CN118221663A

CN118221663A - Continuous synthesis method of pyribenzoxim

Info

Publication number: CN118221663A
Application number: CN202410652075.1A
Authority: CN
Inventors: 陶建; 洪亮; 代攀攀; 陈星钰; 李佳乐; 任虎斌; 张俊旺; 曹文伶; 张飞鹏; 关傲
Original assignee: Tianjin Kailaiying Pharmaceutical Technology Development Co ltd; Asymchem Laboratories Jilin Co Ltd
Current assignee: Tianjin Kailaiying Pharmaceutical Technology Development Co ltd; Asymchem Laboratories Jilin Co Ltd
Priority date: 2024-05-24
Filing date: 2024-05-24
Publication date: 2024-06-21

Abstract

The invention provides a continuous synthesis method of haloxyfop-methyl. The synthesis method comprises the following steps: preheating ethyl trifluoroacetoacetate, methyl hydrazine and a first solvent, and then introducing the preheated ethyl trifluoroacetoacetate, the methyl hydrazine and the first solvent into a continuous reactor to react under the action of a first catalyst to obtain an intermediate product; continuously introducing the products, difluoromethane and the like into a continuous reactor for reaction to obtain an intermediate product; continuously introducing the product, formaldehyde solution and/or paraformaldehyde, concentrated hydrochloric acid and a third catalyst into a continuous reactor for continuous chloromethylation reaction to obtain an intermediate product; introducing the product, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiocimetidine salt, a second base and a fourth solvent into a continuous reactor for condensation reaction to obtain a condensation product; fifth step: and (3) introducing the condensation product, hydrogen peroxide, a fifth catalyst and a fifth solvent into a continuous reactor for oxidation reaction to obtain the fenpyrad. The method remarkably improves the yield of the fenpyrad.

Description

Continuous synthesis method of pyribenzoxim

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a continuous synthesis method of haloxyfop-R-methyl.

Background

The haloxyfop-methyl (pyroxasulfone), also known as rochemical sulfone, belongs to a novel pyrazole selective herbicide, is marketed in 2011 and is a novel pre-emergence herbicide. The haloxyfop-methyl has the advantages of wide weed killing spectrum, high activity, low dosage, good safety and the like, and is widely valued and applied worldwide. The haloxyfop-R-methyl is widely applied to various crops such as corn, wheat, soybean, cotton, sunflower, potato, peanut and the like, prevents and removes annual grassy weeds and broadleaf weeds, is a more environment-friendly and efficient substitute for chloroacetamide herbicides such as acetochlor, metolachlor and the like, and has potential to become a new mainstream variety of herbicides.

The current mainstream synthesis process of the topiramate is shown below.

The key intermediate 1 and the intermediate 2 are important factors affecting the overall yield. Wherein, the molecular formula of the intermediate 1, namely 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomethyl-halonate, is C ₆H₁₂XN₃ OS, wherein X is halogen bromine or chlorine; intermediate 2, 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole, having the formula C ₇H₆ClF₅N₂ O, CAS number: 656825-76-2.

The current mainstream process for synthesizing 5, 5-dimethyl-4, 5-dihydroisoxazole-3-thiocimetidine salt (intermediate 1) mainly comprises the following routes I to III.

Route I

I-step1, in the presence of sodium methoxide or potassium methoxide, hydroxyurea and 3-methyl-2-ethyl butenoate generate amide compounds, and after the post-treatment, acid quenching and dichloromethane extraction are carried out to obtain the product.

I-step2, deoxidizing and chlorinating carbonyl with phosphorus pentachloride or phosphorus oxychloride at normal temperature, and extracting with solvent to obtain the product, post-treatment of phosphorus oxychloride and related pollution problems.

1-Step3, wherein the reaction is substitution reaction, halogenated hydrocarbon reacts with enol structure of thiourea under acidic condition to generate isothiourea salt, and the problem of easy deterioration under post-treatment mode and alkaline condition of the product is needed to be noted.

Regarding Step1 in this synthetic route, sodium methoxide or potassium methoxide is liable to deteriorate due to strong alkali, and hydroxyurea is not suitable for long-term storage, and there is a risk of deterioration. During the reaction, a large amount of white solid is generated, and the operations of filtering, leaching, material transferring and the like are needed to be carried out for many times. The operation cost is high, and the yield loss is easy to cause in the process of transferring and leaching. Patent WO2007096576A1 reports a yield of 49%; WO201962802 reports a yield of 79%. Step2 requires phosphorus pentachloride in the chlorination reaction, and the system for reacting phosphorus oxychloride reported in the general literature is very heterogeneous and even non-reactive. The reaction time is long. A large amount of phosphorus-containing wastewater is easy to generate. Patent WO2007096576A1 reports a yield of 69%.

The isoxazole ring intermediates are unstable, and the product is easy to deteriorate after long-term placement or under alkaline and strong acid conditions.

Route II

II-step1 patent WO2007096576A1 reacts with 50% hydroxylamine hydrochloride and glyoxylic acid, and then decarboxylates and halogenates, and the reaction is carried out to produce oxime dihaloformate. Patent WO2007096576A1 reports a two-step yield of 68% and 37.8%, respectively.

II-step2, after the reaction, isobutene and dihalogen formaldehyde oxime react to generate intermediate halogenated isoxazole, isobutene gas is not easy to store, the yield is low, the dihalogen formaldehyde oxime is a high-energy compound, and the production is not easy to scale up.

By adopting the synthetic route, the reaction time is long, heterogeneous mass transfer is involved in the use of the gas isobutene, the equipment chain is long, and the overall yield is low.

Route III

III-step1, using enal and acetoxime to form 5, 5-dimethyl-4, 5-dihydro-isoxazole in the presence of trifluoroacetate catalyst; WO 2011063842A 1/WO 2011063843A1 reports a yield of 76%;

III-step2: then halogenating by a halogenating reagent to obtain 3-X-5, 5-dimethyl-4, 5-dihydro-isoxazole, wherein X is chlorine or bromine, and the yield is reported to be 70%;

In addition, the acetone oxime and the 5, 5-dimethyl-4, 5-dihydro-isoxazole are high-energy compounds, the thermal risk of the ring closure reaction is large, and because the 5, 5-dimethyl-4, 5-dihydro-isoxazole has poor thermal stability, more halogenated impurities are generated in the halogenation process, and the purification is not easy.

The prior art synthetic methods for the above intermediate 2 generally have the following problems: (1) The difluoromethylation reaction stage in the existing intermittent process is a gas-liquid-solid heterogeneous reaction system, and is limited by mass transfer and heat transfer capacity of intermittent equipment, so that the required reaction time is long, the reaction effect is reduced, and the yield is reduced; (2) The methylolation process needs to strictly control the material equivalent and pH of a reaction system, the reaction condition is sensitive and harsh, byproducts are easy to generate, and the yield is reduced. (3) The chlorination reaction is a high-risk reaction, the reaction exotherm is large and severe, a large amount of acid gas is emitted, the process risk is high, and the pollution is large.

Disclosure of Invention

The invention mainly aims to provide a continuous synthesis method of haloxyfop-methyl, which aims to solve the problems of complex synthesis process and low yield of haloxyfop-methyl in the prior art.

In order to achieve the above object, according to one aspect of the present invention, there is provided a continuous synthesis method of metazachlor, comprising: a first procedure: preheating ethyl trifluoroacetoacetate, methyl hydrazine and a first solvent, continuously introducing the preheated ethyl trifluoroacetoacetate, the methyl hydrazine and the first solvent into a first continuous reactor, reacting under the action of a first catalyst, and performing first purification treatment on the obtained first reaction liquid to obtain 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole; and a second step of: continuously introducing 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole, difluoromethane, a first base and a second solvent into a second continuous reactor for reaction, and continuously extracting, separating and continuously drying the obtained second reaction liquid to obtain 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole; and a third step of: continuously introducing 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole, formaldehyde solution and/or paraformaldehyde, concentrated hydrochloric acid and a third catalyst into a third continuous reactor for continuous chloromethylation reaction, and continuously extracting and separating the obtained third reaction liquid to obtain 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole; fourth step: introducing 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomethylimidazole salt, second base and fourth solvent into a fourth continuous reactor for condensation reaction, and performing continuous liquid-liquid separation and water washing on the obtained fourth reaction liquid to obtain a condensation product with the structure shown in formula I; fifth step: introducing the condensation product with the structure shown in the formula I, hydrogen peroxide, a fifth catalyst and a fifth solvent into a fifth continuous reactor for oxidation reaction, quenching the obtained fifth reaction liquid, and then performing second purification treatment to obtain the fenpyrad with the structure shown in the formula II.

Formula I formula II

Further, the first process meets at least one of the following characteristics: (1) The first solvent is selected from any one or more of triethylamine, ethanol, acetic acid and methanol; (2) The mass volume ratio of the trifluoro acetoacetic ester to the first solvent is 0.30-10.00 g/mL; (3) The molar ratio of methyl hydrazine to ethyl trifluoroacetoacetate is (0.5-2): 1, a step of; (4) The methyl hydrazine comprises any one of methyl hydrazine aqueous solution and methyl hydrazine salt, when the methyl hydrazine is methyl hydrazine aqueous solution, the first catalyst is selected from any one or more of hydrochloric acid, acetic acid, sulfuric acid and trifluoroacetic acid, and when the methyl hydrazine is methyl hydrazine salt, the first catalyst is selected from any one or more of triethylamine, pyridine, sodium hydroxide and potassium hydroxide; (5) the first continuous reactor is a microchannel reactor; (6) The reaction temperature in the first continuous reactor is 40-100 ℃; (7) The reaction residence time in the first continuous reactor is 10-60 min; (8) The first catalyst is selected from any one or more of hydrochloric acid, acetic acid, sulfuric acid and trifluoroacetic acid, the first purification treatment comprises continuous quenching and continuous solid-liquid separation, and the continuous quenching comprises: mixing the first reaction liquid with water, and crystallizing; (9) The first catalyst is selected from any one or more of triethylamine, pyridine, sodium hydroxide and potassium hydroxide, and the first purification treatment comprises a first continuous extraction.

Further, the second process meets at least one of the following features: (1) The molar ratio of 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole to difluoromethane is 1: 1-3; (2) The first base is selected from any one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia water, triethylamine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate and 1, 8-diazabicyclo undec-7-ene; (3) The molar ratio of the first base to the 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole is (0.5-3): 1, a step of; (4) The second solvent is selected from any one or more of acetonitrile, methanol, ethanol, isopropanol, dichloromethane, dioxane, tetrahydrofuran, dimethyl tetrahydrofuran, n-pentane, n-heptane and n-hexane; (5) The mass volume ratio of the 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole to the second solvent is 0.5-3 g/ml; (6) Passing a homogeneous solution of 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole, a first base, and water into a second continuous reactor; (7) the second continuous reactor is a continuous gas-liquid reactor; (8) The reaction temperature in the second continuous reactor is 25-50 ℃; (9) The reaction residence time in the second continuous reactor is 10 to 30 min.

Further, the third process meets at least one of the following features: (1) The third catalyst comprises any one or more of sulfuric acid, acetic acid, ferric chloride, magnesium chloride, aluminum chloride and zinc chloride; (2) The molar ratio of the third catalyst to the 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole is (0.1-2): 1, a step of; (3) The concentration of the formaldehyde aqueous solution is 35-37%, and the mole ratio of formaldehyde in the formaldehyde aqueous solution to 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole is (0.5-2): 1, a step of; (4) the third continuous reactor is a microchannel reactor; (5) the temperature of the continuous chloromethylation reaction is 80-120 ℃; (6) The residence time of the continuous chloromethylation reaction is 30 to 240 minutes.

Further, the fourth procedure satisfies at least one of the following features: (1) The molar ratio of the 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiocimetidine salt to the 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole is 1.0:1.0-1.1, and the molar ratio of the 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiocimetidine salt to the second base is 1.0:3.0-5.0; (2) The second alkali is any one or more of sodium hydroxide, potassium hydroxide, ammonia water, triethylamine, sodium carbonate and potassium carbonate; (3) The fourth solvent is any one or more of acetonitrile, dichloromethane, dichloroethane and chloroform; (4) the temperature of the condensation reaction is 0-80 ℃; (5) the residence time of the condensation reaction is 20-60 min; (6) The fourth continuous reactor is a micro-channel reactor, and the number of the fourth continuous reactor is 1-3.

Further, the fifth process satisfies at least one of the following features: (1) The fifth catalyst is selected from any one or more of sodium tungstate, ferrous sulfate heptahydrate, sulfuric acid, acetic acid, trifluoroacetic acid and tungsten oxide; (2) The molar ratio of the introduced condensation product with the structure of formula I, the fifth catalyst and hydrogen peroxide is 1.0: 0.05-0.10: 2.0 to 3.0; (3) the reaction temperature of the oxidation reaction is 50-100 ℃; (4) the residence time of the oxidation reaction is 60-180 min; (5) the fifth continuous reactor is a microchannel reactor; (6) The fifth reaction liquid is mixed with a quenching agent for quenching, wherein the quenching agent is one or more of sodium sulfite, sodium thiosulfate, sodium pyrosulfate and sodium bisulphite, and the molar ratio of the quenching agent to the condensation product with the structure shown in the formula I is 1.0:0.5 to 0.7; (7) The second purification treatment comprises continuous liquid separation, water washing, concentration and crystallization, pulping purification and drying.

Further, 5-dimethyl-4, 5-dihydroisoxazole-3-thiocimetidine salt is prepared by the following continuous method: continuously introducing acetone oxime, 3-methyl-2-butenal and a sixth catalyst into a microchannel reactor for a first cyclization reaction, and continuously rectifying the obtained sixth reaction liquid to obtain 5, 5-dimethyl-4, 5-dihydro-isoxazole; introducing 5, 5-dimethyl-4, 5-dihydroisoxazole and a first halogenating reagent into a continuous reactor for carrying out a first halogenating reaction to obtain 3-halogen-5, 5-dimethyl-4, 5-dihydroisoxazole; continuously introducing 3-halogen-5, 5-dimethyl-4, 5-dihydro-isoxazole, thiourea, acid and a sixth solvent into a tubular reactor for substitution reaction, continuously extracting and separating the obtained seventh reaction liquid, concentrating and drying to obtain 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiocimetidine salt.

Further, the sixth catalyst is any one or more of trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, sulfuric acid, hydrochloric acid, nitric acid, fluoroboric acid, perchloric acid and benzenesulfonic acid;

And/or, the molar ratio of 3-methyl-2-butenal to acetoxime is 1:0.95-1.5;

And/or the mole ratio of the sixth catalyst to 3-methyl-2-butenal is 0.005-0.8: 1, a step of;

and/or the temperature of the first cyclization reaction is 70-100 ℃ and the time is 10-300 min;

And/or the first halogenating reagent is any one or more of chlorine, sulfonyl chloride, thionyl chloride, phosphorus trichloride and phosphorus pentachloride, and the molar ratio of the 5, 5-dimethyl-4, 5-dihydro-isoxazole to the first halogenating reagent is 1:1 to 2;

and/or the reaction temperature of the first halogenation reaction is 0-5 ℃ and the reaction time is 5-100 min;

And/or the molar ratio of thiourea to 3-halo-5, 5-dimethyl-4, 5-dihydroisoxazole is 1: (0.9-2);

And/or the acid is any one or more of hydrochloric acid, hydrogen bromide and sulfuric acid;

And/or the sixth solvent is any one or more of acetonitrile, methanol, ethanol, isopropanol, dichloromethane, dioxane, tetrahydrofuran, dimethyl tetrahydrofuran, n-pentane, n-heptane and n-hexane, and the mass volume ratio of the 3-halogen-5, 5-dimethyl-4, 5-dihydro isoxazole to the sixth solvent is 0.1-1 g/ml;

And/or the reaction temperature of the continuous substitution reaction is 25-120 ℃ and the retention time is 10-480 min.

Further, 5-dimethyl-4, 5-dihydroisoxazole-3-thiocimetidine salt is prepared by the following continuous method: continuously introducing 3-methyl-2-ethyl butenoate, hydroxyurea, third alkali and a seventh solvent into a continuous dynamic tubular reactor for a second cyclization reaction, and performing continuous solid-liquid separation, dissociation, extraction and liquid separation and drying on the obtained product to obtain 5, 5-dimethyl-3-isoxazolidinone; continuously introducing 5, 5-dimethyl-3-isoxazolidinone, a second halogenating reagent and an eighth solvent into a continuous dynamic tubular reactor for second halogenating reaction, and continuously quenching and separating the obtained product system to obtain 3-halogen-5, 5-dimethyl-4, 5-dihydro isoxazole; continuously introducing 3-halogen-5, 5-dimethyl-4, 5-dihydro-isoxazole, thiourea, acid and a sixth solvent into a tubular reactor for substitution reaction, continuously extracting and separating the obtained eighth reaction liquid, concentrating and drying to obtain 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiocimetidine salt.

Further, the third base is selected from any one or more of potassium methoxide, sodium methoxide, potassium ethoxide, sodium hydroxide, potassium hydroxide, tetramethylguanidine, triethylamine, and a basic resin;

And/or the mass ratio of the 3-methyl-2-ethyl butenoate to the seventh solvent is 1:3-1:20, and the seventh solvent is any one or more of methanol, ethanol, dichloromethane, tetrahydrofuran and DMF;

And/or the molar ratio of hydroxyurea to ethyl 3-methyl-2-butenoate is 0.9:1-5:1;

and/or the reaction temperature of the second cyclization reaction is 10-100 ℃ and the retention time is 0.2-10 h;

And/or the second halogenating agent is phosphorus pentachloride and/or phosphorus oxychloride; the molar ratio of the second halogenating reagent to the 5, 5-dimethyl-3-isoxazolidinone is 0.9:1-10:1;

And/or the reaction temperature of the second halogenation reaction is-20-100 ℃ and the retention time is 0.05-2 h;

And/or the sixth solvent is selected from any one or more of acetonitrile, methanol, ethanol, isopropanol, dichloromethane, dioxane, tetrahydrofuran, dimethyl tetrahydrofuran, n-pentane, n-heptane and n-hexane.

By applying the technical scheme of the application, continuous production of the haloxyfop-R-methyl is realized through the first to fifth working procedures, and the synthesis route is prepared through chloromethylation reaction when the key intermediate 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole is synthesized, so that the reaction steps are shortened, dangerous reagents such as thionyl chloride and the like can be avoided in the synthesis process of the intermediate, and the safety is improved and the method is more friendly to the environment. On the other hand, the continuous reactor adopted by the continuous synthesis method has larger specific heat exchange area, can quickly realize heat exchange, realizes accurate temperature control of reaction temperature, can effectively inhibit side reaction, improves reaction selectivity and yield, and is internally provided with a structure for strengthening mass transfer, thereby improving the mixing effect of a heterogeneous system, promoting the conversion of raw materials and further improving the reaction yield. Particularly, in the second procedure, a gas distributor can be arranged in the continuous reactor, so that the equipment utilization rate and the gas utilization rate are effectively improved, and the reaction yield is improved.

Drawings

The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description serve to explain the application. In the drawings:

FIG. 1 shows a schematic diagram of a reaction system according to embodiments 1 to 16 of the present invention; and

FIG. 2 shows a schematic diagram of a reaction system according to embodiments 24-44 of the present invention.

Wherein the above figures include the following reference numerals: 01. continuous preparation of units of 5- (hydroxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole; 02. continuous preparation of units of 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole; 03. continuous preparation of units of 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole; 04. continuous preparation units of 5, 5-dimethyl-4, 5-dihydroisoxazole; 05. 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole continuous preparation units; 06. continuous preparation of units from 5, 5-dimethyl-4, 5-dihydroisoxazol-3-thiocimetidine salt.

Detailed Description

It should be noted that, without conflict, the embodiments of the present application and features of the embodiments may be combined with each other. The application will be described in detail below with reference to the drawings in connection with embodiments.

As analyzed by the background technology of the application, the problems of complex synthesis process and low yield of the haloxyfop-R-methyl exist in the prior art, and in order to solve the problems, the application provides a continuous synthesis method of the haloxyfop-R-methyl. The continuous synthesis method of the fenpyrad comprises the following steps: a first procedure: preheating ethyl trifluoroacetoacetate, methyl hydrazine and a first solvent, continuously introducing the preheated ethyl trifluoroacetoacetate, the methyl hydrazine and the first solvent into a first continuous reactor, reacting under the action of a first catalyst, and performing first purification treatment on the obtained first reaction liquid to obtain 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole; and a second step of: continuously introducing 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole, difluoromethane, a first base and a second solvent into a second continuous reactor for reaction, and continuously extracting, separating and continuously drying the obtained second reaction liquid to obtain 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole; and a third step of: continuously introducing 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole, formaldehyde solution and/or paraformaldehyde, concentrated hydrochloric acid and a third catalyst into a third continuous reactor for continuous chloromethylation reaction, and continuously extracting and separating the obtained third reaction liquid to obtain 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole; fourth step: introducing 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomethylimidazole salt, second base and fourth solvent into a fourth continuous reactor for condensation reaction, and performing continuous liquid-liquid separation and water washing on the obtained fourth reaction liquid to obtain a condensation product with the structure shown in formula I; fifth step: introducing the condensation product with the structure shown in the formula I, hydrogen peroxide, a fifth catalyst and a fifth solvent into a fifth continuous reactor for oxidation reaction, quenching the obtained fifth reaction liquid, and then performing second purification treatment to obtain the fenpyrad with the structure shown in the formula II.

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Formula I formula II

According to the application, continuous production of the haloxyfop-R-methyl is realized through the first to fifth working procedures, and the synthesis route is prepared through chloromethylation reaction when the key intermediate 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole is synthesized, so that the reaction steps are shortened, dangerous reagents such as thionyl chloride and the like can be avoided in the synthesis process of the intermediate, and the safety is improved and the method is more friendly to the environment. On the other hand, the continuous reactor adopted by the continuous synthesis method has larger specific heat exchange area, can quickly realize heat exchange, realizes accurate temperature control of reaction temperature, can effectively inhibit side reaction, improves reaction selectivity and yield, and is internally provided with a structure for strengthening mass transfer, thereby improving the mixing effect of a heterogeneous system, promoting the conversion of raw materials and further improving the reaction yield. Particularly, in the second procedure, a gas distributor can be arranged in the continuous reactor, so that the equipment utilization rate and the gas utilization rate are effectively improved, and the reaction yield is improved.

Taking 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomedetomidine hydrochloride as an example in the fourth step, the synthetic reaction formula of the fenpyrad is shown as follows:

In the first step, 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole, namely the compound A in the reaction equation, is synthesized by using ethyl trifluoroacetoacetate and methyl hydrazine as raw materials. Wherein the methyl hydrazine is methyl hydrazine aqueous solution or methyl hydrazine salt, and the methyl hydrazine salt can be selected from the prior art, such as methyl hydrazine sulfate and methyl hydrazine hydrochloride.

In some preferred embodiments of the present application, when the methylhydrazine is an aqueous solution of methylhydrazine, the first catalyst is selected from any one or more of hydrochloric acid, acetic acid, sulfuric acid and trifluoroacetic acid, and when the methylhydrazine is a salt of methylhydrazine, the first catalyst is selected from any one or more of triethylamine, pyridine, sodium hydroxide and potassium hydroxide, and different catalysts are selected according to different forms of the raw material methylhydrazine, so that the selectivity and yield of the reaction can be further improved.

Further, the molar ratio of methyl hydrazine to ethyl trifluoroacetoacetate is (0.5-2): 1 when the ethyl trifluoroacetoacetate in the raw material is excessive, the ethyl trifluoroacetoacetate remaining in the reaction can be recovered and used in the reaction, and the recovery method can be selected from the prior art, such as distillation. Preferably, the molar ratio of methyl hydrazine to ethyl trifluoroacetoacetate is 1-1.5: 1, is beneficial to further improving the yield of the product and the utilization rate of atoms and simplifying the process.

In some embodiments of the application, the solvent is selected from any one or more of triethylamine, ethanol, acetic acid and methanol, has good solubility to the system, is beneficial to promoting the reaction and is convenient for product separation. Preferably, the mass volume ratio of the ethyl trifluoroacetoacetate to the solvent is 0.30-10.00 g/mL.

In some exemplary embodiments of the present application, the reaction temperature in the first reactor is 40-100 ℃, preferably, the reaction residence time is 10-60 min, in order to further increase the reaction rate and selectivity.

In some embodiments of the present application, the first continuous reactor is a microchannel reactor, which has better heat and mass transfer effects, and has high integrity, and the number of reactors may be 1, or may be a plurality of reactors connected in series, such as 2,3, 4 or 5.

In some preferred embodiments of the present application, the materials ethyl trifluoroacetoacetate and methyl hydrazine are preheated by a preheater and then fed into the first continuous reactor, preferably at a preheating temperature of 50-70 ℃.

In some exemplary embodiments of the present application, an appropriate first purification treatment is selected based on the type of first catalyst. When the first catalyst is an acid catalyst such as hydrochloric acid, acetic acid, sulfuric acid, trifluoroacetic acid, etc., the first purification treatment comprises continuous quenching and continuous solid-liquid separation; when the first catalyst is a base catalyst, such as triethylamine, pyridine, sodium hydroxide, potassium hydroxide, and the like, the first purification treatment comprises a first continuous extraction.

The manner in which the first reaction solution is quenched may be selected in the art, and in some embodiments of the present application, the continuous quenching described above includes: the first reaction solution is mixed with water, and preferably, water at a low temperature is mixed with the first reaction solution to terminate the reaction, and the produced 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole is precipitated as a solid. Preferably, the water is used in an amount of 2-4V, that is, 2-4 times the volume of the first reaction solution, so that the product is sufficiently separated out, and the product yield of the reaction in the step is further improved. In some embodiments of the application, the continuous quenching comprises: and mixing the first reaction liquid with low-temperature water, and controlling the temperature of a mixing device to be 5-15 ℃ so as to be beneficial to high-yield precipitation of the 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole solid. And overflowing the solid-liquid system obtained by continuous quenching treatment to a continuous solid-liquid separation module to obtain solid, namely 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole, then entering a second process, and recycling the separated mother liquor to recover the solvent and the first catalyst.

In some embodiments of the application, the first continuous extraction is performed in a liquid-liquid separator using an ethereal solvent, which may be selected in the art, such as methyl tert-butyl ether. In some preferred embodiments of the application, the organic phase of the first continuous extraction is dried in a continuous drying module, and the dried product solution is then used in the second process step, or after removal of the solvent, in the second process step.

In the second step, the 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole prepared in the first step reacts with difluoromethane under the action of a first base to obtain 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole.

Further, the molar ratio of 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole to difluoromethane was 1:1 to 3, preferably 1: 1-2.

Further, the first base is any one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia water, triethylamine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate and 1, 8-diazabicyclo undec-7-ene. Preferably, the molar ratio of the first base to 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole is (0.5-3): 1. preferably, the mass-to-volume ratio of the first base to the water is 1-5 g/ml. In some preferred embodiments of the application, a homogeneous solution of 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole, base and water is introduced into a second continuous reactor, which has good flowability and facilitates continuous feeding.

In some embodiments of the application, the second solvent is selected from any one or more of acetonitrile, methanol, ethanol, isopropanol, dichloromethane, dioxane, tetrahydrofuran, dimethyltetrahydrofuran, n-pentane, n-heptane, and n-hexane; preferably, the mass volume ratio of the 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole to the second solvent is 0.5-3 g/ml;

In some typical embodiments of the present application, the second continuous reactor is a continuous gas-liquid reactor, which is one of tower reactors, and the number of the reactors is 1-3, when a plurality of reactors are adopted, the reactors are connected in series, so that the mass transfer and heat transfer effects are improved.

In some embodiments of the present application, the reaction temperature in the second continuous reactor is 25-50 ℃, and the reaction residence time in the second continuous reactor is 10-30 min, which gives consideration to higher reaction rate and product yield. In some preferred embodiments of the application, to reduce side reactions, the feedstock is pre-cooled to 10-20 ℃ and then fed into a second continuous reactor.

The second reaction liquid overflowed from the second continuous reactor enters a continuous extraction liquid separation module, extraction liquid separation is carried out in a liquid-liquid separator, the water phase is separated, the obtained organic phase is dried in a continuous drying module, and then the organic phase enters a third process for reaction.

In the third step, the 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole prepared in the second step undergoes chloromethylation reaction to obtain a key intermediate 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole, namely a compound C in the reaction equation. The hydrochloric acid is used as the chloromethylation reagent, so that the cost is lower than that of other chloromethylation reagents, the danger coefficient is low, the environment is protected, the post treatment is simple, the direct liquid separation is realized, the upper water phase can be continuously used after supplementing the hydrogen chloride gas, and three wastes are hardly generated. However, other chloromethylation reagents in the prior art, such as thionyl chloride, have high cost, can additionally generate sulfur dioxide polluting the atmosphere, have high risk coefficient and are complex in post-treatment.

Further, the concentrated hydrochloric acid is a hydrochloric acid aqueous solution with a concentration of 30-37%. Preferably, the molar quantity of hydrochloric acid in the concentrated hydrochloric acid introduced into the system is 3-40 times of the molar quantity of 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole, which is beneficial to improving the yield of chloromethylation reaction.

The third catalyst may be selected from the existing catalysts for chloromethylation reactions. In some embodiments of the present application, the third catalyst may be sulfuric acid, acetic acid, or a lewis acid, such as any one or more of ferric chloride, magnesium chloride, aluminum chloride, and zinc chloride. Preferably, the molar ratio of the third catalyst to 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole is (0.1-2): 1.

In some embodiments of the present application, the reaction raw materials in the third step are 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole, a formaldehyde solution and concentrated hydrochloric acid, wherein the concentration of the formaldehyde solution is 35-37%, and the molar ratio of formaldehyde in the formaldehyde solution to 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole is (0.5-2): 1, preferably (1 to 1.8): 1. the formaldehyde solution is used as the raw material of chloromethylation reaction, so that continuous feeding is convenient to realize, manual operation is reduced, and the volatilization of harmful gas can be controlled on the basis of reducing cost due to the fact that the reaction stage and the post-treatment stage can realize a full continuous flow, so that the method is more suitable for large-scale production and reduces the production cost.

In some embodiments of the present application, the reaction raw materials in the third step are 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole, paraformaldehyde and concentrated hydrochloric acid, wherein the formaldehyde equivalent of the paraformaldehyde is 0.5-2, preferably 1-1.8, based on 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole.

In some exemplary embodiments of the present application, the third continuous reactor is a microchannel reactor, one of the tubular reactors, the number of the reactors is 1-3, and when the number of the reactors is greater than 1, the plurality of reactors are connected in series.

In some preferred embodiments of the present application, the temperature of the continuous chloromethylation reaction is in the range of 70 to 120 ℃, preferably 80 to 120 ℃, more preferably 90 to 110 ℃. Preferably, the raw materials are preheated to 50-70 ℃ by a preheater and then are introduced into a third continuous reactor, and further, the residence time of the continuous chloromethylation reaction is 60-120 min, and the chloromethylation product yield is higher.

And after the reaction is finished, the third reaction liquid overflowed from the third continuous reactor enters a continuous extraction liquid separation module, extraction liquid separation is carried out in a liquid-liquid separator, and the product obtained by liquid separation is 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole, and then the product is used for a fourth process.

In the fourth step, the 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole prepared in the third step and 5, 5-dimethyl-4, 5-dihydroisoxazole-3-thiocimetidine salt undergo a condensation reaction under the action of a second base to obtain a condensation product with a structure shown in formula I, namely a compound D in the reaction equation.

Further, the molar ratio of the 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiocimetidine salt to the 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole is 1.0:1.0-1.1.

Further, the molar ratio of the 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiocimetidine salt to the second base is 1.0:3.0-5.0. Preferably, the second base is any one or more of sodium hydroxide, potassium hydroxide, ammonia, triethylamine, sodium carbonate and potassium carbonate. In some embodiments of the application, the second base is formulated as a homogeneous aqueous solution and passed into a fourth continuous reactor.

In some embodiments of the present application, the fourth solvent is any one or more of acetonitrile, dichloromethane, dichloroethane and chloroform, which not only facilitates the reaction, but also facilitates the separation of the product.

In some exemplary embodiments of the present application, the condensation reaction temperature is 0-80℃and the residence time is 20-60 minutes, which is advantageous for increasing the reaction rate and product yield. Preferably, the reaction temperature of the condensation reaction is 0 to 20 ℃, and more preferably, the reaction raw material of the fourth step is precooled to the above range and then introduced into the fourth continuous reactor for reaction.

In some exemplary embodiments of the present application, the fourth continuous reactor is a microchannel reactor, and the number of fourth continuous reactors is 1-3.

And (3) carrying out continuous liquid-liquid separation on the fourth reaction liquid flowing out of the fourth reactor, separating an aqueous phase from an organic phase, carrying out continuous water washing on the obtained organic phase, separating and removing alkali from the organic phase, enabling the water washing liquid to be neutral, obtaining a condensation product with the structure shown in the formula I, and then entering a fifth process.

In the fifth step, the thioether group in the condensation product prepared in the fourth step is oxidized into a sulfonyl group to obtain the target product of the fenpyrad.

In some embodiments of the application, the fifth catalyst is selected from any one or more of sodium tungstate, ferrous sulfate heptahydrate, sulfuric acid, acetic acid, trifluoroacetic acid, and tungsten oxide;

further, the molar ratio of the introduced condensation product having the structure of formula I, the fifth catalyst, hydrogen peroxide is 1.0: 0.05-0.10: 2.0 to 3.0.

In some embodiments of the application, the reaction temperature of the oxidation reaction is from 50 to 100 ℃, preferably from 70 to 100 ℃, preferably the fifth continuous reactor is preheated prior to the introduction of the feedstock, more preferably the condensation product having the structure of formula i and the fifth solvent are preheated prior to the introduction into the fifth continuous reactor. Preferably, the residence time of the oxidation reaction is from 60 to 180 minutes.

In some exemplary embodiments of the present application, the fifth continuous reactor is a microchannel reactor, which is one of the tubular reactors, and the number of reactors is 1-3.

In some exemplary embodiments of the present application, the fifth reaction solution is mixed with a quencher for quenching, excess hydrogen peroxide is reacted, the quencher is any one or more of sodium sulfite, sodium thiosulfate, sodium pyrosulfate and sodium bisulphite, and preferably, the molar ratio of the quencher to the condensation product having the structure of formula i is 1.0:0.5 to 0.7.

In some embodiments of the present application, the second purification treatment comprises continuous liquid separation, water washing, concentration and crystallization, pulping purification and drying to obtain the target product of the fenpyrad.

In some exemplary embodiments of the present application, the starting 5, 5-dimethyl-4, 5-dihydroisoxazole-3-thiocimetidine salt in the fourth step is prepared by the following sequential process: continuously introducing acetone oxime, 3-methyl-2-butenal and a sixth catalyst into a microchannel reactor for a first cyclization reaction, and continuously rectifying the obtained sixth reaction liquid to obtain 5, 5-dimethyl-4, 5-dihydro-isoxazole; introducing 5, 5-dimethyl-4, 5-dihydroisoxazole and a first halogenating reagent into a continuous reactor for carrying out a first halogenating reaction to obtain 3-halogen-5, 5-dimethyl-4, 5-dihydroisoxazole; continuously introducing 3-halogen-5, 5-dimethyl-4, 5-dihydro-isoxazole, thiourea, acid and a sixth solvent into a tubular reactor for substitution reaction, continuously extracting and separating the obtained seventh reaction liquid, concentrating and drying to obtain 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiocimetidine salt.

The continuous method for preparing the 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomethyl-imidazole salt has larger specific heat exchange area due to the adoption of continuous reaction equipment, can quickly realize heat exchange, realize accurate temperature control of reaction temperature, effectively inhibit side reaction, and improve reaction selectivity and yield, thereby obviously reducing process cost; in addition, in the process of preparing the 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiocimetidine salt by using the method, the first cyclization reaction and the first halogenation reaction can avoid the use of solvents, improve the yield and the safety, and are more friendly to the environment.

Taking 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiocimetidine hydrochloride as an example, the first halogenation reaction is chloro, and the synthetic route is shown in the following reaction equation:

in some embodiments of the present application, the sixth catalyst used in the first cyclization reaction is any one or more of trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, sulfuric acid, hydrochloric acid, nitric acid, fluoroboric acid, perchloric acid, and benzenesulfonic acid; preferably, the molar ratio of the sixth catalyst to 3-methyl-2-butenal is 0.005-0.8: 1, more preferably 0.05 to 0.3:1, the reaction rate and the product yield can be further accelerated.

Further, the molar ratio of the 3-methyl-2-butenal to the acetoxime is 1:0.95-1.5.

In some embodiments of the application, the temperature of the first cyclization reaction is 70-100 ℃ for a period of 10-600 min, the yield of the cyclization reaction is higher, preferably the period of the first cyclization reaction is 10-300 min, more preferably 10-60 min. Preferably, the microchannel reactor is preheated before introducing the acetoxime, the 3-methyl-2-butenal and the sixth catalyst, and more preferably, the raw materials of the acetoxime, the 3-methyl-2-butenal and the sixth catalyst are preheated to 30-35 ℃ and then introduced into the microchannel reactor.

Further, the number of microchannel reactors is 1-5, and when the number of reactors is greater than 1, a plurality of reactors are connected in series.

In some embodiments of the application, the sixth reaction solution is continuously rectified to separate and purify the product, and the byproducts of acetone and trifluoroacetic acid and the high-purity 5, 5-dimethyl-4, 5-dihydroisoxazole product are separated, wherein the temperature of the top of the tower of the continuous rectification module is 50-55 ℃.

The halogenating agent in the first halogenation reaction can be selected from common chlorinating agents, brominating agents and iodinating agents, and particularly the chlorinating agents are more cheap and easily available. In some embodiments of the application, the first halogenating agent is any one or more of chlorine, sulfonyl chloride, thionyl chloride, phosphorus trichloride and phosphorus pentachloride, preferably the molar ratio of 5, 5-dimethyl-4, 5-dihydroisoxazole to the first halogenating agent is 1:1 to 2.

The first halogenation reaction is preferably carried out without a solvent, and a corresponding solvent such as acetonitrile, methanol, ethanol, isopropanol, methylene chloride, dioxane, tetrahydrofuran, dimethyltetrahydrofuran, n-pentane, n-heptane, n-hexane, etc. may be used.

In some preferred embodiments of the application, the first halogenation reaction is carried out at a reaction temperature of from-10 to 20deg.C, preferably from 0 to 5deg.C, for a reaction time of from 5 to 100 min; in some embodiments of the present application, the first halogenated feedstock is pre-cooled prior to introduction into the continuous reactor, preferably at a pre-cooling temperature of-15 to-10 ℃, such that after entering the reactor, a reduction in the yield of halogenated products due to exothermic reaction is avoided.

The continuous reactor for carrying out the first halogenation reaction may be selected from a continuous gas-liquid reaction apparatus and a continuous liquid-liquid reaction apparatus according to the difference of the first halogenation reagent, that is, a continuous gas-liquid reactor is used when a gaseous first halogenation reagent (for example, chlorine) is used, and a continuous liquid-liquid reactor is used when a liquid first halogenation reagent is used; the continuous liquid-liquid reaction device comprises a tube reactor, a micro-channel reactor and the like, wherein the continuous liquid-liquid reaction device comprises a tube reactor, a micro-channel reactor and the like, and the continuous liquid-liquid reactor is one of tower reactors; the number of the continuous reactors may be 1 to 3.

The reactor can be a gas-liquid reaction device and a liquid-liquid continuous reaction device, including but not limited to a tube array reactor, a micro-channel and the like, wherein the continuous gas-liquid reactor is one of tower reactors, and the number of the reactors is 1-3;

If no solvent is added in the first halogenation reaction, the obtained product can directly enter the next reaction without post-treatment, namely substitution reaction; if solvent is added, the product can be obtained for substitution reaction after separation and purification by referring to the prior art.

Further, in the substitution reaction, the acid to be added is any one or more of hydrochloric acid, hydrogen bromide and sulfuric acid, and among them, concentrated hydrochloric acid having a concentration of 30 to 37% is preferable. It is further preferred that the molar ratio of acid to starting 3-halo-5, 5-dimethyl-4, 5-dihydroisoxazole is from 1:10 to 1:200.

Further, in the substitution reaction, the molar ratio of thiourea to 3-halo-5, 5-dimethyl-4, 5-dihydroisoxazole is 1: (0.9-2).

In some embodiments of the present application, the sixth solvent is any one or more of acetonitrile, methanol, ethanol, isopropanol, dichloromethane, dioxane, tetrahydrofuran, dimethyltetrahydrofuran, n-pentane, n-heptane, and n-hexane, which can increase the reaction rate and reduce the retention time; preferably, the mass volume ratio of the 3-halogen-5, 5-dimethyl-4, 5-dihydro-isoxazole to the sixth solvent is 0.1-1 g/ml.

In some embodiments of the application, the reaction temperature of the continuous substitution reaction is 25-120 ℃ and the retention time is 10-480min.

And (3) a seventh reaction liquid obtained through the continuous substitution reaction enters a continuous extraction liquid separation module, and extraction liquid separation is carried out in a liquid-liquid separator. Concentrating and drying to obtain the product, namely the 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomedetomidine salt.

In other exemplary embodiments of the application, 5-dimethyl-4, 5-dihydroisoxazole-3-thiocimetidine salt is prepared by the following sequential process: continuously introducing 3-methyl-2-ethyl butenoate, hydroxyurea, third alkali and a seventh solvent into a continuous dynamic tubular reactor for a second cyclization reaction, and performing continuous solid-liquid separation, dissociation, extraction and liquid separation and drying on the obtained product to obtain 5, 5-dimethyl-3-isoxazolidinone; continuously introducing 5, 5-dimethyl-3-isoxazolidinone, a second halogenating reagent and an eighth solvent into a continuous dynamic tubular reactor for second halogenating reaction, and continuously quenching and separating the obtained product system to obtain 3-halogen-5, 5-dimethyl-4, 5-dihydro isoxazole; continuously introducing 3-halogen-5, 5-dimethyl-4, 5-dihydro-isoxazole, thiourea, acid and a sixth solvent into a tubular reactor for substitution reaction, continuously extracting and separating the obtained eighth reaction liquid, concentrating and drying to obtain 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiocimetidine salt.

According to the synthesis method of the 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomethyl carbamate, 3-methyl-2-ethyl butenoate and hydroxyurea are used as raw materials, so that full continuous synthesis is realized, all the reaction raw materials are in a liquid state, the dynamic tubular reactor is matched according to the characteristics of the reaction and reactants, the mass transfer and heat transfer effects are improved, the accurate control of the reaction temperature is realized, the side reaction can be effectively inhibited, and the reaction selectivity and the yield are improved.

Taking 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiocimetidine hydrochloride and PCl ₅ as an example, the synthetic route is shown in the following reaction equation:

in some embodiments of the present application, the above-mentioned third base may be an inorganic base including, by way of example, any one or more of potassium methoxide, sodium methoxide, potassium ethoxide, sodium hydroxide and potassium hydroxide, an organic base including, by way of example, any one or more of tetramethylguanidine and triethylamine, or a basic resin.

Further, in the second cyclization reaction, the molar ratio of the hydroxyurea to the ethyl 3-methyl-2-butenoate which are continuously introduced is 0.9:1 to 5:1.

Further, the mass ratio of the 3-methyl-2-ethyl butenoate to the seventh solvent is 1:3-1:20, preferably, the seventh solvent is any one or more of methanol, ethanol, dichloromethane, tetrahydrofuran and DMF. In some embodiments of the application, the mass ratio of hydroxyurea to seventh solvent is 1:1 to 1:6. In some embodiments of the present application, the third base, hydroxyurea and ethyl 3-methyl-2-butenoate are respectively prepared into homogeneous solutions in seventh solvents, and then the homogeneous solutions are introduced into a continuous dynamic tubular reactor for the second cyclization reaction, and the homogeneous solutions can be pre-cooled or pre-heated in advance according to the reaction temperature, so that the reaction temperature can be better controlled, and the retention time of the reactants in the continuous reactor can be fully utilized.

In some embodiments of the present application, the reaction temperature of the second cyclization reaction is 10-100 ℃, preferably 15-70 ℃, and the retention time is 0.2-10 h.

The continuous dynamic tubular reactor for carrying out the second cyclization reaction is one of the tubular reactors, and the number of the reactors is 1-3.

In some embodiments of the present application, the product obtained by the second cyclization reaction is a solid-liquid mixture, and is introduced into a continuous solid-liquid separation module to perform continuous solid-liquid separation, preferably, the temperature of the solid-liquid separation is 0-10 ℃, and the separation efficiency is high. The solid-liquid separation device in the solid-liquid separation module can be one or a plurality of solid-liquid separation devices, namely, products are separated as much as possible through one or a plurality of solid-liquid separation devices. And separating out liquid components through solid-liquid separation, and mixing the obtained solid with acid liquor in a dissociation module to perform continuous dissociation treatment, so that the product salt of the second cyclization reaction is dissociated. The aqueous phase obtained after dissociation is extracted in a liquid-liquid separator, the organic phase obtained after extraction is dried in a continuous drying module, and the dried product is subsequently used for a second halogenation reaction.

And carrying out second halogenation reaction on the product obtained after the second cyclization reaction is purified and separated with a second halogenating reagent, so as to obtain the 3-halogeno-5, 5-dimethyl-4, 5-dihydro isoxazole.

The halogenating agent in the second halogenation reaction can be selected from the prior art, such as common chlorinating agents, brominating agents and iodinating agents, especially chlorinating agents, which are more inexpensive and readily available. In some embodiments of the application, the second halogenating agent is phosphorus pentachloride and/or phosphorus oxychloride; preferably, the molar ratio of the second halogenating agent to 5, 5-dimethyl-3-isoxazolidinone is from 0.9:1 to 10:1.

In some embodiments of the application, the eighth solvent is any one or more of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, toluene, 1, 4-dioxane, methanol, and ethanol; further, the mass ratio of 5, 5-dimethyl-3-isoxazolidinone to eighth solvent is 1:1.5-1:20, and the mass ratio of second halogenated reagent to eighth solvent is 1:1-1:10, preferably 1:1-1:6.

In some embodiments of the present application, the reaction temperature of the second halogenation reaction is-20-120 ℃, the reaction temperature is greatly affected by the type of the halogenating agent, for example, phosphorus pentachloride is used as the second halogenating agent, and the temperature range of the second halogenation reaction is preferably-20-50 ℃; if phosphorus oxychloride is used as the second halogenating reagent, the temperature range of the second halogenating reaction is preferably 70-120 ℃; the retention time is 0.05-2 h.

The continuous dynamic tubular reactor for carrying out the second halogenation reaction is one of the tubular reactors, and the number of the reactors is 1-3.

Overflowing the product of the second halogenation reaction into a continuous quenching module in a continuous reactor to quench; and overflowing the quenched system into a continuous liquid separation module to separate liquid to obtain the 3-halogen-5, 5-dimethyl-4, 5-dihydro isoxazole. The quenching process may be quenching with water at low temperature or room temperature to convert the remaining second halogenated reagent.

The specific process for preparing 5, 5-dimethyl-4, 5-dihydroisoxazole-3-thiomedetomidine salts by substitution reaction using 3-halo-5, 5-dimethyl-4, 5-dihydroisoxazole and thiourea and concentrated hydrochloric acid as starting materials is described in detail in the above, and the continuous preparation process of 5, 5-dimethyl-4, 5-dihydroisoxazole-3-thiomedetomidine salts using 3-methyl-2-butenoic acid ethyl ester and hydroxyurea as starting materials is not different and will not be described here.

The advantageous effects that can be achieved by the present application will be further described below with reference to examples and comparative examples.

Example 1

The 5- (hydroxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole reaction system of this example was shown in FIG. 1 as a continuous production unit 01 of 5- (hydroxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole, in which the continuous reactor for the cyclization reaction was a microchannel tube reactor, the starting materials were ethyl trifluoroacetoacetate and aqueous methyl hydrazine solution, and the solvent and catalyst were acetic acid.

The method for preparing 5- (hydroxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole by using the above reaction system comprises the following steps:

(1) Preparing materials: placing ethyl trifluoroacetoacetate, acetic acid and 40% methyl hydrazine aqueous solution in a raw material storage tank for standby.

(2) Heating: respectively carrying out heating treatment on the continuous reactor and the preheater, and respectively setting the temperature to 90 ℃ and 50 ℃; circulating water is introduced into the condenser, and the temperature is set to be 10 ℃.

(3) The reaction solution is transported: starting a methyl hydrazine aqueous solution feed pump when the temperature in the continuous reactor and the preheater is stabilized at 90 ℃ and 50 ℃, starting a trifluoro acetoacetic acid ethyl ester feed pump, starting an acetic acid feed pump, setting the trifluoro acetoacetic acid ethyl ester feed flow to be 1.0g/min, setting the acetic acid flow to be 0.85g/min, and setting the methyl hydrazine aqueous solution flow to be 0.63g/min;

(4) Continuous cyclization reaction: preheating a methyl hydrazine aqueous solution, ethyl trifluoroacetoacetate and acetic acid by a preheater to 50 ℃ and then entering a continuous reactor, and fully mixing and reacting under the catalysis of acetic acid, wherein the reaction temperature is controlled to be 90 ℃ and the residence time is controlled to be 60min in the reaction process;

(5) Product separation: after the reaction is finished, the reaction solution flows out from the lower part of the reactor, enters a continuous crystallization module, is mixed with water in the continuous crystallization module, is crystallized, and then enters a continuous solid-liquid separation module to obtain the 5- (hydroxy) -1 methyl-3- (trifluoromethyl) -1H-pyrazole, wherein the purity is 99%, and the yield is 93%.

Example 2

The difference from example 1 is that methyl hydrazine sulfate was used instead of methyl hydrazine aqueous solution in example 1, the solvent was replaced with ethanol, and the catalysts were respectively as shown in the following table 1.

The purity and yield of the product 5- (hydroxy) -1 methyl-3- (trifluoromethyl) -1H-pyrazole using various bases as catalysts are shown in Table 1 below.

TABLE 1

Example 3

The 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole reaction system of this example was shown in FIG. 1 as 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole continuous production unit 02, in which the continuous reactor was a continuous dynamic gas-liquid tube reactor.

The method for preparing 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole by using the reaction system comprises the following steps:

(1) Preparing materials: 5- (hydroxy) -1 methyl-3- (trifluoromethyl) -1H-pyrazole was dissolved in 30% aqueous sodium hydroxide solution to prepare a 20% strength aqueous 5- (hydroxy) -1 methyl-3- (trifluoromethyl) -1H-pyrazole solution. Acetonitrile was fed in one stream.

(2) Continuous difluoromethylation reaction: simultaneously starting a feed pump of a liquid alkali solution of the raw material, starting an acetonitrile feed pump, starting a difluoromethane gas vent valve, and setting the feed flow of a sodium hydroxide solution of 5- (hydroxy) -1 methyl-3- (trifluoromethyl) -1H-pyrazole to be 2.0g/min; acetonitrile feed flow rate 0.8g/min, difluoromethane flow rate 41mL/min, the above-mentioned feed liquid is fully mixed in the continuous dynamic gas-liquid tubular reactor, the reaction temperature is 25 ℃, the residence time is 30min;

(3) Product separation: after the reaction is finished, the reaction solution flows out of the upper part of the reactor, enters an extraction and liquid separation module, and then the organic phase enters a drying module for drying to obtain the 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole, wherein the purity is 91%, and the yield is 91%.

Example 4

The difference from example 3 is that the alkali was replaced with potassium hydroxide, sodium carbonate, triethylamine and potassium carbonate, respectively, and the other conditions were unchanged, and the purity and yield of the corresponding products after the treatment are shown in the following table 2.

TABLE 2

Example 5

The reaction system of 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole of this example was the same as that of 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole continuous preparation unit 03 shown in FIG. 1. Wherein the continuous reactor is a microchannel reactor.

The method for preparing 5- (difluoromethoxy) -4-chloromethyl-1-methyl-3- (trifluoromethyl) -1H-pyrazole by using the above reaction system comprises the following steps:

(1) Preparing materials: 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole, concentrated hydrochloric acid and concentrated sulfuric acid are placed in a raw material storage tank for standby.

(2) Heating: heating the continuous reactor and the preheater, wherein the temperatures are respectively set to 90 ℃ and 50 ℃; circulating water is introduced into the condenser, and the temperature is set to be 10 ℃.

(3) The reaction solution is transported: starting 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole, concentrated hydrochloric acid and concentrated sulfuric acid feed pumps when the temperature in the continuous reactor and the preheater is stabilized at 90 ℃ and 50 ℃, wherein the conveying proportion of each component is shown in the table 3;

(4) Continuous chloromethylation reaction: preheating 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole, concentrated hydrochloric acid and concentrated sulfuric acid in a continuous reactor through a preheater, fully mixing, controlling the reaction temperature to 90 ℃, and controlling the residence time of materials in the continuous reactor to 120min;

(5) Product separation: after the reaction is finished, the reaction solution flows out from the lower part of the reactor, enters a crystallization module, then enters a continuous liquid separation module, and the heavy phase is the intermediate 2:5- (difluoromethoxy) 4-chloromethyl-1-methyl-3- (trifluoromethyl) -1H-pyrazole was found to have a purity of 97% and a yield of 91%.

Examples 6 to 9

The same reaction conditions as in example 5 were used, except that the formaldehyde equivalent, hydrochloric acid equivalent or catalyst type shown in Table 3 below were used, and specific parameter indexes and purities, yields were as shown in Table 3 below.

Example 10

The only difference from example 5 is that the aqueous formaldehyde solution is replaced by trioxymethylene having the same formaldehyde equivalent.

TABLE 3 Table 3

Example 11

The difference from example 5 is that the preheating temperature is 50℃and the reaction temperature is 80℃and the residence time of the material in the continuous reactor is 120min.

The purity of the product 5- (difluoromethoxy) 4-chloromethyl-1-methyl-3- (trifluoromethyl) -1H-pyrazole was 75%, yield 72%.

Example 12

The difference from example 5 is that the preheating temperature is 40℃and the reaction temperature is 60℃and the residence time of the material in the continuous reactor is 600min.

The purity of the product 5- (difluoromethoxy) 4-chloromethyl-1-methyl-3- (trifluoromethyl) -1H-pyrazole was 82% and the yield was 81%.

Example 13

The difference from example 5 is that no preheating is carried out, the reaction temperature is 40℃and the residence time of the material in the continuous reactor is 24h.

The purity of the product 5- (difluoromethoxy) 4-chloromethyl-1-methyl-3- (trifluoromethyl) -1H-pyrazole was 78% and the yield was 73%.

Example 14

The difference from example 5 is that no preheating is carried out, the reaction temperature is 25℃and the residence time of the material in the continuous reactor is 24 hours.

The purity of the product 5- (difluoromethoxy) 4-chloromethyl-1-methyl-3- (trifluoromethyl) -1H-pyrazole was 46% and the yield was 44%.

Example 15

The difference from example 5 is that no preheating is carried out, the reaction temperature is 120℃and the residence time of the material in the continuous reactor is 30min.

The purity of the product 5- (difluoromethoxy) 4-chloromethyl-1-methyl-3- (trifluoromethyl) -1H-pyrazole was 96% and the yield was 94%.

Example 16

The difference from example 5 is that no preheating is carried out, the reaction temperature is 140℃and the residence time of the material in the continuous reactor is 30min.

The purity of the product 5- (difluoromethoxy) 4-chloromethyl-1-methyl-3- (trifluoromethyl) -1H-pyrazole was 97%, and the yield was 95%.

Comparative example 1

The difference from example 5 is that the concentrated hydrochloric acid is replaced by sulfoxide chloride with the same molar quantity, the formaldehyde aqueous solution is replaced by trioxymethylene, the reaction temperature is controlled at-5 ℃ and the retention time is 240min.

The purity of the product 5- (difluoromethoxy) 4-chloromethyl-1-methyl-3- (trifluoromethyl) -1H-pyrazole was 0%, and the yield was 0%.

Example 17

This example provides a process for the preparation of the condensation product described above. Wherein the reactor for the condensation reaction is a micro-channel reactor, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomethyl salt (marked as an intermediate 1) is prepared into acetonitrile solution with the content of 45 percent, 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole (marked as an intermediate 2) is prepared into 36 percent, a solvent is acetonitrile, and sodium hydroxide is prepared into aqueous solution with the content of 40 percent.

The preparation of the condensation product comprises the following steps:

(1) And (3) cooling: the reactor and the precooler are subjected to precooling treatment, and the temperatures are respectively set to be 20 ℃ and 10 ℃.

(2) The reaction solution is transported: starting a feeding pump of the intermediate 1, starting a feeding pump of the intermediate 2, starting a feeding pump of sodium hydroxide when the temperature in the reactor and the precooler are stabilized at 20 ℃ and 10 ℃, setting the feeding flow to be 2.3g/min,3.6g/min and 2.0g/min respectively, and pumping the mixture into a continuous reactor after precooling by the precooler;

(3) Continuous reaction: the intermediate 1 and the intermediate 2 are subjected to condensation reaction in a continuous micro-channel reactor, the temperature is controlled to be 20 ℃ in the reaction process, and the residence time of materials in the continuous reactor is 60min.

(4) Continuous separation: separating the organic phase from the aqueous phase;

(5) Washing: the aqueous product solution was washed to neutrality to give the condensation product with purity and yield as shown in Table 4 below.

Examples 18 to 21

The difference from example 17 is that the base type is different, the equivalent ratio is the same as example 17, the purity and yield of examples 18 to 21 are shown in the following Table 4, and the specific examples are shown in Table 4.

TABLE 4 Table 4

Example 22

The embodiment provides a method for preparing the fenpyrad by using condensation products as raw materials to perform oxidation reaction. Wherein the continuous reactor for the oxidation reaction is a micro-channel reactor, the content of the condensation product solution is 57%, the content of hydrogen peroxide is 30%, the content of sodium tungstate is 14%, and the solvents are acetonitrile.

The method for preparing the fenpyrad by using the reaction system comprises the following steps:

(1) Heating: the reactor and the preheater were subjected to a preheating treatment, and the temperatures were set to 90℃and 80℃respectively.

(2) The reaction solution is transported: starting a feeding pump of a condensation product solution when the temperature in the continuous reactor and the temperature in the preheater are stabilized at 90 ℃ and 80 ℃, starting a feeding pump of hydrogen peroxide, and starting a feeding pump of sodium tungstate, wherein the feeding flow is respectively set to be 4.0g/min,2.2g/min and 1.1g/min;

(3) Continuous reaction: under the catalysis of sodium tungstate, the condensation product and hydrogen peroxide are subjected to continuous oxidation reaction, the temperature of a continuous reactor is controlled to be 50-60 ℃, and the retention time is 180min;

(4) Quenching: and quenching the excessive hydrogen peroxide by using sodium sulfite.

(6) Separating and washing: the quench system was separated and the organic phase was washed with water.

(7) Concentrating and crystallizing: concentrating the organic phase, cooling and crystallizing.

(8) Pulping and purifying: the solid product was purified.

(9) And (3) drying: the final product was obtained with purity and yield as shown in Table 5 below.

Example 23

The difference from example 22 is that ozone is used instead of hydrogen peroxide as the oxidizing agent.

Comparative examples 2 to 3

The difference from example 22 is that sodium tungstate was not added as a catalyst, and hydrogen peroxide was replaced with ozone or oxygen, respectively, and the purity and yield of the fenpyrad were as shown in table 5 below.

TABLE 5

Example 24

The 5, 5-dimethyl-4, 5-dihydroisoxazole reaction system of this example is shown in FIG. 2, wherein the continuous preparation unit 04 of 5, 5-dimethyl-4, 5-dihydroisoxazole is a tubular reactor, and the raw materials are 3-methyl-2-butenal and acetoxime.

The method for preparing 5, 5-dimethyl-4, 5-dihydroisoxazole by using the reaction system comprises the following steps:

(1) Preparing materials: continuously adding 3-methyl-2-butenal, acetoxime and trifluoroacetic acid into a raw material continuous batching module for standby, and preserving heat of the continuous batching module at 35 ℃;

(2) Heating: heating the reactor, and setting the temperature to be 70 ℃;

(3) The reaction solution is transported: starting a 3-methyl-2-butenal feed pump, starting a trifluoroacetic acid feed pump, starting a continuous feeding module of the acetone oxime, wherein the feeding speed is 1.0g/min of 3-methyl-2-butenal, the trifluoroacetic acid is 0.07g/min, and the acetone oxime is 0.868 g/min when the temperatures in the continuous batching module and the continuous reactor are stabilized at 35 ℃ and 70 ℃;

(4) Continuous ring closure reaction: opening a system feed pump to pump the ring-closing raw material into a continuous reactor, fully mixing and reacting under the catalysis of trifluoroacetic acid, controlling the temperature of the continuous reactor to be 70 ℃ in the reaction process, and controlling the residence time of materials in the continuous reactor to be 60min;

(5) Product separation: the reaction system is subjected to preset retention time in a reactor and enters a continuous rectification module to obtain 5, 5-dimethyl-4, 5-dihydro isoxazole, and the purity and the yield of the 5, 5-dimethyl-4, 5-dihydro isoxazole are shown in the following table 6.

Examples 25 to 28

The difference from example 24 is in the acetone oxime equivalent (i.e., molar ratio of acetone oxime to 3-methyl-2-butenal), catalyst or catalyst equivalent (i.e., molar ratio of catalyst to 3-methyl-2-butenal), specifically the purity and yield of the corresponding product 5, 5-dimethyl-4, 5-dihydroisoxazole as shown in Table 6 below.

TABLE 6

Example 29

The reaction system of 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole in this example is shown in FIG. 2, wherein the continuous preparation unit 05 of 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole is a microchannel in the continuous reaction module II for chloro reaction.

The method for preparing 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole by using the reaction system comprises the following steps:

(1) Preparing materials: the 5, 5-dimethyl-4, 5-dihydro-isoxazole and chloro reagent liquid chlorine distilled from the previous step.

(2) Continuous halogenation: simultaneously starting a feed pump of the raw material 5, 5-dimethyl-4, 5-dihydroisoxazole, wherein the feed flow is set to be 1.0g/min; starting a liquid chlorine feeding pump, wherein the molar ratio of the pumped liquid chlorine to the raw material 5, 5-dimethyl-4, 5-dihydroisoxazole is 1:1, fully mixing the feed liquid in a continuous reactor, and carrying out chlorination reaction, wherein the temperature of the continuous reactor is controlled to be 15 ℃ in the reaction process, and the residence time of the materials in the continuous reactor is controlled to be 30min; the solvent is not added in the reaction, no post-treatment is needed, and the obtained 3-chloro-5, 5-dimethyl-4, 5-dihydro-isoxazole system directly enters the next reaction, wherein the purity and the yield of the product 3-chloro-5, 5-dimethyl-4, 5-dihydro-isoxazole are shown in the following table 7.

Examples 30 to 33

The difference from example 29 is that the chlorinating reagent equivalents or types are different, as detailed in Table 7 below, and the corresponding product purities and yields are shown in Table 7 below.

TABLE 7

Example 34

The reaction system of 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomedetomidine salt in this example is shown in FIG. 2 as 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomedetomidine salt continuous preparation unit 06, and continuous reaction module III for chloro reaction is a tubular reactor.

The method for preparing 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomethyl halide salt by using the reaction system comprises the following steps:

(1) Preparing materials: and (3) placing concentrated hydrochloric acid and solvent methanol in a raw material storage tank for standby, wherein thiourea is stored in a continuous feeding module.

(2) Heating: heating the tubular reactor and the preheater, wherein the temperatures are set to 45 ℃ and 35 ℃ respectively;

(3) The reaction solution is transported: when the temperature in the reactor and the preheater is stabilized at 90 ℃ and 50 ℃, starting a 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole, concentrated hydrochloric acid and methanol feed pump, and starting a thiourea continuous feeding device;

(4) Continuous substitution reaction: the concentrated hydrochloric acid, thiourea and methanol are preheated by a preheater and fully mixed into homogeneous phase in a continuous batching module to enter a continuous reaction module III, 3-chloro-5, 5-dimethyl-4, 5-dihydro-isoxazole enters the continuous reaction module III at the same time, the feeding flow is set to be 1.0g/min, the molar ratio of the concentrated hydrochloric acid, thiourea and methanol to the raw materials 3-chloro-5, 5-dimethyl-4, 5-dihydro-isoxazole, namely the equivalent value is shown in the following table 8, the reaction temperature is controlled to be 90 ℃ in the reaction process, and the retention time is 30min;

(5) Product separation: after the reaction, the reaction solution flows out from the lower part of the reactor, enters a continuous extraction drying module, is subjected to continuous extraction, evaporative crystallization and drying, and is obtained as an intermediate 1, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomethylimidazole halide, and the purity and the yield are shown in the following table 8.

Examples 35 to 41

The difference from example 34 is the type of solvent or the ratio of the materials fed to the reactor, see in particular Table 8 below, and the corresponding product purities and yields are also given in Table 8 below.

TABLE 8

Example 42

Using the same reaction system as in example 34, the method for producing 5, 5-dimethyl-4, 5-dihydroisoxazole-3-thiocimetidine salt comprises the steps of:

(1) Heating: heating the reactor and the preheater, wherein the temperatures are respectively set to 90 ℃ and 50 ℃; circulating water is introduced into the condenser, and the temperature is set to be 15 ℃.

(3) The reaction solution is transported: when the temperature in the reactor and the preheater is stabilized at 90 ℃ and 50 ℃, starting a feeding pump of a1, 2-dichloroethane solution of 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole, wherein the feeding flow is set to be 1.0g/min, starting a feeding device of thiourea, the feeding speed of thiourea is 0.133 g/min, starting a feeding pump of 35% hydrochloric acid, and the feeding flow is set to be 0.016g/min;

(4) Continuous substitution reaction: the 1, 2-dichloroethane solution of thiourea, 35% hydrochloric acid and 3-chloro-5, 5-dimethyl-4, 5-dihydro-isoxazole is preheated by a preheater and fully mixed in a continuous tubular reactor; the reaction temperature is controlled to be 90 ℃ and the retention time is controlled to be 300min in the reaction process;

(5) Product separation: after the reaction is finished, the reaction solution flows out from the lower part of the reactor, enters a concentration tank for concentration, and is added with tertiary butanol for crystallization to obtain white solid, namely the intermediate 1, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomethylimidazole hydrochloride, wherein the purity is 89% and the yield is 90%.

(6) Material circulation: the solvent 1, 2-dichloroethane distilled under reduced pressure was again fed into the batch autoclave.

Example 43

The difference from example 42 is that the hydrochloric acid is replaced by hydrobromic acid of the same equivalent weight, and the purity of the product 5, 5-dimethyl-4, 5-dihydroisoxazole-3-thiomedetomidine hydrobromide is 72% and the yield is 60%.

Example 44

The difference from example 42 is that the same equivalent of sulfuric acid is used instead of hydrochloric acid, and the purity of the product 5, 5-dimethyl-4, 5-dihydroisoxazol-3-thiomethide sulfate is 90% and the yield is 86%.

Example 45

The reactor for the cyclization reaction of this example was a continuous dynamic tubular reactor, the base was potassium methoxide, and the solvent was methanol.

The method for preparing the 5, 5-dimethyl-3-isoxazolidinone comprises the following steps:

(1) Preparation of a methanol solution of potassium methoxide: in a batching kettle, dissolving potassium methoxide in methanol, preparing a methanol solution of potassium methoxide with the mass fraction of 25%, dissolving hydroxyurea in methanol, preparing a methanol solution of hydroxyurea with the mass fraction of 15%, and placing the prepared solution in a liquid phase raw material storage tank.

(2) Heating: heating the reactor and the preheater, and setting the temperature to 60 ℃ and 40 ℃ respectively; circulating water is introduced into the condenser, and the temperature is set to be 10 ℃.

(3) The reaction solution is transported: when the temperature in the reactor and the preheater is stabilized at 60 ℃ and 40 ℃, starting a feeding pump of a methanol solution of potassium methoxide, wherein the flow is 3.12g/min, starting a feeding pump of a methanol solution of hydroxyurea, the flow is 6.2g/min, starting a feeding pump of 3-methyl-2-ethyl butenoate, and the feeding flow is set to be 1.0g/min;

(4) Continuous cyclization reaction: the methanol solution of potassium methoxide, the methanol solution of hydroxyurea and 3-methyl-2-ethyl butenoate are preheated by a preheater and fully mixed in a continuous dynamic tubular reactor, the reaction temperature is 60 ℃, and the residence time is 90min;

(5) Product separation: after the reaction, the reaction solution flows out from the lower part of the reactor, enters a solid-liquid separator for solid-liquid separation, the liquid phase flows out, the solid enters a dissociation module through a separator, water is added to enter the dissociation module for dissociation, the mixed solution enters an extraction liquid separation module, and then the organic phase enters a drying module for drying, so that the 1, 2-dichloroethane solution of 5, 5-dimethyl-3-isoxazolidinone is obtained, and the purity and the yield are shown in the following table 9.

(6) Material circulation: the solvent methanol distilled under reduced pressure is added into the batching kettle again.

Examples 46 to 54

The difference from example 45 is the different base type, see in particular Table 9 below, the corresponding product purity and yields are also shown in Table 9 below.

TABLE 9

Example 55

The reactor for the chlorination reaction of 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole prepared from 5, 5-dimethyl-3-isoxazolidone is a continuous dynamic tubular reactor, the chlorinating reagent is phosphorus pentachloride, and the solvent is 1, 2-dichloroethane.

The method for preparing 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole comprises the following steps:

(1) Heating: heating the reactor and the preheater, wherein the temperatures are respectively set to 50 ℃ and 30 ℃; circulating water is introduced into the condenser, and the temperature is set to be 10 ℃.

(2) Raw material conveying: starting a feeding module of phosphorus pentachloride when the temperature in the reactor and the preheater is stabilized at 50 ℃ and 30 ℃, wherein the feeding speed is set to be 1.76g/min, and the feeding speed is set to be 2.5g/min;

(3) Continuous chlorination reaction: fully mixing the 1, 2-dichloroethane solution of 5, 5-dimethyl-3-isoxazolidinone and phosphorus pentachloride in a continuous dynamic tubular reactor, wherein the reaction temperature is 50 ℃, and the residence time is 180min;

(4) Continuous quenching: after the reaction is finished, the mixed solution of the system overflows into a quenching module, and meanwhile, a water conveying module is started for quenching.

(5) Product separation: product separation: after quenching, the mixed solution of the system flows out from the lower part of the reactor and enters a liquid-liquid separator for separation to obtain a1, 2-dichloroethane solution of 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole, and the purity and the yield of the 1, 2-dichloroethane solution are shown in the table 10 below.

Examples 56 to 60

The difference from example 55 is the different kinds of chlorinated reagents, see in particular Table 10 below, the corresponding product purities and yields are also given in Table 10 below.

Table 10

From the above description, it can be seen that the above embodiments of the present application achieve the following technical effects: the continuous production of the haloxyfop-R-methyl is realized through the procedures, and the synthesis route is prepared through chloromethylation reaction when the key intermediate 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole is synthesized, so that the reaction steps are shortened, dangerous reagents such as thionyl chloride and the like can be avoided in the synthesis process of the intermediate, and the safety is improved and the method is more friendly to the environment. On the other hand, the continuous reactor adopted by the continuous synthesis method has larger specific heat exchange area, can quickly realize heat exchange, realizes accurate temperature control of reaction temperature, can effectively inhibit side reaction, improves reaction selectivity and yield, and is internally provided with a structure for strengthening mass transfer, thereby improving the mixing effect of a heterogeneous system, promoting the conversion of raw materials and further improving the reaction yield. Particularly, in the second procedure, a gas distributor can be arranged in the continuous reactor, so that the equipment utilization rate and the gas utilization rate are effectively improved, and the reaction yield is improved.

The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. The continuous synthesis method of the pyrifos-methyl is characterized by comprising the following steps of:

A first procedure: preheating ethyl trifluoroacetoacetate, methyl hydrazine and a first solvent, continuously introducing the preheated ethyl trifluoroacetoacetate, the methyl hydrazine and the first solvent into a first continuous reactor, reacting under the action of a first catalyst, and performing first purification treatment on the obtained first reaction liquid to obtain 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole;

and a second step of: continuously introducing the 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole, difluoromethane, a first base and a second solvent into a second continuous reactor for reaction, and continuously extracting, separating and continuously drying the obtained second reaction liquid to obtain 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole;

And a third step of: continuously introducing the 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole, formaldehyde solution and/or paraformaldehyde, concentrated hydrochloric acid and a third catalyst into a third continuous reactor for continuous chloromethylation reaction, and continuously extracting and separating the obtained third reaction liquid to obtain 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole;

fourth step: introducing the 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiocimetidine salt, second base and fourth solvent into a fourth continuous reactor for condensation reaction, and performing continuous liquid-liquid separation and water washing on the obtained fourth reaction liquid to obtain a condensation product;

Fifth step: and introducing the condensation product, hydrogen peroxide, a fifth catalyst and a fifth solvent into a fifth continuous reactor for oxidation reaction, quenching the obtained fifth reaction liquid, and then performing second purification treatment to obtain the fenpyrad.

2. The continuous synthesis method of metazopyr as claimed in claim 1, wherein the first process meets at least one of the following characteristics:

(1) The first solvent is selected from any one or more of triethylamine, ethanol, acetic acid and methanol;

(2) The mass volume ratio of the ethyl trifluoroacetoacetate to the first solvent is 0.30-10.00 g/mL;

(3) The molar ratio of the methyl hydrazine to the ethyl trifluoroacetoacetate is (0.5-2): 1, a step of;

(4) The methyl hydrazine comprises any one of methyl hydrazine aqueous solution and methyl hydrazine salt, when the methyl hydrazine is methyl hydrazine aqueous solution, the first catalyst is selected from any one or more of hydrochloric acid, acetic acid, sulfuric acid and trifluoroacetic acid, and when the methyl hydrazine is methyl hydrazine salt, the first catalyst is selected from any one or more of triethylamine, pyridine, sodium hydroxide and potassium hydroxide;

(5) The first continuous reactor is a microchannel reactor;

(6) The reaction temperature in the first continuous reactor is 40-100 ℃;

(7) The reaction residence time in the first continuous reactor is 10-60 min;

(8) The first catalyst is selected from any one or more of hydrochloric acid, acetic acid, sulfuric acid and trifluoroacetic acid, the first purification treatment comprises continuous quenching and continuous solid-liquid separation, and the continuous quenching comprises: mixing the first reaction liquid with water, and crystallizing;

(9) The first catalyst is selected from any one or more of triethylamine, pyridine, sodium hydroxide and potassium hydroxide, and the first purification treatment comprises a first continuous extraction.

3. The continuous synthesis method of metazopyr as claimed in claim 1, wherein the second process meets at least one of the following characteristics:

(1) The molar ratio of the 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole to the difluoromethane is 1: 1-3;

(2) The first base is selected from any one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia water, triethylamine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate and 1, 8-diazabicyclo undec-7-ene;

(3) The molar ratio of the first base to the 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole is (0.5-3): 1, a step of;

(4) The second solvent is selected from any one or more of acetonitrile, methanol, ethanol, isopropanol, dichloromethane, dioxane, tetrahydrofuran, dimethyl tetrahydrofuran, n-pentane, n-heptane and n-hexane;

(5) The mass volume ratio of the 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole to the second solvent is 0.5-3 g/ml;

(6) Passing said 5-hydroxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole, a first base, and water into said second continuous reactor as a homogeneous solution;

(7) The second continuous reactor is a continuous gas-liquid reactor;

(8) The reaction temperature in the second continuous reactor is 25-50 ℃;

(9) The reaction residence time in the second continuous reactor is 10-30 min.

4. The continuous synthesis method of pyrifos according to claim 1, wherein said third process meets at least one of the following characteristics:

(1) The third catalyst comprises any one or more of sulfuric acid, acetic acid, ferric chloride, magnesium chloride, aluminum chloride and zinc chloride;

(2) The molar ratio of the third catalyst to the 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole is (0.1-2): 1, a step of;

(3) The concentration of the formaldehyde aqueous solution is 35-37%, and the molar ratio of formaldehyde in the formaldehyde aqueous solution to the 5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole is (0.5-2): 1, a step of;

(4) The third continuous reactor is a microchannel reactor;

(5) The temperature of the continuous chloromethylation reaction is 80-120 ℃;

(6) The residence time of the continuous chloromethylation reaction is 30-240 min.

5. The continuous synthesis method of metazopyr as claimed in claim 1, wherein the fourth procedure satisfies at least one of the following characteristics:

(1) The molar ratio of the 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomedetomidine salt to the 4- (chloromethyl) -5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) -1H-pyrazole is 1.0:1.0-1.1, and the molar ratio of the 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomedetomidine salt to the second base is 1.0:3.0-5.0;

(2) The second alkali is any one or more of sodium hydroxide, potassium hydroxide, ammonia water, triethylamine, sodium carbonate and potassium carbonate;

(3) The fourth solvent is any one or more of acetonitrile, dichloromethane, dichloroethane and chloroform;

(4) The temperature of the condensation reaction is 0-80 ℃;

(5) The residence time of the condensation reaction is 20-60 min;

(6) The fourth continuous reactor is a micro-channel reactor, and the number of the fourth continuous reactor is 1-3.

6. The continuous synthesis method of pyrifos according to claim 1, wherein the fifth process satisfies at least one of the following characteristics:

(1) The fifth catalyst is selected from any one or more of sodium tungstate, ferrous sulfate heptahydrate, sulfuric acid, acetic acid, trifluoroacetic acid and tungsten oxide;

(2) The molar ratio of the introduced condensation product to the fifth catalyst to the hydrogen peroxide is 1.0: 0.05-0.10: 2.0 to 3.0;

(3) The reaction temperature of the oxidation reaction is 50-100 ℃;

(4) The residence time of the oxidation reaction is 60-180 min;

(5) The fifth continuous reactor is a microchannel reactor;

(6) The fifth reaction liquid is mixed with a quenching agent for quenching, the quenching agent is any one or more of sodium sulfite, sodium thiosulfate, sodium pyrosulfate and sodium bisulphite, and the molar ratio of the quenching agent to the condensation product is 1.0:0.5 to 0.7;

(7) The second purification treatment comprises continuous liquid separation, water washing, concentration and crystallization, pulping purification and drying.

7. The continuous synthesis method of the fenpyrad according to claim 1, wherein the 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomedetomidine salt is prepared by the following continuous method:

Continuously introducing acetone oxime, 3-methyl-2-butenal and a sixth catalyst into a microchannel reactor for a first cyclization reaction, and continuously rectifying the obtained sixth reaction liquid to obtain 5, 5-dimethyl-4, 5-dihydro-isoxazole;

introducing the 5, 5-dimethyl-4, 5-dihydroisoxazole and a first halogenating reagent into a continuous reactor for carrying out a first halogenating reaction to obtain 3-halogen-5, 5-dimethyl-4, 5-dihydroisoxazole;

Continuously introducing the 3-halogen-5, 5-dimethyl-4, 5-dihydro-isoxazole, thiourea, acid and a sixth solvent into a tubular reactor for substitution reaction, continuously extracting and separating the obtained seventh reaction liquid, concentrating and drying to obtain the 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomedetomidine salt.

8. The continuous synthesis method of the fenpyrad according to claim 7, wherein the sixth catalyst is any one or more of trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, sulfuric acid, hydrochloric acid, nitric acid, fluoroboric acid, perchloric acid and benzenesulfonic acid;

the molar ratio of the 3-methyl-2-butenal to the acetoxime is 1:0.95-1.5;

The molar ratio of the sixth catalyst to the 3-methyl-2-butenal is 0.005-0.8: 1, a step of;

The temperature of the first cyclization reaction is 70-100 ℃ and the time is 10-300 min;

The first halogenated reagent is any one or more of chlorine, sulfonyl chloride, thionyl chloride, phosphorus trichloride and phosphorus pentachloride, and the molar ratio of the 5, 5-dimethyl-4, 5-dihydro-isoxazole to the first halogenated reagent is 1:1 to 2;

the reaction temperature of the first halogenation reaction is 0-5 ℃ and the reaction time is 5-100 min;

The molar ratio of the thiourea to the 3-halogen-5, 5-dimethyl-4, 5-dihydro-isoxazole is 1: (0.9-2);

The acid is any one or more of hydrochloric acid, hydrogen bromide and sulfuric acid;

The sixth solvent is any one or more of acetonitrile, methanol, ethanol, isopropanol, dichloromethane, dioxane, tetrahydrofuran, dimethyl tetrahydrofuran, n-pentane, n-heptane and n-hexane, and the mass volume ratio of the 3-halogen-5, 5-dimethyl-4, 5-dihydro isoxazole to the sixth solvent is 0.1-1 g/ml;

the reaction temperature of the continuous substitution reaction is 25-120 ℃, and the retention time is 10-480 min.

9. The continuous synthesis method of the fenpyrad according to claim 1, wherein the 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomedetomidine salt is prepared by the following continuous method:

Continuously introducing 3-methyl-2-ethyl butenoate, hydroxyurea, third alkali and a seventh solvent into a continuous dynamic tubular reactor for a second cyclization reaction, and performing continuous solid-liquid separation, dissociation, extraction and liquid separation and drying on the obtained product to obtain 5, 5-dimethyl-3-isoxazolidinone;

Continuously introducing the 5, 5-dimethyl-3-isoxazolidone, a second halogenating reagent and an eighth solvent into a continuous dynamic tubular reactor for second halogenation reaction, and continuously quenching and separating the obtained product system to obtain 3-halogen-5, 5-dimethyl-4, 5-dihydro isoxazole;

Continuously introducing the 3-halogen-5, 5-dimethyl-4, 5-dihydro-isoxazole, thiourea, acid and a sixth solvent into a tubular reactor for substitution reaction, continuously extracting and separating the obtained eighth reaction liquid, concentrating and drying to obtain the 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiomedetomidine salt.

10. The continuous synthesis method of the fenpyrad according to claim 9, wherein the third base is selected from any one or more of potassium methoxide, sodium methoxide, potassium ethoxide, sodium hydroxide, potassium hydroxide, tetramethylguanidine, triethylamine and basic resin;

The mass ratio of the 3-methyl-2-ethyl butenoate to the seventh solvent is 1:3-1:20, and the seventh solvent is any one or more of methanol, ethanol, dichloromethane, tetrahydrofuran and DMF;

The molar ratio of the hydroxyurea to the ethyl 3-methyl-2-butenoate is 0.9:1-5:1;

The reaction temperature of the second cyclization reaction is 10-100 ℃ and the retention time is 0.2-10 h;

The second halogenated reagent is phosphorus pentachloride and/or phosphorus oxychloride; the molar ratio of the second halogenating reagent to the 5, 5-dimethyl-3-isoxazolidinone is 0.9:1-10:1;

The reaction temperature of the second halogenation reaction is-20-100 ℃ and the retention time is 0.05-2 h;

The sixth solvent is selected from any one or more of acetonitrile, methanol, ethanol, isopropanol, dichloromethane, dioxane, tetrahydrofuran, dimethyl tetrahydrofuran, n-pentane, n-heptane and n-hexane.