A synthesis process of thiabendazole

Abstract

The present invention relates to a kind of synthesis process of thiabendazole, including:Using lactic acid and o-phenylenediamine as raw materials, solid acid is used as catalyst condensation reaction in water to obtain 2 α hydroxyethyl benzimidazole;2 α hydroxyethyl benzimidazole, micron-grade magnetic iron powder are mixed and put into water, hydrogen peroxide is added for catalytic oxidation, and 2 acetyl benzimidazole is obtained;2 acetyl benzimidazole is put into glacial acetic acid, bromine is added, and the MOF powder of trivalent Fe as central metal is catalyst, bromine substitution reaction is carried out, and 2 dibromoacetyl benzimidazole hydrobromide is obtained;Formamide and phosphorus pentasulfide are put into ethyl acetate, 30 45 DEG C of reaction 1 2h, 2 dibromoacetyl benzimidazole hydrobromide is added, ammonia catalytic cyclization reaction is passed through, and reaction is filtered after terminating, and filtrate cools down and precipitates solid, separates solid, washes, and obtains thiabendazole. The present invention can obtain higher yield than prior art, and reaction conditions are mild, catalyst and solvent are easily separated and recycled, reduces waste of raw materials, and reduces resource recovery difficulty.

Description

Technical Field

[0001] The present invention relates to a pesticide synthesis process, in particular to a synthesis process of thiabendazole. Background Art

[0002] Thiabendazole belongs to the benzimidazole fungicide class, chemically known as 2-(thiazol-4-yl)benzimidazole. The current mainstream synthesis method involves four steps: Step 1: Lactic acid and o-phenylenediamine are condensed in an acidic (but not limited to) aqueous solution (hydrochloric acid) and the pH is adjusted to yield 2-α-hydroxyethylbenzimidazole. Step 2: The 2-α-hydroxyethylbenzimidazole is filtered and dried, then placed in a solvent environment of acetone and sulfuric acid (or other inorganic acid or strong acid and weak base salts), oxidized with potassium permanganate, extracted, evaporated to remove the solvent, and dried to yield 2-acetylbenzimidazole. Step 3: The 2-acetylbenzimidazole is then placed in a solvent environment of glacial acetic acid for halogenation with bromine (or other halogen). The resulting mixture is filtered and the filter cake is dried to yield 2-dibromoacetylbenzimidazole hydrobromide. Step 4: Formamide and phosphorus pentasulfide are reacted in an ethyl acetate solvent to produce thioformamide; phosphorus pentoxide is removed by nitrogen filtration to obtain a thioformamide / ethyl acetate solution, which is then subjected to a cyclization reaction with the 2-dibromoacetylbenzimidazole obtained in step 3, and the pH value is adjusted to obtain a thiabendazole content of ≥99%. This process has the following disadvantages: (1) A large amount of hydrochloric acid aqueous solution is used in the reaction in step 1, and a large amount of waste acid needs to be neutralized with sodium hydroxide. In addition, the sodium chloride produced in the reaction enters the product and becomes an impurity of 2-α-hydroxyethylbenzimidazole, affecting subsequent reactions. (2) Step 2 requires an oxidation reaction with potassium permanganate as an oxidant in the presence of acetone as a solvent (non-aqueous system). Despite the extraction treatment and subsequent solvent removal and drying, 2-acetylbenzimidazole is still mixed with a certain amount of sodium chloride, potassium sulfate, and excess potassium permanganate. These will react with the bromine in the next step, resulting in a large amount of bromine waste. The by-products are dissolved in glacial acetic acid, which needs to be recycled and distilled before it can be recycled. At the same time, the use of potassium permanganate as an oxidant will form a large amount of manganese-containing solid waste, and the processing cost is very high. (3) In the cyclization reaction step, it takes a long time to heat and reflux to dry the ethyl acetate, and the residue is heated to 90-100°C. The long-term high-temperature reaction makes ethyl acetate easily decompose and produce by-products, resulting in the inability to directly recycle ethyl acetate and a low recovery rate. In addition, the reaction conversion rate of each of the above steps needs to be further improved. Summary of the Invention

[0003] (1) Technical issues to be resolved

[0004] In view of the above-mentioned shortcomings and deficiencies of the prior art, the present invention provides a synthesis process of thiabendazole, which adopts lactic acid and o-phenylenediamine, uses an easily separable catalyst in each step, reduces side reactions and raw material waste, shortens process time, simplifies solvent recovery difficulty, avoids heavy metal pollution, and has important environmental significance.

[0005] (2) Technical solution

[0006] The present invention provides a synthesis process of thiabendazole, which comprises the following steps:

[0007] S1, adding lactic acid and o-phenylenediamine to water, using a solid acid as a catalyst, heating to carry out a condensation reaction to generate 2-α-hydroxyethylbenzimidazole, after which the reaction is completed, recovering the solid acid, cooling the reaction solution to 4-25° C. to precipitate, filtering, and washing with water until neutral to obtain 2-α-hydroxyethylbenzimidazole;

[0008] S2, adding 2-α-hydroxyethylbenzimidazole to an aqueous solution, using micron-sized magnetic iron powder as a catalyst and hydrogen peroxide as an oxidant to carry out a catalytic oxidation reaction to oxidize 2-α-hydroxyethylbenzimidazole to 2-acetylbenzimidazole; after the reaction is completed, magnetic separation is performed to recover the magnetic iron powder;

[0009] S3, placing 2-acetylbenzimidazole in glacial acetic acid solvent, adding bromine, adding MOF powder with trivalent Fe as the central metal as a catalyst, heating to carry out bromination reaction, recovering the MOF powder after the reaction, and cooling the reaction solution to ≤40°C, filtering, and drying the filter cake to obtain 2-dibromoacetylbenzimidazole hydrobromide;

[0010] S4. Add formamide and phosphorus pentasulfide to ethyl acetate solvent, react at 30-45°C for 1-2h, add 2-dibromoacetylbenzimidazole hydrobromide, stir at 35-45°C and introduce ammonia gas as a catalyst to carry out cyclization reaction, filter after completion, cool the filtrate to precipitate solid, separate the solid, wash, and obtain thiabendazole without adjusting the pH.

[0011] According to a preferred embodiment of the present invention, in S1, the solid acid is a sulfonic acid solid acid supported by mesoporous carbon, and the mesoporous carbon is activated carbon or biochar.

[0012] According to a preferred embodiment of the present invention, in S1, the reaction temperature is 90-110°C, the reaction time is 1-3 hours, and after the reaction is completed, the solid acid catalyst is recovered by hot filtration. The filtrate is cooled to 10-15°C to precipitate crystals. After solid-liquid separation, the resulting solid is 2-α-hydroxyethylbenzimidazole. The mother liquor after solid-liquid separation is reused in step S1 of the next batch of synthesis, so that the 2-α-hydroxyethylbenzimidazole that has not crystallized in the mother liquor is accumulated and recovered.

[0013] According to a preferred embodiment of the present invention, in step S2, the pH is adjusted to 4.5-6.5 with a small amount of hydrochloric acid or dilute sulfuric acid, and the reaction is carried out at 30-50°C for 1.5-2.5 hours. After the reaction, the magnetic iron powder is first magnetically separated, then cooled to below 20°C (preferably below 15°C or below 10°C), filtered to obtain yellow crystals, and dried to obtain 2-acetylbenzimidazole. The filtrate is reused in step S2 of the next batch of synthesis, so that the unprecipitated 2-acetylbenzimidazole is accumulated and recovered in the circulating liquid. The recovered magnetic iron powder is further used in the next batch of preparation process.

[0014] According to a preferred embodiment of the present invention, in step S3, the bromination reaction temperature is 45-75°C, the reaction time is 1-2 hours, and after completion of the reaction, the MOF powder is recovered by hot filtration. The filtrate is cooled to below 40°C (preferably below 35°C), filtered, and the filter cake is dried to obtain 2-dibromoacetylbenzimidazole hydrobromide. The filtrate can be directly reused in step S3 of the next batch of synthesis without further treatment. The MOF powder recovered by hot filtration is directly fed into the next batch of reaction.

[0015] According to a preferred embodiment of the present invention, in S4, 2-dibromoacetylbenzimidazole hydrobromide is added, ammonia is introduced as a catalyst, and the reaction is continued at 35-45°C with stirring for 0.5-1.5h. After the reaction is completed, hot filtration is performed, the filter cake is stirred and dissolved with water, and activated carbon is used for decolorization. The filtrate is cooled to ≤15°C and filtered to obtain a white solid, which is then dried to obtain a white powder of thiabendazole with a purity of ≥99%.

[0016] Ammonia reacts with hydrogen bromide but not with thioformamide. Ammonia acts as an acid binder, catalyzing the reaction and increasing conversion. The reaction between ammonia and hydrogen bromide produces ammonium bromide, which is insoluble in ethyl acetate and can be separated by filtration. After purification, the ammonium bromide can be exported as a byproduct. Using ammonia as a catalyst, the product can be converted to a neutral salt without further pH adjustment.

[0017] Add formamide and phosphorus pentasulfide to ethyl acetate solvent and react at 30-45°C for 1-2 hours to generate thioformamide and phosphorus pentoxide. Thioformamide is unstable with water, while phosphorus pentoxide remains in the solution as a water absorbent to stabilize thioformamide, improve conversion rate, and reduce side reactions.

[0018] Preferably, the amount of solvent used in each reaction step is 1.5-4 times the volume that can completely immerse / dissolve the reaction raw materials and catalyst. Too much solvent is not conducive to crystallization of solids.

[0019] Preferably, in S1, lactic acid and o-phenylenediamine can be added in a molar ratio of 1.1-1.4:1, and the amount of the solid acid catalyst is 30-50% of the total volume of the solvent; during the reaction, stirring and disturbance can be performed to keep the solid acid catalyst in a suspended fluidized state during the reaction.

[0020] Preferably, in S2, the particle size of the micron-sized magnetic iron powder is 50-500 μm; stirring and disturbance can be used during the reaction process to keep the micron-sized magnetic iron powder in a suspended and fluidized state during the reaction. Compared with nano-sized magnetic iron powder, micron-sized magnetic iron powder is less prone to agglomeration and recovery loss, and its catalytic performance is less likely to be poisoned, which is conducive to efficient recovery and the stability and durability of the catalytic performance. The amount of micron-sized magnetic iron powder used can be 15-25% of the total volume of the solvent. After the reaction is completed, magnetic separation is performed and the powder is directly recycled. The filtrate is reused in step S2 of the next batch of synthesis to recover and accumulate 2-acetylbenzimidazole, and the unreacted hydrogen peroxide can also be further utilized.

[0021] Preferably, in S3, the MOF powder is used in an amount of 8-15% of the total solvent volume. The catalytic efficiency of a MOF with trivalent Fe as the central metal (Fe-MOF) is higher than that of a MOF with Co as the central metal (Co-MOF). When using the former, the MOF dosage can be appropriately reduced. The molar dosage of bromine is slightly in excess of 2-acetylbenzimidazole, preferably controlled at 120-140% of the theoretical requirement. This conserves bromine, prevents large amounts of bromine from entering the wastewater, and reduces the difficulty of bromine recovery and wastewater treatment. The tail gas generated in S3 is absorbed with water to extract bromine, and the filtrate (primarily glacial acetic acid) is directly reused.

[0022] Fe-MOF has good chemical stability and can maintain its structural integrity after multiple uses. Many MOFs catalysts can be regenerated by simple treatment (such as heat treatment, solvent washing or reactivation) and are easy to reuse. MOF with Fe as the central metal has good magnetic properties and catalytic activity: Due to the magnetism of iron ions themselves, Fe-MOF can exhibit interesting magnetic properties such as paramagnetism and ferromagnetism. Catalytic activity: Fe-MOF (with Fe as the central metal) has good magnetic properties and catalytic activity. 3 +, it can exhibit Lewis acidity) is a Lewis acid, which can achieve CH activation and halogen substitution when used as a catalyst. The high specific surface area of ​​Fe-MOF is conducive to improving the catalytic efficiency.

[0023] In S4, formamide and 2-dibromoacetylbenzimidazole hydrobromide undergo cyclization to produce thiabendazole. The molar amount of formamide can be 1.05-1.25 times that of 2-dibromoacetylbenzimidazole hydrobromide. Preferably, the ammonia gas is introduced at a rate of 200-400 mL / L·min based on the volume of the reaction solution.

[0024] (3) Beneficial effects

[0025] The technical effects of the present invention include:

[0026] (1) In step S1, the present invention uses a solid acid that is easy to separate to replace hydrochloric acid or other solutions. The solid acid catalyst is easy to separate and recycle, avoiding the generation of a large amount of waste acid and eliminating the need for alkali solution for neutralization. This reduces the salt impurities contained in 2-α-hydroxyethylbenzimidazole, and reduces acid waste and the cost of treating acidic wastewater. (2) In step S2, the present invention uses micron-sized magnetic iron powder that is easy to separate and hydrogen peroxide to form a high-efficiency catalytic oxidation system, which can quickly oxidize 2-α-hydroxyethylbenzimidazole to 2-acetylbenzimidazole at a low reaction temperature, thereby improving the conversion rate. After the reaction is completed, the micron-sized magnetic iron powder can be recovered by magnetic separation, and the product can be obtained by cold filtration. The filtrate (mainly glacial acetic acid) can be directly reused. This can avoid the problem of heavy metal ions, sodium chloride, and potassium sulfate remaining in the filtrate and accumulating, and the glacial acetic acid needing to be recovered, distilled, or treated for impurities before it can be recycled. (3) Introducing Fe-MOF powder as a catalyst in the bromination reaction has Lewis acid catalysis. At the same time, the ultra-large specific surface area of ​​Fe-MOF ensures efficient catalytic activity, which is used to activate alkyl hydrogen to improve the conversion rate, accelerate the bromination reaction, reduce the amount of bromine added, and lower the reaction temperature requirement. Fe-MOF is easy to recycle, and the filtrate can be directly reused without treatment. (4) In step S4, ammonia is introduced to catalyze and exert an acid binding effect to catalyze the cyclization of thioformamide and 2-dibromoacetylbenzimidazole hydrobromide to generate 2-(thiazol-4-yl)benzimidazole, thereby improving the conversion rate and reaction speed, reducing the reaction temperature, avoiding the decomposition of ethyl acetate and the generation of by-products, and improving the reuse rate of ethyl acetate. Ammonia reacts with hydrogen bromide to generate ammonium bromide that is insoluble in ethyl acetate and can be separated by filtration. After purification, the ammonium bromide can be output as a by-product. DETAILED DESCRIPTION

[0027] In order to better explain the present invention and facilitate understanding, the present invention is described in detail below in conjunction with specific embodiments.

[0028] The synthesis process of thiabendazole provided by the present invention comprises the following steps:

[0029] (1) Lactic acid and o-phenylenediamine are added to water, solid acid is used as a catalyst, and the temperature is raised to carry out a condensation reaction to generate 2-α-hydroxyethylbenzimidazole. After the reaction is completed, the solid acid is recovered, and the reaction solution is cooled to 4-25° C. to precipitate, filtered, and washed with water until neutral (no drying is required) to obtain 2-α-hydroxyethylbenzimidazole.

[0030] Among them, the solid acid is preferably a sulfonic acid solid acid supported by mesoporous carbon, the reaction temperature is 90-110°C, the reaction time is 1-3h, and after the reaction is completed, the solid acid catalyst is recovered by hot filtration, the filtrate is cooled to 10-15°C to precipitate crystals, and after solid-liquid separation, the obtained solid is 2-α-hydroxyethylbenzimidazole.

[0031] The mother liquor after solid-liquid separation is recycled for the next batch of synthesis, so that the 2-α-hydroxyethylbenzimidazole that has not been crystallized in the mother liquor can be accumulated and recovered.

[0032] The molar ratio of lactic acid to o-phenylenediamine is 1.1-1.4:1, and the solid acid catalyst is used in an amount of 30-50% of the total solvent volume. The volume of water used as the solution is 1.5-4 times the volume required to completely immerse / dissolve the reaction raw materials and catalyst. Stirring is performed during the reaction to maintain the solid acid catalyst in a suspended and fluidized state.

[0033] (2) 2-α-hydroxyethylbenzimidazole is put into an aqueous solution, and a catalytic oxidation reaction is carried out using micron-sized magnetic iron powder (preferably with a particle size of 50-500 μm) as a catalyst and hydrogen peroxide as an oxidant to oxidize 2-α-hydroxyethylbenzimidazole into 2-acetylbenzimidazole; after the reaction, the magnetic iron powder is magnetically separated and recovered. Specifically, the method includes: first adjusting the pH to 4.5-6.5 with a small amount of hydrochloric acid or dilute sulfuric acid, and reacting at 30-50°C for 1.5-2.5 hours; after the reaction, the magnetic iron powder is first magnetically separated, and then cooled to below 20°C (preferably below 15°C or below 10°C) and filtered to obtain yellow crystals, which are then dried to obtain 2-acetylbenzimidazole. The filtrate is reused in step S2 of the next batch of synthesis, so that the unprecipitated 2-acetylbenzimidazole is accumulated and recovered in the circulating liquid. The recovered magnetic iron powder is continued to be used in the next batch of preparation process.

[0034] The water as the solution is 1.5-4 times of the volume in which the reaction raw materials and the catalyst are completely immersed / dissolved. The addition amount of the micron-sized magnetic iron powder is relevant to the total volume of the solvent, and is preferably 15-25% of the total volume of the solvent. Stirring is carried out during the reaction process so that the micron-sized magnetic iron powder is in a suspended fluidized state during the reaction process. The specific surface area of ​​the magnetic iron powder with an excessively large particle size is large, and the catalytic activity is low, so it is difficult to suspend. The magnetic iron powder with an excessively small particle size (such as nanometer-sized) is easy to agglomerate between the iron powders when constituting the Fenton reagent with hydrogen peroxide, and the catalytic stability and durability are insufficient.

[0035] This step uses magnetic iron powder and hydrogen peroxide to achieve a synergistic catalytic process. Compared to the prior art catalytic system of acetone, concentrated sulfuric acid, and potassium permanganate, the present invention only needs to be carried out in an aqueous solution, reducing pollution from highly volatile organic compounds such as acetone and significantly reducing the formation of manganese-containing solid waste. It also improves the conversion rate and product yield (reaching over 97%). The product separation process is also very simple, omitting operations such as extraction and desolventizing.

[0036] (3) Put 2-acetylbenzimidazole into glacial acetic acid solvent, add bromine, add Fe 3+The MOF powder containing the central metal is used as a catalyst, the temperature is raised to carry out the bromination reaction, and the MOF powder is recovered after the reaction is completed. At the same time, the reaction solution is cooled to ≤40°C, filtered, and the filter cake is dried to obtain 2-dibromoacetylbenzimidazole hydrobromide.

[0037] Preferably, Fe 3+ The MOF powder with trivalent iron as the central metal has a stronger activity in catalyzing halogenation reactions. This is because the MOF with trivalent iron ion as the central metal is a Lewis acid, and the iron center can participate in the electron transfer process and promote the transfer of halogen atoms.

[0038] Preferably, Fe 3+ When a MOF containing a central metal is used as the catalyst, the bromination reaction temperature is 45-75°C, and the reaction time is 1-2 hours. After the reaction, the MOF powder is recovered by hot filtration. The filtrate is cooled to below 40°C (preferably below 35°C or 30°C), filtered, and the filter cake is dried to obtain 2-dibromoacetylbenzimidazole hydrobromide. The filtrate can be directly reused in step S3 of the next batch of synthesis without treatment. The MOF powder is recovered by hot filtration and directly used in the next batch of reactions. The MOF powder is also easily recovered and regenerated by heat treatment or washing.

[0039] The Fe-MOF powder is used in an amount of 8-15% of the total volume of the solvent. Using the Fe-MOF powder as a catalyst can increase the reaction rate and conversion rate and reduce the reaction temperature. Due to the high catalytic activity of Fe-MOF, the amount of bromine added can be reduced. At the same time, the product of step (2) does not contain impurities such as sodium chloride, potassium sulfate, and excess potassium permanganate, so there is little waste of bromine. Typically, the molar amount of bromine added is slightly excessive relative to 2-acetylbenzimidazole and can be controlled at 120-140% of the theoretical demand. This can save bromine on the one hand and prevent a large amount of bromine from entering wastewater on the other hand, reducing the difficulty of bromine recovery and wastewater treatment.

[0040] The Fe-MOF powder used as the catalyst in this application was prepared as follows:

[0041] Fe 3+ A soluble salt (ferric nitrate or its hydrate, ferric chloride or its hydrate), pyrene-1,3,6,8-tetracarboxylic acid, and 1,3,5-tris(4-pyridyl)benzene are mixed in a molar ratio of 1:1.6-2:0.8-1.2, and added together to a mixed solvent of water and DMF in a volume ratio of 1:2-3, wherein the amount of the mixed solvent is 20-30 times the mass of pyrene-1,3,6,8-tetracarboxylic acid, and ultrasonically dispersed at a frequency of 30-50 kHz for 5-10 minutes; then a 0.5-1 mol / L NaOH solution is added, and the pH of the reaction system is adjusted to 5-6.5 (to prevent Fe 3+Hydrolysis to ensure coordination reaction), react at a constant temperature of 60-80°C for 2-3h. After the reaction is completed, cool to room temperature, filter, rinse the filtrate with deionized water and anhydrous ethanol for more than 2 times, and dry to obtain.

[0042] Each nitrogen atom on the pyridine ring of 1,3,5-Tris(4-pyridyl)benzene (TPB) can serve as a coordination site, forming stable coordination bonds with metal ions. Due to its rigid planar structure, TPB facilitates the construction of highly ordered and stable MOF structures and can introduce aromatic π-π stacking interactions. TPB can provide stronger metal-ligand bonding, thereby improving the overall stability and durability of the MOF and facilitating the construction of more complex MOF structures, such as hierarchical topologies.

[0043] In the prior art, the bromination reaction temperature of this step is at least 85° C., while in the present invention, the bromination reaction temperature can be smoothly carried out below 50° C., and the yield reaches 96-100% in the same reaction time.

[0044] (4) Phosphorus pentasulfide and formamide are added to ethyl acetate solvent, and the mixture is reacted at 35-45° C. for 1-2 hours to generate thioformamide and phosphorus pentoxide. The phosphorus pentoxide is not filtered out, and 2-dibromoacetylbenzimidazole hydrobromide is directly added. The mixture is stirred at 35-45° C. and ammonia gas is introduced as a catalyst to carry out a cyclization reaction for 0.5-1.5 hours. After the reaction is completed, the mixture is hot filtered (to remove ammonium bromide insoluble in ethyl acetate), and the filtrate is retained. The filtrate is cooled to ≤20° C. to precipitate a solid, which is filtered. The filter cake is stirred and dissolved in water, and decolorized with activated carbon. The activated carbon is filtered out, and the filtrate is cooled to ≤15° C. and filtered to obtain a white solid. The solid is dried to obtain a white powder of thiabendazole with a purity of ≥99%.

[0045] Preferably, phosphorus pentasulfide and formamide are added in a molar ratio of approximately 1:2, with the molar amount of formamide being 1.05-1.25 times that of 2-dibromoacetylbenzimidazole hydrobromide. Ammonia is introduced at a rate of 200-400 mL / L·min based on the volume of the reaction solution. Ethyl acetate is used in an amount sufficient to completely submerge or dissolve the starting materials.

[0046] In this step, the ammonia does not react with the thioformamide. Instead, it acts as an acid binder, reacting with the HBr produced, catalyzing the reaction to rapidly increase conversion and yields of 95-97%. After the reaction, ammonium bromide is filtered and purified for output as a byproduct.

[0047] The following describes the present invention in conjunction with specific embodiments.

[0048] Example 1

[0049] This embodiment is a synthesis process of thiabendazole, comprising the following steps:

[0050] (1) 108 g of lactic acid and 152.15 g of o-phenylenediamine were added to a four-necked glass flask containing 400 mL of water, and 40% of the total volume of the solvent was added with mesoporous carbon-supported sulfonic acid solid acid particles (particle size 60-80 mesh). The temperature was raised to 96° C. and refluxed for condensation reaction for 3 h. After the reaction was completed, the reaction solution was cooled to 60° C. and filtered to recover the solid acid particles. The filtrate was further cooled to 10° C. and allowed to stand to precipitate, and filtered to obtain a filter cake. The filter cake was 2-α-hydroxyethylbenzimidazole (mass after dryness was 154 g), and the product yield was 79.2% based on lactic acid.

[0051] (2) 154 g of 2-α-hydroxyethylbenzimidazole was added to 250 mL of aqueous solution, and the pH was adjusted to 5 with a small amount of hydrochloric acid. 20% of the solvent volume of micron magnetic iron powder (Fe3O4 with a particle size of 50-500 μm) was added as a catalyst, and 45 g of hydrogen peroxide was added as an oxidant. The temperature was raised to 45° C. and the reaction was stirred gently for 1.5 hours. After the reaction was completed, the magnetic iron powder was first magnetically separated, then cooled to below 15° C. and filtered to obtain yellow crystals, which were dried to obtain 148.3 g of 2-acetylbenzimidazole. The filtrate was reused in the next batch of synthesis process, and the recovered magnetic iron powder was continued to be used in the next batch of preparation process. The recovery rate was 97.5% based on 2-α-hydroxyethylbenzimidazole.

[0052] (3) 148.3 g of 2-acetylbenzimidazole was placed in 400 mL of anhydrous glacial acetic acid, 10% of the solvent volume of Fe-MOFs powder (average particle size 1-10 μm) was added, 200 g of bromine was added, the temperature was raised to 58 ° C and stirred for reaction for 1 h. After the reaction was completed, the MOFs powder was recovered by hot filtration (washed with hot water and reused), the filtrate was cooled to 30 ° C, filtered, and the filter cake was dried to obtain 358.7 g of 2-dibromoacetylbenzimidazole hydrobromide (recovery rate 97%). The filtrate can be directly reused in the next batch of synthesis without treatment. The MOFs powder recovered by hot filtration was directly put into the next batch of reaction process.

[0053] The preparation method of Fe-MOF powder is as follows:

[0054] FeCl3·6H2O, pyrene-1,3,6,8-tetracarboxylic acid, and 1,3,5-tris(4-pyridyl)benzene were mixed in a molar ratio of 1:2:1.2, and added together to a mixed solvent of water and DMF in a volume ratio of 1:2, where the amount of the mixed solvent was 25 times the mass of pyrene-1,3,6,8-tetracarboxylic acid. The mixture was ultrasonically dispersed at a frequency of 40 kHz for 10 minutes. A 1 mol / L NaOH solution was then added, and the pH of the reaction system was adjusted to 6.0. The mixture was reacted at a constant temperature of 65°C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was rinsed twice with deionized water and anhydrous ethanol, respectively, and dried at 60°C for 12 hours to obtain the catalyst.

[0055] (4) 226 g of phosphorus pentasulfide and 700 mL of ethyl acetate were mixed, 50 g of formamide was added, and the mixture was stirred at 35° C. for 1 h. Then, 358.7 g of 2-dibromoacetylbenzimidazole hydrobromide was added, and ammonia gas (300 mL / L·min) was introduced at 42° C. for catalysis. The cyclization reaction was carried out for 1 h. After the reaction was completed, hot filtration was performed (to remove ammonium bromide insoluble in ethyl acetate). The filtrate was retained and cooled to 18° C. to precipitate a solid. The solid was filtered, and the filter cake was added with water and stirred to dissolve. The solid was decolorized with activated carbon, and the activated carbon was coarsely filtered. The filtrate was further cooled to 12° C. and filtered to obtain a white solid. The solid was dried to obtain 174.8 g of thiabendazole white powder with a purity of ≥99%. The product yield was 96.3% based on 2-dibromoacetylbenzimidazole hydrobromide.

[0056] The total yield of the four-step reaction in this embodiment is 72.13%. In addition, the reaction conditions in each step of the present invention are milder, the reaction temperature is lower, side reactions and raw material consumption are reduced, the catalyst can be recycled, the reaction raw materials are less wasted, and the reaction solvent can be recycled, eliminating the difficulty of impurity removal and other processing, and reducing the difficulty of resource recovery.

[0057] Example 2

[0058] This embodiment is a synthesis process of thiabendazole, comprising the following steps:

[0059] (1) 112.5 g of lactic acid and 152.11 g of o-phenylenediamine were added to a glass four-necked flask containing 400 mL of water, and 40% of the total volume of the solvent was added with mesoporous carbon-supported sulfonic acid solid acid particles (particle size 60-80 mesh). The temperature was raised to 100° C. and refluxed for condensation reaction for 3 h. After the reaction was completed, the reaction solution was cooled to 60° C. and filtered to recover the solid acid particles. The filtrate was further cooled to 10° C. and allowed to stand to precipitate, and filtered to obtain a filter cake. The filter cake was 2-α-hydroxyethylbenzimidazole (mass after dryness was 157 g), and the product yield was 77.5% based on lactic acid.

[0060] (2) 157 g of 2-α-hydroxyethylbenzimidazole was added to 250 mL of aqueous solution, and the pH was adjusted to 4.5 with a small amount of hydrochloric acid. 20% of the solvent volume of micron magnetic iron powder (Fe3O4 with a particle size of 50-500 μm) was added as a catalyst, and 54 g of hydrogen peroxide was added as an oxidant. The temperature was raised to 45°C and the reaction was stirred gently for 1.5 hours. After the reaction was completed, the magnetic iron powder was first magnetically separated, then cooled to below 15°C and filtered to obtain yellow crystals, which were dried to obtain 151.9 g of 2-acetylbenzimidazole. The filtrate was reused in the next batch of synthesis process, and the recovered magnetic iron powder was continued to be used in the next batch of preparation process. The recovery rate was 97.96% based on 2-α-hydroxyethylbenzimidazole.

[0061] (3) 151.9 g of 2-acetylbenzimidazole was placed in 400 mL of anhydrous glacial acetic acid, and 12% of the solvent volume of Fe-MOFs powder (average particle size 1-10 μm) was added. 190 g of bromine was added, and the temperature was raised to 60°C and stirred for reaction for 1 h. After the reaction, the MOFs powder was recovered by hot filtration (washed with hot water and reused). The filtrate was cooled to 30°C, filtered, and the filter cake was dried to obtain 370.5 g of 2-dibromoacetylbenzimidazole hydrobromide (recovery rate 97.8%). The filtrate was directly reused in the next batch of synthesis without treatment. The MOFs powder recovered by hot filtration was directly put into the next batch of reaction process.

[0062] The preparation method of Fe-MOF powder is as follows:

[0063] Fe(NO3)3·9H2O, pyrene-1,3,6,8-tetracarboxylic acid, and 1,3,5-tri(4-pyridyl)benzene are mixed in a molar ratio of 1:2:1.0, and added together to a mixed solvent of water and DMF in a volume ratio of 1:2, where the amount of the mixed solvent is 30 times the mass of pyrene-1,3,6,8-tetracarboxylic acid. The mixture is ultrasonically dispersed at a frequency of 40 kHz for 10 minutes. A 1 mol / L NaOH solution is then added to adjust the pH of the reaction system to 6.0. The mixture is reacted at a constant temperature of 60°C for 3 hours. After the reaction is completed, the mixture is cooled to room temperature and filtered. The filtrate is rinsed twice with deionized water and anhydrous ethanol respectively, and dried at 60°C for 12 hours to obtain the catalyst.

[0064] (4) 226 g of phosphorus pentasulfide and 750 mL of ethyl acetate were mixed, 50 g of formamide was added, and the mixture was stirred at 35° C. for 1 h. 370.5 g of 2-dibromoacetylbenzimidazole hydrobromide was then added. The mixture was stirred at 45° C. and ammonia gas (350 mL / L·min) was introduced to catalyze the reaction. The cyclization reaction was carried out for 1 h. After the reaction was completed, the mixture was hot filtered (to remove ammonium bromide insoluble in ethyl acetate). The filtrate was retained and cooled to 18° C. to precipitate a solid. The solid was filtered. The filter cake was stirred and dissolved in water. The solid was decolorized with activated carbon and the activated carbon was coarsely filtered. The filtrate was further cooled to 12° C. and filtered to obtain a white solid. The solid was dried to obtain 180.65 g of thiabendazole white powder with a purity of ≥99%. The product yield was 96.8% based on 2-dibromoacetylbenzimidazole hydrobromide. The total yield of the above four steps was calculated to be 71.88%.

[0065] In the above embodiment, o-phenylenediamine is in excess relative to lactic acid; in the following embodiment, lactic acid and o-phenylenediamine are added at a molar ratio of 1.1-1.4:1, which is beneficial to improving the yield of step S1.

[0066] Example 3

[0067] This embodiment is a synthesis process of thiabendazole, comprising the following steps:

[0068] (1) 108.1 g of lactic acid and 108.14 g of o-phenylenediamine were added to a glass four-necked flask containing 400 mL of water, and 40% of the total volume of the solvent was added with mesoporous carbon-supported sulfonic acid solid acid particles (particle size 60-80 mesh). The temperature was raised to 96° C. and refluxed for condensation reaction for 3 h. After the reaction was completed, the reaction solution was cooled to 60° C. and filtered to recover the solid acid particles. The filtrate was further cooled to 10° C. and allowed to stand to precipitate, and filtered to obtain a filter cake. The filter cake was 2-α-hydroxyethylbenzimidazole (mass after dryness was 144.9 g), and the product yield based on o-phenylenediamine was 89.34%.

[0069] (2) 144.9 g of 2-α-hydroxyethylbenzimidazole was added to 400 mL of aqueous solution, and the pH was adjusted to 5 with a small amount of hydrochloric acid. 20% of the solvent volume of micron magnetic iron powder (Fe3O4 with a particle size of 50-500 μm) was added as a catalyst, and 45 g of hydrogen peroxide was added as an oxidant. The temperature was raised to 45° C. and the reaction was stirred gently for 1.5 hours. After the reaction was completed, the magnetic iron powder was first magnetically separated, then cooled to below 15° C. and filtered to obtain yellow crystals, which were dried to obtain 139.1 g of 2-acetylbenzimidazole. The filtrate was reused in the next batch of synthesis process, and the recovered magnetic iron powder was continued to be used in the next batch of preparation process. The recovery rate was 97.21% based on 2-α-hydroxyethylbenzimidazole.

[0070] (3) 139.1 g of 2-acetylbenzimidazole was placed in 500 mL of anhydrous glacial acetic acid, and 15% of the solvent volume of Fe-MOF powder with trivalent iron as the central metal (average particle size 1-10 μm) was added. 186 g of bromine was added, and the temperature was raised to 59°C and stirred for reaction for 1.5 h. After the reaction, the MOF powder was recovered by hot filtration (washed with hot water and reused), the filtrate was cooled to 30°C, filtered, and the filter cake was dried to obtain 338.5 g of 2-dibromoacetylbenzimidazole hydrobromide (recovery rate 97.7%). The filtrate was directly reused in the next batch of synthesis without treatment. The MOF powder recovered by hot filtration was directly put into the next batch of reaction process.

[0071] The preparation method of Fe-MOF powder is as follows:

[0072] Fe(NO3)3·9H2O, pyrene-1,3,6,8-tetracarboxylic acid, and 1,3,5-tri(4-pyridyl)benzene are mixed in a molar ratio of 1:2:0.8, and added together to a mixed solvent of water and DMF in a volume ratio of 1:2.5, where the amount of the mixed solvent is 20 times the mass of pyrene-1,3,6,8-tetracarboxylic acid, and ultrasonic dispersion is carried out at a frequency of 40 kHz for 10 minutes; then 1 mol / L NaOH solution is added, the pH of the reaction system is adjusted to 6.5, and the reaction is carried out at a constant temperature of 75°C for 3 hours. After the reaction is completed, the mixture is cooled to room temperature and filtered. The filtrate is rinsed twice with deionized water and anhydrous ethanol respectively, and dried at 60°C for 12 hours to obtain the catalyst.

[0073] (4) 226 g of phosphorus pentasulfide and 800 mL of ethyl acetate were mixed, 47 g of formamide was added, and the mixture was stirred at 40° C. for 1 h. Then, 338.5 g of 2-dibromoacetylbenzimidazole hydrobromide was added, and ammonia gas (300 mL / L·min) was introduced at 42° C. for catalysis. The cyclization reaction was carried out for 1 h. After the reaction was completed, hot filtration was performed (to remove ammonium bromide insoluble in ethyl acetate). The filtrate was retained and cooled to 18° C. to precipitate a solid. The solid was filtered, and the filter cake was stirred and dissolved in water. The solid was decolorized with activated carbon, and the activated carbon was coarsely filtered. The filtrate was further cooled to 12° C. and filtered to obtain a white solid. The solid was dried to obtain 164.4 g of thiabendazole white powder with a purity of ≥99%. The product yield was 96.3% based on 2-dibromoacetylbenzimidazole hydrobromide.

[0074] The total yield of the four-step reaction in this example is 81.71%.

[0075] Example 4

[0076] This embodiment is a synthesis process of thiabendazole, comprising the following steps:

[0077] (1) 126.1 g of lactic acid and 108.14 g of o-phenylenediamine were added to a glass four-necked flask containing 500 mL of water, and 35% of the total volume of the solvent was added with mesoporous carbon-supported sulfonic acid solid acid particles (particle size 60-80 mesh). The temperature was raised to 95° C. and refluxed for condensation reaction for 2.5 h. After the reaction was completed, the reaction solution was cooled to 50° C. and filtered to recover the solid acid particles. The filtrate was further cooled to 4° C. and allowed to stand to precipitate, and filtered to obtain a filter cake. The filter cake was 2-α-hydroxyethylbenzimidazole (mass after dryness was 148.60 g), and the product yield based on o-phenylenediamine was 91.62%.

[0078] (2) 148.60 g of 2-α-hydroxyethylbenzimidazole was added to 400 mL of aqueous solution, and the pH was adjusted to 5.5 with a small amount of hydrochloric acid. 20% of the solvent volume of micron magnetic iron powder (Fe3O4 with a particle size of 50-500 μm) was added as a catalyst, and 50 g of hydrogen peroxide was added as an oxidant. The temperature was raised to 48°C and the reaction was stirred gently for 2.0 h. After the reaction was completed, the magnetic iron powder was first magnetically separated, then cooled to below 10°C and filtered to obtain yellow crystals, which were dried to obtain 142.9 g of 2-acetylbenzimidazole. The filtrate was reused in the next batch of synthesis process, and the recovered magnetic iron powder was continued to be used in the next batch of preparation process. The recovery rate was 97.38% based on 2-α-hydroxyethylbenzimidazole.

[0079] (3) 142.9 g of 2-acetylbenzimidazole was placed in 500 mL of anhydrous glacial acetic acid, and 15% of the solvent volume of Fe-MOF powder with trivalent iron as the central metal (average particle size 1-10 μm) was added. 188 g of bromine was added, and the temperature was raised to 65 ° C. and stirred for reaction for 2 h. After the reaction, the MOF powder was recovered by hot filtration (washed with hot water and reused). The filtrate was cooled to 35 ° C., filtered, and the filter cake was dried to obtain 349.2 g of 2-dibromoacetylbenzimidazole hydrobromide (recovery rate 98.1%). The filtrate can be directly reused in the next batch of synthesis without treatment. The MOF powder recovered by hot filtration was directly put into the next batch of reaction process.

[0080] The preparation method of Fe-MOF powder is as follows:

[0081] FeCl3·6H2O, pyrene-1,3,6,8-tetracarboxylic acid, and 1,3,5-tris(4-pyridyl)benzene were mixed in a molar ratio of 1:1.8:1, and added together to a mixed solvent of water and DMF in a volume ratio of 1:3, where the amount of the mixed solvent was 30 times the mass of pyrene-1,3,6,8-tetracarboxylic acid. The mixture was ultrasonically dispersed at a frequency of 40 kHz for 10 minutes. A 1 mol / L NaOH solution was then added, and the pH of the reaction system was adjusted to 6.0. The mixture was reacted at a constant temperature of 70°C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was rinsed twice with deionized water and anhydrous ethanol, respectively, and dried at 60°C for 12 hours to obtain the catalyst.

[0082] (4) 226 g of phosphorus pentasulfide and 800 mL of ethyl acetate were mixed, 49 g of formamide was added, and the mixture was stirred at 40° C. for 1 h. 349.2 g of 2-dibromoacetylbenzimidazole hydrobromide was then added, and ammonia gas (300 mL / L·min) was introduced at 40° C. to catalyze the reaction. A cyclization reaction was carried out for 1 h. After the reaction was completed, the mixture was hot filtered (to remove ammonium bromide insoluble in ethyl acetate). The filtrate was retained and cooled to 18° C. to precipitate a solid. The solid was filtered, and the filter cake was stirred and dissolved in water. The solid was decolorized with activated carbon, and the activated carbon was coarsely filtered. The filtrate was further cooled to 12° C. and filtered to obtain a white solid. The solid was dried to obtain 169.10 g of thiabendazole white powder with a purity of ≥99%. The product yield was 96.0% based on 2-dibromoacetylbenzimidazole hydrobromide. The total yield of the four-step reaction in this example was 84.02%.

[0083] Comparative Example 1

[0084] This comparative example is based on Example 1, except that the micron magnetic iron powder in step (2) was removed. 154 g of 2-α-hydroxyethylbenzimidazole was added to 250 mL of aqueous solution, the pH was adjusted to 5 with dilute hydrochloric acid, 60 g of hydrogen peroxide was added as an oxidant, and the temperature was raised to 45°C with gentle stirring for 1.5 hours. The reaction yielded 136.9 g of 2-acetylbenzimidazole. The recovery rate, based on 2-α-hydroxyethylbenzimidazole, was 90%.

[0085] Comparative Example 2

[0086] This comparative example is based on Example 1, except that the preparation method of the Fe-MOF powder used in step (3) is modified, the primary ligand is changed to pyromellitic acid, and the auxiliary ligand is 1,10-phenanthroline. The preparation conditions are the same as those of Example 1. An equal amount of the prepared Fe-MOF powder is used to replace the Fe-MOF catalyst used in step (3) of Example 1 to obtain 344.7 g of 2-dibromoacetylbenzimidazole hydrobromide, with a product yield of 93.21%.

[0087] Comparative Example 3

[0088] This comparative example is based on Example 1, but the preparation method of the Fe-MOF powder used in step (3) is changed, and the mixed solvent is replaced with an equal amount of deionized water. The preparation conditions are the same as those of Example 1. The prepared Fe-MOF powder is replaced with an equal amount of the Fe-MOF catalyst used in step (3) of Example 1 to obtain 345.4 g of 2-dibromoacetylbenzimidazole hydrobromide, and the product yield is 93.40%. As can be seen from Comparative Examples 2-3, when the preparation method of Fe-MOF is changed, although the prepared Fe-MOF powder can also catalyze the acetyl α-position bromination reaction of 2-acetylbenzimidazole at a lower reaction temperature, the product yield is significantly reduced compared to Example 1.

[0089] Comparative Example 4

[0090] This comparative example is based on Example 1, except that the ammonia in step (4) is removed. The specific steps are as follows: 358.7 g of 2-dibromoacetylbenzimidazole hydrobromide is added and the reaction is carried out at 45° C. for 1 h. After the reaction is completed, the reaction solution is cooled to 20° C. to precipitate a solid, which is filtered. The filter cake is stirred and dissolved in 500 ml of water, decolorized with activated carbon, filtered to remove the activated carbon, and the filtrate is cooled to 15° C. and then neutralized with 30% sodium hydroxide. The solid is filtered to obtain a white solid, which is dried to obtain 165.1 g of a white powder of thiabendazole with a purity of ≥99%. The product yield is 91.3% based on 2-dibromoacetylbenzimidazole hydrobromide.

[0091] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A synthesis process of thiabendazole, characterized in that: The steps include: S1, adding lactic acid and o-phenylenediamine to water, using a solid acid as a catalyst, heating to carry out a condensation reaction to generate 2-α-hydroxyethylbenzimidazole, after which the reaction is completed, recovering the solid acid, cooling the reaction solution to 4-25° C. to precipitate, filtering, and washing with water until neutral to obtain 2-α-hydroxyethylbenzimidazole; S2, adding 2-α-hydroxyethylbenzimidazole to an aqueous solution, using micron-sized magnetic iron powder as a catalyst and hydrogen peroxide as an oxidant to carry out a catalytic oxidation reaction to oxidize 2-α-hydroxyethylbenzimidazole to 2-acetylbenzimidazole; after the reaction is completed, magnetic separation is performed to recover the magnetic iron powder; S3. 2-acetylbenzimidazole is placed in a glacial acetic acid solvent, bromine is added, and MOF powder with trivalent Fe as the central metal is added as a catalyst. The temperature is raised to carry out a bromination reaction. After the reaction is completed, the MOF powder is recovered. At the same time, the reaction solution is cooled to ≤40° C., filtered, and the filter cake is dried to obtain 2-dibromoacetylbenzimidazole hydrobromide. The MOF powder is prepared according to the following method: Fe 3+ A soluble salt of pyrene-1,3,6,8-tetracarboxylic acid, and 1,3,5-tris(4-pyridyl)benzene are mixed in a molar ratio of 1:1.6-2:0.8-1.2, and added together to a mixed solvent of water and DMF in a volume ratio of 1:2-3, where the amount of the mixed solvent is 20-30 times the mass of pyrene-1,3,6,8-tetracarboxylic acid, and ultrasonically dispersed at a frequency of 30-50 kHz for 5-10 minutes; then a 0.5-1 mol / L NaOH solution is added, and the pH of the reaction system is adjusted to 5-6.

5. The reaction is carried out at a constant temperature of 60-80° C. for 2-3 hours. After the reaction is completed, the reaction is cooled to room temperature, filtered, and the filtrate is rinsed with deionized water and anhydrous ethanol for more than 2 times, and dried to obtain the product; S4. Add formamide and phosphorus pentasulfide to ethyl acetate solvent, react at 30-45°C for 1-2h, add 2-dibromoacetylbenzimidazole hydrobromide, stir at 35-45°C and introduce ammonia gas as a catalyst to carry out cyclization reaction, filter after completion, cool the filtrate to precipitate solid, separate the solid, wash to obtain thiabendazole.

2. The synthesis process according to claim 1, wherein In S1, the solid acid is a sulfonic acid solid acid supported by mesoporous carbon.

3. The synthesis process according to claim 1, wherein In S1, the reaction temperature is 90-110°C, the reaction time is 1-3 hours, and after the reaction is completed, the solid acid catalyst is recovered by hot filtration, and the filtrate is cooled to 10-15°C to precipitate crystals. After solid-liquid separation, the obtained solid is 2-α-hydroxyethylbenzimidazole.

4. The synthesis process according to claim 1, characterized in that In S2, the pH is adjusted to 4.5-6.5 with a small amount of hydrochloric acid or dilute sulfuric acid, and the reaction is carried out at 30-50°C for 1.5-2.5 hours. After the reaction, the magnetic iron powder is first magnetically separated, then cooled to below 20°C and filtered to obtain yellow crystals, which are then dried to obtain 2-acetylbenzimidazole. The filtrate is reused in step S2 of the next batch of synthesis.

5. The synthesis process according to claim 1, characterized in that In S3, the bromination reaction temperature is 45-75°C, the reaction time is 1-2 hours, and after the reaction is completed, the MOF powder is recovered by hot filtration. The filtrate is cooled to below 40°C, filtered, and the filter cake is dried to obtain 2-dibromoacetylbenzimidazole hydrobromide; the filtrate is directly reused in step S3 of the next batch of synthesis.

6. The synthesis process according to claim 1, characterized in that In S4, 2-dibromoacetylbenzimidazole hydrobromide is added, ammonia gas is introduced as a catalyst, and the reaction is continued to stir at 35-45°C for 0.5-1.5h, filtered, the filter cake is added with water and stirred to dissolve, and activated carbon is used for decolorization. The filtrate is cooled to ≤15°C and filtered to obtain a white solid, which is dried to obtain a white powder of thiabendazole with a purity of ≥99%.

7. The synthesis process according to claim 1, characterized in that In S1-S4, the amount of solvent used is 1.5-4 times the volume capable of completely immersing or dissolving the reaction raw materials and catalyst.

8. The synthesis process according to claim 1, characterized in that In S1, lactic acid and o-phenylenediamine are added in a molar ratio of 1.1-1.4:1, and the amount of the solid acid catalyst is 30-50% of the total volume of the solvent; during the reaction, the solid acid catalyst is kept in a suspended fluidized state by disturbance; In S2, the particle size of the micron-sized magnetic iron powder is 50-500 μm; stirring disturbance is used during the reaction process to keep the micron-sized magnetic iron powder in a suspended fluidized state; the amount of the micron-sized magnetic iron powder used can be 15-25% of the total volume of the solvent.

9. The synthesis process according to claim 1, characterized in that In S3, the amount of MOF powder used is 8-15% of the total volume of the solvent; the molar amount of bromine added is 120-140% of the theoretical demand.

10. The synthesis process according to claim 1, characterized in that In S4, the molar amount of formamide is 1.05-1.25 times that of 2-dibromoacetylbenzimidazole hydrobromide; the rate of introduction of ammonia gas is 200-400 mL / L·min based on the volume of the reaction solution.