CN109988176A - The p-bromophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative and its preparation method and application - Google Patents
The p-bromophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative and its preparation method and application Download PDFInfo
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Abstract
The invention discloses one kind p-bromophenyl 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 para-bromoaniline are dissolved separately in acetone solvent, para-bromoaniline 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-bromophenyl substitution is prepared, then maleimide α-terpinene cycloaddition product and 6- fluoro chromone phenylhydrazone that N- p-bromophenyl replaces are mixed in dehydrated alcohol, toluene-sodium-sulfonchloramide is added, the p-bromophenyl substituted maleimide amine of N- containing pyrrazole structure being prepared α-terpinene cycloaddition derivative has stronger inhibitory activity to cancer cell, provides the foundation for its developmental research for being used for potential drug.
Description
Technical field
The invention belongs to pharmaceutical technology fields, more particularly to one kind p-bromophenyl substituted maleimide amine of N- containing pyrrazole structure
α-terpinene cycloaddition derivative and its preparation method and application.
Background technique
N- p-bromophenyl substituted maleimide amine α-terpinene cycloaddition derivative chemical structural formula is as shown in Figure 1.1,
3- Dipolar Cycloaddition becomes the synthesis most important side of 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-bromophenyl maleimide α-terpinene cycloaddition derivative containing chromone structure should have been synthesized, has been ground in drug
Study carefully field to have great importance.
Summary of the invention
The purpose of the present invention is to provide one kind p-bromophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene rings
Additive derivative and its preparation method and application, structure of the 6- fluoro chromone phenylhydrazone for thering is carboxaldehyde radicals to replace using 3 in pyrazoles
On replaced, to N- p-bromophenyl replace maleimide α-terpinene cycloaddition product carry out structure of modification.
To achieve the goals above, technical solution of the present invention is as follows:
One kind p-bromophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative, it is described to contain pyrazoles
Structure N- p-bromophenyl substituted maleimide amine α-terpinene cycloaddition derivative chemical structural formula is as follows:
A kind of system of the p-bromophenyl 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-bromophenyl substituted maleimide of N- containing the pyrrazole structure amine α-terpinene cycloaddition derivative
Preparation method, comprising:
Bicyclic [the 2,2,2] -5- octene -2,3- dicarboxylic anhydride of 1- isopropyl-4-methyl-and para-bromoaniline are dissolved separately in third
In ketone solvent, para-bromoaniline 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-bromophenyl replaces；
Maleimide α-terpinene cycloaddition product and 6- fluoro chromone phenylhydrazone that N- p-bromophenyl replaces are mixed in
In dehydrated alcohol, toluene-sodium-sulfonchloramide is added, flows back 12-15 hours, carries out addition reaction, with recrystallizing methanol, vacuum drying is obtained containing pyrrole
Azoles structure N- p-bromophenyl 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 para-bromoaniline (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 para-bromoaniline of 2mmol is added in the acetone solvent of every 20~30mL.
Into a ground, maleimide α-terpinene cycloaddition product, the 6- fluoro chromone of the N- p-bromophenyl substitution
The molar ratio of 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 color that N- p-bromophenyl is replaced
Ketone phenylhydrazone is mixed in dehydrated alcohol, wherein the Malaysia that 1mmol N- p-bromophenyl replaces is added in every 20-25mL dehydrated alcohol
Acid imide α-terpinene cycloaddition product and 1mmol 6- fluoro chromone phenylhydrazone.
The invention also provides one kind p-bromophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition to spread out
Application of the biology in terms of preparing anti-tumor drug.
One kind N- containing pyrrazole structure p-bromophenyl substituted maleimide amine α proposed by the present invention-terpinene cycloaddition is derivative
Object and its preparation method and application, since the maleimide α-terpinene cycloaddition product replaced in N- p-bromophenyl introduces five
The structure that chromone has been imported on the basis of first pyrazoles ring structure can change pharmacological activity, and the present invention has carboxaldehyde radicals to take using 3
The 6- fluoro chromone phenylhydrazone in generation is replaced in the structure of pyrazoles, the maleimide α-terpinene replaced to N- p-bromophenyl
Cycloaddition product carries out structure of modification, the p-bromophenyl substituted maleimide amine of N- containing the pyrrazole structure α-terpinene ring being prepared
Additive derivative for for 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) all have stronger inhibitory activity, are
Its developmental research for being used for potential drug provides the foundation.
Detailed description of the invention
Fig. 1 is N- p-bromophenyl substituted maleimide amine α-terpinene cycloaddition derivatives chemical structural formula；
Fig. 2 is present invention N- containing pyrrazole structure p-bromophenyl substituted maleimide amine α-terpinene cycloaddition derivatives chemical
Structural formula；
Fig. 3 is present invention N- containing pyrrazole structure p-bromophenyl substituted maleimide amine α-terpinene cycloaddition derivative 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 pyrazoles in N- p-bromophenyl substituted maleimide amine α-terpinene cycloaddition derivative
The structure that chromone has been imported on the basis of 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-bromophenyl replace maleimide α-terpinene cycloaddition product carry out structure of modification.
A kind of change of the p-bromophenyl substituted maleimide of N- containing pyrrazole structure amine α of the application-terpinene cycloaddition derivative
It is as shown in Figure 2 to learn structural formula.
In one embodiment, one kind N- containing pyrrazole structure p-bromophenyl substituted maleimide amine α-terpinene cycloaddition is spread out
The preparation method of biology, comprising:
Bicyclic [the 2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) of 1- isopropyl-4-methyl-and para-bromoaniline (are changed
Close object 2) it is dissolved separately in acetone solvent, para-bromoaniline solution drop (compound 2) is added to containing 1- isopropyl-under stiring
The reaction flask of 4- methyl-bicyclo [2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) solution, exothermic heat of reaction simultaneously gradually generate
Pale yellow precipitate after room temperature reaction 1-2 hours, sequentially adds manganese acetate, triethylamine and aceticanhydride in above-mentioned reaction flask, and reaction rises
Temperature, precipitating are gradually dissolved, are reacted 5-8 hours at 50~60 DEG C, and solution becomes red-black by orange, are cooled to room temperature, precipitating warp
Massive laundering, drying are produced with maleimide α-terpinene cycloaddition that acetone recrystallization obtains the substitution of product N- p-bromophenyl
Object (compound 3)；
The maleimide α that N- p-bromophenyl is replaced-terpinene cycloaddition product (compound 3) and 6- fluoro chromone benzene
Hydrazone (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-bromophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative (compound
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]
Bromophenyl) dicarboximide, referred to as maleimide α-terpinene cycloaddition of N- p-bromophenyl substitution in the present embodiment
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-bromophenyl) dicarboximide, is referred to as in the present embodiment
The p-bromophenyl 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 para-bromoaniline (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 para-bromoaniline of 2mmol is added in the acetone solvent of every 20~30mL.
In one embodiment, maleimide α-terpinene cycloaddition product, the 6- fluoro color of N- p-bromophenyl substitution
The molar ratio of ketone 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- fluoro N- p-bromophenyl replaced
Chromone phenylhydrazone is mixed in dehydrated alcohol, wherein the horse that 1mmol N- p-bromophenyl replaces is added in every 20-25mL dehydrated alcohol
Come acid imide α-terpinene cycloaddition product and 1mmol 6- fluoro chromone phenylhydrazone.
Below by way of specific embodiment, to elaborate the application p-bromophenyl substituted maleimide of N- containing pyrrazole structure
Amine α-terpinene cycloaddition derivative (compound 5) preparation method:
Embodiment 2,
1), maleimide α-terpinene cycloaddition product synthesis that N- p-bromophenyl replaces: by 2mmol 1- isopropyl
Base -4- methyl-bicyclo [2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) and 2mmol para-bromoaniline (compound 2) are respectively
It is dissolved in the acetone solvent of 20mL, is under stiring added dropwise to para-bromoaniline solution bicyclic containing 1- isopropyl-4-methyl-
The reaction flask of [2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) solution, exothermic heat of reaction simultaneously gradually generate pale yellow precipitate,
After room temperature reaction 1 hour, in above-mentioned reaction flask, 0.3 gram of manganese acetate, 15mL triethylamine and 30mL aceticanhydride are sequentially added, is reacted
Heating, precipitating are gradually dissolved, are reacted 5 hours at 50~60 DEG C, and solution becomes red-black by orange, are cooled to room temperature, precipitating warp
Massive laundering, drying are produced with maleimide α-terpinene cycloaddition that acetone recrystallization obtains the substitution of product N- p-bromophenyl
Object (compound 3).
2) pyrrazole structure: the maleimide α that 1mmol N- p-bromophenyl is replaced-terpinene cycloaddition product, is imported
(compound 3) and 1mmol 6- fluoro chromone phenylhydrazone (compound 4) are mixed in 20mL dehydrated alcohol, and 1.2mmol chloramines is added
T flows back 12 hours, carries out addition reaction, and with recrystallizing methanol, vacuum drying obtains the p-bromophenyl of N- containing pyrrazole structure and replaces horse
Carry out acid imide α-terpinene cycloaddition derivative (compound 5).
Embodiment 3,
1), maleimide α-terpinene cycloaddition product synthesis that N- p-bromophenyl replaces: by 2mmol 1- isopropyl
Base -4- methyl-bicyclo [2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) and 2mmol para-bromoaniline (compound 2) are respectively
It is dissolved in the acetone solvent of 30mL, is under stiring added dropwise to para-bromoaniline solution bicyclic containing 1- isopropyl-4-methyl-
The reaction flask of [2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) solution, exothermic heat of reaction simultaneously gradually generate pale yellow precipitate,
After room temperature reaction 2 hours, in above-mentioned reaction flask, 0.5 gram of manganese acetate, 20mL triethylamine and 35mL aceticanhydride are sequentially added, is reacted
Heating, precipitating are gradually dissolved, are reacted 8 hours at 50~60 DEG C, and solution becomes red-black by orange, are cooled to room temperature, precipitating warp
Massive laundering, drying are produced with maleimide α-terpinene cycloaddition that acetone recrystallization obtains the substitution of product N- p-bromophenyl
Object (compound 3).
2) pyrrazole structure: the maleimide α that 1mmol N- p-bromophenyl is replaced-terpinene cycloaddition product, is imported
(compound 3) and 1mmol 6- fluoro chromone phenylhydrazone (compound 4) are mixed in 25mL dehydrated alcohol, and 1.5mmol chloramines is added
T flows back 15 hours, carries out addition reaction, and with recrystallizing methanol, vacuum drying obtains the p-bromophenyl of N- containing pyrrazole structure and replaces horse
Carry out acid imide α-terpinene cycloaddition derivative (compound 5).
Embodiment 4,
1), maleimide α-terpinene cycloaddition product synthesis that N- p-bromophenyl replaces: by 2mmol 1- isopropyl
Base -4- methyl-bicyclo [2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) and 2mmol para-bromoaniline (compound 2) are respectively
It is dissolved in the acetone solvent of 25mL, is under stiring added dropwise to para-bromoaniline solution bicyclic containing 1- isopropyl-4-methyl-
The reaction flask of [2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) solution, exothermic heat of reaction simultaneously gradually generate pale yellow precipitate,
After room temperature reaction 2 hours, in above-mentioned reaction flask, 0.4 gram of manganese acetate, 18mL triethylamine and 33mL aceticanhydride are sequentially added, is reacted
Heating, precipitating are gradually dissolved, are reacted 6 hours at 50~60 DEG C, and solution becomes red-black by orange, are cooled to room temperature, precipitating warp
Massive laundering, drying are produced with maleimide α-terpinene cycloaddition that acetone recrystallization obtains the substitution of product N- p-bromophenyl
Object (compound 3).
2) pyrrazole structure: the maleimide α that 1mmol N- p-bromophenyl is replaced-terpinene cycloaddition product, is imported
(compound 3) and 1mmol 6- fluoro chromone phenylhydrazone (compound 4) are mixed in 25mL dehydrated alcohol, and 1.4mmol chloramines is added
T flows back 13 hours, carries out addition reaction, and with recrystallizing methanol, vacuum drying obtains the p-bromophenyl of N- containing pyrrazole structure and replaces horse
Carry out acid imide 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-bromophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative (compound 5) is yellowish
Color crystallization, yield 63.5%, m.p.192-193 DEG C.
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 p-bromophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative (compound 5) is anti-swollen
Tumor activity 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-bromophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative (chemical combination
Object 5) for Bel-7402 (human liver cancer cell), KB (cancer cell of oral cavity), SGC7901 (stomach cancer cell), (oophoroma is thin by HO8901
Born of the same parents), HL-60 (leukaemia cell), ECA109 (colon-cancer cell) all have stronger inhibitory activity, be used for potential drug for it
Developmental research provides 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-bromophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative, which is characterized in that
The chemical structural formula of the p-bromophenyl substituted maleimide of N- containing the pyrrazole structure amine α-terpinene cycloaddition derivative is as follows:
2. a kind of p-bromophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition as described in claim 1 is spread out
The preparation method of biology, which is characterized in that the p-bromophenyl substituted maleimide of N- containing the pyrrazole structure amine α-terpinene ring adds
At the preparation method of derivative, comprising:
It is molten that bicyclic [the 2,2,2] -5- octene -2,3- dicarboxylic anhydride of 1- isopropyl-4-methyl-and para-bromoaniline are dissolved separately in acetone
In agent, para-bromoaniline solution is added dropwise to containing bicyclic [2,2, the 2] -5- octene -2,3- of 1- isopropyl-4-methyl-under stiring
The reaction flask of diacid anhydride solution, exothermic heat of reaction simultaneously gradually generate pale yellow precipitate, after room temperature reaction 1-2 hours, in above-mentioned reaction
Manganese acetate, triethylamine and aceticanhydride, reaction heating are sequentially added in bottle, precipitating gradually dissolves, and it is small that 5-8 is reacted at 50~60 DEG C
When, solution becomes red-black by orange, is cooled to room temperature, precipitates through massive laundering, drying, obtain N- pairs of product with acetone recrystallization
Maleimide α-terpinene cycloaddition product that bromophenyl replaces；
Maleimide α-terpinene cycloaddition product and 6- fluoro chromone phenylhydrazone that N- p-bromophenyl replaces are mixed in anhydrous
In ethyl alcohol, toluene-sodium-sulfonchloramide is added, flows back 12-15 hours, carries out addition reaction, with recrystallizing methanol, vacuum drying obtains knot containing pyrazoles
Structure N- p-bromophenyl substituted maleimide amine α-terpinene cycloaddition derivative.
3. the p-bromophenyl substituted maleimide of N- containing pyrrazole structure amine α according to claim 2-terpinene cycloaddition is derivative
The preparation method of object, which is characterized in that it is described by bicyclic [2,2,2] -5- octene -2, the 3- dicarboxylic anhydride of 1- isopropyl-4-methyl-and
Para-bromoaniline is dissolved separately in acetone solvent, 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 para-bromoaniline of 2mmol is added in the acetone solvent of every 20~30mL.
4. the p-bromophenyl substituted maleimide of N- containing pyrrazole structure amine α according to claim 2-terpinene cycloaddition is derivative
The preparation method of object, which is characterized in that maleimide α-terpinene cycloaddition product, 6- fluorine that the N- p-bromophenyl replaces
It is 1:1:1-1.5 for the molar ratio of chromone phenylhydrazone and toluene-sodium-sulfonchloramide.
5. the p-bromophenyl substituted maleimide of N- containing pyrrazole structure amine α according to claim 2-terpinene cycloaddition is derivative
The preparation method of object, 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-bromophenyl substituted maleimide of N- containing pyrrazole structure amine α according to claim 2-terpinene cycloaddition is derivative
The preparation method of object, which is characterized in that the maleimide α-terpinene cycloaddition product and 6- that the N- p-bromophenyl replaces
Fluoro chromone phenylhydrazone is mixed in dehydrated alcohol, wherein 1mmol N- p-bromophenyl is added in every 20-25mL dehydrated alcohol and replaces
Maleimide α-terpinene cycloaddition product and 1mmol6- fluoro chromone phenylhydrazone.
7. one kind p-bromophenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative prepare it is antitumor
Application in terms of drug.
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| WO2002076989A1 (en) * | 2001-03-23 | 2002-10-03 | The University Of Newcastle Research Associates Limited | Protein phosphate inhibitors |
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| WO2002076989A1 (en) * | 2001-03-23 | 2002-10-03 | The University Of Newcastle Research Associates Limited | Protein phosphate inhibitors |
| CN103896954A (en) * | 2013-11-15 | 2014-07-02 | 绍兴文理学院 | Pyrazol norcantharidin derivative as well as preparation method and application thereof |
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