A one-pot method for synthesizing quinolinone derivatives by carbonyl insertion reaction

Abstract

The present invention relates to a method for synthesizing quinolinone derivatives in a one-pot method by carbonylation reaction. Specifically, in the presence of a catalyst and a ligand, an aniline derivative is used as a raw material, and a quinolinone derivative formula A compound is directly prepared by a one-pot simple reaction. The method of the present invention reduces the catalyst and the ligand to a minimum of 1%-2%, improves the reaction efficiency, reduces the cost and the difficulty of synthesis, and has industrial application prospects. , wherein R1 is Me or Et; R2 is H or Me; R3 is F, Cl, Br, Me, OMe or CF3.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical synthesis, and particularly relates to a method for simply synthesizing quinolinone derivatives through a one-pot carbonyl insertion reaction. Background Art

[0002] Quinoline, also known as naphthalene azapropazone, is an important nitrogen-containing heterocyclic compound. It is the parent nucleus structure of the antimalarial drug quinine, so the synthesis and application of quinoline compounds have received extensive attention. Due to the diversity of chemical properties brought by the quinoline structure, the biological activity of its derivatives can be effectively increased, so its derivatives have been developed, prepared and applied in large quantities. Studies have shown that many derivatives of quinoline have multiple biological activities such as antibacterial, anti-inflammatory, antimalarial and anti-tumor. Therefore, quinoline derivatives play an irreplaceable role in drug synthesis and are widely used in the research and development of drugs with various functions.

[0003] Among the many derivatives of quinoline, quinolinone is an important class of compounds. It is widely distributed in various biologically active molecules including natural products and a large number of drug molecules. Currently, many drugs are derived from quinolinone, such as norfloxacin, ciprofloxacin, Levaquin, Vigamox, Avelox. Therefore, quinolinone plays an irreplaceable role in the synthesis of antiviral, antibacterial, anti-tumor drugs. In the current reactions for synthesizing quinolinone, there are the following types of synthesis methods:

[0004] In 2022, the patent (CN117800956A) reported a method for preparing quinolinone based on 2-nitroacetophenone. The reaction is relatively simple, but the subsequent derivatization can only be carried out through the carbonyl and imino groups, and there are fewer reaction sites to choose from.

[0005] ;

[0006] Patent (CN108947985A) reported a method for preparing quinolinone based on aniline. The reaction required three steps, but also required highly toxic phosphorus pentoxide for cyclization reaction. The wastewater rich in phosphine was difficult to treat, which was not very friendly to large-scale industrial production or even laboratory repetition.

[0007] ;

[0008] The patent (CN111484477 A) uses halogenated benzoic acid as raw material, and obtains quinolinone by cyclization with amide compounds after carboxyl chlorination. It needs to prepare amide compounds in advance, starting from two raw materials, which prolongs the reaction route and makes the reaction complicated. In addition, it is often undesirable to use DMF as a solvent for the reaction. Therefore, there are still many areas that need to be optimized in this route.

[0009] .

[0010] In terms of synthesis, carbon monoxide is a commercially available and inexpensive gas, and is widely used in various organic synthesis reactions, such as Fischer-Tropsch synthesis and hydroformylation of olefins. Among them, the carbon monoxide insertion reaction is an important reaction in organic chemistry. It is an oxidative addition reaction between the halide and the zero-valent palladium catalyst to form the corresponding palladium complex, and then carbon monoxide (CO) is inserted into the palladium-carbon bond as an insertion agent, and then reduced and eliminated to form the corresponding compound. Considering the structural diversity of organic heterocyclic compounds, they play a prominent role in medicinal chemistry and combinatorial chemistry. New processes need to be developed to prepare these compounds efficiently, simply and cheaply. Summary of the invention

[0011] The present invention relates to a method for synthesizing quinolinone derivatives in a one-pot carbonylation reaction. In order to achieve the technical purpose of the present invention, the technical scheme of the present invention is as follows:

[0012] In the first aspect, the present invention provides a compound of formula A, the specific structure of which is:

[0013] ,

[0014] Among them, R2 is H; R3 is CF3.

[0015] The present invention further provides a compound of formula A36, the specific structure of which is:

[0016] .

[0017] In a second aspect, the present invention provides a method for preparing a compound of formula A, specifically, in the presence of a zero-valent palladium catalyst and a ligand, using an aniline derivative as a raw material, and preparing a quinolinone derivative compound of formula A by a one-pot method through a carbon monoxide carbon insertion reaction:

[0018] ;

[0019] Wherein, R1 is Me or Et; R2 is H or Me; R3 is F, Cl, Br, Me, OMe or CF3;

[0020] The carbon insertion reaction ligand may be triphenylphosphine or Xantphos, and most preferably, the reaction ligand is Xantphos;

[0021] The carbon insertion reaction is carried out in the presence of a base, and the reaction base can be an organic base or an inorganic base, preferably one or any combination of triethylamine, potassium carbonate and sodium carbonate, and most preferably, the reaction base is sodium carbonate and potassium carbonate;

[0022] The zero-valent palladium catalyst for the carbon insertion reaction is palladium chloride, palladium hydroxide or palladium acetate. Most preferably, the reaction catalyst is palladium acetate;

[0023] The carbon insertion reaction is carried out in the presence of a solvent, and the solvent is trifluorotoluene, toluene, acetonitrile or ethanol. Most preferably, the reaction solvent is acetonitrile;

[0024] The carbon insertion reaction needs to be charged with carbon monoxide pressure to 0.2-3.0Mpa, and most preferably, the carbon insertion reaction needs to be charged with carbon monoxide pressure to 2.5Mpa;

[0025] The carbon insertion reaction temperature is 20-80°C, and most preferably, the carbon insertion reaction temperature is 50°C;

[0026] The carbon insertion reaction time is 2-48 hours, and most preferably, the carbon insertion reaction time is 16 hours.

[0027] The preferred embodiment of the present invention is:

[0028] Synthetic formula A36 compound:

[0029] ,

[0030] Wherein, R1 is Me; R2 is H; R3 is CF3;

[0031] In the above reaction, the ligand is Xantphos, the catalyst is palladium acetate, and the base is sodium carbonate or potassium carbonate.

[0032] The present invention is a new method for directly obtaining quinolinone derivatives through a one-pot simple reaction based on the carbonyl insertion reaction and using aniline derivatives as raw materials. The method improves the reaction efficiency, reduces the cost and the difficulty of synthesis, and reduces the palladium catalyst and ligand to a minimum of 1%-2%, which has prospects for industrial application. DETAILED DESCRIPTION

[0033] In order to further understand the present invention, the following is a detailed description of a method for synthesizing quinolinone derivatives by a one-pot carbonylation reaction provided by the present invention in combination with examples. It should be understood that these examples are only for further illustrating the features of the present invention, and are not intended to limit the scope of the present invention or the scope of the claims of the present invention.

[0034] Embodiment 1:

[0035] ,

[0036] Methyl anthranilate (755.83 mg, 5 mmol, 1.0 eq.), bromoacetonitrile (1.5 g, 12.5 mmol, 2.5 eq.), palladium acetate (22.45 mg, 0.1 mmol, 0.02 eq.), Xantphos (57.86 mg, 0.1 mmol, 0.02 eq.), sodium carbonate (795 mg, 7.5 mmol, 1.5 eq.) and 10 mL of acetonitrile were added to a dry 50 mL autoclave in sequence. After the addition was completed, the hydrogenation autoclave was sealed; nitrogen was replaced three times in the hydrogenation autoclave, and carbon monoxide was filled to 2.5 MPa; the hydrogenation autoclave was placed in a 50°C oil bath for 16 h; after 16 h, it was cooled to room temperature; the reaction solution was filtered, and the residue was rinsed with 50 mL of acetonitrile; a magnet was added to the filtrate, and potassium carbonate (1.38 g, 10.0 mmol, 2 eq.); stirred at 25-30 °C for 16 h; after the reaction was completed, the reaction solution was filtered and the solid was rinsed with 100 mL acetonitrile; the filtrate was transferred to a 500 mL single-necked bottle, a magnetic bar was added, and 500 mL of dichloromethane was added dropwise within 1 hour under stirring. A small amount of solid began to precipitate, and stirring was continued for 4 h until the amount of solid no longer increased; a white solid was obtained by filtration, and 800 mg of white solid product A14 (800 mg, 86% yield, Solid) was obtained after drying. 1 H NMR (400 MHz, CD3OD) δ 7.95 (d, J = 8.0 Hz, 1H), 7.45-7.39(m, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.07 (t, J = 8.0 Hz,1H). 13 C NMR (400 MHz, CD3OD) δ 179.59, 166.29, 139.37, 131.61, 124.59, 121.15, 120.67, 119.27,115.40, 82.05. LCMS (ESI) calcd. for C 10 H6N2O2[M+H] + = 187.0503, found:187.0502.

[0037] Embodiment 2:

[0038] ,

[0039] To a dry 50 mL autoclave, methyl N-methyl anthranilate (825.96 mg, 5 mmol, 1.0 eq.), bromoacetonitrile (1.5 g, 12.5 mmol, 2.5 eq.), palladium acetate (56.13 mg, 0.25 mmol, 0.05 eq.), Xantphos (144.66 mg, 0.25 mmol, 0.05 eq.), sodium carbonate (795 mg, 7.5 mmol, 1.5 eq.) and acetonitrile 10 mL were added in sequence. After the addition was completed, the hydrogenation autoclave was sealed; nitrogen was replaced three times in the hydrogenation autoclave, and carbon monoxide was filled to 2.5 MPa; the hydrogenation autoclave was placed in a 50°C oil bath for 16 h; after 16 h, it was cooled to room temperature; the reaction solution was filtered, and the residue was washed with 50% ethanol and 4% ethanol. mL acetonitrile was used for elution; a magnetic particle was added to the filtrate, and potassium carbonate (1.38 g, 10.0 mmol, 2 eq.) was added under magnetic stirring; the mixture was stirred at 25-30 °C for 16 h; after the reaction was completed, the reaction solution was filtered, and the solid was rinsed with 100 mL acetonitrile; the filtrate was transferred to a 500 mL single-necked bottle, a magnetic particle was added, and 500 mL dichloromethane was added dropwise within 1 hour under stirring, and a small amount of solid began to precipitate. The stirring was continued for 4 h until the amount of solid no longer increased; a white solid was obtained by filtration, and 860 mg of white solid product A15 (860 mg, 86 % yield, Solid) was obtained after drying. 1 H NMR (400 MHz, CD3OD) δ 8.14-8.10 (m, 1H),7.63-7.56(m, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 7.2 Hz,1H). 13 C NMR (400MHz, CD3OD) δ 178.14, 165.27, 140.71, 131.96, 125.11, 121.95, 121.11, 119.17,114.21, 27.96. LCMS (ESI) calcd. for C 11 H8N2O2[M+H] + = 201.0659, found:201.0651.

[0040] Embodiment 3:

[0041] ,

[0042] To a dry 50 mL autoclave, methyl 2-amino-4-methylbenzoate (825.96 mg, 5 mmol, 1.0 eq.), bromoacetonitrile (1.5 g, 12.5 mmol, 2.5 eq.), palladium acetate (56.13 mg, 0.25 mmol, 0.05 eq.), Xantphos (144.66 mg, 0.25 mmol, 0.05 eq.), sodium carbonate (795 mg, 7.5 mmol, 1.5 eq.) and acetonitrile 10 mL were added in sequence. After the addition was completed, the hydrogenation autoclave was sealed; nitrogen was replaced three times in the hydrogenation autoclave, and carbon monoxide was filled to 2.5 MPa; the hydrogenation autoclave was placed in a 50°C oil bath for 16 h; after 16 h, it was cooled to room temperature; the reaction solution was filtered, and the residue was washed with 50% ethanol and 4% ethanol. mL acetonitrile was used for elution; a magnetic particle was added to the filtrate, and potassium carbonate (1.38 g, 10.0 mmol, 2 eq.) was added under magnetic stirring; the mixture was stirred at 25-30 °C for 16 h; after the reaction was completed, the reaction solution was filtered, and the solid was rinsed with 100 mL acetonitrile; the filtrate was transferred to a 500 mL single-necked bottle, a magnetic particle was added, and 500 mL dichloromethane was added dropwise within 1 hour under stirring, and a small amount of solid began to precipitate. The stirring was continued for 4 h until the amount of solid no longer increased; a white solid was obtained by filtration, and after drying, 780 mg of white solid product A22 (780 mg, 78 % yield, Solid) was obtained. 1 H NMR (400 MHz, CD3OD) 7.87 (d, J = 8.0 Hz, 1H), 6.99 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 2.38 (s, 3H). 13 C NMR (400 MHz, CD3OD)δ 179.61, 166.40, 142.56, 139.47, 124.57, 122.59, 119.34, 118.48, 115.25,81.63, 20.28. LCMS (ESI) calcd. for C 11 H8N2O2[M+H] + = 201.0659, found: 201.0684.

[0043] Embodiment 4:

[0044] ,

[0045] To a dry 50 mL autoclave, methyl 2-amino-3-methylbenzoate (825.96 mg, 5 mmol, 1.0 eq.), bromoacetonitrile (1.5 g, 12.5 mmol, 2.5 eq.), palladium acetate (56.13 mg, 0.25 mmol, 0.05 eq.), Xantphos (144.66 mg, 0.25 mmol, 0.05 eq.), sodium carbonate (795 mg, 7.5 mmol, 1.5 eq.) and acetonitrile 10 mL were added in sequence. After the addition was completed, the hydrogenation autoclave was sealed; the hydrogenation autoclave was evacuated and replaced with nitrogen three times, and carbon monoxide was filled to 2.5 MPa; the hydrogenation autoclave was placed in a 50°C oil bath and kept warm for 16 h; 16 h later, the temperature was lowered to room temperature; the reaction solution was filtered, and the residue was rinsed with 50 mL of acetonitrile; a magnetic bar was added to the filtrate, and potassium carbonate (1.38 g, 10.0 mmol, 2 eq.) was added under magnetic stirring; the mixture was stirred at 25-30 °C for 16 h; after the reaction was completed, the reaction solution was filtered, and the solid was rinsed with 100 mL of acetonitrile; the filtrate was transferred to a 500 mL single-mouth bottle, a magnetic bar was added, and 500 mL of dichloromethane was added dropwise within 1 hour under stirring, and a small amount of solid began to precipitate. Stirring was continued for 4 h until the amount of solid no longer increased; a white solid was obtained by filtration, and 600 mg of white solid product A24 (600 mg, 60 % yield, Solid) was obtained after drying. 1 H NMR (400 MHz, CD3OD) δ 7.89 (d, J = 8.8Hz, 1H), 7.34 (d, J = 7.2 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 2.39 (s, 3H). 13 CNMR (400 MHz, CD3OD) δ 179.80, 166.18, 137.40, 132.81, 123.18, 122.77,120.93, 120.74, 118.79, 81.88, 15.71. LCMS (ESI) calcd. for C 11 H8N2O2[M+H] + =201.0659, found: 201.0647.

[0046] Embodiment 5:

[0047] ,

[0048] To a dry 50 mL autoclave, methyl 2-amino-4-methoxybenzoate (905.95 mg, 5 mmol, 1.0 eq.), bromoacetonitrile (1.5 g, 12.5 mmol, 2.5 eq.), palladium acetate (56.13 mg, 0.25 mmol, 0.05 eq.), Xantphos (144.66 mg, 0.25 mmol, 0.05 eq.), sodium carbonate (795 mg, 7.5 mmol, 1.5 eq.) and 10 mL of acetonitrile were added in sequence. After the addition was completed, the hydrogenation autoclave was sealed; the hydrogenation autoclave was evacuated with nitrogen three times and filled with carbon monoxide to 2.5 MPa; the hydrogenation autoclave was placed in a 50°C oil bath for 16 h; after 16 h, it was cooled to room temperature; the reaction solution was filtered, and the residue was washed with 50% ethanol and 4% ethanol. mL acetonitrile was used for elution; a magnetic particle was added to the filtrate, and potassium carbonate (1.38 g, 10.0 mmol, 2 eq.) was added under magnetic stirring; the mixture was stirred at 25-30 °C for 16 h; after the reaction was completed, the reaction solution was filtered, and the solid was rinsed with 100 mL acetonitrile; the filtrate was transferred to a 500 mL single-necked bottle, a magnetic particle was added, and 500 mL dichloromethane was added dropwise within 1 hour under stirring, and a small amount of solid began to precipitate. Stirring was continued for 4 h until the amount of solid no longer increased; a white solid was obtained by filtration, and after drying, 755 mg of white solid product A26 (755 mg, 70 % yield, Solid) was obtained. 1 H NMR (400 MHz, CD3OD) δ 7.90 (d, J = 8.8 Hz,1H), 6.73-6.69 (m,1H), 6.67 (d, J = 2.0 Hz, 1H), 3.84 (s, 3H). 13 C NMR (400MHz, CD3OD) δ 179.41, 166.66, 163.08, 141.10, 126.27, 119.35, 114.50, 109.94,97.89, 80.83, 54.57. LCMS (ESI) calcd. for C 11 H8N2O3[M+H] + = 217.0608, found:217.0638.

[0049] Embodiment 6:

[0050] ,

[0051] To a dry 50 mL autoclave, methyl 2-amino-5-chlorobenzoate (928 mg, 5 mmol, 1.0 eq.), bromoacetonitrile (1.5 g, 12.5 mmol, 2.5 eq.), palladium acetate (56.13 mg, 0.25 mmol, 0.05 eq.), Xantphos (144.66 mg, 0.25 mmol, 0.05 eq.), sodium carbonate (795 mg, 7.5 mmol, 1.5 eq.) and acetonitrile 10 mL were added in sequence. After the addition was completed, the hydrogenation autoclave was sealed; the hydrogenation autoclave was evacuated with nitrogen three times and filled with carbon monoxide to 2.5 MPa; the hydrogenation autoclave was placed in a 50°C oil bath for 16 h; after 16 h, it was cooled to room temperature; the reaction solution was filtered, and the residue was washed with 50% ethanol and 4% ethanol. mL acetonitrile was used for elution; a magnetic particle was added to the filtrate, and potassium carbonate (1.38 g, 10.0 mmol, 2 eq.) was added under magnetic stirring; the mixture was stirred at 25-30 °C for 16 h; after the reaction was completed, the reaction solution was filtered, and the solid was rinsed with 100 mL acetonitrile; the filtrate was transferred to a 500 mL single-necked bottle, a magnetic particle was added, and 500 mL dichloromethane was added dropwise within 1 hour under stirring, and a small amount of solid began to precipitate. The stirring was continued for 4 h until the amount of solid no longer increased; a white solid was obtained by filtration, and 860 mg of white solid product A28 (860 mg, 78 % yield, Solid) was obtained after drying. 1 H NMR (400 MHz, CD3OD) 7.95 (d, J = 2.4 Hz, 1H), 7.46-7.40 (m, 1H), 7.18 (d, J = 8.8 Hz, 1H). 13 C NMR (400 MHz, CD3OD) δ178.06, 166.04, 137.99, 131.39, 126.60, 123.96, 121.93, 118.78, 117.19,82.46. LCMS (ESI) calcd. for C 10 H5ClN2O2[M+H] + = 221.0113, found: 221.0134.

[0052] Embodiment 7:

[0053] ,

[0054] To a dry 50 mL autoclave, ethyl 2-amino-5-methylbenzoate (896 mg, 5 mmol, 1.0 eq.), bromoacetonitrile (1.5 g, 12.5 mmol, 2.5 eq.), palladium acetate (56.13 mg, 0.25 mmol, 0.05 eq.), Xantphos (144.66 mg, 0.25 mmol, 0.05 eq.), sodium carbonate (795 mg, 7.5 mmol, 1.5 eq.) and acetonitrile 10 mL were added in sequence. After the addition was completed, the hydrogenation autoclave was sealed; the hydrogenation autoclave was evacuated with nitrogen three times and filled with carbon monoxide to 2.5 MPa; the hydrogenation autoclave was placed in a 50°C oil bath for 16 h; after 16 h, it was cooled to room temperature; the reaction solution was filtered, and the residue was washed with 50% ethanol and 4% ethanol. mL acetonitrile was used for elution; a magnetic particle was added to the filtrate, and potassium carbonate (1.38 g, 10.0 mmol, 2 eq.) was added under magnetic stirring; the mixture was stirred at 25-30 °C for 16 h; after the reaction was completed, the reaction solution was filtered, and the solid was rinsed with 100 mL acetonitrile; the filtrate was transferred to a 500 mL single-necked bottle, a magnetic particle was added, and 500 mL of dichloromethane was added dropwise within 1 hour under stirring, and a small amount of solid began to precipitate. Stirring was continued for 4 h until the amount of solid no longer increased; a white solid was obtained by filtration, and 880 mg of white solid product A30 (880 mg, 88 % yield, Solid) was obtained after drying. 1 H NMR (400 MHz, CD3OD) δ 7.81 (s, 1H), 7.31-7.26 (m, 1H), 7.08 (d, J = 8.4 Hz, 1H), 2.35 (s, 3H). 13 C NMR (400 MHz, CD3OD)δ 179.52, 166.09, 137.15, 132.81, 130.92, 124.20, 120.47, 119.18, 115.36,82.15, 19.52. LCMS (ESI) calcd. for C 11 H8N2O2[M+H] + = 201.0659, found: 201.0681.

[0055] Embodiment 8:

[0056] ,

[0057] To a dry 50 mL autoclave, methyl 2-amino-4-chlorobenzoate (928 mg, 5 mmol, 1.0 eq.), bromoacetonitrile (1.5 g, 12.5 mmol, 2.5 eq.), palladium acetate (56.13 mg, 0.25 mmol, 0.05 eq.), Xantphos (144.66 mg, 0.25 mmol, 0.05 eq.), sodium carbonate (795 mg, 7.5 mmol, 1.5 eq.) and acetonitrile 10 mL were added in sequence. After the addition was completed, the hydrogenation autoclave was sealed; the hydrogenation autoclave was evacuated with nitrogen three times and filled with carbon monoxide to 2.5 MPa; the hydrogenation autoclave was placed in a 50°C oil bath for 16 h; after 16 h, it was cooled to room temperature; the reaction solution was filtered, and the residue was washed with 50% ethanol and 4% ethanol. mL acetonitrile was used for elution; a magnetic particle was added to the filtrate, and potassium carbonate (1.38 g, 10.0 mmol, 2 eq.) was added under magnetic stirring; the mixture was stirred at 25-30 °C for 16 h; after the reaction was completed, the reaction solution was filtered, and the solid was rinsed with 100 mL acetonitrile; the filtrate was transferred to a 500 mL single-necked bottle, a magnetic particle was added, and 500 mL dichloromethane was added dropwise within 1 hour under stirring, and a small amount of solid began to precipitate. The stirring was continued for 4 h until the amount of solid no longer increased; a white solid was obtained by filtration, and after drying, 805 mg of white solid product A32 (805 mg, 73 % yield, Solid) was obtained. 1 H NMR (400 MHz, CD3OD) δ 7.95 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.11-7.06 (m, 1H). 13 C NMR (400 MHz, CD3OD) δ178.60, 160.01, 140.49, 137.27, 126.38, 121.25, 119.37, 118.97, 114.96,82.14. LCMS (ESI) calcd. for C 10 H5ClN2O2[M+H] + = 221.0113, found: 221.0132.

[0058] Embodiment 9:

[0059] ,

[0060] To a dry 50 mL autoclave, methyl 2-amino-4-fluorobenzoate (846 mg, 5 mmol, 1.0 eq.), bromoacetonitrile (1.5 g, 12.5 mmol, 2.5 eq.), palladium acetate (56.13 mg, 0.25 mmol, 0.05 eq.), Xantphos (144.66 mg, 0.25 mmol, 0.05 eq.), sodium carbonate (795 mg, 7.5 mmol, 1.5 eq.) and acetonitrile 10 mL were added in sequence. After the addition was completed, the hydrogenation autoclave was sealed; nitrogen was replaced three times in the hydrogenation autoclave, and carbon monoxide was filled to 2.5 MPa; the hydrogenation autoclave was placed in a 50°C oil bath for 16 h; after 16 h, it was cooled to room temperature; the reaction solution was filtered, and the residue was washed with 50% ethanol and 4% ethanol. mL acetonitrile was used for elution; a magnetic particle was added to the filtrate, and potassium carbonate (1.38 g, 10.0 mmol, 2 eq.) was added under magnetic stirring; the mixture was stirred at 25-30 °C for 16 h; after the reaction was completed, the reaction solution was filtered, and the solid was rinsed with 100 mL acetonitrile; the filtrate was transferred to a 500 mL single-necked bottle, a magnetic particle was added, and 500 mL dichloromethane was added dropwise within 1 hour under stirring, and a small amount of solid began to precipitate. Stirring was continued for 4 h until the amount of solid no longer increased; a white solid was obtained by filtration, and after drying, 663 mg of white solid product A34 (663 mg, 65 % yield, Solid) was obtained. 1 H NMR (400 MHz, CD3OD) δ 8.06-7.98 (m, 1H), 6.93-6.81 (m, 2H). 13 C NMR (400 MHz, CD3OD) δ 178.73, 166.67, 166.27, 163.80,160.04, 141.39, 141.27, 127.43, 127.33, 119.00, 117.56, 117.54, 108.95,108.72, 101.41, 101.15, 81.64. 19 F NMR (400 MHz, CD3OD) δ -110.22. LCMS (ESI)calcd. for C 10 H5FN2O2[M+H] + = 205.0408, found: 205.0430.

[0061] Embodiment 10:

[0062] ,

[0063] To a dry 50 mL autoclave, methyl 2-amino-4-trifluoromethylbenzoate (1096 mg, 5 mmol, 1.0 eq.), bromoacetonitrile (1.5 g, 12.5 mmol, 2.5 eq.), palladium acetate (56.13 mg, 0.25 mmol, 0.05 eq.), Xantphos (144.66 mg, 0.25 mmol, 0.05 eq.), sodium carbonate (795 mg, 7.5 mmol, 1.5 eq.) and acetonitrile 10 mL were added in sequence. After the addition was completed, the hydrogenation autoclave was sealed; the hydrogenation autoclave was evacuated with nitrogen three times and filled with carbon monoxide to 2.5 MPa; the hydrogenation autoclave was placed in a 50°C oil bath for 16 h; after 16 h, it was cooled to room temperature; the reaction solution was filtered, and the residue was washed with 50% ethanol and 4% ethanol. mL acetonitrile was used for elution; a magnetic particle was added to the filtrate, and potassium carbonate (1.38 g, 10.0 mmol, 2 eq.) was added under magnetic stirring; the mixture was stirred at 25-30 °C for 16 h; after the reaction was completed, the reaction solution was filtered, and the solid was rinsed with 100 mL acetonitrile; the filtrate was transferred to a 500 mL single-necked bottle, a magnetic particle was added, and 500 mL dichloromethane was added dropwise within 1 hour under stirring, and a small amount of solid began to precipitate. Stirring was continued for 4 h until the amount of solid no longer increased; a white solid was obtained by filtration, and 876 mg of white solid product A36 (876 mg, 69 % yield, Solid) was obtained after drying. 1 H NMR (400 MHz, CD3OD) δ 8.15 (d, J = 8.4 Hz,1H), 7.50 (s, 1H), 7.38-7.32 (m, 1H). 13 C NMR (400 MHz, CD3OD) δ 178.15,166.08, 139.30, 133.01, 132.68, 125.99, 125.26, 123.18, 122.56, 118.40,116.96, 116.92, 112.49, 112.45, 83.10. 19 F NMR (400 MHz, CDCl3) δ -66.45. LCMS(ESI) calcd. for C 11 H5F3N2O2[M+H] + = 255.0376, found: 255.0400.

[0064] Embodiment 11:

[0065] ,

[0066] To a dry 50 mL autoclave, methyl 2-amino-4,5-dimethoxybenzoate (1056 mg, 5 mmol, 1.0 eq.), bromoacetonitrile (1.5 g, 12.5 mmol, 2.5 eq.), palladium acetate (56.13 mg, 0.25mmol, 0.05 eq.), Xantphos (144.66 mg, 0.25 mmol, 0.05 eq.), sodium carbonate (795 mg, 7.5mmol, 1.5 eq.) and acetonitrile 10 mL were added in sequence. After the addition was completed, the hydrogenation autoclave was sealed; the hydrogenation autoclave was evacuated with nitrogen three times and filled with carbon monoxide to 2.5 MPa; the hydrogenation autoclave was placed in a 50°C oil bath for 16 h; after 16 h, it was cooled to room temperature; the reaction solution was filtered, and the residue was washed with 50% ethanol and the mixture was stirred for 10 minutes. mL acetonitrile was used for elution; a magnetic particle was added to the filtrate, and potassium carbonate (1.38 g, 10.0 mmol, 2eq.) was added under magnetic stirring; the reaction mixture was stirred at 25-30 °C for 16 h; after the reaction was completed, the reaction solution was filtered and the solid was rinsed with 100 mL acetonitrile; the filtrate was transferred to a 500 mL single-necked bottle, a magnetic particle was added, and 500 mL dichloromethane was added dropwise within 1 hour under stirring, and a small amount of solid began to precipitate. Stirring was continued for 4 h until the amount of solid no longer increased; a white solid was obtained by filtration, and 849 mg of white solid product A38 (849 mg, 69 % yield, Solid) was obtained after drying. 1 H NMR (400 MHz, CD3OD) δ 7.48 (s, 1H), 6.75 (s, 1H), 3.89 (s, 3H), 3.86 (s, 3H). 13 C NMR (400 MHz, CD3OD) δ 179.04,166.22, 153.39, 145.09, 134.86, 119.12, 113.53, 105.74, 97.82, 81.19, 55.15,55.06. LCMS (ESI) calcd. for C 12 H 10 N2O4[M+H] + = 247.0714, found: 247.0729.

[0067] Embodiment 12:

[0068] ,

[0069] To a dry 50 mL autoclave, methyl 2-amino-4-bromobenzoate (1150 mg, 5 mmol, 1.0 eq.), bromoacetonitrile (1.5 g, 12.5 mmol, 2.5 eq.), palladium acetate (56.13 mg, 0.25 mmol, 0.05 eq.), Xantphos (144.66 mg, 0.25 mmol, 0.05 eq.), sodium carbonate (795 mg, 7.5 mmol, 1.5 eq.) and acetonitrile 10 mL were added in sequence. After the addition was completed, the hydrogenation autoclave was sealed; the hydrogenation autoclave was evacuated with nitrogen three times and filled with carbon monoxide to 2.5 MPa; the hydrogenation autoclave was placed in a 50°C oil bath for 16 h; after 16 h, it was cooled to room temperature; the reaction solution was filtered, and the residue was washed with 50% ethanol and 4% ethanol. mL acetonitrile was used for elution; a magnetic particle was added to the filtrate, and potassium carbonate (1.38 g, 10.0 mmol, 2 eq.) was added under magnetic stirring; the mixture was stirred at 25-30 °C for 16 h; after the reaction was completed, the reaction solution was filtered, and the solid was rinsed with 100 mL acetonitrile; the filtrate was transferred to a 500 mL single-necked bottle, a magnetic particle was added, and 500 mL dichloromethane was added dropwise within 1 hour under stirring, and a small amount of solid began to precipitate. Stirring was continued for 4 h until the amount of solid no longer increased; a white solid was obtained by filtration, and after drying, 994 mg of a white solid product A40 (994 mg, 75 % yield, Solid) was obtained. 1 H NMR (400 MHz, CD3OD) δ 7.88 (d, J = 8.4 Hz,1H), 7.38 (s, 1H), 7.26-7.20 (m, 1H). 13 C NMR (400 MHz, CD3OD) δ 178.67,166.22, 140.48, 126.44, 125.52, 124.15, 119.70, 118.82, 117.97, 82.25. LCMS(ESI) calcd. for C 10 H5BrN2O2[M+H] + = 264.9608, found: 264.9616.

Claims

1. A method for preparing a compound of formula A, characterized in that: In the presence of a divalent palladium catalyst and Xantphos, a quinolinone derivative compound of formula A is prepared from an aniline derivative as a raw material by a one-pot carbon monoxide carbon insertion reaction: Among them, R1 is Me or Et; R2 is H or Me; R3 is F, Cl, Br, Me, OMe or CF3.

2. The preparation method according to claim 1, characterized in that: The divalent palladium catalyst for the carbon insertion reaction is palladium chloride, palladium hydroxide or palladium acetate.

3. The preparation method according to claim 1, characterized in that: The carbon insertion reaction is carried out in the presence of a base, and the base is selected from one or any combination of triethylamine, potassium carbonate and sodium carbonate.

4. The preparation method according to claim 1, characterized in that: The carbon insertion reaction is carried out in the presence of a solvent, and the solvent is trifluorotoluene, toluene, acetonitrile or ethanol.

5. The preparation method according to claim 1, characterized in that: The carbon insertion reaction requires the carbon monoxide pressure to be filled to 0.2-3.0 MPa.

6. The preparation method according to claim 1, characterized in that: The carbon insertion reaction temperature is 20-80°C.

7. The preparation method according to claim 1, characterized in that: The compound of formula A36 was prepared by a one-pot carbon monoxide carbon insertion reaction:

8. The preparation method according to claim 7, characterized in that: In the carbon insertion reaction, the ligand is Xantphos, the catalyst is palladium acetate, and the base is sodium carbonate or potassium carbonate.

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