Method for preparing bixafen through gas stripping and ion exchange resin deacidification

Abstract

The invention discloses a method for preparing bixafen by utilizing gas stripping and ion exchange resin deacidification, which comprises the following steps: adding 3 ', 4'-dichloro-5-fluoro-2-benzidine and 3-difluoromethyl-1-methyl-1H-pyrazole-4-formyl chloride into an organic solvent, continuously introducing nitrogen into the reaction liquid, heating for reaction, filtering, washing with water, and drying to obtain the bixafen. And separating the obtained hydrogen chloride gas from the reaction liquid along with nitrogen, feeding the hydrogen chloride gas into ion exchange resin for exchange adsorption deacidification, and after the reaction is finished, carrying out cooling crystallization, filtering, washing and drying to obtain the bixafen product. The method disclosed by the invention is high in yield, simple in reaction steps and post-treatment process, convenient in technological operation, safe and environment-friendly.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical industry and relates to a method for preparing bixafen, and specifically relates to a method for preparing bixafen by utilizing gas stripping and ion exchange resin deacidification. Background Art

[0002] Bixafen is a succinate dehydrogenase inhibitor (SDHI) fungicide developed by Bayer AG of Germany. It was made public in 2006, first registered in 2010, and launched in 2011. It is mainly used to control leaf blight, rust and other diseases. The market is growing rapidly and it has become one of the top four SDHI fungicides with huge market prospects. The patent of Bixafen will expire after 2024. In recent years, more and more domestic companies have begun to invest in scientific research to explore the synthesis of Bixafen.

[0003] The synthesis of bixafen mainly uses key intermediates benzidine and 1-methyl-3-difluoromethyl-1H-pyrazole and its derivatives as raw materials. The synthesis methods of bixafen disclosed in the prior art include: (1) Dunkel et al. [WO2008145740] use benzidine and 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride as raw materials, and carry out acylation condensation reaction under the action of an acid binding agent, and then hydrolyze and wash, separate the liquid, evaporate the organic phase under reduced pressure, and crystallize to obtain the finished product of bixafen, with a yield of about 85%; (2) Moradi et al. [US2014128617] use benzidine and 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate as raw materials, and react under the action of a catalyst to obtain a bixafen product. The amidation reaction gave bixafen with a yield of about 86%; (3) Ouyang Jianfeng [CN202210845972.5] used benzidine hydrochloride and 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid as raw materials, added methylsulfonyl chloride and the like as condensation catalysts to synthesize bixafen with a yield of about 90%; (4) Cheng Yanni et al. [CN113149908] condensed 2-iodo-4-fluoroaniline with 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid in the presence of a coupling reagent and 4-dimethylaminopyridine, and then under the action of a palladium metal catalyst, a Suzuki coupling reaction was carried out with 3,4-dichlorophenylboronic acid to give bixafen with a yield of 74.6%.

[0004] The above routes all require the addition of catalysts or acidifying agents, and some routes have harsh reaction conditions, some routes have complex subsequent treatments, and produce large amounts of three wastes, all of which have various deficiencies and are not conducive to industrial production. Therefore, it is urgent to find a more efficient and simple method to synthesize bixafen, so that the synthesis of bixafen is safer, simpler, and more environmentally friendly. Summary of the invention

[0005] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a method for preparing bixafen by gas stripping and ion exchange resin deacidification, which has high yield, simple reaction steps and post-treatment process, convenient process operation, and is safe and environmentally friendly.

[0006] In order to solve the above technical problems, the present invention adopts the following technical solutions.

[0007] A method for preparing bixafen using gas stripping and ion exchange resin deacidification comprises the following steps: adding 3′,4′-dichloro-5-fluoro-2-benzidine and 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride into an organic solvent, continuously introducing nitrogen into the reaction solution, heating the reaction solution to 50°C to 120°C for reaction, separating the obtained hydrogen chloride gas from the reaction solution along with the nitrogen and sending it to an ion exchange resin for exchange adsorption and deacidification, and after the reaction is completed, cooling, crystallizing, filtering, washing and drying to obtain a bixafen product.

[0008] The chemical reaction equation of the present invention is as follows:

[0009]

[0010] In the above-mentioned method for preparing bixafen using gas stripping and ion exchange resin deacidification, preferably, the ion exchange resin is one or more of a macroporous strongly basic styrene-based ion exchange resin D20X and a macroporous weakly basic styrene-based ion exchange resin D30X.

[0011] In the above-mentioned method for preparing bixafen using gas stripping and ion exchange resin deacidification, preferably, the ion exchange resin is filled in a porous glass plate double-layer filling distillation column, and the porous glass plate double-layer filling distillation column has a condensation function, so that the exchange adsorption and deacidification are carried out while condensing and recovering the solvent.

[0012] In the above method for preparing bixafen using gas stripping and ion exchange resin deacidification, preferably, the porous glass plate double-layer packed distillation column is also filled with glass spring filler, and the mass ratio of the ion exchange resin to the glass spring filler is 1 to 5:1.

[0013] In the above method for preparing bixafen using gas stripping and ion exchange resin deacidification, preferably, after the reaction is completed, the ion exchange resin is regenerated by eluting with alkaline solution and then reused.

[0014] In the above method for preparing bixafen using gas stripping and ion exchange resin deacidification, preferably, the flow rate of the nitrogen is 1 L / min to 10 L / min.

[0015] In the above-mentioned method for preparing bixafen by gas stripping and ion exchange resin deacidification, preferably, the molar ratio of the 3′,4′-dichloro-5-fluoro-2-benzidine to 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride is 1:1.0-1.1, the mass ratio of the 3′,4′-dichloro-5-fluoro-2-benzidine to the organic solvent is 1:4-8, and the mass ratio of the ion exchange resin to the 3′,4′-dichloro-5-fluoro-2-benzidine is 1:1-2.1.

[0016] In the above method for preparing bixafen using gas stripping and ion exchange resin deacidification, preferably, the organic solvent is one or more of 1,2-dichloroethane, toluene and xylene.

[0017] In the above method for preparing bixafen using gas stripping and ion exchange resin deacidification, preferably, the reaction time is 1 h to 3 h.

[0018] In the above-mentioned method for preparing bixafen using gas stripping and ion exchange resin deacidification, preferably, the 3′,4′-dichloro-5-fluoro-2-benzidine is mixed with a portion of the organic solvent and added to the reactor, nitrogen is introduced into the liquid and the temperature is increased, and then the mixed solution of the 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride and another portion of the organic solvent is added dropwise.

[0019] The above method for preparing bixafen using gas stripping and ion exchange resin deacidification has a product content of ≥98% and a yield of ≥95%.

[0020] Explanation of terms in this invention:

[0021] Gas stripping utilizes the difference between the actual concentration and the equilibrium concentration of volatile substances in the liquid phase to introduce gas into the liquid phase, so that the volatile gas in the liquid phase is transferred from the liquid phase to the gas phase along with the introduced gas.

[0022] Ion exchange resin is a synthetic polymer material containing ion exchange functional groups and having a cross-linked structure.

[0023] Compared with the prior art, the advantages of the present invention are:

[0024] (1) In the prior art, triethylamine, sodium hydroxide, ammonia, sodium bicarbonate and other organic or inorganic alkali acid-binding agents are used to neutralize the reaction byproduct hydrogen chloride, which consumes alkali and increases costs. On the other hand, the hydrochloride produced needs to be washed and removed in post-treatment, forming a large amount of waste water. In addition, the alkali and water in the reaction system will partially decompose the raw material 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride, resulting in large raw material consumption, increased product cost, and increased impurities. The present invention adopts a gas stripping method to transfer hydrogen chloride in the liquid phase from the liquid phase to the gas phase with nitrogen. The gas phase passes through the ion exchange resin in the condensation filling column, the acidic gas is adsorbed and fixed, and the solvent gas is condensed and refluxed to the reaction system. The rapid removal of the byproduct hydrogen chloride gas greatly improves the reaction rate and reduces the generation of impurities. The obtained bixafen product content is ≥98%, and the yield is ≥95%.

[0025] (2) In the present invention, the ion exchange resin is filled in a porous glass plate double-layer filling distillation column with a condensation function. The airflow passes through the ion exchange resin to remove the acid, while improving the condensation effect of the reflux gas and reducing the solvent loss rate.

[0026] (3) In the present invention, the ion exchange resin and the glass elastic filler are mixed in proportion and filled in the filling column, which solves the problem of too small porosity and too large gas resistance caused by dense filling. When the ion exchange resin is filled in a conventional manner, it will hinder the rise of the gas phase.

[0027] (4) In the present invention, the filled weakly alkaline ion exchange resin can be regenerated and reused by simply washing with alkaline solution.

[0028] In summary, the present invention realizes the clean production of the synthesis step of bixafen, reduces the production cost, and achieves the goal of improving the economic and social benefits of the enterprise. DETAILED DESCRIPTION

[0029] The present invention is further described below in conjunction with specific preferred embodiments, but the protection scope of the present invention is not limited thereby. The materials and instruments used in the following embodiments are all commercially available.

[0030] Example 1

[0031] A method for preparing bixafen using gas stripping and ion exchange resin deacidification of the present invention comprises the following steps:

[0032] 130.7 g (98%, 0.5 mol) of 3′,4′-dichloro-5-fluoro-2-benzidine and 250 g of toluene were added to a 1000 mL four-necked flask, and the four-necked flask, a water separator and a porous glass plate double-layer filled distillation column (commercially available) were connected in sequence. 130.7 g of macroporous strong alkaline styrene-based ion exchange resin D201 and 65 g of glass spring filler were mixed and filled in the distillation column, and the distillation column had a condensation function. The material in the four-necked flask was stirred evenly, nitrogen was introduced into the liquid, and the nitrogen flow rate was 1L / min. After heating to 100°C, 510.8g of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride toluene solution with a mass fraction of 20% (0.52mol) was added dropwise. After the addition was completed, the reaction was kept warm for 1h. The hydrogen chloride gas produced by the reaction escaped from the reaction system due to the dual effects of heating and nitrogen stripping, and exchanged and adsorbed in the ion exchange resin. The solvent gas was condensed and refluxed to the flask. After the reaction was completed, the reaction was cooled, crystallized, filtered, rinsed, and dried to obtain 201.5g of bixafen white crystals with a content of 98.3% and a yield of 95.7%. The filling column equipped with the ion exchange resin was fully rinsed with a sodium hydroxide solution with a mass concentration of 30% and reused.

[0033] Example 2

[0034] A method for preparing bixafen using gas stripping and ion exchange resin deacidification of the present invention comprises the following steps:

[0035] 130.7g (98%, 0.5mol) 3', 4'-dichloro-5-fluoro-2-benzidine and 135g toluene were added to a 1000mL four-necked flask, and the four-necked flask, water separator and porous glass plate double-layer filling distillation column with condensation function were connected in sequence. 65g macroporous weakly alkaline styrene ion exchange resin D301 and 13g glass spring filler were mixed and filled in the distillation column. The materials in the four-necked flask were stirred evenly, nitrogen was introduced into the liquid, and the nitrogen flow rate was 5L / min. After heating to 80°C, 486.4g, 20wt% (0.5mol) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride toluene solution was added dropwise, and the reaction was kept warm for 1.5h after the addition was completed. After the reaction was completed, the crystallization was cooled, filtered, rinsed and dried to obtain 200.8g white crystals of bixafenthion, with a content of 98.1% and a yield of 95.14%. The packed column filled with ion exchange resin is reused after being fully eluted with a 10% by mass sodium hydroxide solution.

[0036] Example 3

[0037] A method for preparing bixafen using gas stripping and ion exchange resin deacidification of the present invention comprises the following steps:

[0038] 130.7g (98%, 0.5mol) 3', 4'-dichloro-5-fluoro-2-benzidine and 620g toluene were added to a 1000mL four-necked flask, and the four-necked flask, the water separator and the porous glass plate double-layer filling distillation column with condensation function were connected in sequence. The distillation column was mixed and filled with 65g of the ion exchange resin D301 regenerated in Example 2 and 13g of glass spring filler. The materials in the four-necked flask were stirred evenly, nitrogen was introduced into the liquid, and the nitrogen flow rate was 10L / min. After heating to 110°C, 535.1g, 20wt% (0.55mol) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride toluene solution was added dropwise, and the reaction was kept warm for 3h after the addition was completed. After the reaction was completed, the reaction was cooled and crystallized, filtered, rinsed and dried to obtain 199.9g of bixafen white crystals, with a content of 98.7% and a yield of 95%.

[0039] Example 4

[0040] A method for preparing bixafen using gas stripping and ion exchange resin deacidification of the present invention comprises the following steps:

[0041] 130.7g (98%, 0.5mol) 3', 4'-dichloro-5-fluoro-2-benzidine and 250g xylene were added to a 1000mL four-necked flask. The four-necked flask was connected to a water separator and a porous glass plate double-layer filling distillation column with a condensing function. 100g macroporous weakly alkaline styrene ion exchange resin D301 and 50g glass spring filler were mixed and filled in the distillation column. The materials in the four-necked flask were stirred evenly, nitrogen was introduced into the liquid, and the nitrogen flow rate was 4L / min. After heating to 120°C, 510.8g, 20wt% (0.52mol) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride in xylene solution was added dropwise. After the addition was completed, the reaction was kept warm for 1h. After the reaction was completed, the mixture was cooled and crystallized, filtered, rinsed, and dried to obtain 200.8g white crystals of bixafen, with a content of 98.05% and a yield of 95.1%.

[0042] Example 5

[0043] A method for preparing bixafen using gas stripping and ion exchange resin deacidification of the present invention comprises the following steps:

[0044] 130.7g (98%, 0.5mol) 3',4'-dichloro-5-fluoro-2-benzidine and 250g 1,2-dichloroethane were added to a 1000mL four-necked flask. A water separator and a porous glass plate double-layer filling distillation column with condensation function were connected to the four-necked flask. 65g macroporous weakly alkaline styrene ion exchange resin D302 and 65g glass spring filler were mixed and filled in the distillation column. The materials in the four-necked flask were stirred evenly, nitrogen was introduced into the liquid at a nitrogen flow rate of 7L / min, and 515.6g 20wt% (0.53mol) 1,2-dichloroethane solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride was added dropwise to the flask after heating to 50°C. After the addition was completed, the mixture was kept warm for 1h. After the reaction was completed, the mixture was cooled for crystallization, filtered, washed and dried to obtain 200.3 g of bixafen white crystals with a content of 98.19% and a yield of 95%.

[0045] Example 6

[0046] A method for preparing bixafen of the present invention comprises the following steps:

[0047] 130.7g (98%, 0.5mol) 3',4'-dichloro-5-fluoro-2-benzidine and 300g 1,2-dichloroethane were added to a 1000mL four-necked flask. A water separator and a porous glass plate double-layer filling distillation column with condensation function were connected to the four-necked flask. 85g macroporous strong alkaline styrene ion exchange resin D202 and 50g glass spring filler were mixed and filled in the distillation column. The materials in the four-necked flask were stirred evenly, nitrogen was introduced into the liquid at a nitrogen flow rate of 6L / min, and 510.8g 20wt% (0.52mol) 1,2-dichloroethane solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride was added dropwise to the flask after heating to 80°C. After the addition was completed, the reaction was kept warm for 1.5h. After the reaction was completed, the mixture was cooled for crystallization, filtered, washed and dried to obtain 200.9 g of white bixafen with a content of 98.11% and a yield of 95.2%.

[0048] Comparative Example 1

[0049] A method for preparing bixafen, comprising the following steps:

[0050] 130.7g (98%, 0.5mol) 3',4'-dichloro-5-fluoro-2-benzidine and 250g 1,2-dichloroethane were added to a 1000mL four-necked flask, and a water separator and a condenser reflux tube were connected to the four-necked flask. After the temperature was raised to 80°C, 510.8g 20wt% (0.52mol) 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride in 1,2-dichloroethane solution was added dropwise, and the temperature was kept for 1h after the addition was completed. After the reaction was completed, the mixture was cooled for crystallization, filtered, rinsed, and dried to obtain 198.4g white crystals of bixafen, with a content of 94.11% and a yield of 90.2%.

[0051] Comparative Example 2

[0052] A method for preparing bixafen, comprising the following steps:

[0053] 130.7g (98%, 0.5mol) 3',4'-dichloro-5-fluoro-2-benzidine and 135g toluene were added to a 1000mL four-necked flask. The four-necked flask was connected to a water separator and a porous glass plate double-layer filling distillation column with a condensing function. 65g macroporous weakly alkaline styrene ion exchange resin D301 and 65g glass spring filler were mixed and filled in the distillation column. After the material in the four-necked flask was heated to 110°C, 486.4g, 20wt% (0.5mol) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride toluene solution was added dropwise. After the addition was completed, the reaction was kept warm for 1.5h. After the reaction was completed, the mixture was cooled, crystallized, filtered, and dried to obtain 197.85g white crystals of bixafen, with a content of 96.4% and a yield of 92.14%.

[0054] Comparative Example 3

[0055] A method for preparing bixafen, comprising the following steps:

[0056] 130.7g (98%, 0.5mol) 3',4'-dichloro-5-fluoro-2-benzidine and 250g toluene were added to a 1000mL four-necked flask, and the four-necked flask was connected to a water separator and a condenser reflux tube, stirred evenly, and nitrogen was introduced into the liquid at a nitrogen flow rate of 10L / min. After heating to 100°C, 510.8g, 20wt% (0.52mol) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride toluene solution was added dropwise, and the temperature was kept for 2h after the addition was completed. After the reaction was completed, the mixture was cooled for crystallization, filtered, and dried to obtain 201.5g of bixafen white crystals with a content of 97.2% and a yield of 92.7%.

[0057] 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 above in the preferred embodiment, it is not used to limit the present invention. Any technician familiar with the art can make many possible changes and modifications to the technical solution of the present invention by using the methods and technical contents disclosed above without departing from the spirit and technical solution of the present invention, or modify it into an equivalent embodiment of equivalent changes. Therefore, any simple modification, equivalent replacement, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention, still fall within the scope of protection of the technical solution of the present invention.

Claims

1. A method for preparing bixafen using gas stripping and ion exchange resin deacidification, characterized in that: The method comprises the following steps: adding 3′,4′-dichloro-5-fluoro-2-benzidine and 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride into an organic solvent, continuously introducing nitrogen into the reaction solution, heating the reaction solution to 50°C to 120°C for reaction, separating the obtained hydrogen chloride gas from the reaction solution along with the nitrogen and sending the gas to an ion exchange resin for exchange, adsorption and deacidification, and after the reaction is completed, cooling, crystallizing, filtering, washing and drying to obtain a bixafen product.

2. The method for preparing bixafen using gas stripping and ion exchange resin deacidification according to claim 1, characterized in that: The ion exchange resin is one or more of macroporous strong alkaline styrene-based ion exchange resin D20X and macroporous weak alkaline styrene-based ion exchange resin D30X.

3. The method for preparing bixafen using gas stripping and ion exchange resin deacidification according to claim 1, characterized in that: The ion exchange resin is filled in a porous glass plate double-layer filling distillation column, and the porous glass plate double-layer filling distillation column has a condensation function, so that the exchange adsorption and deacidification are performed while the solvent is condensed and recovered.

4. The method for preparing bixafen using gas stripping and ion exchange resin deacidification according to claim 3, characterized in that: The porous glass plate double-layer filling type distillation column is also filled with glass spring filler, and the mass ratio of the ion exchange resin to the glass spring filler is 1 to 5:

1.

5. The method for preparing bixafen using gas stripping and ion exchange resin deacidification according to any one of claims 1 to 4, characterized in that: After the reaction is completed, the ion exchange resin is regenerated by eluting with alkaline solution and reused.

6. The method for preparing bixafen using gas stripping and ion exchange resin deacidification according to any one of claims 1 to 4, characterized in that: The flow rate of the nitrogen gas is 1 L / min to 10 L / min.

7. The method for preparing bixafen using gas stripping and ion exchange resin deacidification according to any one of claims 1 to 4, characterized in that: The molar ratio of the 3′,4′-dichloro-5-fluoro-2-benzidine to 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride is 1:1.0-1.1, the mass ratio of the 3′,4′-dichloro-5-fluoro-2-benzidine to the organic solvent is 1:4-8, and the mass ratio of the ion exchange resin to the 3′,4′-dichloro-5-fluoro-2-benzidine is 1:1-2.

1.

8. The method for preparing bixafen using gas stripping and ion exchange resin deacidification according to any one of claims 1 to 4, characterized in that: The organic solvent is one or more of 1,2-dichloroethane, toluene and xylene.

9. The method for preparing bixafen using gas stripping and ion exchange resin deacidification according to any one of claims 1 to 4, characterized in that: The reaction time is 1 h to 3 h.

10. The method for preparing bixafen using gas stripping and ion exchange resin deacidification according to any one of claims 1 to 4, characterized in that: The 3′,4′-dichloro-5-fluoro-2-benzidine and part of the organic solvent are mixed and added into the reactor, nitrogen is introduced into the liquid and the temperature is increased, and then the mixed solution of the 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride and another part of the organic solvent is added dropwise.

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