CN109988178A - The p-nitrophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative and its preparation method and application - Google Patents

The p-nitrophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative and its preparation method and application Download PDF

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CN109988178A
CN109988178A CN201910362676.8A CN201910362676A CN109988178A CN 109988178 A CN109988178 A CN 109988178A CN 201910362676 A CN201910362676 A CN 201910362676A CN 109988178 A CN109988178 A CN 109988178A
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nitrophenyl
maleimide
terpinene cycloaddition
amine
terpinene
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CN109988178B (en
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王玮
周瑾
胡春霞
王萌
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Shanghai Mofan Trading Co.,Ltd.
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Shaoxing University Yuanpei College
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    • A61P35/00Antineoplastic agents
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    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic 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 one kind p-nitrophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivatives and its preparation method and application, by 1- isopropyl-4-methyl-bicyclic [2, 2, 2] -5- octene -2, 3- dicarboxylic anhydride and paranitroanilinum are dissolved separately in acetone solvent, p-nitrophenyl amine aqueous solution is added dropwise to containing 1- isopropyl-4-methyl-bicyclic [2 under stiring, 2, 2] -5- octene -2, the reaction flask of 3- diacid anhydride solution, maleimide α-terpinene cycloaddition product of N- p-nitrophenyl substitution is prepared, then maleimide α-terpinene cycloaddition product and 6- fluoro chromone phenylhydrazone that N- p-nitrophenyl replaces are mixed in dehydrated alcohol, toluene-sodium-sulfonchloramide is added, the p-nitrophenyl of N- containing pyrrazole structure being prepared takes There is stronger inhibitory activity to cancer cell for maleimide α-terpinene cycloaddition derivative, provide the foundation for its developmental research for being used for potential drug.

Description

The p-nitrophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition is spread out Biology and its preparation method and application
Technical field
The invention belongs to pharmaceutical technology fields, more particularly to one kind p-nitrophenyl substituted maleimide of N- containing pyrrazole structure Amine α-terpinene cycloaddition derivative and its preparation method and application.
Background technique
N- p-nitrophenyl substituted maleimide amine α-terpinene cycloaddition derivative chemical structural formula is as shown in Figure 1. It is most important that 1,3- Dipolar Cycloaddition becomes synthesis five member ring heterocyclic compound with its good region and main selectivity More active a kind of reaction in method and heterocyclic drug chemical research.
In recent years, due to the extensive bioactivity of chromone, anticancer, antibacterial, inhibit platelet aggregation etc. and by Concern.So either still from a synthetic point of view from pharmacology, this heterocyclic compounds has very high synthesis to be worth. Pyrazole derivatives are as a kind of useful intermediate and themselves shown a variety of pharmaceutical activity come out and by people Extensive concern.
Study different heterocycles assemble in same molecule and on influence caused by pharmacological activity, it is anti-by dipole-diople interaction Pyrazoles N- p-nitrophenyl maleimide α-terpinene cycloaddition derivative containing chromone structure should be synthesized, in drug Research field has great importance.
Summary of the invention
The purpose of the present invention is to provide one kind p-nitrophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinenes Cycloaddition derivative and its preparation method and application, knot of the 6- fluoro chromone phenylhydrazone for thering is carboxaldehyde radicals to replace using 3 in pyrazoles Replaced on structure, the maleimide α replaced to N- p-nitrophenyl-terpinene cycloaddition product carries out structure of modification.
To achieve the goals above, technical solution of the present invention is as follows:
One kind p-nitrophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative, it is described to contain pyrrole Azoles structure N- p-nitrophenyl substituted maleimide amine α-terpinene cycloaddition derivative chemical structural formula is as follows:
A kind of p-nitrophenyl substituted maleimide of N- containing pyrrazole structure amine α-terpinene cycloaddition derivative of the present invention Preparation method, which is characterized in that the p-nitrophenyl substituted maleimide of N- containing the pyrrazole structure amine α-terpinene cycloaddition is spread out The preparation method of biology, comprising:
Bicyclic [the 2,2,2] -5- octene -2,3- dicarboxylic anhydride of 1- isopropyl-4-methyl-and paranitroanilinum are dissolved separately in In acetone solvent, p-nitrophenyl amine aqueous solution is added dropwise under stiring pungent containing bicyclic [2,2, the 2] -5- of 1- isopropyl-4-methyl - The reaction flask of alkene -2,3- diacid anhydride solution, exothermic heat of reaction simultaneously gradually generate pale yellow precipitate, after room temperature reaction 1-2 hours, upper It states and sequentially adds manganese acetate, triethylamine and aceticanhydride in reaction flask, reaction heating, precipitating is gradually dissolved, reacted at 50~60 DEG C 5-8 hours, solution became red-black by orange, is cooled to room temperature, precipitates through massive laundering, drying, produced with acetone recrystallization Maleimide α-terpinene cycloaddition product that object N- p-nitrophenyl replaces;
Maleimide α-terpinene cycloaddition product and 6- fluoro chromone the phenylhydrazone mixing that N- p-nitrophenyl is replaced In dehydrated alcohol, toluene-sodium-sulfonchloramide is added, flows back 12-15 hours, carries out addition reaction, with recrystallizing methanol, vacuum drying is contained Pyrrazole structure N- p-nitrophenyl substituted maleimide amine α-terpinene cycloaddition derivative.
Further, described by bicyclic [2,2,2] -5- octene -2, the 3- dicarboxylic anhydride (compound 1) of 1- isopropyl-4-methyl - It is dissolved separately in acetone solvent with paranitroanilinum (compound 2), comprising:
Bicyclic [the 2,2,2] -5- of 1- isopropyl-4-methyl-that 2mmol is added in the acetone solvent of every 20~30mL is pungent Alkene -2,3- dicarboxylic anhydride;
The paranitroanilinum of 2mmol is added in the acetone solvent of every 20~30mL.
Into a ground, maleimide α-terpinene cycloaddition product, the 6- fluoro color of the N- p-nitrophenyl substitution The molar ratio of ketone phenylhydrazone and toluene-sodium-sulfonchloramide is 1:1:1-1.5.
It is further, described to sequentially add manganese acetate, triethylamine and aceticanhydride, comprising:
0.3-0.5 grams of manganese acetate is added in the acetone solvent of every 40~60mL;
15-20mL triethylamine is added in the acetone solvent of every 40~60mL;
30-35mL aceticanhydride is added in the acetone solvent of every 40~60mL.
Further, the maleimide α-terpinene cycloaddition product and 6- fluoro that N- p-nitrophenyl is replaced Chromone phenylhydrazone is mixed in dehydrated alcohol, wherein is added what 1mmol N- p-nitrophenyl replaced in every 20-25mL dehydrated alcohol Maleimide α-terpinene cycloaddition product and 1mmol 6- fluoro chromone phenylhydrazone.
The invention also provides one kind p-nitrophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition Application of the derivative in terms of preparing anti-tumor drug.
One kind N- containing pyrrazole structure p-nitrophenyl substituted maleimide amine α-terpinene cycloaddition proposed by the present invention is spread out Biology and its preparation method and application, since the maleimide α-terpinene cycloaddition product replaced in N- p-nitrophenyl draws The structure for entering to have imported on the basis of five yuan of pyrazoles ring structures chromone can change pharmacological activity, and the present invention has formaldehyde using 3 The 6- fluoro chromone phenylhydrazone that base replaces is replaced in the structure of pyrazoles, the maleimide α-replaced to N- p-nitrophenyl Terpinene cycloaddition product carries out structure of modification, the p-nitrophenyl substituted maleimide amine of N- containing the pyrrazole structure α-being prepared Terpinene cycloaddition derivative for for Bel-7402 (human liver cancer cell), KB (cancer cell of oral cavity), (gastric cancer is thin by SGC7901 Born of the same parents), HO8901 (ovarian cancer cell), HL-60 (leukaemia cell), ECA109 (colon-cancer cell) all have stronger inhibition and live Property, it provides the foundation for its developmental research for being used for potential drug.
Detailed description of the invention
Fig. 1 is N- p-nitrophenyl substituted maleimide amine α-terpinene cycloaddition derivatives chemical structural formula;
Fig. 2 is the derivative materialization of present invention N- containing pyrrazole structure p-nitrophenyl substituted maleimide amine α-terpinene cycloaddition Learn structural formula;
Fig. 3 is present invention N- containing pyrrazole structure p-nitrophenyl substituted maleimide amine α-terpinene cycloaddition derivative system Preparation Method chemical formula schematic diagram.
Specific embodiment
Technical solution of the present invention is described in further details with reference to the accompanying drawings and examples, following embodiment is not constituted Limitation of the invention.
It has been investigated that introducing five yuan of pyrroles in N- p-nitrophenyl substituted maleimide amine α-terpinene cycloaddition derivative The structure that chromone has been imported on the basis of azoles ring structure can change pharmacological activity.Experimental data is as follows:
Table 1
Based on the above experimental data, the 6- fluoro chromone phenylhydrazone for having carboxaldehyde radicals to replace using 3 in this application is in pyrazoles Structure on replaced, to N- p-nitrophenyl replace maleimide α-terpinene cycloaddition product carry out structure change It makes.
A kind of p-nitrophenyl substituted maleimide of N- containing pyrrazole structure amine α of the application-terpinene cycloaddition derivative Chemical structural formula is as shown in Figure 2.
In one embodiment, one kind N- containing pyrrazole structure p-nitrophenyl substituted maleimide amine α-terpinene cycloaddition The preparation method of derivative, comprising:
By bicyclic [the 2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) of 1- isopropyl-4-methyl-and paranitroanilinum (compound 2) is dissolved separately in acetone solvent, is under stiring added to p-nitrophenyl amine aqueous solution drop (compound 2) different containing 1- The reaction flask of propyl -4- methyl-bicyclo [2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) solution, exothermic heat of reaction and gradually It generates pale yellow precipitate and sequentially adds manganese acetate, triethylamine and aceticanhydride in above-mentioned reaction flask, instead after room temperature reaction 1-2 hours It should heat up, precipitating gradually dissolves, and reacts 5-8 hours at 50~60 DEG C, and solution becomes red-black by orange, is cooled to room temperature, sinks It forms sediment through massive laundering, drying, obtains maleimide α-terpinene ring of product N- p-nitrophenyl substitution with acetone recrystallization Addition product (compound 3);
The maleimide α that N- p-nitrophenyl is replaced-terpinene cycloaddition product (compound 3) and 6- fluoro chromone Phenylhydrazone (compound 4) is mixed in dehydrated alcohol, and toluene-sodium-sulfonchloramide is added, and is flowed back 12-15 hours, is carried out addition reaction, is tied again with methanol Crystalline substance, vacuum drying obtain the p-nitrophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative (chemical combination Object 5).
Wherein, the chemical full name of compound 3 are as follows: (N- pairs of -5- octene -2,3- of 1- isopropyl-4-methyl-bicyclic [2,2,2] Nitrobenzophenone) dicarboximide, in the present embodiment referred to as N- p-nitrophenyl replace maleimide α-terpinene ring Addition product.
And the chemical full name of compound 5 are as follows: 3- (the fluoro- chromone -3- base of 6-) -1- phenyl -7- methyl -4- isopropyl-bicyclic [2,2,2] octane simultaneously [2,3-d] 3aH, 7aH pyrazoles -2,3- (N- p-nitrophenyl) dicarboximide, in the present embodiment referred to as For the p-nitrophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative.
Wherein, the synthesis of 6- fluoro chromone phenylhydrazone (compound 4), the 6- fluoro chromone that can there is carboxaldehyde radicals to replace with 3 The method of schiff bases is generated with phenylhydrazine dehydration to synthesize.
Embodiment 1 takes the phenylhydrazine of 2mmol to be added to fill in the flask of 10mL tetrahydrofuran, and boiling water bath return stirring is to molten Then the ethanol solution into the 20mL 6- fluoro chromone for having carboxaldehyde radicals to replace dissolved with 2mmol 3 is slowly added dropwise in solution, continue Boiling water bath return stirring 1 hour, 10 drop hydrochloric acid are added dropwise, there is pale yellow precipitate appearance.Continuous boiling water bath return stirring 5 hours, stop Sealing bath, adds people's 20mL distilled water to stir, and pale yellow precipitate darkens, filter 6- fluoro chromone phenylhydrazone, yellowish red color are needle-shaped Product.It is rinsed repeatedly with anhydrous ether, is dried in vacuo to obtain product 6- fluoro chromone phenylhydrazone (compound 4).
It should be noted that the present invention is not limited to the synthetic method of 6- fluoro chromone phenylhydrazone (compound 4), compound 4 Chemical name can also state are as follows: the fluoro- chromone -3- phenylhydrazone of 6-, which is not described herein again.
In one embodiment, by bicyclic [2,2,2] -5- octene -2, the 3- dicarboxylic anhydride (compound of 1- isopropyl-4-methyl - 1) it is dissolved separately in acetone solvent with paranitroanilinum (compound 2), comprising:
Bicyclic [the 2,2,2] -5- of 1- isopropyl-4-methyl-that 2mmol is added in the acetone solvent of every 20~30mL is pungent Alkene -2,3- dicarboxylic anhydride;
The paranitroanilinum of 2mmol is added in the acetone solvent of every 20~30mL.
In one embodiment, maleimide α-terpinene cycloaddition product, 6- fluoro that N- p-nitrophenyl replaces The molar ratio of chromone phenylhydrazone and toluene-sodium-sulfonchloramide is 1:1:1-1.5.
In one embodiment, manganese acetate, triethylamine and aceticanhydride are sequentially added, comprising:
0.3-0.5 grams of manganese acetate is added in the acetone solvent of every 40~60mL;
15-20mL triethylamine is added in the acetone solvent of every 40~60mL;
30-35mL aceticanhydride is added in the acetone solvent of every 40~60mL.
In one embodiment, the maleimide α-terpinene cycloaddition product and 6- fluorine N- p-nitrophenyl replaced It is mixed in dehydrated alcohol for chromone phenylhydrazone, wherein 1mmol N- p-nitrophenyl is added in every 20-25mL dehydrated alcohol and replaces Maleimide α-terpinene cycloaddition product and 1mmol 6- fluoro chromone phenylhydrazone.
Below by way of specific embodiment, replace Malaysia acyl to elaborate the application p-nitrophenyl of N- containing pyrrazole structure Imines α-terpinene cycloaddition derivative (compound 5) preparation method:
Embodiment 2,
1), maleimide α-terpinene cycloaddition product synthesis that N- p-nitrophenyl replaces: 2mmol 1- is different Propyl -4- methyl-bicyclo [2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) and 2mmol paranitroanilinum (compound 2) It is dissolved separately in the acetone solvent of 20mL, p-nitrophenyl amine aqueous solution is added dropwise to containing 1- isopropyl-4-methyl-under stiring The reaction flask of bicyclic [2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) solution, exothermic heat of reaction simultaneously gradually generate faint yellow sink It forms sediment, after room temperature reaction 1 hour, in above-mentioned reaction flask, sequentially adds 0.3 gram of manganese acetate, 15mL triethylamine and 30mL aceticanhydride, instead It should heat up, precipitating gradually dissolves, and reacts 5 hours at 50~60 DEG C, and solution becomes red-black by orange, is cooled to room temperature, precipitates Through massive laundering, drying, added with maleimide α-terpinene ring that acetone recrystallization obtains the substitution of product N- p-nitrophenyl At product (compound 3).
2), import pyrrazole structure: the maleimide α that 1mmol N- p-nitrophenyl is replaced-terpinene cycloaddition produces Object (compound 3) and 1mmol 6- fluoro chromone phenylhydrazone (compound 4) are mixed in 20mL dehydrated alcohol, and 1.2mmol chlorine is added Amine T flows back 12 hours, carries out addition reaction, and with recrystallizing methanol, vacuum drying obtains the p-nitrophenyl of N- containing pyrrazole structure and takes For maleimide α-terpinene cycloaddition derivative (compound 5).
Embodiment 3,
1), maleimide α-terpinene cycloaddition product synthesis that N- p-nitrophenyl replaces: 2mmol 1- is different Propyl -4- methyl-bicyclo [2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) and 2mmol paranitroanilinum (compound 2) It is dissolved separately in the acetone solvent of 30mL, p-nitrophenyl amine aqueous solution is added dropwise to containing 1- isopropyl-4-methyl-under stiring The reaction flask of bicyclic [2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) solution, exothermic heat of reaction simultaneously gradually generate faint yellow sink It forms sediment, after room temperature reaction 2 hours, in above-mentioned reaction flask, sequentially adds 0.5 gram of manganese acetate, 20mL triethylamine and 35mL aceticanhydride, instead It should heat up, precipitating gradually dissolves, and reacts 8 hours at 50~60 DEG C, and solution becomes red-black by orange, is cooled to room temperature, precipitates Through massive laundering, drying, added with maleimide α-terpinene ring that acetone recrystallization obtains the substitution of product N- p-nitrophenyl At product (compound 3).
2), import pyrrazole structure: the maleimide α that 1mmol N- p-nitrophenyl is replaced-terpinene cycloaddition produces Object (compound 3) and 1mmol 6- fluoro chromone phenylhydrazone (compound 4) are mixed in 25mL dehydrated alcohol, and 1.5mmol chlorine is added Amine T flows back 15 hours, carries out addition reaction, and with recrystallizing methanol, vacuum drying obtains the p-nitrophenyl of N- containing pyrrazole structure and takes For maleimide α-terpinene cycloaddition derivative (compound 5).
Embodiment 4,
1), maleimide α-terpinene cycloaddition product synthesis that N- p-nitrophenyl replaces: 2mmol 1- is different Propyl -4- methyl-bicyclo [2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) and 2mmol paranitroanilinum (compound 2) It is dissolved separately in the acetone solvent of 25mL, p-nitrophenyl amine aqueous solution is added dropwise to containing 1- isopropyl-4-methyl-under stiring The reaction flask of bicyclic [2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) solution, exothermic heat of reaction simultaneously gradually generate faint yellow sink It forms sediment, after room temperature reaction 2 hours, in above-mentioned reaction flask, sequentially adds 0.4 gram of manganese acetate, 18mL triethylamine and 33mL aceticanhydride, instead It should heat up, precipitating gradually dissolves, and reacts 6 hours at 50~60 DEG C, and solution becomes red-black by orange, is cooled to room temperature, precipitates Through massive laundering, drying, added with maleimide α-terpinene ring that acetone recrystallization obtains the substitution of product N- p-nitrophenyl At product (compound 3).
2), import pyrrazole structure: the maleimide α that 1mmol N- p-nitrophenyl is replaced-terpinene cycloaddition produces Object (compound 3) and 1mmol 6- fluoro chromone phenylhydrazone (compound 4) are mixed in 25mL dehydrated alcohol, and 1.4mmol chlorine is added Amine T flows back 13 hours, carries out addition reaction, and with recrystallizing methanol, vacuum drying obtains the p-nitrophenyl of N- containing pyrrazole structure and takes For maleimide α-terpinene cycloaddition derivative (compound 5).
Fig. 3 shows the preparation process of the application compound 5, wherein 1 indicates that compound 1,2 indicates that compound 2,3 indicates Compound 3,4 indicates that compound 4,5 indicates compound 5.
Experimental data is as follows:
The p-nitrophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative (compound 5) is light Yellow crystal, yield 63.5%, m.p.192-193 DEG C.
1H NMR (DMSO) δ: 7.32-7.51 (m, 12H, Ar-H), 6.49 (s, 1H, C=C-H), 6.03 (d, J= 8.5Hz, 1H, H-5), 6.10 (1H, d, J=8.5Hz, 1H, H-6), 3.14 (1H, d, J=8.9Hz, 1H H-2), 2.86 (1H, D, J=8.9Hz, 1H, H-3), 1.34 (1H, m, H-7a), 1.47 (1H, m, H-7b), 1.34 (1H, m, H-8a), 1.47 (1H, m, ), H-8b 2.56 (1H, m, H-9), 1.01 (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), 1723 (C=O), 1579 (C=N), 1298 (C-O-C) cm-1
M/e:634 (100.0%).
Anal.calcd.for C36H31FN4O6:C,68.13;H,4.92;N,8.83.
The p-nitrophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative (compound 5) is anti- Tumor promotion measurement result:
Mtt assay measures the In-vitro Inhibitory Effect of 5 pairs of compound different tumor strains:
Compound 5 is dissolved with DMSO, dilute, tumour cell Bel-7402 (human liver cancer cell), KB (cancer cell of oral cavity), SGC7901 (stomach cancer cell), HO8901 (ovarian cancer cell), HL-60 (leukaemia cell), ECA109 (colon-cancer cell) are in 96 holes It is planted on plate into 4000/200 holes μ L/, 2 μ L of compound is added in every hole, final concentration of 12.0 μM, 6.0 μM, 3.0 μM, 1.5 μM, is total to It is same as 37 DEG C, is incubated for 72 hours in 5%CO2 cell incubator, with DMSO (1%) for blank control.After 72 hours, it is added dense eventually Degree is the MTT of 0.25mg/mL, is placed in 37 DEG C, 4 hours in 5%CO2 cell incubator, blots solvent later, and 100 μ are added in every hole L DMSO is measured at 570nm absorbance (OD value) with enzyme linked immunological instrument, and the data obtained is for calculating IC50 value.Select inhibition The high compound of activity measures the compound effects time difference under various concentration to the shadow in human tumor cells period and apoptosis It rings.
The test-compound of various concentration carries out scalping with 96 orifice plates, according to resulting inhibiting rate, calculates IC50 value, as a result It see the table below:
Table 2
Table 2 shows the p-nitrophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative and (changes Close object 5) for Bel-7402 (human liver cancer cell), KB (cancer cell of oral cavity), SGC7901 (stomach cancer cell), HO8901 (oophoroma Cell), HL-60 (leukaemia cell), ECA109 (colon-cancer cell) all have stronger inhibitory activity, be used for potential drug for it Developmental research provide the foundation.
The above embodiments are merely illustrative of the technical solutions of the present invention rather than is limited, without departing substantially from essence of the invention In the case where mind and its essence, those skilled in the art make various corresponding changes and change in accordance with the present invention Shape, but these corresponding changes and modifications all should fall within the scope of protection of the appended claims of the present invention.

Claims (7)

1. one kind p-nitrophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative, feature exist In the chemical structural formula of the p-nitrophenyl substituted maleimide of N- containing the pyrrazole structure amine α-terpinene cycloaddition derivative is such as Under:
2. a kind of p-nitrophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition as described in claim 1 The preparation method of derivative, which is characterized in that the p-nitrophenyl substituted maleimide of N- containing the pyrrazole structure amine α-terpinene The preparation method of cycloaddition derivative, comprising:
Bicyclic [the 2,2,2] -5- octene -2,3- dicarboxylic anhydride of 1- isopropyl-4-methyl-and paranitroanilinum are dissolved separately in acetone In solvent, p-nitrophenyl amine aqueous solution is added dropwise to containing bicyclic [2,2, the 2] -5- octene-of 1- isopropyl-4-methyl-under stiring The reaction flask of 2,3- diacid anhydride solutions, exothermic heat of reaction simultaneously gradually generate pale yellow precipitate, after room temperature reaction 1-2 hours, above-mentioned Manganese acetate, triethylamine and aceticanhydride, reaction heating are sequentially added in reaction flask, precipitating gradually dissolves, and reacts 5-8 at 50~60 DEG C Hour, solution becomes red-black by orange, is cooled to room temperature, precipitates through massive laundering, drying, obtain product N- with acetone recrystallization Maleimide α-terpinene cycloaddition product that p-nitrophenyl replaces;
Maleimide α-terpinene cycloaddition product and 6- fluoro chromone phenylhydrazone that N- p-nitrophenyl replaces are mixed in nothing In water-ethanol, toluene-sodium-sulfonchloramide is added, flows back 12-15 hours, carries out addition reaction, with recrystallizing methanol, vacuum drying is obtained containing pyrazoles Structure N- p-nitrophenyl substituted maleimide amine α-terpinene cycloaddition derivative.
3. the p-nitrophenyl substituted maleimide of N- containing pyrrazole structure amine α-terpinene cycloaddition according to claim 2 is spread out The preparation method of biology, which is characterized in that described by bicyclic [2,2,2] -5- octene -2, the 3- dicarboxylic anhydride of 1- isopropyl-4-methyl - It is dissolved separately in acetone solvent with paranitroanilinum, comprising:
Bicyclic [2,2,2] octene-2-5- of 1- isopropyl-4-methyl-of 2mmol are added in the acetone solvent of every 20~30mL, 3- dicarboxylic anhydride;
The paranitroanilinum of 2mmol is added in the acetone solvent of every 20~30mL.
4. the p-nitrophenyl substituted maleimide of N- containing pyrrazole structure amine α-terpinene cycloaddition according to claim 2 is spread out The preparation method of biology, which is characterized in that maleimide α-terpinene cycloaddition product of the N- p-nitrophenyl substitution, The molar ratio of 6- fluoro chromone phenylhydrazone and toluene-sodium-sulfonchloramide is 1:1:1-1.5.
5. the p-nitrophenyl substituted maleimide of N- containing pyrrazole structure amine α-terpinene cycloaddition according to claim 2 is spread out The preparation method of biology, which is characterized in that described to sequentially add manganese acetate, triethylamine and aceticanhydride, comprising:
0.3-0.5 grams of manganese acetate is added in the acetone solvent of every 40~60mL;
15-20mL triethylamine is added in the acetone solvent of every 40~60mL;
30-35mL aceticanhydride is added in the acetone solvent of every 40~60mL.
6. the p-nitrophenyl substituted maleimide of N- containing pyrrazole structure amine α-terpinene cycloaddition according to claim 2 is spread out The preparation method of biology, which is characterized in that maleimide α-terpinene cycloaddition product that the N- p-nitrophenyl replaces It is mixed in dehydrated alcohol with 6- fluoro chromone phenylhydrazone, wherein 1mmol N- p-nitrophenyl is added in every 20-25mL dehydrated alcohol Maleimide α-terpinene cycloaddition the product and 1mmol6- fluoro chromone phenylhydrazone that base replaces.
7. one kind p-nitrophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative is anti-swollen in preparation Application in terms of tumor medicine.
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