Preparation method of 3, 5-dichloro-1-bromobenzene

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of an important intermediate 3, 5-dichloro-1-bromobenzene of a veterinary anti-parasitic drug fluralana. The method comprises the following steps: dissolving a compound 1 serving as an initial raw material in a hydrobromic acid aqueous solution, dropwise adding hydrogen peroxide to carry out bromination reaction to obtain a compound 2, adding alcohol and inorganic acid after the reaction is finished, dropwise adding a sodium nitrite solution at controlled temperature to prepare a compound 3, dropwise adding hypophosphorous acid after the reaction is finished, and reducing to obtain 3, 5-dichloro-1-bromobenzene. And extracting the product to an organic layer by using dichloromethane, carrying out alkali washing on the organic layer, carrying out primary liquid separation, concentrating and drying, adding ethanol, and recrystallizing to obtain a 3, 5-dichloro-1-bromobenzene refined product. The method has the advantages of simple synthetic route, convenience in operation, low cost, small amount of three wastes, environment friendliness and high product purity, and is more suitable for industrial mass production.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a method for preparing 3,5-dichloro-1-bromobenzene, an important intermediate of veterinary antiparasitic drug flurellan. Background Art

[0002] 3,5-Dichloro-1-bromobenzene is an important intermediate of flurellanine. CAS No.: 19752-55-7, molecular formula: C6H3BrCl2, structural formula is as follows: .

[0003] Fluralaner is the active ingredient of the latest veterinary drug (chewable tablets) on the market. It is an antiparasitic drug for pets (mainly dogs and cats), mainly used to prevent and treat external parasites such as fleas and ticks. It is a new type of isoxazoline insecticide with a broad spectrum of antiparasitic activity, which can kill parasites on pets in a short time and provide long-term protection. Since 2013, researchers at the German Institute for Animal Health Innovation have begun a series of experimental studies on the anthelmintic activity of Fluralaner. Through oral feeding, researchers compared the parasiticidal effects of Fluralaner and the traditional insecticide deltamethrin on dogs. The experimental results showed that Fluralaner showed excellent insecticidal effects when killing ticks and Ctenocephalides, and could quickly and efficiently eliminate these common pet parasites.

[0004] Flurella was first registered in the European Union in January 2014 and was launched in Germany, Spain, Italy, France, the Netherlands and the United Kingdom in April 2014 under the trade name Bravecto. Bravecto (chewable tablets) is the earliest and only veterinary medical product that can quickly and effectively kill lice and fleas.

[0005] Patent WO2021240331 uses 3,5-dichloroaniline in a mixture of acetonitrile and water, adds hydrobromic acid and sodium nitrite to prepare diazonium salt, and then adds copper bromide and hydrobromic acid for bromination to prepare 3,5-dichloro-1-bromobenzene. A large amount of hydrobromic acid is used in the reaction, and the cost of treating the strong acidic waste liquid generated is high. At the same time, copper bromide is used as a catalyst and 0.4 equivalents are expensive. The final two-step yield is only 72%, which is not suitable for industrial production from the perspective of environmental protection and cost. IP Beletskaya et al. replaced hydrobromic acid diazonium salt with fluoroborate diazonium salt in Synthesis. 2007, 16, 2534-2538, and used a phase transfer catalyst, copper salt and potassium bromide in acetonitrile to bromine the amino group. Although the yield has been greatly improved, the cost of its auxiliary materials is too high, and the three wastes generated are also large, which is not worth industrial large-scale production.

[0006] FW Wassmundt et al. reported in J. Org. Chem. 1995, 60, 1713–1719 that 2,4-dichloroaniline was used as a raw material, first brominated in acetic acid, recrystallized from 95% ethanol, and then diazonium fluoroborate was prepared in diethyl ether with boron trifluoride and n-butyl nitrite, and finally the amino group was reduced in a DMF and ferric sulfate system to prepare 3,5-dichloro-1-bromobenzene. The preparation process of this route is complicated, and the intermediates need to be purified before preparing the next step of the reaction. In addition, there are many types of solvents in each step, involving expensive and difficult-to-recover organic reagents such as acetic acid, DMF, and diethyl ether, resulting in high production costs and difficulty in large-scale production.

[0007] D.Phuc Tran et al. reported a method for synthesizing aryl bromides using arylhydrazine hydrochloride in Tetrahedron Lett. 2020, 61, 151959, which requires the amino group to be prepared as a diazonium salt, and then reduced to a hydrazine group, and then reacted with boron tribromide to produce bromobenzene using organic solvents such as THF, DMSO, and CPME as solvents. Although the yield of the last step is as high as 97%, the reaction steps are longer and expensive organic solvents such as THF, DMSO, and CPME are required to react, and the solvent cost is high. At the same time, the bromination reagent boron tribromide has a strong irritating odor, an unstable structure, and smokes when exposed to air. It is very corrosive and toxic, which will bring many inconveniences to production operations. Summary of the invention

[0008] In order to solve the above technical problems, the present invention provides a method for preparing 3,5-dichloro-1-bromobenzene. The method has the advantages of simple synthesis route, convenient operation, low cost, less three wastes, green environmental protection, high product purity, and is more suitable for industrial mass production.

[0009] The present invention is achieved through the following technical solutions: A method for preparing 3,5-dichloro-1-bromobenzene comprises the following steps:

[0010] (1) Preparation of compound 2: Compound 1 is added to water, and then 48% hydrobromic acid is added to stir and dissolve, and then 27.5% hydrogen peroxide is added to carry out bromination reaction to obtain a suspension of compound 2 and water; (2) Preparation of compound 3: Add an alcohol solvent and an inorganic acid to the suspension of compound 2, and add a sodium nitrite aqueous solution dropwise under temperature control to obtain a solution of compound 3; (3) Preparation of 3,5-dichloro-1-bromobenzene: To the solution of compound 3, 50% hypophosphorous acid was added dropwise and the temperature was raised to react. After the reaction was completed, dichloromethane was added for extraction. The dichloromethane layer was washed with alkali, concentrated to dryness, and ethanol was added for recrystallization to obtain 3,5-dichloro-1-bromobenzene.

[0011] In the above-mentioned method for preparing 3,5-dichloro-1-bromobenzene, The mass ratio of the 48% hydrobromic acid solution, compound 1 and 27.5% hydrogen peroxide in step (1) is 1.0-10.0:1:0.6-10.0, preferably 1.0-3.0:1:0.8-2.0.

[0012] The alcohol solvent described in step (2) is one or more of methanol, ethanol, n-propanol, isopropanol, and ethylene glycol.

[0013] Preferably, the alcohol solvent in step (2) is ethanol.

[0014] The inorganic acid in step (2) is one or more of hydrochloric acid, sulfuric acid, fluoroboric acid, hydrobromic acid and perchloric acid.

[0015] Preferably, the inorganic acid in step (2) is sulfuric acid.

[0016] The mass ratio of sodium nitrite to compound 1 in step (2) is 0.3-3.0:1, preferably 0.4-0.6:1.

[0017] The mass percentage concentration of the sodium nitrite aqueous solution in step (2) is 35%.

[0018] The temperature for the temperature-controlled dropwise addition of sodium nitrite in step (2) is -20°C to 50°C, preferably -10°C to 10°C.

[0019] The mass ratio of the amount of 50% hypophosphorous acid to compound 1 in step (3) is 0.5-10.0:1, preferably 0.8-3.0:1.

[0020] The reaction temperature of the temperature-raising reaction of adding 50% hypophosphorous acid dropwise in step (3) is -10°C to 80°C, preferably 10°C to 40°C.

[0021] The alkali used in the alkali washing in step (3) is 30% sodium hydroxide solution.

[0022] In the step (3), the mass ratio of the volume of the dichloromethane to the compound 1 is 1.0-30.0:1, preferably 4.0-10.0:1.

[0023] A method for preparing 3,5-dichloro-1-bromobenzene, the detailed steps are as follows: Add water and compound 1 to the reactor, add 48% hydrobromic acid under stirring, stir until the system is completely dissolved, control the temperature at 45-50°C and add 27.5% hydrogen peroxide, keep warm for 2 hours after the addition is completed, add methanol, control the temperature at 20-30°C and add concentrated sulfuric acid, stir for 3 hours and control the temperature at 0-10°C and add 35% sodium nitrite solution, control the temperature at 0-10°C and add 50% hypophosphorous acid after the liquid phase detects compound 2 <1%, control the temperature at 0-10°C and add 3 hours after the addition is completed, control the temperature below 15°C, and then heat to 30-35°C and keep warm for 2 hours. After the liquid phase detects compound 3 <0.5%, add dichloromethane to extract and separate the liquids, extract the water layer with dichloromethane, combine the organic phases, wash with 30% sodium hydroxide solution until pH>13, concentrate the dichloromethane to dryness under reduced pressure, recrystallize with ethanol, filter and dry to obtain 3,5-dichloro-1-bromobenzene.

[0024] In the technical solution of the present invention, the sulfuric acid is sulfuric acid with a mass percentage concentration of 90%-98%. Beneficial Effects

[0025] The synthetic route of the method is simple to operate, simplifies the post-reaction treatment steps, and the intermediates do not need to be purified separately. The reaction process mainly uses water as a solvent, has low raw material costs and production costs, produces a small amount of mother liquor, and is more environmentally friendly. The obtained 3,5-dichloro-1-bromobenzene has a liquid phase purity of more than 99.7% and a three-step total yield of more than 85.3%, which is more suitable for large-scale industrial production.

[0026] 1. A method for preparing 3,5-dichloro-1-bromobenzene of the present invention uses 2,4-dichloroaniline as a raw material, and after highly selective ortho-bromination of the amino group, the amino group is diazotized and then reduced by an alcohol solvent and hypophosphorous acid, and the alcohol simultaneously plays the role of solubilizing and reducing the diazonium salt. The reaction conversion rate of each step is high, the selectivity is high, the raw and auxiliary materials are cheap and easy to obtain, the raw material cost is low, and it is more suitable for industrial production.

[0027] 2. A method for preparing 3,5-dichloro-1-bromobenzene of the present invention, in step 1, compound 1 is first dissolved in water with hydrobromic acid to form a salt, and then hydrogen peroxide and hydrobromic acid are added dropwise to generate bromine. Since the amino group is an ortho-para-directing group, and the para position and one of the ortho positions of the amino group on the benzene ring have been replaced by chlorine, the bromination occurs at the ortho position of the amino group with almost 100% selectivity at this time. At the same time, the hydrobromic acid generated after bromination is oxidized to bromine by hydrogen peroxide again, forming a free radical chain reaction, which maximizes the utilization rate of bromine atoms, and the bromine content in the generated wastewater is very low. The reaction yield is high, the three wastes are less, and it is more suitable for industrial production.

[0028] 3. A method for preparing 3,5-dichloro-1-bromobenzene of the present invention comprises the following steps: the first step is to dissolve the water-insoluble raw material into hydrobromide and then brominate it, thereby realizing the use of water as solvent; the second step is also to use water as solvent to prepare diazonium salt; the final reduction step is to add hypophosphorous acid aqueous solution to the water system for reduction; the three steps all use water as solvent, compared with other documents in which multiple steps use organic solvents such as DMF, THF, DMSO, acetonitrile, etc., the cost of using water as solvent is obviously lower and waste liquid treatment is easier, thus having obvious raw material cost advantages and environmental advantages.

[0029] 4. The preparation method of 3,5-dichloro-1-bromobenzene of the present invention has extremely high conversion rate and selectivity due to the selection of the synthetic route, and the reaction conditions are all acidic conditions with water as the solvent, so the cumbersome post-processing and purification process of the intermediate is eliminated, and the intermediates of each step are directly reacted in the form of aqueous solution, which saves the post-processing operations such as quenching, washing, extraction, etc. involved in multi-step reactions in the existing literature, and also reduces the number of filtration and drying. The production cost of the product is greatly reduced, the discharge of waste liquid is reduced, it is green and environmentally friendly, and the problem of cumbersome operation is solved.

[0030] 5. A method for preparing 3,5-dichloro-1-bromobenzene of the present invention, after the three-step reaction is completed, dichloromethane is added to extract the product, and the extraction process can separate the target product from excess acid, the vast majority of inorganic substances such as the generated salt, and impurities such as azo compounds and diazo compounds containing basic groups. The dichloromethane phase is then washed with alkali to remove phenol structure impurities containing acidic groups. Most of the impurities in the reaction are removed by extraction and separation, and the product is finally recrystallized from ethanol, and the purity can be as high as 99.7% or more, which is significantly better than other existing documents.

[0031] 6. A method for preparing 3,5-dichloro-1-bromobenzene of the present invention, in the first step of the reaction, the raw materials are firstly dissolved into salt, and the product is precipitated again in the form of solid during the reaction process, and the hydrobromic acid and hydrogen peroxide in the system are almost completely consumed, without other by-products or excess raw materials, and no purification is required after the reaction is completed, and alcohol is directly added for dilution and then sulfuric acid is added to form salt, and sodium nitrite is added dropwise to prepare diazonium salt, and the three-step one-pot reaction is completed in a very clever way, avoiding the loss of the product in the post-treatment process, and obtaining a product yield of more than 85.3% in total yield of three steps, and the product purity is also more than 99.7%. This is a method for preparing high-purity 3,5-dichloro-1-bromobenzene with obvious economic and environmental advantages. DETAILED DESCRIPTION

[0032] The present invention will be further described below in conjunction with specific embodiments, but this is not intended to limit the present invention.

[0033] Unless otherwise specified, the content of each component used below is weight percentage; the experimental methods used are conventional methods; the reagents, biological materials, etc. used can be obtained from commercial channels.

[0034] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0035] In the preparation method of 3,5-dichloro-1-bromobenzene of the present invention, the liquid phase conditions for liquid phase detection of compound 1 <1%; liquid phase detection of compound 2 <1%; liquid phase detection of compound 3 <0.5% are: Column: Xbridge Shield RP18, 4.6 mm × 150 mm, 3.5 μm Mobile phase A: 0.1% phosphoric acid solution; Mobile phase B: acetonitrile; The detection wavelength was 215 nm; the column temperature was 25°C; and the injection volume was 10 μl.

[0036] Perform gradient elution according to the following table:

[0037] Operation process: Take 0.5ml of the reaction solution, place it in a 10ml volumetric flask, add solvent to dilute to the mark, shake well, take 100µl and add solvent to dilute to 2ml, shake well. Accurately measure 10μL of the test solution, inject it into the liquid chromatograph, record the chromatogram, and calculate the results by area normalization method. Example

[0038] 200 kg purified water and 100 kg compound 1 were added to a 3000 L reactor, and 117 kg 48% hydrobromic acid was added dropwise while stirring. After stirring until the system was completely dissolved, 87 kg 27.5% hydrogen peroxide was added dropwise at a temperature of 45-50 ° C. After the addition was completed, the temperature was kept warm for 2 h. After the liquid phase detected that compound 1 was <1%, 450 L methanol was added, 185 kg sulfuric acid was added dropwise at a temperature of 20-30 ° C. After stirring for 3 h, 134 kg 35% sodium nitrite solution (47 kg sodium nitrite + 87 kg purified water) was added dropwise at a temperature of 0-10 ° C. After the liquid phase detected that compound 2 was <1%, 81 kg 50% hypophosphorous acid was added dropwise and the temperature was controlled below 15°C for 3 hours, then the temperature was raised to 30-35°C and kept for 2 hours. After the liquid phase detected compound 3 <0.5%, 335L of dichloromethane was extracted and the aqueous layer was then injected with 110L of dichloromethane. After the organic phases were combined, they were washed with 30% sodium hydroxide solution until the pH was >13. The dichloromethane was concentrated under reduced pressure and injected with 375L of ethanol for recrystallization. The refined 3,5-dichloro-1-bromobenzene was obtained by filtration and drying with a purity of 99.8% and a total molar yield of 85.9%. Example

[0039] 400 kg purified water and 200 kg compound 1 were added to a 5000 L reactor, and 235 kg 48% hydrobromic acid was added dropwise while stirring. After stirring until the system was completely dissolved, 175 kg 27.5% hydrogen peroxide was added dropwise at a temperature of 45-50 ° C. After the addition was completed, the temperature was kept warm for 2 h. After the liquid phase detected that compound 1 was <1%, 900 L ethanol was added, 370 kg sulfuric acid was added dropwise at a temperature of 20-30 ° C. After stirring for 3 h, 268 kg 35% sodium nitrite solution (94 kg sodium nitrite + 174 kg purified water) was added dropwise at a temperature of 0-10 ° C. After the liquid phase detected that compound 2 was <1%, 163 kg 50% hypophosphorous acid was added dropwise and the temperature was controlled below 15°C for 3 hours, then the temperature was raised to 30-35°C and kept for 2 hours. After the liquid phase detected compound 3 <0.5%, 670L of dichloromethane was extracted and the aqueous layer was then injected with 220L of dichloromethane. After the organic phases were combined, they were washed with 30% sodium hydroxide solution until pH>13, and the dichloromethane was concentrated under reduced pressure. 750L of ethanol was injected for recrystallization, and 243.7kg of 3,5-dichloro-1-bromobenzene was obtained by filtration and drying. The purity was 99.8%, and the total molar yield was 87.4%. Example

[0040] Pour 400kg purified water and 200kg compound 1 into a 5000L reactor, add 235kg 48% hydrobromic acid dropwise while stirring, stir until the system is completely dissolved, control the temperature at 45-50℃ and add 175kg 27.5% hydrogen peroxide dropwise, keep warm for 2h after the addition is complete, after the liquid phase detection of compound 1 is <1%, pour in 900L ethanol, control the temperature at 20-30℃ and add 382kg 36% hydrochloric acid dropwise, stir for 3h, control the temperature at 0-10℃ and add 268kg 35% sodium nitrite solution (94kg sodium nitrite + 174kg purified water), after the liquid phase detection of compound 2 is <1%, control the temperature at 0-10℃ and add 163kg 50% hypophosphorous acid was added dropwise and the temperature was controlled below 15°C for reaction for 3h, then the temperature was raised to 30-35°C and kept for 2h. After the liquid phase detected compound 3 <0.5%, 670L of dichloromethane was extracted and the aqueous layer was then injected with 220L of dichloromethane. After the organic phases were combined, they were washed with 30% sodium hydroxide solution until pH>13, and the dichloromethane was concentrated under reduced pressure. 750L of ethanol was injected for recrystallization, and 237.8kg of 3,5-dichloro-1-bromobenzene was obtained by filtration and drying. The purity was 99.7% and the total molar yield was 85.3%.

[0041] The above examples are for the purpose of illustrating the embodiments disclosed by the present invention and are not to be construed as limitations of the present invention. In addition, the various modifications listed herein and the variations of methods and compositions in the invention are obvious to those skilled in the art without departing from the scope and spirit of the present invention. Although the present invention has been specifically described in conjunction with various specific preferred embodiments of the present invention, it should be understood that the present invention should not be limited to these specific embodiments. In fact, various modifications obvious to those skilled in the art as described above to obtain the invention should be included within the scope of the present invention.

Claims

1. A method for preparing 3,5-dichloro-1-bromobenzene, comprising the following steps: ； (1) Preparation of compound 2: Compound 1 is added to water, and then 48% hydrobromic acid is added to stir and dissolve, and then 27.5% hydrogen peroxide is added to carry out bromination reaction to obtain a suspension of compound 2 and water; (2) Preparation of compound 3: Add an alcohol solvent and an inorganic acid to the suspension of compound 2, and add a sodium nitrite aqueous solution dropwise under temperature control to obtain a solution of compound 3; (3) Preparation of 3,5-dichloro-1-bromobenzene: To the solution of compound 3, 50% hypophosphorous acid was added dropwise and the temperature was raised to react. After the reaction was completed, dichloromethane was added for extraction. The dichloromethane layer was washed with alkali, concentrated to dryness, and ethanol was added for recrystallization to obtain 3,5-dichloro-1-bromobenzene.

2. The method for preparing 3,5-dichloro-1-bromobenzene according to claim 1, characterized in that: The mass ratio of the 48% hydrobromic acid solution, compound 1 and 27.5% hydrogen peroxide in step (1) is 1.0-10.0:1:0.6-10.

0.

3. The method for preparing 3,5-dichloro-1-bromobenzene according to claim 2, characterized in that: The mass ratio of the 48% hydrobromic acid solution, compound 1 and 27.5% hydrogen peroxide in step (1) is 1.0-3.0:1:0.8-2.

0.

4. The method for preparing 3,5-dichloro-1-bromobenzene according to claim 1, characterized in that: The alcohol solvent described in step (2) is one or more of methanol, ethanol, n-propanol, isopropanol, and ethylene glycol.

5. The method for preparing 3,5-dichloro-1-bromobenzene according to claim 4, characterized in that: The alcohol solvent described in step (2) is ethanol.

6. The method for preparing 3,5-dichloro-1-bromobenzene according to claim 1, characterized in that: The inorganic acid in step (2) is one or more of hydrochloric acid, sulfuric acid, fluoroboric acid, hydrobromic acid and perchloric acid.

7. The method for preparing 3,5-dichloro-1-bromobenzene according to claim 1, characterized in that: The inorganic acid described in step (2) is sulfuric acid.

8. The method for preparing 3,5-dichloro-1-bromobenzene according to claim 1, characterized in that: The mass ratio of sodium nitrite to compound 1 in step (2) is 0.3-3.0:1, preferably 0.4-0.6:

1.

9. The method for preparing 3,5-dichloro-1-bromobenzene according to claim 1, characterized in that: The temperature for the temperature-controlled dropwise addition of sodium nitrite in step (2) is -20°C to 50°C, preferably -10°C to 10°C.

10. The method for preparing 3,5-dichloro-1-bromobenzene according to claim 1, characterized in that: The mass ratio of the amount of 50% hypophosphorous acid to compound 1 in step (3) is 0.5-10.0:1, preferably 0.8-3.0:1.

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