A process for the synthesis of quinolone carboxylates

Abstract

This invention provides a simple and environmentally friendly method for synthesizing 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester. Unlike the conventional method of first converting excess carboxylic acid to the corresponding acyl chloride using thionyl chloride, removing the excess thionyl chloride, adding fresh solvent, and then adding the corresponding alcohol to form the ester, this method uses the following order of addition: thionyl chloride → ethylene glycol monomethyl ether → thionyl chloride → ethylene glycol monomethyl ether. The thionyl chloride and ethylene glycol monomethyl ether are added alternately. Under a certain amount of solvent, the generated ester is cleverly utilized to promote the dissolution of the acyl chloride, while simultaneously reducing the absolute content of the acyl chloride in the solution. This allows the reaction mixture to form a solution state, promoting complete conversion of the carboxylic acid and driving the reaction forward. This avoids the defect of the carboxylic acid raw material being encapsulated due to the poor solubility of the intermediate, resulting in incomplete reaction.

Description

Technical Field

[0001] This invention belongs to the field of bactericide synthesis technology, specifically relating to a method for synthesizing quinolone carboxylic acid ester 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester (quinolone carboxylic acid ester). Background Technology

[0002] In 1962, Lesher et al. isolated neidic acid and successfully applied it to the treatment of urinary tract infections two years later, marking the emergence of the first generation of quinolone drugs. In 1973, Gerster successfully introduced a fluorine functional group at the C-6 position of the quinolone ring, obtaining a second generation of quinolone drugs with a broader spectrum. Quinolone derivatives are characterized by a broad antibacterial spectrum and long half-life, exhibiting good antibacterial activity against various Gram-negative and Gram-positive bacteria.

[0003] Given the physical properties of quinolone carboxylic acids, their ester derivatives are generally prepared by reacting 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with thionyl chloride to obtain quinolone cyclopropionyl chloride. The acyl chloride then reacts with the corresponding alcohol, using a suitable solvent to release the generated hydrogen chloride gas, or by using organic amines such as triethylamine as acid-binding agents. However, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid has poor solubility in the organic solvents commonly used in the preparation of acyl chlorides, requiring tens of times its mass of solvent to dissolve. Even in large amounts of solvent, the cyclopropionyl chloride intermediate is almost insoluble, resulting in a large amount of carboxylic acid encapsulation, which prevents the reactants from reacting completely. Ultimately, this results in a high content of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid in the product ester, requiring multiple recrystallizations for removal, which seriously affects the product yield. Patent document CN110066245A discloses an esterification method using acyl chlorides, with triethylamine as an acid-binding agent, achieving a two-step reaction yield of 79% (based on a carboxylic acid as the starting material). German Bayer's patent DE19853520295 discloses an esterification process involving quinolone carboxylic acid derivatives and corresponding alcohols using HCl gas or a large amount of concentrated sulfuric acid. This process has a low yield of only 70.6%, generates significant waste, and has a long reaction time, making it unsuitable for industrial production. Patent document CN111320581A discloses an azeotropic distillation reaction of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with excess ethylene glycol monomethyl ether to obtain a high-content ester product, but the single-pass conversion rate is only around 85%, and this process involves product crystallization, separation of unconverted carboxylic acids, and recycling, making it quite cumbersome. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides a method for synthesizing 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester, comprising the following steps:

[0005]

[0006] 7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was mixed with a solvent, a catalyst was added, and thionyl chloride was added under reflux and the mixture was kept at a constant temperature. HPLC analysis showed that the formation rate of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-acyl chloride was ≥88%. Ethylene glycol monomethyl ether was added dropwise and the mixture was kept at a constant temperature until the formation rate of the ester was ≥87% as determined by HPLC. A second addition of thionyl chloride was then performed and the mixture was kept at a constant temperature. The reaction was continued until the residual amount of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was ≤0.45% as determined by HPLC. Then, ethylene glycol monomethyl ether was added dropwise for the second time and the mixture was kept at a constant temperature until the residual amount of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-acyl chloride was ≤0.30% as determined by HPLC. The mixture was then cooled to quench the reaction, the pH of the system was adjusted to 6-8, and water was added to the solvent to remove the solvent through an azeotropic reaction to obtain the product.

[0007] The solvent is a haloalkane solvent;

[0008] The catalyst is selected from organic bases.

[0009] According to an embodiment of the present invention, the haloalkane solvent is chloroform, chlorobenzene, or dichloroethane.

[0010] According to an embodiment of the present invention, the amount of solvent used is 7 to 15 times, for example 8 to 12 times, the mass of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

[0011] According to an embodiment of the present invention, the catalyst is selected from at least one of commonly used organic bases such as DMF, pyridine, triethylamine, DIEA, and DMAP, with DMF being preferred.

[0012] According to an embodiment of the present invention, the amount of catalyst used is 0.01-2% of the mass of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, for example 0.05-1%.

[0013] According to an embodiment of the present invention, the initial addition amount of thionyl chloride is 1.0-1.3 eq, for example 1.0-1.2 eq.

[0014] According to an embodiment of the present invention, the initial addition amount of the ethylene glycol monomethyl ether is 1.0-1.3 eq, for example 1.0-1.2 eq.

[0015] According to an embodiment of the present invention, the amount of thionyl chloride added a second time is 0.1-0.3 eq.

[0016] According to an embodiment of the present invention, the amount of the second addition of the ethylene glycol monomethyl ether is 0.1-0.3 eq.

[0017] According to an embodiment of the present invention, the alkali used to adjust the pH is an inorganic alkali, which is selected from at least one of sodium carbonate, sodium hydroxide, potassium carbonate, and potassium hydroxide, preferably potassium carbonate or sodium carbonate, and the pH is adjusted to 6.5-7.5.

[0018] According to an embodiment of the present invention, water quenching is used to extinguish the reaction.

[0019] According to an embodiment of the present invention, after removing the solvent, the resulting solid is filtered and dried.

[0020] Beneficial effects

[0021] This invention provides a simple and environmentally friendly method for synthesizing 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester. This method differs from the conventional approach of first converting excess carboxylic acid to the corresponding acyl chloride using thionyl chloride, then removing the excess thionyl chloride, adding fresh solvent, and finally adding the corresponding alcohol to form the ester. Instead, the method uses the following order of addition: thionyl chloride → ethylene glycol monomethyl ether → thionyl chloride → ethylene glycol monomethyl ether. The thionyl chloride and ethylene glycol monomethyl ether are added alternately. Under a certain amount of solvent, the generated ester is cleverly utilized to promote the dissolution of the acyl chloride, while simultaneously reducing the absolute content of the acyl chloride in the solution. This allows the reaction mixture to form a solution state, promoting complete conversion of the carboxylic acid. Furthermore, this method monitors the formation rate of intermediates and final products, as well as the residual amounts of raw materials and intermediates during the feeding process. It strictly controls the addition of thionyl chloride and ethylene glycol monomethyl ether only when the contents of the above substances meet the standards, so that the reaction proceeds in the forward direction. This avoids the defect of carboxylic acid raw materials being encapsulated due to the poor solubility of intermediates, resulting in incomplete reaction. After the reaction is completed, only simple filtration is needed to obtain high-purity products with high yield. It has the characteristics of simple and stable process, high product content, low waste, and mild reaction conditions, which are in line with the environmentally friendly production concept. Detailed Implementation

[0022] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0023] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0024] In this application, the formation rate and residual amount are both normalized % values ​​obtained by HPLC detection.

[0025] The yield of the final product in this application is calculated as follows: (mass of ester produced * content / molecular weight of ester) / (mass of acid input * content / molecular weight of acid) * 100%.

[0026] The reaction process involved in the following examples is as follows:

[0027]

[0028] Example 1

[0029] A 2L four-necked reaction flask was equipped with a mechanical stirrer, thermometer, condenser, and tail gas absorption device. 100g of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 1000g of chloroform were added, along with 0.1g of DMF catalyst. The mixture was stirred and heated to 60-65℃ (chloroform reflux). Using 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a reference material, 1.0 eq of thionyl chloride was added dropwise. The mixture was refluxed and stirred for 2 hours until the formation rate of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-acyl chloride was deemed acceptable (88%). Then, 1.0 eq of ethylene glycol monomethyl ether was added dropwise, and the mixture was refluxed and stirred for 1 hour until the final ester formation rate was deemed acceptable (87%). The reaction mixture was then refluxed with 0.2 eq of thionyl chloride for the second time, and stirred for 2 h until the residual amount of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was within acceptable limits (residual amount was 0.3%). Then, 0.2 eq of ethylene glycol monomethyl ether was added dropwise, and the mixture was refluxed with 1 h until the residual amount of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-acyl chloride was within acceptable limits (residual amount was 0.25%). The reaction mixture was cooled to room temperature, and 400 g of water was added to quench the reaction. Then, a 10% potassium carbonate aqueous solution was added to adjust the pH to 6.5-7.5. The mixture was heated to an azeotropic temperature of 90-95℃ to remove chloroform, precipitating the product. The product was filtered, and the filter cake was dried at 80℃ for 4-5 h to obtain the final product. Without further purification, the crude product was directly analyzed by HPLC, and the content was determined to be 98.5%, with a yield of 99.3%.

[0030] Example 2

[0031] A 2L four-necked reaction flask was equipped with a mechanical stirrer, thermometer, condenser, and tail gas absorption device. 100g of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 1000g of chloroform were added, along with 2 drops of DMF catalyst. The mixture was stirred and heated to 60-65℃ (chloroform reflux). Using 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a reference material, 1.3 eq of thionyl chloride was added dropwise. After stirring and maintaining the temperature for 2 hours, the formation rate of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-acyl chloride was measured to be 90.5%. Then, 1.3 eq of ethylene glycol monomethyl ether was added dropwise, and the mixture was stirred and maintained for 1 hour until the final ester formation rate reached 88.4%. The reaction mixture was then subjected to a second addition of 0.2 eq of thionyl chloride and stirred at this temperature for 3 h until the residual amount of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was 0.30%. A second addition of 0.2 eq of ethylene glycol monomethyl ether was then performed, and the mixture was stirred at this temperature for 1 h until the residual amount of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-acyl chloride was 0.25%. The reaction mixture was cooled to room temperature, and 400 g of water was added to quench the reaction. Then, a 10% (w / w) potassium carbonate aqueous solution was added to adjust the pH to 6.5-7.5. The mixture was heated to an azeotropic temperature to remove chloroform, and the product precipitated at 90-95 °C. The product was filtered, and the filter cake was dried at 80 °C for 4-5 h to obtain the final product. Without further purification, the crude product was directly analyzed by HPLC, and the content was determined to be 98.4%, with a yield of 99.1%.

[0032] Example 3

[0033] A 2L four-necked reaction flask was equipped with a mechanical stirrer, thermometer, condenser, and tail gas absorption device. 100g of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1000g of chloroform, and 0.1g of DMF catalyst were added. The mixture was stirred and heated to 60-65℃ (chloroform reflux). Using 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a reference material, 1.2 eq of thionyl chloride was added dropwise. After reflux and stirring for 2 hours, the formation rate of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-acyl chloride was measured to be 90%. Then, 1.2 eq of ethylene glycol monomethyl ether was added dropwise, and the mixture was refluxed and stirred for 1 hour until the final ester formation rate was 88%. The reaction mixture was then refluxed with 0.3 eq of thionyl chloride for the second time, and stirred for 2 h until the residual amount of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was 0.4%. Then, 0.4 eq of ethylene glycol monomethyl ether was added dropwise, and the mixture was refluxed with stirring for 1 h until the residual amount of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-acyl chloride was 0.3%. The reaction mixture was cooled to room temperature, and 400 g of water was added to quench the reaction. Then, a 10% (w / w) potassium carbonate aqueous solution was added to adjust the pH to 6.5-7.5. The mixture was heated to an azeotropic temperature of 90-95 °C to remove chloroform, and the precipitate was collected. The precipitate was filtered, and the filter cake was dried at 80 °C for 4-5 h to obtain the product. Without further purification, the crude product was directly analyzed by HPLC, and the content was determined to be 98.2%, with a yield of 99.0%.

[0034] Comparative Example 1

[0035] A 2L four-necked reaction flask was equipped with a mechanical stirrer, thermometer, condenser, and tail gas absorption device. 100g of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1000g of chloroform, and 0.1g of DMF catalyst were added. The mixture was stirred and heated to 60-65℃ (chloroform reflux). Using 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a reference material, 1.0 eq of thionyl chloride was added dropwise. After the addition was complete, the mixture was kept at this temperature for 20 min. The formation rate of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-acyl chloride was measured to be acceptable (70%). Then, 1.0 eq of ethylene glycol monomethyl ether was added dropwise, and the mixture was refluxed and stirred for 1 h until the final ester formation rate was acceptable (67%). The second addition of 0.2 eq of thionyl chloride was followed by reflux and stirring for 2 h. The residual amount of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was determined to be 15%. The second addition of 0.2 eq of ethylene glycol monomethyl ether was followed by reflux and stirring for 1 h until the residual amount of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-acyl chloride was within acceptable limits (residual amount was 0.25%). The reaction solution was cooled to room temperature, and 400 g of water was added to quench the reaction. Then, a 10% potassium carbonate aqueous solution was added to adjust the pH to 6.5-7.5. The mixture was heated to azeotropically remove chloroform at 90-95℃ to precipitate the product. The product was filtered, and the filter cake was dried at 80℃ for 4-5 h to obtain the final product. Without further purification, the crude product was directly analyzed by HPLC, and the content was determined to be 84%, with a yield of 85%.

[0036] Comparative Example 2

[0037] A 2L four-necked reaction flask was equipped with a mechanical stirrer, thermometer, condenser, and tail gas absorption device. 100g of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 1000g of chloroform were added, along with 0.1g of DMF catalyst. The mixture was stirred and heated to reflux at 60-65℃ (chloroform reflux). Using 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a reference material, 1.2 eq of thionyl chloride was added dropwise. After the addition was complete, the mixture was refluxed and stirred for 6 hours. The acyl chloride formation rate was checked and found to be 90%. Excess thionyl chloride and chloroform were removed under reduced pressure. The reaction solution was cooled to room temperature, and 1000g of fresh chloroform was added. The mixture was stirred and heated to 60-65℃ and refluxed. 1.2 eq of ethylene glycol monomethyl ether was added dropwise. After the addition was complete, the mixture was kept at 60-65℃ for 2 hours. The reaction solution was cooled to room temperature, and 400g of water was added to quench the reaction. A 10% potassium carbonate aqueous solution was added to adjust the pH to 6.5-7.5. The mixture was heated to an azeotropic temperature to remove chloroform, and the product was precipitated at 90-95℃. The product was filtered, and the filter cake was dried at 80℃ for 4-5 hours to obtain the product with a purity of 86.3% and a yield of 87.0%.

[0038] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for synthesizing 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester, characterized in that, Includes the following steps: The structural formula of the 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester is as follows: ； ； 7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was mixed with a solvent, a catalyst was added, and thionyl chloride was added under reflux and the mixture was kept at a constant temperature. HPLC analysis showed that the formation rate of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-acyl chloride was ≥88%. Ethylene glycol monomethyl ether was added dropwise and the mixture was kept at a constant temperature until the formation rate of the ester was ≥87% as determined by HPLC. A second addition of thionyl chloride was then performed and the mixture was kept at a constant temperature. The reaction was continued until the residual amount of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was ≤0.45% as determined by HPLC. Then, ethylene glycol monomethyl ether was added dropwise for the second time and the mixture was kept at a constant temperature until the residual amount of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-acyl chloride was ≤0.30% as determined by HPLC. The mixture was then cooled to quench the reaction, the pH of the system was adjusted to 6-8, and water was added to azeotropically remove the solvent to obtain the product. The solvent is a haloalkane solvent; The catalyst is selected from organic bases or DMF.

2. The method according to claim 1, characterized in that, The haloalkane solvent is chloroform or dichloroethane.

3. The method according to claim 1, characterized in that, The amount of solvent used is 7 to 15 times the mass of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

4. The method according to claim 1, characterized in that, The catalyst is selected from at least one of DMF, pyridine, triethylamine, DIEA, and DMAP.

5. The method according to claim 1, characterized in that, The amount of catalyst used is 0.01-2% of the mass of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

6. The method according to claim 1, characterized in that, The initial addition amount of thionyl chloride is 1.0-1.3 eq.

7. The method according to claim 1, characterized in that, The initial addition amount of the ethylene glycol monomethyl ether is 1.0-1.3 eq.

8. The method according to claim 1, characterized in that, The amount of thionyl chloride added a second time is 0.1-0.3 eq.

9. The method according to claim 1, characterized in that, The amount of the second addition of the ethylene glycol monomethyl ether is 0.1-0.3 eq.

10. The method according to claim 1, characterized in that, The alkali used to adjust the pH is an inorganic alkali, which is selected from at least one of sodium carbonate, sodium hydroxide, potassium carbonate, and potassium hydroxide.

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