CN112552284B - Preparation method of chlorantraniliprole - Google Patents

Preparation method of chlorantraniliprole Download PDF

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CN112552284B
CN112552284B CN202011506151.6A CN202011506151A CN112552284B CN 112552284 B CN112552284 B CN 112552284B CN 202011506151 A CN202011506151 A CN 202011506151A CN 112552284 B CN112552284 B CN 112552284B
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chlorantraniliprole
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water
chloride
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CN112552284A (en
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何小强
陈志忠
张黎
芮正军
胡娜
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Chongqing Huage Biochemistry Co ltd
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • B01J23/70—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper
    • B01J23/89—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper combined with noble metals
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Abstract

The invention relates to the field of pesticide synthesis, and discloses a preparation method of chlorantraniliprole. The method comprises the steps of taking 2,3, 6-trichloropyridine as a raw material, reacting with hydrazine hydrate under the action of a catalyst A to obtain 3, 6-dichloro-2-hydrazinopyridine, carrying out hydrogenation reduction reaction under the action of a catalyst B to obtain an intermediate I, reacting the intermediate I with diethyl maleate to obtain 2- (3-chloropyridine-2-yl) -5-hydroxypyrazole-3-ethyl formate under the action of a catalyst C, carrying out bromination, hydrolyzing to obtain an intermediate II, and preparing chlorantraniliprole from the intermediate II. In the invention, 2,3, 6-trichloropyridine is used for replacing 2, 3-dichloropyridine to prepare the intermediate I, so that the defects of difficult obtainment of 2, 3-dichloropyridine raw materials, harsh synthesis conditions, low yield and the like are overcome, the total reaction yield of the intermediate I is improved, the intermediate II is prepared by a one-pot method, the post-treatment operation is reduced, and the synthesis cost of chlorantraniliprole is reduced.

Description

Preparation method of chlorantraniliprole
Technical Field
The invention relates to the field of pesticide synthesis, and particularly relates to a preparation method of chlorantraniliprole.
Background
Chlorantraniliprole, the trade name is: "Kangkuan", an ISO generic name of Chloratraniniprole, was developed in 2000 by DuPont, USA, as a novel high-efficiency, low-toxicity insecticide, widely used in the control of Lepidoptera pests. It belongs to a ryanodine receptor agent, and leads paralysis and death of pests by selectively activating ryanodine receptors in muscles of the pests and excessively releasing calcium ions in cells. The pesticide has broad spectrum, high efficiency, high safety and low toxicity.
Currently, chlorantraniliprole is prepared in many ways, for example, patent WO2006062978a1 discloses that 3-bromo-1- (3-chloro-2-pyridyl) -1H-pyrazole-5-carboxylic acid and substituted anthranilamide are used to prepare chlorantraniliprole in the presence of methylsulfonyl chloride and acid-binding agent 3-aminopyridine or pyridine, but this method needs to use controlled substances such as methylsulfonyl chloride and the like and acid-binding agent, and needs to be recrystallized and purified after the reaction, and the operation steps are tedious.
For another example, patent CN101298451A discloses that 2, 3-dichloropyridine and diethyl maleate are used as raw materials, and a key intermediate, 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carbonyl chloride, is first synthesized through six-step reactions such as hydrazinolysis, michael addition and cyclization, bromination, oxidation, hydrolysis and acyl chlorination, and then the intermediate is synthesized with substituted aniline under the condition of no acid-binding agent to obtain chlorantraniliprole, which has mild conditions and simple operation, is suitable for industrial production, but has the following disadvantages: the reaction steps are multiple, the yield is low, and solid waste and waste water are more. In addition, the synthesis conditions of the 2, 3-dichloropyridine are harsh, the synthesis cost is high, and the yield is low.
Therefore, although the existing synthesis methods of chlorantraniliprole are more, the existing synthesis methods have the defects of low yield, complicated operation, complex post-treatment and the like, and a synthesis method of chlorantraniliprole with high economy, high yield, few side reactions, simple and safe operation and small environmental pollution is urgently needed.
Disclosure of Invention
The invention aims to provide a preparation method of chlorantraniliprole, which aims to solve the problems of complicated synthesis steps and low yield of the chlorantraniliprole.
In order to achieve the purpose, the invention adopts the following technical scheme: a preparation method of chlorantraniliprole comprises a step of synthesizing an intermediate I, a step of synthesizing an intermediate II and a step of synthesizing chlorantraniliprole;
in the synthesis step of the intermediate I, under the action of a catalyst A, refluxing 2,3, 6-trichloropyridine and hydrazine hydrate solution to obtain 3, 6-dichloro-2-hydrazinopyridine, and under the action of a catalyst B, carrying out hydrogenation refluxing reaction on the 3, 6-dichloro-2-hydrazinopyridine to obtain the intermediate I, wherein the chemical structural formula of the intermediate I is shown as a formula (III), and the intermediate I is obtainedThe catalyst B is Cu-Ag/gamma-Al 2 O 3 。
Figure BDA0002845002200000021
The principle and the advantages of the scheme are as follows: in the synthesis step of the intermediate I, 2,3, 6-trichloropyridine is adopted to replace 2, 3-dichloropyridine as a raw material, so that the defects of harsh conditions and low yield in the synthesis of 2, 3-dichloropyridine are avoided. In addition, in the scheme, other solvents are not used in the process of synthesizing the 3, 6-dichloro-2-hydrazinopyridine, so that the recovery of a hydrazine hydrate solution is facilitated, and the cost of raw materials is further reduced. In addition, the scheme selects Cu-Ag/gamma-Al 2 O 3 As the catalyst B, the synthesis efficiency and yield of the intermediate I are improved.
Preferably, as an improvement, in the synthesis step of the intermediate II, after the 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-ethyl formate is prepared from the intermediate I under the action of a catalyst C, refluxing the 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-ethyl formate and a brominating agent in a solvent b for reaction, removing the solvent b after the reaction is finished, adding a solvent C, dropwise adding liquid alkali under stirring, adjusting the pH value to 12-13, cooling to room temperature or 50 ℃ after the reaction is finished, adjusting the pH value to 2-3, stirring at an ice bath temperature or 50 ℃, and adjusting the stirring speed to 200-250 rpm to obtain the intermediate II, wherein the chemical structural formula of the intermediate II is shown as a formula (VI).
Figure BDA0002845002200000022
In the scheme, the intermediate II can be prepared by directly using 2- (3-chloropyridine-2-yl) -5-hydroxypyrazole-3-ethyl formate through a one-pot method, after bromination of the 2- (3-chloropyridine-2-yl) -5-hydroxypyrazole-3-ethyl formate is finished, post-treatment is not needed, a product after bromination can be directly hydrolyzed into the intermediate II under the action of a solvent c and liquid alkali, operations such as crystallization and extraction of the product after bromination are avoided, and operation steps are reduced. And the intermediate II can be in an oil phase through selection of a brominating agent and optimization of experimental conditions, and the intermediate II can be obtained through oil-water phase separation, so that the steps of difficult crystallization, suction filtration, cleaning, drying and the like of the intermediate II are avoided, and the operation steps are further reduced.
Preferably, in the synthesis step of chlorantraniliprole, the intermediate II and thionyl chloride react under the action of a catalyst D by heating, after the reaction is finished, the thionyl chloride is dried, substituted aniline and acetonitrile are directly added, or the substituted aniline and toluene are directly added, the reaction is heated, after the reaction is finished, the temperature is reduced to 0-20 ℃ for crystallization, and the target product chlorantraniliprole is obtained by filtering.
In the scheme, acyl chlorination and oxidation reactions are simultaneously carried out on the intermediate II to prepare 3-bromo-1- (3-chloropyridine-2-yl) -1H-pyrazole-5-formyl chloride, and then the 3-bromo-1- (3-chloropyridine-2-yl) -1H-pyrazole-5-formyl chloride and substituted aniline are subjected to acid-binding-free reaction to obtain the target product chlorantraniliprole with the yield of 90-94% (based on the intermediate II). In other words, in the scheme, the target product chlorantraniliprole is prepared by the intermediate II through a direct one-pot method, the reaction steps are reduced, and the use of methylsulfonyl chloride is avoided. In addition, the tail gas in the scheme only contains relatively clean hydrogen and hydrogen chloride, and the hydrogen chloride can be directly absorbed as a byproduct and used for adjusting the pH value in the intermediate secondary synthesis process. And compared with the conventional industrial common route of a methylsulfonyl chloride method and a thionyl chloride method, the method saves about 15% of the raw material cost and has good application prospect.
Preferably, as an improvement, in the synthesis step of the intermediate one, the catalyst a is one or more of cupric chloride, cuprous chloride, tetrabutylammonium chloride, benzyltrimethylammonium chloride, tetramethylammonium chloride, triphenylbutylphosphonium bromide, triethylmethylammonium chloride, tetramethylammonium bromide, benzyltriethylammonium chloride and tetrabutylammonium iodide.
In the scheme, the inventor researches and discovers that the catalyst A is limited to be selected within the range, so that the reaction time for synthesizing the 3, 6-dichloro-2-hydrazinopyridine can be shortened, and the reaction efficiency can be improved.
Preferably, as an improvement, in the synthesis step of the intermediate II, in the process of preparing the ethyl 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylate from the intermediate I, the catalyst C is one or more of bis (triphenylphosphine) nickel chloride, bis (tricyclohexylphosphine) nickel dichloride, copper (triphenylphosphine) iodide, copper (triphenylphosphine) bromide and nickel (triphenylphosphine) dibromide; after the reaction is finished and the solvent is removed, adding the solvent a, and obtaining the product 2- (3-chloropyridine-2-yl) -5-hydroxypyrazole-3-ethyl formate in a crystallization or phase separation mode.
In the scheme, the inventor discovers that 2- (3-chloropyridine-2-yl) -5-hydroxypyrazole-3-ethyl formate can be in an oil phase through selection of a solvent a, and the 2- (3-chloropyridine-2-yl) -5-hydroxypyrazole-3-ethyl formate can be obtained through oil-water phase separation, so that the steps of crystallization, suction filtration, cleaning, drying and the like are avoided, and the operation steps are further reduced. According to actual needs, the ethyl 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylate can be obtained in a crystallization mode through selection of the solvent a.
Preferably, as a modification, in the synthesis step of the intermediate II, when the solvent a is pure water or ethanol water solution, the product 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylic acid ethyl ester is obtained in a crystallization manner; when the solvent a is one of a mixture of ethyl acetate and water, a mixture of trichloromethane and water, a mixture of dichloromethane and water, a mixture of 1, 2-dichloroethane and water and a mixture of toluene and water, the product ethyl 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylate is obtained in a phase-separating manner.
In this scheme, the inventors have found through research that the state of the obtained 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylic acid ethyl ester is different according to the selection of the solvent a, and when the solvent a is one of a mixture of ethyl acetate and water, a mixture of trichloromethane and water, a mixture of dichloromethane and water, a mixture of 1, 2-dichloroethane and water and a mixture of toluene and water, the obtained 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylic acid ethyl ester exists in an oil phase, and the phase separation can obtain an oily product, namely 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylic acid ethyl ester; when the solvent a is pure water or ethanol water solution, the 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylic acid ethyl ester is obtained in a crystallization manner.
Preferably, as an improvement, in the synthesis step of the intermediate two, the brominating agent is phosphorus tribromide or phosphorus oxybromide, and when the brominating agent is phosphorus tribromide, the intermediate two exists in the oil phase.
In the scheme, the inventor finds that the obtained intermediate II is different in state according to different selections of brominating agents, when the brominating agent is phosphorus tribromide, the intermediate II can exist in an oil phase, and the intermediate II can be obtained by phase separation; when the brominating agent is tribromooxyphosphorus, the intermediate II is obtained in a crystallization mode.
Preferably, as a modification, in the synthesis step of the intermediate two, the solvent b is one or two of acetonitrile, chloroform, dimethylformamide and dichloromethane.
In this embodiment, the inventors have found that the bromination reaction proceeds normally when the solvent b is selected within the above-mentioned range.
Preferably, as a modification, in the synthesis step of the intermediate two, the solvent c is one of pure water, an aqueous ethanol solution, an aqueous methanol solution, an aqueous dimethylformamide solution or an aqueous acetonitrile solution.
In the scheme, the inventor discovers that when the solvent c is one of pure water, an ethanol aqueous solution, a methanol aqueous solution, a dimethylformamide aqueous solution or an acetonitrile aqueous solution, the pH value of the (3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-ethyl formate can be directly hydrolyzed after the liquid alkali is adjusted to 12-13, so as to obtain an intermediate II.
Preferably, as an improvement, in the synthesis step of chlorantraniliprole, the catalyst D is one or more than two of acetonitrile, dimethyl sulfoxide, dimethylacetamide, 3, 5-dimethylpyridine and 3-chloro-2-methylpyridine.
In this scheme, the inventors have found through research that when the catalyst D is one or more of acetonitrile, dimethyl sulfoxide, dimethylacetamide, 3, 5-lutidine, and 3-chloro-2-methylpyridine, the reaction time can be shortened, the reaction selectivity can be improved, and the simultaneous progress of the acylchlorination reaction and the oxidation reaction can be promoted.
Drawings
FIG. 1 is a sample liquid chromatogram of example 1;
FIG. 2 is a liquid chromatogram of the standard of example 1.
Detailed Description
The following is further detailed by way of specific embodiments:
example 1
A preparation method of chlorantraniliprole is disclosed, wherein the synthesis reaction of the chlorantraniliprole is shown as a formula (i), and the preparation method specifically comprises the following steps.
Figure BDA0002845002200000051
Step one, synthesis of 3, 6-dichloro-2-hydrazinopyridine:
2,3, 6-trichloropyridine (60g,0.33mol) and 80% hydrazine hydrate solution (96.6g,1.55mol) are sequentially added into a 500mL four-neck flask provided with a reflux pipe, and the mixture of the two is stirred at normal temperature and added with a catalyst A, wherein the catalyst A can be one or more than two of copper chloride, cuprous chloride, tetrabutylammonium chloride, benzyltrimethylammonium chloride, tetramethylammonium chloride, triphenylbutylphosphonium bromide, triethylmethylammonium chloride, tetramethylammonium bromide, benzyltriethylammonium chloride and tetrabutylammonium iodide. In the embodiment, the catalyst A is tetrabutylammonium chloride (1.8g,0.006mol), the temperature is raised to 108-110 ℃ after the catalyst A is added, reflux reaction is carried out for 6 hours, then, sampling HPLC (high performance liquid chromatography) is carried out to detect that the content of the raw material (2,3, 6-trichloropyridine) is less than 0.1%, cooling is carried out to 0-10 ℃, a large amount of white solid is separated out, suction filtration is carried out, the filtrate is reserved, the filter cake is washed to be neutral by clear water, the filter cake is dried at 70-80 ℃, and the product 3, 6-dichloro-2-hydrazinopyridine is 57.5g, the HPLC normalization content is 99.2% (the analysis condition is that a chromatographic column is a C18 silica gel reverse phase column 4.6x150mm 5 mu m, the mobile phase is acetonitrile and water, acetic acid is 1: 1: 1%), and the yield is 97.5%.
In the step, the chemical structural formula of the 2,3, 6-trichloropyridine is shown as the formula (I) in the formula (i), and the chemical structural formula of the 3, 6-dichloro-2-hydrazinopyridine is shown as the formula (II) in the formula (i). In addition, other solvents are not used in the step, the hydrazine hydrate solution is very convenient to recycle, and the synthesis cost of the 3, 6-dichloro-2-hydrazinopyridine is reduced.
Step two, synthesizing 3-chloro-2-hydrazinopyridine:
278mL of methanol, 3, 6-dichloro-2-hydrazinopyridine obtained in step one (50g, 99.2%, 0.28mol) and 1.5% of catalyst B (the mass ratio of catalyst B to the starting material, 3, 6-dichloro-2-hydrazinopyridine, was 1.5%), in this example, Cu-Ag/γ -Al, were placed in this order in a 500mL four-necked flask equipped with a reflux tube 2 O 3 Controlling the hydrogen pressure to be 0.8-1.4 MPa, slowly heating to a reflux state, after reacting for 5 hours, sampling and detecting by HPLC (high performance liquid chromatography) to control the raw material (3, 6-dichloro-2-hydrazinopyridine) < 0.5%, stopping introducing hydrogen after the reaction is qualified, cooling the kettle liquid to normal temperature, and filtering to obtain Cu-Ag/gamma-Al 2 O 3 ，Cu-Ag/γ-Al 2 O 3 Washing the filter cake with clear water for 2 times, washing with ethanol for 1 time, and drying for later use; and (2) after the filtrate is decompressed and the methanol is evaporated to dryness, adding 180g of water, cooling to 0-5 ℃, precipitating a large amount of white crystals, carrying out suction filtration, washing a filter cake for 2 times by using 100g of clear water, and drying at 80-90 ℃ to obtain 36.4g of the 3-chloro-2-hydrazinopyridine product with the HPLC normalization content of 99.1% (analysis conditions are that a chromatographic column is a C18 silica gel reverse phase column of 4.6x150mm 5 mu m, a mobile phase is acetonitrile, water and acetic acid are 1: 1: 1%), and the yield is 90.2%.
The chemical structural formula of the 3-chloro-2-hydrazinopyridine is shown as the formula (III) in the formula (i).
In addition, in this step, Cu-Ag/γ -Al 2 O 3 The preparation method comprises the following steps:
a. pretreatment of a carrier: taking a certain amount of gamma-Al 2 O 3 Roasting in a muffle furnace at 500 ℃ for 3 h;
b. dipping: 1449.6mg of Cu (NO) were weighed out separately 3 ) 2 ·3H 2 O and 1018.98mg AgNO 3 Dissolving in 3mL of deionized water to prepare copper nitrate and silver nitrate solutions, then weighing 5g of the roasted carrier in a 100mL beaker, respectively adding 2mL of the copper nitrate and the silver nitrate solutions, quickly stirring for 20min to enable the carrier to be in a wet sticky state, and then standing for 4h at room temperature;
c. and (3) drying: placing the sample after standing in a vacuum drying oven, drying for 12h at 105 ℃, and grinding into powder;
d. roasting: placing the powder sample in a muffle furnace to be roasted for 3h at the temperature of 450 ℃, thus obtaining the catalyst Cu-Ag/gamma-Al 2 O 3 。
The method is simple to operate, the prepared catalyst is good in catalytic effect, high in selectivity on target products, and capable of preparing the intermediate I with high yield.
Step three, synthesizing 2- (3-chloropyridine-2-yl) -5-hydroxypyrazole-3-ethyl formate:
a500 mL four-necked flask equipped with a mechanical stirring and reflux tube was charged with 160mL of anhydrous ethanol, stirring was turned on, and sliced sodium metal (6.3g,0.27mol) was slowly added in N 2 Heating to a reflux state under protection, refluxing for about 10min, cooling to below 0-5 ℃ after all the sodium metal is dissolved, adding a catalyst C, wherein the catalyst C can be one of bis (triphenylphosphine) nickel chloride, bis (tricyclohexylphosphine) nickel dichloride, copper (triphenylphosphine) iodide, copper (triphenylphosphine) bromide or nickel (triphenylphosphine) dibromide, the catalyst C is 1% of bis (tricyclohexylphosphine) nickel dichloride (the mass ratio of the bis (tricyclohexylphosphine) nickel dichloride to the 3-chloro-2-hydrazinopyridine is 1%) in the embodiment, slowly dripping diethyl maleate (75.6g,0.40mol), adding the 3-chloro-2-hydrazinopyridine (30g, 98%, 0.20mol) prepared in the step two in batches, stirring in an ice bath for 25min, slowly heating to 45 ℃, carrying out a heat preservation reaction for 0.5h, sampling and detecting and controlling the raw material (3-chloro-2-hydrazinopyridine) < 1% by HPLC, after the reaction is qualified, the ethanol is removed by negative pressure distillation, and the ethanol fraction is used indiscriminately; slowly adding a solvent a into the kettle liquid, wherein the solvent a is 150g of a mixture of 40% dichloromethane and water (dichloromethane accounts for 40% of the total mass of the mixture), dropwise adding 70% glacial acetic acid aqueous solution (glacial acetic acid accounts for 70% of the total mass of the mixture) at normal temperature, adjusting the pH value to 5-7, stirring uniformly, repeatedly measuring the pH value, continuing stirring for 1h, standing for 1h, separating out an oil phase after standing, distilling the oil phase at normal pressure to recover dichloromethane to obtain 55.3g of reddish brown oily crude product 2- (3-chloropyridine-2-yl) -5-hydroxypyrazole-3-ethyl formate, the water content of which is about 1%, and the HPLC normalization content of 85% (analysis condition: chromatographic column chromatography: HPLC normalization content: 85%)Is C18 silica gel reverse phase column 4.6x150mm 5 μm, mobile phase is acetonitrile: water: acetic acid 1: 1: 1%) and yield 85.2%.
The chemical structural formula of the ethyl 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylate is shown as the formula (IV) in the formula (i).
In this step, the solvent a may be one of a mixture of 60% ethyl acetate and water (ethyl acetate accounts for 60% of the total mass of the mixture), a mixture of 50% chloroform and water (chloroform accounts for 50% of the total mass of the mixture), a mixture of 30% 1, 2-dichloroethane and water (1, 2-dichloroethane accounts for 30% of the total mass of the mixture), and a mixture of 5% toluene and water (toluene accounts for 5% of the total mass of the mixture). The 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-ethyl formate exists in an oil phase, and the product 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-ethyl formate can be obtained by oil-water phase separation.
Step four, synthesizing 3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid from 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-ethyl formate by a one-pot method:
a500 mL four-necked flask equipped with a mechanical stirring and reflux tube was charged with solvent b, which in this example was 150mL of acetonitrile, and phosphorus oxybromide (39.8g,0.139 mol). Starting stirring, adding oily crude ethyl 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylate (55g, 85% and 0.17mol) prepared in the third step, stirring for 20min, heating to a reflux state, reacting for 0.5H, sampling and detecting by HPLC (high performance liquid chromatography) to control the content of raw materials (ethyl 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylate) to be less than 0.1%, and generating 3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylate in the reaction process; after the reaction is qualified, about 80% of the solvent b (accounting for the mass ratio of the initial feeding amount of the solvent b) is removed under negative pressure, and the fraction is directly applied to the next kettle; adding a solvent c into the kettle liquid, wherein the solvent c is 134g of 20% ethanol aqueous solution (ethanol accounts for 20% of the total mass of the solution), then dropwise adding 30% liquid caustic soda (sodium hydroxide accounts for 30% of the total mass of the solution) to adjust the pH value to 12-13 (the pH value is kept constant all the time in the reaction process), heating to 45 ℃ to react for 0.5H, sampling and detecting HPLC (high performance liquid chromatography) to control the raw material (3-bromo-1- (3-chloropyridine-2-yl) -4, 5-dihydro-1H-pyrazole-5-ethyl formate) to be less than 0.1%, cooling to room temperature after the reaction is qualified, adjusting the pH value to 2-3 with 37% hydrochloric acid, stirring uniformly and repeatedly after the pH value is constant, continuing to stir in an ice bath (r is 200-250 rpm) for 2H, performing suction filtration, washing a filter cake with clear water, and performing vacuum drying at 70-80 ℃ to obtain yellow white powder 3-bromo-1- (3-chloropyridine-2-yl) material 51.8g of 4, 5-dihydro-1H-pyrazole-5-carboxylic acid, 95% of HPLC normalization content (analytical conditions: column C18 silica gel reverse phase column 4.6 × 150mm 5 μm, mobile phase acetonitrile: water: acetic acid ═ 1: 1: 1%), 93% yield based on ethyl 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylate.
The chemical structural formula of the ethyl 3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylate is shown as the formula (V) in the formula (i), and the chemical structural formula of the 3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid, namely the intermediate II, is shown as the formula (VI) in the formula (i).
In the step, the solvent c can be one of pure water, 20-50% methanol water solution (methanol accounts for 20-50% of the total mass of the solution), 20% dimethylformamide water solution (dimethylformamide accounts for 20% of the total mass of the solution), and 15% acetonitrile water solution (acetonitrile accounts for 15% of the total mass of the solution).
Step five, synthesizing chlorantraniliprole:
adding 3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid (50g,95 percent and 0.16mol) prepared in the fourth step into a 500mL four-neck flask provided with a mechanical stirring and reflux pipe, quickly adding thionyl chloride (150g,1.26mol) under stirring, then adding a catalyst D (in the example, the catalyst D is acetonitrile (1g,0.024mol), continuously stirring at normal temperature for 5min, heating to a reflux state (80 ℃) for reaction for 15min, sampling and detecting HPLC (high performance liquid chromatography) to control the raw material (3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid) to be less than 0.1 percent, wherein 3-bromo-1- (3-chloropyridin-2-yl) is generated in the reaction process 1H-pyrazole-5-formyl chloride, removing the thionyl chloride, and directly applying fractions to the next kettle; adding 200mL of acetonitrile and 2-amino-5-chloro-N, 3-dimethylbenzamide (28g,0.15mol) into the kettle liquid, slowly heating to a reflux state (80 ℃), reacting for 0.5H, sampling and detecting by HPLC (high performance liquid chromatography) to control the raw material 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-formyl chloride to be less than 0.1%, cooling to 0-5 ℃, continuing stirring for 1H, performing suction filtration, reserving the filtrate, washing the filter cake for 2-3 times by using clean water, drying at 80-90 ℃ to obtain 74.1g of white powdery chlorantraniliprole, wherein the normalized content of HPLC is 95.5% (analysis conditions: chromatographic column is C18 silica gel reverse phase column 4.6x150mm 5 μm, mobile phase is acetonitrile: water: acetic acid: 1: 1: 1%), using 3-bromo-1- (3-chloropyridin-2-yl) -4, the yield of 5-dihydro-1H-pyrazole-5-carboxylic acid was 94%.
The chemical structural formula of the 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-formyl chloride is shown as a formula (VII) in a formula (i), the chemical structural formula of the 2-amino-5-chloro-N, 3-dimethylbenzamide is shown as a formula (VIII) in the formula (i), and the chemical structural formula of the chlorantraniliprole is shown as a formula (IX) in the formula (i).
And (3) structural verification of the compound: the chlorantraniliprole (sample for short) prepared in the sample example is taken, the condition of the synthesized product (sample) is detected by using liquid chromatography, and the chlorantraniliprole with the purity of 95% is used as a standard substance and the standard substance is detected by using liquid chromatography. The liquid chromatogram of the sample is shown in figure 1, the liquid chromatogram of the standard is shown in figure 2, and the retention time of the chlorantraniliprole peak is consistent by comparing figure 1 with figure 2, which indicates that the chlorantraniliprole is successfully synthesized by the scheme.
In this example, in the first and second steps, when synthesizing the compound 3-chloro-2-hydrazinopyridine (intermediate one) represented by formula (iii), 2,3, 6-trichloropyridine was used as a raw material instead of 2, 3-dichloropyridine, tetrabutylammonium chloride was used as a catalyst a, and Cu-Ag/γ -Al was used as a catalyst a 2 O 3 As the catalyst B, the yield of the 3-chloro-2-hydrazinopyridine is 87.9 percent (calculated by the raw material of 2,3, 6-trichloropyridine), the defects of harsh conditions and low yield in the synthesis of the 2, 3-dichloropyridine are avoided, and the reaction time is short.
In the third step, when the compound 2- (3-chloropyridine-2-yl) -5-hydroxypyrazole-3-ethyl formate shown in the formula (IV) is synthesized, the synthesized compound shown in the formula (IV) is in an oil phase by optimizing the solvent a, the compound shown in the formula (IV) can be directly obtained by oil-water layering, the operation steps of crystallization, suction filtration, cleaning and drying are not needed, the operation steps are simplified, and the reaction yield is improved.
In the fourth step, the compound 3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid (intermediate II) shown in the formula (VI) can be directly prepared from the compound shown in the formula (IV) by a one-pot method, and after bromination reaction, no post-treatment is needed, i.e., operations such as crystallization and extraction of the compound 3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester shown in the formula (V) are not needed, so that the operation steps are reduced.
In the fifth step, the compound chlorantraniliprole shown in the formula (IX) can also be directly prepared from the compound shown in the formula (VI) by a one-pot method, so that the operation steps are further reduced, the post-treatment of key steps is simplified, the raw material cost is reduced, and the total reaction yield is improved, wherein in the embodiment, the total reaction yield is 65.5% (calculated by the raw material 2,3, 6-trichloropyridine). In addition, solid waste generated by using solid oxidants such as potassium persulfate and the like is reduced, and dangerous goods such as methylsulfonyl chloride and the like are avoided. Mother liquor after reaction of each intermediate in the synthesis method in the embodiment can be directly used, so that the generation of waste liquid is reduced, tail gas only contains relatively clean hydrogen and hydrogen chloride, and the hydrogen chloride can be directly absorbed as a byproduct and used for acid regulation and crystallization in the synthesis process of the compound shown in the formula (VI). Through calculation, compared with the conventional industrial common route of a methylsulfonyl chloride method and a thionyl chloride method, the synthesis method in the embodiment saves about 15% of the raw material cost, so that the method has a good application prospect.
Example 2
A preparation method of chlorantraniliprole is disclosed, wherein the synthesis reaction of the chlorantraniliprole is shown as a formula (i), and the preparation method specifically comprises the following steps.
Step one, synthesis of 3, 6-dichloro-2-hydrazinopyridine.
This step differs from step one in example 1 in that: in the step, the addition amount of 80% hydrazine hydrate solution is 90.1g (1.44mol), the catalyst A is cuprous chloride (0.6g,0.006mol), the reflux reaction is carried out for 4h, the filter cake is washed to neutrality by clear water and then washed by ethanol for 2 times, and the product 3, 6-dichloro-2-hydrazinopyridine is obtained after drying, the HPLC normalization content is 98% (the analysis condition is that a chromatographic column is a C18 silica gel reverse phase column 4.6x150mm 5 μm, the mobile phase is acetonitrile, water and acetic acid are 1: 1: 1: 1%), and the yield is 92.3%.
Step two, synthesizing 3-chlorine-2-hydrazinopyridine.
The difference between this step and step two in example 1 is that: 300mL of methanol, 54g (98%, 0.297mol) of 3, 6-dichloro-2-hydrazinopyridine prepared in step one, and 0.5% Cu-Ag/. gamma. -Al catalyst B 2 O 3 Catalyst (Cu-Ag/gamma-Al) 2 O 3 Accounting for 0.5 percent of the mass ratio of the raw material 3, 6-dichloro-2-hydrazinopyridine), controlling the hydrogen pressure to be 0.8-1.4 MPa, after reflux reaction for 5 hours, sampling and detecting by HPLC (high performance liquid chromatography) to control the raw material (3, 6-dichloro-2-hydrazinopyridine) < 0.5 percent, stopping introducing hydrogen after the reaction is qualified, cooling the kettle liquid to normal temperature, filtering to obtain Cu-Ag/gamma-Al 2 O 3 The method comprises the steps of (1) evaporating methanol from filtrate under reduced pressure, adding 180g of clear water, cooling to 0-5 ℃, precipitating a large amount of white crystals, carrying out suction filtration, washing a filter cake for 2 times by 108g of clear water, and drying at 80-90 ℃ to obtain 36.6g of the product 3-chloro-2-hydrazinopyridine, wherein the HPLC normalization content is 99.1% (analysis conditions are that a chromatographic column is a C18 silica gel reverse phase column of 4.6x150mm 5 mu m, a mobile phase is acetonitrile, water and acetic acid are 1: 1: 1), and the yield is 85.0%.
Step three, synthesizing 2- (3-chloropyridine-2-yl) -5-hydroxypyrazole-3-ethyl formate.
This step differs from step three in example 1 in that: 187mL of absolute ethanol, 7.4g (0.32mol) of metallic sodium, 1% of bis (triphenylphosphine) nickel chloride as a catalyst C (bis (triphenylphosphine) nickel chloride accounts for 1% of the mass ratio of the raw material 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-ethyl formate), 88.2g (0.46mol) of diethyl maleate, 35g (99.1% and 0.24mol) of the added amount of the 3-chloro-2-hydrazinopyridine prepared in the second step, slowly heating to 55 ℃ after stirring in an ice bath, carrying out heat preservation reaction for 0.5h, sampling HPLC (high performance liquid chromatography) to detect that the raw material (3-chloro-2-hydrazinopyridine) is less than 1%, distilling to remove dry ethanol under negative pressure after the reaction is qualified, slowly adding 60g of pure water as a solvent a into the kettle liquid, cooling to 0-5 ℃, dropwise adding 37% hydrochloric acid solution, and adjusting the pH value to 5-6, after stirring uniformly and repeatedly measuring the pH value, stirring for 1h, carrying out suction filtration, washing a filter cake for 2 times by using 200g of 20% ethanol solution to obtain a crude product of the earthy yellow powder, namely 57.9g of ethyl 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylate, wherein the HPLC normalization content is 90% (analytical conditions: a chromatographic column is a C18 silica gel reverse phase column of 4.6x150mm 5 mu m, a mobile phase is acetonitrile, water and acetic acid is 1: 1: 1%), and the yield is 80%.
In this step, the solvent a may also be 20-50% ethanol water solution (ethanol accounts for 20-50% of the total mass of the solution). Ethyl 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylate was obtained in a crystallization manner.
Step four, synthesizing 3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid from 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-ethyl formate by a one-pot method.
This step differs from step four in example 1 in that: 238mL of acetonitrile, 37.5g (0.139mol) of phosphorus tribromide as a brominating agent, and 56g of powdery crude ethyl 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylate (90%, 0.19mol) prepared in the third step; adding 136g of 20% methanol aqueous solution (methanol accounts for 20% of the total mass of the solution) into the kettle liquid, dropwise adding 30% liquid caustic soda (sodium hydroxide accounts for 30% of the total mass of the solution) to adjust the pH value to 12-13, heating to 55 ℃ to react for 0.5H, sampling and detecting HPLC (high performance liquid chromatography) to control the raw material (3-bromo-1- (3-chloropyridine-2-yl) -4, 5-dihydro-1H-pyrazole-5-ethyl formate) < 0.1%, cooling to 50 ℃ after the reaction is qualified, adjusting the pH value to 2-3 by using 37% hydrochloric acid, keeping the temperature and stirring for 1H (r is 200-250 rpm) after the pH value is constant after stirring, standing for 1H after the stirring is finished, separating an oil phase, washing the oil phase by 100mL of saturated common salt water, drying by using magnesium sulfate to obtain the red brown 3-bromo-1- (3-chloropyridine-2-yl) oily anhydrous sodium chloride 58.9g of 4, 5-dihydro-1H-pyrazole-5-carboxylic acid, 1% of water and 92% of HPLC normalization content (analytical conditions: chromatographic column C18 silica gel reverse phase column 4.6 × 150mm 5 μm, mobile phase acetonitrile: water: acetic acid ═ 1: 1: 1%), yield 95% based on ethyl 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylate.
And step five, synthesizing chlorantraniliprole.
The difference between this step and step five in example 1 is that: adding 55g (92 percent and 0.17mol) of 3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid prepared in the fourth step, adding 165g (1.39mol) of thionyl chloride, adding 1.1g (0.015 mol) of dimethylformamide as a catalyst D, slowly heating to a reflux state (80 ℃) to react for 1H, sampling and detecting by HPLC (high performance liquid chromatography), controlling the content of the raw material (3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid) to be less than 0.1 percent, removing thionyl chloride, generating 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-formyl chloride in the reaction process, directly adding acetonitrile 220mL and 2-amino-5-chloro-N, 3-dimethylbenzamide (29.8g,0.15mol), slowly heating to a reflux state (80 ℃), reacting for 1H, sampling and detecting by HPLC (high performance liquid chromatography) to control the raw material (3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-formyl chloride) < 0.1%, then cooling to 0-5 ℃, continuing stirring for 1H, performing suction filtration, reserving filtrate, washing filter cakes for 2-3 times by using clean water, drying at 80-90 ℃ to obtain 77.47g of white powdery chlorantraniliprole, wherein the normalized content of HPLC is 95.2% (analysis conditions: chromatographic column is C18 silica gel reverse phase column 4.6x150mm 5 μm, mobile phase is acetonitrile: water: acetic acid: 1: 1: 1%), using 3-bromo-1- (3-chloropyridin-2-yl) -4, the yield based on 5-dihydro-1H-pyrazole-5-carboxylic acid was 92%.
In the fourth step of the present example, the compound 3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid represented by formula (vi) in formula (i) can be in the form of oil, and can be obtained by oil-water separation directly, without performing crystallization, suction filtration, washing, drying and the like, which simplifies the operation steps, and the yield of 3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid in this step is 95% compared with 93% for 3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid in example 1, this example indeed improves the reaction yield. In addition, in this example, the total reaction yield was 54.9% (based on the starting material, 2,3, 6-trichloropyridine).
Comparative example 1
The comparative example provides a preparation method of chlorantraniliprole in the prior art, which comprises the following steps:
(1) preparation of starting 2, 3-dichloropyridine
Adding 3-aminopyridine (99%, 47g,0.5mol), concentrated hydrochloric acid (36%, 27g), ferrous chloride (2g,0.016mol) into a 500mL four-neck flask with mechanical stirring in sequence, starting stirring, adding hydrogen peroxide (27%, 94g) into the reaction flask in a dropwise manner, keeping the temperature at 25-30 ℃ for 20min after the dropwise addition is finished, performing HPLC detection on 3-aminopyridine 9%, 2-chloro-3-aminopyridine 81.2% and 2, 6-dichloro-3-aminopyridine 10.8%, wherein the reaction liquid is dark red, adding hydrochloric acid (36%, 190g) and cuprous oxide (36g,0.25mol), controlling the temperature to be 33 ℃, adding sodium nitrite aqueous solution (209g, 33%, 1mol) in a dropwise manner, heating to 60 ℃ after the dropwise addition is finished, performing reaction for 10min, and performing sampling detection: the content of 3-chloropyridine is 5.3 percent, the content of 2, 3-dichloropyridine is 87.2 percent and the content of 2,3, 6-trichloropyridine is 7.6 percent, then the temperature is reduced to 30 ℃, 30 percent sodium hydroxide aqueous solution is used for adjusting the pH value to be more than 11, and the crude product is recrystallized and dried to obtain 51.4g of white crystal, the yield is 69 percent and the content is 99.4 percent.
(2) Synthesis of 3-chloro-2-hydrazinopyridine
20mL of ethanol solution is added into a 500mL four-neck flask provided with a mechanical stirring and return pipe, 25.5mL (0.5mol) of 85% hydrazine hydrate solution is added, stirring is started, the temperature is raised to a reflux state, 2, 3-dichloropyridine (14.8g and 0.1mol) prepared in the step (1) and the ethanol solution (100mL) are added dropwise for 1h, the temperature is kept for reaction for 25h in the reflux state after the dropwise addition is finished, the temperature is reduced to 0 ℃ after the reaction is qualified, and the needle-shaped white crystal 13.8g is obtained by suction filtration, wherein the yield is 96%.
(3) Synthesis of ethyl 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylate
A500 mL four-necked flask equipped with a mechanical stirring and reflux tube was charged with 60mL of absolute ethanol and 2g of metallic sodium, N 2 Heating to reflux under protection, cooling to room temperature after all sodium metal is dissolved, adding 3-chloro-2-hydrazinopyridine (11.5g,0.08mol) prepared in the step (2), heating to reflux, dropwise adding diethyl maleate (14.9mL, 0.09mol), refluxing for 1h until the solution turns to be clear and transparent, then cooling to 65 ℃, adjusting the pH value to 5 with glacial acetic acid, cooling to 0 ℃, freezing, crystallizing, filtering, drying a filter cake to obtain 12.1g of an earthy yellow solid, wherein the yield is 56.1%.
(4) Synthesis of ethyl 3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylate
Adding 80mL of dichloroethane and 10.8g of ethyl 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylate (0.04 mol) prepared in the step (3) into a four-neck flask, adding 5.6mL (0.044mol) of benzenesulfonyl chloride, starting stirring, cooling to 0 ℃, dropwise adding 6.1mL (0.044mol) of triethylamine, keeping the temperature for 3 hours, slowly heating to 10-15 ℃, introducing 4.1g (0.051mol) of HBr gas, after the reaction is controlled to be qualified, dropwise adding 100mL of saturated sodium bicarbonate solution, fully washing until no bubbles are generated, standing for layering, removing a water layer, drying an oil layer with anhydrous sodium sulfate, and performing decompression and desolventization to obtain 11.9g of dark red oily product, wherein the yield is 89.5%.
(5) Synthesis of ethyl 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylate
In a four-necked flask, ethyl 3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylate (6.7g, 0.02mol) was charged, 60mL of acetonitrile and 2.2mL (0.041mol) of concentrated sulfuric acid were added, and then N was introduced 2 Protecting, stirring for 15min, adding 8g (0.03mol) of potassium persulfate, heating and refluxing for 2h, filtering out excessive potassium persulfate and salt waste when the reaction is qualified, then concentrating the filtrate under reduced pressure to about 40mL, cooling to 0 ℃ in an ice bath, precipitating a solid, filtering, drying a filter cake to obtain 6.05g of a yellow solid product, and obtaining the yield of 91.6%.
(6) Synthesis of 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid
15mL of methanol and 10mL of water are added into a four-neck flask, 3.31g (0.01mol) of ethyl 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylate and 0.8g (0.02mol) of sodium hydroxide are added, the temperature is raised to reflux reaction for 0.5H, the methanol is evaporated under reduced pressure after the reaction is qualified, 10mL of water is added, concentrated hydrochloric acid is added dropwise to adjust the pH to be slightly acidic, a large amount of solid is precipitated, stirring is continued at room temperature for 30min, filtering is carried out, a filter cake is dried to obtain 2.7g of light yellow solid, and the yield is 89.4%.
(7) Synthesis of chlorantraniliprole
Adding 200mL of acetonitrile into a four-neck flask, adding 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid (6g,0.02mol) and 2-amino-5-chloro-N, 3-dimethylbenzamide (3.9g,0.02mol), starting stirring, dropwise adding 10mL of pyridine, cooling to 0 ℃ in an ice bath after reaction raw materials are completely dissolved, dropwise adding 5mL of methylsulfonyl chloride, continuing stirring for 10min after dropwise adding is finished, then carrying out heat preservation reaction at room temperature for 3-6H, separating out a large amount of yellow solid, reducing pressure to remove partial solvent after the reaction is controlled to be qualified, filtering and washing to obtain a white solid product 8.4g with the content of 95% and the yield of 83.4%.
Comparative example 2
This comparative example provides another prior art method of preparing chlorantraniliprole comprising the steps of:
(1) preparation of starting 2, 3-dichloropyridine
The preparation was carried out in the same manner as in comparative example 1 to give 60g of 2, 3-dichloropyridine in a yield of 69%.
(2) Synthesis of 3-chloro-2-hydrazinopyridine
2, 3-dichloropyridine (74g,0.5mol), 50% hydrazine hydrate solution (205g,2.5mol) and 300mL dioxane were sequentially added to a 1000mL four-necked flask, and the mixture was stirred at reflux temperature for 20 hours, cooled overnight, filtered and dried to obtain 51g of a white solid with a yield of 69%.
(3) Synthesis of ethyl 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylate
Adding 300mL of absolute ethanol and sodium ethoxide (15.6g,0.229mol) into a 1000mL reaction bottle, heating and refluxing the mixture for 5min, then dropwise adding diethyl maleate (36g,0.25mol), continuously refluxing for 10min after dropwise adding is finished, cooling to 65 ℃ after the reaction is controlled to be qualified, neutralizing the reaction mixture with glacial acetic acid (25.2g,0.42mol), then diluting with 300mL of water, separating out a solid after cooling to room temperature, filtering and collecting the solid, washing for 3 times with 150mL of 40% ethanol solution, and drying to obtain 26.3g of an orange solid with the yield of 47%.
(4) Synthesis of ethyl 3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylate
A1000 mL reaction flask was charged with 195mL acetonitrile, ethyl 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-carboxylate prepared in step (3) (19.5g,0.024mol), and phosphorus oxybromide (8.95g,0.0312 mol). Heating and refluxing for 2h, distilling to remove 90mL of solvent after the reaction is qualified, adding the concentrated reaction liquid mixture into a mixture formed by sodium bicarbonate (30.3g,0.36mol) and 120mL of water, stirring for 20min until no gas escapes, diluting the mixture with 300mL of dichloromethane, stirring for 50min, extracting with 400mL of dichloromethane, washing an organic phase with water, drying with magnesium sulfate, and concentrating by using a rotary evaporator to obtain 21.2g of dark amber oily matter with the yield of 88%.
(5) Synthesis of ethyl 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylate
Adding 3-bromo-1- (3-chloropyridin-2-yl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid ethyl ester (20.7g,0.06mol), 45mL acetonitrile and 98% sulfuric acid (12.6g,0.126mol) into a 500mL reaction bottle, then adding potassium persulfate (27g,0.1mol), refluxing for 3-4H, then cooling to about 60 ℃, filtering out unreacted potassium persulfate and salt waste while the solution is hot, concentrating the rest reaction solution to 45mL under reduced pressure, then adding 225mL water, performing suction filtration, washing a filter cake for 3 times by using 200mL of 25% acetonitrile aqueous solution, and drying to obtain 18.5g of yellow solid with the yield of 90%.
(6) Synthesis of 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid
A1000 mL reaction flask was charged with ethyl 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylate (18g,0.054mol), methanol, 100mL each of water, and sodium hydroxide (2.6g,0.065 mol). After the reaction is qualified, the reaction solution is concentrated to 100mL, 300mL of water is added, the aqueous solution is extracted by 200mL of ether, Ph is adjusted to 4 by concentrated hydrochloric acid, the solid is obtained by filtration, a filter cake is washed by 500mL of water for 2 times, and the white solid 14.6g is obtained after drying, and the yield is 88%.
(7) Synthesis of 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carbonyl chloride
3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid (14g,0.046mol), 100mL of dichloromethane and oxalyl chloride (8.73g, 0.069mol) were added to a 250mL reaction flask, 5 drops of dimethylformamide were added dropwise with generation of a large amount of gas, the reaction mixture was stirred at room temperature for 8 hours, and then concentrated under reduced pressure to substantially dry, 100mL of toluene was added thereto, and 13.6g of a brown oily substance was obtained after concentration under reduced pressure with a yield of 92%.
(8) Synthesis of chlorantraniliprole
1- (3-chloropyridin-2-yl) -3-chloro-1H-pyrazole-5-formyl chloride (13g,0.04mol) and 250mL of acetonitrile are added into a 500mL four-neck flask provided with a mechanical stirring and return pipe, then amino-5-chloro-N, 3-dimethylbenzamide (7.5g,0.04mol) and 2g of pyridine are added, the mixture is slowly heated to a reflux state for reaction for 2-3H, after the reaction liquid is qualified, the reaction liquid is poured into 300mL of saturated sodium bicarbonate solution, filtered, washed and dried to obtain 17.4g of white solid with the content of 95 percent and the yield of 84.6 percent.
Comparing example 1, example 2, comparative example 1 and comparative example 2, it was not difficult to find:
1. in example 1, the total yield of the intermediate, i.e., 3-chloro-2-hydrazinopyridine, based on the starting material, 2,3, 6-trichloropyridine, was 87.9%; in example 2, the total yield of the intermediate, i.e., the 3-chloro-2-hydrazinopyridine, based on the starting material, i.e., the 2,3, 6-trichloropyridine, was 78.. 5%; in comparative example 1, the total yield of 3-chloro-2-hydrazinopyridine was 66.24% based on the starting material, 3-aminopyridine; in comparative example 2, the total yield of 3-chloro-2-hydrazinopyridine was 47.61% based on the starting material, 3-aminopyridine. Therefore, the total yield of the 3-chloro-2-hydrazinopyridine in the examples 1 and 2 is higher than that in the comparative examples 1 and 2 by using the 2,3, 6-trichloropyridine as the raw material and under the action of the catalyst A and the catalyst B, the invention improves the yield of the 3-chloro-2-hydrazinopyridine and reduces the cost of the raw material for synthesizing the chlorantraniliprole.
Further, the synthesis time of 3-chloro-2-hydrazinopyridine (intermediate one) in example 1 and example 2 was about 11 hours and 9 hours, respectively, and the synthesis time of 3-chloro-2-hydrazinopyridine in comparative example 1 and comparative example 2 was about 25.5 hours and 20.5 hours, respectively, and thus it was found that the present invention can shorten the synthesis time of 3-chloro-2-hydrazinopyridine and improve the synthesis efficiency of 3-chloro-2-hydrazinopyridine.
2. The total yields of chlorantraniliprole in example 1 and example 2 were 65.5% and 54.9%, respectively (the total yields in example 1 and example 2 were calculated based on the starting material 2,3, 6-trichloropyridine), and the total yields in comparative example 1 and comparative example 2 were 22.71% and 12.14%, respectively (the total yields in comparative example 1 and comparative example 2 were calculated based on the starting material 3-aminopyridine), and thus it was found that the yield of chlorantraniliprole in the present invention was significantly higher than that in comparative example 1 and comparative example 2, and therefore, the method for preparing chlorantraniliprole provided by the present invention could significantly increase the yield of chlorantraniliprole.
The foregoing is merely an example of the present invention and common general knowledge in the art of designing and/or characterizing particular aspects and/or features is not described in any greater detail herein. It should be noted that, for those skilled in the art, without departing from the technical solution of the present invention, several variations and modifications can be made, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicability of the patent. The scope of the claims of the present application shall be determined by the contents of the claims, and the description of the embodiments and the like in the specification shall be used to explain the contents of the claims.

Claims (4)

1. A preparation method of chlorantraniliprole is characterized by comprising the following steps: the method comprises a step of synthesizing an intermediate I, a step of synthesizing an intermediate II and a step of synthesizing chlorantraniliprole;
in the synthesis step of the intermediate I, 2,3, 6-trichloropyridine and hydrazine hydrate solution are subjected to reflux reaction under the action of a catalyst A to obtain 3, 6-dichloro-2-hydrazinopyridine, and the 3, 6-dichloro-2-hydrazinopyridine is subjected to hydrogenation reflux reaction under the action of a catalyst B to obtain the intermediate I, wherein the chemical structural formula of the intermediate I is shown as a formula (III), and the catalyst B is Cu-Ag/gamma-Al 2 O 3 ；
Under the action of a catalyst C, preparing 2- (3-chloropyridin-2-yl) -5-hydroxypyrazole-3-ethyl formate from the intermediate I and diethyl maleate; after the reaction is finished and the solvent is removed, adding the solvent a to form an oil-water two-phase, and purifying the 2- (3-chloropyridine-2-yl) -5-hydroxypyrazole-3-ethyl formate in a phase-splitting manner; the solvent a is one of a mixture of ethyl acetate and water, a mixture of trichloromethane and water, a mixture of dichloromethane and water, a mixture of 1, 2-dichloroethane and water and a mixture of toluene and water;
Figure 721412DEST_PATH_IMAGE001
the Cu-Ag/gamma-Al 2 O 3 The preparation method comprises the following steps:
a. pretreatment of a carrier: taking a certain amount of gamma-Al 2 O 3 Roasting in a muffle furnace at 500 ℃ for 3 h;
b. dipping: 1449.6mg of Cu (NO) were weighed out separately 3 ) 2 ·3H 2 O and 1018.98mg AgNO 3 Dissolved in 3mL of deionized waterPreparing copper nitrate and silver nitrate solutions, then weighing 5g of the roasted carrier in a 100mL beaker, respectively adding 2mL of the copper nitrate and silver nitrate solutions, quickly stirring for 20min to enable the carrier to be in a wet sticky state, and then standing for 4h at room temperature;
c. and (3) drying: placing the sample after standing in a vacuum drying oven, drying for 12h at 105 ℃, and grinding into powder;
d. roasting: placing the powder sample in a muffle furnace to be roasted for 3h at the temperature of 450 ℃, thus obtaining the catalyst Cu-Ag/gamma-Al 2 O 3 ；
The catalyst A is one or more than two of cupric chloride, cuprous chloride, tetrabutylammonium chloride, benzyltrimethylammonium chloride, tetramethylammonium chloride, triphenylbutylphosphonium bromide, triethylmethylammonium chloride, tetramethylammonium bromide, benzyltriethylammonium chloride and tetrabutylammonium iodide;
the catalyst C is one or more than two of bis (triphenylphosphine) nickel chloride, bis (tricyclohexylphosphine) nickel dichloride, cuprous bistriphenylphosphine iodide, cuprous bistriphenylphosphine bromide and nickel bistriphenylphosphine dibromide.
2. The method for preparing chlorantraniliprole according to claim 1, which is characterized in that: in the synthesis step of the intermediate II, carrying out reflux reaction on 2- (3-chloropyridine-2-yl) -5-hydroxypyrazole-3-ethyl formate and a brominating agent in a solvent b, removing the solvent b after the reaction is finished, adding a solvent c, dropwise adding liquid caustic soda under stirring, adjusting the pH value to 12-13, cooling to room temperature or 50 ℃ after the reaction is finished, adjusting the pH value to 2-3, stirring at an ice bath or 50 ℃ at a stirring speed of 200-250 rpm to obtain an intermediate II, wherein the chemical structural formula of the intermediate II is shown as a formula (VI);
Figure 501149DEST_PATH_IMAGE002
the solvent b is one or a mixture of two of acetonitrile, chloroform, dimethylformamide and dichloromethane;
and the solvent c is one of pure water, an ethanol water solution, a methanol water solution, a dimethylformamide water solution or an acetonitrile water solution.
3. The process for preparing chlorantraniliprole according to claim 2, wherein: in the synthesis step of chlorantraniliprole, heating the intermediate II and thionyl chloride to react under the action of a catalyst D, drying the thionyl chloride after the reaction is finished, directly adding substituted aniline and acetonitrile or directly adding substituted aniline and toluene, heating to react, cooling to 0-20 ℃ after the reaction is finished, crystallizing, and filtering to obtain a target product chlorantraniliprole;
the catalyst D is a mixture formed by one or more than two of acetonitrile, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, 3, 5-dimethylpyridine and 3-chloro-2-methylpyridine.
4. The process for preparing chlorantraniliprole according to claim 3, wherein the step of preparing the chlorantraniliprole comprises the following steps: in the synthesis step of the intermediate II, the brominating agent is phosphorus tribromide or phosphorus oxybromide, and when the brominating agent is phosphorus tribromide, the intermediate II exists in an oil phase.
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