Synthesis process of thiabendazole

Abstract

The synthesis process comprises the following steps: by taking lactic acid and o-phenylenediamine as raw materials, carrying out condensation reaction in water by taking solid acid as a catalyst to obtain 2-alpha-hydroxyethyl benzimidazole; the preparation method comprises the following steps: mixing 2-alpha-hydroxy ethyl benzimidazole and micron-sized magnetic iron powder, putting the mixture into water, and adding hydrogen peroxide for catalytic oxidation to obtain 2-acetyl benzimidazole; the preparation method comprises the following steps: putting 2-acetylbenzimidazole into glacial acetic acid, adding bromine, and carrying out bromine substitution reaction by taking MOF (Metal Organic Framework) powder taking trivalent Fe as a central metal as a catalyst to obtain 2-dibromoacetylbenzimidazole hydrobromide; the preparation method comprises the following steps: adding formamide and phosphorus pentasulfide into ethyl acetate, reacting at 30-45 DEG C for 1-2 hours, adding 2-dibromoacetyl benzimidazole hydrobromide, introducing ammonia gas to catalyze a cyclization reaction, filtering after the reaction is finished, cooling filtrate to separate out a solid, separating the solid, and washing to obtain the thiabendazole. Compared with the prior art, higher yield can be obtained, the reaction conditions are mild, the catalyst and the solvent are easy to separate for recycling, raw material waste is reduced, and the resource recovery difficulty is reduced.

Description

Technical Field

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

[0002] Thiabendazole belongs to the benzimidazole fungicide, and its chemical name is 2-(thiazol-4-yl)benzimidazole. The current mainstream synthesis method includes 4 steps: Step 1: Condensation reaction of lactic acid and o-phenylenediamine in an acidic (hydrochloric acid, but not limited to) aqueous solution, and pH value is adjusted to obtain 2-a-hydroxyethylbenzimidazole. Step 2: Filter and dry 2-a-hydroxyethylbenzimidazole, and then put it into a solvent environment of acetone and sulfuric acid (or other inorganic acids or strong acid and weak base salts), and then oxidize it with potassium permanganate, extract, evaporate and remove the solvent, and dry it to obtain 2-acetylbenzimidazole. Step 3: Put 2-acetylbenzimidazole into a solvent environment of glacial acetic acid, and carry out halogenation reaction with bromine (or other halogens). After filtering, dry the filter cake to obtain 2-dibromoacetylbenzimidazole hydrobromide. Step 4: reacting formamide and phosphorus pentasulfide in ethyl acetate solvent to obtain thioformamide; removing phosphorus pentoxide by nitrogen filtration to obtain thioformamide / ethyl acetate solution, and then performing cyclization reaction with 2-dibromoacetylbenzimidazole in step 3, purifying and adjusting the pH value to obtain thiabendazole with a content of ≥99%. This process has the following disadvantages: (1) a large amount of hydrochloric acid aqueous solution is used in the reaction of step 1, and a large amount of waste acid needs to be neutralized with sodium hydroxide, and the sodium chloride produced by the reaction enters the product and becomes an impurity of 2-α-hydroxyethylbenzimidazole, affecting the subsequent reaction. (2) Step 2 requires an oxidation reaction with potassium permanganate as an oxidant in the presence of acetone as a solvent (non-aqueous system). Although the 2-acetylbenzimidazole is subjected to extraction treatment and subsequent solvent removal and drying, it is still mixed with a certain amount of sodium chloride, potassium sulfate and excess potassium permanganate, which will react with the bromine in the next step, resulting in a large amount of bromine waste; the byproduct is dissolved in glacial acetic acid, which needs to be recycled and distilled to remove impurities 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 easy to 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 the difficulty of solvent recovery, avoids heavy metal pollution, and has important environmental significance.

[0005] (II) 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 solid acid as a catalyst, heating to carry out condensation reaction to generate 2-α-hydroxyethylbenzimidazole, after 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, putting 2-α-hydroxyethylbenzimidazole into an aqueous solution, using micron-sized magnetic iron powder as a catalyst and adding hydrogen peroxide as an oxidant to carry out a catalytic oxidation reaction, thereby oxidizing 2-α-hydroxyethylbenzimidazole into 2-acetylbenzimidazole; after the reaction is completed, magnetic separation is performed to recover the magnetic iron powder;

[0009] S3, putting 2-acetylbenzimidazole into 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 biomass carbon.

[0012] According to a preferred embodiment of the present invention, in S1, the reaction temperature is 90-110°C, the reaction time is 1-3h, 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. 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 been crystallized in the mother liquor is accumulated and recovered.

[0013] According to a preferred embodiment of the present invention, in S2, a small amount of hydrochloric acid or dilute sulfuric acid is used to adjust the pH to 4.5-6.5, and the reaction is carried out at 30-50°C for 1.5-2.5h; after the reaction is completed, 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 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 continuously used in the next batch of preparation process.

[0014] According to a preferred embodiment of the present invention, in S3, the bromination reaction temperature is 45-75°C, the reaction time is 1-2h, and after the reaction is completed, 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 the next batch of synthesis step S3 without treatment. The MOF powder recovered by hot filtration is directly put into the next batch of reaction process.

[0015] According to a preferred embodiment of the present invention, in S4, 2-dibromoacetylbenzimidazole hydrobromide is added, ammonia gas is introduced as a catalyst, and the reaction is continued to be stirred at 35-45°C 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 can react with hydrogen bromide but not with thioformamide. Ammonia can act as an acid binder to catalyze the reaction to proceed quickly and improve the conversion rate. 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. After the reaction is carried out using ammonia as a catalyst, the product does not need to be adjusted in pH to obtain a neutral salt.

[0017] Add formamide and phosphorus pentasulfide to ethyl acetate solvent, 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 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 disturbance can be used during the reaction process to keep the micron-sized magnetic iron powder in a suspended fluidized state during the reaction. Compared with nano-sized magnetic iron powder, micron-sized magnetic iron powder is not easy to agglomerate and lose in recovery, and the catalytic performance is not easy 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 can be 15-25% of the total volume of the solvent, and magnetic separation is performed after the reaction is completed and directly recycled. The filtrate is reused in step S2 of the next batch of synthesis, and 2-acetylbenzimidazole can be recovered and accumulated, and the unreacted hydrogen peroxide can also be further utilized.

[0021] Preferably, in S3, the amount of MOF powder is 8-15% of the total volume of the solvent; wherein, the catalytic efficiency of MOF with trivalent Fe as the central metal (Fe-MOF) is higher than that of MOF with Co as the central metal (Co-MOF), and when the former is used, the amount of MOF added can be appropriately reduced; wherein, the molar amount of bromine added is slightly excessive relative to 2-acetylbenzimidazole, and it is appropriate to control it at 120-140% of the theoretical demand; this can save bromine, avoid a large amount of bromine entering the wastewater, and reduce the difficulty of bromine recovery and wastewater treatment. The tail gas generated in S3 is absorbed by water and bromine is extracted, and the filtrate (mainly 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) for easy 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 show Lewis acidity) as 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 generate thiabendazole. The molar amount of formamide may be 1.05-1.25 times that of 2-dibromoacetylbenzimidazole hydrobromide. Preferably, the rate of introduction of ammonia is 200-400 mL / L·min based on the volume of the reaction solution.

[0024] (III) Beneficial effects

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

[0026] (1) In step S1, the present invention uses an easily separable solid acid to replace hydrochloric acid and 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 to use alkali solution for neutralization, reducing the salt impurities contained in 2-α-hydroxyethylbenzimidazole, reducing acid waste and the cost of treating acidic wastewater. (2) In step S2, the present invention uses easily separable micron-sized magnetic iron powder and hydrogen peroxide to form an efficient 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, the product can be obtained by cooling and filtering, and the filtrate (mainly glacial acetic acid) can be directly reused; thereby, the problem of heavy metal ions, sodium chloride, and potassium sulfate being left in the filtrate and accumulating can be avoided, and the glacial acetic acid needs to be recovered, distilled, and other impurity removal treatments before it can be recycled can be avoided. (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 reduce 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 play an acid binding role to catalyze the cyclization of thioformamide and 2-dibromoacetylbenzimidazole hydrobromide to generate 2-(thiazol-4-yl)benzimidazole, improve the conversion rate and reaction rate, reduce the reaction temperature, avoid the decomposition of ethyl acetate and the generation of by-products, and improve the reuse rate of ethyl acetate. Ammonia reacts with hydrogen bromide to generate ammonium bromide that is insoluble in ethyl acetate and can be filtered and separated. 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 implementation methods.

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

[0029] (1) adding lactic acid and o-phenylenediamine to water, using solid acid as a catalyst, heating to carry out a condensation reaction to generate 2-α-hydroxyethylbenzimidazole, recovering the solid acid after the reaction, cooling the reaction solution to 4-25° C. to precipitate, filtering, and washing with water until neutral (without drying) 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, 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 amount of the solid acid catalyst is 30-50% of the total volume of the solvent. The volume of water used as the solution is 1.5-4 times the volume of the reaction raw materials and the catalyst to be completely immersed / dissolved. Stirring is performed during the reaction so that the solid acid catalyst is in a suspended fluidized state during the reaction.

[0033] (2) 2-α-hydroxyethylbenzimidazole is put into an aqueous solution, and a micron-sized magnetic iron powder (preferably with a particle size of 50-500 μm) is used as a catalyst, and hydrogen peroxide is added as an oxidant to carry out a catalytic oxidation reaction, so that 2-α-hydroxyethylbenzimidazole is oxidized to 2-acetylbenzimidazole; after the reaction, the magnetic iron powder is recovered by magnetic separation. Specifically, it includes: firstly 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 1.5-2.5h; 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 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 continuously used in the next batch of preparation process.

[0034] Wherein, the water used as the solution is 1.5-4 times the volume of the reaction raw materials and the catalyst completely immersed / dissolved. The amount of micron-sized magnetic iron powder added is related to the total volume of the solvent, preferably 15-25% of the total volume of the solvent. Stirring is performed during the reaction process so that the micron-sized magnetic iron powder is in a suspended fluidized state during the reaction process. The magnetic iron powder with too large a particle size has a large specific surface area, low catalytic activity, and is not easy to suspend. When the magnetic iron powder with too small a particle size (such as nanometer-sized) is combined with hydrogen peroxide to form Fenton's reagent, the iron powders are easily agglomerated and the catalytic stability and durability are insufficient.

[0035] In this step, magnetic iron powder and hydrogen peroxide are used to realize a synergistic catalytic process. Compared with the catalytic system of acetone, concentrated sulfuric acid and potassium permanganate in the prior art, the present invention only needs to be carried out in an aqueous solution, thereby reducing the pollution of highly volatile organic compounds such as acetone and greatly reducing the formation of manganese-containing solid waste, improving the conversion rate and product yield (reaching more than 97%), and the product separation process is very simple, omitting operations such as extraction and desolventizing.

[0036] (3) Place 2-acetylbenzimidazole in glacial acetic acid solvent, add bromine, and add Fe 3+The MOF powder containing the central metal is used as a catalyst, and the temperature is raised to carry out a bromination reaction. After the reaction is completed, the MOF powder is recovered, and 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 ions 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 the MOF with the central metal is used as the catalyst, the bromination reaction temperature is 45-75°C, the reaction time is 1-2h, and 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 the next batch of synthesis step S3 without treatment. After the MOF powder is recovered by hot filtration, it is directly put into the next batch of reaction process. The recovery and regeneration of MOF powder is also very easy, and it can be regenerated by heat treatment or washing.

[0039] Wherein, the amount of Fe-MOF powder used is 8-15% of the total volume of the solvent. After using Fe-MOF powder as a catalyst, the reaction speed and conversion rate can be increased and the reaction temperature can be reduced. 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 excessive potassium permanganate, so there is little waste of bromine. Usually, the molar amount of bromine added is slightly excessive relative to 2-acetylbenzimidazole, and can be controlled at 120-140% of the theoretical demand. On the one hand, bromine can be saved, and on the other hand, a large amount of bromine can be avoided from entering the wastewater, reducing the difficulty of bromine recovery and wastewater treatment.

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

[0041] Fe 3+ Soluble salt (ferric nitrate or its hydrate, ferric chloride or its hydrate), pyrene-1,3,6,8-tetracarboxylic acid, 1,3,5-tri(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, 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 30-50kHZ for 5-10min; then 0.5-1mol / 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 the product.

[0042] The nitrogen atom on each pyridine ring of 1,3,5-Tris(4-pyridyl)benzene (TPB) can serve as a coordination site to form a stable coordination bond with metal ions. Due to its rigid planar structure, TPB helps to build 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 MOFs and helping to build more complex MOF structures, such as multi-level topologies.

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

[0044] (4) Add phosphorus pentasulfide and formamide to ethyl acetate solvent, react 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. Stir and introduce ammonia gas as catalyst at 35-45° C. to carry out cyclization reaction for 0.5-1.5 hours. After the reaction is completed, hot filtration is performed (to remove ammonium bromide insoluble in ethyl acetate), and the filtrate is retained. The filtrate is cooled to ≤20° C. to precipitate solids, which are filtered. Water is added to the filter cake and stirred to dissolve, which is decolorized with activated carbon, and the activated carbon is filtered out. 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%.

[0045] Preferably, phosphorus pentasulfide and formamide are added in a molar ratio of approximately 1:2, and the molar amount of formamide can be 1.05-1.25 times that of 2-dibromoacetylbenzimidazole hydrobromide; the rate of introduction of ammonia is 200-400 mL / L·min based on the volume of the reaction liquid. The amount of ethyl acetate used is 1.5-4 times the volume that can completely immerse or dissolve the reaction raw materials.

[0046] In this step, ammonia does not react with thioformamide, but can act as an acid-binding agent and react with HBr produced by the reaction to rapidly catalyze the reaction and improve the conversion rate, with a yield of 95-97%. After the reaction is completed, ammonium bromide is obtained by filtration and can be output as a by-product after purification.

[0047] The following is a description of 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 glass four-necked flask containing 400 mL of water, and 40% of the total volume of the solvent was added with sulfonic acid-type solid acid particles (particle size 60-80 mesh) supported by mesoporous carbon. 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 (the dry mass was 154 g), and the product yield was 79.2% based on lactic acid.

[0051] (2) 154 g of 2-α-hydroxyethylbenzimidazole was put into 250 mL of aqueous solution, and the pH was adjusted to 5 with a small amount of hydrochloric acid, and 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 slightly for 1.5 h. After the reaction was completed, the magnetic iron powder was first magnetically separated, and 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 was 97%), and the filtrate could 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-tri(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, the amount of the mixed solvent being 25 times the mass of pyrene-1,3,6,8-tetracarboxylic acid, and ultrasonically dispersed at a frequency of 40 kHz for 10 min; 1 mol / L NaOH solution was then added, the pH of the reaction system was adjusted to 6.0, and the reaction was carried out at a constant temperature of 65°C for 3 h. After the reaction was completed, the reaction was cooled to room temperature, filtered, and the filtrate was rinsed twice with deionized water and anhydrous ethanol respectively, and dried at 60°C for 12 h 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), and the filtrate was retained. The filtrate was cooled to 18° C. to precipitate a solid, which was filtered. Water was added to the filter cake and stirred to dissolve. The solid was decolorized with activated carbon, and the activated carbon was roughly filtered off. 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 of each step in the present invention are milder, the reaction temperature is lower, the side reactions and raw material consumption are reduced, the catalyst can be recycled, the reaction raw materials are less wasted, the reaction solvent can be recycled, the difficulty of impurity removal and the like is eliminated, and the difficulty of resource recovery is reduced.

[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 sulfonic acid-type solid acid particles (particle size 60-80 mesh) supported on mesoporous carbon. 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 (the dry mass was 157 g), and the product yield was 77.5% based on lactic acid.

[0060] (2) 157 g of 2-α-hydroxyethylbenzimidazole was put into 250 mL of aqueous solution, and the pH was adjusted to 4.5 with a small amount of hydrochloric acid, and 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 slightly for 1.5 h. After the reaction was completed, the magnetic iron powder was first magnetically separated, and 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, 12% of the solvent volume of Fe-MOFs powder (average particle size 1-10 μm) was added, 190 g of bromine was added, the temperature was raised to 60°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 370.5 g of 2-dibromoacetylbenzimidazole hydrobromide (recovery rate was 97.8%), and the filtrate could 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.

[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 were 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, the amount of the mixed solvent being 30 times the mass of pyrene-1,3,6,8-tetracarboxylic acid, and ultrasonically dispersed at a frequency of 40 kHz for 10 min; then 1 mol / L NaOH solution was added, the pH of the reaction system was adjusted to 6.0, and the reaction was carried out at a constant temperature of 60°C for 3 h. After the reaction was completed, it 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 h 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. Then 370.5 g of 2-dibromoacetylbenzimidazole hydrobromide was added, and the mixture was stirred at 45° C. and ammonia (350 mL / L·min) was introduced 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 the filtrate was cooled to 18° C. to precipitate solids, which were filtered. Water was added to the filter cake and stirred to dissolve. The cake was decolorized with activated carbon, and the activated carbon was roughly filtered off. The filtrate was further cooled to 12° C. and filtered to obtain a white solid. The filtrate 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 71.88% after calculation.

[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 improve 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 four-necked glass flask containing 400 mL of water, and 40% of the total volume of the solvent was added with sulfonic acid-type solid acid particles (particle size 60-80 mesh) supported by mesoporous carbon. 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 (the dry mass 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, 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, 45 g of hydrogen peroxide was added as an oxidant, the temperature was raised to 45° C. and the reaction was stirred slightly for 1.5 h. 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, 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, the temperature was raised to 59°C and stirred for reaction for 1.5 h, after the reaction was completed, 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 was 97.7%), and the filtrate could 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.

[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 were 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, the amount of the mixed solvent being 20 times the mass of pyrene-1,3,6,8-tetracarboxylic acid, and ultrasonically dispersed at a frequency of 40 kHz for 10 min; then 1 mol / L NaOH solution was added, the pH of the reaction system was adjusted to 6.5, and the reaction was carried out at a constant temperature of 75°C for 3 h. After the reaction was completed, it 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 h 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. 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), and the filtrate was retained. The filtrate was cooled to 18° C. to precipitate a solid, which was filtered. Water was added to the filter cake and stirred to dissolve. The solid was decolorized with activated carbon, and the activated carbon was roughly filtered off. 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. Sulfonic acid-type solid acid particles (particle size 60-80 mesh) supported by mesoporous carbon were added, and 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 (the dry mass 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 slightly 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, 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, the temperature was raised to 65° C. and stirred for reaction for 2 h. After the reaction was completed, 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 was 98.1%). The filtrate could be directly reused for 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-tri(4-pyridyl)benzene were mixed in a molar ratio of 1:1.8:1, and added together into a mixed solvent of water and DMF in a volume ratio of 1:3, the amount of the mixed solvent being 30 times the mass of pyrene-1,3,6,8-tetracarboxylic acid, and ultrasonically dispersed at a frequency of 40 kHz for 10 min; 1 mol / L NaOH solution was then added, the pH of the reaction system was adjusted to 6.0, and the reaction was carried out at a constant temperature of 70°C for 3 h. After the reaction was completed, the reaction was cooled to room temperature, filtered, and the filtrate was rinsed twice with deionized water and anhydrous ethanol respectively, and dried at 60°C for 12 h 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. Then 349.2 g of 2-dibromoacetylbenzimidazole hydrobromide was added, and ammonia (300 mL / L·min) was introduced at 40° C. for catalysis, and 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), and the filtrate was retained. The filtrate was cooled to 18° C. to precipitate solids, filtered, and the filter cake was stirred and dissolved with water, decolorized with activated carbon, and the activated carbon was roughly filtered off. The filtrate was further cooled to 12° C. and filtered to obtain a white solid, which 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 embodiment 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) is removed, 154 g of 2-α-hydroxyethylbenzimidazole is put into 250 mL of aqueous solution, the pH is adjusted to 5 with dilute hydrochloric acid, 60 g of hydrogen peroxide is added as an oxidant, the temperature is raised to 45° C. and the mixture is stirred slightly for 1.5 hours. 136.9 g of 2-acetylbenzimidazole is obtained by reaction. The recovery rate is 90% based on 2-α-hydroxyethylbenzimidazole.

[0085] Comparative Example 2

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

[0087] Comparative Example 3

[0088] This comparative example is based on Example 1, and the preparation method of the Fe-MOF powder used in step (3) is changed, and the mixed solvent is replaced by an equal amount of deionized water, and the preparation conditions are the same as those of Example 1. The prepared Fe-MOF powder is replaced by an equal amount of the Fe-MOF catalyst used in step (3) of Example 1 to obtain 345.4g of 2-dibromoacetylbenzimidazole hydrobromide, and the product yield is 93.40%. It can be seen from Comparative Examples 2-3 that after 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 with Example 1.

[0089] Comparative Example 4

[0090] This comparative example is based on Example 1, and 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 hour. 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 with 500 ml of water, decolorized with activated carbon, filtered to remove the activated carbon, and the filtrate is cooled to 15°C and 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 aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned 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 solid acid as a catalyst, heating to carry out condensation reaction to generate 2-α-hydroxyethylbenzimidazole, after 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, putting 2-α-hydroxyethylbenzimidazole into an aqueous solution, using micron-sized magnetic iron powder as a catalyst and adding hydrogen peroxide as an oxidant to carry out a catalytic oxidation reaction, thereby oxidizing 2-α-hydroxyethylbenzimidazole into 2-acetylbenzimidazole; after the reaction is completed, magnetic separation is performed to recover the magnetic iron powder; S3, putting 2-acetylbenzimidazole into 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; 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.

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

3. The synthesis process according to claim 1, characterized in that: In S1, 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, 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, a small amount of hydrochloric acid or dilute sulfuric acid is used to adjust the pH to 4.5-6.5, and the reaction is carried out at 30-50°C for 1.5-2.5 hours. After the reaction is completed, the magnetic iron powder is first magnetically separated, and then cooled to below 20°C and filtered to obtain yellow crystals, which are 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 1-2h, 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 be stirred at 35-45°C for 0.5-1.5h, filtered, 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 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 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 introduction rate of ammonia gas is 200-400 mL / L·min based on the volume of the reaction solution.