CN109988177A - The p-methoxyphenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative and its preparation method and application - Google Patents
The p-methoxyphenyl 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-methoxyphenyl 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 P-nethoxyaniline are dissolved separately in acetone solvent, P-nethoxyaniline 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-methoxyphenyl substitution is prepared, then maleimide α-terpinene cycloaddition product and 6- fluoro chromone phenylhydrazone that N- p-methoxyphenyl replaces are mixed in dehydrated alcohol, toluene-sodium-sulfonchloramide is added, N- containing pyrrazole structure pairs be prepared Methoxyphenyl substituted maleimide amine α-terpinene cycloaddition derivative has stronger inhibitory activity for HO8901, HL-60, ECA109, 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-methoxyphenyl of N- containing pyrrazole structure to replace Malaysia acyl
Imines α-terpinene cycloaddition derivative and its preparation method and application.
Background technique
N- p-methoxyphenyl substituted maleimide amine α-terpinene cycloaddition derivative chemical structural formula such as Fig. 1 institute
Show.It is main that 1,3- Dipolar Cycloaddition becomes synthesis five member ring heterocyclic compound with its good region and main selectivity
Method and heterocyclic drug chemical research in more active a kind of reaction.
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-methoxyphenyl maleimide α-terpinene cycloaddition derivative containing chromone structure should be synthesized, in medicine
Object research field has great importance.
Summary of the invention
The purpose of the present invention is to provide one kind p-methoxyphenyl substituted maleimide amine of N- containing pyrrazole structure α-pine tars
Alkene cycloaddition derivative and its preparation method and application, the 6- fluoro chromone phenylhydrazone for having carboxaldehyde radicals to replace using 3 is in pyrazoles
Replaced in structure, the maleimide α replaced to N- p-methoxyphenyl-terpinene cycloaddition product carries out structure and changes
It makes.
To achieve the goals above, technical solution of the present invention is as follows:
One kind p-methoxyphenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative, it is described to contain
Pyrrazole structure N- p-methoxyphenyl substituted maleimide amine α-terpinene cycloaddition derivative chemical structural formula is as follows:
One kind p-methoxyphenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative of the invention
Preparation method, which is characterized in that the p-methoxyphenyl substituted maleimide of N- containing the pyrrazole structure amine α-terpinene ring adds
At the preparation method of derivative, comprising:
Bicyclic [the 2,2,2] -5- octene -2,3- dicarboxylic anhydride of 1- isopropyl-4-methyl-and P-nethoxyaniline are dissolved respectively
In acetone solvent, P-nethoxyaniline solution is added dropwise under stiring bicyclic [2,2,2]-containing 1- isopropyl-4-methyl-
The reaction flask of 5- octene -2,3- diacid anhydride solution, exothermic heat of reaction simultaneously gradually generate pale yellow precipitate, after room temperature reaction 1-2 hours,
Manganese acetate, triethylamine and aceticanhydride are sequentially added in above-mentioned reaction flask, reaction heating, precipitating gradually dissolves, at 50~60 DEG C
Reaction 5-8 hours, solution become red-black by orange, are cooled to room temperature, precipitate through massive laundering, drying, obtained with acetone recrystallization
Maleimide α-terpinene cycloaddition the product replaced to product N- p-methoxyphenyl；
Maleimide α-terpinene cycloaddition product and 6- fluoro chromone phenylhydrazone that N- p-methoxyphenyl replaces are mixed
Together in dehydrated alcohol, toluene-sodium-sulfonchloramide is added, flows back 12-15 hours, carries out addition reaction, with recrystallizing methanol, vacuum drying is obtained
The p-methoxyphenyl substituted maleimide amine of N- containing pyrrazole structure 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 P-nethoxyaniline (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 P-nethoxyaniline of 2mmol is added in the acetone solvent of every 20~30mL.
Into a ground, maleimide α-terpinene cycloaddition product, 6- fluoro of the N- p-methoxyphenyl substitution
The molar ratio of chromone 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- fluorine that N- p-methoxyphenyl is replaced
It is mixed in dehydrated alcohol for chromone phenylhydrazone, wherein 1mmol N- p-methoxyphenyl is added in every 20-25mL dehydrated alcohol and takes
Maleimide α-terpinene cycloaddition the product and 1mmol 6- fluoro chromone phenylhydrazone in generation.
The invention also provides one kind p-methoxyphenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene rings to add
At application of the derivative in terms of preparing anti-tumor drug.
One kind N- containing pyrrazole structure p-methoxyphenyl substituted maleimide amine α-terpinene cycloaddition proposed by the present invention
Derivative and its preparation method and application, since the maleimide α-terpinene cycloaddition replaced in N- p-methoxyphenyl produces
The structure that chromone has been imported on the basis of object five yuan of pyrazoles ring structures of introducing can change pharmacological activity, and the present invention is had using 3
The 6- fluoro chromone phenylhydrazone that carboxaldehyde radicals replaces is replaced in the structure of pyrazoles, the Malaysia acyl replaced to N- p-methoxyphenyl
Imines α-terpinene cycloaddition product carries out structure of modification, and the p-methoxyphenyl of N- containing pyrrazole structure being prepared replaces Malaysia
Acid imide α-terpinene cycloaddition derivative is for HO8901 (ovarian cancer cell), HL-60 (leukaemia cell), ECA109 (intestines
Cancer cell) there is stronger inhibitory activity, it provides the foundation for its developmental research for being used for potential drug.
Detailed description of the invention
Fig. 1 is N- p-methoxyphenyl substituted maleimide amine α-terpinene cycloaddition derivatives chemical structural formula；
Fig. 2 is present invention N- containing pyrrazole structure p-methoxyphenyl substituted maleimide amine α-terpinene cycloaddition derivative
Chemical structural formula；
Fig. 3 is present invention N- containing pyrrazole structure p-methoxyphenyl 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 pyrazole rings in N- p-methoxyphenyl maleimide α-terpinene cycloaddition product
The structure that chromone has been imported on the basis of 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, structure of modification is carried out to N- p-methoxyphenyl maleimide α-terpinene cycloaddition product.
The application one kind p-methoxyphenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative
Chemical structural formula it is as shown in Figure 2.
In one embodiment, one kind N- containing pyrrazole structure p-methoxyphenyl substituted maleimide amine α-terpinene ring adds
At 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 to methoxybenzene
Amine (compound 2) is dissolved separately in acetone solvent, under stiring by P-nethoxyaniline solution drop (compound 2) add to containing
The reaction flask of 1- isopropyl-4-methyl-bicyclic [2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) solution, exothermic heat of reaction is simultaneously
It gradually generates pale yellow precipitate and sequentially adds manganese acetate, triethylamine and vinegar in above-mentioned reaction flask after room temperature reaction 1-2 hours
Acid anhydride, reaction heating, 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 obtain maleimide α-pine of product N- p-methoxyphenyl substitution through massive laundering, drying, with acetone recrystallization
Oily alkene cycloaddition product (compound 3)；
The maleimide α that N- p-methoxyphenyl is replaced-terpinene cycloaddition product (compound 3) and 6- fluoro color
Ketone phenylhydrazone (compound 4) is mixed in dehydrated alcohol, and toluene-sodium-sulfonchloramide is added, and is flowed back 12-15 hours, addition reaction is carried out, with methanol weight
Crystallization, vacuum drying obtain the p-methoxyphenyl 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]
Methoxyphenyl) two formyls, in the present embodiment referred to as N- p-methoxyphenyl 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-methoxyphenyl) dicarboximide, it is simple in the present embodiment
Referred to as N- containing pyrrazole structure p-methoxyphenyl substituted maleimide amine 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 P-nethoxyaniline (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 P-nethoxyaniline of 2mmol is added in the acetone solvent of every 20~30mL.
In one embodiment, maleimide α-terpinene cycloaddition product, 6- fluorine that N- p-methoxyphenyl replaces
It is 1:1:1-1.5 for the molar ratio of chromone phenylhydrazone and toluene-sodium-sulfonchloramide.
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- N- p-methoxyphenyl replaced
Fluoro chromone phenylhydrazone is mixed in dehydrated alcohol, wherein 1mmol N- p-methoxyphenyl is added in every 20-25mL dehydrated alcohol
Substituted maleimide α-terpinene cycloaddition product and 1mmol 6- fluoro chromone phenylhydrazone.
Below by way of specific embodiment, replace Malaysia to elaborate the application p-methoxyphenyl of N- containing pyrrazole structure
Acid imide α-terpinene cycloaddition derivative (compound 5) preparation method:
Embodiment 2,
1), maleimide α-terpinene cycloaddition product synthesis that N- p-methoxyphenyl replaces: by 2mmol 1-
Bicyclic [the 2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) of isopropyl-4-methyl-and 2mmol P-nethoxyaniline (chemical combination
Object 2) it is dissolved separately in the acetone solvent of 20mL, P-nethoxyaniline solution is added dropwise 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, room temperature reaction 1 hour after, in above-mentioned reaction flask, sequentially add 0.3 gram of manganese acetate, 15mL triethylamine and
30mL aceticanhydride, reaction heating, precipitating are gradually dissolved, are reacted 5 hours at 50~60 DEG C, and solution becomes red-black by orange, cooling
To room temperature, precipitating obtains the maleimide of product N- p-methoxyphenyl substitution through massive laundering, drying, with acetone recrystallization
α-terpinene cycloaddition product (compound 3).
2) pyrrazole structure: maleimide α-terpinene cycloaddition that 1mmol N- p-methoxyphenyl is replaced, is imported
Product (compound 3) and 1mmol 6- fluoro chromone phenylhydrazone (compound 4) are mixed in 20mL dehydrated alcohol, and 1.2mmol is added
Toluene-sodium-sulfonchloramide flows back 12 hours, carries out addition reaction, and with recrystallizing methanol, vacuum drying obtains N- containing pyrrazole structure to methoxybenzene
Base substituted maleimide amine α-terpinene cycloaddition derivative (compound 5).
Embodiment 3,
1), maleimide α-terpinene cycloaddition product synthesis that N- p-methoxyphenyl replaces: by 2mmol 1-
Bicyclic [the 2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) of isopropyl-4-methyl-and 2mmol P-nethoxyaniline (chemical combination
Object 2) it is dissolved separately in the acetone solvent of 30mL, P-nethoxyaniline solution is added dropwise 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, room temperature reaction 2 hours after, in above-mentioned reaction flask, sequentially add 0.5 gram of manganese acetate, 20mL triethylamine and
35mL aceticanhydride, reaction heating, precipitating are gradually dissolved, are reacted 8 hours at 50~60 DEG C, and solution becomes red-black by orange, cooling
To room temperature, precipitating obtains the maleimide of product N- p-methoxyphenyl substitution through massive laundering, drying, with acetone recrystallization
α-terpinene cycloaddition product (compound 3).
2) pyrrazole structure: maleimide α-terpinene cycloaddition that 1mmol N- p-methoxyphenyl is replaced, is imported
Product (compound 3) and 1mmol 6- fluoro chromone phenylhydrazone (compound 4) are mixed in 25mL dehydrated alcohol, and 1.5mmol is added
Toluene-sodium-sulfonchloramide flows back 15 hours, carries out addition reaction, and with recrystallizing methanol, vacuum drying obtains N- containing pyrrazole structure to methoxybenzene
Base substituted maleimide amine α-terpinene cycloaddition derivative (compound 5).
Embodiment 4,
1), maleimide α-terpinene cycloaddition product synthesis that N- p-methoxyphenyl replaces: by 2mmol 1-
Bicyclic [the 2,2,2] -5- octene -2,3- dicarboxylic anhydride (compound 1) of isopropyl-4-methyl-and 2mmol P-nethoxyaniline (chemical combination
Object 2) it is dissolved separately in the acetone solvent of 25mL, P-nethoxyaniline solution is added dropwise 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, room temperature reaction 2 hours after, in above-mentioned reaction flask, sequentially add 0.4 gram of manganese acetate, 18mL triethylamine and
33mL aceticanhydride, reaction heating, precipitating are gradually dissolved, are reacted 6 hours at 50~60 DEG C, and solution becomes red-black by orange, cooling
To room temperature, precipitating obtains the maleimide of product N- p-methoxyphenyl substitution through massive laundering, drying, with acetone recrystallization
α-terpinene cycloaddition product (compound 3).
2) pyrrazole structure: maleimide α-terpinene cycloaddition that 1mmol N- p-methoxyphenyl is replaced, is imported
Product (compound 3) and 1mmol 6- fluoro chromone phenylhydrazone (compound 4) are mixed in 25mL dehydrated alcohol, and 1.4mmol is added
Toluene-sodium-sulfonchloramide flows back 13 hours, carries out addition reaction, and with recrystallizing methanol, vacuum drying obtains N- containing pyrrazole structure to methoxybenzene
Base substituted maleimide amine 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-methoxyphenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative (compound 5) is
Pale yellow crystals, yield 46.5%, m.p.164-165 DEG C.
1H NMR (DMSO) δ: 7.245-7.502 (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), 3.78 (s, 3H, OCH3), 3.13 (1H, d, J=8.9Hz,
1H H-2), 2.85 (1H, d, J=8.9Hz, 1H, H-3), 1.33 (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), 1.01 (3H, d, J=7.0Hz, H-10), 1.08 (3H, d, J=
6.7
Hz,H-11),1.50(3H,s,H-12).
IR 3457 (N-C=O), 3082 (ArH), 1720 (C=O), 1573 (C=N), 1294 (C-O-C) cm-1
M/e:619 (100.0%).
Anal.calcd.for C37H34FN3O5:C, 71.71；H,5.53；N,6.78.
The p-methoxyphenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative (compound 5)
Antitumor cytolytic activity 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-methoxyphenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative
The IC of (compound 5) to six kinds of tumor cell lines50As a result value illustrates the p-methoxyphenyl of N- containing pyrrazole structure substituted maleimide
Amine α-terpinene cycloaddition derivative (compound 5) for HO8901 (ovarian cancer cell), HL-60 (leukaemia cell),
ECA109 (colon-cancer cell) has stronger inhibitory activity, provides the foundation for its developmental research for being used for potential drug.
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-methoxyphenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative, feature exist
In the chemical structural formula of the p-methoxyphenyl substituted maleimide of N- containing the pyrrazole structure amine α-terpinene cycloaddition derivative
It is as follows:
2. a kind of p-methoxyphenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene ring as described in claim 1 adds
At the preparation method of derivative, which is characterized in that the p-methoxyphenyl substituted maleimide of N- containing the pyrrazole structure amine α-pine
The preparation method of oily alkene cycloaddition derivative, comprising:
Bicyclic [the 2,2,2] -5- octene -2,3- dicarboxylic anhydride of 1- isopropyl-4-methyl-and P-nethoxyaniline are dissolved separately in third
In ketone solvent, P-nethoxyaniline 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-methoxyphenyl replaces；
Maleimide α-terpinene cycloaddition product and 6- fluoro chromone phenylhydrazone that N- p-methoxyphenyl 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-methoxyphenyl substituted maleimide amine α-terpinene cycloaddition derivative.
3. the p-methoxyphenyl substituted maleimide of N- containing pyrrazole structure amine α-terpinene cycloaddition according to claim 2
The preparation method of derivative, which is characterized in that described by bicyclic [2,2,2] -5- octene -2, the 3- diacid of 1- isopropyl-4-methyl -
Acid anhydride and P-nethoxyaniline are 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 P-nethoxyaniline of 2mmol is added in the acetone solvent of every 20~30mL.
4. the p-methoxyphenyl substituted maleimide of N- containing pyrrazole structure amine α-terpinene cycloaddition according to claim 2
The preparation method of derivative, which is characterized in that maleimide α-terpinene cycloaddition that the N- p-methoxyphenyl replaces
The molar ratio of product, 6- fluoro chromone phenylhydrazone and toluene-sodium-sulfonchloramide is 1:1:1-1.5.
5. the p-methoxyphenyl substituted maleimide of N- containing pyrrazole structure amine α-terpinene cycloaddition according to claim 2
The preparation method of derivative, 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-methoxyphenyl substituted maleimide of N- containing pyrrazole structure amine α-terpinene cycloaddition according to claim 2
The preparation method of derivative, which is characterized in that maleimide α-terpinene cycloaddition that the N- p-methoxyphenyl replaces
Product and 6- fluoro chromone phenylhydrazone are mixed in dehydrated alcohol, wherein 1mmol N- is added in every 20-25mL dehydrated alcohol to first
Maleimide α-terpinene cycloaddition the product and 1mmol6- fluoro chromone phenylhydrazone that phenyl replaces.
7. one kind p-methoxyphenyl substituted maleimide amine of N- containing pyrrazole structure α-terpinene cycloaddition derivative is anti-in preparation
Application in terms of tumour medicine.
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