing suction filtration, drying the solid matter, and performing ethanol-water recrystallization to obtain a first compound, wherein the chemical structural formula of the first compound is as follows:
Figure FDA0002191969290000012
step 2, adding 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate into a flask containing ethanol, refluxing and stirring in a boiling water bath until the mixture is dissolved, slowly dropwise adding an anhydrous ethanol solution in which a first compound is dissolved, continuously refluxing and stirring in the boiling water bath for 1-2 hours, dropwise adding hydrochloric acid until a faint yellow precipitate appears, continuously refluxing and stirring in the boiling water bath for 5-7 hours, stopping the water bath, adding distilled water and stirring, deepening the faint yellow precipitate, performing suction filtration to obtain a yellowish red needle product, washing with anhydrous ether for multiple times, recrystallizing with ethanol and performing vacuum drying to obtain a second compound, wherein the chemical structural formula of the second compound is as follows:
Figure FDA0002191969290000021
step 3, adding maleic anhydride and L-valine into a DMF solvent dried by a molecular sieve, stirring and refluxing for 8-10 hours, cooling to room temperature, adding ethyl acetate for dilution, washing with a saturated ammonium chloride solution, drying an organic phase with anhydrous magnesium sulfate, filtering, performing vacuum distillation and spin drying on the filtered organic phase, and recrystallizing with ethyl acetate to obtain L-valine substituted maleimide;
and 4, dissolving the L-valine substituted maleimide and the second compound in ethanol, adding chloramine T, refluxing for 7-8 hours, obtaining a light yellow precipitate after TLC detection reaction is finished, filtering the precipitate under reduced pressure, recrystallizing the precipitate with methanol, and drying in vacuum to obtain the structural compound of claim 1.
3. The method for preparing L-valine substituted maleimide derivatives according to claim 2, wherein the ratio of the amount of 1,2, 4-triazole to 5-chloro-3-methyl-1-phenyl-4-pyrazolecarboxaldehyde is 7: 5.
4. The method for producing an L-valine-substituted maleimide derivative according to claim 2, wherein the ratio of the amount of the first compound to the 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate substance is 2: 3.
5. The method for producing an L-valine substituted maleimide derivative according to claim 2, wherein the amount ratio of maleic anhydride to the L-valine is 1: 1.
6. The method for producing an L-valine-substituted maleimide derivative according to claim 2, wherein the second compound, the L-valine-substituted maleimide and the chloramine T compound are present in an amount ratio of 10:11: 12.
7. Use of the L-valine substituted maleimide derivative according to claim 1 for the preparation of an antitumor agent.
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