Efficient synthesis process of high-quality fluazinam

Abstract

The invention provides an efficient synthesis process of high-quality fluazinam, which comprises the following steps: step 1, carrying out dissolution pretreatment on a raw material 2, 4-dichloro-3, 5-dinitrobenzotrifluoride (FDA-2) by using tetrahydrofuran (THF) with high purity and low water content as a solvent; meanwhile, another raw material 2-amino-3-chloro-5-(trifluoromethyl) pyridine (FDA-1) is prepared; step 2, adding metered potassium hydroxide (KOH) and potassium carbonate (K2CO3) into a synthesis kettle, and then reacting the pretreated FDA-2 solution with FDA-1 in THF (tetrahydrofuran) under a strictly controlled temperature condition; and step 3, performing post-treatment on the reaction liquid, including salt dissolving treatment to remove generated salt impurities, and acidizing treatment to adjust the pH value and promote precipitation of fluazinam. The method is high in yield and low in impurity content.

Description

Technical Field

[0001] The invention relates to a production method of a chemical raw material, and specifically to an efficient synthesis process of high-quality fluazinam. Background Art

[0002] Fluazinam (chemical name: 3-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)-α,α,α-trifluoro-2,6-dinitro-p-toluidine; English name: fluazinam; trade name: SHIRLAN, IKF-1216) is a new type of substituted aniline broad-spectrum fungicide developed by Ishihara Sangyo Co., Ltd. It is particularly effective against various gray mold diseases caused by Botrytis cinerea, and also has good activity against diseases caused by pathogens such as Alternaria, Phytophthora, Monoaxella, Sclerotinia and Venturia.

[0003] At present, the synthesis method of fluazinam mainly uses compound A (2-amino-3-chloro-5-trifluoromethylpyridine) and compound B (2,4-dichloro-3,5-dinitrotrifluorotoluene) to react under the action of base and solvent. However, this method has the following problems:

[0004] Hydrolysis side reaction: During the synthesis process, due to the presence of water in the solvent, compound B (2,4-dichloro-3,5-dinitrotrifluorotoluene) is prone to hydrolysis side reaction to generate compound 3-chloro-4-trifluoromethyl-2,6-dinitrophenol. This side reaction significantly reduces the yield of the final product.

[0005] Product purity and yield issues: In order to inhibit the hydrolysis side reaction, the existing technology usually achieves this by increasing the amount of alkali and reducing the amount of water in the solvent. However, this increases the workload of alkali removal in post-treatment and limits the range of solvent selection.

[0006] Wastewater and resource waste: In the production of fluazinam, post-treatment usually involves adding a large amount of water to clean the salts and unreacted alkali generated after the reaction. This not only increases the cost of wastewater treatment, but also because solvents (such as tetrahydrofuran, etc.) are miscible with water, adding a large amount of water during post-treatment will take away a large amount of solvent, making it impossible for the solvent to be effectively recycled, resulting in a waste of resources.

[0007] Chinese patent document CN108929264A discloses the problem of hydrolysis side reaction in the synthesis process of fluazinam. By introducing a phase transfer catalyst into the reaction system and carrying out the reaction at a lower reaction temperature, the selectivity of the reaction is effectively improved, the occurrence of hydrolysis side reaction is reduced, and thus the yield of the product is improved. At the same time, the alkali and the generated salt are removed by filtering and neutralization during the post-treatment process, and no water washing is required, thereby reducing the generation of wastewater and the waste of resources.

[0008] Chinese patent document CN110143916A discloses a two-step continuous synthesis process of fluazinam. First, 2-amino-3-chloro-5-trifluoromethylpyridine is generated by amination reaction, and then residual ammonia is removed by deamination treatment, and then a condensation reaction is performed to obtain fluazinam. This process avoids the side reactions caused by residual ammonia, improves the purity and yield of the product, does not require additional purification steps, and the total separation yield of the two steps can reach more than 97%.

[0009] Chinese patent document CN103626695A discloses a mixed solvent of alkyl-substituted aromatic hydrocarbons and methyl isobutyl ketone as a reaction medium, which effectively inhibits the occurrence of side reactions and improves the purity and yield of fluazinam. By optimizing the solvent ratio and reaction conditions, the method simplifies the purification process, improves the recovery rate of the solvent, and reduces the production cost.

[0010] Although a variety of fluazinam synthesis methods have been disclosed and have achieved certain results, it is still necessary to continue in-depth research to further optimize the synthesis process and improve product performance and production efficiency. Summary of the invention

[0011] In view of the deficiencies in the prior art, the present invention provides a high-efficiency synthesis process of high-quality fluazinam.

[0012] In order to achieve the above object, the present invention adopts the following scheme:

[0013] A high-quality and efficient synthesis process of fluazinam comprises the following steps: step 1, using high-purity and low-water-content tetrahydrofuran (THF) as a solvent to dissolve and pre-treat a raw material 2,4-dichloro-3,5-dinitrotrifluorotoluene (FDA-2); at the same time, preparing another raw material 2-amino-3-chloro-5-trifluoromethylpyridine (FDA-1); step 2, adding measured potassium hydroxide (KOH) and potassium carbonate (K2CO3) into a synthesis reactor, and then reacting the pre-treated FDA-2 solution with FDA-1 in THF under strictly controlled temperature conditions; step 3, post-treating the reaction solution, including salt dissolution treatment to remove generated salt impurities, and acidification treatment to adjust the pH value and promote the precipitation of fluazinam.

[0014] The method comprises step 4, wherein crude fluazinam is separated by filter pressing operation, and then subjected to purification and drying treatment to obtain the final product.

[0015] The purity of THF should be above 99%, and the water content should not be higher than 0.05%.

[0016] The purity of FDA-2 and FDA-1 is not less than 99% respectively, and the water content of FDA-2 does not exceed 0.5%.

[0017] The dissolution process of FDA-2 in THF requires continuous stirring to ensure that no solid residue remains.

[0018] The molar ratio of FDA-1:KOH:K2CO3 is 1:3~3.5:0.2~0.3.

[0019] The acidification treatment in step 3 requires the use of 30% hydrochloric acid solution and the pH value of the system is adjusted to the range of 2 to 3.

[0020] The purification steps of crude fluazinam include heating and dissolving in refined ethanol, slowly cooling and crystallizing, and centrifuging.

[0021] The refined ethanol is heated to 75-80°C and then cooled to 15-20°C for crystallization to ensure the best crystallization conditions for the product.

[0022] The percentage of each impurity in the obtained fluazinam finished product is: M421≤0.65%, fluazinam isomer≤0.03%, M453≤0.25%, M474≤0.03%, M713≤0.03%, M286≤0.04%, M624≤0.1%.

[0023] The efficient catalytic system and precise pH value adjustment of the present invention are helpful to reduce the generation of by-products, improve the yield and further enhance the purity of the product. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following briefly introduces the drawings required for use in the description of the embodiments of the present invention. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the contents of the embodiments of the present invention and these drawings without paying any creative work.

[0025] Figure 1 The figure is a schematic diagram of the synthesis process of the present invention. DETAILED DESCRIPTION

[0026] In order to make the technical problems solved by the present invention, the technical solutions adopted and the technical effects achieved clearer, the technical solutions of the embodiments of the present invention will be further described in detail below in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0027] The detailed steps of the present invention are specifically described below:

[0028] 1. Raw material preparation and pretreatment

[0029] 1. Dissolving kettle operation

[0030] While ensuring that the dissolving kettle is clean and free of water, the raw materials are added and dissolved.

[0031] Raw material preparation: 2,4-dichloro-3,5-dinitrotrifluorotoluene (FDA-2 for short, content: ≥99%, moisture content: ≤0.5%, light yellow crystalline solid) and tetrahydrofuran (THF, content: ≥99%, moisture content: ≤0.05%, colorless transparent liquid).

[0032] Feed ratio: feed according to the molar ratio of 2-amino-3-chloro-5-trifluoromethylpyridine (FDA-1) to 2,4-dichloro-3,5-dinitrotrifluorotoluene (FDA-2) of 1:1-1.2, for example, 1:1.1. For example, FDA-2 is 377.3 g, and the amount of THF added at this time is in the range of 1200-1500 ml, such as 1400 ml.

[0033] Operation process: Add the calculated FDA-2 and THF into the dissolving kettle in proportion, turn on the stirring device, set the stirring speed to a moderate level, and fully dissolve FDA-2 in THF. The dissolution time is set to 15 minutes, and pay attention to the dissolution during the period to ensure that there is no undissolved solid residue. After the dissolution is completed, transfer the dissolved FDA-2 tetrahydrofuran solution to the high-temperature drop tank through a pump to prepare for the subsequent drop operation.

[0034] 2. Preparation of Synthesis Reactor

[0035] Raw material preparation: another raw material 2-amino-3-chloro-5-trifluoromethylpyridine (FDA-1, content: ≥99%, white or off-white crystalline solid) and an appropriate amount of THF.

[0036] Feed ratio: Take 1 mol of FDA-1, the corresponding amount of THF is still 1200 ml.

[0037] Operation process: Add the calculated amount of FDA-1 and THF into the synthesis reactor, start the stirring device of the synthesis reactor, set the appropriate stirring speed, so that FDA-1 is evenly dispersed in THF to form a suspension or slightly soluble system.

[0038] 2. Addition of catalyst and additives

[0039] Add catalyst and auxiliary agent into the synthesis reactor, and select potassium carbonate (K2CO3, milky white crystalline solid) and potassium hydroxide (KOH, flake potassium, content: ≥92%, gray-green flake).

[0040] Feeding ratio: 2.5-3.5 mol of alkali is used relative to 1 mol of FDA-1, and 3 mol of potassium hydroxide is taken as the middle value here. Potassium carbonate is 0.2-0.3 mol relative to 1 mol of FDA-1, such as 0.25 mol.

[0041] Operation process: Slowly and evenly add potassium hydroxide and potassium carbonate into the synthesis reactor under stirring. The temperature must be strictly controlled below 30°C during the addition process, which can be achieved by jacket cooling water or ice salt bath. Continue stirring for a while after adding to allow the alkali to fully dissolve and distribute evenly.

[0042] 3. FDA-2 tetrahydrofuran solution addition

[0043] Dropwise addition: After the catalyst and auxiliary agent are added, the pre-dissolved FDA-2 tetrahydrofuran solution is uniformly added to the synthesis reactor through a high-temperature dropwise addition tank. The dropwise addition time is about 2 hours, during which the temperature change in the synthesis reactor must be strictly monitored.

[0044] Temperature control: During the dropping process, it is necessary to ensure that the temperature in the synthesis reactor does not exceed the set range (20-30°C), which can be achieved by adjusting the flow rate of cooling water or changing the dropping speed. If the temperature is too high, the dropping speed can be appropriately reduced and the cooling water flow rate can be increased; otherwise, the dropping speed can be appropriately increased to reduce the reaction time.

[0045] 4. Insulation reaction and central control detection

[0046] Heat preservation reaction: After the addition is completed, the temperature in the synthesis reactor is slightly raised to 45-50°C, and the heat preservation reaction is carried out at this temperature for 1-2 hours. During the heat preservation reaction, a complex chemical reaction occurs between the reactants to generate the target product fluazinam (3-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)-α,α,α-trifluoro-2,6-dinitro-p-toluidine).

[0047] In-process testing: To monitor the progress of the reaction, regular sampling and testing are required. The changes in the components in the reaction system can be monitored by methods such as high performance liquid chromatography (HPLC). Pay attention to the changes in the content of ACTF to ensure that its content drops below 1%. At the same time, pay attention to the color, smell and other appearance characteristics of the reaction system to assist in judging whether the reaction is complete.

[0048] The chemical formula of ACTF is as follows:

[0049]

[0050] The reaction is as follows

[0051]

[0052] 5. Salt treatment and acidification

[0053] Salt dissolving treatment: After the reaction is qualified, add an appropriate amount of deionized water into the synthesis kettle for salt dissolving treatment to remove the salt impurities generated in the reaction.

[0054] Acidification: Transfer the reaction solution to an acidification kettle and use 30% hydrochloric acid to adjust the pH value of the solution to 2-3. When adjusting the pH value, slowly add hydrochloric acid and stir the reaction solution at the same time to ensure that the pH value drops evenly and does not cause side reactions caused by local over-acidification. Keep the pH value stable for 15 minutes to ensure complete reaction and promote the precipitation of fluazinam.

[0055] 6. Filtration and desolventization

[0056] Filter pressing operation: After acidification, the reaction solution is subjected to filter pressing operation to separate the mother liquor and the solid product. The pressure needs to be controlled during the filter pressing process to avoid the solid product from breaking or the mother liquor from leaking. The filter cake is the crude fluazinam product that needs to be further purified; the filtrate is collected in the desolventizing kettle to prepare for solvent recovery.

[0057] Solvent removal operation: The mother liquor is heated to 94-96°C for solvent removal to recover tetrahydrofuran (THF). During the solvent removal process, a suitable vacuum degree must be maintained to promote solvent evaporation and prevent impurities from being mixed into the recovered THF. After the solvent removal is completed, the recovered THF is dried as needed to ensure that its purity meets the requirements for subsequent use. At the same time, an appropriate amount of deionized water is added to the mother liquor to cool it down to induce the crystallization of fluazinam so as to further recover the solid product.

[0058] 7. Recrystallization and finished product preparation

[0059] After obtaining crude fluazinam (external standard: ≥90%, moisture content: ≤12%) by centrifugal separation, further recrystallization treatment is required to improve the purity of the product. The crude fluazinam is dissolved in refined ethanol (content: ≥95%, moisture content: ≤5%, colorless transparent liquid), heated to 75-80°C (ethanol dissolution temperature), stirred and dissolved, and then slowly cooled to 15-20°C (crystallization temperature) for crystallization, and the cooling rate is 10-15°C / hr. After the crystallization is completed, the finished product fluazinam, i.e. refined fluazinam (external standard: ≥98%, loss on drying ≤0.1%, yellow crystalline solid; pH value: 5-9; insoluble matter ≤0.1%; impurity index: M421≤0.65%, fluazinam isomer ≤0.03%, M453≤0.25%, M474≤0.03%, M713≤0.03%, M286≤0.04%, M624≤0.1%, other impurities ≤0.05%) is obtained by centrifugation, and the finished product fluazinam, i.e. refined fluazinam (external standard: ≥98%, loss on drying ≤0.1%, yellow crystalline solid; pH value: 5-9; insoluble matter ≤0.1%; impurity index: M421≤0.65%, fluazinam isomer ≤0.03%, M453≤0.25%, M474≤0.03%, M713≤0.03%, M286≤0.04%, M624≤0.1%, other impurities ≤0.05%) is obtained, and the finished product fluazinam is obtained by centrifugation, and the finished product fluazinam is obtained by centrifugation, and the finished product fluazinam is obtained by centrifugation, and the residual solvent and moisture are removed.

[0060] The structural formula of M421 is as follows:

[0061]

[0062] The structural formula of fluazinam isomers is as follows;

[0063]

[0064] The structural formula of M453 is as follows:

[0065]

[0066] The structural formula of M474 is as follows:

[0067]

[0068] The structural formula of M713 is as follows:

[0069]

[0070] The structural formula of M286 is as follows:

[0071]

[0072] The structural formula of M624 is as follows:

[0073]

[0074] 8. Solvent Recovery

[0075] Ethanol recovery: The mother liquor of recrystallization also needs to be desolventized to recover ethanol for recycling as a solvent. The mother liquor is heated to a suitable temperature (such as 95°C adjusted according to the boiling point of ethanol) to perform desolventization to recover ethanol. The recovered ethanol can be used in subsequent recrystallization or other process processes to achieve resource recycling and reduce production costs and environmental pollution.

[0076] Example 1

[0077] First, prepare and pretreat the raw materials. Weigh 377.3 g of 2,4-dichloro-3,5-dinitrotrifluorotoluene (FDA-2) to ensure that its content is not less than 99% and the moisture content does not exceed 0.5%. At the same time, prepare 1400 ml of tetrahydrofuran (THF), the content of which should reach more than 99% and the water content should not exceed 0.05%. In a clean dissolution kettle, slowly add FDA-2 to THF, turn on the stirring device, and set the stirring speed to a moderate level to ensure that FDA-2 is fully dissolved in THF. The dissolution process lasts for 15 minutes, during which the dissolution needs to be closely observed to ensure that no solid residues remain. After the dissolution is completed, transfer the solution to a high-temperature drop tank by pump for standby use.

[0078] Another raw material, 2-amino-3-chloro-5-trifluoromethylpyridine (FDA-1), also needs to be pretreated. Weigh FDA-1 (about 342.8 g, based on the molar mass of FDA-2) at a molar ratio of 1:1.1 to FDA-2, and add 1200 ml of THF into the synthesis reactor. Start the stirring device to evenly disperse FDA-1 in THF to form a suspension or slightly soluble system.

[0079] Next, add the catalyst and auxiliary agent to the synthesis reactor. According to the feeding ratio, weigh 3 mol potassium hydroxide (KOH) and 0.25 mol potassium carbonate (K2CO3). In this embodiment, the molar ratio of FDA-1: KOH: K2CO3 is about 1: 3.3: 0.275. Under stirring, slowly and evenly add the two alkalis to the synthesis reactor. The temperature must be strictly controlled below 30 ° C during the feeding process, which can be achieved by jacket cooling water or ice salt bath. Continue stirring for a period of time after adding to fully dissolve the alkali and distribute it evenly. This step is crucial for the smooth progress of subsequent reactions. It can catalyze the reaction, increase the yield of the product and reduce the generation of impurities.

[0080] After the addition is completed, start dripping the pre-dissolved FDA-2 tetrahydrofuran solution. The solution is uniformly added to the synthesis reactor through the high-temperature tank, and the dripping time is about 2 hours. During this period, the temperature change in the synthesis reactor must be strictly monitored to ensure that the temperature does not exceed the set range (20-30°C). To achieve this goal, the flow rate of cooling water can be adjusted or the dripping speed can be changed according to actual conditions. If the temperature is too high, the dripping speed can be appropriately reduced and the cooling water flow rate can be increased; otherwise, the dripping speed can be appropriately increased to reduce the reaction time. The precise control of this step has an important impact on the smooth progress of the reaction and the quality of the product.

[0081] After the addition is completed, the temperature in the synthesis reactor is slightly raised to 45-50°C, and the reaction is kept warm at this temperature for 1-2 hours. During the insulation reaction, complex chemical reactions occur between the reactants to generate the target product fluazinam. In order to monitor the progress of the reaction, regular sampling and testing are required. The changes in the components in the reaction system can be monitored by high performance liquid chromatography (HPLC) and other methods, and attention should be paid to the changes in the content of ACTF to ensure that its content drops below 1%. The reaction conditions can be adjusted in time through central control detection to avoid the formation of by-products and waste of raw materials.

[0082] After the reaction is qualified, add an appropriate amount of deionized water to the synthesis kettle for salt dissolution treatment to remove salt impurities generated in the reaction. Subsequently, the reaction solution is transferred to the acidification kettle, and 30% hydrochloric acid is used to adjust the pH value of the solution to 2-3. When adjusting the pH value, hydrochloric acid needs to be slowly added and the reaction solution is stirred at the same time to ensure that the pH value decreases evenly and does not cause side reactions caused by local overacidity. Keep the pH value stable for 15 minutes to ensure that the reaction is complete and promote the precipitation of fluazinam.

[0083] After acidification, the reaction solution is subjected to a filter press operation to separate the mother liquor from the solid product. The pressure needs to be controlled during the filter press to avoid the breakage of the solid product or the leakage of the mother liquor. The filter cake is the crude fluazinam product, which needs to be further purified. The crude fluazinam is dissolved in refined ethanol, heated to 75-80°C and stirred to dissolve, and then slowly cooled to 15-20°C for crystallization. After the crystallization is completed, the finished product fluazinam, i.e. refined fluazinam, is obtained by centrifugation. Finally, the finished product is dried to remove residual solvents and moisture to obtain the final product.

[0084] Embodiment 2:

[0085] Accurately weigh 377.3 g of 2,4-dichloro-3,5-dinitrotrifluorotoluene (FDA-2), ensuring that its purity is not less than 99% and the moisture content is strictly controlled below 0.5%. Prepare 1400 ml of high-purity tetrahydrofuran (THF), ensuring that its content reaches more than 99% and the moisture content is less than 0.05%.

[0086] In a clean and dry dissolution kettle, slowly add FDA-2 to pre-cooled THF, start the stirring device at the same time, adjust to a suitable stirring speed, ensure that FDA-2 is completely dissolved in THF, and the dissolution process lasts for 15 minutes. During this period, carefully observe the dissolution state to avoid solid residue. After the dissolution is completed, use a corrosion-resistant pump to smoothly transfer the solution to a high-temperature drop tank equipped with a temperature control system for standby use.

[0087] According to the molar amount of FDA-2, accurately calculate and weigh 2-amino-3-chloro-5-trifluoromethylpyridine (FDA-1) with a molar ratio of 1:1.05, about 339.4 g. Slowly add FDA-1 into a synthesis reactor filled with 1200 ml of pre-cooled THF, start stirring, and ensure that FDA-1 is evenly dispersed in THF to form a stable suspension or slightly soluble system.

[0088] Accurately weigh 3 mol potassium hydroxide (KOH) and 0.2 mol potassium carbonate (K2CO3). In this embodiment, the molar ratio of FDA-1:KOH:K2CO3 is about 1:3.15:0.21. While stirring, slowly and evenly add the two bases to the synthesis reactor through a special feeding funnel. During the feeding process, the jacket cooling water is used to accurately control the temperature in the synthesis reactor to not exceed 30°C to prevent local overheating.

[0089] After the addition is completed, stirring is continued for a period of time to ensure that the alkali is completely dissolved and evenly dispersed in the reaction system.

[0090] Start the heating and cooling system of the synthesis reactor, accurately set and maintain the reaction temperature within the range of 25±2℃.

[0091] Turn on the dropping system and add the FDA-2 tetrahydrofuran solution in the dissolution kettle to the synthesis kettle at a uniform rate. The dropping process lasts for about 2 hours. During this period, the reaction temperature is closely monitored and the cooling water flow rate is adjusted in time to ensure that the temperature is stable and does not exceed the standard.

[0092] After the addition was completed, the temperature in the synthesis reactor was gradually raised to 50°C and kept at this temperature for 2 hours. During the reaction, samples were taken regularly and high performance liquid chromatography (HPLC) was used for online monitoring, focusing on the conversion rate of the reactants and the formation of by-products to ensure that the reaction was carried out smoothly and efficiently.

[0093] After the reaction is completed, slowly add an appropriate amount of deionized water into the synthesis reactor to dissolve the salt and effectively remove the salt impurities generated during the reaction.

[0094] The reaction solution was transferred to an acidification kettle equipped with a stirring device, and 30% hydrochloric acid solution was slowly added dropwise while stirring, and the pH value of the system was accurately adjusted to the range of 2 to 3. The stirring state was maintained to make the system evenly acidified.

[0095] After the acidification is completed, the system is maintained under acidic conditions and stirred for 15 minutes to ensure that fluazinam is fully precipitated.

[0096] Then, a filter press operation is performed to separate the mother liquor from the solid product. The filter cake is the crude fluazinam, which needs to be further purified.

[0097] The crude fluazinam was added to the refined ethanol, heated to 78±2°C to completely dissolve it, and then slowly cooled to 18±2°C for crystallization. After the crystallization was completed, the finished fluazinam was obtained by centrifugation, and finally dried to completely remove the residual solvent and water.

[0098] Comparative Example 1: Reaction without catalyst

[0099] The procedure of Example 1 was followed, but the step of adding potassium carbonate was omitted and only potassium hydroxide was used as the base catalyst.

[0100] Comparative Example 2: Reactions under different solvent conditions

[0101] Methyl isobutyl ketone (MIBK) was selected as the reaction solvent instead of tetrahydrofuran (THF), and the other raw material ratios, catalyst types and amounts, reaction conditions, etc. were all the same as those in Example 2.

[0102] Comparative Example 3:

[0103] The temperature of the heat preservation reaction is increased to 60-70°C, which is significantly higher than the 45-50°C recommended in the present invention.

[0104] Other conditions (such as solvent, catalyst dosage, reaction time, etc.) remain the same as in Example 2.

[0105] Comparative Example 4: Reducing the amount of catalyst

[0106] The dosage of potassium hydroxide (KOH) and potassium carbonate (K2CO3) was reduced, and the molar ratio of FDA-1:KOH:K2CO3 was adjusted to 1:1:0.1, which is much lower than the recommended ratio in the present invention.

[0107] Other conditions (such as temperature, solvent, reaction time, etc.) remain the same as in Example 2.

[0108] The obtained product was tested and analyzed, and the specific results are as follows:

[0109]

[0110] The yields in Example 1 and Example 2 are higher than those in Comparative Examples 1-4, and the impurities are less than those in Comparative Examples 1 and 2, because the conversion of the raw materials into impurities is reduced.

[0111] In the present invention, potassium carbonate and potassium hydroxide (KOH) act synergistically as auxiliary agents to promote the reaction between the raw materials. An appropriate amount of potassium carbonate can enhance the catalytic effect and increase the reaction rate and yield.

[0112] During the reaction, some acidic byproducts may be produced. If these acidic byproducts are not neutralized in time, they may affect the reaction and even cause side reactions. The addition of potassium carbonate can neutralize these acidic byproducts, maintain the stability of the reaction system, and thus reduce the generation of impurities.

[0113] The addition of potassium carbonate changes the reaction path by affecting the electron cloud density of the reactants, making the reaction more inclined to produce the target product fluazinam rather than other impurities.

[0114] If too much potassium carbonate is added, the reaction system may become over-alkalized, thereby initiating a series of side reactions and generating more impurities. Therefore, the amount of potassium carbonate added needs to be strictly controlled to avoid this.

[0115] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the technical principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A high-quality and efficient synthesis process of fluazinam, characterized in that: The following steps are involved: Step 1, using high-purity and low-water-content tetrahydrofuran (THF) as a solvent to dissolve and pre-treat the raw material 2,4-dichloro-3,5-dinitrotrifluorotoluene (FDA-2); at the same time, preparing another raw material 2-amino-3-chloro-5-trifluoromethylpyridine (FDA-1); Step 2, adding measured potassium hydroxide (KOH) and potassium carbonate (K2CO3) into a synthesis reactor, and then reacting the pre-treated FDA-2 solution with FDA-1 in THF under strictly controlled temperature conditions; Step 3, post-treating the reaction solution, including salt dissolution treatment to remove generated salt impurities, and acidification treatment to adjust the pH value and promote the precipitation of fluazinam.

2. The high-quality and efficient synthesis process of fluazinam according to claim 1, characterized in that: The method comprises step 4, wherein crude fluazinam is separated by filter pressing operation, and then subjected to purification and drying treatment to obtain the final product.

3. The high-quality and efficient synthesis process of fluazinam according to claim 1, characterized in that: The purity of THF should be above 99%, and the water content should not be higher than 0.05%.

4. The high-quality and efficient synthesis process of fluazinam according to claim 1, characterized in that: The purity of FDA-2 and FDA-1 is not less than 99% respectively, and the water content of FDA-2 does not exceed 0.5%.

5. The high-quality and efficient synthesis process of fluazinam according to claim 1, characterized in that: The dissolution process of FDA-2 in THF requires continuous stirring to ensure that no solid residue remains.

6. The high-quality and efficient synthesis process of fluazinam according to claim 1, characterized in that: The molar ratio of FDA-1:KOH:K2CO3 is 1:3~3.5:0.2~0.

3.

7. The high-quality and efficient synthesis process of fluazinam according to claim 1, characterized in that: The acidification treatment in step 3 requires the use of a 30% hydrochloric acid solution, and the pH value of the system is adjusted to a range of 2 to 3.

8. The high-quality and efficient synthesis process of fluazinam according to claim 2, characterized in that: The purification steps of crude fluazinam include heating dissolution in refined ethanol, slowly cooling crystallization and centrifugal separation.

9. The high-quality and efficient synthesis process of fluazinam according to claim 8, characterized in that: The refined ethanol is heated to 75-80°C and then cooled to 15-20°C for crystallization.

10. The high-quality and efficient synthesis process of fluazinam according to claim 1, characterized in that: The percentage of each impurity in the obtained fluazinam finished product is: M421≤0.65%, fluazinam isomer≤0.03%, M453≤0.25%, M474≤0.03%, M713≤0.03%, M286≤0.04%, M624≤0.1%.

Images