A kind of synthetic method of thiofuranamide

Abstract

The invention discloses a synthesis method of thiofuranamide, wherein the method comprises: using 2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid and 4-trifluoromethoxyaniline as starting materials, in the presence of a catalyst, an acid-amine condensation reaction occurs, and a bromination reaction occurs on the benzene ring to obtain thiofuranamide. The invention has simple process, mild reaction conditions, few steps, and little "three wastes", and is a new process with high efficiency and environmental protection, which is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a new method for preparing thiofuranil, and belongs to the technical field of pesticide chemistry. Background Art

[0002] Thifluzamide is a succinate dehydrogenase inhibitor that inhibits succinate dehydrogenase in the tricarboxylic acid cycle of pathogens, interferes with mitochondrial respiration, and causes the pathogens to be unable to synthesize energy normally, and then die of exhaustion, thereby achieving the purpose of preventing and controlling diseases. Initially, it was mainly used to prevent and control rice and wheat sheath blight. With the promotion of registration scope and practical application, Thifluzamide has also begun to be widely used in the prevention and control of peanut white rot, potato black mole disease and some diseases on medicinal materials. At the same time, it is also used in seed treatment in combination with other fungicides and insecticides.

[0003] The CAS registration number is [130000-40-7]. Its relative molecular mass is 528.06; its molecular formula is C 13 H6Br2F6N2O2S. The structure is shown below:

[0004]

[0005] At present, the mainstream synthesis route of thiofuranamide is to use 4-trifluoromethoxyaniline as the starting material, and thiofuranamide is obtained through three steps of bromination reaction, acyl chloride reaction, and amide condensation reaction. The specific synthesis route is as follows:

[0006] .

[0007] European patent EP0371950A2 discloses that 2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid is chlorinated with thionyl chloride, and then distilled under high vacuum to obtain an intermediate acid chloride, which is then reacted with 2,6-dibromo-4-trifluoromethoxyaniline in a xylene solvent to obtain thiofuranamide. This method has many by-products, three wastes, and a yield of only 32.3%.

[0008] Chinese patent CN109369564A discloses a method for obtaining thiofuranamide by chlorinating the intermediate 2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid with triphosgene and then reacting it with 2,6-dibromo-4-trifluoromethoxyaniline in the presence of a catalyst. This method uses highly toxic triphosgene and explosive dibenzoyl peroxide, and industrial production is very dangerous. In addition, zinc chloride is a heavy metal, and the cost of heavy metal wastewater treatment is high, which is not conducive to industrialization.

[0009] Chinese patent CN108059625A uses 2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid and 2,6-dibromo-4-trifluoromethoxyaniline as raw materials, and reacts in acetonitrile solvent in the presence of a catalyst. The molar amount of the catalyst exceeds the molar amount of the raw materials. The catalyst used is actually an acyl chloride reagent, such as phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus pentoxide and other phosphorus-containing reagents. The phosphorus-containing acylating reagent is prone to ignition and explosion when in contact with water, posing a serious safety risk. In addition, the acetonitrile solvent is miscible with water and is difficult to separate. The reaction needs to be carried out under anhydrous conditions, which is not conducive to solvent recovery and application in industrial production. The selected acyl chloride reagent produces phosphorus-containing wastewater, and subsequent wastewater treatment is difficult to meet discharge standards, which is not conducive to industrialization.

[0010] Chinese patent CN102746254A discloses a method for obtaining thiofuranamide by using 2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid as a raw material, chlorinating it with thionyl chloride, and then reacting it with 2,6-dibromo-4-trifluoromethoxyaniline in the presence of an acid binder, a catalyst and an amidation reaction solvent. The thionyl chloride residue in this method is prone to react with 2,6-dibromo-4-trifluoromethoxyaniline to generate a tarry black viscous substance, which affects the yield and product quality; and a large amount of sulfur dioxide is generated during the reaction of this method, which increases the difficulty of tail gas treatment. From an industrial perspective, this method is not suitable for industrial production. Summary of the invention

[0011] According to the background technology, the synthesis method of thiofuran mainly adopts the condensation reaction of 2,6-dibromo-4-trifluoromethoxyaniline and 2-methyl-4-trifluoromethyl-5-thiazolecarbonyl chloride, and it is necessary to use an acylating agent and a condensing agent in excess of equimolar amounts to achieve the condensation of 2,6-dibromo-4-trifluoromethoxyaniline and 2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid to obtain thiofuran. From the analysis of the acid-amine condensation reaction mechanism: first, the amino activity of 2,6-dibromo-4-trifluoromethoxyaniline is insufficient; second, the amino steric hindrance in 2,6-dibromo-4-trifluoromethoxyaniline is too large. Based on the understanding of the reaction mechanism, under the premise of using a trace amount of catalyst, the use of unbrominated raw materials relatively increases the activity of the amino group, making the acid-amine condensation reaction easier to occur, while also reducing the steric hindrance of the amino group. 4-Trifluoromethoxyaniline directly reacts with 2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid to achieve a quantitative acid-amine condensation reaction, and then bromination is performed to obtain thiofuranamide. The purpose of the present invention is to overcome the defects of the above-mentioned prior art and provide a method for synthesizing thiofuranamide; avoid the use of acyl chloride reagents, reduce the emission of "three wastes", and be more energy-saving and environmentally friendly; at the same time, reduce the reaction steps, and the industrialization cost is low. The present invention provides the following technical solutions:

[0012] With 2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid and 4-trifluoromethoxyaniline as starting materials, an acid-amine condensation reaction occurs in the presence of a catalytic amount of a catalyst. After the reaction is completed, the reaction solution is washed with a 10% sodium carbonate aqueous solution and separated, and the organic phase is subjected to a bromination reaction with a brominating agent and an oxidant. After the reaction is completed, the organic phase is separated, and a 10% sodium sulfite solution is added to the organic phase for washing, and the organic phase is separated again. The organic phase is evaporated to dryness under negative pressure to obtain a crude thiofuranamide product, and the crude product is recrystallized with a xylene / n-heptane mixed solvent to obtain a finished thiofuranamide product.

[0013] Preferably, the acid-amine condensation reaction temperature is 60-140°C.

[0014] Preferably, the acid-amine condensation reaction solvent is selected from one of 1,2-dichloroethane, toluene, cyclohexane and xylene, and the amount of the solvent used is 5 to 8 times the mass of 4-trifluoromethoxyaniline.

[0015] Preferably, the molar ratio of 4-trifluoromethoxyaniline, 2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid and the catalyst in the acid-amine condensation reaction is 1:1.05-1.2:0.05-0.20.

[0016] Preferably, the catalyst for the acid-amine condensation reaction is selected from one of phenylboric acid, 3,4,5-trifluorophenylboric acid, boric acid and boric anhydride.

[0017] Preferably, the acid binding agent for the bromination reaction is selected from one of sodium carbonate, potassium carbonate and sodium hydroxide.

[0018] Preferably, the bromination reaction oxidant is selected from one of hydrogen peroxide and sodium hypochlorite.

[0019] Preferably, the brominating agent for the bromination reaction is selected from one of lithium bromide, sodium bromide and potassium bromide.

[0020] Preferably, the bromination reaction solvent is selected from one of 1,2-dichloroethane, toluene, cyclohexane and xylene.

[0021] Preferably, in the bromination reaction, the molar ratio of 4-trifluoromethoxyaniline: acid binding agent: oxidant: sodium bromide is 1:0.3~0.8:2.0~2.8:2.0~2.8.

[0022] Preferably, the bromination reaction temperature is 25-80°C.

[0023] Compared with other synthesis methods, the present invention has the following advantages:

[0024] 1) The product has a high content of 97.5% to 98.0% (liquid chromatography, external standard method);

[0025] 2) The yield is high, and the total yield is 85.0% to 90.0% (based on 4-trifluoromethoxyaniline);

[0026] 3) It avoids the use of acylating agents, does not produce toxic and harmful gases such as sulfur dioxide or phosgene, and does not produce difficult-to-treat phosphorus-containing wastewater, which is environmentally friendly;

[0027] 4) The process route was innovated, and the reaction steps were reduced from three to two, which reduced production costs and shortened the industrial production cycle. DETAILED DESCRIPTION

[0028] The present invention is further described below in conjunction with the specification and specific preferred embodiments, but the protection scope of the present invention is not limited thereby. Example

[0029] 180.0 g of 1,2-dichloroethane, 35.4 g of 4-trifluoromethoxyaniline, 44.3 g of 2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid and 3.0 g of boric acid were added in sequence into a 500 mL four-necked flask equipped with a mechanical stirrer, a condenser and a thermometer. The temperature was raised to reflux, and the reaction was carried out for 8 h under reflux and water separation. Samples were taken, and after liquid chromatography analysis showed that the raw material was ≤0.2%, the system was cooled to 40°C, 100 g of 10% sodium carbonate aqueous solution was added for washing once, and the liquids were separated. The organic phase was directly used for the next reaction.

[0030] Add 6.2g NaOH, 45.4g NaBr and 70.0g water to the organic phase in the previous step, heat to 30°C, drip 70.0g 30% hydrogen peroxide solution for 1h, stir and react for 1h, take samples, analyze the raw material by liquid chromatography ≤ 0.2%, stop the reaction, cool to 25°C, separate the liquids, add 50.0g 10% sodium sulfite solution to the organic phase, separate the liquids, and spin dry. The crude product is recrystallized with xylene / n-heptane = 8 / 2, filtered, and dried to obtain 93.8g thiofuranamide, content: 97.5% (liquid chromatography external standard method), two-step yield based on 4-trifluoromethoxyaniline: 85.6%. Example

[0031] 200.0g toluene, 35.4g 4-trifluoromethoxyaniline, 46.4g 2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid and 5.0g boric anhydride were added in sequence into a 500mL four-necked flask equipped with a mechanical stirrer, a condenser and a thermometer, and the temperature was raised to reflux. The reaction was carried out for 4h after reflux and water separation. Sampling was performed. After the raw material content was ≤0.2% by liquid chromatography analysis, the system was cooled to 40°C, 120g 10% sodium carbonate aqueous solution was added for washing once, and the liquid was separated. The organic phase was directly used for the next reaction.

[0032] Add 11.2g potassium carbonate, 61.4g KBr and 70.0g water to the organic phase in the previous step, heat to 40°C, drip 90.0g 30% hydrogen peroxide solution for 1h, stir and react for 1h, take samples, analyze the raw material by liquid chromatography ≤0.2%, stop the reaction, cool to 25°C, separate the liquids, add 50.0g 10% sodium sulfite solution to the organic phase, separate the liquids, and spin dry. The crude product is recrystallized with xylene / n-heptane = 8 / 2, filtered, and dried to obtain 94.8g thiofuranamide, content: 97.8% (liquid chromatography external standard method), two-step yield based on 4-trifluoromethoxyaniline: 87.0%. Example

[0033] 220 g of cyclohexane, 35.4 g of 4-trifluoromethoxyaniline, 48.5 g of 2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid and 6.0 g of phenylboric acid were added in sequence into a 500 mL four-necked flask equipped with a mechanical stirrer, a condenser and a thermometer, and the temperature was raised to reflux. The reaction was carried out for 8 h under reflux and water separation. Sampling was performed. After the raw material content was ≤0.2% by liquid chromatography analysis, the system was cooled to 40°C, 100 g of 10% sodium carbonate aqueous solution was added for washing once, and the liquid was separated. The organic phase was directly used for the next reaction.

[0034] Add 13.8g potassium carbonate, 81.4g KBr and 70.0g water to the organic phase of the previous step, heat to 60°C, drip 200.3g 14% sodium hypochlorite solution for 1h, stir and react for 1h, take samples, analyze the raw material by liquid chromatography ≤0.2%, stop the reaction, cool to 25°C, separate the liquids, add 60.0g 10% sodium sulfite solution to the organic phase, separate the liquids, and spin dry. The crude product is recrystallized with xylene / n-heptane = 8 / 2, filtered, and dried to obtain 96.1g thiothioamide, content: 97.5% (liquid chromatography external standard method), two-step yield based on 4-trifluoromethoxyaniline: 87.8%. Example

[0035] 160.0 g of xylene, 35.4 g of 4-trifluoromethoxyaniline, 50.6 g of 2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid and 8.0 g of 3,4,5-trifluorophenylboric acid were added in sequence into a 500 mL four-necked flask equipped with a mechanical stirrer, a condenser and a thermometer, and the temperature was raised to reflux. The reaction was carried out for 8 h under reflux and water separation. Sampling was performed. After the liquid chromatography analysis showed that the raw material content was ≤0.2%, the system was cooled to 40°C, 120 g of 10% sodium carbonate aqueous solution was added for washing once, and the liquid was separated. The organic phase was directly used for the next reaction.

[0036] Add 17.3g sodium carbonate, 40.5g LiBr and 70.0g water to the organic phase of the previous step, heat to 80°C, drip 230.2g 14% sodium hypochlorite solution for 1h, stir and react for 1h, take samples, analyze the raw material by liquid chromatography ≤0.2%, stop the reaction, cool to 25°C, separate the liquids, add 60.0g 10% sodium sulfite solution to the organic phase, separate the liquids, and spin dry. The crude product is recrystallized with xylene / n-heptane = 8 / 2, filtered, and dried to obtain 96.9g thiofuranamide, content: 97.8% (liquid chromatography external standard method), two-step yield based on 4-trifluoromethoxyaniline: 88.8%.

[0037] The above is only a preferred embodiment of the present invention, and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment, it is not intended to limit the present invention. Therefore, any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention without departing from the content of the technical solution of the present invention shall fall within the scope of protection of the technical solution of the present invention.

Claims

1. A method for synthesizing thiofuranamide, comprising the following steps: Step 1: Using one of phenylboric acid, 3,4,5-trifluorophenylboric acid, boric acid, and boric anhydride as a catalyst, 2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid, 4-trifluoromethoxyaniline and a reaction solvent are mixed, and an acid-amine condensation reaction is carried out at a certain temperature. After the reaction is completed, a 10% sodium carbonate aqueous solution is added to wash the organic phase, and the organic phase after separation is directly used for the next reaction; Step 2: In the presence of an acid binding agent, the organic phase obtained in step 1 is subjected to a bromination reaction with a brominating agent and an oxidizing agent; Step 3: After the water layer of the reaction solution in step 2 is separated, the organic phase is washed with a 10% sodium sulfite solution, separated, the organic phase is spin-dried, and then recrystallized with a xylene / n-heptane mixed solvent to obtain thiothioamide; The reaction equation is as follows: .

2. The method for synthesizing thiofuranamide according to claim 1, wherein: The acid-amine condensation reaction temperature is 60-140° C., and the reaction time is 4-8 hours.

3. The method for synthesizing thiofuranamide according to claim 1, characterized in that: The acid-amine condensation reaction solvent is one of 1,2-dichloroethane, toluene, cyclohexane, chloroform, xylene, dioxane, methyl isobutyl ketone, di-tert-butyl ether or methyl tert-butyl ether.

4. The method for synthesizing thiofuranamide according to claim 1, characterized in that: The molar ratio of the acid-amine condensation reaction materials 4-trifluoromethoxyaniline:2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid:catalyst is 1:1.05-1.2:0.05-0.

20.

5. The method for synthesizing thiofuranamide according to claim 1, characterized in that: The acid-binding agent for the bromination reaction is one of sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

6. The method for synthesizing thiofuranamide according to claim 1, characterized in that: The bromination reaction oxidant is one of hydrogen peroxide and sodium hypochlorite.

7. The method for synthesizing thiofuranamide according to claim 1, characterized in that: The brominating agent is one of lithium bromide, sodium bromide and potassium bromide.

8. The method for synthesizing thiofuranamide according to claim 1, characterized in that: The amount of the acid-amine condensation reaction solvent used is 5 to 8 times the mass of 4-trifluoromethoxyaniline.

9. The method for synthesizing thiofuranamide according to claim 1, characterized in that: The molar ratio of the bromination reaction materials 4-trifluoromethoxyaniline: acid binding agent: oxidant: brominating agent is 1: 0.3-0.8: 2.0-2.8: 2.0-2.

8.

10. The method for synthesizing thiofuranamide according to claim 1, characterized in that: The temperature of the bromination reaction is 25-80° C., and the reaction time is 1-3 hours.

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