A process for the preparation of 6-bromoquinoline

Abstract

The application discloses a preparation method of 6-bromoquinoline and belongs to the technical field of organic synthesis. Glycerol is used as a raw material, and first, the raw material is reacted with p-toluenesulfonyl chloride / methylsulfonyl chloride under the action of an acid binding agent, then, the raw material is reacted with dichlorosulfoxide, subsequently, the raw material is oxidized with 2,2,6,6-tetramethylpiperidine oxide and chlorine to obtain 4-methylsulfonyloxymethyl / 4-p-tolyloxy methyl-2,2-dioxo-1,3,2-dioxothiophene, and finally, after substitution reaction, ring closure and aromatization are carried out in the presence of boron trifluoride diethyl ether complex and azodicarboxylic acid diester respectively to obtain 6-bromoquinoline. The raw material is easy to obtain and low in price, the operation is coherent, the requirement for equipment is low, and the raw material is more suitable for scale production.

Description

TECHNICAL FIELD

[0001] The application relates to a preparation method of 6-bromoquinoline and belongs to the technical field of organic synthesis. BACKGROUND

[0002] 6-bromoquinoline, CAS: 5332-25-2, English name: 6-bromoquinoline. Quinoline derivatives exist widely in many natural products (especially alkaloids) and synthetic products. 6-bromoquinoline has the structural fragment of an important bioactive substance and is widely applied to the synthesis of pharmaceutical intermediates, pesticides and the like. For example, 6-bromoquinoline is applied to the synthesis of anticancer drug enhancers, receptor tyrosine kinase inhibitors, cardiotonic agents, antibacterial agents, anti-leishmania agents, anti-inflammatory agents, insecticides and the like.

[0003] The methods for synthesizing quinoline are generally Skraup, Friedlander, Combes, Doebner-Miller, Camps, Knorr and Pfizinger quinoline methods. Most of the above reactions need harsh reaction conditions and toxic strong acid compounds, high temperature and low yield. For example, the traditional process of 6-bromoquinoline is to use the Skraup reaction to synthesize 6-bromoquinoline by using p-bromoaniline, glycerol, nitrobenzene and concentrated sulfuric acid as raw materials in one-pot synthesis at 200 DEG C.

[0004] The document [Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical and Analytical, 2016, vol. 55A, #8, p. 919-928] reports that 6-bromoquinoline is synthesized by using the Skraup reaction to use p-bromoaniline, glycerol, tungsten-doped porous silicon W-KIT-6 as an oxidation catalyst in one-pot synthesis, and the reaction yield is as high as 81%, but the temperature is as high as 200 DEG C, and the requirement for equipment is high. The reaction equation is as follows:

[0005]

[0006] The document [Heterocycles, 2001, vol. 54, #1, p. 105-108] reports that propylene aldehyde and N-(4-bromophenyl) methyl sulfonamide or N-(4-bromophenyl)-4-methyl benzene sulfonamide are subjected to Michael addition, then ring closure under the action of trifluoromethanesulfonic acid, and finally desulfonamidation and oxidation of the amino group into imine under the action of potassium hydroxide and DMSO, so that 6-bromoquinoline is finally obtained, the total yield is <30%, and dangerous chemicals such as propylene aldehyde are used, which is not conducive to industrialized production. The reaction equation is as follows:

[0007]

[0008] In view of the above-mentioned deficiencies, the present application adopts a preparation method with simple process, mild reaction conditions, low requirement for equipment, high total yield, and suitability for factory production to meet the growing market demand. SUMMARY

[0009] In order to overcome the above technical defects, the present application provides a preparation method of 6-bromoquinoline. Glycerol is used as raw material, reacted with p-toluenesulfonyl chloride / methylsulfonyl chloride in the presence of an acid-binding agent, then reacted with dichlorosulfoxide, followed by oxidation reaction with 2,2,6,6-tetramethylpiperidine oxide and chlorine to obtain 4-methylsulfonyloxymethyl / 4-p-tolyloxy-methyl-2,2-dioxo-1,3,2-dioxothiophene, and finally substitution reaction, ring closure and aromatization in the presence of boron trifluoride etherate complex and azodicarboxylic acid diester to obtain 6-bromoquinoline. The method has the advantages of easy availability of raw materials, low price, consistent operation, low requirement for equipment, and easier scale production.

[0010] The preparation method of 6-bromoquinoline according to the present application comprises the following steps:

[0011] a) Glycerol is reacted with p-toluenesulfonyl chloride / methylsulfonyl chloride in the presence of an acid-binding agent, then reacted with dichlorosulfoxide at low temperature to obtain 4-methylsulfonyl / 4-toluenesulfonyloxy-methyl-2-oxo-1,3,2-dioxothiophene, followed by reaction with 2,2,6,6-tetramethylpiperidine oxide and chlorine in acetonitrile and sodium carbonate solution to obtain 4-methylsulfonyl / 4-toluenesulfonyloxy-methyl-2,2-dioxo-1,3,2-dioxothiophene;

[0012] b) 4-methylsulfonyl / 4-toluenesulfonyloxy-methyl-2,2-dioxo-1,3,2-dioxothiophene, lithium alcoholate, p-bromoaniline, and dioxane are mixed and reacted, then heated and ring-closed by adding boron trifluoride etherate complex, and finally aromatized in the presence of azodicarboxylic acid ester to obtain 6-bromoquinoline.

[0013] The reaction equation is as follows:

[0014]

[0015] Further, in the above technical solution, in step a), the first step reaction solvent is selected from dichloromethane or 1,2-dichloroethane, and the reaction is accelerated in the presence of DMAP.

[0016] Further, in the above technical solution, in step a), the acid-binding agent is selected from triethylamine or N,N-diisopropyl ethylamine.

[0017] Further, in the above technical solution, in step a), the molar ratio of the glycerol, p-toluenesulfonyl chloride / methylsulfonyl chloride, acid binding agent, dichlorosulfoxide, chlorine and 2,2,6,6-tetramethylpiperidine oxide is 1:1-1.02:3.2-3.5:1.1-1.2:1.01-1.05:0.03-0.05.

[0018] Further, in the above technical solution, in step b), the azodicarboxylic ester is selected from DEAD diethyl azodicarboxylate or DIAD diisopropyl azodicarboxylate.

[0019] Further, in the above technical solution, in step b), the molar ratio of the 4-p-tolyloxy methyl-2,2-dioxo-1,3,2-dithiine or 4-methylsulfonyloxy methyl-2,2-dioxo-1,3,2-dithiine, p-bromoaniline, lithium alcohol, boron trifluoride ether complex and azodicarboxylic ester is 1:1-1.02:1.0-2.5:0.1-0.2:1.1-1.2.

[0020] Further, in the above technical solution, in step b), the lithium alcohol is selected from lithium methoxide or lithium tert-butoxide.

[0021] Advantages of the Invention

[0022] A. The -OMs / OTs leaving group is used to substitute the amino group in p-bromoaniline, then ring closure is performed in the presence of boron trifluoride to generate 6-bromodihydroquinoline, then diester azaarboxylic is used for aromatization, which avoids the condensation of hydroxyl and amino groups in the traditional process, the reaction is rapid, the safety is high, and the use of nitrobenzene for oxidation in the traditional process is avoided.

[0023] B. The process produces products with good quality, relatively low requirements for equipment, and good operation continuity, which is conducive to industrialized production. Specific Embodiments

[0024] The application will be further described in the following specific examples. These examples should be understood as merely illustrative of the application and not limiting the scope of protection of the application. After reading the content described in the application, those skilled in the art can make various changes or modifications to the application, and these equivalent changes and modifications also fall within the scope defined by the claims of the application.

[0025] Synthesis of 6-bromoquinoline

[0026] Example 1

[0027]

[0028] Into a reaction flask was placed glycerol 30.7 g (0.3 mol), 4-dimethylaminopyridine (DMAP) 1.1 g (0.009 mol), dichloromethane 300 mL and methanesulfonyl chloride 34.4 g (0.3 mol) under nitrogen protection, temperature was controlled at -25 to -15 °C, DIPEA 46.5 g (0.36 mol) was added dropwise, the reaction was carried out for 2 hours, then the temperature was raised to -5 °C and the reaction was carried out for 3 hours, dichlorosulfoxide 42.8 g (0.36 mol) was added, DIPEA 77.6 g (0.6 mol) was added at -10 °C, the temperature was raised to 0-5 °C and the reaction was carried out for 5 hours, aqueous citric acid solution was added to quench the reaction, the layers were separated, the organic phase was washed with aqueous sodium bicarbonate solution and water once, the organic phase was concentrated under reduced pressure to a non-flowing liquid, acetonitrile 150 mL and 15% aqueous sodium carbonate solution 280 mL were added, TEMPO 1.56 g (0.01 mol) was added, chlorine gas 21.6 g (0.305 mol) was introduced, the reaction was carried out at room temperature for 1 hour, TLC detection showed that the reaction was complete, 1M hydrochloric acid was added to adjust the pH to 4-5, MTBE was added for extraction, the organic phase was washed with aqueous sodium thiosulfate solution and water once, the organic phase was concentrated under reduced pressure, n-hexane was added and a large amount of white solid was precipitated, filtration gave 4-methylsulfonyloxymethyl-2,2-dioxo-1,3,2-dithiophene 59.3 g, yield 85.1%, HPLC 99.3%. 1 HNMR (400 MHz, CDC13) δ: 4.79-4.77 (m, 1H), 4.73-4.69 (m, 1H), 4.53-4.48 (m, 1H), 4.25-4.00 (m, 2H), 3.06 (s, 3H).

[0029] Example 2

[0030]

[0031] Into a reaction flask was added glycerol 30.7 g (0.3 mol), 4-dimethylaminopyridine (DMAP) 1.1 g (0.009 mol), dichloromethane 300 mL and p-toluenesulfonyl chloride 57.2 g (0.3 mol) under nitrogen protection, temperature was controlled at -30 to -20 °C, TEA 36.4 (0.36 mol) was added dropwise, reaction for 2 hours, then warmed to -10 °C for 2 hours, dichlorosulfoxide 42.8 g (0.36 mol) was added, TEA 60.7 g (0.6 mol) was added at -10 °C, warmed to 0-5 °C for 5 hours, citric acid aqueous solution was added to quench, separated into organic phase, the organic phase was washed with sodium bicarbonate aqueous solution and water once, the organic phase was concentrated under reduced pressure to not flow liquid, acetonitrile 150 mL and 15% sodium carbonate aqueous solution 280 mL were added, TEMPO 1.56 g (0.01 mol) was added, chlorine gas 22.0 g (0.31 mol) was introduced, reaction for 1 hour at room temperature, TLC detection showed that the reaction was complete, 1M hydrochloric acid was added to adjust pH = 4-5, MTBE was added for extraction, the organic phase was washed with sodium thiosulfate aqueous solution and water once, the organic phase was concentrated under reduced pressure, n-hexane was added, a large amount of white solid was precipitated, filtration gave 4-p-methoxyphenylmethyl-2,2-dioxo-1,3,2-dithiophene 83.3 g, yield 90.1%, HPLC 99.4%. 1 HNMR (400 MHz, CDC13) δ: 7.85-7.78 (m, 2H), 7.43-7.36 (m, 2H), 5.14-5.09 (m, 1H), 4.78-4.74 (m, 1H), 4.60-4.57 (m, 1H), 4.33-4.27 (m, 2H), 2.48 (s, 3H).

[0032] Example 3

[0033]

[0034] Into a reaction flask was placed 4-(p-methoxyphenoxy)methyl-2,2-dioxo-1,3,2-dithi- olane 61.7 g (0.2 mol), lithium methoxide 15.2 g (0.4 mol), p-bromoaniline 34.4 g (0.2 mol) and dioxane 400 mL under nitrogen protection, the mixture was heated to 70-80 °C for 12 hours, then cooled to room temperature, extracted with ethyl acetate, washed once with aqueous citric acid solution, the organic phase was concentrated under reduced pressure to a non-flowing liquid, replaced once with toluene 600 mL, added boron trifluoride etherate complex 5.7 g (0.04 mol), heated to reflux for 2 hours, cooled to add diethyl azodicarboxylate 41.8 g (0.24 mol), heated to 90 °C for 2 hours, cooled to 45 °C, concentrated under reduced pressure to a non-flowing liquid, added methyl tert-butyl ether 400 mL, added aqueous ammonium chloride solution to quench, the organic phase was adjusted to pH = 6.5-7.5 with 0.5M NaOH, separated, the organic phase was washed once with water, the organic phase was dried with anhydrous magnesium sulfate, distilled under reduced pressure to 3 volumes, added n-hexane to recrystallize to obtain 6-bromoquinoline 33.5 g, HPLC 99.3%, yield 80.5%; 1 H NMR (400 MHz, CDCl3) δ: 8.93-8.89 (m, 1H), 8.07-8.03 (m, 1H), 7.99-7.96 (m, 1H), 7.94 (s, 1H), 7.78-7.76 (m, 1H), 7.43-7.41 (m, 1H).

[0035] Example 4

[0036]

[0037] Into a reaction flask was added 4-methylsulfonyloxymethyl-2,2-dioxo-1,3,2-dithiophene 46.4 g (0.2 mol), lithium methoxide 15.2 g (0.4 mol), p-bromoaniline 34.4 g (0.2 mol) and dioxane 350 mL under nitrogen protection, and the mixture was heated to 70-75 °C for 6 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate and washed once with an aqueous citric acid solution. The organic phase was concentrated under reduced pressure until no liquid was produced. Toluene 500 mL was added to replace the solvent once. Boron trifluoride etherate 5.7 g (0.04 mol) was added, and the mixture was heated to reflux for 2 hours. Diisopropyl azodicarboxylate 44.5 g (0.22 mol) was added, and the mixture was heated to 100 °C for 1 hour. After cooling to 55 °C, the mixture was concentrated under reduced pressure until no liquid was produced. Methyl tert-butyl ether 350 mL was added, and the mixture was quenched with an aqueous ammonium chloride solution. The organic phase was adjusted to pH 6.5-7.5 with 0.5 M NaOH, and the mixture was separated into layers. The organic phase was retained, and the organic phase was washed once with water. The organic phase was dried over anhydrous magnesium sulfate, distilled under reduced pressure until 3 volumes of residue remained, and recrystallized from n-hexane to obtain 6-bromoquinoline 30.6 g. HPLC 99.3%, yield 73.6%.

[0038] The above description is merely preferred specific embodiments of the application, but the scope of the protection of the application is not limited thereto. Any person skilled in the art, according to the technical range disclosed in the application and the inventive concept of the application, can make equivalent replacements or changes, and all such replacements or changes should be encompassed in the scope of protection of the application.

Claims

1. A process for the preparation of 6-bromoquinoline, characterized in that, The process comprises the following steps: ； a) reacting glycerol with p-toluenesulfonyl chloride / mesyl chloride in the presence of a base binding agent, followed by reaction with dichlorosulfoxide at low temperature to obtain compound A, followed by reaction with 2,2,6,6-tetramethylpiperidine oxide and chlorine in acetonitrile and sodium carbonate solution to obtain compound B; b) reacting compound B, lithium alcoholate, p-bromoaniline and dioxane, followed by the addition of boron trifluoride etherate complex to cyclize at elevated temperature, and finally aromatization in the presence of azodicarboxylic acid ester selected from diethyl azodicarboxylate or diisopropyl azodicarboxylate to obtain 6-bromoquinoline.

2. The process for the preparation of 6-bromoquinoline according to claim 1, characterized in that: In step a), the reaction solvent is selected from dichloromethane or 1,2-dichloroethane; a catalytic amount of DMAP is added to accelerate the reaction.

3. The process for the preparation of 6-bromoquinoline according to claim 1, characterized by the fact that: In step a), the base binding agent is selected from triethylamine or N,N-diisopropylethylamine.

4. The process for the preparation of 6-bromoquinoline according to claim 1, characterized by the fact that: In step a), the molar ratio of glycerol, p-toluenesulfonyl chloride / mesyl chloride, base binding agent, dichlorosulfoxide, chlorine and 2,2,6,6-tetramethylpiperidine oxide is 1:1-1.02:3.2-3.5:1.1-1.2:1.02-1.15:0.03-0.

05.

5. The process for the preparation of 6-bromoquinoline according to claim 1, characterized by the fact that: In step b), the molar ratio of compound B, p-bromoaniline, lithium alcoholate, boron trifluoride etherate complex and azodicarboxylic acid ester is 1:1-1.02:1.0-2.5:0.1-0.2:1.1-1.

2.

6. The process for the preparation of 6-bromoquinoline according to claim 1, characterized by the fact that: In step b), the lithium alcoholate is selected from lithium methoxide or lithium tert-butoxide.

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