CN110759920A - P-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing pyrazole structure and preparation method and application thereof - Google Patents
P-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing pyrazole structure and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a p-methoxyphenyl substituted spiro [ indazole-pyrazoline with a pyrazole structure]Derivatives, and preparation methods and applications thereof. The invention relates to a p-methoxyphenyl substituted spiro [ indazole-pyrazoline with pyrazole structure according to claim 1]The preparation method of the derivative is characterized by comprising the following steps of (1) synthesis of 1-phenyl-3-methyl-5- (1,2, 4-triazolyl) -4-pyrazolecarboxaldehyde, (2) synthesis of 1-phenyl-3-methyl-5- (1,2, 4-triazolyl-1-yl) -4-pyrazolecarboxaldehyde hydrazone, (3) synthesis of 1-phenyl-3-methyl-5- (1,2, 4-triazolyl-1-yl) - α -chloro-4-pyrazolecarboxaldehyde hydrazone, and (4) synthesis of 5- (4-methoxybenzylidene) -1-phenyl-6, 7-dihydro-1-phenylH-indazole-4 (5)H) -synthesis of ketones; (5) p-methoxyphenyl substituted spiro [ indole ] containing pyrazole structureAzole-pyrazolines]And (3) synthesizing a derivative.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a p-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure, and a preparation method and application thereof.
Background
5- (4-methoxybenzylidene) -1-phenyl-6, 7-dihydro-1H-indazol-4 (5H) -one, having the following chemical structure:
the 1, 3-dipolar cycloaddition reaction is the most important method for synthesizing five-membered heterocyclic compounds with good regioselectivity and body selectivity, and is also a more active reaction in heterocyclic pharmaceutical chemistry research. 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. The isoxazole skeleton is an important pharmacophore in the application of medicaments, and has remarkable physiological and pharmacological activities. In addition, spiroisoxazoles synthesized by 1, 3-dipolar cycloaddition of nitrile oxides to exocyclic double bonds have attracted attention by pharmacologists because they exhibit some important physiological properties. Therefore, the heterocyclic compound has high synthetic value in terms of pharmacology and synthesis angle.
Pyrazole derivatives have attracted considerable attention as a class of useful intermediates and as a variety of pharmaceutical activities that they themselves exhibit. In order to better study the influence of different heterocycles on the pharmacological activity caused by the aggregation in the same molecule, a p-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure is synthesized through 1, 3-dipolar cycloaddition reaction.
Disclosure of Invention
The invention aims to provide a p-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure and a preparation method thereof, and the p-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing the pyrazole structure is prepared.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a p-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure has the following chemical structural formula:
wherein: Ar-4-CH3OC6H4-。
A method for producing the p-methoxyphenyl-substituted spiro [ indazole-pyrazoline ] derivative having a pyrazole structure according to claim 1, which comprises the steps of:
(1) synthesis of 1-phenyl-3-methyl-5- (1,2, 4-triazolyl) -4-pyrazolecarboxaldehyde (compound 1): dissolving 21mmol of 1,2, 4-triazole in 50mL of ethanol solvent, adding 25mmol of potassium hydroxide, performing ultrasound at normal temperature of 25 ℃ for half an hour, performing rotary evaporation on ethanol under reduced pressure, adding 40mL of DMSO, adding 15mmol of 5-chloro-1-phenyl-3-methyl-4-formylpyrazole in batches, performing ultrasonic treatment at 50 ℃ for 2 hours, pouring the mixture into 200mL of ice water after TLC detection is finished, precipitating light yellow solid, and performing suction filtration; drying the solid matter, and recrystallizing with ethanol-water to obtain a compound 1-phenyl-3-methyl-5- (1,2, 4-triazolyl) -4-pyrazole formaldehyde (compound 1);
(2) synthesis of 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde hydrazone (compound 2): adding 22mmol of phenylhydrazine into a flask containing 10mL of tetrahydrofuran, refluxing and stirring in a boiling water bath until the phenylhydrazine is dissolved, slowly dropwise adding 20mL of anhydrous ethanol solution in which 20mmol of 1-phenyl-3-methyl-5- (1,2, 4-triazolyl) -4-pyrazole formaldehyde (compound 1) is dissolved, continuing refluxing and stirring in the boiling water bath for 1h, and dropwise adding 10 drops of concentrated hydrochloric acid until a light yellow precipitate appears; refluxing and stirring in a continuous boiling water bath for 5 hours, stopping the water bath, adding 20mL of distilled water, stirring, deepening the color of a light yellow precipitate, and performing suction filtration to obtain a yellowish red needle-shaped product; washing with anhydrous ether for several times, and vacuum drying to obtain 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde hydrazone (compound 2);
(3) synthesizing 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) - α -chloro-4-pyrazole formaldehyde hydrazone (compound 3), namely adding 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde hydrazone (compound 2) into 50ml of 1, 2-dichloroethane and 30ml of isopropanol, magnetically stirring to completely dissolve the 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde hydrazone, then adding tert-butyl hypochlorite into a salt bath at the temperature of-12 ℃, vigorously stirring for 2 hours, during the period, controlling the temperature to be below-5 ℃ to obtain a light blue transparent liquid, transferring the product into a round-bottom flask, evaporating the solvent at the temperature of 50 ℃ under reduced pressure to obtain a light yellow oily substance, adding a small amount of petroleum ether, heating to dissolve the mixture, separating out a large amount of yellow solid, and carrying out suction filtration under reduced pressure to obtain 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) - α -chloro-4-pyrazole formaldehyde hydrazone (compound;
(4) synthesis of 5- (4-methoxybenzylidene) -1-phenyl-6, 7-dihydro-1H-indazol-4 (5H) -one (Compound 4): dissolving 10mmol of 1-phenyl-6, 7-dihydro-1H-indazole-4 (5H) -one and 10mmol of methylbenzaldehyde in 10mL of ethanol, adding 2mL of 40% NaOH aqueous solution, stirring at 80 ℃ for 3 hours, then filtering and separating by using a Buchner funnel, washing a filter cake with water, recrystallizing and purifying by using ethanol, filtering and drying to obtain a product, namely 5- (4-methoxybenzylidene) -1-phenyl-6, 7-dihydro-1H-indazole-4 (5H) -one (a compound 4);
(5) adding 5- (4-methoxybenzylidene) -1-phenyl-6, 7-dihydro-1H-indazol-4 (5H) -one (compound 4) and 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) - α -chloro-4-pyrazole formaldehyde hydrazone (compound 3) into 20mL of ethanol, dropwise adding a mixed solution of 0.5mL of pyridine and 10mL of ethanol into the solution by using a constant-pressure dropping funnel, continuously stirring at normal temperature for 2 hours after the dropwise adding is finished, tracking the reaction by TLC, filtering after the reaction is finished, concentrating the filtrate under reduced pressure, performing silica gel column chromatography, and eluting with ethyl acetate and petroleum ether to obtain a final product.
The mass ratio of the 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde hydrazone (compound 2) to the tert-butyl hypochlorite substance is 5: 8.
The mass ratio of the 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) - α -chloro-4-pyrazole formaldehyde oxime (compound 3) to the 5- (4-methoxybenzylidene) -1-phenyl-6, 7-dihydro-1H-indazol-4 (5H) -one (compound 4) is 3: 2.
V in the eluent(Ethyl acetate):V(Petroleum ether)＝1:8。
The p-methoxyphenyl substitutes the application of spiro [ indazole-pyrazoline ] derivative containing pyrazole structure in antitumor drugs.
The invention provides a p-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure and a preparation method thereof, wherein the preparation method comprises the step of introducing an isoxazole ring into a 5- (4-methoxybenzylidene) -1-phenyl-6, 7-dihydro-1H-indazole-4 (5H) -one structure by using a 1, 3-dipolar cycloaddition method, so that the spiro [ indazole-pyrazoline ] derivative containing 5- (1-phenyl-3-methyl-4-1, 2, 4-triazolyl) structure pyrazole substitution is synthesized. The pyrazole-substituted spiro [ indazole-pyrazoline ] derivative containing a 5- (1-phenyl-3-methyl-4-1, 2, 4-triazolyl) structure, which is prepared by the invention, has a strong tumor cell inhibition effect, and provides a foundation for further application in the field of medicines.
Drawings
FIG. 1 is a flow chart of the preparation method of steps (1) to (3) in the preparation method of a p-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure according to the present invention;
FIG. 2 is a flow chart of a preparation method of step (4) in the preparation method of a p-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure according to the present invention;
FIG. 3 is a flow chart of a preparation method of step (5) in the preparation method of a p-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure according to 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 the aggregation in the same molecule, a p-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure is synthesized through 1, 3-dipolar cycloaddition reaction.
The invention provides a p-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure, which has the following chemical structural formula:
wherein: Ar-4-CH3OC6H4-。
Example 1
(1) Synthesis of 1-phenyl-3-methyl-5- (1,2, 4-triazolyl) -4-pyrazolecarboxaldehyde (compound 1): dissolving 21mmol of 1,2, 4-triazole in 50mL of ethanol solvent, adding 25mmol of potassium hydroxide, performing ultrasound at normal temperature of 25 ℃ for half an hour, performing rotary evaporation on ethanol under reduced pressure, adding 40mL of DMSO, adding 15mmol of 5-chloro-1-phenyl-3-methyl-4-formylpyrazole in batches, performing ultrasonic treatment at 50 ℃ for 2 hours, pouring the mixture into 200mL of ice water after TLC detection is finished, precipitating light yellow solid, and performing suction filtration. Drying the solid matter, and recrystallizing with ethanol-water to obtain the compound 1-phenyl-3-methyl-5- (1,2, 4-triazolyl) -4-pyrazole formaldehyde.
(2) Synthesis of 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde hydrazone (compound 2): 22mmol of phenylhydrazine is added into a flask containing 10mL of tetrahydrofuran, reflux and stirring are carried out in a boiling water bath until the phenylhydrazine is dissolved, then 20mL of absolute ethanol solution dissolved with 1-phenyl-3-methyl-5- (1,2, 4-triazolyl) -4-pyrazole formaldehyde (20 mmol) is slowly dripped, reflux and stirring are carried out in the boiling water bath for 1h, 10 drops of concentrated hydrochloric acid are dripped, and light yellow precipitate appears. And (4) 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, and vacuum drying to obtain 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde hydrazone (compound 2).
(3) Synthesis of 1-phenyl-3-methyl-5- (1,2, 4-triazol-1-yl) - α -chloro-4-pyrazolecarboxaldehyde hydrazone (compound 3) Compound 2(10.0mmol) was added to 50ml of 1, 2-dichloroethane and 30ml of isopropanol, and completely dissolved by magnetic stirring, then 18ml (16g, 16mmol) of tert-butyl hypochlorite was added in three portions in a salt bath at-12 ℃ and vigorously stirred for 2 hours, during which time the temperature was carefully controlled below-5 ℃ to obtain a pale blue transparent liquid, the product was transferred to a round-bottomed flask, the solvent was evaporated under reduced pressure (50 ℃) to obtain a pale yellow oil, a small amount (m.p.: 60-90 ℃) of petroleum ether was added, and the mixture was heated to dissolve, and a large amount of yellow solid precipitated, and suction filtered under reduced pressure to obtain Compound 3.
(4) Synthesis of 5- (4-methoxybenzylidene) -1-phenyl-6, 7-dihydro-1H-indazol-4 (5H) -one (Compound 4): dissolving 10mmol of 1-phenyl-6, 7-dihydro-1H-indazole-4 (5H) -one and 10mmol of methylbenzaldehyde in 10mL of ethanol, adding 2mL of 40% NaOH aqueous solution, stirring at 80 ℃ for 3 hours, filtering and separating by using a Buchner funnel, washing a filter cake with water, recrystallizing and purifying by using ethanol, filtering and drying to obtain the product ketone.
(5) Adding 1mmol of compound 4(5- (4-methoxybenzylidene) -1-phenyl-6, 7-dihydro-1H-indazol-4 (5H) -one) and 1.5mmol of compound 3 (1-phenyl-3-methyl-5- (1,2, 4-triazol-1-yl) - α -chloro-4-pyrazolecarboxaldehyde hydrazone) into 20mL of ethanol, dropwise adding a mixed solution of 0.5mL of pyridine and 10mL of ethanol into the solution by using a constant-pressure dropping funnel, continuously stirring at normal temperature for 2 hours after the dropwise addition is finished, tracking the reaction by TLC, filtering after the reaction is finished, concentrating the filtrate under reduced pressure, carrying out silica gel column chromatography, and obtaining compound 5 by using ethyl acetate/petroleum ether (60-90 ℃) 1/8(V/V as an eluent.
The experimental data are as follows: a p-methoxyphenyl-substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure (compound 5) as a pale yellow powder, in a yield of 56.2%, melting point: 160-161 ℃, and the nuclear magnetic hydrogen spectrum data and the element analysis data are as follows:
1H NMR(CDCl3)δ:8.18(s,1H,N＝C-H),8.06(s,1H,triazole-H),7.98(s,1H,triazole-H),7.51-7.41(m,14H,Ar-H),6.47(s,1H),3.71(s,3H,CH3O),3.13(t,J＝6.5Hz,2H),3.02(t,J＝6.5Hz,2H),2.55(s,3H,CH3).
IR(KBr)v/cm-13101(ArH),1677(C＝O),1657,1635,1576,1464 (C＝N,C＝C),
m/e:671(100.0％)
Anal.calcd.for C40H33N9O2：C,71.52；H,4.95；N,18.77；found C,71.54；H, 4.99；N,18.71。
in this example, MTT method is used to determine the in vitro inhibitory effect of compound 5 on different tumor strains, and the results of the determination of the anti-tumor activity of the spiro [ indazole-pyrazoline ] derivative containing p-methoxyphenyl substituted pyrazole structure are as follows:
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.
Table 1 compound 5 p-methoxyphenyl substituted spiro [ indazole-pyrazoline ] containing pyrazole structure]IC of derivatives on six tumor cell lines50Value of
In Table 1, spiro [ indazole-pyrazoline having pyrazole structure substituted by p-methoxyphenyl group]IC of derivative (Compound 5) against six tumor cell lines50Value, to sayThe Ming compound has strong tumor cell inhibition effect on SW620 (human colorectal adenocarcinoma cells), A549 (lung adenocarcinoma cells), NCL-H460 (non-small cell lung cancer) and provides a foundation for further application in the medical field.
Examples 2 to 5
Examples 2-5 the same as example 1 except that the amount ratio of 1-phenyl-3-methyl-5- (1,2, 4-triazol-1-yl) -4-pyrazolecarboxaldehyde hydrazone (compound 2) to the tert-butyl ester of hypochloride material in step (3) was varied, for comparison, table 2 was prepared:
TABLE 2
Examples 6 to 9
Examples 6-9 were otherwise the same as in example 1 except that in step (5), the ratio of the amounts of 1-phenyl-3-methyl-5- (1,2, 4-triazol-1-yl) - α -chloro-4-pyrazolecarboxaldehyde oxime (compound 3) to 5- (4-methoxybenzylidene) -1-phenyl-6, 7-dihydro-1H-indazol-4 (5H) -one (compound 4) material was varied, for ease of comparison, to prepare table 3:
TABLE 3
Examples 10 to 13
Examples 10-13 were otherwise identical to example 1 except that the addition of tert-butyl hypochlorite in step (3) was different (total amount added, and average addition), for comparison purposes, as shown in Table 4:
TABLE 4
| Number of additions | Yield of | |
| Example 1 | 3 | 92％ |
| Example 10 | 1 | 57％ |
| Example 11 | 2 | 85％ |
| Example 12 | 4 | 87％ |
| Example 13 | 5 | 84％ |
Examples 14 to 16
Examples 14-16 were otherwise identical to example 1 except that the temperature of the ice salt bath in step (3) was different and for ease of comparison, Table 5 was prepared:
TABLE 5
| Temperature of the Ice salt bath | Yield of | |
| Example 1 | -12 | 92％ |
| Example 14 | 0 | 0％ |
| Example 15 | -5 | 37％ |
| Example 16 | -8 | 66％ |
Comparative example 1
Spiro [ indolizine-isoxazoline having a pyrazole structure substituted with methyl group, which was prepared by using example 1 of patent publication No. CN108752364A]Derivatives, which were diluted in DMSO, tumor cells HepG2 (hepatoma cells), A375 (melanoma cells), SW620 (human colorectal adenocarcinoma cells), A549 (lung adenocarcinoma cells), NCL-H460 (non-small cell lung carcinoma), SKOV3 (ovarian cancer cells) were seeded in 4000/200. mu.L/well in 96-well plates, 2. mu.L of compound was added to each well to a final concentration of 12.0. mu.M, 6.0. mu.M, 3.0. mu.M, 1.5. mu.M, 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 measuring at different concentrationsThe effect of different action time on 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 inhibition50The values, results are given in table 6 below.
TABLE 6P-methoxyphenyl substituted spiro [ indolizine-isoxazoline with pyrazole structure]IC of derivatives on six tumor cell lines50Value of
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 (6)
1. The p-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure is characterized in that the chemical structural formula of the p-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing the pyrazole structure is as follows:
wherein: Ar-4-CH3OC6H4-。
2. A method for producing a p-methoxyphenyl-substituted spiro [ indazole-pyrazoline ] derivative having a pyrazole structure according to claim 1, which comprises the steps of:
(1) synthesis of 1-phenyl-3-methyl-5- (1,2, 4-triazolyl) -4-pyrazolecarboxaldehyde: dissolving 21mmol of 1,2, 4-triazole in 50mL of ethanol solvent, adding 25mmol of potassium hydroxide, performing ultrasound at normal temperature of 25 ℃ for half an hour, performing rotary evaporation on ethanol under reduced pressure, adding 40mL of DMSO, adding 15mmol of 5-chloro-1-phenyl-3-methyl-4-formylpyrazole in batches, performing ultrasonic treatment at 50 ℃ for 2 hours, pouring the mixture into 200mL of ice water after TLC detection is finished, precipitating light yellow solid, and performing suction filtration; drying the solid matter, and recrystallizing with ethanol-water to obtain a compound 1-phenyl-3-methyl-5- (1,2, 4-triazolyl) -4-pyrazole formaldehyde;
(2) synthesizing 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde hydrazone: adding 22mmol of phenylhydrazine into a flask containing 10mL of tetrahydrofuran, refluxing and stirring in a boiling water bath until the phenylhydrazine is dissolved, slowly dropwise adding 20mL of anhydrous ethanol solution in which 20mmol of 1-phenyl-3-methyl-5- (1,2, 4-triazolyl) -4-pyrazolecarboxaldehyde is dissolved, continuing refluxing and stirring in the boiling water bath for 1h, and dropwise adding 10 drops of concentrated hydrochloric acid until a light yellow precipitate appears; refluxing and stirring in a continuous boiling water bath for 5 hours, stopping the water bath, adding 20mL of distilled water, stirring, deepening the color of a light yellow precipitate, and performing suction filtration to obtain a yellowish red needle-shaped product; washing with anhydrous ether for many times, and vacuum drying to obtain 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde hydrazone;
(3) synthesizing 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) - α -chloro-4-pyrazole formaldehyde hydrazone, namely adding 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde hydrazone into 50ml of 1, 2-dichloroethane and 30ml of isopropanol, magnetically stirring to completely dissolve the 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde hydrazone, then cooling to-12 ℃ in a salt bath, adding tert-butyl hypochlorite three times, vigorously stirring for 2h, during the period, controlling the temperature to be below-5 ℃ to obtain light blue transparent liquid, transferring the product into a round-bottom flask, evaporating the solvent to dryness at the temperature of 50 ℃ under reduced pressure to obtain light yellow oily matter, adding a small amount of petroleum ether, heating to mix, precipitating a large amount of yellow solid, and carrying out suction filtration under reduced pressure to obtain 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) - α -chloro-4-pyrazole formaldehyde hydrazone;
(4) synthesis of 5- (4-methoxybenzylidene) -1-phenyl-6, 7-dihydro-1H-indazol-4 (5H) -one: dissolving 10mmol of 1-phenyl-6, 7-dihydro-1H-indazole-4 (5H) -one and 10mmol of methylbenzaldehyde in 10mL of ethanol, adding 2mL of 40% NaOH aqueous solution, stirring at 80 ℃ for 3 hours, then filtering and separating by using a Buchner funnel, washing a filter cake with water, recrystallizing and purifying by using ethanol, filtering and drying to obtain a product, namely 5- (4-methoxybenzylidene) -1-phenyl-6, 7-dihydro-1H-indazole-4 (5H) -one;
(5) adding 5- (4-methoxybenzylidene) -1-phenyl-6, 7-dihydro-1H-indazol-4 (5H) -one and 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) - α -chloro-4-pyrazole formaldehyde hydrazone into 20mL of ethanol, dropwise adding a mixed solution of 0.5mL of pyridine and 10mL of ethanol into the solution by using a constant-pressure dropping funnel, continuously stirring at normal temperature for 2 hours after the dropwise adding is finished, tracking the reaction by TLC, filtering after the reaction is completed, concentrating the filtrate under reduced pressure, carrying out silica gel column chromatography, and eluting with ethyl acetate and petroleum ether to obtain a final product.
3. The method for producing a p-methoxyphenyl-substituted spiro [ indazole-pyrazoline ] derivative having a pyrazole structure according to claim 2, wherein: the mass ratio of the 1-phenyl-3-methyl-5- (1,2, 4-triazole-1-yl) -4-pyrazole formaldehyde hydrazone to the tert-butyl hypochlorite substance in the step (3) is 5: 8.
4. The method for preparing p-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure according to claim 2, wherein the ratio of the amount of 1-phenyl-3-methyl-5- (1,2, 4-triazol-1-yl) - α -chloro-4-pyrazolecarboxaldehyde oxime to the amount of 5- (4-methoxybenzylidene) -1-phenyl-6, 7-dihydro-1H-indazol-4 (5H) -one compound in step (4) is 3: 2.
5. The p-methoxyphenyl-substituted spiro [ indazole-pyrazoline ] containing a pyrazole structure according to claim 2]A process for the preparation of derivatives, characterized in that: v in eluent in the step (5)(Ethyl acetate):V(Petroleum ether)＝1:8。
6. The application of the p-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing a pyrazole structure according to claim 1 in antitumor drugs.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115124542A (en) * | 2022-07-08 | 2022-09-30 | 河南师范大学 | Synthetic method of hydroxyphenyl-substituted pyrazolone indazole [ spiro ] pyrazolone compound |
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2019
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115124542A (en) * | 2022-07-08 | 2022-09-30 | 河南师范大学 | Synthetic method of hydroxyphenyl-substituted pyrazolone indazole [ spiro ] pyrazolone compound |
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