Synthesis method of 2-chloro-4-bromobenzonitrile

Abstract

A synthesis method of 2-chloro-4-bromobenzonitrile comprises the following steps: S1, adding methylchloroaniline and hydrobromic acid into a solvent a, dropwise adding a sodium nitrite solution, rapidly cooling to room temperature after the reaction is completed, and filtering to obtain a compound I; s2, adding the compound I, bromine and a solvent b into a reaction kettle, stopping heating after the reaction is completed, naturally cooling to room temperature, and filtering to obtain a compound II; s3, adding the compound II, hydroxylamine hydrochloride and sodium hydroxide into the reaction kettle, stopping heating after the reaction is completed, naturally cooling to room temperature, and filtering to obtain a compound III; s4, adding the compound III into thionyl chloride and a solvent c, stopping heating after the reaction is completed, naturally cooling to room temperature, and filtering to obtain 2-chloro-4-bromophenoxybenzene; and (S5) carrying out cyclohexane refining on the 2-chloro-4-bromobenzonitrile. According to the synthetic method of the 2-chloro-4-bromobenzonitrile, the 2-chloro-4-bromobenzonitrile is synthesized through four-step reaction of diazotization, hydroformylation, oximation and nitrilation, and the method is simple in process, stable in quality, low in energy consumption and easy to produce.

Description

Technical Field

[0001] The invention belongs to the technical field of 2-chloro-4-bromobenzonitrile synthesis, and specifically relates to a method for synthesizing an intermediate 2-chloro-4-bromobenzonitrile. Background Art

[0002] In today's chemical field, organic intermediates play a vital role in drug development, pesticide synthesis, and the preparation of various fine chemicals. As a key organic intermediate, 2-chloro-4-bromobenzonitrile plays an indispensable role in the synthesis of pharmaceutical chemistry, synthetic pesticides, aliphatic amines, benzoic acid derivatives, and other fields. Its unique molecular structure gives it rich chemical transformation potential and provides a broad space for innovation.

[0003] In synthetic transformations, the bromine atom on the benzene ring of 2-chloro-4-bromobenzonitrile can be used to introduce an aromatic or alkyl group on the benzene ring through a Suzuki coupling reaction. The bromine atom can also be easily converted into a boron unit, and then the diverse reactivity of boron can be used for subsequent derivatization applications. The cyano group on the benzene ring can be easily converted into a carboxyl group, an amide group, and an amino group.

[0004] As the market demand for high-quality, high-performance organic compounds continues to grow, developing an efficient, green and economical synthesis method for 2-chloro-4-bromobenzonitrile has become a hot topic and focus of research. Traditional synthesis methods have problems such as complex processes, unstable quality, high energy consumption and difficulty in production, which are difficult to meet the needs of large-scale industrial production.

[0005] Based on an in-depth study of the molecular structure and reaction characteristics of 2-chloro-4-bromobenzonitrile, the present invention explores a more optimized synthesis route, a synthesis method through four-step reactions of diazotization, hydroformylation, oximation and nitrilation. This method has the significant advantages of simple process, stable quality, low energy consumption and easy production, and is expected to provide a feasible and efficient solution for the industrial production of 2-chloro-4-bromobenzonitrile. Summary of the invention

[0006] Purpose of the invention: In order to overcome the above shortcomings, the purpose of the present invention is to provide a method for synthesizing 2-chloro-4-bromobenzonitrile for preparing the intermediate 2-chloro-4-bromobenzonitrile. The synthetic method is reasonably designed, including the steps of diazotization, aldehyde synthesis, oximation and chlorination refining, avoiding the safety hazards caused by the use of toxic raw materials such as trimethylamine. By optimizing the process conditions, high-purity and high-quality products can be obtained, which is environmentally friendly, conducive to process realization and industrial production, and has broad application prospects.

[0007] The objective of the present invention is achieved through the following technical solutions: A method for synthesizing 2-chloro-4-bromobenzonitrile comprises the following steps: S1: Add chloroaniline and hydrobromic acid to solvent a, stir evenly, then slowly dropwise add sodium nitrite solution, control the reaction temperature at 40-60°C, after the reaction is completed, pour the reaction mixture into ice water and quickly cool to room temperature, filter to obtain a white solid, i.e., compound I, as shown below: ; S2: Add compound I obtained in S1, bromine and solvent b into a reaction kettle, stir evenly, control the reaction temperature at 70-90°C, and the reaction time is 1-3h. After the reaction is completed, stop heating, cool naturally to room temperature, and filter to obtain a yellow liquid, namely compound II, as shown in the following formula: ; S3: Add compound II obtained in S2, hydroxylamine hydrochloride and sodium hydroxide into a reaction kettle, stir evenly, control the reaction temperature at 50-70°C, and the reaction time is 1-3h. After the reaction is completed, stop heating, cool naturally to room temperature, and filter to obtain a white powder, namely compound III, as shown in the following formula: ; S4: Add compound III obtained in S3 to thionyl chloride and solvent c, stir evenly, control the reaction temperature at 60-80°C, and the reaction time is 1-3h. After the reaction is completed, stop heating, cool naturally to room temperature, and filter to obtain a white solid, namely 2-chloro-4-bromobenzonitrile, as shown in the following formula: ; S5: Add the 2-chloro-4-bromobenzonitrile obtained in S4 to the solvent d, stir evenly, raise the temperature to 80-100° C., evaporate the solvent under constant temperature conditions, and when the solvent evaporates, take out the white solid to obtain the refined 2-chloro-4-bromobenzonitrile, which is then dried and packaged.

[0008] Preferably, in the above-mentioned synthesis method of 2-chloro-4-bromobenzonitrile, the solvent a is ethylene dichloride; the mass fraction of sodium nitrite in the sodium nitrite solution is 20-25%; and the mass ratio of chloroaniline: hydrobromic acid: ethylene dichloride: sodium nitrite solution is 100-200: 450-450: 100-200: 300-400.

[0009] More preferably, in the above-mentioned method for synthesizing 2-chloro-4-bromobenzonitrile, the mass fraction of sodium nitrite in the sodium nitrite solution is 23.8%; and the mass ratio of chloroaniline: hydrobromic acid: dichloroethane: sodium nitrite solution is 150:500:150:350.

[0010] Preferably, in the above-mentioned method for synthesizing 2-chloro-4-bromobenzonitrile, in step S1, the reaction temperature is controlled at 50°C.

[0011] Preferably, in the above-mentioned method for synthesizing 2-chloro-4-bromobenzonitrile, the solvent b is water; and the mass ratio of the white solid: bromine: water is 150-250: 250-350: 100-200.

[0012] More preferably, in the above-mentioned method for synthesizing 2-chloro-4-bromobenzonitrile, the mass ratio of the white solid: bromine: water is 200:300:150.

[0013] Preferably, in the above-mentioned method for synthesizing 2-chloro-4-bromobenzonitrile, in step S2, the reaction temperature is controlled at 80° C. and the reaction time is 2 h.

[0014] Preferably, in the above-mentioned method for synthesizing 2-chloro-4-bromobenzonitrile, in step S3, the mass ratio of the yellow liquid: hydroxylamine hydrochloride: sodium hydroxide is 200-250: 100-150: 50-100.

[0015] More preferably, the mass ratio of the yellow liquid:hydroxylamine hydrochloride:sodium hydroxide is 220:120:70.

[0016] Preferably, in the above-mentioned method for synthesizing 2-chloro-4-bromobenzonitrile, in step S3, the reaction temperature is controlled at 60° C. and the reaction time is 2 h.

[0017] Preferably, in the above-mentioned method for synthesizing 2-chloro-4-bromobenzonitrile, in step S4, the solvent c is ethylene dichloride; and the mass ratio of the white powder: thionyl chloride: ethylene dichloride is 150-250: 200-300: 1200-1300.

[0018] More preferably, in the above-mentioned method for synthesizing 2-chloro-4-bromobenzonitrile, the mass ratio of the white powder: thionyl chloride: ethylene dichloride is 200:250:1250.

[0019] Preferably, in the above-mentioned method for synthesizing 2-chloro-4-bromobenzonitrile, in step S4, the reaction temperature is controlled at 70° C. and the reaction time is 2 h.

[0020] Preferably, in the above-mentioned method for synthesizing 2-chloro-4-bromobenzonitrile, the solvent d is cyclohexane; the mass ratio of the white solid:cyclohexane is 1:1; the temperature is raised to 90° C., and the solvent is evaporated under constant temperature conditions.

[0021] Compared with the prior art, the present invention has the following beneficial effects: (1) The method for synthesizing 2-chloro-4-bromobenzonitrile of the present invention is reasonably designed. 2-chloro-4-bromobenzonitrile is synthesized by a four-step reaction method of diazotization, hydroformylation, oximation and nitrilation. The reaction yield is high, the reaction is safe and simple, and it is suitable for industrial production. It provides convenience for the large-scale production of the intermediate 2-chloro-4-bromobenzonitrile, and has great social and economic benefits. (2) The method for synthesizing 2-chloro-4-bromobenzonitrile of the present invention uses dichloroethane as a solvent in the diazotization reaction, thereby avoiding the potential safety hazards caused by the use of toxic raw materials such as trimethylamine. By optimizing the process conditions, a high-purity and high-quality product is obtained. At the same time, the synthesis process is pollution-free, easy to operate, and has a low production cost, and has broad application prospects. DETAILED DESCRIPTION

[0022] The technical scheme in the embodiment of the present invention will be clearly and completely described below in conjunction with Example 1 and specific experimental data. Obviously, the described embodiment is only a part of the embodiment of the present invention, rather than all the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in the field without making creative work belong to the protection scope of the present invention. If the specific conditions are not specified in the embodiments, they are carried out according to normal conditions or manufacturer recommended conditions, and the instruments and reagents used can be purchased. The following Example 1 provides a method for synthesizing 2-chloro-4-bromobenzonitrile.

[0023] Example 1 The synthesis method of 2-chloro-4-bromobenzonitrile of Example 1 comprises the following steps: 1. Diazotization reaction Add 150 kg of dichloroethane, 150 kg of chloroaniline and 5000 kg of hydrobromic acid to the reactor and stir evenly. Control the temperature at 50°C and add 350 kg of sodium nitrite solution dropwise. The solution is added in about 5 hours. After the reaction is completed, a reaction mixture is obtained. The reaction mixture is poured into ice water and quickly cooled to room temperature. Filter to obtain 202 kg of white solid, namely compound I, as shown in the following formula: .

[0024] 2. Synthetic aldehyde 200 kg of the white solid obtained by the above diazotization reaction, 300 kg of bromine, and 150 kg of tap water were added to the reactor, and the temperature was controlled at 80°C. The reaction was carried out for 2 hours. After the reaction was completed, it was naturally cooled to room temperature and filtered to obtain 223 kg of yellow liquid, namely compound II, as shown in the following formula: .

[0025] 3. Oximation reaction 220 kg of yellow liquid obtained by synthesizing the aldehyde above, 120 kg of hydroxylamine hydrochloride and 70 kg of sodium hydroxide were added to a reactor, stirred evenly, and the temperature was controlled at 60°C for 2 hours. After the reaction was completed, the mixture was naturally cooled to room temperature and filtered to obtain 208 kg of white powder, namely compound III, as shown in the following formula: .

[0026] 4. Nitrilation refining 200 kg of the white powder obtained by the above oximation reaction, 250 kg of thionyl chloride and 1250 kg of dichloroethane were added to the reactor, stirred evenly, and the temperature was controlled at 70°C for 2 hours. After the reaction was completed, it was naturally cooled to room temperature and filtered to obtain 188.2 kg of white solid, i.e. 2-chloro-4-bromobenzonitrile, as shown in the following formula: .

[0027] 5. Cyclohexane Refining 188.2 kg of the white solid obtained by the above nitrilation purification was added to 188.2 kg of cyclohexane, stirred evenly, heated to 90°C, and the solvent was evaporated. After the solvent evaporated, 182.4 kg of the finished product was obtained, i.e., the target product 2-chloro-4-bromobenzonitrile.

[0028] The calculated yield is 96.92%.

[0029] The purity was 99.94% as determined by HPLC It can be seen from the above that 2-chloro-4-bromobenzonitrile can be prepared by the synthesis method of the present invention, and the synthesis method has higher operation safety, is environmentally friendly and suitable for industrial production, has a high reaction yield, is safe and simple to react, provides convenience for large-scale production of intermediate synthesis methods, and has great social and economic benefits.

[0030] The present invention has many specific application paths, and the above is only a preferred embodiment of the present invention. It should be pointed out that the above embodiments are only used to illustrate the present invention, and are not used to limit the protection scope of the present invention. For those of ordinary skill in the art, several improvements can be made without departing from the principle of the present invention, and these improvements should also be regarded as the protection scope of the present invention.

Claims

1. A method for synthesizing 2-chloro-4-bromobenzonitrile, characterized in that: The steps include: S1: Add chloroaniline and hydrobromic acid to solvent a, stir evenly, then slowly dropwise add sodium nitrite solution, control the reaction temperature at 40-60°C, after the reaction is completed, pour the reaction mixture into ice water and quickly cool to room temperature, filter to obtain a white solid, i.e., compound I, as shown below: ； S2: Add compound I obtained in S1, bromine and solvent b into a reaction kettle, stir evenly, control the reaction temperature at 70-90°C, and the reaction time is 1-3h. After the reaction is completed, stop heating, cool naturally to room temperature, and filter to obtain a yellow liquid, namely compound II, as shown in the following formula: ； S3: Add compound II obtained in S2, hydroxylamine hydrochloride and sodium hydroxide into a reaction kettle, stir evenly, control the reaction temperature at 50-70°C, and the reaction time is 1-3h. After the reaction is completed, stop heating, cool naturally to room temperature, and filter to obtain a white powder, namely compound III, as shown in the following formula: ； S4: Add compound III obtained in S3 to thionyl chloride and solvent c, stir evenly, control the reaction temperature at 60-80°C, and the reaction time is 1-3h. After the reaction is completed, stop heating, cool naturally to room temperature, and filter to obtain a white solid, namely 2-chloro-4-bromobenzonitrile, as shown in the following formula: ； S5: Add the 2-chloro-4-bromobenzonitrile obtained in S4 to the solvent d, stir evenly, raise the temperature to 80-100° C., evaporate the solvent under constant temperature conditions, and when the solvent evaporates, take out the white solid to obtain the refined 2-chloro-4-bromobenzonitrile, which is then dried and packaged.

2. The method for synthesizing 2-chloro-4-bromobenzonitrile according to claim 1, characterized in that: In the step S1, the solvent a is ethylene dichloride; the mass fraction of sodium nitrite in the sodium nitrite solution is 20-25%; the mass ratio of chloroaniline: hydrobromic acid: ethylene dichloride: sodium nitrite solution is 100-200: 450-450: 100-200: 300-400.

3. The method for synthesizing 2-chloro-4-bromobenzonitrile according to claim 1, characterized in that: In step S1, the reaction temperature is controlled at 50°C.

4. The method for synthesizing 2-chloro-4-bromobenzonitrile according to claim 1, characterized in that: In the step S2, the solvent b is water; the mass ratio of the white solid: bromine: water is 150-250: 250-350: 100-200.

5. The method for synthesizing 2-chloro-4-bromobenzonitrile according to claim 1, characterized in that: In step S2, the reaction temperature is controlled at 80° C. and the reaction time is 2 h.

6. The method for synthesizing 2-chloro-4-bromobenzonitrile according to claim 1, characterized in that: In the step S3, the mass ratio of the yellow liquid: hydroxylamine hydrochloride: sodium hydroxide is 200-250: 100-150: 50-100.

7. The method for synthesizing 2-chloro-4-bromobenzonitrile according to claim 1, characterized in that: In step S3, the reaction temperature is controlled at 60° C. and the reaction time is 2 h.

8. The method for synthesizing 2-chloro-4-bromobenzonitrile according to claim 1, characterized in that: In the step S4, the solvent c is ethylene dichloride; the mass ratio of the white powder: thionyl chloride: ethylene dichloride is 150-250: 200-300: 1200-1300.

9. The method for synthesizing 2-chloro-4-bromobenzonitrile according to claim 1, characterized in that: In step S4, the reaction temperature is controlled at 70° C. and the reaction time is 2 h.

10. The method for synthesizing 2-chloro-4-bromobenzonitrile according to claim 1, characterized in that: In the step S5, the solvent d is cyclohexane; the mass ratio of the white solid to cyclohexane is 1:1; the temperature is raised to 90° C., and the solvent is evaporated under constant temperature conditions.

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