CN117362227A - Synthesis method of quinolone carboxylic ester - Google Patents
Synthesis method of quinolone carboxylic ester Download PDFInfo
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- CN117362227A CN117362227A CN202210774792.2A CN202210774792A CN117362227A CN 117362227 A CN117362227 A CN 117362227A CN 202210774792 A CN202210774792 A CN 202210774792A CN 117362227 A CN117362227 A CN 117362227A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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Abstract
The invention provides a simple and environment-friendly method for synthesizing 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ester, which is not to adopt the conventional method that excessive carboxylic acid of thionyl chloride is firstly converted into corresponding acyl chloride, then excessive thionyl chloride is removed, a new solvent is added, and then corresponding alcohol is added to form ester; the charging sequence is sequentially thionyl chloride, ethylene glycol monomethyl ether, thionyl chloride and ethylene glycol monomethyl ether; the sulfoxide chloride and the ethylene glycol monomethyl ether are added at intervals, the generated ester is skillfully utilized to promote the dissolution of the acyl chloride under a certain amount of solvent, and meanwhile, the absolute content of the acyl chloride in the solution is reduced, so that a reaction mixture is in a solution state, the carboxylic acid conversion is promoted thoroughly, the reaction is carried out forward, and the defect that the carboxylic acid raw material is wrapped and cannot react completely due to poor solubility of an intermediate is avoided.
Description
Technical Field
The invention belongs to the technical field of synthesis of bactericides, and particularly relates to a synthesis method of quinolone carboxylic acid ester 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro quinoline-3-carboxylic acid ester (quinolone carboxylic acid ester).
Background
The production of the first generation quinolone drugs was marked by the isolation of nalidixic acid in Lesher et al 1962 and its successful application in the treatment of urinary tract infections after two years. In 1973, gerster successfully introduced fluorine functional groups into C-6 position of quinolone ring to obtain second-generation quinolone medicines with wider spectrum. The quinolone derivative has the characteristics of wide antibacterial spectrum and long half-life, and has good antibacterial effect on various gram-negative and positive bacteria.
In view of the physical properties of quinolone carboxylic acid, at present, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid and thionyl chloride are generally adopted to react to obtain quinolone cyclopropane acyl chloride, the acyl chloride is reacted with corresponding alcohol, and generated hydrogen chloride gas is escaped by utilizing a proper solvent, or organic amine such as triethylamine and the like is adopted as an acid binding agent. The solubility of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid in the common organic solvent used for preparing acyl chloride reaction is poor, and the solvent with the mass of tens of times is needed to be dissolved, even if the raw materials cannot be completely reacted due to the fact that the intermediate of the cyclopropyl chloride is almost insoluble in a large amount of solvents, a large amount of carboxylic acid is still coated, and finally the 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid in the product ester has large content and needs to be recrystallized for many times to be removed, so that the product yield is seriously influenced. Patent document CN110066245a discloses an ester formation method using acyl chloride, triethylamine as an acid-binding agent, and a two-step reaction yield of 79% (calculated starting from a carboxylic acid as a raw material). Patent DE19853520295 of German Bayer application discloses that the esterification process of quinolone carboxylic acid derivatives and corresponding alcohols adopts a mode of introducing HCl gas or adding a large amount of concentrated sulfuric acid, the process yield is low by 70.6%, the three wastes are more, the reaction time process is long, and the process is not suitable for industrial production. Patent document CN111320581A discloses that 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid and excessive ethylene glycol monomethyl ether are adopted for azeotropic distillation reaction to obtain high-content product ester, but the single pass conversion rate is about 85%, and the process relates to the processes of product crystallization, separation and recycling of unconverted carboxylic acid, and is relatively complicated.
Disclosure of Invention
In order to solve the technical problems, the invention provides a method for synthesizing 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylate, which comprises the following steps:
mixing 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid with a solvent, adding a catalyst, adding thionyl chloride in a reflux state, preserving heat, detecting the generation rate of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-acyl chloride to be more than or equal to 88% by HPLC, dropwise adding ethylene glycol monomethyl ether, preserving heat, and detecting the generation rate of product ester to be more than or equal to 87% by HPLC; dropwise adding thionyl chloride for the second time and preserving heat until the residual amount of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid is less than or equal to 0.45 percent through HPLC detection, then dropwise adding ethylene glycol monomethyl ether for the second time and preserving heat until the residual amount of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-acyl chloride is less than or equal to 0.30 percent through HPLC detection, cooling, quenching reaction, regulating the pH value of a system to be less than or equal to 6-8, adding water and a solvent to azeotropically remove the solvent, and obtaining a product;
the solvent is halogenated hydrocarbon solvent;
the catalyst is selected from organic bases.
According to an embodiment of the present invention, the halogenated hydrocarbon solvent is chloroform, chlorobenzene or dichloroethane.
According to an embodiment of the invention, the solvent is used in an amount of 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.
According to an embodiment of the present invention, the catalyst is selected from at least one of common organic bases such as DMF, pyridine, triethylamine, DIEA, DMAP, etc., preferably DMF.
According to an embodiment of the invention, the catalyst is used in an amount of 0.01-2%, such as 0.05-1% by mass of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid.
According to an embodiment of the invention, the first addition of thionyl chloride is in the range of 1.0 to 1.3eq, for example 1.0 to 1.2eq.
According to an embodiment of the invention, the first addition amount of ethylene glycol monomethyl ether is 1.0-1.3eq, for example 1.0-1.2eq.
According to an embodiment of the invention, the second addition of thionyl chloride is in the range of 0.1 to 0.3eq.
According to an embodiment of the present invention, the second addition amount of ethylene glycol monomethyl ether is 0.1 to 0.3eq.
According to an embodiment of the present invention, the base used for the adjustment of the pH is an inorganic base selected from at least one of sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, preferably potassium carbonate or sodium carbonate, the pH being adjusted to 6.5-7.5.
According to an embodiment of the invention, a water quench reaction is used.
According to an embodiment of the invention, the resulting solid is filtered and dried after removal of the solvent.
Advantageous effects
The invention provides a simple and environment-friendly method for synthesizing 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ester, which is not to adopt the conventional method that excessive carboxylic acid of thionyl chloride is firstly converted into corresponding acyl chloride, then excessive thionyl chloride is removed, a new solvent is added, and then corresponding alcohol is added to form ester; the charging sequence is sequentially thionyl chloride, ethylene glycol monomethyl ether, thionyl chloride and ethylene glycol monomethyl ether; the sulfoxide chloride and the ethylene glycol monomethyl ether are added at intervals, the generated ester is skillfully utilized to promote the dissolution of the acyl chloride under a certain amount of solvent, and meanwhile, the absolute content of the acyl chloride in the solution is reduced, so that the reaction mixture forms a solution state, and the thorough conversion of carboxylic acid is promoted. The method detects the formation rate of the intermediate and the final product in the feeding process, strictly controls the residual quantity of the raw materials and the intermediate, and supplements thionyl chloride and ethylene glycol monomethyl ether when the content of the substances reaches the standard, so that the reaction is carried out in the forward direction, the defect that the carboxylic acid raw material is wrapped and cannot be reacted completely due to poor solubility of the intermediate is avoided, and the high-purity product can be obtained in high yield only by simple filtration after the reaction is finished.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
In this application, the formation rate and the residual amount are both normalized% values of HPLC detection.
The yield of the final product in this application is calculated by: (mass of product ester produced/ester molecular weight)/(mass of feed acid to acid content/acid molecular weight) 100%.
The reaction processes involved in the following examples were:
example 1
A2L four-port reaction flask is equipped with mechanical stirring, a thermometer, a condenser and a tail gas absorbing device, 100g of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid and 1000g of chloroform are added, 0.1g of catalyst DMF is added, and the mixture is stirred and heated to 60-65 ℃ (chloroform reflux). Taking 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid as a reference material, dropwise adding 1.0eq of thionyl chloride, refluxing and stirring for 2 hours until the yield of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-acyl chloride is qualified (the yield is 88%), dropwise adding 1.0eq of ethylene glycol monomethyl ether, refluxing and stirring for 1 hour until the yield of final product ester is qualified (the yield is 87%). And dropwise adding 0.2eq of thionyl chloride for the second time, refluxing and stirring for 2 hours until the residual quantity of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid is qualified (the residual quantity is 0.3%), and dropwise adding 0.2eq of ethylene glycol monomethyl ether for the second time, refluxing and stirring for 1 hour until the residual quantity of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-acyl chloride is qualified (the residual quantity is 0.25%). The reaction solution was cooled to room temperature, quenched by adding 400g of water, and then adjusted to ph=6.5 to 7.5 by adding 10 mass% aqueous potassium carbonate. Heating, azeotropically removing chloroform to 90-95 ℃ to precipitate a product, filtering, drying a filter cake at 80 ℃ for 4-5 hours to obtain the product, wherein the product is not subjected to other purification modes, and the crude product is directly subjected to quantitative analysis by HPLC to obtain the content of 98.5% and the yield of 99.3%.
Example 2
A2L four-port reaction flask is equipped with mechanical stirring, a thermometer, a condenser and a tail gas absorbing device, 100g of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid and 1000g of chloroform are added, 2 drops of catalyst DMF are added, and the mixture is stirred and heated to 60-65 ℃ (chloroform reflux). Taking 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid as a reference material, dropwise adding 1.3eq of thionyl chloride, carrying out heat preservation and stirring for 2 hours to detect that the generation rate of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-acyl chloride is 90.5%, dropwise adding 1.3eq of ethylene glycol monomethyl ether, carrying out heat preservation and stirring for 1 hour to obtain the final product with the generation rate of 88.4%. And dropwise adding 0.2eq of thionyl chloride for the second time, and stirring for 3 hours at a constant temperature until the residual quantity of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid is 0.30%, and dropwise adding 0.2eq of ethylene glycol monomethyl ether for the second time, and stirring for 1 hour at a constant temperature until the residual quantity of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-acyl chloride is 0.25%. The reaction solution was cooled to room temperature, quenched by adding 400g of water, and then adjusted to ph=6.5 to 7.5 by adding 10 mass% aqueous potassium carbonate. Heating, azeotropically removing chloroform to 90-95 ℃ to precipitate a product, filtering, drying a filter cake at 80 ℃ for 4-5 hours to obtain the product, wherein the product is not subjected to other purification modes, and the crude product is directly subjected to quantitative analysis by HPLC to obtain the content of 98.4% and the yield of 99.1%.
Example 3
A2L four-port reaction flask is equipped with mechanical stirring, a thermometer, a condenser and a tail gas absorbing device, 100g of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid and 1000g of chloroform are added, 0.1g of catalyst DMF is added, and the mixture is stirred and heated to 60-65 ℃ (chloroform reflux). Taking 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid as a reference material, dropwise adding 1.2eq of thionyl chloride, refluxing and stirring for 2 hours to detect that the generation rate of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-acyl chloride is 90%, dropwise adding 1.2eq of ethylene glycol monomethyl ether, and refluxing and stirring for 1 hour to obtain the final product with the generation rate of 88%. And dropwise adding 0.3eq of thionyl chloride for the second time, refluxing and stirring for 2 hours until the residual quantity of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid is 0.4%, and dropwise adding 0.4eq of ethylene glycol monomethyl ether for the second time, and refluxing and stirring for 1 hour until the residual quantity of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-acyl chloride is 0.3%. The reaction solution was cooled to room temperature, quenched by adding 400g of water, and then adjusted to ph=6.5 to 7.5 by adding 10 mass% aqueous potassium carbonate. Heating, azeotropically removing chloroform to 90-95 ℃ to precipitate a product, filtering, drying a filter cake at 80 ℃ for 4-5 hours to obtain the product, wherein the product is not subjected to other purification modes, and the crude product is directly subjected to quantitative analysis by HPLC to obtain the content of 98.2% and the yield of 99.0%.
Comparative example 1
A2L four-port reaction flask is equipped with mechanical stirring, a thermometer, a condenser and a tail gas absorbing device, 100g of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid and 1000g of chloroform are added, 0.1g of catalyst DMF is added, and the mixture is stirred and heated to 60-65 ℃ (chloroform reflux). Taking 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid as a reference material, dropwise adding 1.0eq of thionyl chloride, keeping the temperature for 20min after the completion of the dropwise adding, detecting that the generation rate of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-acyl chloride is qualified (the generation rate is 70%), dropwise adding 1.0eq of ethylene glycol monomethyl ether, refluxing and stirring for 1h, and the generation rate of the final product ester is qualified (the generation rate is 67%). And dropwise adding 0.2eq of thionyl chloride for the second time, refluxing and stirring for 2 hours, detecting that the residual quantity of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid is 15 percent, and dropwise adding 0.2eq of ethylene glycol monomethyl ether for the second time, and refluxing and stirring for 1 hour until the residual quantity of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-acyl chloride is qualified (the residual quantity is 0.25 percent). The reaction solution was cooled to room temperature, quenched by adding 400g of water, and then adjusted to ph=6.5 to 7.5 by adding 10 mass% aqueous potassium carbonate. Heating, azeotropically removing chloroform to 90-95 ℃ to precipitate a product, filtering, drying a filter cake at 80 ℃ for 4-5 hours to obtain the product, wherein the product is directly subjected to HPLC quantitative analysis without other purification modes to obtain the crude product with the content of 84% and the yield of 85%.
Comparative example 2
A2L four-port reaction flask is equipped with mechanical stirring, a thermometer, a condenser and a tail gas absorbing device, 100g of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid and 1000g of chloroform are added, 0.1g of catalyst DMF is added, and stirring and heating are carried out until reflux is carried out at 60-65 ℃ (chloroform reflux). Taking 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid as a reference material, dropwise adding 1.2eq of thionyl chloride, adding Bi Huiliu, stirring for 6 hours to detect the formation rate of acyl chloride to 90%, decompressing and removing excessive thionyl chloride and chloroform, cooling the reaction solution to room temperature and adding 1000g of new chloroform. Stirring and heating to 60-65 ℃ for reflux, dropwise adding 1.2eq of ethylene glycol monomethyl ether, and preserving heat for 2h at 60-65 ℃ after the completion of dropwise adding. The reaction solution was cooled to room temperature, quenched by adding 400g of water, and adjusted to ph=6.5-7.5 by adding 10 mass% aqueous potassium carbonate. Heating, azeotropically removing chloroform to 90-95 ℃ to precipitate a product, filtering, drying a filter cake at 80 ℃ for 4-5h to obtain the product with 86.3 percent of content and 87.0 percent of yield.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The synthesis method of the 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ester is characterized by comprising the following steps:
mixing 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid with a solvent, adding a catalyst, adding thionyl chloride in a reflux state, preserving heat, detecting the generation rate of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-acyl chloride to be more than or equal to 88% by HPLC, dropwise adding ethylene glycol monomethyl ether, preserving heat, and detecting the generation rate of product ester to be more than or equal to 87% by HPLC; dropwise adding thionyl chloride for the second time and preserving heat until the residual amount of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid is less than or equal to 0.45 percent through HPLC detection, then dropwise adding ethylene glycol monomethyl ether for the second time and preserving heat until the residual amount of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-acyl chloride is less than or equal to 0.30 percent through HPLC detection, cooling, quenching reaction, regulating the pH value of a system to be less than or equal to 6-8, adding water and a solvent to azeotropically remove the solvent, and obtaining a product;
the solvent is halogenated hydrocarbon solvent;
the catalyst is selected from organic bases.
2. The process according to claim 1, wherein the halogenated hydrocarbon solvent is chloroform, chlorobenzene or dichloroethane.
3. The method according to claim 1, wherein the solvent is used in an amount of 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, wherein the catalyst is selected from at least one of DMF, pyridine, triethylamine, DIEA, DMAP.
5. The method according to claim 1, wherein the catalyst is used in an amount of 0.01 to 2% by mass of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid.
6. The method according to claim 1, wherein the first addition amount of thionyl chloride is 1.0-1.3eq.
7. The method according to claim 1, wherein the first addition amount of ethylene glycol monomethyl ether is 1.0 to 1.3eq.
8. The method according to claim 1, wherein the second addition amount of thionyl chloride is 0.1-0.3eq.
9. The method according to claim 1, wherein the second addition amount of ethylene glycol monomethyl ether is 0.1 to 0.3eq.
10. The method according to claim 1, wherein the base used for adjusting the pH is an inorganic base selected from at least one of sodium carbonate, sodium hydroxide, potassium carbonate, and potassium hydroxide.
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