CN112608323A - Chlorine-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative and preparation method and application thereof - Google Patents

Chlorine-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative and preparation method and application thereof Download PDF

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CN112608323A
CN112608323A CN202011549458.4A CN202011549458A CN112608323A CN 112608323 A CN112608323 A CN 112608323A CN 202011549458 A CN202011549458 A CN 202011549458A CN 112608323 A CN112608323 A CN 112608323A
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pyrrolizine
ethanol
spiropyrazole
substituted pyridazinone
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杨鹏
邓莉平
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University of Shaoxing
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic 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 three hetero rings
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Abstract

The invention discloses a chloro-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative (named as 5- (4-chlorphenyl) -3- (3-methyl-1-phenyl-5- (1H-1,2, 4-triazole-1-yl) -1H-pyrazole-4-yl) -1- (6-oxo-1, 6-dihydropyridazine-3-carbonyl) -1, 5-dihydro-1 ' H, 3' H-spiro [ pyrazole-4, 2' -pyrrolizine)]-1' -ketone) and a preparation method and application thereof, wherein the chlorine-substituted pyridazinone-structure-containing spiropyrazole-pyrrolizine derivative has the following chemical structural formula:
Figure DDA0002857294690000011
the chloro-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative prepared by the invention has a strong tumor cell inhibition effect, and provides a foundation for further application in the field of medicine.

Description

Chlorine-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a chloro-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative, and a preparation method and application thereof.
Background
Chemical name: (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizin-1-one having the following chemical formula:
Figure BDA0002857294670000011
pyrrolizine is an important component of alkaloids with biological activity, and derivatives thereof are widely applied in the aspects of inflammation diminishing, pain easing, diabetes resistance, sugar anxiety resistance, tumor resistance and the like.
The triazole has aromaticity and abundant electrons in a molecular structure, can interact with enzymes and receptors in organisms by forming hydrogen bonds, and has various biological activities. In recent years, pyridazinone compounds become hot spots of research in the pharmaceutical field due to the unique physiological activity of pyridazinone compounds, and have strong effects of inhibiting cancer cell diffusion, resisting bacteria and viruses, reducing blood fat, reducing blood sugar, promoting metabolism and the like. Therefore, the heterocyclic compound has high synthetic value in terms of pharmacology and synthesis angle.
Pyrazole derivatives have attracted considerable attention as a class of useful intermediates and as a variety of pharmaceutical activities that they themselves exhibit. 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. Therefore, the heterocyclic compound has high synthetic value in terms of pharmacology and synthesis angle.
Disclosure of Invention
The invention aims to provide a chlorine-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative, and a preparation method and application thereof.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the invention provides a chlorine-substituted pyridazinone-structure-containing spiropyrazole-pyrrolizine derivative, which has the following chemical structural formula:
Figure BDA0002857294670000021
the invention also provides a preparation method of the chlorine-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative, which comprises the following steps:
step 1, synthesis of 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, removing ethanol under reduced pressure, adding 40mL of DMSO, adding 15mmol of 1-phenyl-3-methyl-4-formylpyrazole in batches, performing ultrasound at 50 ℃ for 2 hours, after the raw materials are reacted by TLC, pouring the mixture into 200mL of ice water, precipitating light yellow solid, and performing suction filtration. Drying the solid matter, and recrystallizing the dried solid matter by using ethanol-water to obtain the 1-phenyl-3-methyl-4-formyl-5- (1,2, 4-triazolyl) pyrazole (compound 1).
Step 2, synthesis of compound 2: the Schiff base is generated by the dehydration reaction of 1-phenyl-3-methyl-4-formyl-5- (1,2, 4-triazolyl) pyrazole and 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate.
The method comprises the following specific operations: adding 3mmol of 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate into a flask containing 20mL of ethanol, refluxing and stirring in a boiling water bath until the mixture is dissolved, slowly dropwise adding 15mL of absolute ethanol solution in which 2mmol of 1-phenyl-3-methyl-4-formyl-5- (1,2, 4-triazolyl) pyrazole, continuing refluxing and stirring in the boiling water bath for 1 hour, and dropwise adding 10 drops of hydrochloric acid until a light yellow precipitate appears. And (3) refluxing and stirring in a continuous boiling water bath for 5 hours, stopping the water bath, adding 20mL of distilled water, stirring, deepening the color of the light yellow precipitate, and performing suction filtration to obtain a yellowish red needle-shaped product. Washed with anhydrous ether for several times, recrystallized from ethanol and dried under vacuum to give Schiff's base (name: N' - ((3-methyl-1-phenyl-5- (1H-1,2, 4-triazol-1-yl) -1H-pyrazol-4-yl) methylene) -6-oxo-1, 6-dihydropyridazine-3-carbohydrazide) (Compound 2).
Step 3, synthesis of (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-one: dissolving 10mmol2, 3-dihydropyrrolizine-1-ketone (compound 3) and 10mmol 4-chlorobenzaldehyde (compound 4) in 20mL ethanol, adding 2mL 40% NaOH aqueous solution, stirring at 80 ℃ for 3 hours, then filtering and separating by a Buchner funnel, washing a filter cake with water, recrystallizing and purifying by ethanol, filtering and drying to obtain a product (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-ketone (compound 5);
step 4, as shown in fig. 3, synthesis of compound 6 (chloro-substituted spiropyrazole-pyrrolizine derivative containing pyridazinone structure): dissolving 1mmol of white solid compound 5((E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-one) and 1.1mmol of compound 2 in 30mL of 95% ethanol, adding 1.2mmol of chloramine T, refluxing for 3 hours, obtaining a light yellow precipitate after TLC detection reaction is finished, filtering the precipitate under reduced pressure, recrystallizing the precipitate with methanol, and drying in vacuum to obtain the chlorine-substituted spiropyrazole-pyrrolizine derivative containing a pyridazinone structure (compound 6).
Further, the amount ratio of the 1,2, 4-triazole to the 1-phenyl-3-methyl-4-formylpyrazole substance is 7: 5.
Further, the ratio of the amount of the 1-phenyl-3-methyl-4-formyl-5- (1,2, 4-triazolyl) pyrazole to the 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate species was 2: 3.
Further, the ratio of the amount of the 2, 3-dihydropyrrolizine-1-one to the amount of the 4-chlorobenzaldehyde substance is 1: 1.
Further, the amount ratio of the compound 2 to the compound 5((E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizin-1-one) to the chloramine T substance is 10:11: 12.
The invention also provides application of the chlorine-substituted pyridazinone-structure-containing spiropyrazole-pyrrolizine derivative in an antitumor drug.
The invention provides a chlorine-substituted pyridazinone-structure-containing spiropyrazole-pyrrolizine derivative and a preparation method and application thereof, wherein in the preparation method, a 1, 3-dipolar cycloaddition method is used for introducing a pyrazole ring into a chemical structure of (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-one, so that a novel chlorine-substituted pyridazinone-structure-containing spiropyrazole-pyrrolizine derivative is finally synthesized. The chloro-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative prepared by the invention has a strong tumor cell inhibition effect, and provides a foundation for further application in the field of medicine.
In summary, the pyrrolizine derivatives have attracted much attention as a class of useful intermediates and various pharmaceutical activities exhibited by themselves. The general idea of the invention is that pyridazinone with biological activity, 1,2, 4-triazole pharmacodynamic structure and five-membered pyrazole ring are skillfully introduced into the molecular structure of (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-one, and the chlorine-substituted spiropyrazole-pyrrolizine derivative containing the pyridazinone structure is finally prepared, so that the pharmacological activity can be effectively improved.
Drawings
FIG. 1 is a schematic diagram of the chemical structural formulas of 1-phenyl-3-methyl-4-formyl-5- (1,2, 4-triazolyl) pyrazole and Schiff base for preparation according to the invention;
FIG. 2 is a schematic diagram of the chemical structure of the preparation of (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizin-1-one of the present invention;
FIG. 3 is a chemical structural diagram of the preparation of the chloro-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative.
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.
The invention provides a chlorine-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative, which has the following chemical structural formula:
Figure BDA0002857294670000051
the invention also provides a preparation method of the chlorine-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative. In this embodiment, the preparation method of the chloro-substituted pyridazinone-structure-containing spiropyrazole-pyrrolizine derivative includes the following steps:
step 1, synthesis of compound 1 (shown in fig. 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, removing ethanol under reduced pressure, adding 40mL of DMSO, adding 15mmol of 1-phenyl-3-methyl-4-formylpyrazole in batches, performing ultrasound at 50 ℃ for 2 hours, after the raw materials are reacted by TLC, pouring the mixture into 200mL of ice water, precipitating light yellow solid, and performing suction filtration. Drying the solid matter, and recrystallizing the dried solid matter by using ethanol-water to obtain the 1-phenyl-3-methyl-4-formyl-5- (1,2, 4-triazolyl) pyrazole (compound 1).
Preferably, the ratio of the amount of 1,2, 4-triazole to 1-phenyl-3-methyl-4-formylpyrazole species is 7: 5.
Step 2, synthesis of compound 2: a method of dehydrating 1-phenyl-3-methyl-4-formyl-5- (1,2, 4-triazolyl) pyrazole with 6-oxo-1, 6-dihydropyridazin-3-carbohydrazide to give Schiff's base (named: N' - ((3-methyl-1-phenyl-5- (1H-1,2, 4-triazol-1-yl) -1H-pyrazol-4-yl) methylene) -6-oxo-1, 6-dihydropyridazin-3-carbohydrazide) (Compound 2) (shown in FIG. 1) was employed.
The method comprises the following specific operations: adding 3mmol of 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate into a flask containing 20mL of ethanol, refluxing and stirring in a boiling water bath until the mixture is dissolved, slowly dropwise adding 15mL of absolute ethanol solution in which 2mmol of 1-phenyl-3-methyl-4-formyl-5- (1,2, 4-triazolyl) pyrazole, continuing refluxing and stirring in the boiling water bath for 1 hour, and dropwise adding 10 drops of hydrochloric acid until a light yellow precipitate appears. And (3) refluxing and stirring in a continuous boiling water bath for 5 hours, stopping the water bath, adding 20mL of distilled water, stirring, deepening the color of the light yellow precipitate, and performing suction filtration to obtain a yellowish red needle-shaped product. Washing with anhydrous ether for several times, recrystallizing with ethanol, and vacuum drying to obtain compound 2.
Preferably, the ratio of the amount of 1-phenyl-3-methyl-4-formyl-5- (1,2, 4-triazolyl) pyrazole (compound 1) to 6-oxo-1, 6-dihydropyridazine-3-carbohydrazide species is 2: 3.
Step 3, synthesis of (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizin-1-one (shown in figure 2): dissolving 10mmol of 2, 3-dihydropyrrolizine-1-ketone (compound 3) and 10mmol of 4-chlorobenzaldehyde (compound 4) in 20mL 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 (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-ketone (compound 5).
Preferably, the ratio of the amounts of 2, 3-dihydropyrrolizin-1-one (compound 3) to 4-chlorobenzaldehyde (compound 4) species is 1: 1.
Step 4, as shown in fig. 3, synthesis of a chloro-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative (compound 6): dissolving 1mmol of white solid compound 5((E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizin-1-one) and 1.1mmol of compound 2 in 30mL of 95% ethanol, adding 1.2mmol of chloramine T, refluxing for 3 hours, detecting by TLC to obtain a light yellow precipitate, filtering the precipitate under reduced pressure, recrystallizing the precipitate with methanol, and drying in vacuum to obtain compound 6.
Preferably, the ratio of the amounts of N' - ((3-methyl-1-phenyl-5- (1H-1,2, 4-triazol-1-yl) -1H-pyrazol-4-yl) methylene) -6-oxo-1, 6-dihydropyridazin-3-carbohydrazide (compound 2), (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizin-1-one (compound 5) and chloramine T species is 10:11: 12.
As shown in fig. 3, the chemical structural formula 6 is the generated chlorine substituted spiropyrazole-pyrrolizine derivative containing pyridazinone structure.
The experimental data are as follows: the chlorine-substituted pyridazinone-structure-containing spiropyrazole-pyrrolizine derivative (compound 6) is light yellow powder, the yield is 67.4%, the melting point is m.p.173-174 ℃, and the nuclear magnetic hydrogen spectrum, the infrared spectrum and the element analysis data are as follows:
1H NMR(DMSO-d6)δ:8.62(d,J＝10.0Hz,1H),8.40(dd,J＝2.1,0.8Hz,1H),8.03(s,2H，N＝C-H),7.29-7.48(m,5H,Ar-H),7.08(s,1H,NHN),7.62(1H,d,J＝6.4Hz),7.32-7.16(m,4H,Ar-H),6.71(s,1H,C＝C-H),6.55(dd,J＝4.1,2.3Hz,1H),6.03(d,J＝10.0Hz,1H),4.30-4.06(m,2H,CH2),2.79(s,3H,CH3)。
IR(KBr)v/cm-1 3453,3433,2912,17064 1603,1458,1242,1096,1048,755m/e:631(100.0％)。
Anal.calcd.for C32H23ClN10O3：C,60.91；H,3.69；N,22.19。
in this example, the MTT method was used to determine the in vitro inhibitory effect of compound 6 (named: 5- (4-chlorophenyl) -3- (3-methyl-1-phenyl-5- (1H-1,2, 4-triazol-1-yl) -1H-pyrazol-4-yl) -1- (6-oxo-1, 6-dihydropyridazine-3-carbonyl) -1, 5-dihydro-1 'H, 3' H-spiro [ pyrazole-4, 2 '-pyrrolizin ] -1' -one) on different tumor strains, and the results of the determination of the antitumor activity of the chloro-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative were as follows:
compound 6 was diluted with DMSO, and tumor cells HepG2 (liver cancer cells), A375 (melanoma cells), SW620 (human colorectal adenocarcinoma cells), A549 (lung adenocarcinoma cells), SGC7901 (stomach cancer cells), 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 determining the influence of different action times of the compounds at different concentrations on the human tumor cell cycle and apoptosis.
The test compounds of different concentrations were coarse-screened in 96-well plates and IC was calculated from the resulting inhibition50Values, results are given in the table below.
Table 1 shows that the 6-chloro substituted pyridazinone-structure-containing spiropyrazole-pyrrolizine derivative has IC (integrated Circuit) effect on six tumor cell strains50Value of
Figure BDA0002857294670000081
In Table 1, the IC of the chloro-substituted pyridazinone-structure-containing spiropyrazole-pyrrolizine derivative (Compound 6) on six tumor cell lines is shown50The value shows that the compound 6 has stronger tumor cell inhibition effect on SW620 (human colorectal adenocarcinoma cells), and provides a foundation for further application in the medical field.
The above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and those skilled in the art can make various corresponding changes and modifications according to the present invention without departing from the spirit and the essence of the present invention, but these corresponding changes and modifications should fall within the protection scope of the appended claims.

Claims (7)

1. A chlorine-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative (named: 5- (4-chlorophenyl) -3- (3-methyl-1-phenyl-5- (1H-1,2, 4-triazol-1-yl) -1H-pyrazol-4-yl) -1- (6-oxo-1, 6-dihydropyridazine-3-carbonyl) -1, 5-dihydro-1 'H, 3' H-spiro [ pyrazole-4, 2 '-pyrrolizine ] -1' -one), characterized in that the chemical structural formula of the chlorine-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative is as follows:
Figure FDA0002857294660000011
2. a process for preparing a chloro-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative according to claim 1, which comprises:
step 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, removing ethanol under reduced pressure, adding 40mL of DMSO, adding 15mmol of 1-phenyl-3-methyl-4-formylpyrazole in batches, performing ultrasound at 50 ℃ for 2h, performing TLC detection, pouring the mixture into 200mL of ice water after the raw materials are reacted, precipitating a light yellow solid, performing suction filtration, drying the solid matter, and recrystallizing the solid matter with ethanol-water to obtain 1-phenyl-3-methyl-4-formyl-5- (1,2, 4-triazolyl) pyrazole (compound 1);
step 2: adding 3mmol of 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate into a flask containing 20mL of ethanol, refluxing and stirring in a boiling water bath until the 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate is dissolved, slowly dropwise adding 15mL of absolute ethanol solution in which 2mmol of the compound 1 is dissolved, continuously refluxing and stirring in the boiling water bath for 1 hour, dropwise adding 10 drops of hydrochloric acid until a light yellow precipitate appears, continuously refluxing and stirring in the boiling water bath for 5 hours, stopping stirring in the water bath, adding 20mL of distilled water, stirring until the light yellow precipitate turns dark, performing suction filtration to obtain a yellowish red needle product, washing with absolute ethyl ether for multiple times, recrystallizing with ethanol, and performing vacuum drying to obtain Schiff base (named as N' - ((3-methyl-1-phenyl-5- (1H-1,2, 4-triazol-1-yl) -1H-pyrazol-4-yl) methylene) -6-, 6-dihydropyridazine-3-carbohydrazide) (compound 2);
and step 3: dissolving 10mmol of 2, 3-dihydropyrrolizine-1-ketone (compound 3) and 10mmol of 4-chlorobenzaldehyde (compound 4) in 20mL 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 (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-ketone (compound 5);
and 4, step 4: dissolving 1mmol of white solid compound 5 and 1.1mmol of compound 2 in 30mL of 95% ethanol, adding 1.2mmol of chloramine T, refluxing for 3 hours, obtaining light yellow precipitate after TLC detection reaction is finished, filtering out the precipitate under reduced pressure, recrystallizing the precipitate with methanol, and drying in vacuum to obtain the chlorine-substituted pyridazinone-structure spiropyrazole-pyrrolizine derivative (compound 6).
3. The method for preparing chloro-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivatives according to claim 2, wherein the ratio of the amount of the 1,2, 4-triazole to the amount of the 1-phenyl-3-methyl-4-formylpyrazole substance is 7: 5.
4. The method for preparing a chloro-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative according to claim 2, wherein the amount ratio of the compound 1 to the 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate species is 2: 3.
5. The process for preparing chloro-substituted pyridazinone structure containing spiropyrazole-pyrrolizine derivatives as claimed in claim 2, wherein the amount of the compound 3 to the compound 4 is 1: 1.
6. The method for preparing a chloro-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative according to claim 2, wherein the amount ratio of the compound 2, the compound 5 and the chloramine T substance is 10:11: 12.
7. The use of the chloro-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative according to claim 1 in the preparation of an antitumor agent.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109053731A (en) * 2018-10-09 2018-12-21 绍兴文理学院元培学院 A kind of pair of chlorine replaces spiral shell [indolizine-pyrazoline] derivative and the preparation method and application thereof of the structure containing pyridazinone

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109053731A (en) * 2018-10-09 2018-12-21 绍兴文理学院元培学院 A kind of pair of chlorine replaces spiral shell [indolizine-pyrazoline] derivative and the preparation method and application thereof of the structure containing pyridazinone

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* Cited by examiner, † Cited by third party
Title
胡小莲: "腈亚胺的1,3-偶极环加成反应合成螺吡唑-吡咯里嗪类化合物", 《有机化学》 *

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Application publication date: 20210406