3-methylene-2, 3-dihydro-4-quinolinone derivative as well as synthesis method and application thereof

Abstract

The invention relates to a 3-methylene-2, 3-dihydro-4-quinolinone derivative and a synthetic method and application thereof.The synthetic method includes the steps that S1, an o-iodine / bromaniline derivative 2 and propargyl alcohol are subjected to a Sonogashira coupling reaction, and a 3-(2-aminophenyl) propane-2-alkyne-1-alcohol derivative 3 is obtained; s2, under the action of pyridine, the 3-(2-aminophenyl) propan-2-alkyne-1-alcohol derivative 3 and sulfonyl chloride are subjected to a reaction, and a sulfonyl protected 3-(2-aminophenyl) propan-2-alkyne-1-alcohol derivative 4 is obtained; and S3, carrying out Meyer-Schuster rearrangement reaction on three components, namely the 3-(2-aminophenyl) propane-2-alkyne-1-alcohol derivative 4 protected by sulfonyl, an aldehyde compound with R1 and trimethyl orthoformate, so as to obtain the 3-methylene-2, 3-dihydro-4-quinolinone derivative 1, namely, the 3-(2-aminophenyl) propane-2-alkyne-1-alcohol derivative 4 protected by sulfonyl, an aldehyde compound with R1 and trimethyl orthoformate. Compared with the prior art, the 3-methylene-2, 3-dihydro-4-quinolinone derivative disclosed by the invention is a neuraminidase inhibitor with a novel structure, can be applied to the anti-cancer, antibacterial and antiviral fields and the like, and is simple in synthetic route, simple in steps and convenient to operate.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a 3-methylene-2,3-dihydro-4-quinolinone derivative, a synthesis method and application thereof. Background Art

[0002] 3-Methylene-2,3-dihydro-4-quinolinone derivatives are a class of heterocyclic compounds with significant biological activity, demonstrating significant potential in anticancer, antibacterial, and antiviral applications. For example, AJ-374, a 3-methylene-2,3-dihydro-4-quinolinone compound, has been shown to induce apoptosis in HL-60 leukemia cells, activate the caspase pathway, disrupt mitochondrial membrane potential, and modulate the MAPK signaling pathway, thereby exhibiting anticancer effects.

[0003] The synthetic route of AJ-374 is as follows Figure 1 As shown: Methyl 2-(p-toluenesulfonylamino)benzoate 2 is prepared from anthranilic acid. In the presence of three equivalents of LDA, diethyl methylphosphonate 1 reacts with methyl 2-(p-toluenesulfonylamino)benzoate 2 to produce diethyl 2-oxo-2-(2-N-p-toluenesulfonylphenyl)ethylphosphonate 3. This 3 is condensed with propionaldehyde and then undergoes intramolecular cyclization to yield 3-(diethoxyphosphoryl)-2-ethyl-1-p-toluenesulfonyl-1,2-dihydroquinolin-4-ol 4. Finally, the HWE reaction converts 4 into AJ-374. This synthetic method is lengthy, complex, and inconvenient to operate, as each step involves specific functional group reactions. The raw materials include a phosphine-containing reagent (Me-P(O)(OEt)2), a methyl anthranilate derivative (2, containing a Ts protecting group), and the strong base LDA (lithium diisopropylamide), all of which require a strict anhydrous and oxygen-free environment, making industrial scale-up difficult. If the substrate contains other sensitive groups (such as additional hydroxyl or carbonyl groups), it is easily affected by strong bases (LDA) and formaldehyde, and functional group compatibility is relatively limited. Summary of the Invention

[0004] The present invention aims to overcome the shortcomings of the prior art, such as lengthy synthetic routes, complex steps, inconvenient operation, and low functional group compatibility, by providing a 3-methylene-2,3-dihydro-4-quinolinone derivative, its synthesis method, and its application. The present invention features milder reaction conditions (low energy consumption, ease of operation), simpler steps, and strong functional group compatibility, making it suitable for rapid laboratory preparation and possessing potential for industrial scalability.

[0005] The purpose of the present invention can be achieved by the following technical solutions:

[0006] One of the technical solutions of the present invention is to provide a 3-methylene-2,3-dihydro-4-quinolinone derivative, the structural formula of which is shown in formula (1):

[0007]

[0008] wherein R is substituted at the 5, 6, 7 or 8 position of the quinolinone ring, and R is selected from any one of methyl, methoxy, tert-butyl, hydrogen, halogen;

[0009] R 1 selected from the group consisting of phenyl; 2-naphthyl; 2-thienyl; cyclohexyl; C1-6 alkyl; substituted phenyl, the 2-, 3- or 4-position of the phenyl ring is substituted by one or more substituents independently selected from methyl, methoxy, cyano, halogen;

[0010] R 2 selected from the group consisting of phenyl; C1-6 alkyl; substituted phenyl, the 2-, 3- or 4-position of the phenyl ring is substituted by one or more substituents independently selected from methyl, methoxy, cyano, halogen.

[0011] Further, the halogen includes fluorine, chlorine, bromine, iodine.

[0012] Further, the C1-6 alkyl refers to a straight chain or branched chain saturated hydrocarbon group with carbon atom number of 1 to 6 (general formula -C n H 2n+1 ).

[0013] Further, the C1-6 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, sec-pentyl, n-hexyl, isohexyl, tert-hexyl.

[0014] The second technical solution of the present application provides a synthesis method of 3-methylene-2,3-dihydro-4-quinolinone derivative, comprising the following steps:

[0015] S1, o-iodo / bromo aniline derivative 2 is coupled with propargyl alcohol by Sonogashira coupling reaction to obtain 3-(2-aminophenyl)prop-2-yn-1-ol derivative 3;

[0016] S2, under the action of pyridine, 3-(2-aminophenyl)prop-2-yn-1-ol derivative 3 is reacted with sulfuryl chloride to obtain sulfuryl-protected 3-(2-aminophenyl)prop-2-yn-1-ol derivative 4;

[0017] S3, sulfuryl-protected 3-(2-aminophenyl)prop-2-yn-1-ol derivative 4, aldehyde compound with R 1 , and trimethyl orthoformate are subjected to three-component Meyer-Schuster rearrangement reaction to obtain 3-methylene-2,3-dihydro-4-quinolinone derivative 1;

[0018] The structural formula of the o-iodine / bromoaniline derivative 2 is shown in formula (2), the structural formula of the 3-(2-aminophenyl)prop-2-yn-1-ol derivative 3 is shown in formula (3), and the structural formula of the sulfonyl-protected 3-(2-aminophenyl)prop-2-yn-1-ol derivative 4 is shown in formula (4);

[0019] Wherein, in formula (2), (3) and (4), the 2-position, 3-position or 4-position of the benzene ring is substituted by one or more independent R groups, and X is iodine or bromine;

[0020]

[0021] Furthermore, in step S1, the molar ratio of the o-iodine / bromoaniline derivative 2 to the propargyl alcohol is 1:1-1.5, preferably 1:1.1-1.3;

[0022] In step S2, the molar ratio of the 3-(2-aminophenyl)prop-2-yn-1-ol derivative 3 to the sulfonyl chloride is 1:1 to 1.5, preferably 1:1.1 to 1.3;

[0023] In step S3, the sulfonyl-protected 3-(2-aminophenyl)prop-2-yn-1-ol derivative 4, with R 1 The molar ratio of the aldehyde compound to trimethyl orthoformate is 1:1-2:1-2, preferably 1:1.2-1.8:1.2-1.8.

[0024] Furthermore, the specific process of step S1 is: under nitrogen protection, the o-iodine / bromoaniline derivative 2, the first organic solvent, the first catalyst, and the co-catalyst are mixed, propargyl alcohol is added dropwise in an ice-water bath, and heated at 50-60° C. until the o-iodine / bromoaniline derivative 2 is completely converted.

[0025] Furthermore, the first organic solvent includes triethylamine;

[0026] The first catalyst includes bistriphenylphosphine palladium chloride (Pd(PPh3)2Cl2);

[0027] The co-catalyst includes cuprous iodide (CuI);

[0028] The usage ratio of the o-iodine / bromoaniline derivative 2, the first catalyst, the co-catalyst and the first organic solvent is 1 mmol: 0.01-0.5 mmol: 0.01-0.1 mmol: 1-2 mL, preferably 1 mmol: 0.05-0.3 mmol: 0.02-0..8 mmol: 1.2-1.8 mL.

[0029] Furthermore, the specific process of step S2 is: under ice-water bath conditions, 3-(2-aminophenyl)prop-2-yn-1-ol derivative 3 and pyridine are added to the second organic solvent, sulfonyl chloride is added dropwise, and the reaction is stirred at room temperature until the 3-(2-aminophenyl)prop-2-yn-1-ol derivative 3 is completely reacted.

[0030] Furthermore, the second organic solvent comprises dichloromethane (DCM);

[0031] The usage ratio of the 3-(2-aminophenyl)prop-2-yn-1-ol derivative 3, pyridine, and the second organic solvent is 1 mmol: 1-5 mmol: 0.5-5 mL, preferably 1 mmol: 2-4 mmol: 1-3 mL.

[0032] Furthermore, the specific process of step S3 is as follows: sulfonyl protected 3-(2-aminophenyl)prop-2-yn-1-ol derivative 4, with R 1 An aldehyde compound, trimethyl orthoformate, a second catalyst, and a third organic solvent are mixed and reacted at room temperature until the 3-(2-aminophenyl)prop-2-yn-1-ol derivative 4 is completely reacted.

[0033] Furthermore, the second catalyst includes trifluoromethanesulfonic acid (TfOH);

[0034] The third organic solvent includes dichloromethane (DCM), nitromethane (CH3NO2), 1,4-dioxane (Dioxane), CH3OH, acetonitrile (CH3CN), toluene (Toluene), tetrahydrofuran (THF), 1,2-dichloroethane (DCE);

[0035] The usage ratio of the sulfonyl-protected 3-(2-aminophenyl)prop-2-yn-1-ol derivative 4, the second catalyst, and the third organic solvent is 1 mmol: 0.01-0.05 mmol: 0.1-10 mL, preferably 1 mmol: 0.02-0.04 mmol: 2-8 mL.

[0036] Furthermore, the trimethyl orthoformate (CH(OCH3)3) can be replaced by triethyl orthoformate (CH(OC2H5)3), tripropyl orthoformate (CH(OC3H7)3), methanol (CH3OH), ethanol (CH3CH2OH), and propylthiol (CH3CH2CH2SH), with trimethyl orthoformate having the best effect.

[0037] The third technical solution of the present invention is to provide an application of a 3-methylene-2,3-dihydro-4-quinolinone derivative in the preparation of a neuraminidase inhibitor. The neuraminidase inhibitor prepared from the 3-methylene-2,3-dihydro-4-quinolinone derivative exhibits neuraminidase inhibitory activity and can be used in the fields of anti-cancer, antibacterial and antiviral.

[0038] Compared with the prior art, the present invention has the following advantages:

[0039] (1) The 3-methylene-2,3-dihydro-4-quinolinone derivatives provided by the present invention are a class of novel neuraminidase inhibitors that can be used in the fields of anticancer, antibacterial and antiviral. It has not been reported that such structural compounds can be used as neuraminidase inhibitors.

[0040] (2) The present invention will have R 1 The acetal generated by the aldehyde compound and trimethyl orthoformate is introduced into the Meyer-Schuster rearrangement reaction as an electrophilic breaking reagent to realize the three-component reaction of propargyl alcohol, aldehyde compound and trimethyl orthoformate, thereby efficiently constructing 3-methylene-2,3-dihydro-4-quinolinone derivatives in one pot. The synthetic route is simple, the steps are simple, the operation is convenient and the reaction conditions are mild.

[0041] (3) The preparation method of the present invention has cheap and readily available raw materials, mild reaction conditions, and a wide range of substrate applications.

[0042] (4) The present invention prepares a 3-methylene-2,3-dihydro-4-quinolinone derivative through three steps of Sonogashira coupling → nitrogen sulfonyl protection → Meyer-Schuster rearrangement reaction. 2 SO2 can be flexibly selected to adapt to different subsequent reaction requirements; Sonogashira coupling has good compatibility with aromatic ring substituents (R, X) (X = common halogen atoms such as Br, I, R = alkyl, alkoxy, etc.), and is more suitable for diversified substrate expansion. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 The synthetic route of AJ-374;

[0044] Figure 2 This is the synthetic route of the 3-methylene-2,3-dihydro-4-quinolinone derivative of the present invention, comprising step a (1), step b (2), and step c (3);

[0045] Figure 3 is the H NMR spectrum of the 3-methylene-2,3-dihydro-4-quinolinone derivative shown in Example 1;

[0046] Figure 4Carbon spectrum nuclear magnetic resonance spectrum of the 3-methylene-2,3-dihydro-4-quinolinone derivative shown in Example 1. DETAILED DESCRIPTION

[0047] The application will be described in detail below with reference to the drawings and specific examples. The examples are implemented on the premise of the technical solutions of the application, and detailed implementation and specific operation processes are given, but the protection scope of the application is not limited to the examples below. All other examples obtained by those skilled in the art on the premise that no creative work is done based on the examples given are within the scope of protection of the application.

[0048] Unless otherwise specified, the reagents, methods, instruments and equipment used in the application are conventional reagents, methods, instruments and equipment in the art.

[0049] The original formic acid trimethyl ester, aldehyde, Pd(PPh3)2Cl2, triflic acid and other drugs and reagents used in the following examples are purchased from Shanghai Titan Technology Co., Ltd.

[0050] The equipment and manufacturer information used in the following examples are as follows: the stirrer is a Shanghai Meiyinqiu MYPII-2 constant temperature magnetic stirrer; the circulating water pump is a Shanghai Yukang circulating multi-purpose vacuum pump SHB-IIIA; the rotary evaporator is a Shanghai Yukang rotary evaporator W.S206B; and the oil pump is a Shanghai Yukang 2XZ-2 rotary vane vacuum pump.

[0051] A synthesis method of a 3-methylene-2,3-dihydro-4-quinolinone derivative, comprising the following steps, as shown in Figure 2

[0052] (1) Synthesis of 3-(2-aminophenyl)prop-2-yn-1-ol derivative 3:

[0053] Under nitrogen protection, 10 mmol, 15 mmol of triethylamine, 1 mmol of Pd(PPh3)2Cl2, and 0.5 mmol of CuI are sequentially added to a reaction bottle. Then, 12 mmol of propargyl alcohol is slowly added dropwise in an ice water bath at 0°C. The reaction system is heated at 55°C until thin layer chromatography detects that the o-iodo / bromo aniline derivative 2 is completely converted. After the reaction is completed, the reaction mixture is naturally cooled to room temperature, and then quenched with an ammonium chloride solution, extracted with ethyl acetate (EtOAc) three times (3×7 mL), and dried with anhydrous sodium sulfate (Na2SO4). After the extract is concentrated under reduced pressure, it is purified by silica gel column chromatography (a mixture of petroleum ether and ethyl acetate (4:1) as the developing agent) to obtain the unprotected 3-(2-aminophenyl)prop-2-yn-1-ol derivative 3. The yield of this step is 80% to 95%.

[0054] ​(2) Synthesis of sulfonyl-protected 3-(2-aminophenyl)prop-2-yn-1-ol derivative 4:

[0055] In a 0°C ice-water bath, unprotected 3-(2-aminophenyl)prop-2-yn-1-ol derivative 3 (10 mmol) and pyridine (30 mmol) were added to a dry DCM (20 mL) solution, and 12 mmol of sulfonyl chloride was slowly added dropwise. The reaction was stirred at room temperature until complete conversion of the o-anilinopropargyl alcohol was detected by TLC. After completion, the reaction was quenched with aqueous ammonium chloride and extracted with EtOAc (3 × 5 mL). The extract was washed with saturated brine (3 × 5 mL) and dried over anhydrous Na2SO4. Finally, the product was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate as eluent) to obtain the nitrogen sulfonyl-protected 3-(2-aminophenyl)prop-2-yn-1-ol derivative 4. This represents the synthesis of the sulfonyl-protected 3-(2-aminophenyl)prop-2-yn-1-ol derivative 4. The yield of this step is 85% to 98%.

[0056] (3) Synthesis of 3-methylene-2,3-dihydro-4-quinolinone derivative 1:

[0057] In a 15 mL reaction tube, sulfonyl-protected 3-(2-aminophenyl)prop-2-yn-1-ol derivative 4 (0.1 mmol), trimethyl orthoformate (0.15 mmol), R 1 The aldehyde compound (0.15 mmol), DCM (0.5 mL), and CH(OCH3)3 (0.003 mmol) were added. The reaction mixture was allowed to react at room temperature for a three-component Meyer-Schuster rearrangement to afford the 3-methylene-2,3-dihydro-4-quinolinone derivative 1. TLC confirmed the complete reaction of the sulfonyl-protected 3-(2-aminophenyl)prop-2-yn-1-ol derivative 4. The reaction was quenched with saturated sodium bicarbonate solution (2.0 mL) and extracted with ethyl acetate (3 × 10 mL). The extract was washed with saturated brine (1.0 mL) and dried over anhydrous sodium sulfate (Na2SO4). Finally, the product was concentrated under reduced pressure to afford a residue. The residue was purified by flash column chromatography using a mixture of petroleum ether and ethyl acetate (PE:EA 4:1) as the mobile phase to afford the desired product, 3-methylene-2,3-dihydro-4-quinolinone derivative 1. The yield of this step was 48% to 93%.

[0058] The structural formula of 3-methylene-2,3-dihydro-4-quinolinone derivative 1 is shown in formula (1):

[0059]

[0060]

[0061] wherein R is substituted at position 5, 6, 7 or 8 of quinolinone, and R is selected from any one of methyl, methoxy, tert-butyl, hydrogen and halogen;

[0062] R 1 Selected from the group consisting of: phenyl; 2-naphthyl; 2-thienyl; cyclohexyl; C1-6 alkyl; substituted phenyl, wherein the 2-position, 3-position or 4-position of the phenyl ring is substituted by one or more substituents independently selected from methyl, methoxy, cyano and halogen;

[0063] R 2 Selected from the group consisting of: phenyl; C1-6 alkyl; substituted phenyl, wherein the 2-position, 3-position or 4-position of the phenyl ring is substituted by one or more substituents independently selected from methyl, methoxy, cyano, and halogen. The halogen includes fluorine, chlorine, bromine, and iodine. The C1-6 alkyl refers to a straight-chain or branched saturated hydrocarbon group with 1 to 6 carbon atoms (general formula -C n H 2n+1 The C1-6 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, sec-pentyl, n-hexyl, isohexyl, and tert-hexyl.

[0064] The present invention adopts the above reaction to obtain a series of compounds of formula (1), whose structural formulas, H-NMR spectrum data, and step-by-step yields are listed in Examples 1 to 10 of Table 1.

[0065] The prepared 3-methylene-2,3-dihydro-4-quinolinone derivative 1 was tested for neuraminidase inhibitory activity.

[0066] The 3-methylene-2,3-dihydro-4-quinolinone derivative 1 sample was diluted with dimethyl sulfoxide (DMSO) to the preset test concentration (5×10 -3 mol / L、5×10 -4 mol / L、5×10 -5 mol / L、5×10 -6mol / L). The reaction system was constructed in a 96-well fluorescence enzyme plate: 70 μL of neuraminidase detection buffer, 10 μL of neuraminidase solution, 5 μL of Milli-Q ultrapure water, and 5 μL of the neuraminidase inhibitor sample solution to be screened were sequentially added to each well, and three groups of blank control experiments (containing only buffer, enzyme, and substrate, without 3-methylene-2,3-dihydro-4-quinolinone derivative 1 sample) were set. After mixing by a room temperature shaker, incubation was performed at 37°C for 2 minutes to allow the enzyme and the inhibitor to fully interact. Subsequently, 10 μL of the neuraminidase fluorescence substrate solution was added to each well, and the mixture was again mixed by shaking, and incubation was continued at 37°C for 30 minutes. After incubation, the fluorescence intensity (RFU) was measured using a fluorescence microplate reader, with the detection parameters set to an excitation wavelength of 322 nm and an emission wavelength of 450 nm. The inhibition rate of each concentration gradient sample was calculated based on the detection results, and non-linear fitting was performed using Origin software to obtain the corresponding IC 50 values, which are listed in Table 1.

[0067] Table 1: Structural formula, nuclear magnetic hydrogen spectrum data, step yield, and IC 50 value of Examples 1-10

[0068]

[0069]

[0070]

[0071] Note: Ts is the standard abbreviation for p-toluenesulfonyl (Tosyl), with the chemical formula p-CH3-C6H4-SO2 + .

[0072] Figure 3 and 4 The hydrogen spectrum and carbon spectrum nuclear magnetic spectrum of Example 1 are shown in the above table. The structure of 3-methylene-2,3-dihydro-4-quinolinone derivative 1 obtained in Example 1 is verified.

[0073] In summary, the yield of each step of the present application is relatively excellent and is at a leading level. The route of the present application is simple, the raw materials are easy to obtain, and except for the synthesis of the raw material alkyne alcohol which requires nitrogen protection, the other steps do not require anhydrous and anaerobic environment, there is no complex operation, the reaction conditions are milder (low energy consumption, easy operation), the steps are more concise, and the functional group compatibility is strong, which is suitable for rapid preparation in the laboratory and also has potential for industrialization. The substrate has wide applicability and can synthesize dozens of derivatives, and the above examples only select ten compounds. The present application prepares a kind of 3-methylene-2,3-dihydro-4-quinolinone derivative through Sonogashira coupling, nitrogen sulfonyl protection, and Meyer-Schuster rearrangement reaction. The protecting group R2 SO2 can be flexibly selected to adapt to different subsequent reaction requirements; Sonogashira coupling has good compatibility with aromatic ring substituents (R, X) (X = common halogen atoms such as Br, I, R = alkyl, alkoxy, etc.), and the condensation ring closure only involves the reaction of aldehydes, ketals and alkynols / protected amino groups, with less functional group interference, which is more suitable for diversified substrate expansion.

[0074] Although the present invention has been described in detail above using general explanations, specific embodiments, and experiments, it will be apparent to those skilled in the art that modifications and improvements may be made based on the present invention. Therefore, such modifications and improvements, which do not depart from the spirit of the present invention, are intended to be within the scope of protection claimed herein.

Claims

1. A 3-methylene-2,3-dihydro-4-quinolinone derivative, characterized in that: Its structural formula is shown in formula (1): wherein R is substituted at position 5, 6, 7 or 8 of quinolinone, and R is selected from any one of methyl, methoxy, tert-butyl, hydrogen and halogen; R 1 Selected from the group consisting of: phenyl; 2-naphthyl; 2-thienyl; cyclohexyl; C1-6 alkyl; substituted phenyl, wherein the 2-position, 3-position or 4-position of the phenyl ring is substituted by one or more substituents independently selected from methyl, methoxy, cyano and halogen; R 2 Selected from the group consisting of: phenyl; C1-6 alkyl; substituted phenyl, wherein the 2-position, 3-position or 4-position of the phenyl ring is substituted by one or more substituents independently selected from methyl, methoxy, cyano and halogen.

2. The method for synthesizing a 3-methylene-2,3-dihydro-4-quinolinone derivative according to claim 1, wherein: The following steps are involved: S1, o-iodine / bromoaniline derivative 2 and propargyl alcohol were reacted by Sonogashira coupling to give 3-(2-aminophenyl)prop-2-yn-1-ol derivative 3; S2. Under the action of pyridine, 3-(2-aminophenyl)prop-2-yn-1-ol derivative 3 reacts with sulfonyl chloride to obtain sulfonyl-protected 3-(2-aminophenyl)prop-2-yn-1-ol derivative 4; S3, sulfonyl protected 3-(2-aminophenyl)prop-2-yn-1-ol derivatives 4, with R 1 The aldehyde compound and trimethyl orthoformate were subjected to a three-component Meyer-Schuster rearrangement reaction to obtain 3-methylene-2,3-dihydro-4-quinolinone derivative 1; The structural formula of the o-iodine / bromoaniline derivative 2 is shown in formula (2), the structural formula of the 3-(2-aminophenyl)prop-2-yn-1-ol derivative 3 is shown in formula (3), and the structural formula of the sulfonyl-protected 3-(2-aminophenyl)prop-2-yn-1-ol derivative 4 is shown in formula (4); Wherein, in formula (2), (3) and (4), the 2-position, 3-position or 4-position of the benzene ring is substituted by one or more independent R groups, and X is iodine or bromine; 3. The method for synthesizing a 3-methylene-2,3-dihydro-4-quinolinone derivative according to claim 2, wherein: In step S1, the molar ratio of the o-iodine / bromoaniline derivative 2 to propargyl alcohol is 1:1 to 1.5; In step S2, the molar ratio of the 3-(2-aminophenyl)prop-2-yn-1-ol derivative 3 and sulfonyl chloride is 1:1 to 1.5; In step S3, the sulfonyl-protected 3-(2-aminophenyl)prop-2-yn-1-ol derivative 4, with R 1 The molar ratio of the aldehyde compound and trimethyl orthoformate is 1:1~2:1~2.

4. The method for synthesizing a 3-methylene-2,3-dihydro-4-quinolinone derivative according to claim 2, wherein: The specific process of step S1 is as follows: under nitrogen protection, the o-iodine / bromoaniline derivative 2, the first organic solvent, the first catalyst, and the co-catalyst are mixed, propargyl alcohol is added dropwise in an ice-water bath, and the mixture is heated at 50-60° C. until the o-iodine / bromoaniline derivative 2 is completely converted.

5. The method for synthesizing a 3-methylene-2,3-dihydro-4-quinolinone derivative according to claim 4, wherein: The first organic solvent includes triethylamine; The first catalyst comprises Pd(PPh3)2Cl2; The co-catalyst includes CuI; The usage ratio of the o-iodine / bromoaniline derivative 2, the first catalyst, the co-catalyst, and the first organic solvent is 1 mmol: 0.01-0.5 mmol: 0.01-0.1 mmol: 1-2 mL.

6. The method for synthesizing a 3-methylene-2,3-dihydro-4-quinolinone derivative according to claim 2, characterized in that: The specific process of step S2 is as follows: under ice-water bath conditions, 3-(2-aminophenyl)prop-2-yn-1-ol derivative 3 and pyridine are added to a second organic solvent, sulfonyl chloride is added dropwise, and the reaction is stirred at room temperature until the 3-(2-aminophenyl)prop-2-yn-1-ol derivative 3 is completely reacted.

7. The method for synthesizing a 3-methylene-2,3-dihydro-4-quinolinone derivative according to claim 6, wherein: The second organic solvent comprises DCM; The usage ratio of the 3-(2-aminophenyl)prop-2-yn-1-ol derivative 3, pyridine, and the second organic solvent is 1 mmol: 1-5 mmol: 0.5-5 mL.

8. The method for synthesizing a 3-methylene-2,3-dihydro-4-quinolinone derivative according to claim 2, characterized in that: The specific process of step S3 is: sulfonyl protected 3-(2-aminophenyl) prop-2-yn-1-ol derivative 4, with R 1 An aldehyde compound, trimethyl orthoformate, a second catalyst, and a third organic solvent are mixed and reacted at room temperature until the 3-(2-aminophenyl)prop-2-yn-1-ol derivative 4 is completely reacted.

9. The method for synthesizing a 3-methylene-2,3-dihydro-4-quinolinone derivative according to claim 8, wherein: The second catalyst comprises TfOH; The third organic solvent includes DCM, CH3NO2, Dioxane, MeOH, CH3CN, Toluene, THF, DCE; The usage ratio of the sulfonyl-protected 3-(2-aminophenyl)prop-2-yn-1-ol derivative 4, the second catalyst, and the third organic solvent is 1 mmol: 0.01-0.05 mmol: 0.1-10 mL.

10. Use of the 3-methylene-2,3-dihydro-4-quinolinone derivative according to claim 1 in the preparation of a neuraminidase inhibitor.

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