Process for the preparation of an intermediate in the synthesis of indoxacarb

Abstract

This invention relates to the field of agricultural chemicals, particularly to the insecticide indoxacarb, and specifically to a method for preparing the synthetic intermediate of indoxacarb. The method involves constructing an α,β-unsaturated carbonyl compound using the Knoevenagel reaction, followed by further reduction to obtain the target compound. Compared to the nucleophilic substitution reaction conditions in the original literature, this method offers milder conditions and greater solvent selectivity, making it suitable for large-scale industrial production of acyl halide derivatives. This method is not only simple and efficient, but also boasts high yield and high purity, allowing the target compound to be obtained through simple purification steps.

Description

Technical Field

[0001] This invention relates to the field of agricultural chemicals, and in particular to the insecticide indoxacarb, specifically to a method for preparing an intermediate indoxacarb synthesis. Background Technology

[0002] Indoxacarb is a broad-spectrum diazinon insecticide that works by blocking sodium ion channels in insect nerve cells, causing the nerve cells to lose their function. It has contact and stomach poison effects and can effectively control a variety of pests on crops such as grains, cotton, fruits, and vegetables.

[0003] The key to synthesizing indoxacarb is constructing the hydroxymethoxycarbonyl indanone intermediate. A novel acyl halide derivative (Formula I) is disclosed in CN1583712A.

[0004] In the formula, X and Y may be the same or different, representing halogen atoms, and R represents a lower alkyl group.

[0005] The document further discloses a method for synthesizing indoxacarb by reacting a benzyl halide derivative with dimethyl malonate in the presence of a base to obtain a dimethyl malonate derivative, hydrolyzing the derivative to obtain a monomethyl malonate derivative, then reacting it with a halogenating agent to obtain an acyl halide derivative, and then further cyclizing the acyl halide derivative with a catalyst to obtain the indoxacarb intermediate compound indanone carboxylic acid ester, thus providing a new route for synthesizing indoxacarb in the prior art.

[0006] According to the published literature, this method is safer and more efficient than the traditional method for synthesizing indoxacarb.

[0007] However, we found that this synthetic route is a nucleophilic substitution SN2 reaction, which requires the participation of a strong nucleophile and a polar aprotic solvent. The requirements for reaction conditions are quite stringent, which limits its application in large-scale industrial production. Summary of the Invention

[0008] The present invention aims to provide a novel method for synthesizing acyl halide derivatives of Formula I.

[0009] To achieve this objective, this invention discloses a method for preparing an indoxacarb synthetic intermediate, wherein the indoxacarb synthetic intermediate refers to the acyl halide derivative shown in Formula I, i.e., compound 7, when X=Y=Cl, and its structural formula is as follows:

[0010] The synthesis steps are as follows: (1) Compound 1 and compound 2 react in the presence of a base and a protic acid / Lewis acid to form compound 3; (2) Compound 3 is converted into compound 4; (3) Compound 4 further reacts with a halogenating agent to form compound 7; in: Compound 1 is ; Compound 2 is or ; When compound 2 is When, compound 3 is

[0011] When compound 2 is When, compound 3 is ; Compound 4 is .

[0012] The aforementioned base is a weak base. In some specific technical solutions, the aforementioned base is arbitrarily selected from one of pyridine, amine, piperidine, pyrrolidine, quinoline, and DBU.

[0013] In some specific technical solutions, the aforementioned protic acid is arbitrarily selected from acetic acid, hydrochloric acid, and sulfuric acid.

[0014] In some specific technical solutions, the Lewis acids mentioned above are arbitrarily selected from... One of them.

[0015] The halogenating agent is a chlorinating agent, such as any one of thionyl chloride, oxalyl chloride, phosphorus pentachloride, and phosphorus trichloride.

[0016] Specifically, when compound 3 is At that time, compound 3 further generates compound 4 with the participation of a reducing agent.

[0017] In another technical solution, when compound 3 is hour, a. Reduced to compound 6 under the action of a reducing agent. Then, it is further converted into compound 4 by ring-opening in methanol solution; Alternatively, in methanol solution, the ring is opened to form compound 3, which is then further converted to compound 4 with the participation of a reducing agent.

[0018] The reducing agent mentioned therein is H2 / Pd-C or NaBH4.

[0019] The present invention further discloses a method for preparing compound monomethyl malonate: reacting malonic acid in methanol solvent in the presence of an acidic catalyst to obtain compound 2. .

[0020] The acidic catalyst is arbitrarily selected from concentrated sulfuric acid, p-toluenesulfonic acid, or dry HCl gas.

[0021] Meanwhile, in another technical solution, Michaelis acid is converted into compound 2 in methanol solvent. .

[0022] Further, step (1) specifically involves: mixing m-chlorobenzaldehyde, monomethyl malonate, and the reaction solvent until completely dissolved, then adding the base and protic acid sequentially, and heating to reflux temperature for reaction. After the reaction is complete, cooling to room temperature, pouring the solution into ice water, adding hydrochloric acid to adjust the pH to acidic, filtering, and obtaining white crystals, which is the product (E)-3-(3-chlorophenyl)-2-(methoxycarbonyl)acrylic acid.

[0023] Further, step (1) specifically involves: mixing m-chlorobenzaldehyde, monomethyl malonate, Lewis acid, and reaction solvent until completely dissolved, then adding alkali sequentially, and reacting at room temperature. After the reaction is complete, hydrochloric acid is added to adjust the pH to acidic, the mixture is separated, the aqueous phase is extracted with ethyl acetate, the organic phase is collected, dried, and the product (E)-3-(3-chlorophenyl)-2-(methoxycarbonyl)acrylic acid is obtained.

[0024] This invention departs from the conventional synthetic approach of nucleophilic substitution in existing technologies. It employs the Knoevenagel reaction to construct α,β-unsaturated carbonyl compounds, followed by further reduction to obtain the target compound. Compared to existing nucleophilic substitution reactions, this method offers milder reaction conditions and greater solvent selectivity, making it suitable for large-scale industrial production of acyl halide derivatives. This method is not only simple and efficient but also boasts high yields and high purity, allowing the target compound to be obtained through simple purification steps. Detailed Implementation

[0025] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that the following specific embodiments are for illustrative purposes only and are not intended to limit the scope of the invention, nor should they be construed as limiting the scope of the invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.

[0026] Example 1 Synthesis of (E)-3-(3-chlorophenyl)-2-(methoxycarbonyl)acrylic acid

[0027]

[0028] Add m-chlorobenzaldehyde (5.0 g), monomethyl malonate (4.2 g), and anhydrous ethanol (50 mL) to a dry flask and stir until completely dissolved. Then add piperidine (0.5 mL) and glacial acetic acid (1 drop) sequentially. The mixture becomes a pale yellow transparent liquid. Heat to 80 °C and reflux for 4–6 h. After the reaction is complete, cool to room temperature and pour the solution into 100 mL of ice water. A white solid appears. Add an appropriate amount of hydrochloric acid to adjust the pH to acidic. Filter and wash three times with cold water to obtain white crystals. Dry to obtain the final product with a yield of 82%.

[0029] Example 2 Synthesis of (E)-3-(3-chlorophenyl)-2-(methoxycarbonyl)acrylic acid

[0030] Add m-chlorobenzaldehyde (5.0 g), monomethyl malonate (4.2 g), anhydrous ZnCl2 (0.49 g), and anhydrous toluene (100 mL) to a dry flask, and stir until completely dissolved. Slowly add DBU (1.08 g), and stir the reaction at room temperature for 4-6 hours. After the reaction is complete, add hydrochloric acid (50 mL) to adjust the pH to acidic. Separate the mixture, extract the aqueous phase three times with ethyl acetate, combine the organic phases, dry with anhydrous ammonium sulfate, and concentrate under reduced pressure to obtain the product in 80% yield.

[0031] Example 3 Synthesis of 3-(3'-chlorophenyl)-2-methoxycarbonylpropionic acid

[0032]

[0033] (E)-3-(3-chlorophenyl)-2-(methoxycarbonyl)acrylic acid (6.8 g) and anhydrous methanol (100 mL) were added to a clean flask and stirred until completely dissolved. Then, 10% Pd / C (0.68 g) was added, the mixture was purged with nitrogen three times, and then purged with hydrogen at 0.5 MPa. The mixture was stirred at room temperature for 4–6 h. After the reaction was complete, the Pd / C catalyst was removed by vacuum filtration through a diatomaceous earth mat, the solvent was removed by rotary evaporation, and the product was dried to obtain a yield of 89%.

[0034] Example 4 Synthesis of 3-(3'-chlorophenyl)-2-methoxycarbonylpropionic acid

[0035] Add (E)-3-(3-chlorophenyl)-2-(methoxycarbonyl)acrylic acid (6.8 g) and anhydrous methanol (10 mL) to a round-bottom flask and stir until completely dissolved. Add nickel chloride (0.35 g). Maintain the temperature at 0-5°C in an ice bath. Add NaBH4 (1.1 g) in three batches, with a 5-minute interval between each batch, stirring in the ice bath for 30 minutes. After the addition is complete, continue stirring at room temperature for 2 hours. After the reaction is complete, pour the solution into ice water (50 mL), add hydrochloric acid to adjust the pH to acidic, extract three times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, and rotary evaporate to obtain the product, with a yield of 83%.

[0036] Example 5 Synthesis of methyl 2-chloroformyl-3-(3'-chlorophenyl)-propionate

[0037]

[0038] 6.1 g of 3-(3'-chlorophenyl)-2-methoxycarbonylpropionic acid and 60 mL of anhydrous DCM were added to a dry round-bottom flask and stirred until completely dissolved. 6.2 mL of thionyl chloride was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. The mixture was then refluxed at 40 °C for 3 h. After the reaction was complete, the solution was poured into ice water (50 mL), stirred thoroughly, and saturated sodium bicarbonate was slowly added to adjust the pH to 7-8. The aqueous phase was extracted with DCM, the organic phases were combined, dehydrated with anhydrous sodium sulfate, filtered, and dried to obtain the product with a yield of 92%. Example 6 Synthesis of 5-(3-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0039] Add Michaelis-Menten acid (10.0 g) and ethanol (100 mL) sequentially to a dry flask, stirring until completely dissolved. Then add m-chlorobenzaldehyde (9.75 g), piperidine (0.6 mL), and glacial acetic acid (1.0 mL) sequentially, and stir at room temperature for 2–4 h. Cool the mixture in an ice bath for 30 min to remove impurities, filter, wash the solid with cold ethanol, and dry to obtain the product, with a yield of 85%.

[0040]

[0041] Example 7 Synthesis of 5-(3-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0042] In a dry flask, Michaelis acid (10.0 g), anhydrous ethanol (80 mL), m-chlorobenzaldehyde (9.75 g), anhydrous ZnCl2 (0.95 g), and piperidine (0.6 mL) were added sequentially. The mixture was stirred until the solid was completely dissolved, and the temperature was raised to 80 °C. The mixture was stirred for 4 h. After the reaction was complete, the mixture was cooled to room temperature, and a yellow solid precipitated. The solid was then placed in an ice bath for 1 h, filtered, washed with cold anhydrous ethanol, and dried to give the product, with a yield of 82%.

[0043] Example 8 Synthesis of methyl 2-chloroformyl-3-(3'-chlorophenyl)-propionate

[0044] Preparation of step (A) (E)-3-(3-chlorophenyl)-2-(methoxycarbonyl)acrylic acid

[0045] In a dry reaction flask, 14.8 g of 5-(3-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione and 150 mL of methanol were added and stirred until basically dissolved. Concentrated sulfuric acid (1.5 mL) was slowly added dropwise, with the addition temperature controlled below 30°C. After the addition was complete, the temperature was raised to 65-70°C, and the reaction was stirred for 4-6 hours. After the reaction was complete, the mixture was cooled to room temperature, and most of the methanol was recovered by rotary evaporation. The remaining liquid was poured into ice water, precipitating a white solid. The pH was adjusted to weakly acidic with saturated sodium bicarbonate, filtered, washed twice with cold water, and dried to obtain the product, with a yield of 91%.

[0046] Step (B) Preparation of 3-(3'-chlorophenyl)-2-methoxycarbonylpropionic acid

[0047] (E)-3-(3-chlorophenyl)-2-(methoxycarbonyl)acrylic acid (10.5 g) and methanol (100 mL) were added to a dry reaction flask and stirred until completely dissolved. Then, 10% Pd / C (1.05 g) was added, the mixture was purged with nitrogen three times, and then purged with hydrogen at 0.5 MPa. The reaction was stirred at room temperature for 4–6 h. After the reaction was complete, Pd / C was removed by filtration with diatomaceous earth, the catalyst was washed with methanol, and the product was obtained by rotary evaporation with a yield of 92%.

[0048] Step (C) Preparation of methyl 2-chloroformyl-3-(3'-chlorophenyl)-propionate

[0049] In a dry round-bottom flask, 9.5 g of 3-(3'-chlorophenyl)-2-methoxycarbonylpropionic acid and 100 mL of anhydrous DCM were added and stirred until completely dissolved. Two drops of DMF were added, and the mixture was cooled to 0-5°C in an ice bath. Oxaloyl chloride (5.1 mL) was slowly added dropwise, with the temperature controlled below 10°C. After the addition was complete, the mixture was stirred at room temperature for 2-3 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The remaining liquid was washed with anhydrous n-hexane, and the product was obtained by rotary evaporation with a yield of 93%.

[0050] Example 9 Synthesis of methyl 2-chloroformyl-3-(3'-chlorophenyl)-propionate

[0051] Step (A) Preparation of 5-(3-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0052] 14.8 g of 5-(3-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione and 150 mL of methanol were added to a clean reaction flask, followed by 1.5 g of 10% Pd / C. The mixture was purged with nitrogen three times, and hydrogen was introduced at 0.5 MPa. The mixture was stirred at room temperature for 3–6 h. After the reaction was complete, Pd / C was removed by filtration with diatomaceous earth, the catalyst was washed with methanol, and the product was obtained by rotary evaporation with a yield of 93%.

[0053] Step (B) Preparation of 3-(3'-chlorophenyl)-2-methoxycarbonylpropionic acid

[0054] In a clean reaction flask, 13.5 g of 5-(3-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione and 100 mL of methanol were added and stirred until completely dissolved. The mixture was cooled to 0°C in an ice bath, and 20 mL of concentrated hydrochloric acid was slowly added dropwise, keeping the temperature below 10°C. After the addition was complete, the mixture was heated to 60°C and refluxed for 4–6 h. After the reaction was complete, the solvent was removed by rotary evaporation. The remaining liquid was dissolved in ethyl acetate, neutralized with saturated sodium bicarbonate, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and then rotary evaporated to obtain the product with a yield of 90%.

[0055] Step (C) Preparation of methyl 2-chloroformyl-3-(3'-chlorophenyl)-propionate

[0056] 11.0 g of 3-(3'-chlorophenyl)-2-methoxycarbonylpropionic acid and 100 mL of anhydrous DCM were added to a dry flask and stirred until completely dissolved. The mixture was cooled to 0°C in an ice bath, and 10.4 mL of thionyl chloride was slowly added dropwise while maintaining the temperature below 5°C. Two drops of DMF were then added, and the mixture was stirred at room temperature for 2–3 h after the addition was complete. After the reaction was complete, the solvent was removed by rotary evaporation. The remaining liquid was dissolved in 50 mL of ice-cold diethyl ether and slowly poured into saturated sodium bicarbonate in an ice bath. The mixture was separated, and the organic phase was dehydrated with anhydrous sodium sulfate. After filtration, the product was obtained by rotary evaporation with a yield of 94%.

[0057] It should be noted that the above are merely preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. For those skilled in the art, several improvements and modifications can be made on the basis of the above embodiments without departing from the principle of the present invention, and all such improvements and modifications fall within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing an intermediate for the synthesis of indoxacarb, wherein the intermediate for the synthesis of indoxacarb refers to the acyl halide derivative shown in Formula I, i.e., compound 7, when X=Y=Cl, and its structural formula is as follows: , Its characteristics are, The synthesis steps are as follows: (1) Compound 1 and compound 2 react in the presence of a base and a protic acid / Lewis acid to form compound 3; (2) Compound 3 is converted into compound 4; (3) Compound 4 further reacts with a halogenating agent to form compound 7; in: Compound 1 is ; Compound 2 is or ; When compound 2 is When, compound 3 is ; When compound 2 is When, compound 3 is ; Compound 4 is .

2. The method for preparing the indoxacarb synthetic intermediate according to claim 1, characterized in that: The base is a weak base, which is arbitrarily selected from pyridine, amine, piperidine, pyrrolidine, quinoline, and DBU.

3. The method for preparing the indoxacarb synthetic intermediate according to claim 1, characterized in that: The protic acid is arbitrarily selected from acetic acid, hydrochloric acid, and sulfuric acid.

4. The method for preparing the indoxacarb synthetic intermediate according to claim 1, characterized in that: The Lewis acid is arbitrarily selected from... One of them.

5. The method for preparing the indoxacarb synthetic intermediate according to claim 1, characterized in that: The halogenating agent is a chlorinating agent, such as any one of thionyl chloride, oxalyl chloride, phosphorus pentachloride, and phosphorus trichloride.

6. The method for preparing the indoxacarb synthetic intermediate according to claim 1, characterized in that: When compound 3 is Then, compound 3 further generates compound 4 with the participation of a reducing agent; a. Reduced to compound 6 under the action of a reducing agent. Then, it is further converted into compound 4 by ring-opening in methanol solution; Alternatively, in methanol solution, the ring is opened to form compound 3, which is then further converted to compound 4 with the participation of a reducing agent.

7. The method for preparing the indoxacarb synthetic intermediate according to claim 6, characterized in that: The reducing agent is H2 / Pd-C or NaBH4.

8. The method for preparing the indoxacarb synthetic intermediate according to claim 1, characterized in that, Preparation method of compound monomethyl malonate: Malonic acid is reacted in methanol solvent in the presence of an acidic catalyst to obtain compound 2. The acidic catalyst is arbitrarily selected from concentrated sulfuric acid, p-toluenesulfonic acid, or dry HCl gas.

9. The method for preparing the indoxacarb synthetic intermediate according to claim 1, characterized in that: Michaelis acid is converted to compound 2 in methanol solvent. .

10. The method for preparing the indoxacarb synthetic intermediate according to claim 1, characterized in that: Step (1) specifically involves mixing m-chlorobenzaldehyde, monomethyl malonate, and the reaction solvent until completely dissolved. Then, alkali and protic acid are added sequentially, and the mixture is heated to reflux temperature. After the reaction is complete, the mixture is cooled to room temperature, poured into ice water, and hydrochloric acid is added to adjust the pH to acidic. The mixture is then filtered to obtain white crystals, which are the product (E)-3-(3-chlorophenyl)-2-(methoxycarbonyl)acrylic acid. Alternatively, step (1) can be specifically described as follows: m-chlorobenzaldehyde, monomethyl malonate, Lewis acid, and reaction solvent are mixed until completely dissolved, and then alkali is added sequentially. The reaction is carried out at room temperature. After the reaction is complete, hydrochloric acid is added to adjust the pH to acidic. The mixture is separated, the aqueous phase is extracted with ethyl acetate, the organic phase is collected, dried, and the product (E)-3-(3-chlorophenyl)-2-(methoxycarbonyl)acrylic acid is obtained.

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