2-quinolinone compound and a method for synthesizing the same

Abstract

The application belongs to the technical field of nitrogen-containing heterocyclic compounds, and aims at solving the problems of weak substrate adaptability and non-green and non-environmental oxidation agent in the prior art, and provides a 2-quino line ketone compound and a synthesis method thereof.The synthesis method comprises the following steps: S1, taking 2-amino benzyl alcohol as raw material, and synthesizing 2-benzyl alcohol amide intermediate; and S2, taking the 2-benzyl alcohol amide intermediate as raw material, and synthesizing quinolinone compound through KMnO4 and CH2Cl2 system action and one-pot oxidation tandem Knoevenagel condensation reaction.23 2-benzyl alcohol amide key intermediates are synthesized by taking 2-amino benzyl alcohol as raw material, and taking monoethyl malonate and monomethyl malonate as amide reagents respectively. In the application, the green oxidation agent KMnO4 is used in the synthesis of 2-(1H)-quinolinone, the oxidation agent is stable in performance, and is common and easy to obtain; secondly, the one-pot method is used to synthesize 2-(1H)-quinolinone, which has the advantages of short steps, good reproducibility and the like; in addition, it is found in the mechanism verification experiment of the reaction that KMnO4 has a certain catalytic effect on Knoevenagel condensation.

Description

Technical Field

[0001] This invention belongs to the field of nitrogen-containing heterocyclic compound technology, specifically relating to a 2-quinolinone compound and its synthesis method. Background Technology

[0002] Quinolinones and their derivatives are a very important class of nitrogen-containing heterocyclic compounds. Their skeletal structures are widely found in natural products or pharmaceutically active molecules. Molecules containing quinolinone skeletons also possess broad-spectrum pharmacological activities and can be used as anticancer, antibacterial, and antituberculosis drugs. Numerous drugs containing quinolinone structural fragments are used clinically, such as aripiprazole (an atypical psychiatric drug), rebapide (a drug for treating gastric ulcers and chronic gastritis), and telbifabide (a drug for treating myeloma). In addition, quinolinones are also important fluorophores, and their derivatives can be used as fluorescent probes to detect and identify metal cations and small biological molecules such as biothiols. Development and research in this field are increasingly active and rapidly progressing. They exhibit unique properties in many fields such as medicine, biology, and fluorescent materials, and have very wide applications. Among them, 2-(1H)-quinolinone compounds have received widespread attention due to their excellent biological and pharmacological activities and their applications in clinical drugs.

[0003] Quinolinones are an important structural unit found in many drugs, and their synthesis and application have been studied continuously for decades, remaining a research hotspot. Many of these compounds possess significant biological activities, playing important roles in antibacterial, anti-inflammatory, anthelmintic, and antifungal activity. Substituted 2-quinolinones have also been found to possess potential biological activities. Therefore, the synthesis of substituted 2-quinolinone compounds is of great significance for the search for new drug lead compounds.

[0004] Based on a review of previous literature on the synthesis of 2-(1H)-quinolinone, there are roughly two methods: The first method involves a two-step synthesis of the quinolinone skeleton, which first involves the condensation of 2-aminobenzophenone and malonic acid monoethyl ester chloride under the action of a base, followed by a reaction under the action of a strong base to obtain the quinolinone skeleton; The second method involves reacting aminobenzyl alcohol with malonic acid monoethyl ester chloride to obtain an intermediate, followed by oxidative condensation with 3 eq. activated manganese dioxide. However, the manganese dioxide in this method is not stable enough, and only one product is synthesized, resulting in poor substrate adaptability. Summary of the Invention

[0005] To overcome the problems in the prior art, this invention synthesizes a 2-benzyl alcohol amide intermediate from 2-aminobenzyl alcohol and malonic acid monoethyl ester chloride, followed by a one-pot oxidative tandem Norvongel condensation reaction promoted by KMnO4 to obtain the 2-(1H)-quinolinone skeleton. The effects of the type and amount of oxidant, solvent, temperature, and concentration on the reaction yield were analyzed experimentally. The results show that the ideal reaction conditions are: 2-benzyl alcohol amide intermediate (1.0 equiv), KMnO4 (0.5 mmol), CH2Cl2 (0.3 M), reaction temperature 50 °C, reaction time 15 h, and a separation yield of 71%.

[0006] To achieve the aforementioned technical effects, this invention provides a 2-quinolinone compound with the following structural formula: .

[0007] Another aspect of the present invention provides a method for synthesizing 2-quinolinone compounds, comprising: S1: Using 2-aminobenzyl alcohol as a raw material, synthesize 2-benzyl alcohol amide intermediate; S2: Quinolinone compounds were synthesized from 2-benzyl alcohol amide intermediate, KMnO4 and CH2Cl2 using a one-pot oxidative tandem Knoevenagel condensation reaction.

[0008] 3. The method for synthesizing a 2-quinolinone compound according to claim 2, characterized in that the 2-benzyl alcohol amide intermediate of S1 is any one of aryl-substituted 2-benzyl alcohol amide intermediate, benzyl alcohol-substituted 2-benzyl alcohol amide intermediate, N-substituted 2-benzyl alcohol amide intermediate or 2a-23.

[0009] The preferred method for synthesizing the aryl-substituted 2-benzyl alcohol amide intermediate is as follows: After adding aryl-substituted 2-aminobenzyl alcohol, imidazole and CH2Cl2 to a round-bottom flask equipped with a magnetic stirrer, magnetic stirring was started at room temperature. Weigh out monoethyl malonate chloride, dilute it with CH2Cl2, and add it dropwise to the reaction system using a glass dropper to carry out the reaction. After the reaction was completed, the product was extracted with CH2Cl2, dried with anhydrous Na2SO4, filtered, concentrated under vacuum, and then separated by column chromatography to obtain the aryl-substituted 2-benzyl alcohol amide intermediate. When aryl-substituted 2-aminobenzyl alcohol is 2-aminobenzyl alcohol, the intermediate of aryl-substituted 2-benzyl alcohol amide is 2a-1; when aryl-substituted 2-aminobenzyl alcohol is 3-methyl-2-aminobenzyl alcohol, the intermediate of aryl-substituted 2-benzyl alcohol amide is 2a-2; when aryl-substituted 2-aminobenzyl alcohol is substituted 4-methyl-2-aminobenzyl alcohol, the intermediate of aryl-substituted 2-benzyl alcohol amide is 2a-3 to 2a-9. The molar ratio of aryl-substituted 2-aminobenzyl alcohol, malonic acid monoethyl ester chloride, and imidazole is 5:5:7.

[0010] The preferred method for synthesizing the benzyl alcohol-substituted 2-benzyl alcohol amide intermediate is as follows: The substituted aminobenzyl alcohol, monoethyl malonate chloride or monomethyl malonate chloride and imidazole were reacted in CH2Cl2 solution by rt ​​reaction, and then separated by column chromatography to obtain the benzyl alcohol substituted 2-benzyl alcohol amide intermediate; When the raw materials are substituted aminobenzyl alcohol, monomethyl malonate chloride and imidazole, the intermediate for substituted 2-benzyl alcohol amide is 2a-10-2a-18; when the raw materials are substituted aminobenzyl alcohol, monomethyl malonate chloride and imidazole, the intermediate for substituted 2-benzyl alcohol amide is 2a-19-2a-21. The molar ratio of substituted aminobenzyl alcohol, monoethyl malonate chloride or monomethyl malonate chloride and imidazole is 5:5:7.

[0011] The preferred method for synthesizing the N-substituted 2-benzyl alcohol amide intermediate is as follows: 2-Benzylaminomethanol, monoethyl malonate chloride and imidazole were reacted in CH2Cl2 solution by rt ​​reaction, followed by column chromatography to obtain N-substituted 2-benzyl alcohol amide intermediate 2a-22; The molar ratio of 2-benzylaminomethanol, malonic acid monoethyl ester chloride, and imidazole is 5:5:7.

[0012] The preferred method for synthesizing 2a-23 is as follows: 2-aminobenzyl alcohol is added to a round-bottom flask containing CH2Cl2 and stirred in an ice bath. Diethyl ketone is slowly added dropwise, followed by a reaction at rt. After the reaction is completed, column chromatography is used to separate the intermediate 2a-23.

[0013] Preferably, S2 specifically involves adding 2-benzyl alcohol amide intermediate, KMnO4, and CH2Cl2 to a capped reaction tube equipped with a magnetic stirrer, heating under reflux, and then separating the quinolinone compound by column chromatography after the reaction is complete.

[0014] Preferably, the molar ratio of 2-benzyl alcohol amide intermediate, KMnO4 and CH2Cl2 is 5:5:3, the reaction temperature is 50℃, and the reaction time is 15h.

[0015] Compared with the prior art, the technical solution provided by the present invention has the following beneficial effects or advantages: 1. In this application, 23 key intermediates of 2-benzyl alcohol amide were synthesized using 2-aminobenzyl alcohol as a raw material and monoethyl malonate and monomethyl malonate as amidating agents, respectively.

[0016] 2. In the synthesis of 2-(1H)-quinolinone in this application, the green oxidant KMnO4 was used. This oxidant is not only stable but also common and readily available. Secondly, the one-pot synthesis of 2-(1H)-quinolinone is adopted, which has the advantages of short steps and good reproducibility. In addition, during the mechanism verification experiment of this reaction, it was discovered for the first time that KMnO4 has a certain catalytic effect on the condensation of Knoevenagel.

[0017] 3. In this application, 2-(1H)-quinolinone was synthesized from 2-benzyl alcohol amide intermediate and its influencing factors were screened. The experiment showed that the optimal reaction conditions for this template reaction were as follows: Synthesis of 2-(1H)-quinolinone skeleton: 0.119 g (0.5 mmol) of 2-benzyl alcohol amide intermediate, 79 mg KMnO4 (0.5 mmol), CH2Cl2 (0.3 M), reaction temperature 50 °C, reaction time 15 h, and reaction separation yield 71%. Attached Figure Description

[0018] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used together with the embodiments of the invention to explain the invention and do not constitute a limitation thereof.

[0019] In the attached diagram: Figure 1 This is a flowchart of the preparation method of the present invention. Detailed Implementation

[0020] The technical solution of the present invention will be described below with reference to the embodiments. However, the present invention is not limited to the following embodiments.

[0021] This invention synthesizes a 2-quinolinone compound with the following structural formula:

[0022] This invention first synthesizes a 2-benzyl alcohol amide intermediate (2a), then synthesizes a quinolinone skeleton (3a) via a one-pot oxidative tandem Knoevenagel condensation reaction. The experimental process for the oxidative condensation synthesis of quinolinone from the 2-benzyl alcohol amide intermediate under different oxidants is described, and the optimization of conditions in the quinolinone skeleton synthesis experiment under a single-variable control method is discussed. The overall experimental reaction is as follows: .

[0023] Examples 1-7 are examples of intermediate preparation.

[0024] Preparation of intermediate raw materials

[0025] Example 1 Synthesis of key intermediate 2a-1, aryl substitution of 2-aminobenzyl alcohol to 2-aminobenzyl alcohol: 2-Aminobenzyl alcohol (0.616 g, 5 mmol) and imidazole (0.476 g, 7 mmol) were added to a 50 mL round-bottom flask equipped with a magnetic stirrer. 10 mL of CH2Cl2 was added, and the mixture was magnetically stirred at 300 r / min at room temperature. 0.753 g, 5 mmol of malonic acid monoethyl ester chloride was weighed into a small sample vial and diluted with 6 mL of CH2Cl2. The solution was then added dropwise to the reaction system using a glass dropper at a rate of 1 D / s. The reaction was stirred for approximately 12 h. After the reaction was complete, the mixture was extracted with CH2Cl2, dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and then separated by column chromatography (PE:EA = 2:1, V / V) to obtain the 2-benzyl alcohol amide intermediate (intermediate 2a-1), a white solid with a yield of 91.7%.

[0026] Synthesis of key intermediate 2a-2, aryl substitution of 2-aminobenzyl alcohol to 3-methyl-2-aminobenzyl alcohol: Add 50 mL of anhydrous THF to a three-necked flask, protect it with N2, and then place it in an ice bath (seal all glass joints with sealing film before the ice bath to prevent moisture ingress). Add 1.38 g (36 mmol) of LiAlH4 to the anhydrous THF solution, then dissolve 5 g (30 mmol) of methyl 3-methyl-2-aminobenzoate in 30 mL of clean anhydrous THF solution, mix thoroughly, and slowly add the mixture dropwise to the reaction system while stirring for 4 h (monitored by TLC). After the reaction is complete, adjust the pH to neutral with NH4Cl, extract, concentrate, and dry to obtain 3-methyl-2-aminobenzyl alcohol (3.9 g, yield 94.7%).

[0027] 3-Methyl-2-aminobenzyl alcohol (0.686 g, 5 mmol), malonyl monoethyl ester chloride (0.754 g, 5 mmol) and imidazole (0.477 g, 7 mmol) were reacted in CH2Cl2 solution at rt for 6-7 h (monitored by TLC) and separated by column chromatography to obtain intermediate 2a-2 (0.574 g, yield 45.6%).

[0028] Synthesis of the key intermediate 2a-3—2a-9, transforming aryl-substituted 2-aminobenzyl alcohol into substituted 4-methyl-2-aminobenzyl alcohol: Substituted 2-aminobenzoic acid (100 mmol) was dissolved in MeOH (250 mL) under ice bath conditions. Then, 150 mmol of H₂SO₄ was slowly added dropwise to the reaction mixture, and the mixture was stirred for 10 min. The mixture was then refluxed at 80 °C for 12 h (monitored by TLC). After cooling to room temperature, the mixture was concentrated under vacuum. The pH of the reaction mixture was adjusted to 9-10 with water and Na₂CO₃. Extraction with EA and drying were performed, followed by purification by column chromatography (PE:EA = 3:1, V / V). Methyl substituted 2-aminobenzoate was obtained.

[0029] Add 50 mL of anhydrous THF to a three-necked flask, protect it with N2, and then place it in an ice bath (seal all glass joints with sealing film before the ice bath to prevent moisture from entering). Add 36 mmol of LiAlH4 to the anhydrous THF solution, then dissolve 30 mmol of substituted 2-aminobenzoate in 30 mL of clean anhydrous THF solution, mix thoroughly, and slowly add the solution dropwise to the reaction system while stirring for 4 h (monitored by TLC). After the reaction is complete, adjust the pH to neutral with NH4Cl, extract, concentrate, and dry to obtain substituted 2-aminobenzyl alcohol.

[0030] The key intermediate 2a-3—2a-9 was obtained by reacting substituted 4-methyl-2-aminobenzyl alcohol (5 mmol), malonic acid monoethyl ester chloride (5 mmol) and imidazole (7 mmol) in CH2Cl2 solution at rt for 6–7 h (monitored by TLC) and separated by column chromatography.

[0031] Example 2 benzyl alcohol-substituted 2-benzyl alcohol amide intermediate Synthesis of key intermediates 2a-10-2a-18: substituted aminobenzophenone (4 mmol) was added to a round-bottom flask containing anhydrous ethanol (0.3 M), mixed thoroughly, and placed in an ice bath for 10 min. NaBH4 (8 mmol) was then slowly added and stirred for 4 h (TLC monitoring). After the reaction was completed, the mixture was diluted with water, the pH was adjusted to 7-8 with NH4Cl, extracted, dried, and separated by column chromatography to obtain substituted aminobenzyl alcohol.

[0032] The key intermediate 2a-10—2a-18 was obtained by reacting substituted aminobenzyl alcohol (5 mmol), malonic acid monoethyl ester chloride (5 mmol) and imidazole (7 mmol) in CH2Cl2 solution at rt for 6–7 h (monitored by TLC) and then separated by column chromatography.

[0033] Synthesis of key intermediates 2a-19-2a-21: substituted aminobenzophenone (4 mmol) was added to a round-bottom flask containing anhydrous ethanol (0.3 M), mixed thoroughly, and placed in an ice bath for 10 min. NaBH4 (8 mmol) was then slowly added and stirred for 4 h (TLC monitoring). After the reaction was complete, the mixture was diluted with water, the pH was adjusted to 7-8 with NH4Cl, extracted, dried, and separated by column chromatography to obtain substituted aminobenzyl alcohol.

[0034] The key intermediates 2a-19–2a-21 were obtained by reacting substituted aminobenzyl alcohol (5 mmol), monomethyl malonate chloride (5 mmol) and imidazole (7 mmol) in CH2Cl2 solution at rt for 6–7 h (monitored by TLC) and then separated by column chromatography.

[0035] Example 3 N-substituted 2-benzyl alcohol amide intermediate Synthesis of key intermediate 2a-22: 2-Aminobenzyl alcohol (3.5 g, 28.42 mmol) was added to a round-bottom flask containing anhydrous ethanol (80 mL) and mixed thoroughly. Benzaldehyde (3.02 g, 28.42 mmol) was added and stirred for 4 h (TLC monitoring). After the reaction was complete, NaBH4 (2.69 g, 71.05 mmol) was slowly added and stirred for 4 h (TLC monitoring). After the reaction was complete, water was added to dilute the solution, and the pH was adjusted to 7-8 with NH4Cl. The solution was then extracted, dried, and separated by column chromatography to obtain 2-benzylaminobenzyl alcohol (4 g, yield 66.0%).

[0036] 2-Benzylaminomethanol (0.686 g, 5 mmol), malonyl monoethyl ester chloride (0.754 g, 5 mmol) and imidazole (0.477 g, 7 mmol) were reacted in CH2Cl2 solution at rt for 6-7 h (monitored by TLC) and separated by column chromatography to obtain intermediate 2a-22 (0.574 g, yield 45.6%).

[0037] Example 4 Synthesis of key intermediate 2a-23: 2-aminobenzyl alcohol (123 mg, 1 mmol) was added to a round-bottom flask containing CH2Cl2 (3 mL) and stirred in an ice bath for 10 min. Diketene (84 mg, 1 mmol) was slowly added dropwise, and the reaction was carried out at rt for 6-7 h (monitored by TLC). After the reaction was completed, the intermediate 2a-23 (143.7 mg, yield 69.4%) was obtained by column chromatography (PE / EA=1 / 1).

[0038] Example 5 Optimization of reaction conditions Example As shown below, this embodiment first determines the template reaction for synthesizing the 2-(1H)-quinolinone skeleton. The reaction steps are as follows: 0.119 g, 0.5 mmol) of 2-benzyl alcohol amide intermediate and 0.13 g, 1.5 mmol) of MnO2 are added to a capped reaction tube equipped with a magnetic stirrer. The mixture is heated to reflux at 50 °C for about 15 h with 1.6 mL of THF. After the reaction is completed, column chromatography (PE:EA = 1:1, V / V) is used to separate the solid 2-(1H)-quinolinone, with a yield of 64.4%.

[0039] ; Scheme 2.3 Synthesis of 2-(1H)-quinolinone Using the above reaction as a template reaction, the type and amount of oxidant, solvent, temperature, and reaction concentration were screened using the single controlled variable method to obtain an optimal condition for the reaction.

[0040] By analyzing Entry 1-7 in Table 2, and through parallel experiments with several single-variable oxidants, the results showed that the reaction yields of 3.0 eq. MnO2 and 1.0 eq. KMnO4 were 64.4% and 60.0%, respectively. Therefore, KMnO4 was selected as the oxidant for this reaction. As shown in Entry 8-17 of Table 2, the results obtained from several parallel experiments with single-variable solvents showed that CH2Cl2 had the highest reaction yield, so CH2Cl2 was chosen as the solvent.

[0041] By analyzing Entry 18-22 in Table 2, and through several parallel experiments with single-variable temperature, the results showed that the highest yield was obtained when the temperature of the reaction was 50℃.

[0042] As shown in Entry 23-27 of Table 2, after several parallel experiments with single-variable oxidant dosage, the highest reaction yield of 71.0% was obtained when the KMnO4 dosage was 1.0 eq.; as shown in Entry 28-31 of Table 2, after several parallel experiments with single-variable reaction concentration, the highest reaction yield of 71.0% was obtained when the KMnO4 dosage was 0.3 M; in order to further improve the reaction yield, activators TBAB, TBAF, and TBAHS were added to the experiment respectively, but the reaction yield was not improved.

[0043] Table 2. Screening and optimization of template reaction conditions ; .

[0044] Example 6 Under the above-mentioned optimal reaction conditions, substrate expansion was carried out as follows: Synthetic route of 2-(1H)-quinolinone derivatives Table 3 Substrate expansion for quinolinone compounds ; .

[0045] Example 7 Synthesis of ethyl 2-chloroquinoline-3-carboxylate: ethyl 2-oxo-1,2-dihydroquinoline-3-carboxylate (0.434 g, 2 mmol) was dissolved in 1,4-dioxane (4 mL), and then phosphorus oxychloride (0.46 g, 3 mmol) was added. The mixture was refluxed at 90 °C for 5 h (TLC monitoring). After the reaction was complete, the reaction system was quenched in ice water. After extraction with CH2Cl2, drying and concentration, the mixture was purified by column chromatography (PE / EA = 5 / 1) to obtain ethyl 2-chloroquinoline-3-carboxylate (0.462 g, yield 98.0%), as shown below.

[0046] ; Synthesis of ethyl 2-chloroquinoline-3-carboxylate

[0047] Example 8: Synthesis of ethyl 2-(phenylamino)quinoline-3-carboxylate: ethyl 2-chloroquinoline-3-carboxylate (0.236, 1 mmol), aniline (93 mg, 1 mmol), and KI (0.249 g, 1.5 mmol) were added to round-bottom flasks, and then heated under nitrogen protection in DMF at 100 °C for 4 h (monitored by TLC). After the reaction was completed, the reaction system was cooled to room temperature and quenched in ice water. After extraction with ethyl acetate and drying with anhydrous sodium sulfate, the product was concentrated under vacuum and purified by column chromatography to obtain ethyl 2-(phenylamino)quinoline-3-carboxylate (0.257 g, yield 88.0%). The reaction is shown below.

[0048] ; Synthesis of ethyl 2-(phenylamino)quinoline-3-carboxylate Experimental Analysis: 1. Reaction Mechanism To gain a deeper understanding of the reaction mechanism, the following blank control experiment and mechanism verification experiment were designed to obtain more useful information reflecting the reaction mechanism.

[0049] In the screening of template reaction conditions, it was found that 1 eq. KMnO4 could produce the highest reaction yield, but KMnO4 participating in the template reaction produced the byproduct MnO2. Therefore, a blank control experiment of reaction (1) was performed, and no product quinolinone was produced. The results indicate that KMnO4 and MnO2 may participate in the Knoevenagel condensation reaction.

[0050] To verify this hypothesis, reactions (2), (3), (4), and (5) were performed. When the activated MnO2 was added to 3 eq., the reaction yield did not significantly increase. Therefore, reactions (6), (7), and (8) were also performed. The experimental results showed that adding 5% KMnO4 increased the reaction yield to 61.4%, indicating that MnO2 did not play a promoting role in the Knoevenagel condensation reaction, while KMnO4 did.

[0051] ; Blank control experiment ; Experiments to verify the promoting effect of MnO2 on the Knoevenagel condensation reaction ; Experiments to verify the promoting effect of KMnO4 on the Knoevenagel condensation reaction. Therefore, the reaction mechanism is speculated to be as follows: KMnO4 oxidizes the benzyl alcohol amide intermediate to the aldehyde amide intermediate. Then, under the catalysis of KMnO4, the carbanion on the active methylene group attacks the carbocation on the aldehyde carbonyl group to undergo a Knoevenagel condensation reaction. Subsequently, one molecule of water is removed to obtain the quinolinone skeleton. The specific reaction mechanism is as follows.

[0052] 2. Experimental Results 2.1 Structural characterization of key intermediates and quinolinone compounds from raw materials 2.1.1 Structural characterization data of 2-benzyl alcohol amide intermediate ethyl 3-((2-(hydroxymethyl)phenyl)amino)-3-oxopropanoate (2a-1)

[0053] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate:n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, Chloroform- d ) δ 9.55 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 4.66 (s,2H), 4.23 (q, J = 7.2 Hz, 2H), 3.46 (s, 2H), 1.30 (t, J = 7.2 Hz, 3H) ppm; 13 CNMR (101 MHz, Chloroform- d ) δ 169.30, 164.07, 136.48, 131.05, 129.28, 129.06,125.15, 123.24, 63.58, 61.99, 42.61, 14.16 ppm; HRMS (ESI) m / z calcd forC 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. 3-((2-(hydroxymethyl)-6-methylphenyl)amino)-3-oxopropanoate(2a-2)

[0054] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 9.47 (s, 1H), 7.32 (d,J = 7.4 Hz, 1H), 7.19 (t, J = 7.5Hz, 1H), 7.12 (d, J = 7.1 Hz, 1H), 5.08 (t, J = 5.7 Hz, 1H), 4.43 (d, J = 5.7Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.44 (s, 2H), 2.15 (s, 3H), 1.22 (t, J =7.1 Hz, 3H) ppm; 13 C NMR (101 MHz, DMSO- d 6) δ 168.45, 164.49, 140.10, 135.31,133.08, 128.78, 127.09, 124.58, 61.19, 59.83, 43.16, 18.25, 14.56 ppm; HRMS(ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. ethyl 3-((2-(hydroxymethyl)-5-methylphenyl)amino)-3-oxopropanoate(2a-3)

[0055] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, Chloroform- d ) δ 9.41 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.10 (d, J= 9.3 Hz, 1H), 7.05 (s, 1H), 4.60 (s, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.45 (s,2H), 2.29 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H) ppm; 13 C NMR NMR (100 MHz,Chloroform- d ) δ 169.37, 164.19, 135.10, 133.63, 131.53, 130.04, 129.47,123.52, 63.44, 61.95, 42.45, 20.93, 14.15 ppm; HRMS (ESI) m / z calcd forC 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. 2,4-dibromo-6-(3-ethoxy-3-oxopropanamido)benzyl ethyl malonate(2a-4)

[0056] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 10.07 (s, 1H), 7.96 (s, 1H), 7.63 (s, 1H), 5.08 (s, 2H),4.13 (qd, J = 7.1, 2.8 Hz, 4H), 3.63 (s, 2H), 3.49 (s, 2H), 1.20 (td, J =7.1, 2.7 Hz, 6H)ppm; 13 C NMR (101 MHz, DMSO- d6) δ 167.48, 166.63, 166.39,164.58, 137.92, 134.25, 133.34, 129.77, 123.85, 120.68, 62.32, 61.13, 60.91,42.49, 41.10, 14.07 ,14.05ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. ethyl 3-((2-(1-hydroxyethyl)phenyl)amino)-3-oxopropanoate(2a-10)

[0057] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, Chloroform- d ) δ 9.72 (s, 1H), 7.89 (dd, J = 8.1, 1.0 Hz, 1H), 7.24– 7.18 (m, 1H), 7.17 (dd, J = 7.7, 1.5 Hz, 1H), 7.06 (td, J = 7.5, 1.2 Hz,1H), 4.89 (t, J = 6.6 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.35 (s, 2H), 1.48(d, J = 6.6 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H) ppm; 13 C NMR (101 MHz,Chloroform- d) δ 168.71, 164.02, 135.60, 134.77, 128.19, 126.64, 125.04,123.36, 69.14, 61.86, 43.26, 22.69, 14.14 ppm; HRMS (ESI) m / z calcd forC 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. ethyl 3-((2-(hydroxy(phenyl)methyl)phenyl)amino)-3-oxopropanoate(2a-11)

[0058] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 10.62 (s, 1H), 7.39 – 7.30 (m, 3H), 7.30 – 7.24 (m, 3H),7.19 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 7.2 Hz, 1H), 6.89 (t, J = 8.0 Hz, 1H),6.64 (d, J = 7.6 Hz, 1H), 4.54 (d, J = 10.5 Hz, 1H), 4.04 (s, 1H), 3.96 (q, J = 7.1 Hz, 2H), 0.94 (t, J = 7.1 Hz, 3H) ppm; 13 C NMR (101 MHz, DMSO- d6) δ169.09, 166.55, 139.95, 137.69, 129.23, 129.01, 128.42, 128.26, 127.89,126.02, 123.13, 115.92, 61.06, 54.29, 45.27, 14.34 ppm; HRMS (ESI) m / z calcdfor C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. ethyl 3-(benzyl(2-(hydroxymethyl)phenyl)amino)-3-oxopropanoate(2a-19)

[0059] White solid (45.6 mg, yield: 82%); mp:138-139℃ purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 13 C NMR(101 MHz, Chloroform- d ) δ 168.24, 166.57, 139.10, 138.92, 136.54, 130.43,129.54, 129.45, 128.97, 128.83, 128.59, 127.92, 61.64, 60.49, 53.03, 41.68,14.11 ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found:342.1164. N-(2-(hydroxymethyl)phenyl)-3-oxobutanamide(2a)

[0060] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 9.49 (s, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 7.4Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.17 (t, J = 8.1 Hz, 1H), 5.25 (t, J = 5.6Hz, 1H), 4.49 (d, J = 5.5 Hz, 2H), 3.58 (s, 2H), 2.22 (s, 3H) ppm; 13 C NMR(101 MHz, DMSO- d 6) δ 240.88, 202.86, 173.05, 172.44, 164.93, 164.62, 162.79,162.01, 97.42, 89.44, 67.93 ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. 2-cyano-N-(2-(hydroxymethyl)phenyl)acetamide(17a)

[0061] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f= 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 9.66 (s, 1H), 7.47 – 7.43 (m, 2H), 7.25 (td, J = 7.7,1.9 Hz, 1H), 7.20 (td, J = 7.4, 1.5 Hz, 1H), 5.29 (t, J = 5.6 Hz, 1H), 4.49(d, J = 5.5 Hz, 2H), 3.94 (s, 2H)ppm; 13 C NMR (101 MHz, DMSO- d 6) δ 161.43,135.63, 134.25, 127.38, 127.06, 125.56, 124.45, 116.16, 59.61, 26.20 ppm;HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. methyl 3-((2-(hydroxy(phenyl)methyl)phenyl)amino)-3-oxopropanoate

[0062] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, Chloroform- d ) δ 9.44 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 10.4 Hz, 2H), 7.26 – 7.13 (m, 4H), 7.03 (q, J= 7.8 Hz, 2H), 5.85 (s, 1H),3.63 (s, 3H), 3.20 (s, 2H) ppm; 13 C NMR (101 MHz, Chloroform- d ) δ 169.09,163.78, 141.75, 135.89, 133.85, 128.90, 128.72, 128.48, 127.66, 126.44,125.09, 123.94, 74.33, 52.68, 42.63 ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. methyl 3-((4-bromo-2-(hydroxy(phenyl)methyl)phenyl)amino)-3-oxopropanoate(2a-12)

[0063] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 9.75 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.43 – 7.39 (m,2H), 7.29 – 7.26 (m, 5H), 6.22 (d, J = 4.3 Hz, 1H), 5.94 (d, J = 4.3 Hz, 1H),3.60 (s, 3H), 3.42 (d, J = 3.1 Hz, 2H) ppm; 13 C NMR (101 MHz, DMSO- d6) δ168.14, 164.19, 143.61, 140.67, 133.98, 130.08, 129.88, 128.20, 127.18,127.12, 126.33, 117.81, 69.87, 52.10, 42.96 ppm; HRMS (ESI) m / z calcd forC 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. ethyl 3-((4-chloro-2-(hydroxy(phenyl)methyl)phenyl)amino)-3-oxopropanoate(2a-13)

[0064] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, Chloroform- d ) δ 9.54 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.39 – 7.29(m, 6H), 7.06 (d, J = 2.5 Hz, 1H), 5.90 (s, 1H), 4.18 (q, J = 7.2 Hz, 2H),3.32 (s, 2H), 1.28 (t, J = 7.2 Hz, 3H) ppm; 13 C NMR (101 MHz, Chloroform- d) δ169.10, 163.78, 140.85, 135.61, 134.39, 130.29, 128.74, 128.67,128.64,128.16, 126.55, 125.31, 73.72, 61.99, 42.37, 14.15 ppm; HRMS (ESI) m / z calcdfor C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. methyl 3-((4-chloro-2-(hydroxy(phenyl)methyl)phenyl)amino)-3-oxopropanoate

[0065] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 9.80 (s, 1H), 7.53 – 7.50 (m, 2H), 7.33 (d, J = 1.8 Hz,3H), 7.31 – 7.28 (m, 2H), 7.25 – 7.20 (m, 1H), 5.99 (s, 1H), 3.65 (s, 3H),3.47 (d, J = 3.4 Hz, 2H) ppm; 13 C NMR (101 MHz, DMSO- d 6) δ 168.63, 164.70,144.08, 140.93, 134.00, 130.02, 128.66, 127.62, 127.59, 127.43, 127.38,126.82, 70.39, 52.56, 43.41 ppm; HRMS (ESI) m / z calcd for C 19 H20 NO3S [M+H] + : 342.1163, Found: 342.1164. methyl 3-((2-(hydroxymethyl)phenyl)amino)-3-oxopropanoate

[0066] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, Chloroform- d ) δ 9.56 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.32 (t, J = 8.4 Hz, 1H), 7.24 (d, J = 7.3 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 4.68 (s,2H), 3.79 (s, 3H), 3.49 (s, 2H) ppm; 13 C NMR (101 MHz, Chloroform- d ) δ 169.72,163.79, 136.57, 130.81, 129.29, 129.17, 125.14, 123.16, 63.79, 52.84, 42.37ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. ethyl 3-((2-((4-chlorophenyl)(hydroxy)methyl)phenyl)amino)-3-oxopropanoate(2a-14)

[0067] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, Chloroform- d ) δ 9.49 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.27 (s, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.11 (t, J = 7.5 Hz,1H), 7.06 (dd, J = 7.7, 1.5 Hz, 1H), 5.86 (s, 1H), 4.15 (q, J = 7.1 Hz, 2H),1.26 (t, J = 7.2 Hz, 3H) ppm; 13 C NMR (101 MHz, Chloroform- d ) δ 168.83,164.19, 140.49, 135.62, 134.13, 133.25, 128.86, 128.50, 128.14, 127.87,125.41, 124.35, 73.39, 61.93, 42.53, 14.11 ppm; HRMS (ESI) m / z calcd forC 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. ethyl 3-((4-chloro-2-((2-chlorophenyl)(hydroxy)methyl)phenyl)amino)-3-oxopropanoate(2a-15)

[0068] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, Chloroform- d ) δ 9.64 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.60 (dd, J = 7.4, 1.6 Hz, 1H), 7.36 – 7.33 (m, 1H), 7.32 (s, 1H), 7.31 – 7.28 (m, 1H),7.24 – 7.21 (m, 1H), 6.87 (d, J = 2.4 Hz, 1H), 6.14 (d, J = 3.4 Hz, 1H), 4.17(dd, J = 7.1, 4.8 Hz, 2H), 3.51 – 3.46 (m, 1H), 3.43 (d, J = 4.4 Hz, 2H),1.25 (d, J = 7.2 Hz, 3H) ppm; 13 C NMR (101 MHz, Chloroform- d ) δ 169.36,164.72, 138.69, 135.84, 134.14, 132.61, 131.15, 129.72, 129.40, 128.73,128.30, 128.27, 127.32, 125.70, 69.52, 62.09, 41.94, 14.13 ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. ethyl 3-((4-chloro-2-((2-fluorophenyl)(hydroxy)methyl)phenyl)amino)-3-oxopropanoate(2a-16)

[0069] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, Chloroform- d ) δ 9.65 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.48 (td, J = 7.6, 1.8 Hz, 1H), 7.32 (tdd, J = 7.4, 5.4, 1.8 Hz, 1H), 7.26 (d, J = 6.2Hz, 1H), 7.19 (td, J = 7.6, 1.2 Hz, 1H), 7.07 – 7.01 (m, 2H), 6.15 (d, J =3.5 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.55 (d, J = 4.0 Hz, 1H), 3.43 (d, J =2.6 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H)ppm; ethyl 3-((2-((4-fluorophenyl)(hydroxy)methyl)phenyl)amino)-3-oxopropanoate(2a-17)

[0070] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR (400 MHz, Chloroform- d ) δ 9.49 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.35 – 7.29(m, 3H), 7.13 (t, J = 7.5 Hz, 1H), 7.07 (dd, J = 7.7, 1.5 Hz, 1H), 7.02 (t, J = 8.7 Hz, 2H), 5.94 (s, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.34 (s, 2H), 2.04 (s,1H), 1.29 (t, J = 7.1 Hz, 3H)ppm; 13 C NMR (101 MHz, Chloroform- d ) δ 169.19,163.90, 161.05, 137.43, 135.68, 134.07, 128.94 (d, J = 15.2 Hz), 128.23 (d, J = 8.1 Hz), 125.41, 124.40, 115.35 (d, J = 21.5 Hz), 73.55, 61.95, 42.32,14.14ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. 2.1.2 Structural characterization data of quinolinone compounds ethyl 2-oxo-1,2-dihydroquinoline-3-carboxylate (1a')

[0071] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 12.06 (s, 1H), 8.48 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H),7.60 (t, J = 8.2 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H),4.26 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H) ppm; 13 C NMR (100 MHz,DMSO- d 6) δ 164.5, 158.6, 143.7, 140.2, 132.8, 129.5, 123.4, 122.3, 117.7,115.1, 60.8, 14.2 ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163,Found: 342.1164. ethyl 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (2a’)

[0072] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate:n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 12.03 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.57 (t, J =7.7 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 4.30 (q, J =7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H) ppm; 13 C NMR (100 MHz, DMSO- d 6) δ 166.2,158.7, 144.5, 138.1, 131.4, 126.6, 125.6, 122.4, 118.6, 115.7, 61.15, 16.0,14.1 ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found:342.1164. ethyl 2-oxo-4-phenyl-1,2-dihydroquinoline-3-carboxylate(3a’)

[0073] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 12.28 (s, 1H), 7.58 (ddd, J= 8.4, 6.8, 1.7 Hz, 1H),7.52 (dd, J = 5.1, 1.9 Hz, 3H), 7.41 (d, J = 8.3 Hz, 1H), 7.34 – 7.31 (m,2H), 7.18 – 7.13 (m, 1H), 7.11 (dd, J = 8.1, 1.6 Hz, 1H), 3.94 (q, J = 7.1Hz, 2H), 0.85 (t, J = 7.1 Hz, 3H)ppm; 13 C NMR (100 MHz, DMSO- d 6) δ 165.07,158.56, 148.49, 138.71, 134.07, 131.63, 128.98, 128.61,128.51, 127.12,126.67, 122.54, 118.30, 115.82, 60.63, 13.58.ppm; HRMS (ESI) m / z calcd forC 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. ethyl 1-benzyl-2-oxo-1,2-dihydroquinoline-3-carboxylate(6a’)

[0074] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, Chloroform- d ) δ 8.48 (s, 1H), 7.66 (dd, J = 7.8, 1.4 Hz, 1H), 7.52(ddd, J= 8.7, 7.3, 1.5 Hz, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.27 (s, 1H), 7.24(s, 2H), 7.22 (s, 2H), 5.58 (s, 2H), 4.44 (q, J = 7.1 Hz, 2H), 1.43 (t, J =7.1 Hz, 3H)ppm; 13 C NMR (100 MHz, Chloroform- d ) δ 165.09, 159.33, 144.39,141.00, 136.13, 133.11, 130.61, 128.93, 127.49, 126.86, 122.75, 119.30,115.23, 77.36, 61.77, 46.41, 14.45ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. ethyl 7-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate(4a’)

[0075] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, Methanol- d 4) δ 8.51 (s, 1H), 7.52 (s, 1H), 7.46 (d, J = 8.5 Hz,1H), 7.23 (d, J = 8.4 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 1.39(t,J = 7.1 Hz, 3H) ppm; 13 C NMR (101 MHz, Methanol- d 4) δ 165.30, 161.01,145.96, 138.79, 135.29, 133.63, 129.36, 122.44, 119.27, 115.70, 61.76, 20.17,13.96 ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found:342.1164. ethyl 8-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate(5a’)

[0076] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, Methanol- d 4) δ 8.60 (s, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.51 (d, J =7.0 Hz, 1H), 7.22 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.48 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H) ppm; 13 C NMR (101 MHz, Methanol- d4) δ 169.74, 165.19, 161,29,155.77, 146.83, 135.01, 128.34, 124.43, 123.48, 119.28, 61.79, 16.45, 13.94ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. ethyl 5,7-dibromo-2-oxo-1,2-dihydroquinoline-3-carboxylate(7a’)

[0077] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 11.05 (s, 1H), 8.47 (s, 1H), 8.15 (s, 1H), 8.14 (s, 1H),4.29 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H) ppm ; 13 C NMR (100 MHz,DMSO- d 6) δ 173.21, 167.82, 151.87, 146.85, 140.87, 138.00, 130.06, 123.36,80.46, 70.65, 23.60, 15.11ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. ethyl 6-chloro-2-oxo-4-phenyl-1,2-dihydroquinoline-3-carboxylate(8a’)

[0078] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 12.44 (s, 1H), 7.63 (dd, J = 8.8, 2.4 Hz, 1H), 7.54 (dd, J = 5.0, 1.7 Hz, 3H), 7.42 (d, J = 8.8 Hz, 1H), 7.34 (dd, J = 6.6, 3.0 Hz,2H), 7.00 (d, J = 2.3 Hz, 1H), 3.95 (q, J = 7.1 Hz, 2H), 0.84 (t, J = 7.1 Hz,3H)ppm; 13 C NMR (100 MHz, DMSO- d 6) δ 164.71, 158.35, 147.39, 137.48, 133.37,131.53, 129.26, 128.66, 128.57, 127.71, 126.36, 125.76, 119.60, 117.88,60.78, 13.54ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found:342.1164. ethyl 6-bromo-2-oxo-4-phenyl-1,2-dihydroquinoline-3-carboxylate(9a’)

[0079] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 12.43 (s, 1H), 7.75 (dd, J = 8.8, 2.2 Hz, 1H), 7.55 (d, J = 1.4 Hz, 1H), 7.54 (d, J = 2.2 Hz, 2H), 7.38 – 7.33 (m, 3H), 7.14 (d, J =2.2 Hz, 1H), 3.95 (q, J = 7.1 Hz, 2H), 0.85 (t, J = 7.1 Hz, 3H)ppm; 13 C NMR(100 MHz, DMSO- d 6) δ 164.66, 158.32, 147.32, 137.79, 134.19, 133.35, 129.27,128.76, 128.66, 128.57, 127.65, 120.11, 118.12, 114.15, 60.77, 13.54ppm; HRMS(ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. ethyl 6-chloro-4-(2-fluorophenyl)-2-oxo-1,2-dihydroquinoline-3-carboxylate(10a’)

[0080] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 7.67 (dd, J = 8.8, 2.3 Hz, 1H), 7.63 (d, J = 4.8 Hz,1H), 7.47 – 7.36 (m, 4H), 6.95 – 6.90 (m, 1H), 3.97 (dd, J = 7.1, 5.1 Hz,2H), 0.85 (t, J = 7.1 Hz, 3H)ppm; ethyl 4-(4-fluorophenyl)-2-oxo-1,2-dihydroquinoline-3-carboxylate(11a’)

[0081] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 12.30 (s, 1H), 7.61 – 7.56 (m, 1H), 7.41 (d, J = 8.5 Hz,1H), 7.39 (s, 2H), 7.37 (d, J = 2.5 Hz, 2H), 7.16 (t, J = 8.1 Hz, 1H), 7.11(dd, J = 8.2, 1.5 Hz, 1H), 3.97 (q,J = 7.1 Hz, 2H), 0.89 (t, J = 7.1 Hz, 3H)ppm; 13 C NMR (101 MHz, DMSO- d 6) δ 165.50, δ 162.87 (d, J = 246.0 Hz), 158.96,148.07, 139.18, 132.17, 131.47 (d, J = 8.4 Hz), 130.86 (d, J = 3.1 Hz),127.52, 127.47, 123.07, 118.81, δ 116.24 (d, J = 14.9 Hz), 115.95, 61.21,14.11ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found:342.1164. methyl 2-oxo-4-phenyl-1,2-dihydroquinoline-3-carboxylate(12a’)

[0082] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 12.32 (s, 1H), 7.57 (d, J = 1.8 Hz, 1H), 7.53 (dd, J =5.0, 1.8 Hz, 1H), 7.51 (dd, J = 3.5, 1.3 Hz, 2H), 7.41 (d, J = 8.1 Hz, 1H),7.33 (d,J = 2.9 Hz, 1H), 7.32 – 7.31 (m, 1H), 7.18 – 7.14 (m, 1H), 7.12 (dd, J = 8.2, 1.6 Hz, 1H), 3.47 (s, 3H) ppm; 13 C NMR (101 MHz, DMSO- d 6) δ 165.85,158.63, 148.65, 138.76, 134.08, 131.74, 129.09, 128.63, 128.52, 127.21,126.59, 122.62, 118.27, 115.89, 52.01 ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S[M+H] + : 342.1163, Found: 342.1164. ethyl 6-chloro-1-methyl-2-oxo-4-phenyl-1,2-dihydroquinoline-3-carboxylate(13a’)

[0083] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, Chloroform- d ) δ 7.54 (ddd, J = 9.0, 4.9, 2.4 Hz, 1H), 7.50 – 7.45(m, 3H), 7.39 – 7.30 (m, 3H), 7.25 (s, 1H), 4.11 – 4.04 (m, 2H), 3.77 (d, J =4.9 Hz, 3H), 0.95 (td, J = 7.1, 5.0 Hz, 3H)ppm; 13C NMR (101 MHz, Chloroform- d ) δ 165.35, 158.81, 147.01, 138.49, 133.79, 131.71, 129.30, 128.93, 128.70,128.22, 127.88, 127.78, 121.57, 115.99, 61.59, 30.02, 13.83 ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. ethyl 4-(4-chlorophenyl)-2-oxo-1,2-dihydroquinoline-3-carboxylate(14a’)

[0084] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 12.33 (s, 1H), 7.63 – 7.56 (m, 3H), 7.41 (d, J = 8.2 Hz,1H), 7.38 – 7.34 (m, 2H), 7.18 – 7.13 (m, 1H), 7.10 (dd, J = 8.2, 1.4 Hz,1H), 3.98 (q, J = 7.1 Hz, 2H), 0.90 (t, J = 7.1 Hz, 3H)ppm; 13 C NMR NMR (101MHz, DMSO- d6) δ 164.97, 158.44, 147.39, 138.72, 133.89, 132.92, 131.78,130.61, 128.66, 127.03, 126.81, 122.65, 118.08, 115.86, 60.81, 13.62 ppm;HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. ethyl 6-chloro-4-(2-chlorophenyl)-2-oxo-1,2-dihydroquinoline-3-carboxylate(15a’)

[0085] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 12.55 (s, 1H), 7.66 (ddd, J = 8.8, 4.1, 1.7 Hz, 2H),7.57 (td, J = 7.8, 1.7 Hz, 1H), 7.51 (td, J = 7.5, 1.2 Hz, 1H), 7.44 (d, J =8.8 Hz, 1H), 7.38 (dd, J = 7.5, 1.6 Hz, 1H), 6.79 (d, J = 2.3 Hz, 1H), 3.99 –3.89 (m, 2H), 0.82 (t, J = 7.1 Hz, 3H)ppm; 13 C NMR (101 MHz, DMSO- d6) δ164.58, 158.79, 145.72, 137.82, 132.62,132.52, 132.31, 131.83, 131.25,130.10, 128.55, 128.08, 127.15, 125.60, 119.35, 118.52, 61.29, 13.97 ppm;HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. methyl 6-bromo-2-oxo-4-phenyl-1,2-dihydroquinoline-3-carboxylate

[0086] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 12.48 (s, 1H), 7.76 (dd, J = 8.8, 2.2 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.54 (d, J = 1.9 Hz, 2H), 7.38 – 7.33 (m, 3H), 7.15 (d, J =2.2 Hz, 1H), 3.48 (s, 3H)ppm; 13 C NMR (101 MHz, DMSO- d 6) δ 165.43, 158.38,147.48, 137.84, 134.30, 133.37, 129.39, 128.85, 128.79, 128.48, 127.57,120.07, 118.18, 114.23, 52.10 ppm; HRMS (ESI)m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. methyl 6-chloro-2-oxo-4-phenyl-1,2-dihydroquinoline-3-carboxylate

[0087] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, DMSO- d 6) δ 12.48 (s, 1H), 7.66 (dd, J = 8.8, 2.4 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.54 (d, J = 2.0 Hz, 2H), 7.43 (d, J = 8.8 Hz, 1H), 7.37 –7.33 (m, 2H), 7.01 (d, J = 2.3 Hz, 1H), 3.48 (s, 3H) ppm; 13 C NMR (101 MHz,DMSO- d 6) δ 165.47, 158.41, 147.54, 137.54, 133.38, 131.65, 129.38, 128.79,128.48, 127.62, 126.41, 125.86, 119.57, 117.97, 52.10 ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. ethyl 2-chloroquinoline-3-carboxylate(lyy-a)

[0088] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR(400 MHz, Chloroform- d ) δ 8.65 (s, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.83 – 7.78 (m, 1H), 7.60 (t, J = 8.1 Hz, 1H), 4.46 (q, J =7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H)ppm; 13 C NMR (101 MHz, Chloroform- d ) δ164.70, 148.29, 147.70, 141.63, 132.65, 128.52,128.47, 127.91, 125.94,124.59, 62.26, 14.31ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163,Found: 342.1164. ethyl 2-(phenylamino)quinoline-3-carboxylate(lyy-b)

[0089] White solid (45.6 mg, yield: 82%); mp:138-139℃; purification bysilica gel chromatography (ethyl acetate: n -hexane= 1:4, R f = 0.42); 1 H NMR (400 MHz, Chloroform- d ) δ 10.33 (s, 1H), 8.78 (s, 1H), 7.99 (dd, J = 8.6, 1.0Hz, 2H), 7.80 (d, J = 8.4 Hz, 1H), 7.72 – 7.64 (m, 2H), 7.42 – 7.35 (m, 2H),7.29 (t, J = 7.5 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H)ppm; 13 C NMR (101 MHz, Chloroform- d ) δ 167.35, 152.70,149.80, 142.63, 140.29, 132.63, 129.00, 128.92, 126.99, 123.45, 122.52,122.43, 120.15, 110.70, 61.85, 14.42ppm; HRMS (ESI) m / z calcd for C 19 H 20 NO3S [M+H] + : 342.1163, Found: 342.1164. 3. Conclusion (1) In this invention, 25 key intermediates of 2-benzyl alcohol amide were synthesized using 2-aminobenzyl alcohol as raw material and monoethyl malonate and monomethyl malonate as amidation reagents, respectively.

[0090] (2) In this invention, 2-(1H)-quinolinone was synthesized from 2-benzyl alcohol amide intermediate and its influencing factors were screened. The experiment showed that the optimal reaction conditions for this template reaction were: Synthesis of 2-(1H)-quinolinone skeleton: 0.119 g (0.5 mmol) of 2-benzyl alcohol amide intermediate, 79 mg KMnO4 (0.5 mmol), CH2Cl2 (0.3 M), reaction temperature 50 °C, reaction time 15 h.

[0091] (3) This invention uses template reaction as an example to expand the substrate, synthesizing 17 quinolinone compounds and 2 derivatives. After measuring the melting point and IR, the results were obtained. 1 HNMR, 13 C-wave spectrometry determined their respective chemical structures.

[0092] (4) In the synthesis of 2-(1H)-quinolinone, the present invention uses the green oxidant KMnO4, which is not only stable but also common and readily available; secondly, the one-pot synthesis of 2-(1H)-quinolinone has the advantages of short steps and good reproducibility; in addition, during the mechanism verification experiment of the reaction, it was found that KMnO4 has a certain catalytic effect on the condensation of Knoevenagel.

[0093] As described above, the basic principles, main features, and advantages of the present invention have been well described. The above embodiments and specifications are merely descriptions of preferred embodiments of the present invention, and the present invention is not limited to the above embodiments. Various changes and improvements made to the technical solutions of the present invention by those skilled in the art without departing from the spirit and scope of the present invention should fall within the protection scope defined by the present invention.

Claims

1. A 2-quinolinone compound, characterized in that, The structural formula is: 。 2. A method for synthesizing a 2-quinolinone compound, characterized in that, include: S1: Using 2-aminobenzyl alcohol as a raw material, synthesize 2-benzyl alcohol amide intermediate; S2: Using 2-benzyl alcohol amide intermediate, KMnO4 and CH2Cl2 as raw materials, 2-quinolinone compounds were synthesized by one-pot oxidation-tandem Knoevenagel condensation reaction.

3. The method for synthesizing a 2-quinolinone compound according to claim 2, characterized in that, The 2-benzyl alcohol amide intermediate of S1 is any one of aryl-substituted 2-benzyl alcohol amide intermediate, benzyl alcohol-substituted 2-benzyl alcohol amide intermediate, N-substituted 2-benzyl alcohol amide intermediate, or 2a-23.

4. The method for synthesizing a 2-quinolinone compound according to claim 3, characterized in that, The synthetic method for aryl-substituted 2-benzyl alcohol amide intermediates is as follows: After adding aryl-substituted 2-aminobenzyl alcohol, imidazole and CH2Cl2 to a round-bottom flask equipped with a magnetic stirrer, magnetic stirring was started at room temperature. Weigh out monoethyl malonate chloride, dilute it with CH2Cl2, and add it dropwise to the reaction system using a glass dropper to carry out the reaction. After the reaction was completed, the product was extracted with CH2Cl2, dried with anhydrous Na2SO4, filtered, concentrated under vacuum, and then separated by column chromatography to obtain the aryl-substituted 2-benzyl alcohol amide intermediate. When aryl-substituted 2-aminobenzyl alcohol is 2-aminobenzyl alcohol, the intermediate of aryl-substituted 2-benzyl alcohol amide is 2a-1; when aryl-substituted 2-aminobenzyl alcohol is 3-methyl-2-aminobenzyl alcohol, the intermediate of aryl-substituted 2-benzyl alcohol amide is 2a-2; when aryl-substituted 2-aminobenzyl alcohol is substituted 4-methyl-2-aminobenzyl alcohol, the intermediate of aryl-substituted 2-benzyl alcohol amide is 2a-3 to 2a-9. The molar ratio of aryl-substituted 2-aminobenzyl alcohol, malonic acid monoethyl ester chloride, and imidazole is 5:5:

7.

5. The method for synthesizing a 2-quinolinone compound according to claim 4, characterized in that, The synthetic method for benzyl alcohol-substituted 2-benzyl alcohol amide intermediates is as follows: The substituted aminobenzyl alcohol, monoethyl malonate chloride or monomethyl malonate chloride and imidazole were reacted in CH2Cl2 solution by rt ​​reaction, and then separated by column chromatography to obtain the benzyl alcohol substituted 2-benzyl alcohol amide intermediate; When the raw materials are substituted aminobenzyl alcohol, monomethyl malonate chloride and imidazole, the intermediate for substituted 2-benzyl alcohol amide is 2a-10-2a-18; when the raw materials are substituted aminobenzyl alcohol, monomethyl malonate chloride and imidazole, the intermediate for substituted 2-benzyl alcohol amide is 2a-19-2a-21. The molar ratio of substituted aminobenzyl alcohol, monoethyl malonate chloride or monomethyl malonate chloride and imidazole is 5:5:

7.

6. The method for synthesizing a 2-quinolinone compound according to claim 5, characterized in that, The synthetic method for the N-substituted 2-benzyl alcohol amide intermediate is as follows: 2-Benzylaminomethanol, monoethyl malonate chloride and imidazole were reacted in CH2Cl2 solution by rt ​​reaction, followed by column chromatography to obtain N-substituted 2-benzyl alcohol amide intermediate 2a-22; The molar ratio of 2-benzylaminomethanol, malonic acid monoethyl ester chloride, and imidazole is 5:5:

7.

7. The method for synthesizing a 2-quinolinone compound according to claim 6, characterized in that, The synthesis method of 2a-23 is as follows: 2-aminobenzyl alcohol is added to a round-bottom flask containing CH2Cl2 and stirred in an ice bath. Diethyl ketone is slowly added dropwise and the reaction is carried out at rt. After the reaction is completed, the intermediate 2a-23 is obtained by column chromatography.

8. The method for synthesizing a 2-quinolinone compound according to claim 7, characterized in that, S2 specifically involves adding 2-benzyl alcohol amide intermediate, KMnO4, and CH2Cl2 to a capped reaction tube equipped with a magnetic stirrer, heating under reflux, and then separating the quinolinone compounds by column chromatography after the reaction is complete.

9. The method for synthesizing a 2-quinolinone compound according to claim 8, characterized in that, The molar ratio of 2-benzyl alcohol amide intermediate, KMnO4 and CH2Cl2 was 5:5:3, the reaction temperature was 50℃, and the reaction time was 15h.

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