An improved method for preparing thiabendazole

Abstract

The present invention relates to the field of thiabendazole preparation, specifically an improved thiabendazole preparation method. Comprise the following steps: S1 methylglyoxal is added to a container, the temperature is raised to 30-35 DEG C to melt, a catalyst is added, stirred evenly, air is blown in, and then o-phenylenediamine and acetic acid are added in batches, and the temperature is raised to 50-60 DEG C after adding, and the reaction is carried out for 2-5h to obtain a reaction solution containing 2-acetylbenzimidazole; S2 The reaction solution obtained in step S1 is added with liquid bromine, reacted, and after the reaction is completed, cooled, filtered, washed, and dried to obtain 2-dibromoacetylbenzimidazole hydrobromide; S3 The 2-dibromoacetylbenzimidazole hydrobromide obtained in step S2 is added to ethyl acetate, and then formamide and phosphorus pentasulfide are added for ring-closure reaction to obtain a closed-loop reaction liquid; S4 The thiabendazole in the closed-loop reaction liquid obtained in step 3 is purified to obtain a thiabendazole product. The process is simple, the prepared product has high purity, and the purity is 99.3%, and it is expected to be industrialized as soon as possible.

Description

Technical Field

[0001] The present invention relates to the field of thiabendazole preparation, in particular to an improved thiabendazole preparation method. Background Art

[0002] Thiabendazole, a benzimidazole fungicide with the chemical name thiabendazole, is an odorless white powder with a melting point of 297–298°C and a relative density of 1.3989. It is insoluble in water, slightly soluble in alcohol and acetone, and freely soluble in ether and chloroform. It is stable in acids, bases, and aqueous solutions and is commonly used to control various fungal diseases on crops, fruits, and vegetables. It inhibits tubulin polymerization within fungal cells, affecting fungal cell division and hyphal growth, thereby exerting its fungicidal effect. Application must be carried out according to the prescribed dosage and method to ensure agricultural product safety and compliance with pesticide residue standards. Thiabendazole is not only used as a fungicide and antifungal agent, but in recent years, thiabendazole and its derivatives have also been discovered for medicinal uses. Thiabendazole has been approved by the US Food and Drug Administration (FDA) for systemic oral administration in humans (as an antifungal and antiparasitic treatment) and has been shown to be a vascular disruptor, making it an adjunct to current antiangiogenic therapy combinations.

[0003] The disclosed preparation methods mainly include the following:

[0004] 1. Mix thiazole-4-carboxylic acid bromide and o-phenylenediamine, add polyphosphoric acid, and heat to 240°C with stirring for 3 hours. Pour the hot reaction mixture into ice, filter, and wash the filtrate with 30% sodium hydroxide solution. 2-(4'-thiazolyl)-benzimidazole precipitates at approximately pH 6. Filter, wash, and dry to obtain crystals with a melting point of 296-298°C. Recrystallize from boiling ethanol to a melting point of 301-302°C. Another process involves stirring and heating a mixture of 4-ethoxyformylthiazole, o-phenylenediamine, and polyphosphoric acid to 125°C, then heating at 175°C for 2 hours. Pour the mixture into ice water, neutralize with sodium hydroxide solution to pH 6, precipitate crystals, filter, and extract with hot acetone. The extract is decolorized with activated carbon, concentrated, and dried in vacuo to obtain thiabendazole.

[0005] 2. Preparation of 4-ethoxycarboxylic acid: Tartaric acid is used as the starting material. Pyruvic acid is cleaved and then esterified, brominated, and cyclized with thiocarboxamide to produce 4-ethoxycarboxylic acid. Synthesis of Thiabendazole: A mixture of 4-ethoxycarboxylic acid, o-phenylenediamine, and polyphosphoric acid is heated to 125°C with stirring, then heated at 175°C for 2 hours. The mixture is poured into ice water and neutralized with sodium hydroxide solution to a pH of 6. Crystals precipitate, filter, and extract with hot acetone. The extract is decolorized with activated carbon, concentrated, and vacuum-dried to produce thiabendazole. Preparation Method: Dithiazol-4-hydroxycarboxylic acid bromide and o-phenylenediamine are mixed, polyphosphoric acid is added, and the mixture is heated to 240°C with stirring for 3 hours. The hot reaction mixture is poured into ice water, filtered, and the filtrate is washed with 30% sodium hydroxide solution. 2-(4'-thiazolyl)-benzimidazole precipitates at a pH of approximately 6. The precipitate is filtered, washed with water, and dried to produce thiabendazole. Recrystallized from boiling ethanol, mp301~302℃.

[0006] 3. React 4-ethoxyformylthiazole with o-phenylenediamine in condensed phosphoric acid at 175°C for 2 hours. Pour the reaction mixture into ice water and neutralize with sodium hydroxide to a pH of 6. Crystals precipitate, filter, recrystallize from acetone, and decolorize with activated carbon. Concentrate the decolorized solution and vacuum dry to obtain the finished product. Method 2: React 4-thiazolecarboxylic acid amide (or bromide) with o-phenylenediamine in condensed phosphoric acid at 240°C for 3 hours. Pour the reaction mixture into ice water, filter, and wash the filtrate with 30% sodium hydroxide solution to a pH of 6. Benzimidazole crystals precipitate. Filter, wash, and dry to obtain the crude product, which is then recrystallized from ethanol to obtain the finished product. CN 112358162 A discloses an additive for sludge dewatering, comprising the following raw materials in the following mass fractions: 2-5% surfactant, 5-9% flocculant, 5-10% antibiotic residue ash, and 3-7% auxiliary agent. A quaternary ammonium salt cationic surfactant is combined with the flocculant to uniformly increase the density of the sludge cake during filtration, rather than making the cake very dense immediately after formation, thereby reducing filtration resistance, improving filtration performance, and achieving a water content of less than 60% by weight in the dehydrated sludge. Furthermore, auxiliary agents comprising magnesium chloride, modified dolomite, calcium chloride, and ground calcium carbonate are added to solidify heavy metals carried in the sludge during dewatering, preventing them from being absorbed by plant roots and from being diffused into soil and water. Dewatered sludge produced by the sludge dewatering additive does not produce secondary pollution, and the dehydrated sludge can be used as a fertilizer, fuel, or building material, thereby achieving energy conservation and environmental protection. However, the dewatering effect still needs to be improved, and the effect is limited.

[0007] 4. The copper-catalyzed reaction of o-chloroaniline with 4-thiazolecarboxaldehyde to synthesize thiabendazole in a single step yields 85%, requiring the use of sodium azide. o-iodoaniline is more effective than o-chloroaniline, achieving a yield of 98%. However, the industrial cost of using o-haloaniline is high, and the use of azide in the reaction is also hazardous, making it difficult to scale up.

[0008] CN106349235A discloses a thiabendazole production process, wherein lactic acid and o-phenylenediamine are subjected to condensation reaction in an acidic (but not limited to hydrochloric acid) aqueous solution, the pH value is adjusted to obtain 2-α-hydroxyethylbenzimidazole, and then placed in a container with acetone and sulfuric acid (not limited to sulfuric acid, including hydrochloric acid and other inorganic acids and strong acid and weak base salts) as solvents and subjected to oxidation reaction with potassium permanganate (not limited to potassium permanganate, including hydrogen peroxide and organic peroxides), and after extraction, desolventization and drying, 2-acetylbenzimidazole is obtained. Benzimidazole is placed in a container with glacial acetic acid as a solvent and reacts with bromine (not limited to bromine, but also including chlorine and other halogens) for a halogenation reaction. After the filter cake is dried, 2-dibromoacetylbenzimidazole hydrobromide is obtained. Formamide and phosphorus pentasulfide are reacted in a container with ethyl acetate as a solvent to obtain thioformamide. After nitrogen pressure filtration to remove phosphorus pentoxide, the thioformamide / ethyl acetate solution is then subjected to a cyclization reaction with 2-dibromoacetylbenzimidazole. After purification and pH adjustment, a thiabendazole content of ≥99% is obtained. This production process reduces costs, reduces safety and environmental risks, alleviates environmental pollution, and improves production efficiency. The entire reaction process is carried out at room temperature and pressure, the reaction conditions are mild, and the yield of each step is very stable. The total yield reaches more than 75% based on o-phenylenediamine. However, the preparation process is complex and produces a large amount of three wastes. Summary of the Invention

[0009] In response to the shortcomings of the existing technology, the present invention provides an improved method for preparing thiabendazole, which has a simple process and a high purity of 99.3% for the prepared product, and is expected to be industrialized as soon as possible.

[0010] To achieve the above-mentioned object, the present invention provides an improved method for preparing thiabendazole, comprising the following steps:

[0011] S1: Add methylglyoxal to a container, raise the temperature to 30-35°C to melt, add a catalyst, stir evenly, blow in air, and then add o-phenylenediamine and acetic acid in batches. After the addition, raise the temperature to 50-60°C and react for 2-5 hours to obtain a reaction solution containing 2-acetylbenzimidazole. The present invention uses methylglyoxal as a reaction substrate. Compared with the prior art, it reduces the subsequent oxidation step and the generation of a large amount of waste acid in the oxidation step. At the same time, it reduces the generation of a large amount of waste acid in the ring-closing step of synthesizing 2-acetylbenzimidazole. The process is simpler, the reaction is mild, and the yield is high. The mechanism of the ring-closing step of synthesizing 2-acetylbenzimidazole may be a catalytic air oxidation mechanism. In the initial reaction stage, the molten methylglyoxal and o-phenylenediamine react well. As the product is generated, the fluidity deteriorates, and acetic acid needs to be added to ensure the smooth progress of the reaction. The added acetic acid can be used as a solvent in step S2.

[0012] S2: adding liquid bromine to the reaction solution obtained in step S1 to carry out a reaction. After the reaction is completed, cooling, filtering, washing, and drying to obtain 2-dibromoacetylbenzimidazole hydrobromide;

[0013] S3: adding the 2-dibromoacetylbenzimidazole hydrobromide obtained in step S2 to ethyl acetate, and then adding formamide and phosphorus pentasulfide to carry out a ring-closure reaction to obtain a ring-closure reaction solution;

[0014] S4 purifying the thiabendazole in the closed-loop reaction solution obtained in step 3 to obtain a thiabendazole product.

[0015] Furthermore, in step S1, the catalyst is at least one of NaHSO4, p-toluenesulfonic acid and 50wt% hydrogen peroxide solution, and the amount of the catalyst added is 0.15 to 2 times the molar number of o-phenylenediamine. In the loop closing step, no large amount of inorganic acid such as hydrochloric acid is used, and the oxidant is environmentally friendly and pollution-free, with ideal results.

[0016] Furthermore, in step S1, the molar ratio of o-phenylenediamine to methylglyoxal is 1:(1.2-1.5), and the amount of acetic acid added is 4-8 times the mass of o-phenylenediamine.

[0017] Furthermore, the amount of liquid bromine added in step S2 is 2.5 to 2.6 times the molar number of o-phenylenediamine in step S1, the reaction temperature is 85 to 95° C., and the reaction time is 0.5 to 1.5 h.

[0018] Furthermore, the amount of formamide added in step S3 is 1.0 to 1.2 times the molar number of o-phenylenediamine in step S1, the amount of phosphorus pentasulfide added is 1.2 to 2.5 times the molar number of o-phenylenediamine in step S1, and the amount of ethyl acetate added is 5 to 8 times the mass of o-phenylenediamine in step S1.

[0019] Furthermore, in step S3, the reaction temperature is 50-60° C., and the reaction time is 1-3 h. Appropriate temperature control conditions can ensure that the reaction occurs smoothly and the color and purity of the product are guaranteed.

[0020] Furthermore, the purification method in step S4 is to remove the solvent in vacuo, wash with hot water, neutralize with sodium carbonate to neutrality, separate a small amount of organic matter, cool the aqueous phase to precipitate, filter, wash, and dry to obtain a thiabendazole product with a purity of >99.3%. Sodium carbonate is used for neutralization, and gas is generated during the reaction, which can be blown to the upper part of the liquid to remove ethyl acetate, formamide, etc. in the solution.

[0021] Furthermore, the preparation method of methylglyoxal in step S1 is: under reduced pressure, 1,2-dipropanol and glycerol are gasified, and then mixed with oxygen to form a mixed gas, and the mixed gas is selectively oxidized to generate methylglyoxal under the catalysis of supported silver and gold catalysts.

[0022] Furthermore, in step S8, silver and gold are loaded on a molecular sieve containing magnesium oxide, the oxidation reaction temperature is 180-200° C., the molar ratio of 1,2-dipropanol and glycerol is (0-1):1, and the oxygen flow rate is 5-30 times that of the mixed gas of 1,2-dipropanol and glycerol. DETAILED DESCRIPTION

[0023] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention. Example 1

[0024] An improved method for preparing thiabendazole comprises the following steps:

[0025] S1: Add 87 g of methylglyoxal to a container and heat it to 30-35°C to melt it. Add 36 g of NaHSO4 and stir evenly. Blow air into the container. Then, add 108 g of o-phenylenediamine and 540 g of acetic acid in batches. After the addition, heat it to 50-60°C and react for 3 hours to obtain a reaction solution containing 2-acetylbenzimidazole.

[0026] S2: Add 400 g of liquid bromine to the reaction solution obtained in step S1, and react at 85-90° C. for 1 hour. After the reaction is completed, cool, filter, wash, and dry to obtain 2-dibromoacetylbenzimidazole hydrobromide;

[0027] S3: Add 2-dibromoacetylbenzimidazole hydrobromide obtained in step S2 to 550 g of ethyl acetate, then add 45 g of formamide and 270 g of phosphorus pentasulfide, and react at a temperature of 50-60° C. for 2 h to perform a ring-closure reaction to obtain a ring-closure reaction solution;

[0028] S4: The closed-loop reaction solution obtained in step 3 was vacuum-solventized, washed with hot water, and neutralized with sodium carbonate until neutral. A small amount of organic matter was separated, and the aqueous phase was cooled to precipitate, which was filtered, washed, and dried to obtain 165 g of thiabendazole product with a purity of 99.4% and an overall yield of 82% (based on o-phenylenediamine). The vacuum during vacuum solvent removal was -0.05 MPa to -0.08 MPa, and the temperature was 30-40°C. Example 2

[0029] An improved method for preparing thiabendazole comprises the following steps:

[0030] S1: Add 94 g of methylglyoxal to a container, heat it to 30-35°C to melt it, add 50 g of 50 wt% hydrogen peroxide solution, stir evenly, blow air into the container, then add 108 g of o-phenylenediamine and 700 g of acetic acid in batches. After the addition, heat it to 50-60°C and react for 2 h to obtain a reaction solution containing 2-acetylbenzimidazole.

[0031] S2: Add 400 g of liquid bromine to the reaction solution obtained in step S1, and react at 90-95° C. for 1 hour. After the reaction is completed, cool, filter, wash, and dry to obtain 2-dibromoacetylbenzimidazole hydrobromide;

[0032] S3: Add 2-dibromoacetylbenzimidazole hydrobromide obtained in step S2 to 550 g of ethyl acetate, then add 46 g of formamide and 270 g of phosphorus pentasulfide, and react at a temperature of 50-60° C. for 2 h to perform a ring-closure reaction to obtain a ring-closure reaction solution;

[0033] S4 The closed-loop reaction solution obtained in step 3 was vacuum-dried to remove the solvent, washed with hot water, neutralized with sodium carbonate to neutrality, a small amount of organic matter was separated, the aqueous phase was cooled to precipitate, filtered, washed, and dried to obtain 169 g of thiabendazole product with a purity of 99.5% and a total yield of 84% (calculated as o-phenylenediamine). Example 3

[0034] An improved method for preparing thiabendazole comprises the following steps:

[0035] S1: Add 95 g of methylglyoxal to a container and heat it to 30-35°C to melt it. Add 60 g of p-toluenesulfonic acid and stir evenly. Blow air into the container. Then, add 108 g of o-phenylenediamine and 700 g of acetic acid in batches. After the addition, heat it to 50-60°C and react for 4 hours to obtain a reaction solution containing 2-acetylbenzimidazole.

[0036] S2: Add 400 g of liquid bromine to the reaction solution obtained in step S1, and react at 90-95° C. for 1 hour. After the reaction is completed, cool, filter, wash, and dry to obtain 2-dibromoacetylbenzimidazole hydrobromide;

[0037] S3: Add 2-dibromoacetylbenzimidazole hydrobromide obtained in step S2 to 600 g of ethyl acetate, then add 46 g of formamide and 270 g of phosphorus pentasulfide, and react at a temperature of 50-60° C. for 2 h to perform a ring-closure reaction to obtain a ring-closure reaction solution;

[0038] S4 The closed-loop reaction solution obtained in step 3 was vacuum-dried to remove the solvent, washed with hot water, neutralized with sodium carbonate to neutrality, a small amount of organic matter was separated, the aqueous phase was cooled to precipitate, filtered, washed, and dried to obtain 167 g of thiabendazole product with a purity of 99.6% and a total yield of 83% (calculated as o-phenylenediamine).

[0039] The preparation method of methylglyoxal in the above step S1 is as follows: 1,2-dipropanol and glycerol are gasified under reduced pressure at 180-200° C., and then mixed with oxygen at a flow rate 10 times that of the gas to form a mixed gas. The mixed gas is selectively oxidized in a fixed bed equipped with a silver and gold catalyst to produce a crude methylglyoxal product, which is then purified to obtain acrolein, wherein the molar ratio of 1,2-dipropanol to glycerol is 1:1. Example 4

[0040] An improved method for preparing thiabendazole comprises the following steps:

[0041] S1: Add 95 g of methylglyoxal to a container and heat it to 30-35°C to melt it. Add 60 g of p-toluenesulfonic acid and stir evenly. Blow air into the container. Then, add 108 g of o-phenylenediamine and 700 g of acetic acid in batches. After the addition, heat it to 50-60°C and react for 4 hours to obtain a reaction solution containing 2-acetylbenzimidazole.

[0042] S2: Add 400 g of liquid bromine to the reaction solution obtained in step S1, and react at 90-95° C. for 1 hour. After the reaction is completed, cool, filter, wash, and dry to obtain 2-dibromoacetylbenzimidazole hydrobromide;

[0043] S3: Add 2-dibromoacetylbenzimidazole hydrobromide obtained in step S2 to 600 g of ethyl acetate, then add 46 g of formamide and 270 g of phosphorus pentasulfide, and react at a temperature of 50-60° C. for 2 h to perform a ring-closure reaction to obtain a ring-closure reaction solution;

[0044] S4 The closed-loop reaction solution obtained in step 3 was vacuum-dried to remove the solvent, washed with hot water, neutralized with sodium carbonate to neutrality, a small amount of organic matter was separated, the aqueous phase was cooled to precipitate, filtered, washed, and dried to obtain 167 g of thiabendazole product with a purity of 99.6% and a total yield of 83% (calculated as o-phenylenediamine).

[0045] The preparation method of methylglyoxal in the above step S1 is as follows: 1,2-dipropanol is gasified at 180-200° C. under reduced pressure, and then mixed with oxygen at a flow rate 5 times that of the 1,2-dipropanol to form a mixed gas. The mixed gas is selectively oxidized in a fixed bed equipped with a loaded silver and gold catalyst to produce crude methylglyoxal, which is then purified to obtain acrolein. Example 5

[0046] An improved method for preparing thiabendazole comprises the following steps:

[0047] S1: Add 87 g of methylglyoxal to a container and heat it to 30-35°C to melt it. Then, add 10 g of NaHSO4 and 30 g of 50 wt% hydrogen peroxide solution, stir evenly, and introduce air. Then, add 108 g of o-phenylenediamine and 540 g of acetic acid in batches. After the addition, heat it to 50-60°C and react for 3 h to obtain a reaction solution containing 2-acetylbenzimidazole.

[0048] S2: Add 400 g of liquid bromine to the reaction solution obtained in step S1, and react at 85-90° C. for 1 hour. After the reaction is completed, cool, filter, wash, and dry to obtain 2-dibromoacetylbenzimidazole hydrobromide;

[0049] S3: Add 2-dibromoacetylbenzimidazole hydrobromide obtained in step S2 to 550 g of ethyl acetate, then add 45 g of formamide and 270 g of phosphorus pentasulfide, and react at a temperature of 50-60° C. for 2 h to perform a ring-closure reaction to obtain a ring-closure reaction solution;

[0050] S4 The closed-loop reaction solution obtained in step 3 was vacuum-dried to remove the solvent, washed with hot water, neutralized with sodium carbonate to neutrality, a small amount of organic matter was separated, the aqueous phase was cooled to precipitate, filtered, washed, and dried to obtain 175 g of thiabendazole product with a purity of 99.4% and a total yield of 87% (calculated as o-phenylenediamine).

[0051] Comparative Example 1

[0052] In Example 1, “S3 is reacted at a temperature of 50-60° C. for 2 h” is modified to “S3 is reacted at a temperature of 40-50° C. for 1 h, and heated under reflux for 1 h to remove the solvent”. The final product is dark in color and cannot meet the requirements.

[0053] The data of Example 1 and Example 5 show that the catalytic oxidation using NaHSO4 and 50 wt% hydrogen peroxide solution has better effect and higher yield.

Claims

1. An improved method for preparing thiabendazole, characterized in that: The following steps are involved: S1: Add methylglyoxal to a container, raise the temperature to 30-35°C to melt, add the catalyst, stir evenly, blow in air, then add o-phenylenediamine and acetic acid in batches. After addition, raise the temperature to 50-60°C and react for 2-5 hours to obtain a reaction solution containing 2-acetylbenzimidazole. S2: adding liquid bromine to the reaction solution obtained in step S1 to carry out a reaction. After the reaction is completed, cooling, filtering, washing, and drying to obtain 2-dibromoacetylbenzimidazole hydrobromide; S3: adding the 2-dibromoacetylbenzimidazole hydrobromide obtained in step S2 to ethyl acetate, and then adding formamide and phosphorus pentasulfide to carry out a ring-closure reaction to obtain a ring-closure reaction solution; S4 purifying the thiabendazole in the closed-loop reaction solution obtained in step S3 to obtain a thiabendazole product; In step S1, the catalyst is at least one of NaHSO4, p-toluenesulfonic acid and 50 wt% hydrogen peroxide solution, and the amount of the catalyst added is 0.15 to 2 times the molar number of o-phenylenediamine; In step S3, the reaction temperature is 50-60° C., and the reaction time is 1-3 hours.

2. The method for preparing thiabendazole according to claim 1, characterized in that: In step S1, the molar ratio of o-phenylenediamine to methylglyoxal is 1:(1.2-1.5), and the amount of acetic acid added is 4-8 times the mass of o-phenylenediamine.

3. The method for preparing thiabendazole according to claim 1, characterized in that: The amount of liquid bromine added in step S2 is 2.5 to 2.6 times the molar number of o-phenylenediamine in step S1, the reaction temperature is 85 to 95° C., and the reaction time is 0.5 to 1.5 h.

4. The method for preparing thiabendazole according to claim 1, characterized in that: The amount of formamide added in step S3 is 1.0 to 1.2 times the molar number of o-phenylenediamine in step S1, the amount of phosphorus pentasulfide added is 1.2 to 2.5 times the molar number of o-phenylenediamine in step S1, and the amount of ethyl acetate added is 5 to 8 times the mass of o-phenylenediamine in step S1.

5. The method for preparing thiabendazole according to claim 1, characterized in that: The purification method in step S4 is to remove the solvent in vacuo, wash with hot water, neutralize with sodium carbonate until neutral, separate a small amount of organic matter, cool the aqueous phase to precipitate, filter, wash, and dry to obtain the thiabendazole product with a purity of >99.3%.

6. The method for preparing thiabendazole according to claim 1, characterized in that: The preparation method of methylglyoxal in step S1 is as follows: 1,2-dipropanol and glycerol are gasified under reduced pressure, and then mixed with oxygen to form a mixed gas, and the mixed gas is selectively oxidized to generate methylglyoxal under the catalysis of supported silver and gold catalysts.

7. The method for preparing thiabendazole according to claim 6, characterized in that: The silver and gold are loaded on a molecular sieve containing magnesium oxide, the oxidation reaction temperature is 180-200°C, the molar ratio of 1,2-dipropanol to glycerol is (0-1):1, and the flow rate of oxygen is 5-30 times that of the mixed gas of 1,2-dipropanol and glycerol.