A method for synthesizing 7-bromo-2-chloroquinolin-4-ol

Abstract

The application discloses a synthesis method of 7-bromo-2-chloroquinolin-4-ol, which comprises the following steps: taking 7-bromo-2,4-dichloroquinoline as raw material, converting into 7-bromo-4-(tert-butoxy)-2-chloroquinoline, and reacting under the action of p-toluenesulfonic acid to obtain 7-bromo-2-chloroquinolin-4-ol. The synthesis method of 7-bromo-2-chloroquinolin-4-ol is short in steps, relatively mild in reaction condition, and high in product yield, which not only provides a potential route for the process synthesis of 7-bromo-2-chloroquinolin-4-ol, but also helps the development and utilization of quinoline compounds.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing 7-bromo-2-chloroquinoline-4-ol. Background Technology

[0002] Quinoline compounds can be used to prepare pharmaceuticals, dyes, photosensitive materials, rubber, solvents, and chemical reagents. In the pharmaceutical field, they are primarily used to prepare three main classes of drugs: nicotinic acid-based, 8-hydroxyquinoline-based, and quinine-based. Nicotinic acid-based drugs include nicotinamide, cardiotonic agents, stimulants, and drugs for treating tapeworm infections. 8-hydroxyquinoline-based drugs can be used to prepare drugs for treating amoebiasis, wound disinfectants, antifungal agents, and textile auxiliaries. Primaquinine, chloroquinine, and hydroxyquinine are used to synthesize highly effective antimalarial drugs. Isoquinolines can be used to prepare insecticides, antimalarial drugs, rubber vulcanization accelerators, and chemical reagents for determining rare metals. Methylquinoline can be used to prepare color film sensitizers and dyes, and also serves as a solvent, impregnating agent, corrosion inhibitor, quinine-based drugs, and insecticides.

[0003] 7-Bromo-2-chloroquinolin-4-ol is an important quinoline compound and a crucial building block in molecular structures. As a key intermediate, it was used in the synthesis of some analogs of the antitumor drugs 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid and 2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic acid, as described in an article by Stuart T. Hazeldine et al. (Part 3: Synthesis and biological evaluation of some analogs of theantitumor agents, 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid, and 2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic acid). Therefore, developing a synthetic method for 7-bromo-2-chloroquinolin-4-ol is of great significance.

[0004] In the prior art, the synthesis method of 7-bromo-2-chloroquinoline-4-ol generally uses 7-bromo-4-chloroquinoline as a raw material and obtains the target product E through four steps of reaction, as shown in formula (1):

[0005]

[0006] The preparation of compound C from compound B requires the use of the peroxide m-chloroperoxybenzoic acid, which poses certain risks. The preparation of compound E from compound D involves strong acid demethylation, which produces byproducts of halogen exchange and 2-position chlorination hydrolysis, leading to difficult purification and low yield. Therefore, based on the current technological status, it is necessary to develop a method for preparing 7-bromo-2-chloroquinoline-4-ol that is simpler, has milder reaction conditions, and yields a higher product. Summary of the Invention

[0007] To address the shortcomings of existing methods for synthesizing 7-bromo-2-chloroquinoline-4-ol, the present invention aims to provide a method for synthesizing 7-bromo-2-chloroquinoline-4-ol that is low-cost, simple, has relatively mild reaction conditions, and achieves ideal yields.

[0008] To achieve the above objectives, the present invention provides the following technical solution:

[0009] A method for synthesizing 7-bromo-2-chloroquinoline-4-ol includes: using compound 1 (7-bromo-2,4-dichloroquinoline) as a starting material, converting it into compound 2 (7-bromo-4-(tert-butoxy)-2-chloroquinoline), and then reacting compound 2 with p-toluenesulfonic acid to obtain compound 3 (7-bromo-2-chloroquinoline-4-ol). The synthetic route is shown in formula (2).

[0010]

[0011] Preferably, the method for synthesizing the 7-bromo-2-chloroquinoline-4-ol includes the following steps:

[0012] (1) Dissolve compound 1 in organic solvent I, then add alkali, heat the mixture to 40-150°C and stir for 2-5 hours; after the reaction is completed, the resulting reaction solution is post-treated to obtain compound 2;

[0013] (2) Compound 2 was added to organic solvent II, and then p-toluenesulfonic acid was added. The mixture was heated to 50-150°C and stirred for 2-5 hours. After the reaction was completed, the resulting reaction solution was post-treated to obtain compound 3.

[0014] Preferably, in step (1), the organic solvent I is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, acetone, 1,3-dimethyl-2-imidazolinone, hexamethylphosphoric triamine, and N-methylpyrrolidone.

[0015] Preferably, in step (1), the base is selected from potassium tert-butoxide and / or sodium tert-butoxide.

[0016] Preferably, in step (1), the mass-to-volume ratio of compound 1 to organic solvent I is 1:5 to 40 (g / mL).

[0017] Preferably, in step (1), the molar ratio of compound 1 to the base is 1.0:1.0 to 3.0.

[0018] Preferably, in step (1), the post-processing includes: after the reaction is completed, the reaction solution is cooled to room temperature and poured into ice water, extracted with organic solvent III, the organic phases are combined, and the obtained organic phase is washed, dried, filtered, and evaporated to obtain crude compound 2.

[0019] More preferably, in step (1), the organic solvent III is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

[0020] Preferably, in step (2), the organic solvent II is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, and 1,4-dioxane.

[0021] Preferably, in step (2), the mass-to-volume ratio of compound 2 to organic solvent II is 1:5 to 40 (g / mL).

[0022] Preferably, in step (2), the molar ratio of compound 2 to p-toluenesulfonic acid is 1.0:1.0 to 1.5.

[0023] Preferably, in step (2), the post-processing includes: after the reaction is completed, pour the reaction solution into ice water and stir for 20 to 60 minutes, filter, collect the solid on the filter cake, and dry it to obtain the final product.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0025] This invention uses 7-bromo-2,4-dichloroquinoline as a starting material, converts it into 7-bromo-4-(tert-butoxy)-2-chloroquinoline, and then reacts it under the action of p-toluenesulfonic acid to obtain the target compound 7-bromo-2-chloroquinoline-4-ol. The synthetic method of 7-bromo-2-chloroquinoline-4-ol in this invention is simple in steps, relatively mild in reaction conditions, and has a high product yield. It not only provides a potential route for the process synthesis of 7-bromo-2-chloroquinoline-4-ol, but also contributes to the development and utilization of quinoline compounds. Attached Figure Description

[0026] Figure 1 The image shows the 1H NMR spectrum of 7-bromo-2-chloroquinoline-4-ol from Example 1. Detailed Implementation

[0027] The present invention will now be described in detail with reference to specific embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way. It should be noted that those skilled in the art can make several changes and improvements without departing from the concept of the present invention. These all fall within the protection scope of the present invention.

[0028] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0029] The following embodiment proposes a method for synthesizing 7-bromo-2-chloroquinoline-4-ol, comprising: using compound 1 (7-bromo-2,4-dichloroquinoline) as a starting material, converting it into compound 2 (7-bromo-4-(tert-butoxy)-2-chloroquinoline), and then reacting it in the presence of p-toluenesulfonic acid to obtain the target compound 3 (7-bromo-2-chloroquinoline-4-ol). The synthetic route is as follows:

[0030]

[0031] In some embodiments, the method for synthesizing 7-bromo-2-chloroquinoline-4-ol includes the following steps:

[0032] (1) Compound 1 was dissolved in organic solvent I, and then alkali was added. The mixture was heated to 40-150°C and stirred for 2-5 hours. After the reaction was completed, the resulting reaction solution was post-treated to obtain compound 2.

[0033] (2) Compound 2 was added to organic solvent II, and then p-toluenesulfonic acid was added. The mixture was heated to 50-150°C and stirred for 2-5 hours. After the reaction was completed, the resulting reaction solution was post-treated to obtain compound 3.

[0034] In some embodiments, in step (1), organic solvent I can be selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, acetone, 1,3-dimethyl-2-imidazolinone, hexamethylphosphoric triamine, and N-methylpyrrolidone; the base can be selected from potassium tert-butoxide and / or sodium tert-butoxide; the mass-volume ratio of compound 1 to organic solvent I is 1:5 to 40 g / mL; the molar ratio of compound 1 to base is 1.0:1.0 to 3.0; the post-treatment process includes: after the reaction is completed, the reaction solution is cooled to room temperature and poured into ice water, extracted with organic solvent III, the organic phases are combined, the obtained organic phase is washed, dried, filtered, and evaporated to dryness to obtain crude compound 2; organic solvent III can be selected from ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

[0035] In some embodiments, in step (2), organic solvent II can be selected from tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or 1,4-dioxane; the mass-to-volume ratio of compound 2 to organic solvent II is 1:5-40 g / mL; the molar ratio of compound 2 to p-toluenesulfonic acid is 1.0:1.0-1.5; the post-processing includes: after the reaction is completed, the reaction solution is poured into ice water and stirred for 20-60 minutes, filtered, the solid on the filter cake is collected, and dried to obtain compound 3.

[0036] The present invention will be further explained and illustrated below through specific embodiments.

[0037] Example 1

[0038] This embodiment provides a method for synthesizing 7-bromo-2-chloroquinoline-4-ol, the specific steps of which are as follows:

[0039] (1) Dissolve 7-bromo-2,4-dichloroquinoline (200.00 g, 722.17 mmol, 1.0 eq) in N,N-dimethylformamide (2.0 L), then add potassium tert-butoxide (97.24 g, 866.61 mmol, 1.20 eq). Heat the mixture to 50 °C and stir for 2 hours. After the reaction is complete, cool the reaction mixture to room temperature and pour it into ice water (2.0 L). Extract three times with ethyl acetate (1.5 L × 3). Combine the organic phases and wash them once with saturated brine (2.0 L). Dry the mixture with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain crude 7-bromo-4-(tert-butoxy)-2-chloroquinoline (221.10 g, purity 97%, yield 94%). The crude product does not require further purification and can be used directly in the next step.

[0040] (2) Crude 7-bromo-4-(tert-butoxy)-2-chloroquinoline (200.00 g, 635.71 mmol, 1.00 eq) was added to tetrahydrofuran (2.0 L), followed by p-toluenesulfonic acid (109.47 g, 635.71 mmol, 1.00 eq). The mixture was heated to 70 °C and stirred for 2 hours. After the reaction was complete, the reaction mixture was poured into ice water (1.0 L), stirred for 20 minutes, filtered, and the solid on the filter cake was collected, dried, and the target compound 7-bromo-2-chloroquinoline-4-ol (158.90 g, 98% purity, 95% yield) was obtained.

[0041] The 1H NMR spectrum of the compound 7-bromo-2-chloroquinoline-4-ol obtained in this example is as follows: Figure 1 As shown, the characterization data is as follows: 1 H NMR (400MHz, dmso) δ12.40 (s, 1H), 8.03 (d, J = 8.8Hz, 2H), 7.67 (d, J = 8.4Hz, 1H), 6.79 (s, 1H).

[0042] Examples 2-9

[0043] Examples 2 to 9 are basically the same as Example 1, except that the alkali and organic solvent I in step (1) and the toluenesulfonic acid and organic solvent II in step (2) are adjusted, as shown in Table 1.

[0044] Examples 1-9 were used to investigate the effects of various reaction conditions on the reaction yield during the synthesis of the intermediate compound 7-bromo-4-(tert-butoxy)-2-chloroquinoline and the target compound 7-bromo-2-chloroquinoline-4-ol. The results are shown in Table 1.

[0045] Table 1

[0046]

[0047] Comparing Examples 1-3, the reaction was already very good when the molar ratio of compound 1 to base was 1.00:1.20.

[0048] Comparing Examples 1 and 4, the reaction was already very good when the molar ratio of compound 1 to p-toluenesulfonic acid was 1.00:1.00.

[0049] Comparing Examples 1 and 5, both reactions using potassium tert-butoxide or sodium tert-butoxide as a base yielded the product in high yield, with potassium tert-butoxide being more effective as a base.

[0050] Comparing Examples 1 and 6-7, the product can be obtained in high yields in solvents N,N-dimethylformamide, N,N-dimethylacetamide and toluene, with N,N-dimethylformamide being the most effective solvent.

[0051] Comparing Examples 1 and 8-9, the product could be obtained in high yields in solvents tetrahydrofuran, toluene, and 1,4-dioxane, with tetrahydrofuran being the most effective solvent.

[0052] The above are merely preferred embodiments of the present invention and are not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing 7-bromo-2-chloroquinoline-4-ol, characterized in that, include: Using compound 1, 7-bromo-2,4-dichloroquinoline, as a starting material, it is converted into compound 2, 7-bromo-4-(tert-butoxy)-2-chloroquinoline. Then, compound 2 reacts with p-toluenesulfonic acid to give compound 3, 7-bromo-2-chloroquinoline-4-ol. The synthetic route is shown in formula (2): ； The synthesis method includes the following steps: (1) Dissolve compound 1 in organic solvent I, then add alkali, heat the mixture to 40-150°C and stir for 2-5 hours; after the reaction is completed, the resulting reaction solution is post-treated to obtain compound 2; The organic solvent I is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, acetone, 1,3-dimethyl-2-imidazolinone, hexamethylphosphoric triamine, and N-methylpyrrolidone; The base is selected from potassium tert-butoxide and / or sodium tert-butoxide; The mass-to-volume ratio of compound 1 to organic solvent I is 1:5-40 (g / mL); The molar ratio of compound 1 to the base is 1.0:1.0 to 3.0; (2) Compound 2 was added to organic solvent II, and then p-toluenesulfonic acid was added. The mixture was heated to 50-150°C and stirred for 2-5 hours. After the reaction was completed, the resulting reaction solution was post-treated to obtain compound 3. The organic solvent II is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, and 1,4-dioxane; The mass-to-volume ratio of compound 2 to organic solvent II is 1:5-40 (g / mL); The molar ratio of compound 2 to p-toluenesulfonic acid is 1.0:1.0-1.

5.

2. The method for synthesizing 7-bromo-2-chloroquinoline-4-ol according to claim 1, characterized in that, In step (1), the post-processing process includes: after the reaction is completed, the reaction solution is cooled to room temperature and poured into ice water, extracted with organic solvent III, the organic phases are combined, and the obtained organic phase is washed, dried, filtered, and evaporated to obtain crude compound 2.

3. The method for synthesizing 7-bromo-2-chloroquinoline-4-ol according to claim 2, characterized in that, In step (1), the organic solvent III is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

4. The method for synthesizing 7-bromo-2-chloroquinoline-4-ol according to claim 1, characterized in that, In step (2), the post-processing process includes: after the reaction is completed, pour the reaction solution into ice water and stir for 20 to 60 minutes, filter, collect the solid on the filter cake, and dry it to obtain the final product.

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