CN117164576A

CN117164576A - Synthesis method of flumioxazin

Info

Publication number: CN117164576A
Application number: CN202311129431.3A
Authority: CN
Inventors: 王攀登; 吴海琴; 吴克崇; 贾俊超; 郭凯杰; 贺凯
Original assignee: Shanghai Nongfan Biotechnology Co ltd
Current assignee: Shanghai Nongfan Biotechnology Co ltd
Priority date: 2023-09-04
Filing date: 2023-09-04
Publication date: 2023-12-05

Abstract

The invention relates to a synthesis method of flumioxazin, and belongs to the technical field of pesticide chemical industry. The method comprises the following steps: step 1: reacting 2, 4-difluoro nitrobenzene, 1, 2-dichloroethane and mixed acid to obtain an intermediate 1; step 2: reacting the intermediate 1, 2-dichloroethane and triethylamine obtained in the step 1 to obtain an intermediate 2 after the reaction is finished; step 3: and (3) obtaining an intermediate 3 after the reaction of the intermediate 2 obtained in the step (2), the organic solvent A and the catalyst is finished, and step (4): adding an organic solvent B into a reaction kettle, and then adding the intermediate 3, sodium hydroxide and 3-chlorpropyne obtained in the step 3 to react to obtain an intermediate 4; step 5: adding 3,4,5, 6-tetrahydrophthalic anhydride into the intermediate 4 and acetic acid under the protection of nitrogen, adding benzyl ammonium salt aqueous solution, carrying out reflux reaction, and separating to obtain the final product flumioxazin. The preparation method provided by the invention has the advantages of high yield, low cost, good safety and good application prospect.

Description

Synthesis method of flumioxazin

Technical Field

The invention relates to a synthesis method of flumioxazin, and belongs to the technical field of pesticide chemical industry.

Background

The flumioxazin (commonly called as 'quick harvest') is a phthalimide herbicide developed by Sumitomo industry chemical Co., ltd., is also a typical contact herbicide, can effectively prevent and remove 1-year-old broadleaf weeds and part of gramineous weeds, is easy to degrade in the environment, is safe to succeeding crops, has wide application in agricultural production, and has great economic market value.

At present, in actual production of flumioxazin, the problems of difficult production route selection and low yield exist, the problems of low kettle type reaction efficiency, high potential safety hazards of kettle type nitration reaction, kettle type etherification reaction and kettle type hydrogenation reaction, more product impurities, difficult solvent recovery, low product purity, inconvenient production operation, high energy consumption and high cost exist. In order to improve market competitiveness, a process route which is suitable for production, low in cost, high in efficiency, high in yield, safe and reliable needs to be found. The process route of the flumioxazin mainly comprises the following steps:

route one: 1, 5-dichloro-2, 4-dinitrobenzene is taken as a starting material, the intermediate substituted aniline is prepared by fluorination, etherification, hydrogenation reduction and cyclization reaction with bromopropyne, and finally the target product is obtained by reaction with anhydride, but in the route, the fluorination is difficult to control, the side reaction is more, and the yield is low.

Route two: the method is simple to operate, the reaction yield of each step is high, but the price of the adopted raw material 2-nitro-5-fluorophenol is higher, in addition, the nitro is reduced by iron powder, the yield is low, in addition, the route requires two hydrogenation reduction, the cost is greatly increased, the industrialized production is not facilitated, the intermediate is firstly subjected to propynyl and then to nitro reduction, the nitro is difficult to selectively reduce, and difficult-to-remove impurities are easy to generate.

Route three: the method is characterized in that m-fluorophenol is used as a raw material, and the m-fluorophenol is prepared through etherification, nitration, iron powder reduction, alkylation and finally reaction with acid anhydride, wherein the side reaction is more during the nitration of the route, particularly the ether bond is easy to break and oxidize during the nitration, the iron powder reduction is adopted, the yield is low, and the produced iron mud is difficult to treat.

Route four: the m-difluorobenzene is adopted as a raw material and is prepared through six steps of reactions, the price of the m-difluorobenzene which is the raw material is lower, but the nitro positioning is more complex when the m-difluorobenzene is nitrified, the byproducts are more, the separation is difficult, and the preparation of a product with high content is relatively difficult.

Route five: reference CN105837563 uses 2, 4-difluoro nitrobenzene as initial raw material, and uses the processes of nitration, etherification, palladium-carbon hydrogenation reduction and cyclization, then makes them undergo the process of reaction with chloropropionine so as to obtain intermediate substituted aniline, and finally makes them undergo the process of reaction with acid anhydride so as to obtain the invented target product. In view of the above, there is still no process route which is easy for mass production, low in cost, high in yield, safe and reliable.

For the above reasons, a method for preparing flumioxazin is needed to solve the problems of difficulty in production route selection and cost control, low yield, low efficiency, poor safety and the like of flumioxazin, and improve market competitiveness.

Meanwhile, in actual production of flumioxazin, the problem of product quality still exists, the quality content of the product is difficult to reach more than 99.0%, the content of organic impurities is difficult to control below 0.1%, the process stability is poor, and particularly when two impurities M350 and M354-2 in the following formula are controlled, the situation that the content of the two impurities exceeds the standard often occurs. In order to meet the requirements of the market on the product quality, a process route which is suitable for production, high in product quality and stable and reliable in process needs to be found.

The synthesis methods for improving the quality of flumioxazin mainly comprise the following steps:

US4640707 discloses a process for the preparation of flumioxazin, comprising in particular (example 1): a mixture of 6-amino-7-fluoro-4- (2-propynyl) -2H-1, 4-benzoxazin-3 (4H) -one (0.8 g), 3,4,5, 6-tetrahydrophthalic anhydride (0.61 g) and acetic acid (20 mL) was heated under reflux for 2 hours; after cooling, water was added to the resulting mixture, and precipitated crystals were obtained by filtration and washing with water.

Liu Anchang et al (research on the synthesis of the novel herbicide flumioxazin, world pesticides, 2011, 33 (2), 27-29) disclose a method for preparing flumioxazin comprising: 22g (0.lmol) 6-amino-7-fluoro-4- (2-propynyl) -2H-1, 4-benzoxazin-3 (4H) -one (7), 15.2g (0.1 mol) 3,4,5, 6-tetrahydrophthalic anhydride and 40mL glacial acetic acid were added to a 250mL four-necked flask with stirring and heated to reflux. The reaction was terminated after 2 hours. After addition of 50mL of water, the mixture was extracted 3 times with 150mL of ethyl acetate and the organic phases were combined. Subsequently, 100mL of water and 50mL of NaHCO, respectively, are used ₃ The saturated solution was washed, concentrated and cooled to precipitate 26.5g of white crystals.

JPH0597848 discloses a method for preparing flumioxazin, which comprises: 560 g of methyl isobutyl ketone solution containing 90 g of (1, 3-dimethylbutenylamino) -7-fluoro-4- (2-propargyl) -1, 4-benzoxazin-3 (4H) -one 55 g of 3,4,5, 6-tetrahydrophthalic anhydride, 5g of p-toluenesulfonic acid and 5g of methanol are added. Stirring and reacting at 100 ℃ for 6 hours, removing the solvent under reduced pressure, filtering, washing the obtained crystal with 60% methanol aqueous solution to obtain 100 g flumioxazin, wherein the yield is 95%, and the calibration content of a gas phase internal standard method is 99%.

CN105061416 discloses a method for preparing propyne flubendiamide, 6-amino-7-fluoro-4- (2-propynyl) -2H-1, 4-benzoxazine-3 (4H) -ketone and 3,4,5, 6-tetrahydrophthalic anhydride are in contact reaction, the catalyst is alkaline nitrogen-containing organic matter or a mixture of organic acid and alkaline nitrogen-containing organic matter, the yield of the propyne flubendiamide product prepared by the method can reach more than 99%, the mass content can reach more than 99%, and the content of organic impurities is lower than 0.1%.

The method for synthesizing the propyzamide with improved quality has the advantages that the purity of the propyzamide obtained by the preparation process of the propyzamide is still not high enough, or the process is not stable, and the conventional catalyst has the problems of higher price, difficult acquisition, larger use amount and increased three-waste amount and industrialization cost. It is well known that higher amounts of the drug substance have higher commercial value and better processing characteristics and better safety in use. Therefore, the preparation method of the flumioxazin needs to be developed, which is easy to industrialize, high in productivity, short in process route, low in cost and easy to obtain raw materials, high in reaction yield and high in purity, and the obtained flumioxazin has the content of more than or equal to 99.2 percent, and all single organic impurities have the content of less than or equal to 0.1 percent.

The reason why the purity of the flumioxazin obtained by the method in the prior art is not high enough is that the generation rate of the flumioxazin is not high enough due to the defects of the preparation process route, and the generation rate of impurities which are difficult to remove in the obtained product is large. There is a need to develop a good process and an effective catalyst that solves both of the above problems.

In summary, in the actual production of the flumioxazin, particularly in the industrial production, the problems of low kettle-type reaction efficiency, high potential safety hazards of kettle-type nitration reaction, kettle-type etherification reaction and kettle-type hydrogenation reaction, more trouble in recycling of the kettle-type hydrogenation catalyst, lower yield, low efficiency, higher cost, inconvenient production operation, low intermediate content and high cost exist, and the problems of low product quality content of the flumioxazin and exceeding of the standard of single impurity quality content also exist. Therefore, there is a need in the art for a high yield, low cost method of preparing flumioxazin.

Disclosure of Invention

The invention aims to solve the problems that: in the prior art, the industrial production of the flumioxazin has the problems of low kettle-type reaction efficiency, large potential safety hazards of kettle-type nitration reaction, kettle-type etherification reaction and kettle-type hydrogenation reaction, large dosage of kettle-type hydrogenation catalyst, troublesome recovery, low yield, low efficiency, high cost, inconvenient production operation, low intermediate content and high cost, and simultaneously has the problems of low product quality content of the flumioxazin and exceeding standard quality content of single impurity.

In order to solve the problems, the technical scheme adopted by the invention is to provide a synthesis method of flumioxazin, which comprises the following steps:

step 1: nitric acid and sulfuric acid are prepared into mixed acid, and 2, 4-difluoro nitrobenzene and 1, 2-dichloroethane are prepared into mixed solution; inputting the two materials into a micro-channel continuous flow reactor, and staying and reacting; after the reaction is finished, standing and layering are carried out, and 1, 5-difluoro-2, 4-dinitrobenzene in an organic layer is separated, namely an intermediate 1;

step 2: preparing a mixed solution from the intermediate 1, 2-dichloroethane and triethylamine obtained in the step 1, respectively passing the prepared mixed solution and methyl glycolate through a advection pump to ensure that reactants stay in a microchannel continuous flow reactor and react, and separating after the reaction is finished to obtain 3-fluoro-4, 6-dinitrophenoxy methyl acetate, namely an intermediate 2;

step 3: the mixture prepared by the intermediate 2, the organic solvent A and the catalyst obtained in the step 2 is input into a micro-channel continuous flow reactor through a advection pump in a stirring and dispersing state; hydrogen enters the micro-channel continuous flow reactor through a gas meter; after the reaction is finished, separating to obtain 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -ketone, namely an intermediate 3, wherein the catalyst is a platinum carbon catalyst or a palladium carbon catalyst;

step 4: adding an organic solvent B into a reaction kettle, adding the intermediate 3, sodium hydroxide and 3-chlorpropyne obtained in the step 3, and separating after the reaction is finished to obtain 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone, namely an intermediate 4;

step 5: sequentially adding the intermediate 4 and acetic acid obtained in the step 3 into a reaction kettle, adding 3,4,5, 6-tetrahydrophthalic anhydride under the protection of nitrogen, adding a benzyl ammonium salt aqueous solution, carrying out reflux reaction, and separating after the reaction is finished to obtain a final product flumioxazin.

The reaction route is as follows:

preferably, the step 1 satisfies one or more of the following conditions:

the condition 1 is that the molar ratio of the concentrated nitric acid to the concentrated sulfuric acid is 1:1.0-5.0, the mass concentration of the concentrated nitric acid is 85-98%, and the mass concentration of the concentrated sulfuric acid is 85-98%;

the condition 2 is that the mass ratio of the 2, 4-difluoro nitrobenzene to the 1, 2-dichloroethane is 1:0.1-0.5;

the condition 3 is that the mole number ratio of the 2, 4-difluoronitrobenzene in the mixed solution to the nitric acid in the mixed acid is 1:1.0-1.4;

condition 4 is that the temperature of the reaction is 40-85 ℃, and the residence time is 40-180 seconds;

condition 5 is that the pressure at which the microchannel continuous flow reactor starts feeding is 0.2-0.4MPa; the standing time in the standing delamination is 0.5-1 hour.

Further preferably, in the step 1, the separation method is as follows: washing with alkaline water, washing with water, azeotropic distillation with water, recovering 1, 2-dichloroethane, filtering the substrate, and drying, wherein the alkaline water is 5% sodium hydroxide aqueous solution and/or 5% sodium bicarbonate aqueous solution by mass.

Preferably, said step 2 satisfies one or more of the following conditions:

the condition 1 is that in the mixed solution, the mass ratio of the intermediate 1 to the 1, 2-dichloroethane is 1:0.2-3.0,1,5, the molar ratio of the difluoro-2, 4-dinitrobenzene to the triethylamine is 1:0.85-1.0, and the molar ratio of the 1, 5-difluoro-2, 4-dinitrobenzene to the methyl glycolate in the reactant is 1:0.90-1.10;

the condition 2 is that the temperature of the reaction is-10-15 ℃ and the residence time is 60-480 seconds;

condition 3 is that the pressure at which the microchannel continuous flow reactor begins to feed is from 0.01 to 0.20MPa.

Further preferably, in the step 2, the separation method is as follows: washing with aqueous hydrochloric acid, separating, washing the organic phase with water, distilling under reduced pressure, recovering 1, 2-dichloroethane, recrystallizing the residue with ethanol, filtering, and drying.

Preferably, said step 3 satisfies one or more of the following conditions:

the condition 1 is that the organic solvent A is n-butyl acetate and/or 2-methyltetrahydrofuran;

the condition 2 is that the mass ratio of the 3-fluoro-4, 6-dinitrophenoxyacetic acid methyl ester to the organic solvent A is 1:5.0-30.0;

the condition 3 is that the molar ratio of the 3-fluoro-4, 6-dinitrophenoxyacetic acid methyl ester to the catalyst is 1:0.0002-0.0005;

the condition 4 is that the mass specification of platinum or palladium noble metal in the catalyst is 2-10%, and the water content specification of the catalyst is 0-70%;

condition 5 is that the preheating temperature of the continuous flow micro-channel reactor is 70-140 ℃; further preferably 80-140 ℃;

the condition 6 is that the reaction pressure is 0.5Mpa-3.0Mpa, and the residence time of the materials in the microchannel reactor is 2-20 minutes.

Further preferably, in the step 3, the separation method is as follows: after passing through two stages of filters with heat tracing, the organic layer is conveyed to an organic storage tank, the 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -ketone solution in the organic storage tank is cooled, a crude product is obtained after filtration, hydrochloric acid and water are acidified to form salt and are adsorbed by active carbon, filtration is carried out, the acid water phase is alkalized, cooling is carried out to room temperature for crystallization, filtration is carried out again, water washing and drying are carried out, and the heat tracing temperature of the heat tracing filter is more preferably 80-140 ℃.

Preferably, said step 4 satisfies one or more of the following conditions:

the condition 1 is that the organic solvent B is N, N-dimethylformamide and/or N, N-dimethylacetamide;

the mass ratio of the 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -ketone to the organic solvent B is 1:1.0-5.0,6, and the molar ratio of the amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -ketone to the sodium hydroxide is 1:1.0-1.5;

the condition 3 is that the mol ratio of 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -ketone to 3-chlorpropyne is 1:1.0-1.3;

the condition 4 is that the temperature of the reaction is 25-60 ℃ and the time is 2-8 hours;

the condition 5 is that the mass ratio of the 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -ketone to the ethanol is 1:1.0-5.0.

Further preferably, in the step 4, the separation method is as follows: filtering, filtering inorganic salt, recovering solvent from filtrate under reduced pressure, adding water into residue, pulping and washing, and filtering to obtain crude product; adding water into the crude product, dropwise adding hydrochloric acid, adding active carbon, heating and stirring, filtering, extracting the filtrate with ethyl acetate for layering, adjusting the pH of the water phase to 6.5-7.0 with sodium hydroxide, filtering, heating the filter cake with ethanol, refluxing for recrystallization, and filtering.

Preferably, said step 5 satisfies one or more of the following conditions:

the mass ratio of the 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone to the acetic acid is 1:1.0-5.0;

the condition 2 is that the molar ratio of the 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone to the 3,4,5, 6-tetrahydrophthalic anhydride is 1:1.0-1.3;

the condition 3 is that the mass ratio of the 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone to the aqueous solution of the benzyl ammonium salt is 1:0.001-0.01;

the condition 4 is that the mass concentration of the aqueous solution of the benzyl ammonium salt is 2-20%, wherein the benzyl ammonium salt is at least one of benzyl triethyl ammonium chloride and benzyl trimethyl ammonium chloride;

the condition 5 is that the mass ratio of the 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone to the 95% ethanol is 1:1.0-5.0.

Further preferably, in the step 5, the separation method is as follows: after the reaction is finished, cooling, crystallizing, filtering, refluxing and pulping the obtained crude product by using 95% ethanol, cooling to room temperature, and filtering.

Compared with the prior art, the invention has the following beneficial effects:

1. the invention takes 2, 4-difluoronitrobenzene as raw material, synthesizes 2, 4-difluoronitrobenzene by adopting microchannel continuous flow reaction, greatly reduces the process risk and reduces the amount of three wastes in the reaction and post-treatment processes; the purpose of recycling sulfuric acid can be achieved by a simple water removal method, and the pollution to the environment is reduced; the solvent can be simply distilled and recovered, the product separation efficiency is high, the method yield is high, the reaction time is short, the efficiency and the safety are high, and the method is suitable for mass production.

2. In the step 2, the 3-fluoro-4, 6-dinitrophenoxy methyl acetate is synthesized by adopting a micro-channel continuous flow reactor, so that the process risk is greatly reduced, the solvent can be simply distilled and recovered, the product separation efficiency is high, the method yield is high, the reaction time is short, the efficiency and the safety are high, and the production cost is further reduced.

3. In the step 3, a micro-channel continuous flow reactor is adopted to synthesize 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -ketone, so that the process risk is greatly reduced, and the amount of three wastes in the reaction and post-treatment processes is reduced; the catalyst dosage is low, and the aim of recycling the catalyst can be achieved by a heat preservation and filtration method; the solvent can be simply distilled and recovered, the product separation efficiency is high, the method yield is high, the reaction time is short, the efficiency and the safety are high, the production cost is further reduced, and the method is suitable for mass production.

4. The preparation process in the step 4 is simple, the product purification process is simple and convenient, and the purification effect is achieved by simply adjusting the PH value and the extraction scheme; the method has high comprehensive utilization rate of raw materials, and can greatly improve the mass content and quality of the intermediate 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone.

5. In the method, in the step 5, benzyl ammonium salt aqueous solution is used as a catalyst, and in proper organic solvent acetic acid, propyne flufenacet is obtained by reaction at proper temperature, and by adding a small amount of benzyl ammonium salt aqueous solution as the catalyst, the selectivity of the reaction is improved, the generation of two impurities M350 and M354-2 in the product is inhibited, and the content of single organic impurity can be controlled to be less than or equal to 0.1%; and the benzyl ammonium salt has the advantages of small dosage, good catalytic effect, easy obtainment and low cost. The product yield of the method is more than or equal to 91%, the mass content of flumioxazin is more than or equal to 99.2%, and the content of single organic impurities is less than or equal to 0.1%.

Detailed Description

In order to make the invention more comprehensible, preferred embodiments accompanied with the present invention are described in detail as follows:

the percentages not specifically described in the present invention refer to mass concentrations or mass percentages.

Example 1

The synthesis method of flumioxazin comprises the following steps:

step 1: and (3) preparing mixed acid: 96.5% sulfuric acid and 97% nitric acid are mixed to obtain mixed acid, wherein the molar ratio of nitric acid to sulfuric acid is 1:3.3. Raw material preparation: 2, 4-difluoronitrobenzene and 1, 2-dichloroethane are formulated as a solution, wherein the mass ratio of 2, 4-difluoronitrobenzene to 1, 2-dichloroethane is 1:0.15. The solution of 2, 4-difluoronitrobenzene and 1, 2-dichloroethane and the mixed acid are respectively introduced into the reaction module of the microchannel continuous flow reactor by a tetrafluoro advection pump. The flow rate of the solution of 2, 4-difluoronitrobenzene and 1, 2-dichloroethane and the flow rate of the mixed acid are regulated to ensure that the mol ratio of the 2, 4-difluoronitrobenzene to the nitric acid is 1:1.32, the pressure when the microchannel continuous flow reactor starts feeding is 0.2MPa, the reaction temperature is controlled to be 78 ℃, the residence time of reactants in the microchannel reactor is controlled to be 120 seconds, the reaction products flow into a collecting tank, the reactants collected by the collecting tank are cooled to room temperature, stirred uniformly and naturally cooled, and the reaction products are kept stand for 1 hour. Separating the liquid, and allowing the inorganic phase to flow into the inorganic storage tank, and allowing the organic layer to flow into the organic storage tank. The material in the inorganic storage tank is mainly sulfuric acid, and can be reused after the concentration is measured by removing water. The material in the organic tank was washed with a small amount of 5% aqueous sodium hydroxide solution to neutrality, azeotropically distilled with water, 1, 2-dichloroethane was recovered, filtered, and dried to give the product 1, 5-difluoro-2, 4-dinitrobenzene, with a single batch yield of 97.6% and a product purity of 98.0%.

Step 2: preparing a mixed solution: preparing a mixed solution from the 1, 5-difluoro-2, 4-dinitrobenzene, 1, 2-dichloroethane and triethylamine, wherein the mass ratio of the 1, 5-difluoro-2, 4-dinitrobenzene to the 1, 2-dichloroethane is 1:2.5, and the molar ratio of the 1, 5-difluoro-2, 4-dinitrobenzene to the triethylamine is 1:0.95; pumping the prepared mixed solution and methyl glycolate into a micro-channel continuous flow reactor through a advection pump respectively, and adjusting the flow speed of the advection pump to ensure that the molar ratio of 1, 5-difluoro-2, 4-dinitrobenzene to methyl glycolate in the reactant is 1:0.96; the pressure of the micro-channel continuous flow reactor at the beginning of feeding is 0.05MPa, the reaction temperature is controlled to be 3-4 ℃, the residence time of reactants in the micro-channel reactor is controlled to be 240 seconds, and after the reaction is finished, the 1, 2-dichloroethane solution of the 3-fluoro-4, 6-dinitrophenoxyacetic acid methyl ester is obtained. Washing with aqueous hydrochloric acid, separating, washing an organic phase with water, distilling under reduced pressure, recovering 1, 2-dichloroethane, recrystallizing the residue with ethanol, filtering, and drying to obtain methyl 3-fluoro-4, 6-dinitrophenoxy acetate, wherein the yield of single-batch products is 94.0% and the purity of the products is 97.5%.

Step 3: raw material preparation: and (2) preparing a mixture of the 3-fluoro-4, 6-dinitrophenoxy methyl acetate, the n-butyl acetate and 5% of platinum carbon catalyst (containing 50% of water) obtained in the step (2), wherein the mass ratio of the 3-fluoro-4, 6-dinitrophenoxy methyl acetate to the n-butyl acetate is 1:20.0, and the molar ratio of the 3-fluoro-4, 6-dinitrophenoxy methyl acetate to the 5% of platinum carbon catalyst is 1:0.0004. Feeding the mixture into a microchannel continuous flow reactor through a advection pump in a stirring dispersion state; hydrogen enters the micro-channel continuous flow reactor through a gas meter; the preheating temperature of the continuous flow micro-channel reactor is 115 ℃; the reaction temperature is controlled to be 115-120 ℃, the reaction pressure is controlled to be 2.0-2.1Mpa, and the residence time of the reaction materials in the microchannel reactor is controlled to be 5 minutes. After the reaction is finished, the materials pass through a two-stage filter with the heat tracing temperature of 125 ℃, and then the organic layer is conveyed to an organic storage tank, wherein the organic storage tank is an n-butyl acetate solution of a product 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -ketone, and a platinum carbon catalyst is arranged in the two-stage filter and can be recycled; the method comprises the steps of cooling n-butyl acetate solution of 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -ketone in an organic storage tank, filtering to obtain a crude product, acidifying the crude product into salt by hydrochloric acid and water, adding activated carbon for adsorption, filtering, alkalizing the obtained acid aqueous phase by sodium hydroxide aqueous solution, cooling to room temperature for crystallization, filtering again, washing with water, and drying to obtain 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -ketone, wherein the yield of single-batch products is calculated to be 96.2%, and the purity of the products is calculated to be 99.0%.

Step 4: to the reaction vessel, N-dimethylformamide (736.0 g) was added as an organic solvent, followed by addition of 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -one (184.0 g) (1.0 mol) obtained in step 3, sodium hydroxide (44.0 g) (1.1 mol) at a temperature of 20 to 25℃and dropwise addition of 3-chloropropionine (89.4 g) (1.2 mol) under stirring, after completion of the dropwise addition over 1 hour, heating to 35℃and holding for 4 hours until the reaction was completed. Filtering, filtering inorganic salt, recovering solvent from filtrate under reduced pressure, adding water (736.0 g) into residue, pulping, washing, and filtering to obtain crude product; adding water (552.0 g) into the crude product, dropwise adding 36% concentrated hydrochloric acid (100 g), adding 3.0 g of active carbon, heating and stirring for 15 min, filtering, using toluene (184 g) for extraction and delamination, using 30% sodium hydroxide aqueous solution for adjusting pH of the aqueous phase to 6.5-7.0, filtering, using absolute ethyl alcohol (552.0 g) for filter cake, heating, refluxing and recrystallizing, cooling, filtering to obtain the product 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone, pure product, product yield of 92.0%, product purity of 99.2%, and mass content of 98.8%.

Step 5: 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone (222.9 g) (1.0 mol) obtained in the step 4 and acetic acid (668.7 g) are sequentially added into a reaction kettle, 3,4,5, 6-tetrahydrophthalic anhydride (173.2 g) (1.1 mol) with the content of 96.0 percent and benzyl trimethyl ammonium chloride aqueous solution (2.2 g) with the concentration of 5 percent are added under the protection of nitrogen under the stirring, reflux reaction is carried out for 5 hours, after the reaction is finished, cooling crystallization is carried out, filtering is carried out, the obtained crude product is subjected to reflux beating by 95 percent ethanol (445.8 g), after cooling to room temperature, filtering is carried out, and drying is carried out, thus obtaining the propyne flubendiamide with the product yield of 91.7 percent, the product purity of 99.6 percent, the mass content of 99.3 percent, and the content of single organic impurity is less than or equal to 0.1 percent.

Example 2

The synthesis method of flumioxazin comprises the following steps:

step 1: and (3) preparing mixed acid: 96.5% sulfuric acid and 97% nitric acid are mixed to obtain mixed acid, wherein the molar ratio of nitric acid to sulfuric acid is 1:3.1. Raw material preparation: 2, 4-difluoronitrobenzene and 1, 2-dichloroethane are formulated as a solution, wherein the mass ratio of 2, 4-difluoronitrobenzene to 1, 2-dichloroethane is 1:0.2. The solution of 2, 4-difluoronitrobenzene and 1, 2-dichloroethane and the mixed acid are respectively introduced into the reaction module of the microchannel continuous flow reactor by a tetrafluoro advection pump. The flow rate of the solution of 2, 4-difluoronitrobenzene and 1, 2-dichloroethane and the flow rate of the mixed acid are regulated to ensure that the mol ratio of the 2, 4-difluoronitrobenzene to the nitric acid is 1:1.35, the pressure when the microchannel continuous flow reactor starts feeding is 0.1MPa, the reaction temperature is controlled to be 78 ℃, the residence time of reactants in the microchannel reactor is controlled to be 130 seconds, the reaction products flow into a collecting tank, the reactants collected by the collecting tank are cooled to room temperature, stirred uniformly and naturally cooled, and the reaction products are kept stand for 1 hour. Separating the liquid, and allowing the inorganic phase to flow into the inorganic storage tank, and allowing the organic layer to flow into the organic storage tank. The material in the inorganic storage tank is mainly sulfuric acid, and can be reused after the concentration is measured by removing water. The material in the organic tank was washed to neutrality with a small amount of 5% aqueous sodium hydroxide solution, azeotropically distilled with water, 1, 2-dichloroethane was recovered, filtered, and dried to obtain the product 1, 5-difluoro-2, 4-dinitrobenzene, and the product yield of a single batch was calculated to be 97.1% and the product purity was calculated to be 97.8%.

Step 2: preparing a mixed solution: preparing a mixed solution of the 1, 5-difluoro-2, 4-dinitrobenzene, 1, 2-dichloroethane and triethylamine, wherein the mass ratio of the 1, 5-difluoro-2, 4-dinitrobenzene to the 1, 2-dichloroethane is 1:2.0, and the molar ratio of the 1, 5-difluoro-2, 4-dinitrobenzene to the triethylamine is 1:0.94; pumping the prepared mixed solution and methyl glycolate into a micro-channel continuous flow reactor through a advection pump respectively, and adjusting the flow speed of the advection pump to ensure that the molar ratio of 1, 5-difluoro-2, 4-dinitrobenzene to methyl glycolate in the reactant is 1:0.97; the pressure of the micro-channel continuous flow reactor at the beginning of feeding is 0.02MPa, the reaction temperature is controlled to be 0-1 ℃, the residence time of reactants in the micro-channel reactor is controlled to be 300 seconds, and after the reaction is finished, the 1, 2-dichloroethane solution of the 3-fluoro-4, 6-dinitrophenoxyacetic acid methyl ester is obtained. Washing with aqueous hydrochloric acid, separating, washing an organic phase with water, distilling under reduced pressure, recovering 1, 2-dichloroethane, recrystallizing the residue with ethanol, filtering, and drying to obtain methyl 3-fluoro-4, 6-dinitrophenoxy acetate, wherein the yield of single-batch products is 93.5% and the purity of the products is 96.5%.

Step 3: raw material preparation: and (3) preparing a mixture of the 3-fluoro-4, 6-dinitrophenoxy methyl acetate obtained in the step (2), 2-methyltetrahydrofuran and 5% of platinum carbon catalyst (containing 50% of water), wherein the mass ratio of the 3-fluoro-4, 6-dinitrophenoxy methyl acetate to the 2-methyltetrahydrofuran is 1:18.0, and the molar ratio of the 3-fluoro-4, 6-dinitrophenoxy methyl acetate to the 5% of platinum carbon catalyst is 1:0.0003. Feeding the mixture into a microchannel continuous flow reactor through a advection pump in a stirring dispersion state; hydrogen enters the micro-channel continuous flow reactor through a gas meter; the preheating temperature of the continuous flow micro-channel reactor is 100 ℃; the reaction temperature is controlled to be 100-105 ℃, the reaction pressure is controlled to be 1.9-2.0Mpa, and the residence time of the reaction materials in the microchannel reactor is controlled to be 6 minutes. After the reaction is finished, the materials pass through a two-stage filter with the heat tracing temperature of 110 ℃, then the organic layer is conveyed to an organic storage tank, a 2-methyltetrahydrofuran solution of a product 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -ketone is in the organic storage tank, a platinum-carbon catalyst is in the two-stage filter, and the catalyst can be recycled; cooling the 2-methyltetrahydrofuran solution of 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -ketone in an organic storage tank, filtering to obtain a crude product, acidifying with hydrochloric acid and water to form salt, adding activated carbon for adsorption, filtering, alkalizing the obtained acid aqueous phase with sodium hydroxide aqueous solution, cooling to room temperature for crystallization, filtering again, washing with water, and drying to obtain 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -ketone, wherein the yield of single-batch products is calculated to be 95.5%, and the purity of the products is calculated to be 98.6%.

Step 4: to the reaction vessel was added an organic solvent N, N-dimethylacetamide (736.0 g), and 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -one (184.0 g) (1.0 mol) obtained in step 3, sodium hydroxide (48.0 g) (1.2 mol) was added at a temperature of 20 to 25℃under stirring, 3-chloropropionine (89.4 g) (1.2 mol) was added dropwise, and the temperature was raised to 37℃after completion of the dropwise addition over 1 hour, followed by heat preservation for 5 hours until the reaction was completed. Filtering, filtering inorganic salt, recovering solvent from filtrate under reduced pressure, adding water (736.0 g) into residue, pulping, washing, and filtering to obtain crude product; adding water (552.0 g) into the crude product, dropwise adding 36% concentrated hydrochloric acid (100 g), adding 3.0 g of active carbon, heating and stirring for 15 min, filtering, using toluene (184 g) for extraction and delamination, using 30% sodium hydroxide aqueous solution for adjusting pH of the aqueous phase to 6.5-7.0, filtering, using absolute ethyl alcohol (736.0 g) for filter cake, heating, refluxing and recrystallizing, cooling, filtering to obtain the product 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone, pure product, product yield of 91.5%, product purity of 99.1% and mass content of 98.6%.

Step 5: 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone (222.9 g) (1.0 mol) obtained in the step 4 and acetic acid (780.2 g) are sequentially added into a reaction kettle, 3,4,5, 6-tetrahydrophthalic anhydride (173.2 g) (1.1 mol) with the content of 96.0 percent and benzyl triethylammonium chloride aqueous solution (3.0 g) with the concentration of 5 percent are added under the protection of nitrogen under the stirring, reflux reaction is carried out for 4 hours, after the reaction is finished, cooling crystallization and filtering are carried out, the obtained crude product is subjected to reflux beating by 95 percent ethanol (668.7 g), after cooling to room temperature, the product yield of the propyne fluxafen is 91.3 percent, the product purity is 99.5 percent, the mass content of the product is 99.2 percent, and the content of single organic impurity is less than or equal to 0.1 percent.

Example 3

The synthesis method of flumioxazin comprises the following steps:

step 1: and (3) preparing mixed acid: 97% sulfuric acid and 97.5% nitric acid are mixed to obtain mixed acid, wherein the molar ratio of nitric acid to sulfuric acid is 1:3.1. Raw material preparation: 2, 4-difluoronitrobenzene and 1, 2-dichloroethane are formulated as a solution, wherein the mass ratio of 2, 4-difluoronitrobenzene to 1, 2-dichloroethane is 1:0.2. The solution of 2, 4-difluoronitrobenzene and 1, 2-dichloroethane and the mixed acid are respectively introduced into the reaction module of the microchannel continuous flow reactor by a tetrafluoro advection pump. The flow rate of the solution of 2, 4-difluoronitrobenzene and 1, 2-dichloroethane and the flow rate of the mixed acid are regulated to ensure that the mol ratio of the 2, 4-difluoronitrobenzene to the nitric acid is 1:1.35, the pressure when the microchannel continuous flow reactor starts feeding is 0.1MPa, the reaction temperature is controlled to be 75 ℃, the residence time of reactants in the microchannel reactor is controlled to be 150 seconds, the reaction products flow into a collecting tank, the reactants collected by the collecting tank are cooled to room temperature, stirred uniformly and naturally cooled, and the reaction products are kept stand for 1 hour. Separating the liquid, and allowing the inorganic phase to flow into the inorganic storage tank, and allowing the organic layer to flow into the organic storage tank. The material in the inorganic storage tank is mainly sulfuric acid, and can be reused after the concentration is measured by removing water. The material in the organic tank was washed to neutrality with a small amount of 5% aqueous sodium hydroxide solution, azeotropically distilled with water, 1, 2-dichloroethane was recovered, filtered, and dried to give the product 1, 5-difluoro-2, 4-dinitrobenzene, and the product yield of a single batch was calculated to be 97.8% and the product purity was 97.6%.

Step 2: preparing a mixed solution: preparing a mixed solution of the 1, 5-difluoro-2, 4-dinitrobenzene, 1, 2-dichloroethane and triethylamine, wherein the mass ratio of the 1, 5-difluoro-2, 4-dinitrobenzene to the 1, 2-dichloroethane is 1:1.0, and the molar ratio of the 1, 5-difluoro-2, 4-dinitrobenzene to the triethylamine is 1:0.94; pumping the prepared mixed solution and methyl glycolate into a micro-channel continuous flow reactor through a advection pump respectively, and adjusting the flow speed of the advection pump to ensure that the molar ratio of 1, 5-difluoro-2, 4-dinitrobenzene to methyl glycolate in the reactant is 1:0.95; the pressure of the micro-channel continuous flow reactor at the beginning of feeding is 0.05MPa, the reaction temperature is controlled to be 9-10 ℃, the residence time of reactants in the micro-channel reactor is controlled to be 180 seconds, and after the reaction is finished, the 1, 2-dichloroethane solution of the 3-fluoro-4, 6-dinitrophenoxyacetic acid methyl ester is obtained. Washing with aqueous hydrochloric acid, separating, washing an organic phase with water, distilling under reduced pressure, recovering 1, 2-dichloroethane, recrystallizing the residue with ethanol, filtering, and drying to obtain methyl 3-fluoro-4, 6-dinitrophenoxy acetate, wherein the yield of single-batch products is 93.2%, and the purity of the products is 96.7%.

Step 3: raw material preparation: and (3) preparing a mixture of the 3-fluoro-4, 6-dinitrophenoxy methyl acetate, the n-butyl acetate and the 5% palladium carbon catalyst (containing 50% of water) obtained in the step (2), wherein the mass ratio of the 3-fluoro-4, 6-dinitrophenoxy methyl acetate to the n-butyl acetate is 1:25.0, and the molar ratio of the 3-fluoro-4, 6-dinitrophenoxy methyl acetate to the 5% palladium carbon catalyst is 1:0.0004. Feeding the mixture into a microchannel continuous flow reactor through a advection pump in a stirring dispersion state; hydrogen enters the micro-channel continuous flow reactor through a gas meter; the preheating temperature of the continuous flow micro-channel reactor is 120 ℃; the reaction temperature is controlled to be 125-130 ℃, the reaction pressure is controlled to be 2.3-2.4Mpa, and the residence time of the reaction materials in the microchannel reactor is controlled to be 4 minutes. After the reaction is finished, the materials pass through a two-stage filter with the heat tracing temperature of 135 ℃, then the organic layer is conveyed to an organic storage tank, the n-butyl acetate solution of the product 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -ketone is in the organic storage tank, a palladium-carbon catalyst is in the two-stage filter, and the catalyst can be recycled; the method comprises the steps of cooling n-butyl acetate solution of 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -ketone in an organic storage tank, filtering to obtain a crude product, acidifying the crude product into salt by hydrochloric acid and water, adding activated carbon for adsorption, filtering, alkalizing the obtained acid aqueous phase by sodium hydroxide aqueous solution, cooling to room temperature for crystallization, filtering again, washing with water, and drying to obtain 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -ketone, wherein the yield of single-batch products is calculated to be 95.7%, and the purity of the products is calculated to be 98.7%.

Step 4: to the reaction vessel was added an organic solvent N, N-dimethylformamide (828.0 g), followed by addition of 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -one (184.0 g) (1.0 mol) obtained in step 3, sodium hydroxide (44.0 g) (1.1 mol) at a temperature of 20 to 25℃and dropwise addition of 3-chloropropionine (85.7 g) (1.15 mol) under stirring, after completion of the dropwise addition over 1 hour, the temperature was raised to 38℃and kept for 4.5 hours until the reaction was completed. Filtering, filtering inorganic salt, recovering solvent from filtrate under reduced pressure, adding water (736.0 g) into residue, pulping, washing, and filtering to obtain crude product; adding water (552.0 g) into the crude product, dropwise adding 36% concentrated hydrochloric acid (100 g), adding 3.0 g of active carbon, heating and stirring for 15 min, filtering, extracting and layering the filtrate with toluene (184 g), adjusting the pH of the water phase to 6.5-7.0 with 30% sodium hydroxide aqueous solution, filtering, re-crystallizing the filter cake with absolute ethyl alcohol (644.0 g) under heating and refluxing, cooling, filtering to obtain the product 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone, wherein the yield of the product is 91.3%, the purity of the product is 99.1% and the mass content is 98.5%.

Step 5: 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone (222.9 g) (1.0 mol) obtained in the step 4 and acetic acid (668.7 g) are sequentially added into a reaction kettle, 3,4,5, 6-tetrahydrophthalic anhydride (176.3 g) (1.12 mol) with the content of 96.0 percent and benzyl trimethyl ammonium chloride aqueous solution (1.8 g) with the concentration of 10 percent are added under the protection of nitrogen under the stirring, reflux reaction is carried out for 6 hours, after the reaction is finished, cooling crystallization is carried out, filtering is carried out, the obtained crude product is subjected to reflux beating by 95 percent ethanol (557.3 g), after cooling to room temperature, the product yield of the propyne fluben is 91.1 percent, the product purity is 99.4 percent, the mass content of the propyne fluben is 99.2 percent, and the content of single organic impurity is less than or equal to 0.1 percent.

The above-described embodiments are only preferred embodiments of the present invention, and are not intended to be limiting in any way and in nature, and it should be noted that several modifications and additions may be made to those skilled in the art without departing from the invention, which modifications and additions are also intended to be construed as within the scope of the invention.

Claims

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

2. The method for synthesizing flumioxazin as claimed in claim 1, wherein said step 1 satisfies one or more of the following conditions:

3. The method for synthesizing flumioxazin according to claim 1 or 2, wherein in the step 1, the separation method is as follows: washing with alkaline water, washing with water, azeotropic distillation with water, recovering 1, 2-dichloroethane, filtering the substrate, and drying, wherein the alkaline water is 5% sodium hydroxide aqueous solution and/or 5% sodium bicarbonate aqueous solution by mass.

4. The method for synthesizing flumioxazin as claimed in claim 1, wherein said step 2 satisfies one or more of the following conditions:

5. The method for synthesizing flumioxazin according to claim 1 or 4, wherein in the step 2, the separation method comprises: washing with aqueous hydrochloric acid, separating, washing the organic phase with water, distilling under reduced pressure, recovering 1, 2-dichloroethane, recrystallizing the residue with ethanol, filtering, and drying.

6. The method for synthesizing flumioxazin as claimed in claim 1, wherein said step 3 satisfies one or more of the following conditions:

condition 5 is that the preheating temperature of the continuous flow micro-channel reactor is 70-140 ℃;

7. The method for synthesizing flumioxazin according to claim 1 or 6, wherein in the step 3, the separation method comprises: after passing through two-stage filters with heat tracing, the organic layer is conveyed to an organic storage tank, the 6-amino-7-fluoro-2H-1, 4-benzoxazine-3 (4H) -ketone solution in the organic storage tank is cooled, a crude product is obtained after filtration, hydrochloric acid and water are acidified to form salt and are adsorbed by active carbon, filtration is carried out, the acid water phase is alkalized, cooling is carried out to room temperature for crystallization, filtration is carried out again, water washing and drying are carried out, and the heat tracing temperature of the heat tracing filter is 80-140 ℃.

8. The method for synthesizing flumioxazin as claimed in claim 1, wherein said step 4 satisfies one or more of the following conditions:

9. The method for synthesizing flumioxazin according to claim 1 or 8, wherein in the step 4, the separation method is as follows: filtering, filtering inorganic salt, recovering solvent from filtrate under reduced pressure, adding water into residue, pulping and washing, and filtering to obtain crude product; adding water into the crude product, dropwise adding hydrochloric acid, adding active carbon, heating and stirring, filtering, extracting the filtrate with ethyl acetate for layering, adjusting the pH of the water phase to 6.5-7.0 with sodium hydroxide, filtering, heating the filter cake with ethanol, refluxing for recrystallization, and filtering.

10. The method for synthesizing flumioxazin as claimed in claim 1, wherein said step 5 satisfies one or more of the following conditions:

the condition 2 is that the mol ratio of the 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone to the 3,4,5, 6-tetrahydrophthalic anhydride is 1:1.0-1.3,

the condition 3 is that the mass ratio of the 6-amino-7-fluoro-4-propynyl-1, 4-benzoxazine-3 (4H) -ketone to the aqueous solution of the benzyl ammonium salt is 1:0.001-0.01,

11. The method for synthesizing flumioxazin according to claim 1 or 10, wherein in the step 5, the separation method is as follows: after the reaction is finished, cooling, crystallizing, filtering, refluxing and pulping the obtained crude product by using 95% ethanol, cooling to room temperature, and filtering.