Preparation method of 6-hydroxyquinoline-4-carboxylic acid
When preparing 6-hydroxyquinoline-4-carboxylic acid, 5-methoxyindenone and sodium pyruvate were used to form a quinoline dicarboxylic acid intermediate under the action of sodium hydroxide, and demethyl groups in the hydrobromic acid solution, and finally decarboxylate at high temperature in diphenyl ether, the safety hazards of the use of hazardous products and high temperatures in the prior art were solved, and the high purity preparation effect with simple operation, high yield and low impurities was achieved.
Patent Information
- Application Number
- CN202411886349.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-20
- Publication Date
- 2025-03-28
AI Technical Summary
The prior art uses dangerous nitrobenzene and high temperature when preparing 6-hydroxyquinoline-4-carboxylic acid, which poses safety risks, and is complicated after-treatment, low yield and high impurity content, making it difficult to meet the requirements of later process research.
Under the action of sodium hydroxide, 5-methoxyindenone and sodium pyruvate were used to form a quinoline dicarboxylic acid intermediate, and then demethyl groups were decarboxylated in hydrobromic acid solution, and finally decarboxylation was high temperature in diphenyl ether to obtain the target compound. This method uses diphenyl ether to replace nitrobenzene, lowering the temperature to 220°C, simplifying the process route and post-treatment process.
It realizes simplicity of operation and post-treatment, improves yield, reduces impurity content, ensures the preparation of high-purity raw materials, reduces process risks, and meets the requirements of later process research.
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Figure CN119707805A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of material synthesis and relates to a preparation method of 6-hydroxyquinoline-4-carboxylic acid. Background Art
[0002] Patents WO2022 / 135326 and WO2021 / 160825 publicly report a method for preparing 6-hydroxyquinoline-4-carboxylic acid, by using 5-methoxyindanone and sodium pyruvate under the action of sodium hydroxide, and the high-temperature ring-closure product is decarboxylated at high temperature in a nitrobenzene solution under the catalysis of sulfuric acid to obtain 6-methoxyquinoline-4-carboxylic acid, and finally the methyl group is removed in a hydrobromic acid solution to obtain the target compound. The above route uses dangerous nitrobenzene, and there are great safety hazards when used in large quantities at high temperatures. At the same time, this route has cumbersome post-processing, low yield, high impurity content, and is difficult to remove, which cannot meet the requirements of later process research. The specific path is as follows Figure 2 . Summary of the invention
[0003] The object of the present invention is to provide a method for preparing 6-hydroxyquinoline-4-carboxylic acid, which has the characteristics of simple operation and post-treatment and high yield.
[0004] The purpose of the present invention can be achieved through the following technical solutions:
[0005] A method for preparing 6-hydroxyquinoline-4-carboxylic acid, the specific process of the preparation method is as follows:
[0006] S1: Add deionized water to the reactor, cool the reactor to 0°C while stirring, add 5-methoxyisatin, sodium pyruvate and sodium hydroxide in a mass ratio of 1:0.62:1.35, wherein the solid-liquid ratio (g / ml) is 0.297:1, stir until dissolved to obtain a mixed solution A, heat to 100°C, reflux for 3 hours at a constant temperature, after the reaction is completed, add concentrated hydrochloric acid to the mixed solution A under ice bath conditions to adjust the pH value to 2, filter, collect the filter cake, and place the filter cake in a 50°C oven to dry for 48 hours to obtain a black solid 6-methoxyquinoline-2,4-dicarboxylic acid, which is Figure 1 Intermediate product 2;
[0007] S2: Add product 2 to a three-necked round-bottom flask, and then slowly add hydrobromic acid. The solid-liquid ratio (g / ml) of product 2 and hydrobromic acid is 1:0.9. Use an electric heating jacket to control the external temperature of the flask to 180°C and the internal temperature to 120°C. After constant temperature, reflux for 12 hours. After the reaction is completed, cool to room temperature, add sodium hydroxide dropwise to adjust the pH value to 8, filter, then add concentrated hydrochloric acid dropwise to adjust the pH value to 2, filter again, collect the filter cake, and dry it at 60°C to obtain a black solid 6-hydroxyquinoline-2,4-dicarboxylic acid, which is Figure 1 Intermediate product 3;
[0008] S3: Add product 3 to a three-necked flask, and then add diphenyl ether and sulfuric acid in a volume ratio of 83:1, wherein the solid-liquid ratio (g / ml) is 1:10.12, and use an electric heating jacket to control the external temperature of the flask to 280°C and the internal temperature to 220°C. After constant temperature, react for 0.5h, cool to room temperature after the reaction is completed, filter, collect the filter cake, dissolve the filter cake in deionized water, and the solid-liquid ratio (g / ml) is 0.65:1, and then drop an inorganic base to adjust the pH value to 11, filter, collect the filtrate, extract the filtrate three times with ethyl acetate, separate the liquids, collect the aqueous phase, and then drop concentrated hydrochloric acid to adjust the pH value to 2, add a mixed solution of tetrahydrofuran and ethyl acetate, wherein the volume ratio of deionized water to the mixed solution is 1:1, stir, precipitate a large amount of solid, filter, collect the filter cake, wash with deionized water, and then use tetrahydrofuran for pulping, filter again, collect the filter cake, and dry to obtain a gray solid 6-hydroxyquinoline-4-carboxylic acid.
[0009] Furthermore, the stirring rate in S1 is 120 r / min.
[0010] Furthermore, the ice bath condition in S1 is a mixture of water and crushed ice at a temperature of 0 to 5°C.
[0011] Furthermore, the rate of slowly adding hydrofluoric acid into S2 is 1 s / drop.
[0012] Furthermore, the inorganic base added in S3 is one of sodium bicarbonate and sodium hydroxide.
[0013] Furthermore, the volume ratio of the amount of ethyl acetate used for each extraction in S3 to the collected filtrate is 0.5:1.
[0014] Furthermore, the volume ratio of tetrahydrofuran to ethyl acetate in the mixed solution of tetrahydrofuran and ethyl acetate in S3 is 1:1.
[0015] Furthermore, the stirring rate in S3 is 150 r / min.
[0016] Furthermore, the parameters of the pulping process in S3 are a rotation speed of 300 r / min and a duration of 2 h.
[0017] Furthermore, the drying parameters in S3 are a temperature of 60° C. and a drying time of 12 hours.
[0018] Beneficial effects of the present invention:
[0019] The present invention obtains a quinoline dicarboxylic acid intermediate by using 5-methoxyindanone and sodium pyruvate under the action of sodium hydroxide. In the alkaline environment provided by sodium hydroxide, the negative ion of sodium pyruvate performs nucleophilic addition on the keto carbonyl of 5-methoxyindanone, and then undergoes proton transfer and elimination reaction to form a new ring structure, i.e., a quinoline dicarboxylic acid intermediate; then, quinoline phenol is obtained by heating in a hydrobromic acid solution to remove the methyl group; in the acidic environment provided by hydrobromic acid, the methoxy group in the quinoline dicarboxylic acid intermediate is attacked by bromide ions, a substitution reaction occurs, and a brominated intermediate is generated; then, the brominated intermediate removes hydrogen bromide through an elimination reaction to form quinoline phenol; finally, the target compound is obtained by high-temperature decarboxylation in diphenyl ether; in an environment of high temperature and diphenyl ether as a solvent, the carboxyl group in quinoline phenol undergoes a decarboxylation reaction under the action of high temperature and diphenyl ether to generate the target compound. The present invention is adjusted in terms of process route and post-processing. The present invention uses diphenyl ether to replace dangerous goods nitrobenzene, and the temperature is reduced to 220° C., which reduces process risks from two aspects. Meanwhile, the process method of the present invention is simple to operate and post-process, and has a high yield. The 6-hydroxyquinoline-4-carboxylic acid prepared by the present invention does not need to undergo excessive post-processing, and a high-purity raw material that meets the process requirements can be obtained. BRIEF DESCRIPTION OF THE DRAWINGS
[0020] In order to facilitate understanding by those skilled in the art, the present invention is further described below with reference to the accompanying drawings.
[0021] Figure 1 The present invention provides a synthetic route for preparing 6-hydroxyquinoline-4-carboxylic acid;
[0022] Figure 2 The prior art provides a synthetic route for preparing 6-hydroxyquinoline-4-carboxylic acid. DETAILED DESCRIPTION
[0023] In order to further explain the technical means and effects adopted by the present invention to achieve the predetermined invention purpose, the specific implementation methods, structures, features and effects of the present invention are described in detail below in conjunction with the accompanying drawings and preferred embodiments.
[0024] Example 1
[0025] S1: Add 20L of deionized water to the reactor, cool the reactor to 0°C while stirring, with a stirring rate of 120r / min, add 2.0kg of 5-methoxyisatin, 1.24kg of sodium pyruvate and 2.7kg of sodium hydroxide, stir until dissolved to obtain a mixed solution A, heat to 100°C, and reflux for 3h at a constant temperature. After the reaction is completed, add concentrated hydrochloric acid to the mixed solution A under ice bath conditions to adjust the pH value to 2, filter, collect the filter cake, and place the filter cake in a 50°C oven to dry for 48h to obtain 5.0kg of black solid 6-methoxyquinoline-2,4-dicarboxylic acid, which is Figure 1Intermediate product 2, MS-ESI=248, [M+H]+;
[0026] S2: Add 5.0 kg of product 2 to a three-necked round-bottom flask, then slowly add 4.5 L of hydrobromic acid, and slowly add hydrofluoric acid at a rate of 1 s / drop. Use an electric heating jacket to control the external temperature of the flask to 180°C and the internal temperature to 120°C. After constant temperature, reflux for 12 hours. After the reaction is completed, cool to room temperature, add sodium hydroxide dropwise to adjust the pH value to 8, filter, then add concentrated hydrochloric acid dropwise to adjust the pH value to 2, filter again, collect the filter cake, and dry it at 60°C to obtain 2.7 kg of black solid 6-hydroxyquinoline-2,4-dicarboxylic acid, which is Figure 1 Intermediate product 3, MS-ESI=234, [M+H]+;
[0027] S3: Add 650.0g of product 3 to a three-necked flask, then add 6.5L of diphenyl ether and 78mL of sulfuric acid, use an electric heating jacket to control the external temperature of the flask to 280°C and the internal temperature to 220°C, react for 0.5h at constant temperature, cool to room temperature after the reaction is completed, filter, collect the filter cake, dissolve the filter cake in 1L of deionized water, add sodium hydroxide dropwise to adjust the pH value to 11, filter, collect the filtrate, extract the filtrate three times with ethyl acetate, each extraction amount of ethyl acetate is 500ml, separate the liquids, collect the aqueous phase, and then add concentrated hydrochloric acid dropwise to adjust the pH The value was increased to 2, 1L of a mixed solution of tetrahydrofuran and ethyl acetate was added, wherein the volume ratio of tetrahydrofuran to ethyl acetate was 1:1, and the mixture was stirred at a rate of 150 r / min to precipitate a large amount of solid. The mixture was filtered and the filter cake was collected. After washing with 50 mL of deionized water, 1L of tetrahydrofuran was used for pulping treatment. The parameters of the pulping treatment were a speed of 300 r / min and a duration of 2 h. The mixture was filtered again and the filter cake was collected. After drying at 60°C for 12 h, 210 g of a gray solid 6-hydroxyquinoline-4-carboxylic acid was obtained, MS-ESI=190, [M+H]+.
[0028] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment as above, it is not used to limit the present invention. Any technical personnel in this field can make some changes or modify the technical contents disclosed above into equivalent embodiments without departing from the scope of the technical solution of the present invention. However, any brief modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention are still within the scope of the technical solution of the present invention.
Claims
1. A method for preparing 6-hydroxyquinoline-4-carboxylic acid, characterized in that: The specific process of the preparation method is as follows: S1: Add deionized water to the reactor, cool the reactor to 0°C while stirring, add 5-methoxyisatin, sodium pyruvate and sodium hydroxide in a mass ratio of 1:0.62:1.35, wherein the solid-liquid ratio (g / ml) is 0.297:1, stir until dissolved to obtain a mixed solution A, heat to 100°C, and reflux for 3 hours at a constant temperature. After the reaction is completed, add concentrated hydrochloric acid to the mixed solution A under ice bath conditions to adjust the pH value to 2, filter, collect the filter cake, and place the filter cake in a 50°C oven to dry for 48 hours to obtain a black solid 6-methoxyquinoline-2,4-dicarboxylic acid, which is the product 2 in Figure 1; S2: Add product 2 to a three-necked round-bottom flask, and then slowly add hydrobromic acid, the solid-to-liquid ratio (g / ml) of product 2 and hydrobromic acid is 1:0.9, use an electric heating jacket to control the external temperature of the flask to 180°C and the internal temperature to 120°C, reflux for 12 hours after constant temperature, cool to room temperature after the reaction, dropwise add sodium hydroxide to adjust the pH value to 8, filter, then dropwise add concentrated hydrochloric acid to adjust the pH value to 2, filter again, collect the filter cake, and dry at 60°C to obtain a black solid 6-hydroxyquinoline-2,4-dicarboxylic acid, which is product 3 in Figure 1; S3: Add product 3 to a three-necked flask, and then add diphenyl ether and sulfuric acid in a volume ratio of 83:1, wherein the solid-liquid ratio (g / ml) is 1:10.12, and use an electric heating jacket to control the external temperature of the flask to 280°C and the internal temperature to 220°C. After constant temperature, react for 0.5h, cool to room temperature after the reaction is completed, filter, collect the filter cake, dissolve the filter cake in deionized water, and the solid-liquid ratio (g / ml) is 0.65:1, and then drop an inorganic base to adjust the pH value to 11, filter, collect the filtrate, extract the filtrate three times with ethyl acetate, separate the liquids, collect the aqueous phase, and then drop concentrated hydrochloric acid to adjust the pH value to 2, add a mixed solution of tetrahydrofuran and ethyl acetate, wherein the volume ratio of deionized water to the mixed solution is 1:1, stir, precipitate a large amount of solid, filter, collect the filter cake, wash with deionized water, and then use tetrahydrofuran for pulping, filter again, collect the filter cake, and dry to obtain a gray solid 6-hydroxyquinoline-4-carboxylic acid.
2. The method for preparing 6-hydroxyquinoline-4-carboxylic acid according to claim 1, characterized in that: The stirring rate in S1 is 120 r / min.
3. The method for preparing 6-hydroxyquinoline-4-carboxylic acid according to claim 1, characterized in that: The ice bath condition in S1 is a mixture of water and crushed ice at a temperature of 0-5°C.
4. The method for preparing 6-hydroxyquinoline-4-carboxylic acid according to claim 1, characterized in that: The hydrofluoric acid in S2 is slowly added at a rate of 1 s / drop.
5. The method for preparing 6-hydroxyquinoline-4-carboxylic acid according to claim 1, characterized in that: The inorganic base added in S3 is one of sodium bicarbonate and sodium hydroxide.
6. The method for preparing 6-hydroxyquinoline-4-carboxylic acid according to claim 1, characterized in that: The volume ratio of the ethyl acetate used for each extraction in S3 to the collected filtrate is 0.5:
1.
7. The method for preparing 6-hydroxyquinoline-4-carboxylic acid according to claim 1, characterized in that: The volume ratio of tetrahydrofuran to ethyl acetate in the mixed solution of tetrahydrofuran and ethyl acetate in S3 is 1:
1.
8. The method for preparing 6-hydroxyquinoline-4-carboxylic acid according to claim 1, characterized in that: The stirring rate in S3 is 150 r / min.
9. The method for preparing 6-hydroxyquinoline-4-carboxylic acid according to claim 1, characterized in that: The parameters of the pulping process in S3 are a rotation speed of 300 r / min and a duration of 2 h.
10. The method for preparing 6-hydroxyquinoline-4-carboxylic acid according to claim 1, characterized in that: The drying parameters in S3 are a temperature of 60° C. and a drying time of 12 h.
Citation Information
Patent Citations
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