阅读说明：本技术 一种双酰胺类杀虫剂的合成方法 (Synthesis method of bisamide insecticide ) 是由 丛云波 韩金涛 蒋爱忠 刘军 解银萍 王滢秀 郝泽生 江忠萍 于 2021-07-22 设计创作，主要内容包括：本发明公开了一种双酰胺类杀虫剂的合成方法,涉及有机合成技术领域,所述合成方法以通式(III)所示的吡唑啉羧酸类化合物和通式(II)所示的邻氨基苯甲酰胺类化合物为原料,以甲磺酰氯作为氧化剂和缩合剂一步合成通式(I)所示的双酰胺类杀虫剂。本发明的合成方法以吡唑啉羧酸类化合物和邻氨基苯甲酰胺类化合物为原料,以甲磺酰氯作为氧化剂和缩合剂,在一定的叔胺作用下同时进行偶联反应和氧化反应,在偶联反应过程中,可以同时将吡唑啉环氧化为吡唑环,制备出纯度高、收率高的双酰胺类杀虫剂,成功地替代了传统的采用氧化剂进行的氧化反应,简化了反应步骤,减少了对环境的污染,并增加反应的安全性。(The invention discloses a synthesis method of bisamide insecticides, which relates to the technical field of organic synthesis and is characterized in that pyrazoline carboxylic acid compounds shown in a general formula (III) and anthranilamide compounds shown in a general formula (II) are used as raw materials, and methanesulfonyl chloride is used as an oxidant and a condensing agent to synthesize the bisamide insecticides shown in the general formula (I) in one step. The synthetic method of the invention takes pyrazoline carboxylic acid compounds and anthranilamide compounds as raw materials, takes methanesulfonyl chloride as an oxidant and a condensing agent, and simultaneously carries out coupling reaction and oxidation reaction under the action of certain tertiary amine, and in the coupling reaction process, pyrazoline can be epoxidized into pyrazole rings at the same time, so that bisamide insecticides with high purity and high yield are prepared, the traditional oxidation reaction adopting the oxidant is successfully replaced, the reaction steps are simplified, the pollution to the environment is reduced, and the reaction safety is increased.)

1. A synthetic method of bisamide insecticides is characterized in that pyrazoline carboxylic acid compounds shown in a general formula (III) and anthranilamide compounds shown in a general formula (II) are used as raw materials, methanesulfonyl chloride is used as an oxidizing agent and a condensing agent to synthesize the bisamide insecticides shown in the general formula (I) in one step, and the reaction formula is as follows:

in the formula:

R₁selected from H, CH₃Cl or Br;

R₂selected from H, Cl or Br.

2. The synthetic method according to claim 1, comprising the following steps:

adding pyrazoline carboxylic acid compounds shown in a general formula (III) and a proper solvent into a reaction bottle, uniformly stirring, and cooling to-5 ℃; dropwise adding methanesulfonyl chloride into the reaction bottle at a temperature of between-5 and 0 ℃ under the stirring condition, and stirring at room temperature for 8 to 12min after dropwise adding; then heating the liquid in the reaction bottle to 45-55 ℃, and reacting for 8-12 h under the condition of heat preservation to obtain a reaction mixed liquid;

cooling the reaction mixed solution to 25 +/-1 ℃, adding an anthranilamide compound shown in a general formula (II) and tertiary amine, stirring at 25 +/-1 ℃ for 2.5h-3.5h, then dropwise adding water, and stirring at room temperature for 0.8h-1.2h to obtain a crude product;

filtering, washing and drying the obtained crude product to obtain the bisamide insecticide shown in the general formula (I).

3. The synthetic method according to claim 1 or 2, characterized in that the pyrazoline carboxylic acid-based compound is 3-bromo-1- (3, 5-dichloro-2-pyridinyl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid; the anthranilamide compound is 2-amino-3, 5-dichlorobenzamide; the reaction formula is as follows:

4. the method of claim 2, wherein the suitable solvent is selected from chlorobenzene, toluene, ethyl acetate, butyl acetate, acetone, 2-butanone, tetrahydrofuran, dioxane, acetonitrile, dichloromethane, or chloroform.

5. The method of synthesis according to claim 2, wherein the tertiary amine is selected from trimethylamine, triethylamine and pyridine.

6. The synthesis method according to claim 2, wherein the molar ratio of the pyrazoline carboxylic acid-based compound, the anthranilamide-based compound, and the methanesulfonyl chloride is 1.0:1.0 to 1.2:2.0 to 3.0.

7. The method according to claim 2, wherein the pyrazoline carboxylic acid-based compound, the anthranilamide compound and the methanesulfonyl chloride have a purity of 95% or more.

8. The method of claim 2, wherein the ratio of the molar amount of the pyrazoline carboxylic acid compound to the volume of the suitable solvent is 1.0 to 2.0.

9. The method of claim 2, wherein the molar ratio of the anthranilamide compound to the tertiary amine is 1.0: 2.0-3.0.

10. The synthesis method according to claim 1, wherein the yield of the bisamide insecticide is more than 97%.

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing bisamide insecticides.

Background

The bisamide insecticide is a hotspot in the field of insecticide research in recent years, acts on a ryanodine receptor of insects, has the characteristics of novel action mechanism, high efficiency, no cross resistance with the traditional pesticide, safety to non-target organisms, good environmental compatibility and the like, draws people's attention, and becomes a hotspot in the research and development of insecticides.

Bisamide insecticides widely known in the market include chlorantraniliprole developed by dupont and chlorantraniliprole developed by shenyang chemical research institute, ltd.

Chlorantraniliprole developed by DuPont is prepared by oxidizing pyrazoline carboxylate compounds into pyrazole carboxylate compounds by using potassium persulfate and concentrated sulfuric acid as oxidants, hydrolyzing the pyrazoline carboxylate compounds into pyrazole carboxylate compounds by one step, then using the pyrazole carboxylate compounds and benzamide as raw materials, using acetonitrile as a solvent and pyridine as an organic base, dropwise adding methanesulfonyl chloride at-5 ℃, and performing a one-pot method at room temperature. The method has the advantages of mild conditions, high reaction speed, good selectivity, less side reactions and higher yield in the whole reaction process, but the method has complicated reaction steps and high synthesis cost.

The cost of the tetrachloro-zoon amide prepared by Shenyang chemical research institute company Limited is lower than that of chlorantraniliprole, and the synthesis methods of the tetrachloro-zoon amide comprise a dihydropyrazolecarboxylic acid-acyl chloride method, a pyrazolecarboxylic acid-benzoxazinone ring opening method and a dihydropyrazolecarboxylic acid-benzoxazinone ring opening method.

Disclosure of Invention

Therefore, the invention provides a method for synthesizing bisamide insecticides, which aims to solve the problems that the existing method for synthesizing bisamide insecticides has complicated reaction steps, more side reactions, low product yield, and is easy to generate acid gases such as hydrogen chloride and the like, and can corrode equipment.

In order to achieve the above purpose, the invention provides the following technical scheme:

according to the first aspect of the invention, a synthetic method of a bisamide insecticide is provided, the synthetic method takes a pyrazoline carboxylic acid compound shown in a general formula (III) and an anthranilamide compound shown in a general formula (II) as raw materials, and takes methanesulfonyl chloride as an oxidant and a condensing agent to synthesize the bisamide insecticide shown in the general formula (I) in one step, and the reaction formula is as follows:

in the formula:

R₁selected from H, CH₃Cl or Br;

R₂selected from H, Cl or Br.

The synthetic method of the bisamide insecticide takes the pyrazoline carboxylic acid compounds and the anthranilamide compounds as raw materials, takes methanesulfonyl chloride as an oxidant and a condensing agent, and simultaneously performs coupling reaction and oxidation reaction under the action of certain tertiary amine to synthesize the bisamide insecticide in one step, so that the reaction steps are simplified, side reactions are few in the reaction process, the obtained product has high purity and good yield, and substances harmful to the environment cannot be generated, so that the reaction safety is improved.

Further, the synthesis method comprises the following specific steps:

adding pyrazoline carboxylic acid compounds shown in a general formula (III) and a proper solvent into a reaction bottle, uniformly stirring, and cooling to-5 ℃; dropwise adding methanesulfonyl chloride into the reaction bottle at a temperature of between-5 and 0 ℃ under the stirring condition, and stirring at room temperature for 8 to 12min after dropwise adding; then heating the liquid in the reaction bottle to 45-55 ℃, and reacting for 8-12 h under the condition of heat preservation to obtain a reaction mixed liquid;

cooling the reaction mixed solution to 25 +/-1 ℃, adding an anthranilamide compound shown in a general formula (II) and tertiary amine, stirring at 25 +/-1 ℃ for 2.5h-3.5h, then dropwise adding water, and stirring at room temperature for 0.8h-1.2h to obtain a crude product;

filtering, washing and drying the obtained crude product to obtain the bisamide insecticide shown in the general formula (I).

In the synthetic method, the methanesulfonyl chloride is limited to be dripped at the temperature of between-5 ℃ and 0 ℃, compared with the method of dripping the sulfuryl chloride at room temperature, the method can prevent the initial reaction from being too violent, reduce the occurrence of side reactions, effectively avoid the generation of by-products and further improve the purity of the product. The invention can ensure that the oxidation reaction can be more completely carried out when the methylsulfonyl chloride is used as the oxidant by limiting reaction parameters such as reaction time, reaction temperature and the like.

Further, the pyrazoline carboxylic acid compounds are 3-bromo-1- (3, 5-dichloro-2-pyridyl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid; the anthranilamide compound is 2-amino-3, 5-dichlorobenzamide; the reaction formula is as follows:

further, the suitable solvent is selected from chlorobenzene, toluene, ethyl acetate, butyl acetate, acetone, 2-butanone, tetrahydrofuran, dioxane, acetonitrile, dichloromethane or chloroform.

Further, the tertiary amine is selected from trimethylamine, triethylamine or pyridine.

Further, the feeding molar ratio of the pyrazoline carboxylic acid compounds, the anthranilamide compounds and the methanesulfonyl chloride is 1.0:1.0-1.2: 2.0-3.0.

Furthermore, the purities of the pyrazoline carboxylic acid compounds, the anthranilamide compounds and the methanesulfonyl chloride are all more than 95%.

Further, the ratio of the molar amount of the pyrazoline carboxylic acid-based compound to the volume of the suitable solvent is 1.0-1.0-2.0.

Further, the charging molar ratio of the anthranilamide compound to the tertiary amine is 1.0: 2.0-3.0.

The synthesis method further limits the types of suitable solvents and tertiary amines and further limits the proportion of raw materials in the reaction process, so that the reaction can be more sufficient and thorough, the purity of the obtained product is higher, and the yield is better.

Further, the yield of the bisamide insecticide is more than 97%.

The invention has the following advantages:

the synthetic method of the bisamide insecticide takes a pyrazoline carboxylic acid compound and an anthranilamide compound as raw materials, takes methanesulfonyl chloride as an oxidant and a condensing agent, and simultaneously performs a coupling reaction and an oxidation reaction under the action of a certain tertiary amine, and can simultaneously epoxidize pyrazoline into a pyrazole ring in the coupling reaction process, so that the bisamide insecticide with high purity and high yield is prepared, the traditional oxidation reaction adopting the oxidant is successfully replaced, the reaction steps are simplified, the pollution to the environment is reduced, and the reaction safety is improved.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below. It should be apparent that the drawings in the following description are merely exemplary, and that other embodiments can be derived from the drawings provided by those of ordinary skill in the art without inventive effort.

The structures, ratios, sizes, and the like shown in the present specification are only used for matching with the contents disclosed in the specification, so that those skilled in the art can understand and read the present invention, and do not limit the conditions for implementing the present invention, so that the present invention has no technical significance, and any structural modifications, changes in the ratio relationship, or adjustments of the sizes, without affecting the functions and purposes of the present invention, should still fall within the scope of the present invention.

FIG. 1 is a 1H NMR spectrum of a bisamide insecticide provided in example 1 of the present invention;

FIG. 2 is a HRMS spectrum of the bisamide insecticide provided in example 1 of the present invention;

FIG. 3 is an IR spectrum of the bisamide insecticide provided in example 1 of the present invention;

fig. 4 is a HRLC spectrum of the bisamide insecticide provided in example 1 of the present invention.

Detailed Description

The present invention is described in terms of particular embodiments, other advantages and features of the invention will become apparent to those skilled in the art from the following disclosure, and it is to be understood that the described embodiments are merely exemplary of the invention and that it is not intended to limit the invention to the particular embodiments disclosed. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1

A synthetic method of bisamide insecticide is disclosed, wherein the reaction formula is as follows:

the synthesis method comprises the following specific steps:

to a 100mL reaction flask, 3-bromo-1- (3, 5-dichloro-2-pyridinyl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid (3.57g, 95%, 10mmol) and acetonitrile (15mL) were added, the mixture was cooled to-5 ℃, and methanesulfonyl chloride (2.78g, 99%, 24mmol) was then added dropwise to the reaction flask at-5 ℃ to 0 ℃. After the dropwise addition, stirring at room temperature for 10min, slowly heating to 50 ℃, and carrying out heat preservation reaction for 10h to obtain a reaction mixed solution.

The resulting reaction mixture was cooled to 25 ℃ and 2-amino-3, 5-dichlorobenzamide (2.40g, 97%, 10.5mmol) and pyridine (2.24g, 99%, 28mmol) were added, and after stirring at this temperature for 3h, water (5mL) was added dropwise, and the mixture was stirred at room temperature for 1h to give the crude product.

The crude product was filtered and the solid was washed with 3:1 acetonitrile-water (2X 3mL) followed by acetonitrile (3mL), filtered and dried to give the bisamide insecticides of formula (I).

The synthesis method is repeated three times, and the average value is taken, so that the yield of the bisamide insecticide is 97.0%.

The obtained bisamide pesticide is subjected to nuclear magnetic resonance, LC-MS and infrared spectrum detection respectively, and the obtained 1H NMR spectrum is shown in figure 1, HRMS spectrum is shown in figure 2, IR spectrum is shown in figure 3, and HRLC spectrum is shown in figure 4.

The 1H NMR spectrum of FIG. 1 gave 535.6 for the (M + H) peak and 557.9 for the (M + Na) peak, which is consistent with the molecular weight of tetrachloro-worm-amide (534.88). The HRMS spectrogram of FIG. 2 shows that the obtained bisamide insecticide (M + H)⁺535.88447m/z, the molecular formula is presumed to be C₁₇H₁₀BrC_l4N₅O₂This is consistent with the tetrachloro worm amide formula. The IR spectrum of the obtained bisamide insecticide is consistent with that of the tetrachloro insect amide as can be seen from the result of the IR spectrum of the figure 3.

When the obtained bisamide insecticide sample is subjected to HPLC analysis, the specific method comprises the following steps: column type Agilent C18, 150 × 4.6mm, 5 um; detection wavelength: 236 nm; mobile phase composition: acetonitrile: 70 parts of phosphoric acid water: 30, of a nitrogen-containing gas; flow rate of mobile phase: 1.0 mL/min. The HPLC spectra shown in FIG. 4 were combined to obtain the quantitative analysis of substances of the sample shown in Table 1.

TABLE 1 quantitative analysis table of substance of sample

As can be seen from the results in Table 1, the bisamide insecticide samples obtained by the synthesis method of the invention have high purity of 99.57 percent and high purity.

Example 2

To a 100mL reaction flask, 3-bromo-1- (3, 5-dichloro-2-pyridinyl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid (3.57g, 95%, 10mmol) and toluene (15mL) were added, the mixture was cooled to-5 ℃, and methanesulfonyl chloride (2.78g, 99%, 24mmol) was then added dropwise to the reaction flask at-5 ℃ to 0 ℃. After the dropwise addition, stirring at room temperature for 10min, slowly heating to 50 ℃, and carrying out heat preservation reaction for 10h to obtain a reaction mixed solution.

The resulting reaction mixture was cooled to 25 ℃ and 2-amino-3, 5-dichlorobenzamide (2.40g, 97%, 10.5mmol) and pyridine (2.24g, 99%, 28mmol) were added, and after stirring at this temperature for 3h, water (5mL) was added dropwise, and the mixture was stirred at room temperature for 1h to give the crude product.

The crude product was filtered and the solid was washed with 3:1 toluene-water (2X 3mL) and then toluene (3mL), the solid was filtered and dried to give the bisamide insecticides of formula (I).

The synthesis method is repeated three times, and the average value is taken, so that the yield of the bisamide insecticide is 97.5%.

And respectively carrying out nuclear magnetic resonance, LC-MS and infrared spectrum detection on the obtained bisamide insecticide to verify that the bisamide insecticide with the structural formula shown as the general formula (I), namely the tetrachloro-worm amide.

Example 3

To a 100mL reaction flask, 3-bromo-1- (3, 5-dichloro-2-pyridinyl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid (3.57g, 95%, 10mmol) and acetonitrile (15mL) were added, the mixture was cooled to-5 ℃, and methanesulfonyl chloride (2.78g, 99%, 24mmol) was then added dropwise to the reaction flask at-5 ℃ to 0 ℃. After the dropwise addition, stirring at room temperature for 10min, slowly heating to 50 ℃, and carrying out heat preservation reaction for 10h to obtain a reaction mixed solution.

The resulting reaction mixture was cooled to 25 ℃ and 2-amino-3, 5-dichlorobenzamide (2.40g, 97%, 10.5mmol) and triethylamine (2.86g, 99%, 28mmol) were added and stirred at that temperature for 3h, then water (5mL) was added dropwise and the mixture was stirred at room temperature for 1h to give the crude product.

The crude product was filtered and the solid was washed with 3:1 acetonitrile-water (2X 3mL) followed by acetonitrile (3mL), filtered and dried to give the bisamide insecticides of formula (I).

The synthesis method is repeated three times, and the average value is taken, so that the yield of the bisamide insecticide is 98%.

And respectively carrying out nuclear magnetic resonance, LC-MS and infrared spectrum detection on the obtained bisamide insecticide to verify that the bisamide insecticide with the structural formula shown as the general formula (I), namely the tetrachloro-worm amide.

Example 4

To a 100mL reaction flask, 3-bromo-1- (3, 5-dichloro-2-pyridinyl) -4, 5-dihydro-1H-pyrazole-5-carboxylic acid (3.57g, 95%, 10mmol) and acetonitrile (15mL) were added, the mixture was cooled to-5 ℃, and methanesulfonyl chloride (2.32g, 99%, 20mmol) was then added dropwise to the reaction flask at-5 ℃ to 0 ℃. After the dropwise addition, stirring at room temperature for 10min, slowly heating to 50 ℃, and carrying out heat preservation reaction for 10h to obtain a reaction mixed solution.

The resulting reaction mixture was cooled to 25 ℃ and 2-amino-3, 5-dichlorobenzamide (2.40g, 97%, 10.5mmol) and pyridine (2.24g, 99%, 28mmol) were added, and after stirring at this temperature for 3h, water (5mL) was added dropwise, and the mixture was stirred at room temperature for 1h to give the crude product.

The crude product was filtered and the solid was washed with 3:1 acetonitrile-water (2X 3mL) followed by acetonitrile (3mL), filtered and dried to give the bisamide insecticides of formula (I).

The synthesis method is repeated three times, and the average value is taken, so that the yield of the bisamide insecticide is 97.5%.

And respectively carrying out nuclear magnetic resonance, LC-MS and infrared spectrum detection on the obtained bisamide insecticide to verify that the bisamide insecticide with the structural formula shown as the general formula (I), namely the tetrachloro-worm amide.

Comparative example 1

The comparative example uses 1- (3, 5-dichloropyridin-2-yl) -3-bromo-1H-pyrazole-5-carboxylic acid and 2-amino-3, 5-dichlorobenzoic acid as main raw materials, and methanesulfonyl chloride as an oxidant and a condensing agent to synthesize tetrachloro-worm-amide, and the specific reaction formula is as follows:

the synthesis method comprises the following specific steps:

adding methylsulfonyl chloride (1.1g,9.8mmol) and acetonitrile 20mL into a three-necked flask, dropwise adding acetonitrile solution of 1- (3, 5-dichloropyridin-2-yl) -3-bromo-1H-pyrazole-5-carboxylic acid (3.0g,8.9mmol) and triethylamine (0.9g,8.9mmol) at room temperature for 30mL, reacting for 1H after 10min, adding 2-amino-3, 5-dichlorobenzoic acid (1.6g,8.9mmol) into the reaction system, stirring for 30min, dropwise adding acetonitrile solution of triethylamine (1.8g,17mmol) for 10mL, stirring for 1H, adding acetonitrile solution of methylsulfonyl chloride (1.1g,9.8mmol) for 10mL, reacting for 1H, further dropwise adding acetonitrile solution of triethylamine (0.9g,8.9mmol) for 4mL, then, the reaction mixture was reacted overnight at room temperature, the reaction mixture was poured into 100mL of water, extracted with 2 × 100mL of ethyl acetate, the organic layer was washed with a saturated sodium carbonate solution and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated, and the residue was purified by column chromatography (eluent: ethyl acetate: petroleum ether ═ 1:2) to give 2- (3-bromo-1- (3, 5-dichloropyridin-2-yl) -1H-5-pyrazolyl) -6-chloro-8-methyl-4H-benzo [ d ] [1,3] oxazin-4-one as a yellow solid.

The tetrachloro-zooxamide is prepared by the ring opening of 2- (3-bromo-1- (3, 5-dichloropyridin-2-yl) -1H-5-pyrazolyl) -6-chloro-8-methyl-4H-benzo [ d ] [1,3] oxazin-4-one through methylamine water solution, and the reaction equation is as follows:

sequentially adding 2- (3-bromo-1- (3, 5-dichloropyridin-2-yl) -1H-5-pyrazolyl) -6-chloro-8-methyl-4H-benzo [ d ] [1,3] oxazine-4-one (0.3g,0.6mmol) and 4mL of tetrahydrofuran into a three-necked bottle, stirring to dissolve, dropwise adding methylamine (0.09g,0.9mmol, 30%) at room temperature, reacting for 30min, completely reacting, adding ethyl acetate, performing liquid-liquid extraction, sequentially washing an organic layer with anhydrous saturated saline solution, drying magnesium sulfate, and evaporating the solvent under reduced pressure to obtain 0.14g of a white solid compound, wherein the yield is as follows: and 43 percent.

The method takes pyrazole carboxylic acid compounds as raw materials to prepare the benzoxazinone intermediate, and then the benzoxazinone intermediate reacts with methylamine to obtain the tetrachloro-zoon amide.

Comparative example 2

Compared with the example 1, the comparison adopts thionyl chloride as an oxidizing agent and a condensing agent to replace methanesulfonyl chloride in the example 1, so that the tetrachloro-worm amide with the yield of 88% can be synthesized, but a large amount of hydrochloric acid gas is generated in the reaction process, and the corrosion to reaction equipment is serious.

Although the invention has been described in detail above with reference to a general description and specific examples, it will be apparent to one skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.