CN110117256B

CN110117256B - Synthesis method of bixafen

Info

Publication number: CN110117256B
Application number: CN201910551960.XA
Authority: CN
Inventors: 范晨; 孙军; 孙小丽; 颜红侠
Original assignee: Ruicheng County Sipulundi Biological Engineering Co ltd
Current assignee: Shanxi Sprundi Bioengineering Co ltd
Priority date: 2019-06-25
Filing date: 2019-06-25
Publication date: 2023-06-30
Anticipated expiration: 2039-06-25
Also published as: CN110117256A8; CN110117256A

Abstract

The invention relates to a synthesis method of bixafen, which comprises the steps of preparing 3, 4-dichlorophenylhydrazine hydrochloride from 3, 4-dichloroaniline by using a reducing agent, introducing air into the 3, 4-dichlorobenzene hydrochloride in an alkaline environment, performing oxidative coupling on the 3 ', 4' -dichloro-5-fluoro-2-benzidine and 1-methyl-3-difluoromethyl-4-pyrazole formyl chloride to obtain an intermediate, and performing amidation reaction on the intermediate and the intermediate. The process adopted by the invention has mild and controllable reaction conditions, simple and convenient operation, easy product purification and capability of directly recrystallizing to obtain the product. The intermediate control method of each step is simple and accurate, the product yield is higher, the atom economy is better, the complicated post-treatment of the old method is avoided, and the method has great competitive advantage and industrial production utilization value. Meanwhile, the solid waste generated by using high-risk raw materials such as butyl lithium and a large amount of tar-like substances is avoided, the three wastes are extremely low, and the method accords with the concept of green chemistry.

Description

Synthesis method of bixafen

Technical Field

The invention belongs to a synthesis method of bixafen, and relates to a preparation method of bixafen serving as a pyrazole amide fungicide.

Background

The Bixafen is a pyrazole amide succinic acid dehydrogenation mediator inhibitor developed by Bayer company, the action mechanism of the Bixafen is a novel cereal bactericide, the mitochondrial inhibitor disturbs the electron transfer function of a complex II in respiration, the Bixafen mainly acts on the prevention and treatment of leaf rust and leaf spot, and is expected to become an important variety for the resistance treatment of the bactericide, and the Bixafen has the effects of 'incomparable', long-acting and broad-spectrum disease prevention and treatment with a mixture of prothioconazole. The compound agent has positive effects on plant physiology, can enhance stress resistance and increase yield, and combines the foliar protection of a patent emulsion formula to improve the crop coverage rate and rain resistance.

At present, two main methods exist for preparing bixafen, namely, a method for preparing intermediate 3 ', 4' -dichloro-5-fluoro-2-benzidine by carrying out Suzuki coupling reaction on 2-bromo-4-fluoroaniline and 3, 4-dichlorobenzoic acid serving as raw materials in the presence of a palladium catalyst. Then the benzidine intermediate and 1-methyl-3-difluoromethyl-4-pyrazole formyl chloride are subjected to acylation reaction to obtain the target product. The total yield of the route is about 63%, european patent WO2008145740 describes the method, but the raw materials 2-bromo-4-fluoroaniline and 3, 4-dichlorobenzoic acid adopted by the route are expensive, and the Suzuki reaction needs to adopt an expensive palladium catalyst, so that the technical scheme has high cost, is not beneficial to industrial production, and prevents the popularization of the high-efficiency pesticide variety.

The other is to construct benzidine intermediate by diazotizing 3, 4-dichloroaniline as raw material and coupling with p-fluoroaniline, then acylating with 1-methyl-3-difluoromethyl-4-pyrazole formyl chloride to generate target product with total yield of 55.8% (for example Chemistry-A European Journal,2012,18 (37): 11555-11559), but the coupling reaction of diazonium reagent and p-fluoroaniline by the method has extremely low conversion rate, the reaction process is not easy to control, a large amount of tar byproducts are generated in the reaction process, purification difficulty is caused in the subsequent process, and serious problems of large amount of solid waste and the like which are unfavorable for industrial production are caused. And then (Journal of Organic Chemistry,2014, vol.79, #5, 2314-2320) further improves the method, adopts stannous chloride to reduce diazonium salt to form biphenyl hydrazine hydrochloride solid, and then adds the biphenyl hydrazine hydrochloride solid into a reaction system for oxidative coupling, but the yield of the method is lower than 44%, the adopted stannous chloride is expensive and difficult to store, and in the practical application process, new tin metal oxychloride pollution is introduced into the nature, so that the method is unfavorable for realizing two principles of economy and environmental protection in industrial production.

Disclosure of Invention

Technical problem to be solved

In order to avoid the defects of the prior art, the invention provides a method for synthesizing bixafen, and provides an economic, green and environment-friendly bixafen preparation method suitable for industrial production.

Technical proposal

The synthesis method of bixafen is characterized by comprising the following steps:

step 1: mixing and dissolving a compound 3, 4-dichloroaniline, an acid substance and a solvent, adding sodium nitrite to react for 0.5-2 hours at the temperature of-20-10 ℃, and filtering to obtain clear liquid; mixing the clear solution and the reducing agent in a molar ratio of 1:1-1:4, and reacting for 1-8 hours at 40-80 ℃ to generate 3, 4-dichlorobenzene; adding hydrochloric acid to react for 30min to 1.5h at the temperature of between 40 and 80 ℃ and filtering to obtain a white solid of the 3, 4-dichlorobenzene hydrazine hydrochloride; the molar ratio of the compound 3, 4-dichloroaniline to the acid substances is 1:2.5-1:5, the molar ratio of the compound to the sodium nitrite is 1:1-1:2, and the mass and volume ratio of the compound to the solvent is 1g:0.5 ml-1 g:10ml; the mol ratio of the 3, 4-dichlorophenylhydrazine to the hydrochloric acid is 1:1-1:4;

step 2: mixing 3, 4-dichlorobenzene hydrazine hydrochloride, a solvent, a base catalyst and p-fluoroaniline, introducing air under stirring, reacting at 30-90 ℃ for 8-48 hours, cooling to room temperature, washing the reaction liquid, separating out an organic phase, drying, and performing rotary evaporation to obtain an intermediate 3 ', 4' -dichloro-5-fluoro-2-benzidine; the volume ratio of the mass of the 3, 4-dichlorobenzene hydrazine hydrochloride to the solvent is 1g:0.5 ml-1 g:10ml, the molar ratio of the 3, 4-dichlorobenzene hydrazine hydrochloride to the base catalyst is 1:1-1:3, and the molar ratio of the 3, 4-dichlorobenzene hydrazine hydrochloride to the p-fluoroaniline is 1:1-1:15;

step 3: reacting an intermediate 3 ', 4' -dichloro-5-fluoro-2-benzidine, 1-methyl-3-difluoromethyl-4-pyrazole formyl chloride, a solvent and a catalyst at the temperature of 30-90 ℃ for 1-5 h, cooling to room temperature after the reaction, washing the reaction solution with water, separating out an organic phase, drying, rotary steaming, concentrating and recrystallizing to obtain bixafen; the molar ratio of the intermediate 3 ', 4' -dichloro-5-fluoro-2-benzidine to the 1-methyl-3-difluoromethyl-4-pyrazole formyl chloride is 1:1-1:0.8, the mass and volume ratio of the intermediate to the solvent is 1g:4 ml-1 g:15ml, and the molar ratio of the intermediate to the catalyst is 1:0.3-1:2.

The acid substance is one or more of hydrochloric acid, sulfuric acid, nitric acid and acetic acid.

The solvent in the steps 1 to 3 is as follows: ethyl acetate, ethyl formate, acetonitrile, water, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dimethyl tetrahydrofuran, benzene, toluene, xylene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride.

The reducing agent is one or more of zinc powder, iron powder, potassium borohydride, sodium bisulphite, sodium sulfite, ferrous sulfate and ethanol.

The base catalyst comprises one or more of sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide and sodium borohydride.

The catalyst comprises one or more of triethylamine, pyridine, N-diisopropylethylamine, sodium hydroxide, cesium carbonate, potassium carbonate, sodium bicarbonate, ammonium carbonate and tetrabutylammonium bromide.

Advantageous effects

According to the synthesis method of bixafen, 3, 4-dichloroaniline is firstly prepared into 3, 4-dichlorobenzene hydrochloride by using a reducing agent, then air is introduced into the 3, 4-dichlorobenzene hydrochloride in an alkaline environment to be subjected to oxidative coupling with p-fluoroaniline to obtain an intermediate 3 ', 4' -dichloro-5-fluoro-2-benzidine, and finally amidation reaction is carried out with 1-methyl-3-difluoromethyl-4-pyrazole formyl chloride to prepare the bixafen. The invention has high synthesis conversion rate and selectivity, adopts cheap and easily available raw materials, and greatly reduces the production cost of the product. In addition, the reaction condition of the process adopted by the invention is mild and easy to control, the operation is simple and convenient, the product is easy to purify, and the product can be obtained by direct recrystallization. The intermediate control method of each step is simple and accurate, the product yield is higher, the atom economy is better, the complicated post-treatment of the old method is avoided, and the method has great competitive advantage and industrial production utilization value. Meanwhile, the solid waste generated by using high-risk raw materials such as butyl lithium and a large amount of tar-like substances is avoided, the three wastes are extremely low, and the method accords with the concept of green chemistry.

Compared with the prior art, the invention has the following advantages: the method for preparing bixafen has the advantages of mild reaction conditions, cheap and easily obtained preparation raw materials, simple and convenient steps, green and clean selected reagents and reaction processes, great reduction of three wastes, suitability for industrial production, and higher yield and content of final products.

When 3,4 ' -dichloro-5-fluoro-2-benzidine is used for preparing the intermediate 3 ', 4 ' -dichloro-5-fluoro-2-benzidine, the intermediate 3, 4-dichlorobenzene hydrochloride is more stable, the use of the reagent amount is reduced, the operation steps are simplified, the occurrence of side reactions is avoided, the reaction efficiency is improved, the three wastes are less in pollution, and the method is suitable for industrial production. In addition, the preparation raw materials are cheap and easy to obtain, and the yield and the content of the compound 3 ', 4' -dichloro-5-fluoro-2-benzidine are higher.

Drawings

FIG. 1 is a schematic diagram of the principle of the method for synthesizing bixafen according to the invention

Detailed Description

The invention will now be further described with reference to examples, figures:

example 1

The preparation method of bixafen in the embodiment comprises the following steps:

step (1) Compound 3, 4-dichloroaniline (38.88 g,0.2399 mol) was dissolved in dichloroethane (30 ml), then 12mol/L of concentrated hydrochloric acid (70 ml,0.84 mol) and sodium nitrite (18.06 g,0.261 mol) were added, the reaction mixture was stirred at 5℃for 30min, then the clear liquid was filtered off with suction, and the mixture was added dropwise to 140ml of sodium sulfite-containing solution (90.71 g,0.7197 mol) and reacted at 80℃for about 3 hours to give 3, 4-dichlorobenzyl hydrazine, and then after about (60 ml,0.72 mol) of concentrated hydrochloric acid was added and reacted at a constant temperature for 1 hour, stirring was carried out overnight at normal temperature, and the obtained 3, 4-dichlorobenzyl hydrazine hydrochloride was obtained as a white solid 46.1g by filtration, yield: 90%.

Step 2: 3, 4-Dichlorophenylhydrazine hydrochloride (46.1 g,0.2159 mol) was added in portions to a mixed system of water (30 ml) and chloroform (30 ml) mixed solvent and potassium carbonate (59.68 g,0.4318 mol), p-fluoroaniline (26.66 g,0.2399 mol) was introduced into the system under stirring at 70℃for 24 hours, the reaction mixture was cooled to room temperature and washed with water, the organic phase was separated, and dried and distilled to give intermediate 3 ', 4' -dichloro-5-fluoro-2-benzidine (48.65 g), yield: 88%.

Step 3: dissolving (48.65 g,0.19 mol) intermediate 3 ', 4' -dichloro-5-fluoro-2-benzidine in 300ml of solvent dichloroethane, adding sodium hydroxide (7.6 g,0.19 mol) as catalyst, adding 1-methyl-3-difluoromethyl-4-pyrazole formyl chloride (36.96 g,0.19 mol) under stirring at 60 ℃, reacting for 4h at 60 ℃, cooling to room temperature after the reaction, washing the reaction solution, separating out an organic phase, drying, evaporating and concentrating in a rotary manner, and recrystallizing to obtain 77.13g of bixafen with yield: 98 percent of

Example 2

step (1) Compound 3, 4-dichloroaniline (38.88 g,0.2399 mol) is dissolved in ethyl acetate (15 ml), 18.4mol/L of concentrated hydrochloric acid (70 ml,0.84 mol) and sodium nitrite (18.06 g,0.261 mol) are added, the reaction solution is stirred at 5 ℃ for reaction for 30min, clear liquid is filtered out, the clear liquid is dripped into 140ml of solution containing (200 g,0.7197 mol) ferrous sulfate, the reaction is carried out for about 3 hours at 80 ℃, 3, 4-dichlorobenzyl hydrazine is generated after the reaction is carried out, and after the reaction is carried out for 1 hour by adding about (60 ml,0.72 mol) of concentrated hydrochloric acid, the mixture is stirred at normal temperature for overnight, and the white solid of 3, 4-dichlorobenzyl hydrazine hydrochloride is obtained by filtration, 45g is obtained, the yield: 87.8%.

Step 2: 3, 4-Dichlorophenylhydrazine hydrochloride (46.1 g,0.2159 mol) was added in portions to a mixed system of water (30 ml) and ethyl acetate (30 ml) mixed solvent and potassium hydroxide (24.22 g,0.4318 mol), p-fluoroaniline (26.66 g,0.2399 mol) and air was introduced into the system under stirring at 60℃for 24 hours, the reaction mixture was cooled to room temperature and washed with water, the organic phase was separated, and the organic phase was dried and distilled off by rotary evaporation to give intermediate 3 ', 4' -dichloro-5-fluoro-2-benzidine 44.22g, yield: 80%.

Step 3: the intermediate 3 ', 4' -dichloro-5-fluoro-2-benzidine (48.65 g,0.19 mol) was completely dissolved in 280ml of tetrahydrofuran, pyridine (15 g,0.19 mol) as a catalyst was added thereto, 1-methyl-3-difluoromethyl-4-pyrazole carbonyl chloride (36.96 g,0.19 mol) was added thereto under stirring at 40℃and reacted at 40℃for 4 hours, the reaction mixture was cooled to room temperature after the reaction, the organic phase was separated, dried, concentrated by rotary evaporation, and recrystallized to give 75.55g of bipyramid as a yield: 96 percent of

Example 3

step (1) Compound 3, 4-dichloroaniline (38.88 g,0.2399 mol) is dissolved in tetrahydrofuran (30 ml), then 12mol/L of concentrated hydrochloric acid (70 ml,0.84 mol) and sodium nitrite (18.06 g,0.261 mol) are added, the reaction solution is stirred at 5 ℃ for reaction for 30min, then the solution is filtered out by suction, the clear liquid is dripped into 140ml of solution containing sodium bisulphite (74.89 g,0.7197 mol), the solution is reacted for about 3 hours at 70 ℃ to generate 3, 4-dichlorobenzyl hydrazine, then about (60 ml,0.72 mol) of concentrated hydrochloric acid is added for reaction for 1h, and then the solution is stirred at normal temperature for overnight, and the solution is filtered to obtain 47.12g of 3, 4-dichlorobenzyl hydrazine hydrochloride white solid with yield: 92%.

Step 2: 3, 4-Dichlorophenylhydrazine hydrochloride (46.1 g,0.2159 mol) was added in portions to a mixed system of water (30 ml) and a mixed solvent of tetrahydrofuran (30 ml) and cesium carbonate (70.34 g,0.2159 mol), p-fluoroaniline (26.66 g,0.2399 mol) was introduced into the system under stirring at 70℃for 24 hours, the reaction mixture was cooled to room temperature, the reaction mixture was washed with water, the organic phase was separated, and the organic phase was dried and rotary distilled to give intermediate 3 ', 4' -dichloro-5-fluoro-2-benzidine 49.2g, yield: 89%.

Step 3: the intermediate 3 ', 4' -dichloro-5-fluoro-2-benzidine (48.65 g,0.19 mol) was completely dissolved in 500ml of toluene, N-diisopropylethylamine (24.55 g,0.19 mol) as a catalyst was added, 1-methyl-3-difluoromethyl-4-pyrazole formyl chloride (36.96 g,0.19 mol) was added under stirring at 60℃to react for 4 hours at 60℃and the reaction mixture was cooled to room temperature after the reaction, and the organic phase was separated, dried, concentrated by rotary evaporation and recrystallized to give 77.91g of bipyramid, yield: 99%.

Claims

1. The synthesis method of bixafen is characterized by comprising the following steps:

step 1: mixing and dissolving a compound 3, 4-dichloroaniline, an acid substance and a solvent, adding sodium nitrite to react for 0.5-2 hours at the temperature of-20-10 ℃, and filtering to obtain clear liquid; mixing the clear solution and the reducing agent in a molar ratio of 1:1-1:4, and reacting at 40-80 ℃ for 1-8 hours to generate 3, 4-dichlorobenzene; adding hydrochloric acid to react for 30 min-1.5 h at the temperature of 40-80 ℃ and filtering to obtain a white solid of 3, 4-dichlorobenzene hydrazine hydrochloride; the molar ratio of the compound 3, 4-dichloroaniline to the acid substances is 1:2.5-1:5, the molar ratio of the compound to the sodium nitrite is 1:1-1:2, and the mass and volume ratio of the compound to the solvent is 1g:0.5 ml-1 g:10ml; the molar ratio of the 3, 4-dichlorophenylhydrazine to the hydrochloric acid is 1:1-1:4;

step 2: mixing 3, 4-dichlorobenzene hydrazine hydrochloride, a solvent, a base catalyst and p-fluoroaniline, introducing air under stirring, reacting at the temperature of 30-90 ℃ for 8-48 hours, cooling to room temperature, washing the reaction liquid, separating out an organic phase, drying, and performing rotary evaporation to obtain an intermediate 3 ', 4' -dichloro-5-fluoro-2-benzidine; the volume ratio of the mass of the 3, 4-dichlorobenzene hydrazine hydrochloride to the solvent is 1g:0.5 ml-1 g:10ml, the molar ratio of the 3, 4-dichlorobenzene hydrazine hydrochloride to the base catalyst is 1:1-1:3, and the molar ratio of the 3, 4-dichlorobenzene hydrazine hydrochloride to the p-fluoroaniline is 1:1;

step 3: reacting an intermediate 3 ', 4' -dichloro-5-fluoro-2-benzidine, 1-methyl-3-difluoromethyl-4-pyrazole formyl chloride, a solvent and a catalyst at 30-90 ℃ for 1-5 h, cooling to room temperature after the reaction, washing the reaction solution with water, separating out an organic phase, drying, rotary steaming, concentrating, and recrystallizing to obtain bixafen; the molar ratio of the intermediate 3 ', 4' -dichloro-5-fluoro-2-benzidine to 1-methyl-3-difluoromethyl-4-pyrazole formyl chloride is 1:1-1:0.8, the mass and volume ratio of the intermediate to the solvent is 1g:4 ml-1 g:15ml, and the molar ratio of the intermediate to the catalyst is 1:0.3-1:2;

the solvents in the step 1 and the step 3 are as follows: one or more of ethyl acetate, ethyl formate, acetonitrile, water, diethyl ether, methyl tertiary butyl ether, tetrahydrofuran, dimethyl tetrahydrofuran, benzene, toluene, xylene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride; the solvent in the step 2 is water and one or more of chloroform, ethyl acetate and tetrahydrofuran;

the reducing agent is one or more of sodium bisulphite, sodium sulfite and ferrous sulfate;

the base catalyst comprises one or more of potassium hydroxide, potassium carbonate and cesium carbonate.

2. The method for synthesizing bixafen according to claim 1, which is characterized in that: the acid substance is one or more of hydrochloric acid, sulfuric acid, nitric acid and acetic acid.

3. The method for synthesizing bixafen according to claim 1, which is characterized in that: the catalyst comprises one or more of triethylamine, pyridine, N-diisopropylethylamine, sodium hydroxide, cesium carbonate, potassium carbonate, sodium bicarbonate, ammonium carbonate and tetrabutylammonium bromide.