Synthesis method of 7-bromo-2-chloroquinoline-4-alcohol

Abstract

The invention discloses a synthesis method of 7-bromine-2-chloroquinoline-4-alcohol, which comprises the following steps of: converting 7-bromine-2, 4-dichloroquinoline serving as a raw material into 7-bromine-4-(tert-butoxy)-2-chloroquinoline, and reacting under the action of p-toluenesulfonic acid to obtain the 7-bromine-2-chloroquinoline-4-alcohol. The synthesis method of the 7-bromo-2-chloroquinoline-4-alcohol has the advantages of short steps, relatively mild reaction conditions and high product yield, not only provides a potential route for the process synthesis of the 7-bromo-2-chloroquinoline-4-alcohol, but also contributes to the development and utilization of quinoline compounds.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 7-bromo-2-chloroquinoline-4-ol. Background Art

[0002] Quinoline compounds can be used to prepare medicines, dyes, photosensitive materials, rubbers, solvents and chemical reagents, etc., especially in the field of medicine, they are mainly used to prepare three major types of drugs: nicotinic acid, 8-hydroxyquinoline and quinine. Among them, nicotinic acid drugs include nicotinamide, cardiotonic, stimulant and anti-tapeworm drugs; 8-hydroxyquinoline can be used to prepare drugs for treating amoebiasis and wound disinfectants, as well as mildew inhibitors and textile auxiliaries; primaquinine, chloroquine and hydroxyaminoquine are used to synthesize special anti-malarial drugs; isoquinoline 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 can also be used as solvents, impregnants, corrosion inhibitors, quinine drugs and insecticides.

[0003] 7-Bromo-2-chloroquinolin-4-ol is an important quinoline compound and also an important molecular building block. As a key intermediate, it was used in the synthesis of some analogs of the antitumor agents 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid and 2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic acid in the article published 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, it is of great significance to develop a synthetic method for 7-bromo-2-chloroquinolin-4-ol.

[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. The technical route is shown in formula (1):

[0005]

[0006] Among them, in the process of preparing compound C from compound B, the peroxide meta-chloroperbenzoic acid is needed, which is dangerous; in the process of preparing compound E from compound D, the use of strong acid demethylation will produce byproducts of halogen exchange and 2-chlorine hydrolysis, which makes purification difficult and the yield is low. Therefore, based on the current process status, it is necessary to develop a preparation method of 7-bromo-2-chloroquinoline-4-ol with short steps, relatively mild reaction conditions and high product yield. Summary of the invention

[0007] In view of the shortcomings of the synthesis method of 7-bromo-2-chloroquinoline-4-ol in the prior art, the present invention aims to provide a synthesis method of 7-bromo-2-chloroquinoline-4-ol, the whole synthesis process is low in cost, short in steps, relatively mild in reaction conditions and ideal in yield.

[0008] In order to achieve the above object, the present invention provides the following technical solutions:

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

[0010]

[0011] Preferably, the synthesis method of 7-bromo-2-chloroquinoline-4-ol comprises the following steps:

[0012] (1) Compound 1 is dissolved in an organic solvent I, and a base is added. The mixture is heated to 40 to 150° C. and stirred for reaction for 2 to 5 hours. After the reaction is completed, the reaction solution is post-treated to obtain Compound 2;

[0013] (2) Compound 2 is added to an organic solvent II, and then p-toluenesulfonic acid is added. The mixed solution is heated to 50-150° C. and stirred for reaction for 2-5 hours. After the reaction is completed, the obtained reaction solution is 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-imidazolidinone, hexamethylphosphoric triamide, 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 volume ratio of compound 1 to organic solvent I is 1:5-40 (g / mL).

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

[0018] Preferably, in step (1), the post-treatment process comprises: after the reaction is completed, cooling the reaction solution to room temperature and pouring it into ice water, extracting with organic solvent III, combining the organic phases, washing the obtained organic phases, drying, filtering, and spin-drying to obtain a crude product of 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 volume ratio of the compound 2 to the 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 1.0:1.0-1.5.

[0023] Preferably, in step (2), the post-treatment process comprises: after the reaction is completed, pouring the reaction solution into ice water and stirring for 20 to 60 minutes, filtering, collecting the solid on the filter cake, and drying to obtain.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The invention uses a compound 7-bromo-2,4-dichloroquinoline as a raw material, converts it into 7-bromo-4-(tert-butoxy)-2-chloroquinoline, and then reacts under the action of p-toluenesulfonic acid to obtain a target compound 7-bromo-2-chloroquinoline-4-ol. The synthesis method of 7-bromo-2-chloroquinoline-4-ol in the invention has short steps, relatively mild reaction conditions and high product yield, which 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 It is the H NMR spectrum of 7-bromo-2-chloroquinoline-4-ol in Example 1. DETAILED DESCRIPTION

[0027] The present invention is described in detail below in conjunction with specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those of ordinary skill in the art, several changes and improvements can also be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

[0028] Unless otherwise specified in the following examples, all reagents and materials used were 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 raw material, converting it into compound 2 (7-bromo-4-(tert-butoxy)-2-chloroquinoline), and then reacting it under the action of p-toluenesulfonic acid to obtain the target compound 3 (7-bromo-2-chloroquinoline-4-ol), and the synthesis route is as follows:

[0030]

[0031] In some embodiments, the synthesis method of 7-bromo-2-chloroquinoline-4-ol comprises the following steps:

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

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

[0034] In some embodiments, in step (1), the organic solvent I can be selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, acetone, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric acid triamide, 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 1:5-40 g / mL; the molar ratio of compound 1 to base is 1.0:1.0-3.0; 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, combined with organic phases, the obtained organic phases are washed, dried, filtered, and spin-dried to obtain a crude product of 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), the organic solvent II can be selected from tetrahydrofuran, 2-methyltetrahydrofuran, toluene, and 1,4-dioxane; the mass volume ratio of compound 2 to organic solvent II is 1:5 to 40 g / mL; the molar ratio of compound 2 to p-toluenesulfonic acid is 1.0:1.0 to 1.5; and the post-treatment process comprises: after the reaction is completed, pouring the reaction solution into ice water and stirring for 20 to 60 minutes, filtering, collecting the solid on the filter cake, and drying to obtain compound 3.

[0036] The present invention is further explained below by means of specific examples.

[0037] Example 1

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

[0039] (1) 7-bromo-2,4-dichloroquinoline (200.00 g, 722.17 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (2.0 L), and potassium tert-butoxide (97.24 g, 866.61 mmol, 1.20 eq) was added. The mixture was heated to 50°C and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and poured into ice water (2.0 L). It was extracted with ethyl acetate three times (1.5 L×3), and the organic phases were combined. The organic phases were washed once with saturated brine (2.0 L), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product of 7-bromo-4-(tert-butoxy)-2-chloroquinoline (weight 221.10 g, purity 97%, yield 94%). The crude product did not need to be further purified and could be directly used in the next step.

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

[0041] The H NMR spectrum of the compound 7-bromo-2-chloroquinoline-4-ol obtained in this example is as follows Figure 1 The characterization data are as follows: 1 HNMR(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] Embodiments 2 to 9

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

[0044] Through Examples 1 to 9, 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 were explored, and the results are shown in Table 1.

[0045] Table 1

[0046]

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

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

[0049] Comparing Examples 1 and 5, the reaction can obtain the product with a high yield using potassium tert-butoxide or sodium tert-butoxide as the base, among which potassium tert-butoxide has a better effect as the base.

[0050] Comparing Examples 1, 6-7, the product can be obtained in high yield in the solvents N,N-dimethylformamide, N,N-dimethylacetamide and toluene, among which N,N-dimethylformamide is more effective as a solvent.

[0051] Comparing Examples 1, 8-9, the product can be obtained in high yield in the solvents of tetrahydrofuran, toluene and 1,4-dioxane, among which tetrahydrofuran is more effective as a solvent.

[0052] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 7-bromo-2-chloroquinoline-4-ol, characterized in that: include: Compound 1, 7-bromo-2,4-dichloroquinoline, is used as a raw material to convert it into compound 2, 7-bromo-4-(tert-butoxy)-2-chloroquinoline. Compound 2 then reacts under the action of p-toluenesulfonic acid to obtain compound 3, 7-bromo-2-chloroquinoline-4-ol. The synthetic route is shown in formula (2):

2. The synthetic method of 7-bromo-2-chloroquinoline-4-ol according to claim 1, characterized in that: The synthesis method comprises the following steps: (1) Compound 1 is dissolved in an organic solvent I, and a base is added. The mixture is heated to 40 to 150° C. and stirred for reaction for 2 to 5 hours. After the reaction is completed, the reaction solution is post-treated to obtain Compound 2; (2) Compound 2 is added to an organic solvent II, and then p-toluenesulfonic acid is added. The mixed solution is heated to 50-150° C. and stirred for reaction for 2-5 hours. After the reaction is completed, the obtained reaction solution is post-treated to obtain Compound 3.

3. The synthetic method of 7-bromo-2-chloroquinoline-4-ol according to claim 2, characterized in that: 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-imidazolidinone, hexamethylphosphoric acid triamide, and N-methylpyrrolidone; And / or the base is selected from potassium tert-butoxide and / or sodium tert-butoxide.

4. The synthetic method of 7-bromo-2-chloroquinoline-4-ol according to claim 2, characterized in that: In step (1), the mass volume ratio of the compound 1 to the organic solvent I is 1:5 to 40 g / mL.

5. The synthetic method of 7-bromo-2-chloroquinoline-4-ol according to claim 2, characterized in that: In step (1), the molar ratio of the compound 1 to the base is 1.0:1.0-3.

0.

6. The method for synthesizing 7-bromo-2-chloroquinoline-4-ol according to claim 2, characterized in that: In step (1), 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, and the obtained organic phases are washed, dried, filtered, and spin-dried to obtain a crude product of compound 2.

7. The method for synthesizing 7-bromo-2-chloroquinoline-4-ol according to claim 6, 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.

8. The method for synthesizing 7-bromo-2-chloroquinoline-4-ol according to claim 2, characterized in that: In step (2), the organic solvent II is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, and 1,4-dioxane.

9. The method for synthesizing 7-bromo-2-chloroquinoline-4-ol according to claim 2, characterized in that: In step (2), the mass volume ratio of the compound 2 to the organic solvent II is 1:5 to 40 g / mL; And / or the molar ratio of the compound 2 to p-toluenesulfonic acid is 1.0:1.0-1.

5.

10. The method for synthesizing 7-bromo-2-chloroquinoline-4-ol according to claim 2, characterized in that: In step (2), the post-treatment process includes: after the reaction is completed, pouring the reaction solution into ice water and stirring for 20 to 60 minutes, filtering, collecting the solid on the filter cake, and drying to obtain.

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