A kind of preparation method of 6-bromoquinoline

Abstract

The invention discloses a preparation method of 6-bromoquinoline, and belongs to the technical field of organic synthesis. 4-(hydroxymethyl)-1,3,2-dioxathiolane-2-oxide is reacted with an oxidizing agent to obtain 4-(hydroxymethyl)-1,3,2-dioxathiolane-2,2-dioxide; 4-(hydroxymethyl)-1,3,2-dioxathiolane-2,2-dioxide is dehydrated and condensed with 4-bromoaniline in the presence of Lewis acid, and then manganese dioxide is aromatized to obtain 6-bromoquinoline. The present invention uses strong Lewis acid dehydration and manganese dioxide aromatization to avoid the side reaction of nitrobenzene oxidative aromatization under traditional high temperature acid catalysis, resulting in low yield and other deficiencies.

Description

Technical Field

[0001] The invention relates to a preparation method of 6-bromoquinoline, and belongs to the technical field of organic synthesis. Background Art

[0002] 6-Bromoquinoline, English name 6-Bromoquinoline, is a structural fragment with important physiologically active substances. It is widely used in the synthesis of pharmaceutical intermediates, such as anticancer drug enhancers, receptor tyrosine kinase inhibitors, cardiotonic agents, anti-inflammatory and insecticides.

[0003] Quinoline, especially halogenated quinoline compounds, have a wide spectrum of biological activities, such as antifungal, antituberculosis, antifilarial, anti-HIV, etc. It can be synthesized by the methods of combse, Pfitzinger, Skraup, Friedlander, etc.

[0004] The traditional process of 6-bromoquinoline is to use 4-bromoaniline, glycerol, nitrobenzene and concentrated sulfuric acid as raw materials to synthesize by Skraup reaction at 200°C, and adjust the pH to 5.0-6.0 with sodium hydroxide aqueous solution after the reaction. However, this process uses nitrobenzene, and there are safety hazards in the process of distilling nitrobenzene, which is not conducive to industrial-scale production.

[0005] In view of the above-mentioned shortcomings of the prior art, the object of the present invention is to provide a method for preparing 6-bromoquinoline to solve the problems in the prior art. Summary of the invention

[0006] In order to overcome the above technical defects, the present invention provides an improved preparation method of 6-bromoquinoline. 4-(hydroxymethyl)-1,3,2-dioxathiolane-2-oxide is reacted with an oxidizing agent to obtain 4-(hydroxymethyl)-1,3,2-dioxathiolane-2,2-dioxide; 4-(hydroxymethyl)-1,3,2-dioxathiolane-2,2-dioxide is dehydrated and condensed with 4-bromoaniline in the presence of a Lewis acid, followed by aromatization with manganese dioxide to obtain 6-bromoquinoline. The present invention uses strong Lewis acid dehydration and manganese dioxide aromatization to avoid the side reactions of nitrobenzene oxidative aromatization under traditional high-temperature acid catalysis, which leads to the disadvantages of low yield and the like.

[0007] A method for preparing 6-bromoquinoline according to the present invention comprises the following steps:

[0008] S1: 4-(hydroxymethyl)-1,3,2-dioxathiolane-2-oxide reacts with an oxidizing agent in an organic solvent to obtain 4-(hydroxymethyl)-1,3,2-dioxathiolane-2,2-dioxide; the reaction equation is as follows:

[0009]

[0010] Furthermore, in the above technical solution, in step S1, the organic solvent is selected from dichloromethane or 1,2-dichloroethane; and the reaction temperature is selected from 20-30°C.

[0011] Furthermore, in the above technical solution, in step S1, the molar ratio of 4-(hydroxymethyl)-1,3,2-dioxathiolane-2-oxide to the oxidizing agent is 1:3.5-5.0.

[0012] Furthermore, in the above technical solution, in step S1, the oxidizing agent is selected from Oxone (potassium persulfate).

[0013] S2: 4-(Hydroxymethyl)-1,3,2-dioxathiolane-2,2-dioxide and 4-bromoaniline are subjected to dehydration condensation in an organic solvent under the catalysis of Lewis acid, followed by aromatization with manganese dioxide to obtain 6-bromoquinoline; the reaction equation is as follows:

[0014]

[0015] Furthermore, in the above technical solution, in step S2, the reaction solvent is selected from toluene or dioxane, and the reaction temperature is 90-110°C.

[0016] Furthermore, in the above technical solution, in step S2, the Lewis acid catalyst is selected from B(C6F5)3.

[0017] Furthermore, in the above technical solution, in step S2, the molar ratio of 4-(hydroxymethyl)-1,3,2-dioxathiolane-2,2-dioxide, 4-bromoaniline and Lewis acid is 1:0.98-1.05:0.01-0.03.

[0018] Furthermore, in the above technical solution, in step S2, the amount of manganese dioxide used is 20-30% by weight of 4-bromoaniline.

[0019] Advantageous Effects of the Invention

[0020] 1. The present invention adopts strong Lewis acid dehydration and manganese dioxide aromatization to avoid the side reactions of nitrobenzene oxidative aromatization under traditional high-temperature acid catalysis and reduce potential safety hazards.

[0021] 2. The present invention has high product content, low wastewater volume, low equipment requirements, and is more convenient to operate. Specific embodiments

[0022] The present invention will be further described below by specific examples. These embodiments should be understood to be only used to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0023] Synthesis of 6-bromoquinoline

[0024] Example 1

[0025]

[0026] Add 13.8 g (0.1 mol) of 4-(hydroxymethyl)-1,3,2-dioxathiolane-2-oxide into the reaction bottle and mix with 150 mL of dichloromethane. Add 58.9 g (0.35 mol) of Oxone in batches while maintaining the temperature at 20-30°C for oxidation reaction. Filter and rinse the filter cake with dichloromethane. Concentrate the filtrate under reduced pressure until no liquid flows to obtain 13.6 g of 4-(hydroxymethyl)-1,3,2-dioxathiolane-2,2-dioxide with a yield of 88.1% and an HPLC value of 98.8%. 1 HNMR(400MHz, CDCl3)δ:4.68-4.51(m,3H),4.51-4.43(m,1H),4.41-4.36(m,1H),3.92(s,1H).

[0027] Example 2

[0028] Add 13.8 g (0.1 mol) of 4-(hydroxymethyl)-1,3,2-dioxathiolane-2-oxide and 200 mL of 1,2-dichloroethane into the reaction bottle and mix. Keep the temperature at 20-30°C and add 84.1 g (0.5 mol) of Oxone in batches for oxidation reaction. Filter and rinse the filter cake with dichloromethane. Concentrate the filtrate under reduced pressure until no liquid flows to obtain 14.5 g of 4-(hydroxymethyl)-1,3,2-dioxathiolane-2,2-dioxide. The yield is 94.1%. HPLC97.9%.

[0029] Example 3

[0030]

[0031] Add 15.4 g (0.1 mol) of 4-(hydroxymethyl)-1,3,2-dioxathiolane-2,2-dioxide, 17.2 g (0.1 mol) of 4-bromoaniline and 150 mL of toluene into the reaction bottle and mix. Then add 31.5 g (0.003 mol) of B(C6F5) and heat to reflux for 8 hours until no more water is separated. Then cool the reaction system.

[0032] Under air atmosphere, 5.2 g of manganese dioxide was added to the reaction system, and then the temperature was raised to 90-100 ° C for reaction for 4 hours, cooled to 40-45 ° C, filtered, the filtrate was quenched with water, 30% sodium hydroxide was added to adjust the pH to 5.0-6.0, the layers were separated, the organic phase was washed with water to pH = 6.5-7.0, and the crude product was concentrated under reduced pressure and isopropyl ether was added to cool and crystallize to obtain 16.1 g of 6-bromoquinoline, HPLC 99.5%, yield 77.6%. 1 HNMR(400MHz, CDCl3):8.92-8.90(m,1H),8.06-8.04(m,1H),8.03-7.93(m,2H),7.78-7.72(m,1H),7.42-7.38(m,1H).

[0033] Example 4

[0034] Add 15.4 g (0.1 mol) of 4-(hydroxymethyl)-1,3,2-dioxathiolane-2,2-dioxide, 16.9 g (0.098 mol) of 4-bromoaniline and 100 mL of dioxane into the reaction bottle and mix. Then add 31.5 g (0.003 mol) of B(C6F5) and heat to reflux for 2 hours. Then, add more dioxane while distilling at normal pressure until almost no raw materials remain, and cool the reaction system.

[0035] Under air atmosphere, 3.4 g of manganese dioxide was added to the reaction system, and then the temperature was raised to 90-100 ° C for reaction for 5 hours, cooled to 30-35 ° C, filtered, and the filtrate was concentrated under reduced pressure until no liquid flowed, replaced with ethyl acetate, and water and 30% sodium hydroxide were added to adjust the pH to 5.0-6.0. The layers were separated, and the organic phase was washed with water to pH = 6.5-7.0. The crude product was concentrated under reduced pressure and added with isopropyl ether to cool and crystallize to obtain 16.8 g of 6-bromoquinoline, HPLC 99.6%, and the yield was 80.6%.

[0036] Example 5

[0037] Add 15.4 g (0.1 mol) of 4-(hydroxymethyl)-1,3,2-dioxathiolane-2,2-dioxide, 18.1 g (0.105 mol) of 4-bromoaniline and 150 mL of toluene into the reaction bottle and mix. Then add 31.0 g (0.002 mol) of B(C6F5) and heat to reflux for 15 hours until no more water is separated. Then cool the reaction system.

[0038] Under air atmosphere, 5.4 g of manganese dioxide was added to the reaction system, and then the temperature was raised to 90-100 ° C for reaction for 4 hours, cooled to 40-45 ° C, filtered, the filtrate was quenched with water, 30% sodium hydroxide was added to adjust the pH to 5.0-6.0, the layers were separated, the organic phase was washed with water to pH = 6.5-7.0, and the crude product was concentrated under reduced pressure and isopropyl ether was added to cool and crystallize to obtain 16.4 g of 6-bromoquinoline, HPLC 99.4%, yield 78.7%.

[0039] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing 6-bromoquinoline, characterized in that, The steps include: S1: 4-(hydroxymethyl)-1,3,2-dioxathiolane-2-oxide reacts with an oxidizing agent in an organic solvent to obtain 4-(hydroxymethyl)-1,3,2-dioxathiolane-2,2-dioxide; the reaction equation is as follows: ； S2: 4-(Hydroxymethyl)-1,3,2-dioxathiolane-2,2-dioxide and 4-bromoaniline are subjected to dehydration condensation in an organic solvent under the catalysis of Lewis acid B(C6F5)3, followed by aromatization with manganese dioxide to obtain 6-bromoquinoline; the organic solvent is selected from toluene or dioxane, and the reaction temperature is 90-110°C; the reaction equation is as follows: 。 2. The preparation method of 6-bromoquinoline according to claim 1, wherein: In step S1, the organic solvent is selected from dichloromethane or 1,2-dichloroethane; and the reaction temperature is selected from 20-30°C.

3. The preparation method of 6-bromoquinoline according to claim 1, wherein: In step S1, the molar ratio of 4-(hydroxymethyl)-1,3,2-dioxathiolane-2-oxide to the oxidizing agent is 1:3.5-5.

0.

4. The preparation method of 6-bromoquinoline according to claim 1, wherein: In step S1, the oxidizing agent is selected from Oxone.

5. The preparation method of 6-bromoquinoline according to claim 1, wherein: In step S2, the molar ratio of 4-(hydroxymethyl)-1,3,2-dioxathiolane-2,2-dioxide, 4-bromoaniline and Lewis acid is 1:0.98-1.05:0.01-0.

03.

6. The method for preparing 6-bromoquinoline according to claim 1, wherein: In step S2, the amount of manganese dioxide used is 20-30% by weight of 4-bromoaniline.

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