A method for synthesizing a polyhalogenated quinoline compound

Abstract

This invention discloses a synthetic method for polyhalogenated quinoline compounds, belonging to the field of fine chemical technology. Using 5,6,7,8-tetrahydro-8-hydroxyquinoline as a starting material, it undergoes an oxidative dihalogenation reaction with sodium hypochlorite or sodium hypobromite to obtain 7,7-dihalo-6,7-dihydroquinoline-8(5H)-one; subsequently, it is aromatized in the presence of manganese dioxide to obtain 7,7-dihaloquinoline-8(7H)-one. This method is simple and safe, avoiding the use of chlorine or bromine, and provides a synthetic method for polyhalogenation (i.e., α-polyhalogenation of alkyl ketones).

Description

Technical Field

[0001] This invention belongs to the field of fine chemical technology, specifically relating to a method for synthesizing polyhalogenated quinoline compounds. Background Technology

[0002] 7,7-Dihaloquinoline-8(7H)-one is a polyhalogenated quinoline ketone compound. This type of compound can be used for asymmetric α-chlorination or α-bromination reactions of 1,3-dicarbonyl compounds with high enantioselectivity (Angewandte Chemie-International Edition, 2005, vol. 44, #38, pp. 6219-6222). After asymmetric α-chlorination or α-bromination of 1,3-dicarbonyl compounds, it can yield 7-chloro / bromo-8-hydroxyquinoline.

[0003] There is no relevant literature on the synthesis method of 7,7-dihaloquinoline-8(7H)-one. The applicant discovered this byproduct during the oxidation of 5,6,7,8-tetrahydro-8-hydroxyquinoline with sodium hypochlorite under TEMPO catalysis. By increasing the amount of sodium hypochlorite and controlling different pH values, the applicant explored the process of hydroxyl oxidation to ketone as the oxidation proceeds. With the increase of sodium hypochlorite, the α-position of the ketone undergoes an electrophilic reaction to obtain a dichloro compound, and the separation yield is relatively ideal. Summary of the Invention

[0004] This invention provides a method for synthesizing polyhalogenated quinoline compounds through an accidental discovery during the reaction process. Using 5,6,7,8-tetrahydro-8-hydroxyquinoline as a starting material, it undergoes an oxidative dihalogenation reaction with sodium hypochlorite or sodium hypobromite to yield 7,7-dihalo-6,7-dihydroquinoline-8(5H)-one; followed by aromatization in the presence of manganese dioxide to obtain 7,7-dihaloquinoline-8(7H)-one. This method is simple and safe, avoids the use of chlorine or bromine, and provides a synthetic method for polyhalogenation (i.e., α-polyhalogenation of alkyl ketones).

[0005] This invention provides a polyhalogenated quinoline compound, comprising the following steps:

[0006] 1) Oxidation dihalogenation reaction:

[0007]

[0008] 5,6,7,8-tetrahydro-8-hydroxyquinoline and TEMPO were added to an organic solvent, and the pH was controlled at 10-11. Sodium hypohalate was added dropwise to react and give 7,7-dihalo-6,7-dihydroquinoline-8(5H)-one.

[0009] 2) Oxidative aromatization reaction

[0010]

[0011] 7,7-Dihalo-6,7-Dihydroquinoline-8(5H)-one was dissolved in an organic solvent and oxidized with manganese dioxide to obtain 7,7-dihaloquinoline-8(7H)-one.

[0012] The two-step reaction of this invention is represented by the following equation:

[0013]

[0014] Furthermore, in the above technical solution, the organic solvent is selected from dichloromethane or 1,2-dichloroethane.

[0015] Furthermore, in the above technical solution, the sodium hypohalite mentioned in step 1) is selected from sodium hypochlorite aqueous solution or sodium hypobromite aqueous solution, wherein: the effective chlorine content of sodium hypochlorite aqueous solution is 9-13%, and the effective bromine content of sodium hypobromite aqueous solution is 10-15%.

[0016] Furthermore, in the above technical solution, the molar ratio of 5,6,7,8-tetrahydro-8-hydroxyquinoline, TEMPO and sodium hypohalite in step 1) is 1:0.005-0.01:3.5-4.0.

[0017] Furthermore, in the above technical solution, the manganese dioxide in step 2) is selected from active manganese dioxide with a particle size of 8-12 μm; it needs to be ultrasonicated before use.

[0018] Furthermore, in the above technical solution, the molar ratio of 7,7-dihalo-6,7-dihydroquinoline-8(5H)-one to manganese dioxide in step 2) is 1:2.0-5.0.

[0019] In the free radical reaction, sodium hypochlorite or sodium hypobromite is selected from sodium hypochlorite aqueous solution or sodium hypobromite aqueous solution, wherein the effective chlorine content of sodium hypochlorite aqueous solution is 9-13% and the effective bromine content of sodium hypobromite aqueous solution is 10-15%. Detailed Implementation

[0020] The present invention will be further described in detail through the following embodiments to better understand the content of the present invention, but the present invention is not limited to the following embodiments.

[0021] Example 1: Synthesis of 7,7-dichloro-6,7-dihydroquinoline-8(5H)-one

[0022]

[0023] Specific procedures: Under nitrogen protection, add 29.8 g (0.2 mol) of 5,6,7,8-tetrahydro-8-hydroxyquinoline to 250 mL of dichloromethane in a 500 mL four-necked reaction flask and stir until dissolved. Cool to 5-10 °C and add TEMPO. 0.17 g of sodium hypochlorite was added dropwise, while the pH was adjusted to 10.0-10.5 with 2N sodium hydroxide solution. After the addition was completed, the temperature was slowly raised to room temperature and reacted for 5 hours. The HPLC raw material residue was <0.5%. The mixture was allowed to stand and separate into layers. The aqueous phase was extracted with 100 mL of dichloromethane. The lower organic phase was combined and washed with water. The organic phase was dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and replaced with isopropanol. The crude product was recrystallized from isopropanol and isopropyl ether to give 35.3 g of 7,7-dichloro-6,7-dihydroquinoline-8(5H)-one. Yield: 81.8%, HPLC: 98.4%, m / z: 215.1 [M-1]. 1 HNMR(400MHz, CDCl3):8.75-7.73(m,1H),7.96-7.94(m,1H),7.48-7.46(m,1H),2.76-2.72(m,2H),2.45-2.41(m,2H).

[0024] Example 2: Synthesis of 7,7-dichloroquinoline-8(7H)-one

[0025]

[0026] Specific procedures: 21.6 g (0.1 mol) of 7,7-dichloro-6,7-dihydroquinoline-8(5H)-one was added to 120 mL of dichloromethane in a 500 mL four-necked reaction flask and stirred until dissolved. A mixture of 40.2 g of manganese dioxide (after sonication) and 200 mL of dichloromethane was added. The beaker was washed with 20 mL of dichloromethane, and the reaction was carried out at room temperature for 9 hours. 2.3 mL of acetic acid was added, and the mixture was filtered. The filter cake was rinsed with 100 mL of dichloromethane, and the filtrate was washed with saturated sodium bicarbonate solution and water. The organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then slurried with isopropyl ether at elevated temperature to obtain 19.2 g of 7,7-dichloroquinoline-8(7H)-one. Yield: 89.6%, HPLC: 98.5%, m / z: 213.1 [M-1]. 1 HNMR(400MHz, CDCl3):8.63-8.60(m,1H),8.02-8.00(m,1H),7.68-7.65(m,1H),6.55-6.53(m,1H),5.86-5.84(m,1H).

[0027] Example 3: Synthesis of 7,7-dibromo-6,7-dihydroquinoline-8(5H)-one

[0028]

[0029] Specific procedures: Under nitrogen protection, add 29.8 g (0.2 mol) of 5,6,7,8-tetrahydro-8-hydroxyquinoline and 300 mL of 1,2-dichloroethane to a 500 mL four-necked reaction flask and stir until dissolved. Cool to 5-10℃, add 0.31 g of TEMPO, and dropwise add 518.8 g of sodium hypobromite. Simultaneously adjust the pH to 10.0-10.5 using 2N sodium hydroxide solution. After the addition is complete, slowly raise the temperature to room temperature and react for 4 hours. The remaining HPLC starting material should be <0.5%. Allow to stand and separate the phases. Use 100 mL of aqueous phase. Extracted with 1,2-dichloroethane, the lower organic phases were combined and washed with water. The organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and replaced with isopropanol. The crude product was recrystallized from isopropanol and isopropyl ether to give 51.7 g of 7,7-dibromo-6,7-dihydroquinoline-8(5H)-one, yield: 84.7%, HPLC: 99.1%, m / z: 303.8 [M-1]. 1 HNMR(400MHz, CDCl3):8.73-8.71(m,1H),7.94-7.92(m,1H),7.46-7.44(m,1H),2.89-2.85(m,2H),2.71-2.67(m,2H).

[0030] Example 4: Synthesis of 7,7-dibromoquinoline-8(7H)-one

[0031]

[0032] Specific procedures: 30.5 g (0.1 mol) of 7,7-dibromo-6,7-dihydroquinoline-8(5H)-one was added to a 1000 mL four-necked reaction flask and mixed with 200 mL of 1,2-dichloroethane. The mixture was stirred until dissolved. 43.5 g of manganese dioxide (after sonication) was added to a mixture of 250 mL of 1,2-dichloroethane. The beaker was washed with 20 mL of 1,2-dichloroethane. The reaction was carried out at room temperature for 9 hours. 4.0 mL of acetic acid was added, and the mixture was filtered. The filter cake was rinsed with 100 mL of 1,2-dichloroethane. The filtrate was washed with saturated sodium bicarbonate solution and water. The organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then slurried with isopropyl ether at elevated temperature to obtain 27.3 g of 7,7-dibromoquinoline-8(7H)-one. Yield: 90.1%, HPLC: 98.9%. m / z: 301.8 [M-1]. 1 HNM R(400MHz, CDCl3):8.65-8.62(m,1H),8.04-8.02(m,1H),7.70-7.67(m,1H),6.49-6.47(m,1H),5.92-5.90(m,1H).

[0033] The above embodiments describe the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the present invention. Various changes and modifications can be made to the present invention without departing from its principles, and all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing polyhalogenated quinoline compounds, characterized in that, Includes the following steps: 1) Oxidation dihalogenation reaction: 5,6,7,8-tetrahydro-8-hydroxyquinoline and TEMPO were added to an organic solvent, and the pH was controlled at 10-11. Sodium hypohalate was added dropwise to react and give 7,7-dihalo-6,7-dihydroquinoline-8(5H)-one. 2) Oxidative aromatization reaction 7,7-Dihalo-6,7-Dihydroquinoline-8(5H)-one was dissolved in an organic solvent and oxidized with manganese dioxide to obtain 7,7-dihaloquinoline-8(7H)-one.

2. The method for synthesizing polyhalogenated quinoline compounds according to claim 1, characterized in that: The organic solvent is selected from dichloromethane or 1,2-dichloroethane.

3. The method for synthesizing polyhalogenated quinoline compounds according to claim 1, characterized in that: In step 1), sodium hypohalite is selected from sodium hypochlorite aqueous solution or sodium hypobromite aqueous solution, wherein: the effective chlorine content of sodium hypochlorite aqueous solution is 9-13%, and the effective bromine content of sodium hypobromite aqueous solution is 10-15%.

4. The method for synthesizing polyhalogenated quinoline compounds according to claim 1, characterized in that: In step 1), the molar ratio of 5,6,7,8-tetrahydro-8-hydroxyquinoline, TEMPO and sodium hypohalite is 1:0.005-0.01:3.5-4.

0.

5. The method for synthesizing polyhalogenated quinoline compounds according to claim 1, characterized in that: In step 2), the manganese dioxide is selected from active manganese dioxide with a particle size of 8-12 μm.

6. The method for synthesizing polyhalogenated quinoline compounds according to claim 1, characterized in that: In step 2), the molar ratio of 7,7-dihalo-6,7-dihydroquinoline-8(5H)-one to manganese dioxide is 1:2.0-5.0.

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