A preparation method of 2-amino-3,5-dibromobenzaldehyde

Abstract

The invention discloses a preparation method of 2-amino-3,5-dibromobenzaldehyde, comprising the following steps: (1) sodium sulfide is dissolved in an acid solution, an organic solution containing o-nitrobenzaldehyde is added dropwise, and the reaction is carried out by heating. After the reaction is completed, the pH value is adjusted to 5-8, and the filtrate is retained by suction filtration; the filtrate is steamed to produce the product, and the organic phase is retained by organic solvent extraction; the organic phase is distilled under reduced pressure to remove the organic solvent to obtain o-aminobenzaldehyde; (2) o-aminobenzaldehyde is dissolved in an organic solvent immiscible with water, mixed with hydrogen peroxide, and a hydrobromic acid solution of potassium bromide is added dropwise, and the reaction is heated; a quencher solution is added to the reaction solution to quench the reaction, and the pH value is adjusted to 5-8, and the filtrate is retained by suction filtration, and the organic layer is retained by liquid separation; the organic layer is distilled to remove the organic solvent to obtain a crude product, methanol is added to heat and dissolve the crude product, and crystallization by cooling obtains 2-amino-3,5-dibromobenzaldehyde. The preparation method of the present invention can improve product purity and yield, and also saves cost.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically, it relates to a method for preparing 2-amino-3,5-dibromobenzaldehyde. Background Technology

[0002] 2-Amino-3,5-dibromobenzaldenhyde (molecular formula: C7H5Br2NO, molecular weight: 278.9, melting point: 136-139℃) is a white or light yellow solid powder and an important pharmaceutical intermediate. Its chemical structure is as follows:

[0003]

[0004] 2-Amino-3,5-dibromobenzaldehyde has wide applications in drug synthesis. One of its main uses is as an important intermediate in the synthesis of ambroxol, which was first developed and marketed by Boehringer Inglés GmbH in Germany in 1984 and is now a well-regarded expectorant approved for use in many countries worldwide. Simultaneously, 2-amino-3,5-dibromobenzaldehyde, as a pharmaceutical intermediate, is also an important raw material for the synthesis of Schiff bases. Schiff bases possess biological properties such as anticancer, antibacterial, antifungal, and antiviral activity. In addition to these biological properties, Schiff base ligands and their complexes also have applications in electrocatalysis, corrosion prevention, and biological conduction. Therefore, the synthesis of 2-amino-3,5-dibromobenzaldehyde is currently an important research direction.

[0005] The following are some of the reported synthetic methods for the pharmaceutical intermediate 2-amino-3,5-dibromobenzaldehyde in the prior art:

[0006] (1) Using methyl anthranilate as a raw material, bromination reaction is carried out to generate methyl 2-amino-3,5-dibromobenzoate, which is then reacted with hydrazine hydrate to generate 2-amino-3,5-dibromobenzoylhydrazine, which is then oxidized by K3Fe(CN)6 to obtain the target product. However, due to the relatively complex reaction steps, the difficulty in obtaining the raw material, the harsh reaction conditions, and the high risk of 2-amino-3,5-dibromobenzoylhydrazine generated by hydrazine hydrate, this method is not suitable for large-scale industrial production.

[0007] (2) Using methyl anthranilate as raw material and N-methyl-N-butylimidazolium tribromide as brominating agent, bromination reaction is carried out to obtain methyl 2-amino-3,5-dibromobenzoate; then NaBH3 is added to carry out reduction reaction to obtain the target product; the brominating agent used in this scheme is expensive, and the reduction reaction with NaBH3 is difficult to control, and benzyl alcohol is easily generated, resulting in many impurities and low yield.

[0008] (3) Using SBA-15 supported 1-methyl-3-(propyltrioxysilane)imidazolium-FeBr4 ionic liquid (FeSIL) as a catalyst, bromine is generated in situ by NH4Br / H2O2, and 2-aminobenzaldehyde is brominated to prepare the target product. This scheme uses expensive and complex catalysts, has high production costs, and is not suitable for industrial production.

[0009] (4) Starting with o-nitrobenzaldehyde, o-aminobenzaldehyde is generated by nitro reduction and then bromination with a brominating agent to obtain the target product. Compared with the previous three schemes, this scheme is simple to operate, the raw materials are easy to obtain, the reaction conditions are relatively mild, and the generated product has high purity, which can be used for large-scale industrial production. The reduction reaction of this scheme includes Fe / hydrochloric acid system, Pd / C hydrogenation system, etc., each with its own advantages and disadvantages. Brominating agents include NBS, bromine, bromine plus KBr, and hydrogen peroxide oxidation of hydrobromic acid to generate bromine in situ. Among them, NBS as a brominating agent has the problems of high cost and difficult post-processing. Bromine is highly dangerous, highly corrosive to equipment, has low yield, and is difficult to achieve green, environmentally friendly and safe production. At present, hydrogen peroxide oxidation of hydrobromic acid to generate bromine in situ is the best scheme, with the advantages of low cost, high yield and high purity.

[0010] However, further research revealed the following problems with the above-mentioned scheme of oxidizing hydrobromic acid with hydrogen peroxide to generate bromine in situ: (1) In the bromination reaction, o-aminobenzaldehyde and hydrobromic acid are mixed first, and then hydrogen peroxide is added dropwise. The reaction system is an aqueous phase. In actual operation, it was found that because hydrogen peroxide is a strong oxidant, it will oxidize the raw material when it comes into direct contact with o-aminobenzaldehyde, introducing a large number of impurities; (2) The hydrogen peroxide mass concentration used in this scheme is 10% to 25%. This high concentration not only easily oxidizes the raw materials and products, but also makes it unsafe to produce in the post-processing; (3) In the reduction reaction, palladium on carbon is used as a catalyst and hydrogen is added under high pressure to carry out the reaction. This has problems such as expensive catalyst, high requirements for production equipment, and safety hazards associated with the use of hydrogen.

[0011] In view of this, the present invention is hereby proposed. Summary of the Invention

[0012] The technical problem to be solved by the present invention is to overcome the shortcomings of the prior art and provide a method for preparing 2-amino-3,5-dibromobenzaldehyde, which can protect the reaction intermediate o-aminobenzaldehyde and the target product from being oxidized and destroyed by oxidants, thereby ensuring product purity and improving yield.

[0013] To solve the above-mentioned technical problems, the basic concept of the technical solution adopted by the present invention is as follows:

[0014] A method for preparing 2-amino-3,5-dibromobenzaldehyde includes the following steps:

[0015] (1) Sodium sulfide is dissolved in an acidic aqueous solution, and then an organic solution containing o-nitrobenzaldehyde is added dropwise. After the addition is complete, the solution is heated to carry out a reduction reaction. After the reaction is complete, the pH is adjusted to 5-8, and the filtrate is retained by suction filtration.

[0016] The filtrate is steam distilled, the distillate is collected and condensed, then extracted with an organic solvent, and the organic phase is retained; the organic phase is distilled to remove the organic solvent, yielding the intermediate o-aminobenzaldehyde;

[0017] (2) Dissolve the o-aminobenzaldehyde obtained in step (1) in an organic solvent that is immiscible with water, mix it evenly with hydrogen peroxide, and then add potassium bromide hydrobromic acid solution dropwise. After the addition is complete, heat to carry out the bromination reaction.

[0018] Quenching agent solution is added to the reaction solution to quench the reaction, the pH of the reaction solution is adjusted to 5-8, the filtrate is retained by suction filtration, and then the organic layer is retained by separation.

[0019] The organic layer is distilled to remove the organic solvent to obtain a crude product. Methanol or ethanol is then added and heated to dissolve the crude product. After cooling and crystallization, the solid target product 2-amino-3,5-dibromobenzaldehyde is obtained.

[0020] In this invention, o-nitrobenzaldehyde is used as the basic raw material. First, o-nitrobenzaldehyde is reduced to o-aminobenzaldehyde using a sodium sulfide reduction system. Then, the target product is synthesized by bromination reaction, in situ, of hydrogen peroxide oxidizing hydrobromic acid to bromine. This route has advantages such as inexpensive and readily available raw materials, mild reaction conditions, simple operation, high yield, and high product purity, while ensuring safety, stability, and effectiveness.

[0021] In the reduction reaction, sodium sulfide is used as the reducing agent, which is less expensive and requires less sophisticated equipment than palladium on carbon hydrogenation. In the bromination reaction, an o-aminobenzaldehyde is dissolved in a water-immiscible organic solvent. This solvent forms two phases in the reaction system, an organic layer and an aqueous layer, separating the o-aminobenzaldehyde and target product in the organic layer from oxidants such as hydrogen peroxide in the aqueous layer. This protects the o-aminobenzaldehyde and target product from oxidation by the oxidant, preventing impurities and contributing to high product purity and increased yield. Potassium bromide is used as a catalyst to promote the oxidation of Br₂ by hydrogen peroxide. - Oxidation to Br2 not only helps to deplete the hydrogen peroxide in the system, but also accelerates the bromination reaction, thus speeding up the reaction rate.

[0022] Therefore, the solution of the present invention simplifies the process flow, saves costs, and is more conducive to large-scale industrial production.

[0023] Further, in step (1), the molar ratio of sodium sulfide to o-nitrobenzaldehyde is 1.0 to 2.5:1, and the volume ratio of the acid solution to the organic solution containing o-nitrobenzaldehyde is 1:1 to 3.

[0024] Preferably, the molar ratio of sodium sulfide to o-nitrobenzaldehyde is 1.5 to 2.5:1;

[0025] Preferably, the acid solution is one of acetic acid aqueous solution, hydrochloric acid, or dilute sulfuric acid;

[0026] More preferably, the concentration of the acid solution is 0.5–2.0 mol / L;

[0027] Preferably, the sodium sulfide is dissolved in an acid solution, and the concentration of sodium sulfide is 1.0–3.0 mol / L;

[0028] Preferably, in the organic solution containing o-nitrobenzaldehyde, the organic solvent is one of methanol, ethanol, isopropanol or tetrahydrofuran.

[0029] In a further step, after sodium sulfide is fully dissolved in the acid solution, the temperature of the mixed solution is kept at 10°C, and an organic solution containing o-nitrobenzaldehyde is slowly added dropwise.

[0030] As one specific implementation method, sodium sulfide can be mixed with an acid solution and then heated to aid dissolution.

[0031] Furthermore, in step (1), during the reduction reaction, the pH value of the reaction solution is maintained at 11-12; after the reaction is completed, dilute sulfuric acid is added to the reaction solution to adjust the pH value to 5-8.

[0032] Preferably, the concentration of the dilute sulfuric acid is 1 to 5 mol / L.

[0033] In one specific implementation, in step (1), after the organic solution containing o-nitrobenzaldehyde is added dropwise, the reaction solution is heated to reflux and a reduction reaction is carried out under stirring conditions. The reaction process is monitored by TLC.

[0034] As one specific implementation method, after the reduction reaction is completed, dilute sulfuric acid is added to adjust the pH value, and the mixture is filtered while hot. The filtrate is purified by steam distillation and then extracted with an organic solvent. The extraction process is monitored by TLC. Finally, the organic solvent used for extraction is removed by rotary evaporation or vacuum distillation.

[0035] The organic solvent used for extraction can be ethyl acetate, dichloromethane, or chloroform.

[0036] In the above scheme, sodium sulfide is used to reduce o-nitrobenzaldehyde to obtain o-aminobenzaldehyde. By controlling the feed ratio and pH value of the reaction system, and by following the post-reaction treatment schemes such as filtration, steam distillation purification, extraction, rotary evaporation or vacuum distillation, the purity of the obtained o-aminobenzaldehyde is consistently above 98%, which is beneficial to ensuring the purity of the product synthesized from o-aminobenzaldehyde in the subsequent synthesis of 2-amino-3,5-dibromobenzaldehyde.

[0037] Furthermore, in step (2), the mass concentration of the hydrogen peroxide is 2.0% to 9.5%.

[0038] Compared with existing technologies that use hydrogen peroxide with a mass concentration of 10% to 25%, this invention reduces the hydrogen peroxide concentration, thereby further reducing the possibility of oxidation of the intermediate o-aminobenzaldehyde and the target product. At the same time, it also improves the safety of post-processing and meets the safety requirements of large-scale industrial production.

[0039] Further, in step (2), the ratio of o-aminobenzaldehyde to an organic solvent that is immiscible with water is 1g: 5-30ml;

[0040] Preferably, the water-immiscible organic solvent is one of dichloromethane, chloroform, ethyl acetate, and diethyl ether.

[0041] Furthermore, in step (2), the molar ratio of o-aminobenzaldehyde, hydrogen bromide in hydrobromic acid, hydrogen peroxide in hydrogen peroxide, and potassium bromide is 1:2~8:1~4:0.5~2.

[0042] Furthermore, in step (2), the mass concentration of the hydrobromic acid is 20% to 48%, preferably 25% to 35%.

[0043] In the above scheme, by controlling the feed ratio in the bromination reaction stage, it is beneficial to ensure the yield and purity of the target product 2-amino-3,5-dibromobenzaldehyde.

[0044] Further, in step (2), the potassium bromide hydrobromic acid solution is added dropwise to the reaction system at -5 to 10°C; after the addition is complete, the system is heated to 5 to 35°C and the bromination reaction is carried out under stirring.

[0045] Preferably, the bromination reaction takes more than or equal to 2 hours, and then an aqueous sodium sulfite solution is added to quench the reaction.

[0046] As one specific implementation method, a potassium bromide hydrobromic acid solution is slowly added dropwise to the reaction system at -5 to 10°C under stirring conditions.

[0047] Further, in step (2), the quenching agent solution is an aqueous solution of one of sodium sulfite, sodium bisulfite, sodium dithionite or sodium thiosulfate. After the reaction is quenched, an aqueous solution of sodium carbonate is added to the reaction solution to adjust the pH value to 5-8.

[0048] Preferably, the mass concentration of the solute in the quenching agent solution is 5% to 20%;

[0049] Preferably, the mass concentration of the sodium carbonate aqueous solution is 10% to 30%.

[0050] In one specific implementation, after the potassium bromide hydrobromic acid solution is added dropwise, the reaction solution is heated to 5-35°C and stirred for more than 2 hours. Then, a quenching agent solution with a mass concentration of 10-30% is added and stirred for 30 minutes to quench the reaction.

[0051] In one specific implementation, the volume ratio of the quenching agent solution to the organic solvent used to dissolve o-aminobenzaldehyde is 1:1.

[0052] Furthermore, in step (2), the ratio of crude product to methanol or ethanol is 1g: 5-20ml.

[0053] In one specific implementation, the crude product is added to methanol, heated to reflux to dissolve the crude product, and then cooled to room temperature to crystallize, yielding a pale yellow solid, which is the target product 2-amino-3,5-dibromobenzaldehyde.

[0054] In the above scheme, the water-immiscible organic solvent can protect o-aminobenzaldehyde and the target product from oxidation and the generation of impurities. The use of low-concentration hydrogen peroxide further reduces the possibility of o-aminobenzaldehyde and the target product being oxidized. Combined with a suitable feed ratio and purification treatment of crude product by recrystallization after dissolving in methanol, the purity of the target product 2-amino-3,5-dibromobenzaldehyde can reach more than 99%, which meets the requirements for use as a pharmaceutical intermediate.

[0055] As one specific embodiment, the present invention uses the following preparation method to prepare 2-amino-3,5-dibromobenzaldehyde:

[0056] (1) Add sodium sulfide and acid solution to a three-necked flask. If necessary, heat to aid dissolution. After the sodium sulfide is fully dissolved, keep the temperature of the mixed solution at 10°C and slowly add an organic solution containing o-nitrobenzaldehyde. The molar ratio of sodium sulfide to o-nitrobenzaldehyde is 1.0 to 2.5:1, and the volume ratio of acid solution to organic solution containing o-nitrobenzaldehyde is 1:1 to 3. After the addition is complete, heat the reaction solution to reflux and react with stirring for 3 to 6 hours. Monitor the consumption of o-nitrobenzaldehyde by TLC. After the reaction is complete, add 1 to 5 M dilute sulfuric acid to adjust the pH to 7 and filter while hot.

[0057] The filtrate obtained by vacuum filtration was distilled off by steam distillation, and the product was extracted with an organic solvent after condensation. The extraction process was monitored by TLC. The organic solvent was then removed by vacuum distillation or rotary evaporation to obtain a pale yellow oily intermediate, o-aminobenzaldehyde.

[0058] (2) Dissolve the o-aminobenzaldehyde obtained in step (1) in an organic solvent that is immiscible with water at a ratio of 1g: 5-30ml. Add the dissolved solution to a three-necked flask, then add hydrogen peroxide with a mass concentration of 2.0%-9.5%, and stir thoroughly. Take hydrobromic acid with a mass concentration of 20%-48%, add potassium bromide to dissolve it, and slowly add the potassium bromide hydrobromic acid solution to the reaction system at -5-10℃ with stirring. The molar ratio of o-aminobenzaldehyde, hydrogen bromide in hydrobromic acid, hydrogen peroxide in hydrogen peroxide, and potassium bromide is 1:2-8:1-4:0.5-2. After the addition is complete, heat the reaction solution to 5-35℃ and stir for more than 2 hours.

[0059] Add a quenching agent solution with a mass concentration of 5% to 20% to the reaction solution, stir for 30 minutes to quench the reaction, and then add a sodium carbonate aqueous solution with a mass concentration of 10% to 30% to adjust the pH value to 7; after filtering the reaction solution, retain the filtrate, and then separate the liquid to retain the organic layer;

[0060] The organic layer is subjected to vacuum distillation to remove the organic solvent to obtain a crude product. Methanol or ethanol is then added at a ratio of 5-20 ml per 1 g of crude product. The mixture is heated to reflux to dissolve the crude product, and then cooled to crystallize to obtain a pale yellow solid, which is the target product 2-amino-3,5-dibromobenzaldehyde.

[0061] By adopting the above technical solution, the present invention has the following beneficial effects compared with the prior art.

[0062] 1. The method for preparing 2-amino-3,5-dibromobenzaldehyde provided by this invention uses sodium sulfide as a reducing agent in the reaction stage of reducing o-nitrobenzaldehyde to o-aminobenzaldehyde. Compared with the palladium-carbon hydrogenation reduction in the prior art, this method has lower costs and lower equipment requirements. In the bromination reaction stage, by using an organic solvent that is immiscible with water, reducing the concentration of hydrogen peroxide, and adding potassium bromide as a catalyst, the intermediate o-aminobenzaldehyde and the target product are effectively protected from oxidation and destruction by oxidants, thus ensuring product purity, improving yield, and accelerating the reaction rate.

[0063] 2. The preparation method of the present invention simplifies the process flow, saves costs, and is more conducive to large-scale industrial production; the purity of the obtained target product 2-amino-3,5-dibromobenzaldehyde can reach more than 99%, which meets the requirements for use as a pharmaceutical intermediate.

[0064] The specific embodiments of the present invention will be described in further detail below. Detailed Implementation

[0065] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The following embodiments are used to illustrate the present invention, but are not intended to limit the scope of the present invention.

[0066] Example 1

[0067] In this embodiment, 2-amino-3,5-dibromobenzaldehyde was prepared according to the following steps.

[0068] (1) Synthesis of o-aminobenzaldehyde:

[0069] Add sodium sulfide (70.24 g, 0.9 mol) and 600 mL of aqueous acetic acid solution (containing 60.0 g, 1.0 mol of acetic acid) to a 2000 mL three-necked flask to dissolve the sodium sulfide. Heating may be necessary to aid dissolution if required. After complete dissolution, maintain the temperature of the mixed solution at 10 °C and slowly add 600 mL of an ethanol solution of o-nitrobenzaldehyde (containing 90.0 g, 0.6 mol of o-nitrobenzaldehyde) dropwise over 30 minutes. After the addition is complete, heat the reaction solution to reflux and react with stirring for 3 hours. Monitor the consumption of o-nitrobenzaldehyde by TLC. After the reaction is complete, add 4 M dilute sulfuric acid to adjust the pH to 7 and filter while hot.

[0070] The filtrate obtained by vacuum filtration was distilled off by steam distillation, and the product was extracted with dichloromethane after condensation. 300 mL of dichloromethane was used for each extraction operation. The extraction process was monitored by TLC. The extraction was carried out three times in total. Then, the dichloromethane was removed by vacuum distillation to obtain a pale yellow oily o-aminobenzaldehyde.

[0071] The yield was 87.35% and the product purity was 98.56%.

[0072] (2) Synthesis of 2-amino-3,5-dibromobenzaldehyde:

[0073] Dissolve 60.57 g (0.50 mol) of o-aminobenzaldehyde obtained in the previous step in 600 mL of ethyl acetate. Add the resulting solution to a 4000 mL three-necked flask, then add 1020.3 g of 5.0% hydrogen peroxide (containing 51.02 g (1.50 mol)) and stir thoroughly. Dissolve 809.1 g (containing 242.73 g (3.0 mol) of 30% hydrobromic acid in potassium bromide (59.5 g (0.5 mol)). Then, add the potassium bromide hydrobromic acid solution dropwise to the reaction system over 30 minutes at 0 °C with stirring. After the addition is complete, raise the temperature of the reaction solution to 25 °C and stir for at least 2 hours.

[0074] Then, add 600 ml of 10% sodium sulfite aqueous solution, stir for 30 minutes to quench the reaction, and then add 30% sodium carbonate aqueous solution to adjust the pH of the reaction solution to 7; after filtering the reaction solution, retain the filtrate, and then separate the liquid to retain the ethyl acetate layer;

[0075] Ethyl acetate was removed by vacuum distillation to obtain a crude product; methanol was then added at a ratio of 10 ml methanol per 1 g of crude product, and the mixture was heated to reflux to dissolve the crude product. After cooling, the product was crystallized to obtain a pale yellow solid, which is the target product 2-amino-3,5-dibromobenzaldehyde.

[0076] The yield was 87.75%, and the purity of the target product was 99.44%.

[0077] Comparative Example 1

[0078] This comparative example was prepared according to the following steps: 2-amino-3,5-dibromobenzaldehyde was prepared.

[0079] (1) Synthesis of o-aminobenzaldehyde:

[0080] Add 5 mol of methanol, 2.0 g of 5% palladium on carbon, and 0.066 mol of o-nitrobenzaldehyde to a 500 ml high-pressure reactor. Seal the reactor and replace it with nitrogen and hydrogen 2-3 times each. Then, purge with hydrogen and control the pressure at 0.5 MPa. Maintain the temperature at 60 °C and stir the reaction for 90 minutes.

[0081] Cool to room temperature, reduce pressure, replace with nitrogen, and concentrate under reduced pressure to obtain the intermediate o-aminobenzaldehyde;

[0082] The yield was 91.36% and the product purity was 90.33%.

[0083] (2) Synthesis of 2-amino-3,5-dibromobenzaldehyde:

[0084] Add the o-aminobenzaldehyde prepared in the previous step and 15% hydrobromic acid (containing 0.1944 mol of hydrogen bromide) to a 250 ml three-necked flask. Cool to 5 °C and stir vigorously. Slowly add 15% hydrogen peroxide (containing 0.066 mol of hydrogen peroxide) dropwise over 60 minutes. After the addition is complete, heat to 20 °C and stir to react for 3 hours.

[0085] After the reaction is complete, add a large amount of water and adjust the pH to 7.0 by adding a 10% sodium carbonate aqueous solution; filter, rinse, and dry to obtain the crude product;

[0086] Take the crude product (0.0358 mol) and slowly add it to methanol (2.4713 mol) under stirring. Heat to reflux until completely dissolved. Decolorize with activated carbon, filter, and crystallize at 0℃ to obtain the target product 2-amino-3,5-dibromobenzaldehyde.

[0087] The yield was 63.14%, and the purity of the target product was 93.47%.

[0088] By comparing Example 1 and Comparative Example 1, it can be seen that the preparation method provided by the present invention can significantly improve the yield of 2-amino-3,5-dibromobenzaldehyde and improve the purity of the obtained 2-amino-3,5-dibromobenzaldehyde, which can be used for the industrial production of the pharmaceutical intermediate 2-amino-3,5-dibromobenzaldehyde.

[0089] Comparative Example 2

[0090] In this comparative example, o-aminobenzaldehyde was synthesized according to step (1) in Example 1. The yield of the obtained product was 87.59% and the purity was 98.97%.

[0091] Then, the prepared o-aminobenzaldehyde (60.57 g, 0.5 mol) was used to synthesize 2-amino-3,5-dibromobenzaldehyde according to step (2) in Comparative Example 1. The yield of the target product was 65.54% and the purity of the target product was 94.05%.

[0092] Compared to Example 1, this comparative example used a single aqueous phase in the bromination reaction stage and employed a higher concentration of hydrogen peroxide. Consequently, both the final yield and the purity of the target product were significantly lower than in Example 1. This demonstrates that the present invention, by using a water-immiscible organic solvent to dissolve o-aminobenzaldehyde and employing a reduced hydrogen peroxide concentration, can significantly improve the yield and purity of 2-amino-3,5-dibromobenzaldehyde.

[0093] Comparative Example 3

[0094] In this comparative example, o-aminobenzaldehyde was synthesized according to step (1) in Comparative Example 1. The yield of the obtained product was 90.88% and the purity was 92.37%.

[0095] Then, the prepared o-aminobenzaldehyde (60.57 g, 0.5 mol) was used to synthesize 2-amino-3,5-dibromobenzaldehyde according to step (2) in Example 1. The yield of the target product was 89.58% and the purity of the target product was 99.39%.

[0096] Compared to Example 1, this comparative example uses palladium on carbon as a catalyst in the reduction reaction, and hydrogen is added under high pressure to carry out the reaction. After the reaction, the product is directly concentrated under reduced pressure to obtain o-aminobenzaldehyde. The yield is comparable to that of Example 1, but the purity of the product is significantly lower than that of Example 1. Therefore, in this invention, using sodium sulfide to reduce o-nitrobenzaldehyde and combining it with a specific post-treatment scheme is beneficial for obtaining o-aminobenzaldehyde with higher purity.

[0097] Example 2

[0098] In this embodiment, 2-amino-3,5-dibromobenzaldehyde was prepared according to the following steps.

[0099] (1) Synthesis of o-aminobenzaldehyde:

[0100] Add sodium sulfide (46.83 g, 0.6 mol) and 600 mL of hydrochloric acid (containing 10.95 g, 0.3 mol of HCl) to a 2000 mL three-necked flask to dissolve the sodium sulfide. Heating may be necessary to aid dissolution if required. After complete dissolution, maintain the temperature of the mixed solution at 20 °C and slowly add 600 mL of an ethanol solution of o-nitrobenzaldehyde (containing 90.0 g, 0.6 mol of o-nitrobenzaldehyde) dropwise over 30 minutes. After the addition is complete, heat the reaction solution to reflux and react with stirring for 4 hours. Monitor the consumption of o-nitrobenzaldehyde by TLC. After the reaction is complete, add 1 M dilute sulfuric acid to adjust the pH to 7 and filter while hot.

[0101] The filtrate obtained by vacuum filtration was distilled off by steam distillation, and the product was extracted with ethyl acetate after condensation. 300 mL of ethyl acetate was used for each extraction operation, and the extraction process was monitored by TLC. The extraction was carried out 3 times in total. Then, the ethyl acetate was removed by vacuum distillation to obtain a pale yellow oily o-aminobenzaldehyde.

[0102] The yield was 82.15% and the product purity was 95.17%.

[0103] (2) Synthesis of 2-amino-3,5-dibromobenzaldehyde:

[0104] Dissolve 60.57 g (0.5 mol) of o-aminobenzaldehyde obtained in the previous step in 330 mL of diethyl ether. Add the resulting solution to a 2000 mL three-necked flask, then add 179.1 g of 9.5% hydrogen peroxide (containing 17.01 g (0.5 mol)) and stir thoroughly. Dissolve 231.17 g (containing 80.91 g (1.0 mol) of 35% hydrobromic acid in potassium bromide (59.5 g (0.5 mol)) in the solution. Then, add the potassium bromide hydrobromic acid solution dropwise to the reaction system over 30 minutes at 10 °C with stirring. After the addition is complete, raise the temperature of the reaction solution to 35 °C and stir for at least 2 hours.

[0105] Then, add 300 ml of 20% sodium sulfite aqueous solution, stir for 30 minutes to quench the reaction, and then add 20% sodium carbonate aqueous solution to adjust the pH of the reaction solution to 7; after filtering the reaction solution, retain the filtrate, and then separate the liquid to retain the ether layer;

[0106] The crude product was obtained by removing diethyl ether by vacuum distillation; ethanol was added at a ratio of 10 ml ethanol per 1 g of crude product, and the mixture was heated to reflux to dissolve the crude product. The product was then cooled and crystallized to obtain a pale yellow solid, which was the target product 2-amino-3,5-dibromobenzaldehyde.

[0107] The yield was 88.75%, and the purity of the target product was 99.62%.

[0108] Example 3

[0109] In this embodiment, 2-amino-3,5-dibromobenzaldehyde was prepared according to the following steps.

[0110] (1) Synthesis of o-aminobenzaldehyde:

[0111] Add sodium sulfide (93.66 g, 1.2 mol) and 600 mL of dilute sulfuric acid (containing 117.6 g, 1.2 mol) to a 2000 mL three-necked flask to dissolve the sodium sulfide. Heating may be necessary to aid dissolution if required. After complete dissolution, maintain the temperature of the mixed solution at 20 °C and slowly add 600 mL of an ethanol solution of o-nitrobenzaldehyde (containing 90.0 g, 0.6 mol) dropwise over 30 minutes. After the addition is complete, heat the reaction solution to reflux and react with stirring for 6 hours. Monitor the consumption of o-nitrobenzaldehyde by TLC. After the reaction is complete, add 4 M dilute sulfuric acid to adjust the pH to 7 and filter while hot.

[0112] The filtrate obtained by vacuum filtration was distilled off by steam distillation, and the product was extracted with chloroform after condensation. 300 mL of chloroform was used for each extraction operation, and the extraction process was monitored by TLC. The extraction was carried out 3 times in total. Then, the chloroform was removed by vacuum distillation to obtain a pale yellow oily o-aminobenzaldehyde.

[0113] The yield was 88.05% and the product purity was 99.13%.

[0114] (2) Synthesis of 2-amino-3,5-dibromobenzaldehyde:

[0115] Dissolve 60.57 g (0.5 mol) of o-aminobenzaldehyde obtained in the previous step in 500 mL of dichloromethane. Add the resulting solution to a 4000 mL three-necked flask, then add 720 g of 9.5% hydrogen peroxide (containing 68.4 g (2.0 mol) and stir thoroughly. Dissolve 1295 g (4.0 mol) of 25% hydrobromic acid (containing 323.64 g (4.0 mol)) in potassium bromide (119.0 g (1.0 mol) and add the potassium bromide hydrobromic acid solution dropwise to the reaction system over 30 minutes at 10 °C with stirring. After the addition is complete, raise the temperature of the reaction solution to 30 °C and stir for at least 2 hours.

[0116] Then, add 300 ml of 20% sodium sulfite aqueous solution, stir for 30 minutes to quench the reaction, and then add 10% sodium carbonate aqueous solution to adjust the pH of the reaction solution to 7; after filtering the reaction solution, retain the filtrate, and then separate the liquid to retain the dichloromethane layer;

[0117] Dichloromethane was removed by vacuum distillation to obtain a crude product; methanol was then added at a ratio of 20 ml methanol per 1 g of crude product, and the mixture was heated to reflux to dissolve the crude product. After cooling, the product was crystallized to obtain a pale yellow solid, which is the target product 2-amino-3,5-dibromobenzaldehyde.

[0118] The yield was 88.56%, and the purity of the target product was 99.91%.

[0119] Experimental Example 1

[0120] This experiment investigated the effect of hydrogen peroxide concentration on the target product. Specifically, referring to the preparation method provided in Example 1, only the mass concentration of hydrogen peroxide in step (2) was changed; all other preparation steps and process parameters were the same as in Example 1. The yield of step (2) and the purity of the obtained target product were tested and are shown in Table 1 below.

[0121] Table 1. Results of hydrogen peroxide mass concentration test

[0122] Hydrogen peroxide mass concentration (%) Yield (%) purity(%) 1.5 85.64 99.79 2.0 88.75 99.62 5.0 87.75 99.44 9.5 88.56 99.91 15.0 86.21 99.37 20.0 85.49 98.57 25.0 85.64 98.02

[0123] The above experimental results show that when the mass concentration of hydrogen peroxide used exceeds 9.5%, both the yield and purity exhibit a certain downward trend, indicating that higher concentrations of hydrogen peroxide are not conducive to the synthesis of 2-amino-3,5-dibromobenzaldehyde. In this invention, using hydrogen peroxide with a mass concentration of 2.0% to 9.5% achieves a yield higher than 87.75%, and the purity of the obtained 2-amino-3,5-dibromobenzaldehyde can reach over 99.44%.

[0124] Experimental Example 2

[0125] This experiment investigated the effect of the ratio of sodium sulfide to o-nitrobenzaldehyde on the target product. Specifically, referring to the preparation method provided in Example 1, only the amount of sodium sulfide in step (1) was changed, while other preparation steps and process parameters were the same as in Example 1. The yields and product purities of the two steps were tested and are shown in Table 2 below.

[0126] Table 2 Results of sodium sulfide dosage test

[0127]

[0128] The above experimental results show that increasing the amount of sodium sulfide can improve the yield and purity of the product to a certain extent. However, when the molar ratio of sodium sulfide to o-nitrobenzaldehyde exceeds 1.5:1, further increasing the amount of sodium sulfide results in only a small increase in yield and purity. Considering the production cost in industrial production, the molar ratio of sodium sulfide to o-nitrobenzaldehyde in this invention is preferably controlled between 1.5 and 2.5:1.

[0129] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A method for preparing 2-amino-3,5-dibromobenzaldehyde, characterized in that: The following steps are involved: (1) Sodium sulfide is dissolved in an acid solution, and then an organic solution containing o-nitrobenzaldehyde is added dropwise thereto. After the addition is complete, the solution is heated to perform a reduction reaction. After the reaction is completed, the pH value is adjusted to 5 to 8, and the filtrate is filtered and retained; The filtrate is subjected to steam distillation, the evaporated components are collected and condensed, and then extracted with an organic solvent, and the organic phase is retained; the organic phase is distilled to remove the organic solvent to obtain the intermediate o-aminobenzaldehyde; (2) dissolving the o-aminobenzaldehyde obtained in step (1) in a water-immiscible organic solvent, mixing the mixture evenly with hydrogen peroxide having a mass concentration of 2.0% to 9.5%, and then dropping a solution of potassium bromide in hydrobromic acid therein, heating the mixture after the dropping is complete to carry out a bromination reaction; the water-immiscible organic solvent is one of dichloromethane, chloroform, ethyl acetate and ether; and the ratio of the o-aminobenzaldehyde to the water-immiscible organic solvent is 1 g: 5 to 30 ml; Add a quenching agent solution to the reaction solution to quench the reaction, adjust the pH value of the reaction solution to 5-8, filter and retain the filtrate, and then separate and retain the organic layer; The organic layer is distilled to remove the organic solvent to obtain a crude product, methanol or ethanol is added and heated to dissolve the crude product, and then cooled and crystallized to obtain a solid target product 2-amino-3,5-dibromobenzaldehyde.

2. The method for preparing 2-amino-3,5-dibromobenzaldehyde according to claim 1, characterized in that: In step (1), the molar ratio of the sodium sulfide to o-nitrobenzaldehyde is 1.0-2.5:1, and the volume ratio of the acid solution to the organic solution containing o-nitrobenzaldehyde is 1:1-3.

3. The method for preparing 2-amino-3,5-dibromobenzaldehyde according to claim 2, characterized in that: The molar ratio of the sodium sulfide to o-nitrobenzaldehyde is 1.5-2.5:

1.

4. The method for preparing 2-amino-3,5-dibromobenzaldehyde according to claim 2, characterized in that: The acid solution is one of acetic acid aqueous solution, hydrochloric acid or dilute sulfuric acid.

5. The method for preparing 2-amino-3,5-dibromobenzaldehyde according to claim 4, characterized in that: The concentration of the acid solution is 0.5-2.0 mol / L.

6. The method for preparing 2-amino-3,5-dibromobenzaldehyde according to claim 2, characterized in that: The sodium sulfide is dissolved in the acid solution, and the concentration of the sodium sulfide is 1.0-3.0 mol / L.

7. The method for preparing 2-amino-3,5-dibromobenzaldehyde according to claim 2, characterized in that: In the organic solution containing o-nitrobenzaldehyde, the organic solvent is one of methanol, ethanol, isopropanol or tetrahydrofuran.

8. The method for preparing 2-amino-3,5-dibromobenzaldehyde according to claim 1, characterized in that: In step (1), during the reduction reaction, the pH value of the reaction solution is maintained at 10 to 12; after the reaction is completed, sulfuric acid is added to the reaction solution to adjust the pH value to 5 to 8.

9. The method for preparing 2-amino-3,5-dibromobenzaldehyde according to claim 8, characterized in that: The concentration of the sulfuric acid is 1-5 mol / L.

10. The method for preparing 2-amino-3,5-dibromobenzaldehyde according to any one of claims 1 to 9, characterized in that: In step (2), the molar ratio of o-aminobenzaldehyde, hydrogen bromide in hydrobromic acid, hydrogen peroxide in hydrogen peroxide, and potassium bromide is 1:2-8:1-4:0.5-2.

11. The method for preparing 2-amino-3,5-dibromobenzaldehyde according to any one of claims 1 to 9, characterized in that: In step (2), the mass concentration of the hydrobromic acid is 20% to 48%.

12. The method for preparing 2-amino-3,5-dibromobenzaldehyde according to claim 11, characterized in that: The mass concentration of the hydrobromic acid is 25% to 35%.

13. The method for preparing 2-amino-3,5-dibromobenzaldehyde according to any one of claims 1 to 9, characterized in that: In step (2), the potassium bromide hydrobromic acid solution is added dropwise to the reaction system at -5 to 10°C; after the addition is completed, the mixture is heated to 5 to 35°C and subjected to bromination reaction under stirring.

14. The method for preparing 2-amino-3,5-dibromobenzaldehyde according to claim 13, characterized in that: The reaction time of the bromination reaction is greater than or equal to 2 hours, and then a sodium sulfite aqueous solution is added to quench the reaction.

15. The method for preparing 2-amino-3,5-dibromobenzaldehyde according to any one of claims 1 to 9, characterized in that: In step (2), the quencher solution is an aqueous solution of sodium sulfite, sodium bisulfite, sodium dithionite or sodium thiosulfate. After the reaction is quenched, an aqueous sodium carbonate solution is added to the reaction solution to adjust the pH value to 5-8.

16. The method for preparing 2-amino-3,5-dibromobenzaldehyde according to claim 15, characterized in that: The mass concentration of the solute in the quencher solution is 5% to 20%.

17. The method for preparing 2-amino-3,5-dibromobenzaldehyde according to claim 15, characterized in that: The mass concentration of the sodium carbonate aqueous solution is 10% to 30%.

18. The method for preparing 2-amino-3,5-dibromobenzaldehyde according to any one of claims 1 to 9, characterized in that: In step (2), the ratio of the crude product to methanol or ethanol added is 1 g: 5-20 ml.

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