A process for the preparation of a quinolone compound

Abstract

This invention provides a method for preparing quinolone compounds, belonging to the field of pharmaceutical intermediate synthesis technology. The invention involves mixing a phenolic compound, a fluorosulfonating reagent, an organic base, and an organic solvent to perform a fluorosulfonation reaction, yielding a fluorosulfonated product. The fluorosulfonated product, a borate ester compound, a transition metal catalyst, a ligand, an inorganic base, and a solvent are then mixed and coupled to obtain the quinolone compound. The purpose of this invention is to address the problems existing in current synthetic methods for C7 carbon-carbon bond-substituted quinolone compounds, such as long reaction steps, low yields, and numerous hazardous processes. It provides a new synthetic method for quinolone compounds, requiring inexpensive and readily available chemical reagents, featuring a short process, high yield, and avoiding the use of hydrogen or diazonium salts, making it suitable for both rapid laboratory synthesis and industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, and in particular to a method for preparing quinolone compounds. Background Technology

[0002] Quinolones are a class of synthetic anti-infective drugs with a pyridoxine core structure. Due to their broad antibacterial spectrum and strong antibacterial activity, they have become one of the most widely used antibacterial drugs in clinical practice. Through structural modification of substituents at different positions on the core, five generations and dozens of quinolone antibacterial drugs have been developed. For example, introducing a fluorine atom at the C6 position of a quinolone can improve its lipophilicity and antibacterial activity against Gram-positive cocci; introducing a substituent at the C7 position can significantly enhance antibacterial activity, improve pharmacokinetics, and even generate new biological activities. Currently, the vast majority of quinolone drugs are compounds with an amino group substituted at the C7 position. In contrast, while quinolone compounds with carbon-carbon bonds substituted at the C7 position also possess excellent antibacterial activity, the difficulty in synthesizing the active pharmaceutical ingredient has hindered the development of these drugs. Currently, only a few quinolone drugs with carbon-carbon bonds substituted at the C7 position are on the market or under investigation, such as:

[0003] Toyama Chemicals of Japan developed mesylate plus rafloxacin using bromoquinolones as substrates and introducing an isoindole group at the C7 position via Suzuki coupling. This product is suitable for the treatment of pneumococcal pneumonia. The preparation principle is shown in the following formula:

[0004] ;

[0005] Ferrer Internacional, a Spanish company, developed ozelafloxacin using chloroquinolones as substrates and incorporating a polysubstituted pyridine at the C7 position via Suzuki coupling. Ozefloxacin is indicated for impetigo caused by Staphylococcus aureus or Streptococcus pyogenes. The preparation principle is shown in the following formula:

[0006] ;

[0007] Otsuka Pharmaceutical Co., Ltd. of Japan developed a novel fluoroquinolone compound using iodoquinolones as a substrate and introducing a polysubstituted pyridine group at the C7 position via Suzuki coupling. This compound exhibits excellent antimicrobial activity against Clostridium difficile. The preparation principle is shown in the following formula:

[0008] ;

[0009] Shenzhen Alpha Molecular Technology has reported a series of novel phenylquinolone compounds with antibacterial and anticancer properties by introducing different aryl substituents at the C7 position using bromoquinolones as substrates via Suzuki coupling. The preparation principle is shown in the following formula:

[0010] .

[0011] It can be seen that the Suzuki coupling reaction can conveniently modify different aryl substituents at the C7 position of quinolone. However, there are still some problems in the preparation of the halogenated quinolone precursor of the coupling reaction, such as (1) in order to introduce the halogen atom required for the coupling reaction, an additional 3 to 5 reaction steps are required, which is a long process; (2) the reaction needs to involve dangerous processes such as hydrogenation, diazotization or azidation; (3) the reaction yield is low and the amount of waste generated is large; (4) the amount of transition metal catalyst used is large and the cost is high. Summary of the Invention

[0012] In view of this, the purpose of this invention is to provide a method for preparing quinolone compounds. This invention provides a novel method for synthesizing quinolone compounds, which uses readily available raw materials, involves a short procedure, achieves high yield, and does not involve hazardous compounds such as hydrogen or diazonium salts. It is suitable for both rapid laboratory synthesis and industrial production.

[0013] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0014] This invention provides a method for preparing a quinolone compound, comprising the following steps:

[0015] A fluorosulfonation reaction is carried out by mixing a phenolic compound, a fluorosulfonating reagent, an organic base, and an organic solvent to obtain the fluorosulfonated product; the phenolic compound has the structure shown in Formula I:

[0016] Formula I;

[0017] In Formula I, R1 and R2 are substituents;

[0018] The fluorosulfonation product, borate ester compound, transition metal catalyst, ligand, inorganic base and solvent are mixed and coupled to obtain the quinolone compound.

[0019] Preferably, R1 and R2 are independently hydrogen or alkyl.

[0020] Preferably, the fluorosulfonation reaction is further preceded by an esterification reaction.

[0021] Preferably, the fluorosulfonating agent includes one or more of thioyl fluoride, thioyl fluoride chloride, and thioyl fluoride imidazole salt.

[0022] Preferably, the molar ratio of the phenolic compound to the organic base is 1:1 to 1:5.

[0023] Preferably, the organic base comprises triethylamine and / or 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0024] Preferably, the borate esters include aryl borate esters.

[0025] Preferably, the aryl borate esters include pinacol phenylboronic acid, pinacol trans-2-phenylvinylboronic acid, pinacol 3,4-dimethylenedioxyphenylboronic acid, pinacol 2-naphthoboronic acid, pinacol 3-pyridineboronic acid, or pinacol 2-furanboronic acid.

[0026] Preferably, the molar ratio of the fluorosulfonated product to the borate ester compound is 1:1 to 1:3.

[0027] Preferably, the molar ratio of the fluorosulfonation product to the transition metal catalyst is 1:0.001 to 1:0.1, the molar ratio of the transition metal catalyst to the ligand is 1:1 to 1:4, and the molar ratio of the fluorosulfonation product to the inorganic base is 1:1 to 1:5.

[0028] This invention provides a method for preparing a quinolone compound, comprising the following steps: mixing a phenolic compound, a fluorosulfonating agent, an organic base, and an organic solvent to carry out a fluorosulfonation reaction to obtain a fluorosulfonated product; and mixing the fluorosulfonated product, a borate ester compound, a transition metal catalyst, a ligand, an inorganic base, and a solvent to carry out a coupling reaction to obtain the quinolone compound.

[0029] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0030] The purpose of this invention is to solve the problems existing in the synthesis methods of C7 carbon-carbon bond-substituted quinolone compounds, such as long reaction steps, low yield, and many dangerous processes. It provides a new synthesis method for quinolone compounds, which requires inexpensive and readily available chemical reagents, has a short procedure, high yield, and does not involve dangerous compounds such as hydrogen or diazonium salts. It is suitable for rapid laboratory synthesis as well as industrial production. Attached Figure Description

[0031] Figure 1 The 1H NMR spectrum of the quinolone compound obtained in Example 1;

[0032] Figure 2 The 1H NMR spectrum of the quinolone compound obtained in Example 2;

[0033] Figure 3 The 1H NMR spectrum of the quinolone compound obtained in Example 3;

[0034] Figure 4 The 1H NMR spectrum of the quinolone compound obtained in Example 4;

[0035] Figure 5 The 1H NMR spectrum of the quinolone compound obtained in Example 5;

[0036] Figure 6 The 1H NMR spectrum of the quinolone compound obtained in Example 6;

[0037] Figure 7 The 1H NMR spectrum of the quinolone compound obtained in Example 7;

[0038] Figure 8 The 1H NMR spectrum of the quinolone compound obtained in Example 8;

[0039] Figure 9 The image shows the 1H NMR spectrum of the quinolone compound obtained in Example 9. Detailed Implementation

[0040] This invention provides a method for preparing a quinolone compound, comprising the following steps:

[0041] A fluorosulfonation reaction is carried out by mixing a phenolic compound, a fluorosulfonating reagent, an organic base, and an organic solvent to obtain the fluorosulfonated product; the phenolic compound has the structure shown in Formula I:

[0042] Formula I;

[0043] In Formula I, R1 and R2 are substituents;

[0044] The fluorosulfonation product, borate ester compound, transition metal catalyst, ligand, inorganic base and solvent are mixed and coupled to obtain the quinolone compound.

[0045] Unless otherwise specified, all raw materials used in this invention are commercially available products or products obtained by conventional methods.

[0046] This invention involves mixing phenolic compounds, fluorosulfonating reagents, organic bases, and organic solvents to carry out a fluorosulfonation reaction, thereby obtaining fluorosulfonated products.

[0047] In this invention, R1 and R2 in the phenolic compound are independently preferably hydrogen or alkyl, and the alkyl group is preferably a C1-6 alkyl group, more preferably a methyl group.

[0048] In this invention, the phenolic compounds are preferably obtained by hydrolysis of ester compounds. This invention does not impose any special limitations on the specific parameters of the hydrolysis, and any method known to those skilled in the art can be used.

[0049] In this invention, the fluorosulfonating agent preferably includes one or more of thioyl fluoride (gas), thioyl fluoride chloride, and thioyl fluoride imidazole salt.

[0050] In this invention, the molar ratio of the phenolic compound to the organic base is preferably 1:1 to 1:5, specifically 1:1, 1:2, 1:3, 1:4 or 1:1.

[0051] In this invention, the organic base preferably includes triethylamine (TEA) and / or 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0052] In this invention, the temperature of the fluorosulfonation reaction is preferably room temperature, i.e., no additional heating or cooling is required, and the time is preferably until the raw material conversion rate is greater than 95%.

[0053] In this invention, the organic solvent preferably includes one or more of acetonitrile (ACN), dichloromethane, tetrahydrofuran, and toluene.

[0054] In this invention, the phenolic compound and an organic base are dissolved in an organic solvent, sulfuryl fluoride gas is introduced, and the reaction is stirred at normal pressure and room temperature until the raw material conversion rate is greater than 95%. The resulting reaction solution is washed with water and evaporated to dryness to obtain the fluorosulfonated product.

[0055] In this invention, the esterification reaction is preferably performed before the fluorosulfonation reaction.

[0056] In this invention, the alcohols added during the esterification reaction preferably include methanol, ethanol, or propanol.

[0057] In this invention, the molar ratio of the quinolone compound to the alcohol is preferably 1:1.

[0058] In this invention, the esterification reaction is preferably carried out under concentrated sulfuric acid conditions, and the mass concentration of the concentrated sulfuric acid is preferably not less than 70%.

[0059] In this invention, the esterification reaction is preferably carried out under reflux conditions, and the esterification reaction time is preferably 12 hours.

[0060] In this invention, after the esterification reaction is completed, the resulting reaction solution is preferably cooled and then adjusted to neutral with sodium carbonate solution. The solid precipitates out, and the white solid product is obtained by filtration, which is the esterification product. Then, the fluorosulfonation reaction is carried out.

[0061] After obtaining the fluorosulfonated product, the present invention performs a coupling reaction by mixing the fluorosulfonated product, borate ester compound, transition metal catalyst, ligand, inorganic base and solvent to obtain the quinolone compound.

[0062] In this invention, the borate esters preferably include aryl borate esters.

[0063] In this invention, the aryl borate esters preferably include pinacol phenylboronic acid, pinacol trans-2-phenylvinylboronic acid, pinacol 3,4-dimethylenedioxyphenylboronic acid, pinacol 2-naphthoboronic acid, pinacol 3-pyridineboronic acid, or pinacol 2-furanboronic acid.

[0064] In this invention, the molar ratio of the fluorosulfonated product to the borate ester compound is preferably 1:1 to 1:3, specifically 1:1, 54:75, 1:2 or 1:3.

[0065] In this invention, the molar ratio of the fluorosulfonation product to the transition metal catalyst is preferably 1:0.001 to 1:0.1, specifically 1:0.001, 1:0.05, or 1:0.1; the molar ratio of the transition metal catalyst to the ligand is preferably 1:1 to 1:4, specifically 1:1, 1:2, 1:3, or 1:4; and the molar ratio of the fluorosulfonation product to the inorganic base is preferably 1:1 to 1:5, specifically 1:1, 1:2, 1:3, 1:4, or 1:1.

[0066] In this invention, the transition metal catalyst preferably includes one or more of palladium acetate, palladium chloride, tetra(triphenylphosphine)palladium(O) and nickel chloride.

[0067] In this invention, the ligand preferably includes a phosphine ligand, which preferably includes one or more of triphenylphosphine, tricyclohexylphosphine, triphenylphosphine tri-m-sulfonic acid, 1,1'-bis(diphenylphosphine)ferrocene and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl.

[0068] In this invention, the inorganic base preferably includes potassium phosphate and / or potassium carbonate.

[0069] In this invention, the solvent preferably includes one or more of water, ethers, ketones, and benzenes. The ethers preferably include one or more of 1,2-dimethoxyethane, dioxane, and tetrahydrofuran. The ketones preferably include one or more of methyl ketone, ethyl ketone, and methyl isobutyl ketone. The benzenes preferably include toluene.

[0070] In this invention, the temperature of the coupling reaction is preferably 80~100℃, specifically 80, 85, 90, 95 or 100℃, and the time is preferably 2~6h, specifically 2, 3, 4, 5 or 6h.

[0071] In this invention, the fluorosulfonation product, borate ester compound, ligand, inorganic base and solvent are mixed, and the resulting mixture is bubbled with nitrogen for 15 min. Then, the transition metal catalyst is added, the nitrogen is replaced, and the mixture is placed in an oil bath and stirred to carry out the coupling reaction.

[0072] After the coupling reaction is completed, preferably the resulting reaction solution is cooled and water is added, the solid precipitates out, and then filtered to obtain the quinolone compound.

[0073] In this invention, the preparation principle of the quinolone compound is shown in Formula A:

[0074] Formula A,

[0075] In the structural formula of the quinolone compound, R1 and R2 are substituents, R3 is an aromatic ring group, heteroaromatic ring group, alkenyl group, alkynyl group or methyl group, and R4 is H or alkyl. When no esterification reaction is carried out in the preparation process, R4 is H. When an esterification reaction is carried out in the preparation process, R4 is alkyl.

[0076] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0077] Example 1

[0078]

[0079] 1-Cyclopropyl-6-fluoro-7-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (15.20 mmol) and 50 mL of anhydrous ethanol were added to a reaction flask at room temperature. 5 g of concentrated sulfuric acid (98% by mass) was slowly added dropwise, and the mixture was refluxed. HPLC analysis after 12 h showed that the starting material had reacted completely. After cooling the reaction solution, sodium carbonate solution was added to adjust the pH to neutral. A solid precipitated, and filtration yielded a white solid product (3.5 g, 12.03 mmol, 79%).

[0080] MS: Calculated result: 292.09, Actual result: 292.09

[0081]

[0082] Ethyl 1-cyclopropyl-6-fluoro-7-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (12.03 mmol), 50 mL of anhydrous acetonitrile, and triethylamine (60.15 mmol) were added to a reaction flask at room temperature. Sulfonyl fluoride gas was introduced, and the reaction was stirred at ambient pressure and room temperature. HPLC analysis after 2 hours showed that the starting material had reacted completely. The reaction solution was adjusted to neutral with hydrochloric acid, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to obtain the crude product. Column chromatography purification yielded a white solid product (4.1 g, 10.86 mmol, 90%).

[0083]

[0084] At room temperature, 0.54 mmol of 1-cyclopropyl-6-fluoro-7-((fluorosulfonyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester was added to a reaction flask. Then, 5 mL of 1,4-dioxane, 0.5 mL of water, 0.75 mmol of pinacol phenylboronic acid, 0.11 mmol of triphenylphosphine, and 1.60 mmol of potassium phosphate were added. After bubbling the mixture under nitrogen for 15 min, 27 μmol of palladium acetate was added, and the mixture was placed in an oil bath at 85 °C with stirring. HPLC analysis after 2 h showed that the reaction proceeds were completely reacted. After cooling the reaction solution, 5 mL of water was added, and a solid precipitated. Filtering yielded a white solid product (168 mg, 0.48 mmol, 89%).

[0085] MS: Calculated result: 352.13, Actual result: 352.13

[0086] Nuclear magnetic resonance (NMR) characterization spectra are as follows Figure 1 As shown, 1 H NMR (500 M Hz, CDCl3) δ 8.55 (s, 1H), 8.15-8.13 (d, J=10 Hz, 1H), 7.91-7.90 (d, J=10 Hz, 1H), 7.56,-7.54 (d, J=10 Hz , 2H), 7.46-7.39 (m, 3H), 4.36-4.31 (q, J=10 Hz, 2H), 3.46-3.42 (m, 1H), 1.37- 1.34 (t, J=7Hz, 3H), 1.30-1.26 (q, J=6.5 Hz, 2H), 1.13-1.10 (q, J=7 Hz, 2H).

[0087] Example 2

[0088]

[0089] 1-Cyclopropyl-6-fluoro-7-((fluorosulfonyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester was prepared in Example 1.

[0090] At room temperature, 0.54 mmol of 1-cyclopropyl-6-fluoro-7-((fluorosulfonyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester was added to a reaction flask. Then, 5 mL of 1,4-dioxane, 0.5 mL of water, 0.75 mmol of trans-2-phenylvinylboronic acid pinacol ester, 0.11 mmol of triphenylphosphine, and 1.61 mmol of potassium phosphate were added. After bubbling the mixture under nitrogen for 15 min, 27 μmol of palladium acetate was added, and the mixture was placed in an oil bath at 85 °C with stirring. HPLC analysis after 2 h showed that the starting material had reacted completely. After cooling the reaction solution, 5 mL of water was added, and a solid precipitated. Filtering yielded a white solid (160 mg, 0.43 mmol, 80%).

[0091] MS: Calculated result: 378.14, Actual result: 378.17

[0092] Nuclear magnetic resonance (NMR) characterization spectra are as follows Figure 2 As shown, 1 H NMR (500 M Hz, CDCl3) δ 8.53 (s, 1H), 8.08-8.06 (d, J=10 Hz, 1H), 8.02-8.01 (d, J=5 Hz, 1H), 7.53-7.52 (m, 2H), 7.36-7.33 (m, 2H), 7.31-7.27 (m, 3H), 4.35-4.31 (q, J=7 Hz, 2H), 3.50-3.45 (m, 1H), 1.36-1.31 (m, 5H), 1.14-1.11 (m, 2H).

[0093] Example 3

[0094]

[0095] 1-Cyclopropyl-6-fluoro-7-((fluorosulfonyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester was prepared in Example 1.

[0096] At room temperature, 0.54 mmol of 1-cyclopropyl-6-fluoro-7-((fluorosulfonyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester was added to a reaction flask. Then, 5 mL of 1,4-dioxane, 0.5 mL of water, 0.75 mmol of pinacol 3,4-dimethylenedioxyphenylboronic acid, 0.11 mmol of triphenylphosphine, and 1.61 mmol of potassium phosphate were added. After bubbling the mixture under nitrogen for 15 min, 27 μmol of palladium acetate was added, and the mixture was placed in an 85°C oil bath with stirring. HPLC analysis after 2 h showed that the reaction proceeds were completely reacted. After cooling the reaction solution, 5 mL of water was added, and a solid precipitated. Filtering yielded a white solid (174 mg, 0.44 mmol, 83%).

[0097] MS: Calculated result: 396.12, Actual result: 396.12

[0098] Nuclear magnetic resonance (NMR) characterization spectra are as follows Figure 3 As shown, 1 H NMR (500 M Hz, CDCl3) δ 8.54 (s, 1H), 8.13-8.10 (d, J=10 Hz, 1H), 7.85-7.84 (d, J=6.5 Hz, 1H), 7.04-7.02 (m, 2H), 6.89-6.87 (m, 1H), 5.99 (s, 2H), 4.36-4.31 (q, J=7 Hz, 2H), 3.45-3.41 (m, 1H), 1.37-1.34 (t, J=7 Hz, 3H), 1.30-1.26 (m, 1H), 1.12-1.09 (m, 1H).

[0099] Example 4

[0100]

[0101] 1-Cyclopropyl-6-fluoro-7-((fluorosulfonyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester was prepared in Example 1.

[0102] At room temperature, 0.54 mmol of 1-cyclopropyl-6-fluoro-7-((fluorosulfonyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester was added to a reaction flask. Then, 5 mL of 1,4-dioxane, 0.5 mL of water, 0.75 mmol of pinacol 2-naphthoic acid, 0.11 mmol of triphenylphosphine, and 1.61 mmol of potassium phosphate were added. After bubbling the mixture under nitrogen for 15 min, 27 μmol of palladium acetate was added, and the mixture was placed in an oil bath at 85 °C with stirring. HPLC analysis after 2 h showed that the starting material had reacted completely. After cooling the reaction solution, 5 mL of water was added, and a solid precipitated. Filtering yielded a white solid (196 mg, 0.48 mmol, 89%).

[0103] MS: Calculated result: 402.14, Actual result: 402.12

[0104] Nuclear magnetic resonance (NMR) characterization spectra are as follows Figure 4 As shown, 1 H NMR (500 M Hz, CDCl3) δ 8.57 (s, 1H), 8.20-8.17 (d, J=10.5 Hz, 1H), 8.02- 8.00 (m, 2H), 7.92-7.90 (d, J=8.5 Hz, 1H), 7.88-7.84 (m, 2H), 7.66-7.63 (m, 1H), 7.51-7.48 (m, 1H), 4.37-4.32 (q, J=7 Hz, 1H), 3.63-3.45 (m, 1H), 1.38-1.35 (t, J=7 Hz, 1H), 1.31-1.27 (m, 2H), 1.14-1.11 (m, 2H).

[0105] Example 5

[0106]

[0107] 1-Cyclopropyl-6-fluoro-7-((fluorosulfonyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester was prepared in Example 1.

[0108] At room temperature, 0.54 mmol of 1-cyclopropyl-6-fluoro-7-((fluorosulfonyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester was added to a reaction flask. Then, 5 mL of 1,4-dioxane, 0.5 mL of water, 0.75 mmol of pinacol 3-pyridineboronic acid, 0.11 mmol of triphenylphosphine, and 1.61 mmol of potassium phosphate were added. After bubbling the mixture under nitrogen for 15 min, 27 μmol of palladium acetate was added, and the mixture was placed in an oil bath at 85 °C with stirring. HPLC analysis after 2 h showed that the reaction proceeds were completely reacted. After cooling the reaction solution, 5 mL of water was added, and a solid precipitated. Filtering yielded a white solid (175 mg, 0.50 mmol, 92%).

[0109] MS: Calculated result: 353.12, Actual result: 353.13

[0110] Nuclear magnetic resonance (NMR) characterization spectra are as follows Figure 5 As shown, 1 H NMR (500 M Hz, CDCl3) δ 8.80 (s, 1H), 8.66-8.65 (m, 1H), 8.57 (s, 1H), 8.20- 8.18 (d, J=15 Hz, 1H), 7.96-7.92 (m, 2H), 7.43-7.41 (m ,1H), 4.37-4.32 (q, J=7 Hz, 2H), 3.48-3.44 (m, 1H), 1.37-1.34 (t, J=7 Hz, 3H), 1.33-1.29 (m, 2H), 1.14-1.11 (m, 2H).

[0111] Example 6

[0112]

[0113] 1-Cyclopropyl-6-fluoro-7-((fluorosulfonyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester was prepared in Example 1.

[0114] At room temperature, 0.54 mmol of 1-cyclopropyl-6-fluoro-7-((fluorosulfonyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester was added to a reaction flask. Then, 5 mL of 1,4-dioxane, 0.5 mL of water, 0.75 mmol of pinacol 2-furanborate, 0.11 mmol of triphenylphosphine, and 1.61 mmol of potassium phosphate were added. After bubbling the mixture under nitrogen for 15 min, 27 μmol of palladium acetate was added, and the mixture was placed in an oil bath at 85 °C with stirring. HPLC analysis after 2 h showed that the reaction proceeds were completely reacted. After cooling the reaction solution, 5 mL of water was added, and a solid precipitated. Filtering yielded a white solid (162 mg, 0.49 mmol, 88%).

[0115] MS: Calculated result: 342.11, Actual result: 342.11

[0116] Nuclear magnetic resonance (NMR) characterization spectra are as follows Figure 6 As shown, 1 H NMR (500 M Hz, CDCl3) δ 8.53 (s, 1H), 8.29-8.28 (d, J=6 Hz, 1H), 8.10-8.08 (d, J=11 Hz, 1H), 7.53-7.52 (d, J=1.5 Hz, 1H), 7.03-7.01 (t, J=4 Hz, 1H), 6.54-6.53 (m, 1H), 4.35-4.30 (q, J=7 Hz, 2H), 3.51-3.46 (m, 1H), 1.36-1.32 (m, 5H), 1.13-1.10 (m ,2H).

[0117] Example 7

[0118]

[0119] Ethyl 1-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (10 g, 32.57 mmol) was added to a reaction flask at room temperature. 100 mL of 16 wt% sodium hydroxide solution was added to the reaction vessel, and after thorough stirring, the mixture was placed in an oil bath at 130 °C. HPLC analysis after 7 hours showed that the reaction proceeds had completely reacted. After cooling the reaction solution, hydrochloric acid was added to adjust the pH to acidity, causing a solid to precipitate. Filtration yielded a white solid product (6.5 g, 23.47 mmol, 72%).

[0120] MS: Calculated result: 278.08, Actual result: 278.08.

[0121]

[0122] 1-Cyclopropyl-6-fluoro-7-hydroxy-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (7.21 mmol), 20 mL of anhydrous acetonitrile, and triethylamine (36.05 mmol) were reacted with sulfonyl fluoride gas at room temperature under stirring. HPLC analysis after 2 h showed that the starting material had reacted completely. The reaction solution was adjusted to neutral with hydrochloric acid, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to obtain the crude product. Column chromatography purification gave a white solid product (2.32 g, 6.46 mmol, 89%).

[0123] MS: Calculated result: 360.03, Actual result: 360.03.

[0124]

[0125] At room temperature, 0.56 mmol of 1-cyclopropyl-6-fluoro-7-((fluorosulfonyl)oxy)-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was added to a reaction flask. Then, 5 mL of 1,4-dioxane, 0.5 mL of water, pinacol phenylboronic acid ester (0.84 mmol), triphenylphosphine (0.11 mmol), and potassium phosphate (1.68 mmol) were added. After bubbling the mixture under nitrogen for 15 min, 27 μmol of palladium acetate was added, and the mixture was placed in an oil bath at 85 °C with stirring. HPLC analysis after 2 h showed that the reaction proceeds were completely reacted. After cooling the reaction solution, 5 mL of water was added, and a solid precipitated. Filtering yielded a white solid product (158 mg, 0.47 mmol, 84%).

[0126] MS: Calculated result: 338.11, Actual result: 338.11.

[0127] Nuclear magnetic resonance (NMR) characterization spectra are as follows Figure 7 As shown, 1 H NMR (500 M Hz, CDCl3) δ 14.50 (s, 1H), 8.91 (s, 1H), 8.02-8.00 (d, J=10 Hz, 1H), 7.48-7.42 (m, 3H), 7.25-7.24 (d, J=10 Hz, 1H), 4.09-4.04 (m, 1H), 2.56 (s, 3H), 1.26-1.22 (m, 2H), 1.02- 0.98 (m, 2H).

[0128] Example 8

[0129]

[0130] 1-Cyclopropyl-6-fluoro-7-((fluorosulfonyl)oxy)-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was prepared in Example 7.

[0131] At room temperature, 0.56 mmol of 1-cyclopropyl-6-fluoro-7-((fluorosulfonyl)oxy)-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was added to a reaction flask. Then, 5 mL of 1,4-dioxane, 0.5 mL of water, 0.84 mmol of pinacol 3,4-dimethylenedioxyphenylboronic acid, 0.11 mmol of triphenylphosphine, and 1.68 mmol of potassium phosphate were added. After bubbling the mixture under nitrogen for 15 min, 27 μmol of palladium acetate was added, and the mixture was placed in an 85°C oil bath with stirring. HPLC analysis after 2 h showed that the reaction proceeds were completely reacted. After cooling the reaction solution, 5 mL of water was added, and a solid precipitated. Filtering yielded a white solid product (185 mg, 0.48 mmol, 87%).

[0132] MS: Calculated result: 382.10, Actual result: 382.10.

[0133] Nuclear magnetic resonance (NMR) characterization spectra are as follows Figure 8 As shown, 1 H NMR (500 M Hz, CDCl3) δ 14.58 (s, 1H), 9.00 (s, 1H), 8.10-8.08 (d, J=10 Hz, 1H), 6.99-6.98 (m, 1H), 6.80- 6.78 (m, 2H), 6.09 (s, 2H), 4.17-4.13 (m, 1H), 2.67 (s, 3H), 1.35-1.31 (m, 2H), 1.09-1.06 (m, 2H).

[0134] Example 9

[0135]

[0136] 1-Cyclopropyl-6-fluoro-7-((fluorosulfonyl)oxy)-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was prepared in Example 7.

[0137] At room temperature, 0.56 mmol of 1-cyclopropyl-6-fluoro-7-((fluorosulfonyl)oxy)-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was added to a reaction flask. Then, 5 mL of 1,4-dioxane, 0.5 mL of water, 0.84 mmol of pinacol 3-pyridineboronic acid, 0.11 mmol of triphenylphosphine, and 1.68 mmol of potassium phosphate were added. After bubbling the mixture under nitrogen for 15 min, 27 μmol of palladium acetate was added, and the mixture was placed in an oil bath at 85 °C with stirring. HPLC analysis after 2 h showed that the reaction proceeds were completely reacted. After cooling the reaction solution, 5 mL of water was added, and a solid precipitated. Filtering yielded a white solid product (166 mg, 0.49 mmol, 87%).

[0138] MS: Calculated result: 339.11, Actual result: 339.12.

[0139] Nuclear magnetic resonance (NMR) characterization spectra are as follows Figure 9 As shown, 1 HNMR (500 M Hz, CDCl3) δ 14.35 (s, 1H), 8.93 (s, 1H), 8.68 (s, 1H), 8.54 (s, 1H), 8.07-8.05 (d, J=8 Hz, 1H), 7.66-7.64 (d, J=8 Hz, 1H), 7.46-7.43 (m, 1H), 4.09-4.05 (m, 1H), 2.59 (s, 3H), 1.28-1.24 (m, 2H), 1.03-1.01 (m, 2H).

[0140] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A process for the preparation of a quinolone compound, characterized by, Includes the following steps: A fluorosulfonation reaction is carried out by mixing phenolic compounds, fluorosulfonating reagents, organic bases and organic solvents to obtain fluorosulfonated products; The phenolic compounds have the structure shown in Formula I: Formula I; The organic base is triethylamine; The fluorosulfonating agent is thioyl fluoride; The fluorosulfonation product, borate ester compound, transition metal catalyst, ligand, inorganic base, and solvent are mixed and coupled to obtain the quinolone compound; the borate ester compound is pinacol phenylboronic acid, trans-2-phenylvinylboronic acid, 3,4-dimethylenedioxyphenylboronic acid, 2-naphthoboronic acid, 3-pyridineboronic acid, or 2-furanboronic acid; the transition metal catalyst is palladium acetate; the ligand is triphenylphosphine; and the inorganic base is potassium phosphate. After the coupling reaction is completed, the resulting reaction solution is cooled and water is added, the solid precipitates out, and then filtered to obtain the quinolone compound; The structural formula of the quinolone compound is shown below: ， R1 and R2 are independently hydrogen or alkyl, R3 is phenyl, trans-2-phenylvinyl, 3,4-dimethylenedioxyphenyl, 2-naphthyl, 3-pyridyl or 2-furanyl, and R4 is H or alkyl.

2. The production method according to claim 1, characterized by, The fluorosulfonation reaction is preceded by an esterification reaction.

3. The preparation method according to claim 1, characterized in that, The molar ratio of the phenolic compound to the organic base is 1:1 to 1:

5.

4. The preparation method according to claim 1, characterized in that, The molar ratio of the fluorosulfonated product to the borate ester compound is 1:1 to 1:

3.

5. The preparation method according to claim 4, characterized in that, The molar ratio of the fluorosulfonation product to the transition metal catalyst is 1:0.001 to 1:0.1, the molar ratio of the transition metal catalyst to the ligand is 1:1 to 1:4, and the molar ratio of the fluorosulfonation product to the inorganic base is 1:1 to 1:5.

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