Method for safely producing 3, 5-dichloro-1-bromobenzene

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for safely producing 3, 5-dichloro-1-bromobenzene. The method comprises the following steps: by taking 3, 5-dichloroaniline as an initial raw material, firstly adding an organic solvent and 48% hydrobromic acid for salifying, after salifying is completed, carrying out reflux water separation, after moisture is detected to be qualified, dropwise adding nitrite at a controlled temperature, after dropwise adding is completed, carrying out heat preservation reaction, after the reaction is completed, carrying out acid pickling, alkali washing, water washing and concentration drying on an organic phase, adding ethanol, and recrystallizing to obtain the 3, 5-dichloro-1-bromobenzene. According to the method for safely producing the 3, 5-dichloro-1-bromobenzene, the problems that reaction heat release is violent and difficult to control, reaction selectivity is poor, impurities are large, treatment and purification after reaction are complex, the yield is low, the cost is high, the amount of waste liquid is large and difficult to treat and the like are solved at the same time, and in industrial large-scale production, the method is more obvious in safety, economical efficiency, greenness and environment friendliness.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a method for safely producing 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] Flueran is a new type of isoxazoline external insecticide, which has a strong inhibitory effect on the γ-aminobutyric acid (GABA) receptors of the nervous system of invertebrates. It is widely used to prevent and treat external parasitic diseases of companion animals such as dogs and cats, and has good anti-insect effects on parasites such as ticks, fleas, mites, etc. Compared with other types of insecticides, Flueran has the characteristics of simple operation, easy absorption, safety, high efficiency, long-term effect and good tolerance.

[0004] Fluorana was first developed by Nissan Chemical Industries, Ltd. in Japan. Fluorana chewable tablets were first launched in the European market in April 2014. In July 2016, the U.S. Food and Drug Administration (FDA) approved Merck's application for a topical solution of Fluorana. Currently, it has multiple dosage forms and has been marketed in many regions around the world. Recently, several papers have reported on its ability to control crop pests. Experiments have shown that when used in combination with a compound agent, it has a better insecticide effect. It can be seen that Fluorana also has great potential in the pesticide market.

[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 and copper salt and potassium bromide in acetonitrile for bromination. 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. At the same time, the biggest disadvantage of this route is safety. It adopts the method of preparing diazonium salt first and then adding metal bromide as a catalyst. This method of adding materials cannot be intervened once the reaction is underway. In particular, the decomposition of diazonium salt will release a large amount of heat and gas, which is very dangerous in large-scale production.

[0006] FW Wassmundt et al. reported in J. Org. Chem. 1995, 60, 1713–1719 that 2,4-dichloroaniline was used as the raw material, first brominated in acetic acid, recrystallized from 95% ethanol, and then prepared diazonium fluoroborate in ether through boron trifluoride and n-butyl nitrite, and finally reduced the amino group 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, which are difficult to recycle and the production cost is high. At the same time, the reaction solvent ether is a dangerous and easily made drug-making chemical, which is strictly controlled by the public security department. Because it has a low flash point and low explosion limit, it can form an explosive mixture with air, and it is very easy to burn and explode when exposed to open flames and high heat, which poses a high safety hazard in large-scale production.

[0007] TD Phuc et al. reported a technique for synthesizing aryl bromides using arylhydrazine hydrochloride in Tetrahedron Lett. 2020, 61, 151959. This method first requires the conversion of the amino group into a diazonium salt, and then the formation of the hydrazine group through a reduction step. Using organic solvents such as THF, DMSO or CPME as a medium, the hydrazine group reacts with boron tribromide to produce the target compound bromobenzene. Although this method achieves a yield of up to 97% in the last step, it has many steps and high solvent costs. In addition, because the bromination reagent used, boron tribromide, has a strong pungent odor, instability, and smoke when exposed to air, coupled with its high corrosiveness and toxicity, it will cause operational difficulties and safety risks in large-scale production. Summary of the invention

[0008] In order to solve the above technical problems, the present invention provides a method for safely producing 3,5-dichloro-1-bromobenzene. The method has the advantages of simple synthesis route, safety, environmental protection, and low cost, and is more suitable for large-scale industrial production.

[0009] The present invention is achieved through the following technical solutions: A method for safely producing 3,5-dichloro-1-bromobenzene comprises the following steps: The organic solvent and 3,5-dichloroaniline were stirred and mixed, 48% hydrobromic acid was added dropwise under temperature control, after the reaction was completed, the water was refluxed and separated, and after the water content of the system was qualified, nitrite was added dropwise under temperature control, after the addition was completed, the heat was kept to react until the raw materials reacted completely, after acid washing, alkali washing and water washing, the organic layer was concentrated to dryness, and ethanol was added for recrystallization to obtain 3,5-dichloro-1-bromobenzene.

[0010] The reaction equation of the preparation method is as follows:

[0011] The organic solvent is one or more of benzene, toluene, cyclohexane, ethylene dichloride, chloroform, carbon tetrachloride, and n-heptane. Preferably, the organic solvent is n-heptane.

[0012] The mass ratio of the organic solvent to 3,5-dichloroaniline is 1.0-30.0:1, preferably 4.0-10.0:1.

[0013] The mass ratio of the 48% hydrobromic acid to 3,5-dichloroaniline is 1.0-10.0:1, preferably 1.4-2.0:1.

[0014] The nitrite is one or more of tert-butyl nitrite, n-butyl nitrite, isobutyl nitrite, and isoamyl nitrite, preferably n-butyl nitrite.

[0015] The molar ratio of the nitrite to 3,5-dichloroaniline is 0.8-10.0:1, preferably 1.0-1.5:1.

[0016] The controlled temperature of the temperature-controlled dropwise addition of nitrite is 30°C to 40°C.

[0017] The qualified moisture range of the moisture detection is 0.0%~5.0%, preferably 0.0%~0.2%.

[0018] The dripping time of the 48% hydrobromic acid is 1 to 3 hours, and the dripping time of the nitrite is 4 to 6 hours.

[0019] The above-mentioned method for safely producing 3,5-dichloro-1-bromobenzene comprises the following steps: Add organic solvent and 3,5-dichloroaniline to the reaction kettle, add 48% hydrobromic acid dropwise under temperature control, reflux and separate water until the water content of the system is 0.0%-5.0%, add nitrite dropwise under temperature control, keep the temperature at 20°C-50°C after the addition is completed until the raw materials react completely, wash with acid, wash with alkali and wash with water, concentrate the organic layer to dryness, add ethanol for recrystallization to obtain 3,5-dichloro-1-bromobenzene.

[0020] The acid used in the acid washing step is a 5% hydrochloric acid aqueous solution; the alkali used in the alkali washing step is a 5% sodium hydroxide aqueous solution. Beneficial Effects

[0021] The method has a simple synthetic route, convenient operation, high reaction selectivity, few side reactions, a safe and controllable reaction process, low raw material costs and production costs, and a greener and more environmentally friendly production. The obtained 3,5-dichloro-1-bromobenzene has a liquid phase purity of more than 99.5% and a yield of more than 86.7%, which is more suitable for large-scale industrial production.

[0022] 1. A method for safely producing 3,5-dichloro-1-bromobenzene of the present invention, wherein nitrite is added dropwise at the decomposition temperature of diazonium salt to carry out bromination reaction, which can solve the problem of controlling the exothermic reaction. In other documents, after sodium nitrite is added dropwise at a controlled temperature to prepare diazonium salt, copper, copper bromide, potassium bromide and other catalysts are added to carry out bromination reaction. Whether it is Sandmeyer reaction or Gattermann reaction, all the reaction materials are added first and the catalyst is added last. Such operation is very dangerous for a reaction with intense exothermic reaction, because once the reaction starts, there will be no means to terminate the reaction. Although other documents avoid the problem of unstable reactants by separating diazonium fluoroborate, the separation step is added, making the process more cumbersome and complicated. In the present invention, nitrite is added dropwise at the decomposition temperature of diazonium salt, that is, while generating diazonium salt, diazonium salt immediately decomposes to produce aromatic radicals, which are substituted with bromide ions. The originally intense exothermic reaction is broken down into pieces, the exothermic reaction heat can be controlled according to the dripping speed, the source of danger is effectively controlled, the risk factor is greatly reduced, and it is safer and controllable.

[0023] 2. A method for safely producing 3,5-dichloro-1-bromobenzene of the present invention uses 3,5-dichloroaniline as a raw material, first prepares hydrobromide, and then adds nitrite dropwise at 30-40° C. Compared with adding copper, copper bromide and potassium bromide in other documents, the present invention does not need to add a catalyst separately, and uses a method of increasing the temperature to decompose the diazonium salt itself to generate a phenyl radical, which exists in the form of a transition state and instantly captures bromine atoms from hydrogen bromide to generate bromobenzene. The bromine source comes entirely from hydrobromic acid, and no other bromination reagent is required. The bromination reaction is more economical, the atomic utilization rate is high, and the economy is more advantageous.

[0024] 3. A method for safely producing 3,5-dichloro-1-bromobenzene of the present invention is to add 48% hydrobromic acid to an organic solvent to form a salt, and then reflux and separate the water to remove the water. At the same time, nitrite is used in the diazotization step to avoid the introduction of water. Compared with the solution of using water as a solvent or adding a sodium nitrite aqueous solution to prepare a diazonium salt in other documents, the possibility of the diazonium salt and water reacting to generate 3,5-dichlorophenol impurities is greatly reduced. The impurity structure is as follows:

[0025] The impurity is an impurity that is introduced into a hydroxyl group by nucleophilic substitution with water molecules in an acidic solution after the diazonium salt is decomposed into phenyl radicals. The present invention avoids the generation of the impurity by reacting in an anhydrous and non-strong acid system, so the post-treatment method is simpler and does not require column separation or complex distillation. The obtained solid can be directly recrystallized from ethanol, and the yield and purity are also higher.

[0026] 4. In a method for safely producing 3,5-dichloro-1-bromobenzene of the present invention, the organic solvent obtained in the post-processing concentration step mainly contains impurities of water and alcohol solvents which are byproducts of nitrite. The alcohol solvent can be washed to less than 1% during the post-processing acid washing, alkali washing and water washing. The salt-forming step itself also contains water, and the water will not affect the reaction. Therefore, the distilled solvent can be directly applied to the next batch of production without treatment, which can reduce environmental pressure and greatly reduce the cost of raw materials.

[0027] 5. The method for safely producing 3,5-dichloro-1-bromobenzene of the present invention solves the problems described in other documents, such as the violent exothermic reaction that is difficult to control, the poor reaction selectivity and large impurities, the complex post-reaction treatment and purification, the high yield and low cost, and the large amount of waste liquid that is difficult to handle. Especially in industrial large-scale production, it has more obvious safety, economy, greenness and environmental protection. DETAILED DESCRIPTION

[0028] The present invention will be further described below in conjunction with specific embodiments, but this is not intended to limit the present invention.

[0029] 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.

[0030] 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. Example

[0031] Into a 2000L reactor, 890kg of n-heptane and 100kg of 3,5-dichloroaniline were added. After stirring and mixing, 146kg of 48% hydrobromic acid was added dropwise at a temperature of 20-40°C for about 2h. After the addition was completed, the temperature was raised to reflux and the water was separated for about 8h. The water content of the solvent in the reactor was sampled and tested to be 0.04%. The system was cooled to 30°C, and 76kg of n-butyl nitrite was slowly added dropwise at a temperature of 37-42°C for about 5h. After the addition was completed, the reaction was kept at 30-40°C for 2h. After the reaction was completed, the temperature was lowered to 20-25°C, and the mixture was washed once with 100kg of 5% hydrochloric acid aqueous solution, 5% sodium hydroxide aqueous solution, and purified water, respectively. The organic layer was concentrated under reduced pressure until no solvent was discharged, and 300 kg of ethanol was added for recrystallization. The product was filtered and dried to obtain 124.3 kg of 3,5-dichloro-1-bromobenzene with a purity of 99.7% and a yield of 89.1%. The impurity content of 3,5-dichlorophenol was 0.09% calculated by the area normalization method.

[0032] The recovery rate of distilled n-heptane is 87.7%, and the detected gas phase purity is 98.6% (containing 0.64% n-butanol), which can be directly applied to the next batch. Example

[0033] Into a 5000L reactor, 1780kg of n-heptane and 200kg of 3,5-dichloroaniline were added. After stirring and mixing, 292kg of 48% hydrobromic acid was added dropwise at a temperature of 20-40°C for about 2h. After the addition was completed, the temperature was raised to reflux and water was separated for about 10h. The moisture content of the solvent in the reactor was sampled and tested to be 0.09%. The system was cooled to 30°C, and 152kg of n-butyl nitrite was slowly added dropwise at a temperature of 37-42°C for about 5h. After the addition was completed, the reaction was kept at 30-40°C for 2h. After the reaction was completed, the temperature was lowered to 20-25°C, and the mixture was washed once with 200kg of 5% hydrochloric acid aqueous solution, 5% sodium hydroxide aqueous solution, and purified water, respectively. The organic layer was concentrated under reduced pressure until no solvent came out, and 600 kg of ethanol was added for recrystallization. The product was filtered and dried to obtain 247.6 kg of 3,5-dichloro-1-bromobenzene with a purity of 99.5% and a yield of 88.8%. The impurity content of 3,5-dichlorophenol was 0.12% calculated by the area normalization method.

[0034] The recovery rate of distilled n-heptane is 85.7%, and the detected gas phase purity is 99.0% (containing 0.45% n-butanol), which can be directly applied to the next batch. Example

[0035] Into a 2000L reactor, add 830kg of toluene and 100kg of 3,5-dichloroaniline. After stirring and mixing, add 146kg of 48% hydrobromic acid at a temperature of 20-40°C for about 2h. After the addition is completed, heat the temperature to reflux and separate the water for about 8h. Sampling and testing the solvent water content in the reactor is 0.07%. Cool the system to 30°C, control the temperature at 37-42°C, and slowly add 87kg of isoamyl nitrite at a temperature of 37-42°C for about 5h. After the addition is completed, keep the temperature at 30-40°C for 2h. After the reaction is completed, cool to 20-25°C and wash once with 100kg of 5% hydrochloric acid aqueous solution, 5% sodium hydroxide aqueous solution, and purified water, respectively. The organic layer was concentrated under reduced pressure until no solvent was discharged, and 300 kg of ethanol was added for recrystallization. The product was filtered and dried to obtain 120.9 kg of 3,5-dichloro-1-bromobenzene with a purity of 99.6% and a yield of 86.7%. The impurity content of 3,5-dichlorophenol was 0.20% calculated by the area normalization method.

[0036] The recovery rate of distilled toluene is 92.3%, and the detected gas phase purity is 98.3% (containing 0.90% isopentanol), which can be directly applied to the next batch.

[0037] Example 4: (Recovery of solvent for application) Into a 2000L reactor, 890kg of recovered n-heptane and 100kg of 3,5-dichloroaniline were added, and 146kg of 48% hydrobromic acid was added dropwise at a temperature of 20-40°C for about 2h. After the addition was completed, the temperature was raised to reflux and the water was separated for about 8h. The moisture content of the solvent in the kettle was sampled and tested to be 0.05%. The system was cooled to 30°C, and 76kg of n-butyl nitrite was slowly added dropwise at a temperature of 37-42°C for about 5h. After the addition was completed, the temperature was kept at 30-40°C for 2h. After the reaction was completed, the temperature was lowered to 20-25°C, and the mixture was washed once with 100kg of 5% hydrochloric acid aqueous solution, 5% sodium hydroxide aqueous solution, and purified water, respectively. The organic layer was concentrated under reduced pressure until no solvent came out, and 300 kg of ethanol was added for recrystallization. The product was filtered and dried to obtain 121.3 kg of 3,5-dichloro-1-bromobenzene with a purity of 99.5% and a yield of 87.0%. The impurity content of 3,5-dichlorophenol was 0.17% calculated by the area normalization method.

[0038] The recovery rate of distilled n-heptane is 83.7%, and the detected gas phase purity is 98.0% (containing 0.74% n-butanol), which can be directly applied to the next batch.

[0039] 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 safely producing 3,5-dichloro-1-bromobenzene, comprising the following steps: The organic solvent and 3,5-dichloroaniline were stirred and mixed, 48% hydrobromic acid was added dropwise under temperature control, after the reaction was completed, the water was refluxed and separated, and after the water content of the system was qualified, nitrite was added dropwise under temperature control, after the addition was completed, the heat was kept to react until the raw materials reacted completely, after acid washing, alkali washing and water washing, the organic layer was concentrated to dryness, and ethanol was added for recrystallization to obtain 3,5-dichloro-1-bromobenzene.

2. The method for safely producing 3,5-dichloro-1-bromobenzene according to claim 1, characterized in that: The organic solvent is one or more of benzene, toluene, cyclohexane, ethylene dichloride, chloroform, carbon tetrachloride and n-heptane.

3. The method for safely producing 3,5-dichloro-1-bromobenzene according to claim 2, characterized in that: The organic solvent is n-heptane.

4. The method for safely producing 3,5-dichloro-1-bromobenzene according to claim 1, characterized in that: The mass ratio of the organic solvent to 3,5-dichloroaniline is 1.0-30.0:1, preferably 4.0-10.0:

1.

5. The method for safely producing 3,5-dichloro-1-bromobenzene according to claim 1, characterized in that: The mass ratio of the 48% hydrobromic acid to 3,5-dichloroaniline is 1.0-10.0:1, preferably 1.4-2.0:

1.

6. The method for safely producing 3,5-dichloro-1-bromobenzene according to claim 1, characterized in that: The nitrite is one or more of tert-butyl nitrite, n-butyl nitrite, isobutyl nitrite, and isoamyl nitrite, preferably n-butyl nitrite.

7. The method for safely producing 3,5-dichloro-1-bromobenzene according to claim 1, characterized in that: The molar ratio of the nitrite to 3,5-dichloroaniline is 0.8-10.0:1, preferably 1.0-1.5:

1.

8. The method for safely producing 3,5-dichloro-1-bromobenzene according to claim 1, characterized in that: The controlled temperature of the temperature-controlled dropwise addition of nitrite is 30°C to 40°C.

9. The method for safely producing 3,5-dichloro-1-bromobenzene according to claim 1, characterized in that: The qualified moisture range of the moisture detection is 0.0%~5.0%, preferably 0.0%~0.2%.

10. The method for safely producing 3,5-dichloro-1-bromobenzene according to claim 1, characterized in that: The dripping time of the 48% hydrobromic acid is 1 to 3 hours, and the dripping time of the nitrite is 4 to 6 hours.

Images