CN110357891B

CN110357891B - Chromone-substituted 2-hydroxypyrrole derivative and synthesis method and application thereof

Info

Publication number: CN110357891B
Application number: CN201910602021.3A
Authority: CN
Inventors: 严胜骄; 林军; 资全兴; 黄荣; 罗琴
Original assignee: Yunnan University YNU
Current assignee: Yunnan University YNU
Priority date: 2019-07-05
Filing date: 2019-07-05
Publication date: 2022-02-01
Anticipated expiration: 2039-07-05
Also published as: CN110357891A

Abstract

The invention discloses a chromone-substituted 2-hydroxypyrrole derivative and a synthesis method and application thereof, belonging to the technical field of medicinal chemistry. The structural formula of the chromone-substituted 2-hydroxypyrrole derivative is shown in the specification

Wherein n is 0 or 1; r is hydrogen, fluorine, chlorine or methyl; r¹Is hydrogen or fluorine; r²Is hydrogen, fluorine, chlorine or bromine; EWG is benzoyl, p-methylbenzoyl, p-fluorobenzoyl, p-chlorobenzoyl or p-bromobenzoyl. The invention adopts the benzoylformaldehyde derivative, the coumarin derivative and the heterocyclic ketene aminal as raw materials, and obtains the target compound chromone-substituted 2-hydroxypyrrole derivative with anti-inflammatory activity through a one-pot method series reaction.

Description

Chromone-substituted 2-hydroxypyrrole derivative and synthesis method and application thereof

Technical Field

The invention relates to chromone-substituted 2-hydroxypyrrole derivatives, and a synthesis method and application thereof, and belongs to the technical field of pharmaceutical chemistry.

Background

Azoles are widely found in natural products and bioactive molecules. The pyrrole derivatives are widely used in the fields of anti-inflammation, antiemetic, blood pressure reduction, antidepressant, migraine treatment, anti-tumor and the like. For example, hydroxypyrroles have anti-inflammatory, antibacterial, antimicrobial, anti-tumor, antidepressant, and blood pressure lowering and heart rate slowing effects. To date, chemists and pharmacologists have established various synthetic methods and synthesized a large number of pyrrole compounds. From the aspect of constructing pyrrole skeleton, the synthesis methods mainly comprise Hantzsch, Knorr, Paal-Knorr, Barton-Zard, Huisgen method, cyclization, cycloaddition, transition metal-catalyzed C-H bond activation and the like. And examples of synthesizing an azole compound by three components without a metal catalyst are less common. The pyrrole compound synthesized by the existing method is generally a pyrrole compound with a simple structure, while the synthesis of the 2-hydroxypyrrole derivative is more difficult or the synthesis method of the derivative generally requires harsh conditions. Especially for synthesizing high-functional 2-hydroxypyrrole derivatives, such as chromone-substituted 2-hydroxypyrrole compounds, have not been reported at present.

Disclosure of Invention

The invention provides a chromone-substituted 2-hydroxypyrrole derivative, a synthetic method and application thereof, aiming at the problem of synthesizing 2-hydroxypyrrole compounds in the prior art, the invention adopts benzoyl formaldehyde derivatives, coumarin derivatives and heterocyclic ketene aminal as raw materials, and obtains the chromone-substituted 2-hydroxypyrrole derivatives which are target compounds with anti-inflammatory activity through a one-pot method series reaction.

Chromone-substituted 2-hydroxypyrrole derivatives having the formula (I):

wherein n is 0 or 1;

r is hydrogen, fluorine, chlorine or methyl;

R¹is hydrogen or fluorine;

R²is hydrogen, fluorine, chlorine or bromine;

EWG is benzoyl, p-methylbenzoyl, p-fluorobenzoyl, p-chlorobenzoyl or p-bromobenzoyl.

The synthesis method of the chromone-substituted 2-hydroxypyrrole derivative comprises the following specific steps:

adding a benzoylformaldehyde derivative, a coumarin derivative and heterocyclic ketene aminal into a solvent, carrying out stirring reaction for 8-24 h under the conditions of heating reflux or 70-120 ℃ to obtain a reaction liquid, cooling the reaction liquid to room temperature, and carrying out purification treatment to obtain a chromone-substituted 2-hydroxypyrrole derivative with the structure of the formula (I); wherein the structural formula of the benzoyl formaldehyde derivative is shown as a formula (II), the structural formula of the coumarin derivative is shown as a formula (III), the structural formula of the heterocyclic ketene aminal is shown as a formula (IV),

in formula (II), R is hydrogen, fluorine, chlorine or methyl;

R¹is hydrogen or fluorine;

in the formula (III), R²Hydrogen, fluorine, chlorine or bromine;

in formula (IV), n is 0 or 1;

The synthetic reaction formula of the chromone-substituted 2-hydroxypyrrole derivative is

TLC detection and tracking are adopted in the reaction process, and the reaction yield is 60-90%;

the benzoyl formaldehyde derivative and the coumarin derivative are commercially available; heterocyclic ketene aminals according to the literature "z. -t.huang; m. -X.Wang, Synthesis,1992,12, 1273-; -j.li; C.D.Smith, Syn.Commun.2001,31, 527-;

preferably, the solvent is 1, 4-dioxane, ethanol, hydrogen peroxide or water.

Preferably, the mol ratio of the molar weight of the benzoyl formaldehyde derivative to the volume of the solvent is 1 (6-15);

preferably, the molar ratio of the benzoyl formaldehyde derivative, the coumarin derivative and the heterocyclic ketene aminal is 1:1: 1.

Preferably, the purification treatment is column chromatography or recrystallization.

More preferably, the eluent for column chromatography is a dichloromethane/petroleum ether mixed solvent, an ethyl acetate/petroleum ether mixed solvent or an ethyl acetate/acetone mixed solvent.

More preferably, the solvent for recrystallization is a dichloromethane/petroleum ether mixed solvent or an ethyl acetate/petroleum ether mixed solvent.

The chromone-substituted 2-hydroxypyrrole derivative is applied to the preparation of anti-inflammatory drugs.

The daily administration dosage of the chromone-substituted 2-hydroxypyrrole derivative in the anti-inflammatory drug is 0.01 mg-10 mg/kg.

Preferably, the chromone-substituted 2-hydroxypyrrole derivative is administered in an amount of 0.2mg to 10mg per kg per day in the anti-inflammatory agent.

The anti-inflammatory effect of the invention adopts NO detection method: mouse macrophage strain Raw 264.7 cells were purchased from american cell bank (ATCC) and cultured in DEME medium containing 10% FBS; raw 264.7 cells (2X 10)⁵One/well) is inoculated on a 24-well plate, compounds with different concentrations are added at the same time, the culture is carried out for 24 hours under the stimulation of LPS with the concentration of 1 mug/mL, and a solvent control and a non-irritant background control are additionally arranged; centrifuging to collect culture supernatant (5000rpm, 4 deg.C, 5min), and detecting NO in the supernatant by Griess method₂ ^-The specific method comprises the following steps: with NaNO₂And (3) diluting the standard substance in a gradient manner, adding 100 mu L of the standard substance into each well, adding 100 mu L of the collection culture medium into each sample well, adding 100 mu L of Griess reagent into each well, oscillating, detecting absorbance at 540nm of an enzyme-labeling instrument, calculating the content of NO in different sample wells according to the obtained standard curve, and calculating the inhibition rate of the compound, wherein the inhibition rate of NO is (concentration of NO in the combined action group-concentration of NO in LPS group)/concentration of NO in LPS group multiplied by 100%.

The invention has the beneficial effects that:

(1) the invention adopts the benzoyl formaldehyde derivative, the coumarin derivative and the heterocyclic ketene aminal as raw materials, and obtains the target compound chromone-substituted 2-hydroxypyrrole derivative with anti-inflammatory activity through the 'one-pot' series reaction, the method has the advantages of easily obtained synthetic raw materials, simple synthetic process, no need of a metal catalyst for reaction, low synthetic cost, and realization of synthesizing complex and various chromone-substituted 2-hydroxypyrrole derivatives without the catalyst, conciseness, high efficiency and the 'one-pot' method;

(2) the chromone-substituted 2-hydroxypyrrole derivative constructs a compound library of 2-hydroxypyrrole derivative compounds, and molecular diversity is realized;

(3) the chromone-substituted 2-hydroxypyrrole derivative has good anti-inflammatory activity and can be used for preparing anti-inflammatory drugs.

Drawings

FIG. 1 is a NMR spectrum of Compound 2 of example 2;

FIG. 2 is a NMR carbon spectrum of Compound 2 of example 2;

FIG. 3 is a NMR hydrogen spectrum of Compound 12 of example 12;

FIG. 4 is a NMR carbon spectrum of Compound 12 of example 12;

FIG. 5 is a single crystal structural diagram of Compound 21 of example 21.

Detailed Description

The present invention will be described in further detail with reference to specific embodiments, but the scope of the present invention is not limited to the description. The examples do not specify particular techniques or conditions, and are performed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available by purchase.

Example 1: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

The compound is named as (E) -3- (7-benzoyl-5-hydroxy-5- (p-tolyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) chroman-2, 4-dione and is marked as a compound 1;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (7-benzoyl-5-hydroxy-5- (p-tolyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ylidene) chroman-2, 4-dione) comprises the following specific steps:

adding 6mL of 1, 4-dioxane serving as a solvent into a 25mL round-bottom flask, and sequentially adding p-tolualdehyde hydrate, 4-hydroxycoumarin and 2- (imidazolidine-2-ylidene) -1-phenyleth-1-one, wherein the molar ratio of the p-tolualdehyde hydrate, the 4-hydroxycoumarin and the 2- (imidazolidine-2-ylidene) -1-phenyleth-1-one is 1:1:1, and the mol ratio of the molar amount of a phenylglyoxal derivative (tolualdehyde hydrate) to the volume of the solvent is 1: 6; heating and refluxing, stirring for reaction, detecting by TLC (thin layer chromatography) for 12H, completely reacting the raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (7-benzoyl-5-hydroxy-5- (p-tolyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ylidene) chroman-2, 4-dione); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

(E) the synthetic reaction formula of the (E) -3- (7-benzoyl-5-hydroxy-5- (p-tolyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ylidene) chroman-2, 4-dione is shown as follows;

(E) -3- (7-benzoyl-5-hydroxy-5- (p-tolyl) -2, 3-dihydro-1H-pyrrolo [1, 2-a)]Structural characterization data for imidazol-6- (5H) -ylidene) chroman-2, 4-dione: (NMR, hydrogen Spectroscopy, deuterated dimethylsulfoxide, Bruker AM600 Instrument): delta-2.13 (s,3H, CH)₃),3.21～3.24(m,1H,NCH₂),3.70～3.75(m,1H,NCH₂),4.10～4.14(m,2H,NHCH₂),6.88～6.94(m,1H,ArH),7.03～7.06(m,3H,ArH),7.15～7.17(m,2H,ArH),7.26～7.28(m,2H,ArH),7.33～7.36(m,2H,ArH),7.63～7.66(m,3H,ArH),10.11(br,1H,NH),10.94(s,1H,OH)；

(E) -3- (7-benzoyl-5-hydroxy-5- (p-tolyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) chroman-2, 4-dione (nmr carbon spectrum, deuterated dimethylsulfoxide, Bruker AM600 instrument): δ ═ 21.14,41.4,50.6,93.1,98.1,113.9,116.3,120.6,123.7,125.7,126.0,128.2,128.6,129.4,133.1,133.5,136.0,137.6,138.5,153.3,162.5,169.3,172.8,175.6,188.2;

this example (E) -3- (7-benzoyl-5-hydroxy-5- (p-tolyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) chroman-2, 4-dione in 76% yield and a melting point of 234.0 ℃;

high resolution mass spectrum C₂₉H₂₃N₂O₅[M+H]⁺Theoretical value 479.1601; found 479.1603.

Example 2: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

The compound was named (E) -3- (7- (4-chlorobenzoyl) -5-hydroxy-5- (p-tolyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) chroman-2, 4-dione as compound 2;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (7- (4-chlorobenzoyl) -5-hydroxy-5- (p-tolyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -subunit) chroman-2, 4-dione) comprises the following specific steps:

adding 10mL of 1, 4-dioxane serving as a solvent into a 25mL round-bottom flask, and sequentially adding benzoylformaldehyde, 4-hydroxycoumarin and 1- (4-chlorophenyl) -2- (imidazolidin-2-ylidene) ethan-1-one, wherein the molar ratio of the benzoylformaldehyde, the 4-hydroxycoumarin and the 1- (4-chlorophenyl) -2- (imidazolidin-2-ylidene) ethan-1-one is 1:1:1, and the mol ratio L of the molar amount of the benzoylformaldehyde derivative (benzoylformaldehyde) to the volume of the solvent is 1: 10; heating to 120 ℃, stirring for reaction, detecting by TLC (thin layer chromatography) for reaction for 8H, completely reacting the raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (7- (4-chlorobenzoyl) -5-hydroxy-5- (p-tolyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ylidene) chroman-2, 4-dione); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 3: 1;

(E) the synthetic reaction formula of the (E) -3- (7- (4-chlorobenzoyl) -5-hydroxy-5- (p-tolyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ylidene) chroman-2, 4-dione is shown as follows;

(E) -3- (7- (4-chlorobenzoyl) -5-hydroxy-5- (p-tolyl) -2, 3-dihydro-1H-pyrrolo [1, 2-a)]The NMR spectrum of imidazole-6- (5H) -ylidene) chroman-2, 4-dione is shown in FIG. 1, (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): delta-2.21 (s,3H, CH)₃),3.29～3.30(d,1H,NCH₂,J＝27Hz),3.76～3.82(m,1H,NCH₂),4.17～4.22(m,2H,NHCH₂),7.00～7.02(m,1H,ArH),7.12～7.14(m,3H,ArH),7.22～7.24(m,2H,ArH),7.44～7.46(m,3H,ArH),7.71～7.75(m,3H,ArH),10.18(br,1H,NH),10.88(s,1H,OH)；；

(E) The NMR spectrum of 3- (7- (4-chlorobenzoyl) -5-hydroxy-5- (p-tolyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) chroman-2, 4-dione is shown in FIG. 2, (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): delta-21.1, 41.4,50.1,93.0,98.1,113.3,116.4,120.5,123.9,125.7,126.1,128.8,129.4,130.0,133.6,135.9,136.4,137.8,138.5,153.3,162.6,169.1,172.7,175.7,187.0;

this example (E) -3- (7- (4-chlorobenzoyl) -5-hydroxy-5- (p-tolyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) chroman-2, 4-dione in 82% yield and a melting point of 225.8 ℃;

high resolution mass spectrum C₂₉H₂₂ClN₂O₅[M+H]⁺Theoretical value 513.1212 found 513.1209.

Example 3: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

Named (E) -3- (7-benzoyl-5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) -6-chlorochroman-2, 4-dione, as compound 3;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivatives ((E) -3- (7-benzoyl-5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ylidene) -6-chlorochroman-2, 4-dione) comprises the following specific steps:

adding 10mL of 1, 4-dioxane serving as a solvent into a 25mL round-bottom flask, and sequentially adding benzoyl formaldehyde hydrate, 6-chloro-4-hydroxycoumarin and 2- (imidazolidin-2-ylidene) -1-phenylethane-1-one, wherein the molar ratio of the benzoyl formaldehyde hydrate, the 6-chloro-4-hydroxycoumarin and the 2- (imidazolidin-2-ylidene) -1-phenylethane-1-one is 1:1:1, and the mol ratio of the molar weight of a benzoyl formaldehyde derivative (benzoyl formaldehyde hydrate) to the volume of the solvent is 1: 10; heating and refluxing, stirring for reaction, detecting by TLC (thin layer chromatography) for 10H, completely reacting the raw materials to obtain a reaction solution, cooling the reaction solution to room temperature, and purifying by column chromatography to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (7-benzoyl-5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ylidene) -6-chlorochroman-2, 4-dione); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

(E) the synthetic reaction formula of the (E) -3- (7-benzoyl-5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ylidene) -6-chlorochroman-2, 4-diketone is shown as follows;

(E) -3- (7-benzoyl-5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1, 2-a)]Imidazole-6- (5H) -Subunit) -6-chlorochroman-2, 4-dione: (hydrogen nuclear magnetic resonance spectroscopy, deuterated dimethylsulfoxide, Bruker AM 500 instrument) < delta > 3.33-3.34 (m,1H, NCH)₂),3.38～3.84(m,1H,NCH₂),4.22～4.23(m,2H,NHCH₂),7.03～7.05(m,1H,ArH),7.29～7.30(m,1H,ArH),7.30～7.38(m,6H,ArH),7.44～7.48(m,2H,ArH),7.63～7.64(m,1H,ArH),7.73～7.74(m,2H,ArH),10.31(br,1H,NH),10.80(s,1H,OH)；

(E) -3- (7-benzoyl-5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) -6-chlorochroman-2, 4-dione: (nmr carbon spectrum, deuterated dimethylsulfoxide, Bruker AM 500 instrument): δ 41.4,50.2,93.1,97.9,114.8,118.6,121.9,124.9,125.7,128.1,128.3,128.6,128.9,129.2,133.1,133.2,137.3,138.7,151.8,162.0,169.3,172.1,174.0,188.1;

this example provides 78% yield of (E) -3- (7-benzoyl-5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) -6-chlorochroman-2, 4-dione having a melting point of 202.4 ℃;

high resolution mass spectrum C₂₈H₂₀ClN₂O₅[M+H]⁺Theoretical value 499.1055; found 499.1055.

Example 4: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

The compound is named as (E) -3- (7- (4-fluorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ylidene) chroman-2, 4-dione and is marked as a compound 4;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (7- (4-fluorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -subunit) chroman-2, 4-diketone) comprises the following specific steps:

adding 10mL of 1, 4-dioxane serving as a solvent into a 25mL round-bottom flask, and sequentially adding benzoyl formaldehyde hydrate, 4-hydroxycoumarin and 1- (4-fluorophenyl) -2- (imidazolidine-2-ylidene) ethane-1-ketone, wherein the molar ratio of the benzoyl formaldehyde hydrate, the 4-hydroxycoumarin and the 1- (4-fluorophenyl) -2- (imidazolidine-2-ylidene) ethane-1-ketone is 1:1:1, and the mol ratio L of the molar amount of the benzoyl formaldehyde derivative (benzoyl formaldehyde hydrate) to the volume of the solvent is 1: 10; heating and refluxing, stirring for reaction, detecting by TLC (thin layer chromatography) for 10H, completely reacting the raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (7- (4-fluorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ylidene) chroman-2, 4-dione); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

(E) the synthetic reaction formula of the (E) -3- (7- (4-fluorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ylidene) chroman-2, 4-dione is shown as follows;

(E) -3- (7- (4-fluorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1, 2-a)]Imidazol-6- (5H) -ylidene) chroman-2, 4-dione: (hydrogen nuclear magnetic resonance spectroscopy, deuterated dimethylsulfoxide, Bruker AM 500 instrument) < delta > 3.28-3.32 (t,1H, NCH)₂),3.79～3.84(m,1H,NCH₂),4.16～4.25(m,1H,NHCH₂),6.99～7.00(m,1H,ArH),7.12～7.15(m,1H,ArH),7.19～7.23(m,2H,ArH),7.26～7.28(m,1H,ArH),7.32～7.37(m,4H,ArH),7.43～7.46(m,1H,ArH),7.71～7.73(m,1H,ArH),7.80～7.83(m,1H,ArH),10.22(br,1H,NH),10.97(s,1H,OH)；

(E) -3- (7- (4-fluorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) chroman-2, 4-dione: (nmr carbon spectrum, deutero dimethyl sulfoxide, Bruker AM 500 instruments): δ 41.4,50.1,93.0,98.0,113.8,115.7(d, J22.5 Hz),116.3,120.5,123.8,125.7,126.0,128.8,129.2,131.1,133.6,134.3,138.9,153.3,162.5,164.0,166.0,169.3,175.7,186.8;

this example (E) -3- (7- (4-fluorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) chroman-2, 4-dione in 83% yield and a melting point of 216.3 ℃;

high resolution mass spectrum C₂₈H₁₉FN₂NaO₅[M+Na]⁺Theoretical value 505.1170 found 505.1166.

Example 5: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

Named (E) -6-chloro-3- (7- (4-fluorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) chroman-2, 4-dione as compound 5;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivative ((E) -6-chloro-3- (7- (4-fluorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -subunit) chroman-2, 4-diketone) comprises the following specific steps:

adding 10mL of 1, 4-dioxane serving as a solvent into a 25mL round-bottom flask, and sequentially adding benzoyl formaldehyde hydrate, 6-chloro-4-hydroxycoumarin and 1- (4-fluorophenyl) -2- (imidazolidine-2-ylidene) ethane-1-ketone, wherein the molar ratio of the benzoyl formaldehyde hydrate, the 6-chloro-4-hydroxycoumarin and the 1- (4-fluorophenyl) -2- (imidazolidine-2-ylidene) ethane-1-ketone is 1:1:1, and the mol ratio L of the molar amount of a benzoyl formaldehyde derivative (benzoyl formaldehyde hydrate) to the volume of the solvent is 1: 10; heating and refluxing, stirring for reaction, detecting by TLC (thin layer chromatography) for 10H, completely reacting the raw materials to obtain a reaction solution, cooling the reaction solution to room temperature, and purifying by column chromatography to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -6-chloro-3- (7- (4-fluorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ylidene) chroman-2, 4-dione); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

(E) the synthetic reaction formula of the (E) -6-chloro-3- (7- (4-fluorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ylidene) chroman-2, 4-dione is shown as follows;

(E) -6-chloro-3- (7- (4-fluorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1, 2-a)]Structural characterization data for imidazol-6- (5H) -ylidene) chroman-2, 4-dione; (hydrogen nuclear magnetic resonance, deuterated dimethylsulfoxide, Bruker AM600 instrument): delta is 3.32 to 3.34(m,1H, NCH)₂),3.81～3.83(m,1H,NCH₂),4.20～4.24(m,2H,NHCH₂),7.06～7.07(m,1H,ArH),7.20～7.23(m,2H,ArH),7.28～7.29(m,1H,ArH),7.33～7.36(m,4H,ArH),7.47～7.49(m,1H,ArH),7.64～7.64(m,1H,ArH),7.79～7.82(M,2H,ArH),10.29(br,1H,NH),10.74(s,1H,OH)；

E) -6-chloro-3- (7- (4-fluorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) chroman-2, 4-dione: (nmr carbon spectrum, deuterated dimethylsulfoxide, Bruker AM600 instrument): δ 41.4,50.2,93.1,97.8,114.6,115.7(d, J21 Hz),118.7,121.9,125.0,125.7,128.1,129.0,131.1(d, J9 Hz),133.2,134.1,138.6,151.9,162.1,164.2,165.9,169.2,172.0,174.1,186.7;

this example (E) -6-chloro-3- (7- (4-fluorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) chroman-2, 4-dione in 80% yield and melting point 199.8 ℃;

high resolution mass spectrum C₂₈H₁₉ClFN₂O₅[M+H]⁺Theoretical value 517.0961; found 517.0961.

Example 6: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

The compound is named as (E) -3- (7- (4-chlorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) chroman-2, 4-dione and is recorded as a compound 6;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (7- (4-chlorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -subunit) chroman-2, 4-diketone) comprises the following specific steps:

adding 10mL of ethanol serving as a solvent into a 25mL round-bottom flask, and then sequentially adding benzoyl formaldehyde hydrate, 4-hydroxycoumarin and 1- (4-chlorophenyl) -2- (imidazolidin-2-ylidene) ethan-1-one, wherein the molar ratio of the benzoyl formaldehyde hydrate, the 4-hydroxycoumarin and the 1- (4-chlorophenyl) -2- (imidazolidin-2-ylidene) ethan-1-one is 1:1:1, and the mol ratio of the molar amount of the benzoyl formaldehyde derivative (benzoyl formaldehyde hydrate) to the volume of the solvent is 1: 10; heating to 70 ℃, stirring for reaction, detecting by TLC (thin layer chromatography) for reaction for 24H, completely reacting raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (7- (4-chlorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ylidene) chroman-2, 4-dione); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

(E) the synthetic reaction formula of the (E) -3- (7- (4-chlorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ylidene) chroman-2, 4-dione is shown as follows;

(E) -3- (7- (4-chlorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1, 2-a)]Imidazol-6- (5H) -ylidene) chroman-2, 4-dione: (hydrogen nuclear magnetic resonance, deuterated dimethylsulfoxide, Bruker AM600 instrument): δ 3.293-3.31 (m,1H, NCH)₂),3.79～3.81(m,1H,NCH₂),4.19～4.20(m,2H,NHCH₂),7.00～7.01(m,1H,ArH),7.14～7.15(m,1H,ArH),7.27～7.28(m,1H,ArH),7.32～7.36(m,4H,ArH),7.44～7.47(m,3H,ArH),7.70～7.75(m,3H,ArH),10.21(br,1H,NH),10.86(s,1H,OH)；

(E) -3- (7- (4-chlorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) chroman-2, 4-dione: (nmr carbon spectrum, deuterated dimethylsulfoxide, Bruker AM600 instrument): δ 41.4,50.1,93.0,98.1,113.4,116.4,120.5,123.9,125.7,126.0,126.3,128.8,128.8,129.2,130.0,133.7,136.4,137.8,138.8,153.3,169.2,176.9,186.9;

this example (E) -3- (7- (4-chlorobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) chroman-2, 4-dione in 60% yield and a melting point of 222.4 ℃;

Example 7: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

The compound is named as (E) -3- (7- (4-bromobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) -6-chlorochroman-2, 4-dione and is marked as compound 7;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivatives ((E) -3- (7- (4-bromobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -subunit) -6-chlorochroman-2, 4-diketone) comprises the following specific steps:

adding 10mL of ethanol serving as a solvent into a 25mL round-bottom flask, and then sequentially adding benzoyl formaldehyde hydrate, 6-chloro-4-hydroxycoumarin and 1- (4-bromophenyl) -2- (imidazolidin-2-ylidene) ethan-1-one, wherein the molar ratio of the benzoyl formaldehyde hydrate, the 6-chloro-4-hydroxycoumarin and the 1- (4-bromophenyl) -2- (imidazolidin-2-ylidene) ethan-1-one is 1:1:1, and the mol ratio L of the molar weight of a benzoyl formaldehyde derivative (benzoyl formaldehyde hydrate) to the volume of the solvent is 1: 10; heating to 75 ℃, stirring for reaction, detecting by TLC (thin layer chromatography) for reaction for 20H, completely reacting the raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (7- (4-bromobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ylidene) -6-chlorochroman-2, 4-dione); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1: 1;

(E) the synthetic reaction formula of the (E) -3- (7- (4-bromobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ylidene) -6-chlorochroman-2, 4-dione is shown as follows;

(E) -3- (7- (4-bromobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1, 2-a)]Imidazol-6- (5H) -ylidene) -6-chlorochroman-2, 4-dione: (hydrogen nuclear magnetic resonance, deuterated dimethylsulfoxide, Bruker AM600 instrument): delta is 3.30 to 3.32(m,1H, NCH)₂),3.80～3.82(m,1H,NCH₂),4.21～4.22(m,2H,NHCH₂),7.07～7.09(m,1H,ArH),7.28～7.29(m,5H,ArH),7.48～7.50(m,1H,ArH),7.59～7.67(m,5H,ArH),10.28(br,1H,NH),10.66(s,1H,OH)；

(E) -3- (7- (4-bromobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) -6-chlorochroman-2, 4-dione: (nmr carbon spectrum, deuterated dimethylsulfoxide, Bruker AM600 instrument) δ 41.4,50.2,93.1,97.9,114.2,118.7,121.9,125.0,125.7,127.1,128.2,128.9,129.2,130.2,131.8,133.3,136.6,138.6,151.8,162.2,169.1,172.0,174.2,187.1;

this example provides 70% yield of (E) -3- (7- (4-bromobenzoyl) -5-hydroxy-5-phenyl-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) -6-chlorochroman-2, 4-dione, m.p. 225.7 ℃;

high resolution mass spectrum C₂₈H₁₉BrClN₂O₅[M+H]⁺Theoretical value 577.0160; found 577.0160.

Example 8: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

Designated (E) -3- (5- (3, 4-difluorophenyl) -5-hydroxy-7- (4-methylbenzoyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ethylene) chroman-2, 4-dione as compound 8;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (5- (3, 4-difluorophenyl) -5-hydroxy-7- (4-methylbenzoyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ethylidene) chroman-2, 4-diketone) comprises the following specific steps:

adding 10mL of 1, 4-dioxane serving as a solvent into a 25mL round-bottom flask, and sequentially adding 3, 4-difluorobenzoyl formaldehyde hydrate, 4-hydroxycoumarin and 2- (imidazolidine-2-ylidene) -1- (p-tolyl) ethan-1-one, wherein the molar ratio of the 3, 4-difluorobenzoyl formaldehyde hydrate, the 4-hydroxycoumarin and the 2- (imidazolidine-2-ylidene) -1- (p-tolyl) ethan-1-one is 1:1:1, and the mol: L of the molar amount of the benzoyl formaldehyde derivative (3, 4-difluorobenzoyl formaldehyde hydrate) to the volume of the solvent is 1: 10; heating to 110 ℃, stirring for reaction, detecting by TLC (thin layer chromatography) for reaction for 16H, completely reacting the raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (5- (3, 4-difluorophenyl) -5-hydroxy-7- (4-methylbenzoyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ethylidene) chroman-2, 4-dione); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

(E) the synthetic reaction formula of-3- (5- (3, 4-difluorophenyl) -5-hydroxy-7- (4-methylbenzoyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ethylidene) chroman-2, 4-dione is shown as follows;

(E) -3- (5- (3, 4-difluorophenyl) -5-hydroxy-7- (4-methylbenzoyl) -2, 3-dihydro-1H-pyrrolo [1, 2-a)]Imidazole-6- (5H) -ethylene) chroman-2, 4-dione: (hydrogen nuclear magnetic resonance, deuterated dimethylsulfoxide, Bruker AM600 instrument); delta 2.25(s,3H, CH)₃),3.38～3.43(m,1H,NCH₂),3.79～3.81(d,J＝10.0Hz,1H,NCH₂),4.18～4.24(m,2H,NHCH₂),7.00～7.02(m,1H,ArH),7.14～7.19(m,4H,ArH),7.39～7.48(m,3H,ArH),7.65～7.66(m,2H,ArH),7.74～7.75(m,1H,ArH),10.31(br,1H,NH),11.21(s,1H,OH)；

(E) -3- (5- (3, 4-difluorophenyl) -5-hydroxy-7- (4-methylbenzoyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ethylene) chroman-2, 4-dione: (nuclear magnetic resonance carbon spectroscopy, deuterated dimethylsulfoxide, Bruker AM600 instrument); δ — 21.5,41.4,50.3,92.3,97.7,114.5,115.4,115.4,116.4,118.2,118.2,120.5,122.9,123.9,126.0,128.4,129.3,133.6,134.9,137.0,143.6,143.6,153.4,169.6,171.1,175.7,187.5;

this example shows 73% yield of (E) -3- (5- (3, 4-difluorophenyl) -5-hydroxy-7- (4-methylbenzoyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ethylene) chroman-2, 4-dione, melting point 197.8 ℃;

high resolution mass spectrum C₂₉H₂₀F₂N₂NaO₅[M+Na]⁺Theoretical value 537.1232; found 537.1227.

Example 9: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

Designated (E) -3- (7- (4-chlorobenzoyl) -5- (3, 4-difluorophenyl) -5-hydroxy-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) chroman-2, 4-dione as compound 9;

the synthesis method of the chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (7- (4-chlorobenzoyl) -5- (3, 4-difluorophenyl) -5-hydroxy-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -subunit) chroman-2, 4-diketone) comprises the following specific steps:

adding 10mL of hydrogen peroxide serving as a solvent into a 25mL round-bottom flask, and then sequentially adding 3, 4-difluorobenzoyl formaldehyde hydrate, 4-hydroxycoumarin and 1- (4-chlorophenyl) -2- (imidazolidine-2-subunit) ethane-1-ketone, wherein the molar ratio of the 3, 4-difluorobenzoyl formaldehyde hydrate to the 4-hydroxycoumarin to the 1- (4-chlorophenyl) -2- (imidazolidine-2-subunit) ethane-1-ketone is 1:1:1, and the mol ratio L of the molar amount of the benzoyl formaldehyde derivative (3, 4-difluorobenzoyl formaldehyde hydrate) to the volume of the solvent is 1: 10; heating to 90 ℃, stirring for reaction, detecting by TLC (thin layer chromatography) for reaction for 10H, completely reacting raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (7- (4-chlorobenzoyl) -5- (3, 4-difluorophenyl) -5-hydroxy-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -ylidene) chroman-2, 4-dione); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

(E) the synthetic reaction formula of the-3- (7- (4-chlorobenzoyl) -5- (3, 4-difluorophenyl) -5-hydroxy-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-6- (5H) -subunit) chroman-2, 4-diketone is shown as follows;

(E) -3- (7- (4-chlorobenzoyl) -5- (3, 4-difluorophenyl) -5-hydroxy-2, 3-dihydro-1H-pyrrolo [1, 2-a)]Imidazol-6- (5H) -ylidene) chroman-2, 4-dione: (hydrogen nuclear magnetic resonance, deuterated dimethylsulfoxide, Bruker AM600 instrument); delta is 3.34 to 3.42(m,1H, NCH)₂),3.78～3.83(m,1H,NHCH₂),4.17～4.26(m,1H,NHCH₂),7.02～7.04(m,1H,ArH),7.14～7.17(m,2H,ArH),7.39～7.49(m,5H,ArH),7.34～7.78(m,3H,ArH),10.32(br,1H,NH),10.99(s,1H,OH)；

(E) -3- (7- (4-chlorobenzoyl) -5- (3, 4-difluorophenyl) -5-hydroxy-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) chroman-2, 4-dione: (nmr carbon spectrum, deuterated dimethylsulfoxide, Bruker AM600 instrument): δ 41.3,50.3,92.2,97.9,113.6,115.4,116.4,118.1,120.4,122.9,124.0,126.0,128.8,130.0,133.8,136.6,136.9,137.9,149.7(d, J244.5 Hz),149.9(d, J244.5 Hz),153.4,162.5,169.3,171.6,175.8,186.8;

this example provides 77% yield of (E) -3- (7- (4-chlorobenzoyl) -5- (3, 4-difluorophenyl) -5-hydroxy-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) chroman-2, 4-dione, m.p. 217.7 ℃;

high resolution mass spectrum C₂₈H₁₇ClF₂N₂NaO₅[M+H]⁺Theory 557.0686; found 557.0684.

Example 10: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

Designated (E) -3- (7- (4-chlorobenzoyl) -5- (3, 4-difluorophenyl) -5-hydroxy-2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazol-6- (5H) -ylidene) chroman-2, 4-dione as compound 10;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (8-benzoyl-6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) -6-methylchroman-2, 4-dione) comprises the following specific steps:

adding 10mL of water serving as a solvent into a 25mL round-bottom flask, and then sequentially adding p-tolualdehyde hydrate, 6-methyl-4-hydroxycoumarin and 1-phenyl-2- (tetrahydropyrimidine-2 (1H) -ylidene) ethan-1-one, wherein the molar ratio of the p-tolualdehyde hydrate, the 6-methyl-4-hydroxycoumarin and the 1-phenyl-2- (tetrahydropyrimidine-2 (1H) -ylidene) ethan-1-one is 1:1:1, and the mol: L of the molar amount of a phenylglyoxal derivative (p-tolualdehyde hydrate) to the volume of the solvent is 1: 10; heating and refluxing, stirring for reaction, detecting by TLC (thin layer chromatography) for 20H, completely reacting the raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (8-benzoyl-6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) -6-methylchroman-2, 4-dione); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

(E) the synthetic reaction formula of the (E) -3- (8-benzoyl-6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) -6-methylchroman-2, 4-dione is shown as follows;

(E) -3- (8-benzoyl-6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1, 2-a)]Pyrimidin-7 (6H) -ylidene) -6-methylchroman-2, 4-dione: (hydrogen nuclear magnetic resonance, deuterated dimethylsulfoxide, Bruker AM 500 instrument); δ is 1.86 to 1.88(m,1H, CH)₂),1.96～1.98(m,1H,CH₂),2.21(s,3H,CH₃),2.25(s,3H,CH₃),2.90～2.94(m,1H,NCH₂),3.43～3.52(m,3H,NHCH₂,NCH₂),6.81～6.83(m,1H,ArH),7.11～7.12(m,2H,ArH),7.20～7.22(m,3H,ArH),7.31～7.34(m,2H,ArH),7.40～7.43(m,1H,ArH),7.52～7.53(m,1H,ArH),7.72～7.74(m,2H,ArH),9.27(br,1H,NH),11.56(s,1H,OH)；

(E) -3- (8-benzoyl-6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) -6-methylchroman-2, 4-dione: (nuclear magnetic resonance carbon spectroscopy, deuterated dimethylsulfoxide, Bruker AM 500 instrument); δ -19.1, 20.7,21.1,37.1,39.1,96.5,96.8,116.0,116.6,120.3,125.5,125.8,128.4,128.5,129.4,132.7,133.1,133.9,135.9,137.6,138.5,151.4,158.5,160.0,162.7,175.2,189.2;

this example (E) -3- (8-benzoyl-6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) -6-methylchroman-2, 4-dione in 88% yield and a melting point of 225.8 ℃;

high resolution mass spectrum C₃₁H₂₆N₂NaO₅[M+Na]⁺Theory 529.1734; found 529.1736.

Example 11: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

The compound is named as (E) -3- (8-benzoyl-6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) -6-chlorochroman-2, 4-dione and is marked as a compound 11;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (8-benzoyl-6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) -6-chlorochroman-2, 4-dione) comprises the following specific steps:

adding 10mL of 1, 4-dioxane serving as a solvent into a 25mL round-bottom flask, and sequentially adding p-tolualdehyde hydrate, 6-methyl-4-hydroxycoumarin and 1-phenyl-2- (tetrahydropyrimidine-2 (1H) -ylidene) ethane-1-ketone, wherein the molar ratio of the p-tolualdehyde hydrate, the 6-methyl-4-hydroxycoumarin and the 1-phenyl-2- (tetrahydropyrimidine-2 (1H) -ylidene) ethane-1-ketone is 1:1:1, and the mol ratio L of the molar amount of a phenylglyoxal derivative (p-tolualdehyde hydrate) to the volume of the solvent is 1: 10; heating and refluxing, stirring for reaction, detecting by TLC (thin layer chromatography) for 10H, completely reacting the raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (8-benzoyl-6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) -6-chlorochroman-2, 4-dione); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

(E) the synthetic reaction formula of the (E) -3- (8-benzoyl-6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) -6-chlorochroman-2, 4-dione is shown as follows;

(E) -3- (8-benzoyl-6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1, 2-a)]Pyrimidin-7 (6H) -ylidene) -6-chlorochroman-2, 4-dione: (hydrogen nuclear magnetic resonance, deuterated dimethylsulfoxide, Bruker AM 500 instrument); δ is 1.78 to 1.79(m,2H, CH)₂),2.13(s,3H,CH₃),2.83～2.86(t,1H,NHCH₂),3.35～3.44(m,3H,NHCH_2,NCH₂),6.88～6.90(m,1H,ArH),7.03～7.15(m,7H,ArH),7.32～7.35(m,1H,ArH),7.65～7.73(m,3H,ArH),9.20(br,1H,NH),11.32(s,1H,OH)；

(E) -3- (8-benzoyl-6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) -6-chlorochroman-2, 4-dione: (nmr carbon spectrum, deutero dimethyl sulfoxide, Bruker AM 500 instruments): δ 19.0,21.1,37.2,39.1,96.3,96.8,115.5(d, J21.3 Hz),116.2,116.7,120.6,123.6,125.8,125.9,131.3,133.2,134.3,135.8,138.6,153.3,158.3,164.0,163.6(d, J242.5 Hz),166.0,175.2,187.8;

this example (E) -3- (8-benzoyl-6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) -6-chlorochroman-2, 4-dione in 89% yield and melting point 210.6 ℃;

high resolution mass spectrum C₃₀H₂₄ClN₂O₅[M+H]⁺527.1368, theory 527.1368; found 527.1368.

Example 12: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

The compound is named as (E) -3- (8- (4-fluorobenzoyl) -6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione and is marked as compound 12;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (8- (4-fluorobenzoyl) -6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) chroman-2, 4-dione) comprises the following specific steps:

adding 10mL of 1, 4-dioxane serving as a solvent into a 25mL round-bottom flask, and sequentially adding p-tolualdehyde hydrate, 4-hydroxycoumarin and 1- (4-fluorophenyl) -2- (tetrahydropyrimidine-2 (1H) -ylidene) ethane-1-ketone, wherein the molar ratio of the p-tolualdehyde hydrate, the 4-hydroxycoumarin and the 1- (4-fluorophenyl) -2- (tetrahydropyrimidine-2 (1H) -ylidene) ethane-1-ketone is 1:1:1, and the mol ratio L of the molar amount of a phenylglyoxal derivative (p-tolualdehyde hydrate) to the volume of the solvent is 1: 10; heating and refluxing, stirring for reaction, detecting by TLC (thin layer chromatography) for 10H, completely reacting the raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (8- (4-fluorobenzoyl) -6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) chroman-2, 4-dione); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

(E) the synthetic reaction formula of the (E) -3- (8- (4-fluorobenzoyl) -6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione is shown as follows;

(E) a hydrogen nuclear magnetic resonance spectrum of 3- (8-benzoyl-6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) -6-chlorochroman-2, 4-dione (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ ═ 1.78-1.79 (m,2H, CH2),2.13(s,3H, CH3), 2.83-2.86 (t,1H, NHCH2), 3.35-3.44 (m,3H, NHCH2, NCH2), 6.88-6.90 (m,1H, ArH), 7.03-7.15 (m,7H, ArH), 7.32-7.35 (m,1H, ArH), 7.65-7.73 (m,3H, ArH),9.20(br H, 1H, NH 11H, 11H);

(E) a nmr carbon spectrum of 3- (8-benzoyl-6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) -6-chlorochroman-2, 4-dione is shown in fig. 4, (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ ═ 19.0,21.1,37.2,39.1,96.3,96.8,115.5(d, J ═ 21.3Hz),116.2,116.7,120.6,123.6,125.8,125.9,131.3,133.2,134.3,135.8,138.6,153.3,158.3,164.0,163.6(d, J ═ 242.5Hz),166.0,175.2,187.8;

this example (E) -3- (8-benzoyl-6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) -6-chlorochroman-2, 4-dione in 90% yield and a melting point of 242.8 ℃;

high resolution mass spectrum C₃₀H₂₄FN₂O₅[M+H]+ theoretical 511.1664; found 511.1664.

Example 13: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

The compound is named as (E) -3- (8- (4-chlorobenzoyl) -6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) -6-methylchroman-2, 4-dione, and is marked as compound 13;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (8- (4-chlorobenzoyl) -6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) -6-methylchroman-2, 4-dione) comprises the following specific steps:

adding 10mL of 1, 4-dioxane serving as a solvent into a 25mL round-bottom flask, and sequentially adding p-tolualdehyde hydrate, 6-methyl-4-hydroxycoumarin and 1- (4-chlorophenyl) -2- (tetrahydropyrimidine-2 (1H) -ylidene) ethane-1-ketone, wherein the molar ratio of the p-tolualdehyde hydrate, the 6-methyl-4-hydroxycoumarin and the 1- (4-chlorophenyl) -2- (tetrahydropyrimidine-2 (1H) -ylidene) ethane-1-ketone is 1:1:1, and the mol ratio of the molar amount of a phenylglyoxal derivative (p-tolualdehyde hydrate) to the volume of the solvent is 1: 10; heating and refluxing, stirring for reaction, detecting by TLC (thin layer chromatography) for 10H, completely reacting the raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (8- (4-chlorobenzoyl) -6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) -6-methylchroman-2, 4-dione); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

(E) the synthetic reaction formula of the (E) -3- (8- (4-chlorobenzoyl) -6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) -6-methylchroman-2, 4-dione is shown as follows;

(E) -3- (8- (4-chlorobenzoyl) -6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a]Pyrimidin-7 (6H) -ylidene) -6-methylchroman-2, 4-dione: (hydrogen nuclear magnetic resonance, deuterated dimethylsulfoxide, Bruker AM600 instrument); delta is 1.80-1.97 (m,2H, CH)_2,),2.21(s,3H,CH₃),2.26(s,2H,CH₃),2.92～2.93(m,1H_,NCH₂),3.47～3.51(m,3H,NCH_2,NHCH_2,NHCH₂),6.86～6.87(m,1H,ArH),7.11～7.12(m,2H,ArH),7.20～7.24(m,3H,ArH),7.42～7.44(m,2H,ArH),7.52(m,1H,ArH),7.71～7,73(m,2H,ArH),9.26(br,1H,NH),11.41(s,1H,OH)；

(E) -3- (8- (4-chlorobenzoyl) -6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) -6-methylchroman-2, 4-dione, (nmr carbon spectroscopy, deuterated dimethyl sulfoxide, Bruker AM600 instrument); δ -19.1, 20.7,21.1,37.1,39.6,96.5,96.8,116.0,116.2,120.2,125.6,125.7,128.6,129.4,130.2,132.8,134.1,135.8,136.5,137.7,138.5,151.4,158.3,162.8,165.0,175.4,188.0;

this example (E) -3- (8- (4-chlorobenzoyl) -6-hydroxy-6- (p-tolyl) -1,2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) -6-methylchroman-2, 4-dione in 87% yield and a melting point of 220.0 ℃;

high resolution mass spectrum C₃₁H₂₅ClN₂NaO₅[M+Na]⁺Theory 563.1344; found 563.1343.

Example 14: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

Named (E) -3- (6-hydroxy-8- (4-methylbenzoyl) -6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione as compound 14;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (6-hydroxy-8- (4-methylbenzoyl) -6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -subunit) chroman-2, 4-diketone) comprises the following specific steps:

adding 10mL of 1, 4-dioxane serving as a solvent into a 25mL round-bottom flask, and sequentially adding benzoyl formaldehyde hydrate, 4-hydroxycoumarin and 2- (tetrahydropyrimidine-2 (1H) -ylidene) -1- (p-tolyl) ethan-1-one, wherein the molar ratio of the benzoyl formaldehyde hydrate, the 4-hydroxycoumarin and the 2- (tetrahydropyrimidine-2 (1H) -ylidene) -1- (p-tolyl) ethan-1-one is 1:1:1, and the molar ratio of the molar weight of a benzoyl formaldehyde derivative (benzoyl formaldehyde hydrate) to the volume of the solvent is 1: 10; stirring and reacting at the temperature of 80 ℃, detecting by TLC (thin layer chromatography) for 10H, completely reacting raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography separation to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (6-hydroxy-8- (4-methylbenzoyl) -6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -subunit) chroman-2, 4-dione); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

(E) the synthetic reaction formula of the-3- (6-hydroxy-8- (4-methylbenzoyl) -6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) chroman-2, 4-dione is shown as follows;

(E) -3- (6-hydroxy-8- (4-methylbenzoyl) -6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1, 2-a)]Pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione: (hydrogen nuclear magnetic resonance, deuterated dimethylsulfoxide, Bruker AM 500 instrument); delta is 1.87 to 1.96(m,2H, CH)_2,),2.22(s,3H,CH₃),2.90～2.93(m,1H,NCH₂),3.40～3.41(m,1H,NCH₂),3.50～3.53(m,2H,NHCH₂),6.94～6.95(m,1H,ArH),7.10～7.15(m,3H,ArH),7.26～7.35(m,5H,ArH),7.40～7.42(m,1H,ArH),7.65～7.67(m,2H,ArH),7.73～7.74(m,1H,ArH),9.28(br,1H,NH),11.59(s,1H,OH)；

(E) -3- (6-hydroxy-8- (4-methylbenzoyl) -6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione: (nuclear magnetic resonance carbon spectroscopy, deuterated dimethylsulfoxide, Bruker AM 500 instrument); δ -19.1, 21.5,37.2,39.1,96.3,96.8,116.2,117.3,120.6,123.6,125.8,125.9,128.6,128.8,129.1,129.2,133.1,135.1,138.8,143.5,153.3,158.6,162.5,164.0,175.2,188.7;

this example (E) -3- (6-hydroxy-8- (4-methylbenzoyl) -6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione in 85% yield and a melting point of 214.7 ℃;

high resolution mass spectrum C₃₀H₂₅N₂O₅[M+H]⁺Theory 493.1758; found 493.1762.

Example 15: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

Named (E) -6-bromo-3- (6-hydroxy-8- (4-methylbenzoyl) -6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione as compound 15;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivative ((E) -6-bromo-3- (6-hydroxy-8- (4-methylbenzoyl) -6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -subunit) chroman-2, 4-diketone) comprises the following specific steps:

adding 10mL of 1, 4-dioxane serving as a solvent into a 25mL round-bottom flask, and sequentially adding benzoyl formaldehyde hydrate, 4-hydroxycoumarin and 2- (tetrahydropyrimidine-2 (1H) -ylidene) -1- (p-tolyl) ethan-1-one, wherein the molar ratio of the benzoyl formaldehyde hydrate, the 6-bromo-4-hydroxycoumarin and the 2- (tetrahydropyrimidine-2 (1H) -ylidene) -1- (p-tolyl) ethan-1-one is 1:1:1, and the mol ratio L of the molar amount of a benzoyl formaldehyde derivative (benzoyl formaldehyde hydrate) to the volume of the solvent is 1: 10; stirring and reacting at the temperature of 100 ℃, detecting by TLC (thin layer chromatography) for 10H, completely reacting raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography separation to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -6-bromo-3- (6-hydroxy-8- (4-methylbenzoyl) -6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) chroman-2, 4-dione); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

(E) the synthetic reaction formula of the-6-bromo-3- (6-hydroxy-8- (4-methylbenzoyl) -6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) chroman-2, 4-dione is shown as follows;

(E) -6-bromo-3- (6-hydroxy-8- (4-methylbenzoyl) -6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1, 2-a)]Pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione: (hydrogen nuclear magnetic resonance, deuterated dimethylsulfoxide, Bruker AM600 instrument); delta is 1.90-1.97 (m,2H, CH)₂),2.22(s,3H,CH₃),2.92～2.94(t,1H,NCH₂),3.44～3.54(m,3H,NCH_2,NHCH₂),6.94～6.96(m,1H,ArH),7.14～7.16(m,2H,ArH),7.27～7.27(m,5H,ArH),7.54～7.55(m,1H,ArH),7.65～7.67(m,2H,ArH),7.80～7.80(m,1H,ArH),9.36(br,1H,NH),11.32(s,1H,OH)；

(E) -6-bromo-3- (6-hydroxy-8- (4-methylbenzoyl) -6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione: (nuclear magnetic resonance carbon spectroscopy, deuterated dimethylsulfoxide, Bruker AM600 instrument); δ 19.0,21.5,37.2,39.1,96.1,96.8,115.6,118.0,118.8,122.5,125.8,127.9,128.7,128.9,129.1,129.2,134.9,135.5,138.6,143.7,151.8,158.5,162.1,163.5,173.7,188.6;

this example (E) -6-bromo-3- (6-hydroxy-8- (4-methylbenzoyl) -6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione in 87% yield and melting point 234.2 ℃;

high resolution mass spectrum C₃₀H₂₄BrN₂O₅[M+H]⁺Theory 571.0863; found 571.0864.

Example 16: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

The compound is named as (E) -3- (8-benzoyl-6-hydroxy-6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione and is marked as a compound 16;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (8-benzoyl-6-hydroxy-6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) chroman-2, 4-dione) comprises the following specific steps:

adding 10mL of 1, 4-dioxane serving as a solvent into a 25mL round-bottom flask, and sequentially adding benzoyl formaldehyde hydrate, 4-hydroxycoumarin and 1-phenyl-2- (tetrahydropyrimidine-2 (1H) -ylidene) ethan-1-one, wherein the molar ratio of the benzoyl formaldehyde hydrate, the 6-bromo-4-hydroxycoumarin and the 1-phenyl-2- (tetrahydropyrimidine-2 (1H) -ylidene) ethan-1-one is 1:1:1, and the mol: L ratio of the molar amount of the benzoyl formaldehyde derivative (benzoyl formaldehyde hydrate) to the volume of the solvent is 1: 10; stirring and reacting at the temperature of 110 ℃, detecting by adopting TLC (thin layer chromatography) for 10H, completely reacting raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography separation to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (8-benzoyl-6-hydroxy-6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -subunit) chroman-2, 4-diketone); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

(E) the synthetic reaction formula of the-3- (8-benzoyl-6-hydroxy-6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) chroman-2, 4-dione is shown as follows;

(E) -3- (8-benzoyl-6-hydroxy-6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1, 2-a)]Pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione: (hydrogen nuclear magnetic resonance, deuterated dimethylsulfoxide, Bruker AM 500 instrument); δ is 1.88 to 1.99(m,2H, CH)₂),2.91～2.94(m,1H,NCH₂),3.44～3.55(m,3H,NCH_2,NHCH₂),6.92～6.93(m,1H,ArH),7.10～7.12(m,1H,ArH),7.25～7.43(m,9H,ArH),7.72～7.75(m,3H,ArH),9.31(br,1H,NH),11.54(s,1H,OH)；

(E) -3- (8-benzoyl-6-hydroxy-6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione: (nuclear magnetic resonance carbon spectroscopy, deuterated dimethylsulfoxide, Bruker AM 500 instrument); δ 19.1,37.2,39.1,96.4,96.8,116.1,117.0,120.6,123.6,125.8,125.8,128.4,128.5,128.8,129.2,133.1,133.1,137.6,138.8,153.3,158.5,162.6,164.5,175.2,189.2;

this example (E) -3- (8-benzoyl-6-hydroxy-6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione in 87% yield and melting point at 253.1 ℃;

high resolution mass spectrum C₂₉H₂₃N₂O₅[M+H]⁺Theory 479.1601; found 479.1600.

Example 17: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

Named (E) -6-chloro-3- (8- (4-chlorobenzoyl) -6-hydroxy-6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione as compound 17;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivative ((E) -6-chloro-3- (8- (4-chlorobenzoyl) -6-hydroxy-6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -subunit) chroman-2, 4-diketone) comprises the following steps:

adding 10mL of 1, 4-dioxane serving as a solvent into a 25mL round-bottom flask, and sequentially adding benzoyl formaldehyde hydrate, 4-hydroxycoumarin and 1- (4-fluorophenyl) -2- (tetrahydropyrimidine-2 (1H) -ylidene) ethane-1-ketone, wherein the molar ratio of the benzoyl formaldehyde hydrate, the 6-bromo-4-hydroxycoumarin and the 1- (4-fluorophenyl) -2- (tetrahydropyrimidine-2 (1H) -ylidene) ethane-1-ketone is 1:1:1, and the mol ratio of the molar amount of a benzoyl formaldehyde derivative (benzoyl formaldehyde hydrate) to the volume of the solvent is 1: 10; stirring and reacting at the temperature of 120 ℃, detecting by TLC (thin layer chromatography) for 12H, completely reacting raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography separation to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -6-chloro-3- (8- (4-chlorobenzoyl) -6-hydroxy-6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) chroman-2, 4-dione); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

(E) the synthetic reaction formula of the-6-chloro-3- (8- (4-chlorobenzoyl) -6-hydroxy-6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) chroman-2, 4-dione is shown as follows;

(E) -6-chloro-3- (8- (4-chlorobenzoyl) -6-hydroxy-6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1, 2-a)]Pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione: (hydrogen nuclear magnetic resonance, deuterated dimethylsulfoxide, Bruker AM600 instrument); delta is 1.89 to 1.98(m,2H, CH)₂),2.91～2.94(m,1H,NCH₂),3.43～3.53(m,3H,NCH_2,NHCH₂),7.03～7.04(m,1H,ArH),7.27～7.9(m,1H,ArH),7.31～7.33(m,4H,ArH),7.43～7.46(m,3H,ArH),7.65～7.65(m,2H,ArH),7.74(m,1H,ArH),9.37(br,1H,NH),11.16(s,1H,OH)；

(E) -6-chloro-3- (8- (4-chlorobenzoyl) -6-hydroxy-6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione: (nuclear magnetic resonance carbon spectroscopy, deuterated dimethylsulfoxide, Bruker AM600 instrument); δ 19.0,37.2,39.2,96.2,96.8,117.3,118.6,121.9,124.9,128.0,125.8,128.7,128.9,129.3,130.3,132.9,136.3,138.0,138.4,151.8,158.4,162.3,164.0,173.8,188.0;

this example (E) -6-chloro-3- (8- (4-chlorobenzoyl) -6-hydroxy-6-phenyl-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione in 87% yield and melting point 247.2 ℃;

high resolution mass spectrum C₂₉H₂₀Cl₂N₂NaO₅[M+Na]⁺Theory 569.0461; found 569.0463.

Example 18: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

The compound is named as (E) -3- (8-benzoyl-6- (4-fluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) -6-chlorochroman-2, 4-dione and is marked as a compound 18;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (8-benzoyl-6- (4-fluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) -6-chlorochroman-2, 4-diketone) comprises the following steps:

adding 10mL of 1, 4-dioxane serving as a solvent into a 25mL round-bottom flask, and sequentially adding benzoyl formaldehyde hydrate, 6-chloro-4-hydroxycoumarin and 1- (4-chlorophenyl) -2- (tetrahydropyrimidine-2 (1H) -ylidene) ethane-1-ketone, wherein the molar ratio of the benzoyl formaldehyde hydrate, the 6-chloro-4-hydroxycoumarin and the 1- (4-chlorophenyl) -2- (tetrahydropyrimidine-2 (1H) -ylidene) ethane-1-ketone is 1:1:1, and the mol ratio of the molar amount of a benzoyl formaldehyde derivative (benzoyl formaldehyde hydrate) to the volume of the solvent is 1: 10; stirring and reacting at the temperature of 110 ℃, detecting by TLC (thin layer chromatography) for 14H, completely reacting raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography separation to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (8-benzoyl-6- (4-fluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -subunit) -6-chlorochroman-2, 4-diketone); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

(E) the synthetic reaction formula of the (E) -3- (8-benzoyl-6- (4-fluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) -6-chlorochroman-2, 4-diketone is shown as follows;

(E) -3- (8-benzoyl-6- (4-fluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1, 2-a)]Pyrimidin-7 (6H) -ylidene) -6-chlorochroman-2, 4-dione: (nmr hydrogen spectroscopy, deuterated dimethylsulfoxide, Bruker AM 5600 instrument); delta is 1.90-1.99 (m,2H, CH)₂),2.94～2.98(m,1H,NCH₂),3.44～3.55(m,3H,NCH₂,NHCH₂),7.00～7.01(m,1H,ArH),7.15～7.18(m,2H,ArH),7.32～7.39(m,4H,ArH),7.41～7.45(m,.2H,ArH),7.65～7.66(m,1H,ArH),7.73～7.74(m,2H,ArH),9.42(br,1H,NH),11.34(s,1H,OH)；

(E) -3- (8-benzoyl-6- (4-fluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) -6-chlorochroman-2, 4-dione: (nuclear magnetic resonance carbon spectroscopy, deuterated dimethylsulfoxide, Bruker AM600 instrument); 19.0,37.2,39.2,96.1,96.4,115.8(d, J ═ 21Hz),117.8,118.5,121.9,124.8,128.0,128.2,128.5,128.6,132.8,133.3,134.8,137.3,151.8,158.4,162.4(d, J ═ 243Hz),162.9(d, J ═ 220Hz),173.7,189.1;

this example gives 89% yield of (E) -3- (8-benzoyl-6- (4-fluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) -6-chlorochroman-2, 4-dione having a melting point of 270.6 ℃;

high resolution mass spectrum C₂₉H₂₁ClFN₂O₅[M+H]⁺Theory 531.1118; found 531.1116.

Example 19: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

Designated (E) -3- (8- (4-fluorobenzoyl) -6- (4-fluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione as compound 19;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (8- (4-fluorobenzoyl) -6- (4-fluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -subunit) chroman-2, 4-diketone) comprises the following specific steps:

adding 10mL of 1, 4-dioxane serving as a solvent into a 25mL round-bottom flask, and sequentially adding p-fluorobenzoyl formaldehyde hydrate, 6-chloro-4-hydroxycoumarin and 1-phenyl-2- (tetrahydropyrimidine-2 (1H) -ylidene) ethane-1-ketone, wherein the molar ratio of the p-fluorobenzoyl formaldehyde hydrate, the 6-chloro-4-hydroxycoumarin and the 1-phenyl-2- (tetrahydropyrimidine-2 (1H) -ylidene) ethane-1-ketone is 1:1:1, and the mol ratio of the molar amount of a phenylglyoxal derivative (p-fluorobenzoyl formaldehyde hydrate) to the volume of the solvent is 1: 10; stirring and reacting under a reflux condition, detecting and reacting for 10H by adopting TLC (thin layer chromatography), completely reacting raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography separation to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (8- (4-fluorobenzoyl) -6- (4-fluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -subunit) chroman-2, 4-diketone); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

(E) the synthetic reaction formula of the (E) -3- (8- (4-fluorobenzoyl) -6- (4-fluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -ylidene) chroman-2, 4-dione is shown as follows;

(E) -3- (8- (4-fluorobenzoyl) -6- (4-fluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1, 2-a)]Pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione: (hydrogen nuclear magnetic resonance, deuterated dimethylsulfoxide, Bruker AM 500 instrument); delta is 1.89 to 1.98(m,2H, CH)₂),2.92～2.97(m,,1H,NHCH₂),3.50～3.55(m,1H,NHCH₂),3.50～3.55(m,2H,NCH₂),6.97～6.98(m,1H,ArH),7.12～7.20(m,5H,ArH),7.36～7.45(m,1H,ArH),7.73～7.82(m,3H,ArH),9.34(br,1H,NH),11.52(s,1H,OH)；

(E) -3- (8- (4-fluorobenzoyl) -6- (4-fluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione: (nuclear magnetic resonance carbon spectroscopy, deuterated dimethylsulfoxide, Bruker AM 500 instrument); δ 20.1,38.2,40.2,97.2,94.4,116.7,117.3,117.9,121.5,124.7,126.9,129.2(d, J ═ 8.8Hz),129.2(d, J ═ 8.8Hz),132.3(d, J ═ 8.8Hz),134.3,135.3,136.0,154.3,159.4,163.3(d, J ═ 243.8Hz),163.6,165.1,167.0,176.4,188.8;

this example gives 86% yield of (E) -3- (8- (4-fluorobenzoyl) -6- (4-fluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione having a melting point of 247.4 ℃;

high resolution mass spectrum C₂₉H₂₁F₂N₂O₅[M+H]⁺Theory 515.1413; found 515.1413.

Example 20: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

Designated (E) -3- (8- (4-chlorobenzoyl) -6- (3, 4-difluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione as compound 20;

the synthesis method of chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (8- (4-chlorobenzoyl) -6- (3, 4-difluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -subunit) chroman-2, 4-diketone) comprises the following specific steps:

adding 10mL of 1, 4-dioxane serving as a solvent into a 25mL round-bottom flask, and sequentially adding p-fluorobenzoyl formaldehyde hydrate, 4-hydroxycoumarin and 1- (4-fluorophenyl) -2- (tetrahydropyrimidine-2 (1H) -ylidene) ethane-1-ketone, wherein the molar ratio of the p-fluorobenzoyl formaldehyde hydrate, the 4-hydroxycoumarin and the 1- (4-fluorophenyl) -2- (tetrahydropyrimidine-2 (1H) -ylidene) ethane-1-ketone is 1:1:1, and the mol ratio of the molar amount of a benzoylaldehyde derivative (p-fluorobenzoyl formaldehyde hydrate) to the volume of the solvent is 1: 10; stirring and reacting under a reflux condition, detecting and reacting for 10 hours by adopting TLC (thin layer chromatography), completely reacting raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography separation to obtain a chromone-substituted 2-hydroxypyrrole derivative ((E) -3- (8- (4-chlorobenzoyl) -6- (3, 4-difluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -subunit) chroman-2, 4-diketone); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

(E) the synthetic reaction formula of the-3- (8- (4-chlorobenzoyl) -6- (3, 4-difluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7 (6H) -subunit) chroman-2, 4-diketone is shown as follows;

(E) -3- (8- (4-chlorobenzoyl) -6- (3, 4-difluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1, 2-a)]Pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione: (hydrogen nuclear magnetic resonance, deuterated dimethylsulfoxide, Bruker AM 500 instrument); δ is 1.95 to 1.96(m,2H, CH)₂),2.96～3.00(m,1H,NCH₂),3.41～3.55(m,3H,NCH₂,NHCH₂),6.98～7.00(m,1H,ArH),7.13～7.16(m,2H,ArH),7.37～7.46(m,5H,ArH),7.73～7.76(m,3H,ArH),9.39(br,1H,NH),11.57(s,1H,OH)；¹³C NMR(125MHz,DMSO):δ＝19.9,36.5,39.7,95.8,96.0,115.5(d,J＝18.8Hz),116.3,116.8,118.2(d,J＝7.5Hz),120.4,123.0,123.8,125.9,128.7,130.2,133.4,136.3,136.7,137.9,149.5(d,J＝243.8Hz),149.7(d,J＝250Hz),153.3,158.5,162.7,163.4,175.4,187.9；

(E) -3- (8- (4-chlorobenzoyl) -6- (3, 4-difluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione: (nuclear magnetic resonance carbon spectroscopy, deuterated dimethylsulfoxide, Bruker AM 500 instrument); δ 19.9,36.5,39.7,95.8,96.0,115.5(d, J ═ 18.8Hz),116.3,116.8,118.2(d, J ═ 7.5Hz),120.4,123.0,123.8,125.9,128.7,130.2,133.4,136.3,136.7,137.9,149.5(d, J ═ 243.8Hz),149.7(d, J ═ 250Hz),153.3,158.5,162.7,163.4,175.4,187.9;

this example (E) -3- (8- (4-chlorobenzoyl) -6- (3, 4-difluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7 (6H) -ylidene) chroman-2, 4-dione in 80% yield and melting point 219.1 ℃;

high resolution mass spectrum C₂₉H₂₀F₂N₂NaO₅[M+Na]⁺Theoretical, 571.0843, found, 571.0843.

Example 21: the structure of the chromone-substituted 2-hydroxypyrrole derivative of this example is shown in the following formula

Designated 3- (8- (4-chlorobenzoyl) -6- (3, 4-difluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7- (6H) -ylidene) chroman-2, 4-dione as compound 21;

the synthesis method of the chromone-substituted 2-hydroxypyrrole derivative (3- (8- (4-chlorobenzoyl) -6- (3, 4-difluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7- (6H) -subunit) chroman-2, 4-diketone) comprises the following specific steps:

adding 10mL of 1, 4-dioxane serving as a solvent into a 25mL round-bottom flask, and sequentially adding 3, 4-difluorobenzoyl formaldehyde hydrate, 4-hydroxycoumarin and 1- (4-chlorophenyl) -2- (tetrahydropyrimidine-2 (1H) -ylidene) ethane-1-ketone, wherein the molar ratio of the 3, 4-difluorobenzoyl formaldehyde hydrate, the 4-hydroxycoumarin and the 1- (4-chlorophenyl) -2- (tetrahydropyrimidine-2 (1H) -ylidene) ethane-1-ketone is 1:1:1, and the mol ratio of the molar amount of the benzoyl formaldehyde derivative (3, 4-difluorobenzoyl formaldehyde hydrate) to the volume of the solvent is 1: 10; stirring and reacting under a reflux condition, detecting and reacting for 10 hours by adopting TLC (thin layer chromatography), completely reacting raw materials to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying by column chromatography separation to obtain a chromone-substituted 2-hydroxypyrrole derivative (3- (8- (4-chlorobenzoyl) -6- (3, 4-difluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7- (6H) -subunit) chroman-2, 4-diketone); wherein the column chromatography eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 2: 1;

the synthesis reaction formula of 3- (8- (4-chlorobenzoyl) -6- (3, 4-difluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidine-7- (6H) -subunit) chroman-2, 4-diketone is shown as follows;

3- (8- (4-chlorobenzoyl) -6- (3, 4-difluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1, 2-a)]Pyrimidin-7- (6H) -ylidene) chroman-2, 4-dione: (NMR, hydrogen spectrum, deuterated dimethyl sulfoxide, Bruker AM 500 instrument) < delta > 2.02(s,2H, CH2), 3.45-3.54 (m,2H, NCH2), 3.75-7.77 (m,2H, NHCH)₂),6.88～6.89(m,2H,ArH),7.06～7.08(m,2H,ArH),7.13～7.15(m,2H,ArH),7.19～7.30(m,6H,ArH),7.47～7.55(s,1H,ArH),7.55～7.56(m,1H,ArH),7.99(br,1H,NH),10.76(s,1H,OH)；

3- (8- (4-chlorobenzoyl) -6- (3, 4-difluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7- (6H) -ylidene) chroman-2, 4-dione: (NMR carbon Spectroscopy, deuterated dimethylsulfoxide, Bruker AM 500 instrument): δ ═ 21.3,38.3,42.0,100.7,102.2,107.5,115.9,116.0,123.5,124.0,127.01,127.7,127.9,128.0,129.5,131.2,132.2,133.4,141.2,148.7,152.6,161.5,162.1,187.4;

this example provides 87% yield of 3- (8- (4-chlorobenzoyl) -6- (3, 4-difluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7- (6H) -ylidene) chroman-2, 4-dione as shown at 224.3 ℃;

high resolution mass spectrum C₂₉H₂₂ClN₂O₄[M+H]⁺Theory 497.1263; found, 497.1268;

the single crystal structure of 3- (8- (4-chlorobenzoyl) -6- (3, 4-difluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7- (6H) -ylidene) chroman-2, 4-dione of this example is shown in fig. 5. as can be seen from fig. 5, the crystal data and the structure refinement data are shown in table 1, and the single crystal structure is 3- (8- (4-chlorobenzoyl) -6- (3, 4-difluorophenyl) -6-hydroxy-1, 2,3, 4-tetrahydropyrrolo [1,2-a ] pyrimidin-7- (6H) -ylidene) chroman-2, 4-dione;

table 1 crystal data and structure refinement

The chromone-substituted 2-hydroxypyrrole derivatives of examples 1-21 have the structural formulas shown in Table 2;

TABLE 2 chromone-substituted 2-hydroxypyrrole derivatives structural formulas and numbering

Anti-inflammatory effects were measured using NO assay: mouse macrophage strain Raw 264.7 cells were purchased from the U.S. cell bank (ATCC) and cultured in DEME medium containing 10% FBS. Raw 264.7 cells (2X 10)⁵One/well) were inoculated in 24-well plates, while adding different concentrations of the compound, incubated for 24h under 1 μ g/ml LPS stimulation, and a solvent control and a non-irritant background control were added. Centrifuging to collect culture supernatant (5000rpm, 4 deg.C, 5min), and detecting NO in the supernatant by Griess method₂ ^-The specific method comprises the following steps: with NaNO₂Diluting a standard substance in a gradient manner, adding 100 mu l of the standard substance into each hole, adding 100 mu l of a collecting culture medium into each sample hole, then adding 100 mu l of Griess reagent into each hole, oscillating, detecting absorbance at 540nm of an enzyme-labeling instrument, calculating the NO content of different sample holes according to the obtained standard curve, and calculating the inhibition rate of a compound, wherein the inhibition rate of NO is (the concentration of NO in a combined action group-the concentration of NO in an LPS group)/the concentration of NO in the LPS group multiplied by 100%;

the anti-inflammatory activity test of the chromone-substituted 2-hydroxypyrrole derivatives synthesized in examples 1-21 showed that the chromone-substituted 2-hydroxypyrrole derivatives synthesized in examples 1-21 have better anti-inflammatory activity against mouse macrophage strain Raw 264.7 (see Table 3),

TABLE 3 chromonyl-substituted 2-hydroxypyrrole derivatives have inhibitory activity on mouse macrophage strain Raw 264.7

As can be seen from Table 3, IC of Compound 9₅₀(μmol/L) 8.91; IC of Compound 11₅₀(μmol/L) 8.40; IC of Compound 13₅₀(μmol/L) 3.41; IC of Compound 15₅₀(μmol/L) 7.07; IC of Compound 18₅₀(. mu. mol/L) 7.63, IC of these five compounds₅₀The concentration of the five compounds is less than 10 mu mol/L, and the five compounds show more excellent anti-inflammatory activity; and the IC50 of the

compounds

10, 12, 14, 19 and 21 is less than 20 mu mol/L, which shows that the five compounds have good anti-inflammatory activity.

The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims

1. Chromone-substituted 2-hydroxypyrrole derivatives, wherein the structural formula of the derivatives is shown in formula (I):

wherein n is 0 or 1;

r is hydrogen, fluorine, chlorine or methyl;

R¹is hydrogen or fluorine;

R²is hydrogen, fluorine, chlorine or bromine;

2. The method for synthesizing chromone-substituted 2-hydroxypyrrole derivatives according to claim 1, comprising the following steps:

adding a benzoylformaldehyde derivative, a coumarin derivative and heterocyclic ketene aminal into a solvent, stirring and reacting for 8-24 hours at the temperature of 70-120 ℃ to obtain a reaction liquid, cooling the reaction liquid to room temperature, and purifying to obtain a chromone-substituted 2-hydroxypyrrole derivative with the structure of formula (I); wherein the structural formula of the benzoyl formaldehyde derivative is shown as a formula (II), the structural formula of the coumarin derivative is shown as a formula (III), the structural formula of the heterocyclic ketene aminal is shown as a formula (IV),

in formula (II), R is hydrogen, fluorine, chlorine or methyl;

R¹is hydrogen or fluorine;

in the formula (III), R²Hydrogen, fluorine, chlorine or bromine;

in formula (IV), n is 0 or 1;

3. The method of synthesis as claimed in claim 2, wherein: the solvent is 1, 4-dioxane, ethanol, hydrogen peroxide or water.

4. The method of synthesis as claimed in claim 2, wherein: the molar ratio of the benzoyl formaldehyde derivative to the coumarin derivative to the heterocyclic ketene aminal is 1:1: 1.

5. The method of synthesis as claimed in claim 2, wherein: the purification treatment is column chromatography separation or recrystallization.

6. The method of synthesis of claim 5, wherein: the eluent for column chromatographic separation is dichloromethane/petroleum ether mixed solvent, ethyl acetate/petroleum ether mixed solvent or ethyl acetate/acetone mixed solvent.

7. The method of synthesis of claim 5, wherein: the solvent for recrystallization is a dichloromethane/petroleum ether mixed solvent or an ethyl acetate/petroleum ether mixed solvent.

8. Use of the chromone-substituted 2-hydroxypyrrole derivatives of claim 1 in the preparation of anti-inflammatory drugs.