One-pot process for the preparation of 5-chloro-7-methylisatin

Abstract

The application provides a one-pot preparation method of 5-chloro-7-methyl isatin, and is characterized by comprising the following steps: adding solid acid and o-toluidine into a solvent in sequence, and adding oxalyl chloride drop by drop in a stirring process to obtain 2-oxo-2-(2-methylphenyl)amino acyl chloride; the solid acid is a H2SO4-SiO2 porous material prepared by sol-gel method from tetraethyl orthosilicate; the above reaction solution is cooled, anhydrous aluminum chloride is added, and stirring is performed to obtain 7-methyl isatin; chlorine gas is continuously introduced, the solid acid is recovered after filtration after the reaction is completed, water is added for quenching, filtration and drying are performed to obtain 5-chloro-7-methyl isatin. The one-pot preparation method reduces the process steps, is simple to operate and easy to realize, has simple post-treatment, the product can be directly obtained after the whole step is completed, there is no high environmental control requirement in the synthesis step, the amount of oxalyl chloride is reduced, the cost is reduced, the improved solvent selection increases the fluidity, the safety risk is reduced, and the needs of industrial production can be realized.

Description

Technical Field

[0001] The present invention relates to the technical field of pesticide preparation, in particular to a method for preparing 5-chloro-7-methylisatin. Background Art

[0002] Chlorantraniliprole, developed by DuPont and launched in 2007, achieved global sales of $580 million in 2011. Chlorantraniliprole has now obtained all necessary pesticide registration and sales certificates, enabling widespread application. Chlorantraniliprole's chemical structure exhibits a novel insecticidal mechanism, unique to other insecticides. It effectively activates insect ryanodine (muscle) receptors. Excessive release of calcium ions from intracellular calcium stores paralyzes and kills insects. It is highly active against lepidopteran larvae, possesses a broad spectrum of insecticides, and exhibits long-lasting efficacy. According to current test results, chlorantraniliprole is 10-100 times more active against target pests than other products and can disrupt mating in some lepidopteran insects. Studies have shown that it can reduce the egg-laying rate of various noctuid pests. This is due to its long-lasting efficacy and resistance to rainwater erosion—properties that are a combination of its permeability, conductivity, chemical stability, high insecticidal activity, and its ability to immediately stop feeding in pests. This ensures that it provides longer-lasting and more stable crop protection than most other currently used insecticides. Currently registered for control of major rice pests, it rapidly protects rice growth and is particularly effective against pests resistant to other rice insecticides, such as the rice leaf roller, the striped stem borer, the yellow stem borer, and the rice borer. It also offers excellent control effects against the rice gall midge, the rice weevil, and the rice water weevil. This pesticide is mildly toxic, making it very safe for applicators and beneficial insects, fish, and shrimp in rice fields. It has a long-lasting effect of over 15 days, leaves no residue on agricultural products, and mixes well with other pesticides.

[0003] 5-Chloro-7-methylisatin is an important intermediate in the synthesis of chlorantraniliprole. The current synthetic routes are:

[0004] 1. o-Toluidine is condensed with chloral hydrate and hydroxylamine hydrochloride to form an oxime. The oxime undergoes cyclization in the presence of concentrated sulfuric acid to produce inatin, which is then chlorinated with NCS to produce 5-chloro-7-methylisatin. This route has low yields, high costs, and generates large amounts of waste, waste gas, and wastewater, posing significant environmental challenges.

[0005] 2. Ortho-toluidine is neutralized with hydrochloric acid to form the hydrochloride. The o-toluidine hydrochloride is then cyclized with oxalyl chloride in nitrobenzene using aluminum chloride as a catalyst to produce isatin. The isatin is then chlorinated with NCS to produce 5-chloro-7-methylisatin. While this route offers acceptable yields, the high cost of oxalyl chloride is due to the high amount of oxalyl chloride used. Furthermore, quenching with nitrobenzene results in a viscous solution that is difficult to filter and poses safety risks.

[0006] Therefore, it is of great significance to study a simple and practical method for synthesizing 5-chloro-7-methylisatin with high economic efficiency and low environmental pollution. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a one-pot preparation method of 5-chloro-7-methylisatin in view of the problems that the current synthesis of 5-chloro-7-methylisatin has complex operation, high production cost, low yield, serious three wastes, etc.

[0008] The present invention is achieved by adopting the following technical solutions:

[0009] A one-pot preparation method of 5-chloro-7-methylisatin comprises the following steps:

[0010] S1, adding a solid acid and o-toluidine in sequence to a solvent, and adding oxalyl chloride dropwise during stirring to obtain 2-oxo-2-(2-methylphenyl)aminoacetyl chloride, wherein the solid acid is an H2SO4-SiO2 porous material prepared from ethyl orthosilicate by a sol-gel method;

[0011] S2, cooling the reaction solution, adding anhydrous aluminum chloride, and stirring to close the ring to obtain 7-methylisatin;

[0012] S3, continue to pass chlorine gas, after the reaction is completed, filter and recover the solid acid, add water to quench, filter and dry to obtain 5-chloro-7-methylisatin.

[0013] The reaction process of each step is as follows:

[0014]

[0015]

[0016] The solid acid is prepared by mixing tetraethyl orthosilicate, water, and hydrochloric acid, stirring until a transparent silica sol is formed. An appropriate amount of sulfuric acid is then added and stirred until a gel forms. After aging for 2 hours, the mixture is dried in an oven at 95-105°C for 1-3 hours to obtain the solid acid. Preferably, the tetraethyl orthosilicate, water, and hydrochloric acid are mixed in a molar ratio of 1:6-10:0.05-0.2, more preferably 1:7-9:0.08-0.12, and most preferably 1:8:0.1. The amount of sulfuric acid added is preferably 1.5 times the amount of tetraethyl orthosilicate.

[0017] The solvent can be selected from inert solvents such as dichlorobenzene, 1,2,4-trichlorobenzene, nitrobenzene, carbon disulfide, etc., preferably dichlorobenzene.

[0018] The reaction temperature for dropwise addition of oxalyl chloride in step S1 is 0-50°C, preferably 30-40°C.

[0019] Preferably, the amount of oxalyl chloride used is 1.0 to 3.0 times the molar amount of o-toluidine used.

[0020] Preferably, the amount of anhydrous aluminum chloride used is 1.0 to 3.0 times the molar amount of o-toluidine used.

[0021] Preferably, the amount of chlorine used is 1.0 to 3.0 times the molar amount of o-toluidine used.

[0022] The chlorination reaction temperature in step S3 is 0-50°C, preferably 30-40°C.

[0023] The invention uses o-toluidine, oxalyl chloride and chlorine as raw materials to obtain 5-chloro-7-methylisatin in a one-pot method. By adding solid acid in the reaction system, reaction impurities are reduced, the yield is high, the solid acid is easy to be recycled and used, and the cost is low.

[0024] The invention reduces process steps through one-pot preparation, is simple and easy to operate, has simple post-processing, and can directly obtain the product after the entire step is completed. There is no high environmental control requirement in the synthesis step, and the amount of oxalyl chloride used is reduced, which reduces the cost. The improved solvent selection increases the fluidity and reduces the safety risk, which is conducive to meeting the needs of industrial production. DETAILED DESCRIPTION

[0025] The following description is intended to disclose the present invention so that those skilled in the art can implement the present invention. The preferred embodiments described below are provided for illustrative purposes only and are not intended to limit the scope of the present invention. Those skilled in the art will readily appreciate other obvious variations. The basic principles of the present invention defined in the following description may be applied to other embodiments, variations, improvements, equivalents, and other technical solutions that do not depart from the spirit and scope of the present invention.

[0026] The instruments or raw materials in the present invention that do not indicate the manufacturer are all conventional commercial instruments or raw materials. If the detection indicators involved in the embodiments of the present invention are not mentioned, they are all detected using conventional detection methods in the field.

[0027] The solid acid was prepared by the following method:

[0028] Ethyl orthosilicate, deionized water, and 0.04 M HCl were added to a beaker in a molar ratio of 1:8:0.1 and stirred at room temperature until a transparent silica sol was formed. Then, 1.5 molar equivalents of V(H2SO4):V(H2O)=1:1 were added to the silica sol solution and stirred until a gel was formed. After aging for 2 h, the mixture was dried in an oven at 373 K for 2 h to obtain a solid acid.

[0029] Example 1

[0030] To a 500mL four-necked flask, 326.42g of dichlorobenzene, 54.10g of o-toluidine, and 50g of a homemade solid acid were added; then 97.14g of oxalyl chloride was added dropwise at 40°C and stirred at this temperature for 2 hours. The reaction system was cooled to 30°C and 101.02g of anhydrous aluminum chloride was added. After the addition was complete, the mixture was stirred at this temperature for 4 hours. 3eq of chlorine gas was passed through the reaction system and the temperature was maintained for 6 hours. The solid acid was recovered by filtration, quenched with water, and filtered and dried to yield 86.15g of 5-chloro-7-methylisatin with a mass content of 98.1% and a yield of 86.5%.

[0031] Example 2

[0032] To a 500mL four-necked flask, add 244.18g of dichlorobenzene, 54.10g of o-toluidine, and 50g of a homemade solid acid. Then, add 77.71g of oxalyl chloride dropwise at 30°C and stir at that temperature for 2 hours. Add 80.81g of anhydrous aluminum chloride, and stir for 4 hours. Then, pass 2eq of chlorine gas through the reaction system and keep it warm for 6 hours. The solid acid is recovered by filtration, quenched with water, and filtered and dried to yield 83.26g of 5-chloro-7-methylisatin with a mass content of 98.5% and a yield of 83.9%.

[0033] Example 3

[0034] To a 500mL four-necked flask, 326.42g of dichlorobenzene, 54.10g of o-toluidine, and 50g of a homemade solid acid were added; then 181.33g of oxalyl chloride was added dropwise at 40°C and stirred at this temperature for 2 hours. The reaction system was cooled to 30°C and 188.56g of anhydrous aluminum chloride was added. After the addition was complete, the mixture was stirred at this temperature for 4 hours. 2.8q of chlorine gas was passed through the reaction system and the temperature was maintained for 6 hours. The solid acid was recovered by filtration, quenched with water, and filtered and dried to yield 86.84g of 5-chloro-7-methylisatin with a mass content of 98.4% and a yield of 87.4%.

[0035] Example 4

[0036] To a 500mL four-necked flask, add 244.18g of nitrobenzene, 54.10g of o-toluidine, and 50g of a homemade solid acid. Then, add 77.71g of oxalyl chloride dropwise at 30°C and stir at that temperature for 2 hours. Add 80.81g of anhydrous aluminum chloride. After addition, stir at this temperature for 4 hours. Pass 2eq of chlorine gas through the reaction system and keep it warm for 6 hours. Filter and recover the solid acid, quench with water, and filter and dry to yield 80.43g of 5-chloro-7-methylisatin with a mass content of 96.3% and a yield of 79.2%.

[0037] Comparative Example

[0038] To a 500mL four-necked flask, add 326.42g of dichlorobenzene, 54.10g of o-toluidine, and pass 36.87g of hydrochloric acid gas. Then, add 97.14g of oxalyl chloride dropwise at 40°C and stir at this temperature for 2h. The reaction system is cooled to 30°C, and 101.02g of anhydrous aluminum chloride is added. After the addition is complete, stir at this temperature for 4h. Then, pass 3eq of chlorine gas through the reaction system, keep the temperature for 6h, quench with water, and filter and dry to obtain 67.41g of 5-chloro-7-methylisatin with a mass content of 94.6% and a yield of 65.2%.

[0039] This comparative example uses hydrochloric acid instead of solid acid, with all other conditions being the same as in Example 1. It can be seen that the use of solid acid unexpectedly significantly improves yield. The mechanism for this is not entirely clear, but it may be due to the unique porous structure of the solid acid used in the present invention providing a more suitable reaction environment and reducing the occurrence of side reactions.

[0040] Those skilled in the art will appreciate that the above embodiments are intended to be illustrative only and are not intended to limit the present invention. The objectives of the present invention have been fully and effectively achieved. The functions and principles of the present invention have been demonstrated and illustrated in the embodiments. Any variations or modifications may be made to the embodiments of the present invention without departing from the principles described.

Claims

1. A one-pot preparation method of 5-chloro-7-methylisatin, characterized in that: The steps include: S1, adding a solid acid and o-toluidine to a solvent in sequence, and adding oxalyl chloride dropwise during stirring to obtain 2-oxo-2-(2-methylphenyl)aminoacetyl chloride, wherein the solid acid is an H2SO4-SiO2 porous material prepared from ethyl orthosilicate by a sol-gel method, specifically prepared by the following method: ethyl orthosilicate, water, and hydrochloric acid are mixed and stirred to form a transparent silica sol, and then an appropriate amount of sulfuric acid is added and stirred until a gel is formed. After aging for 2 hours, the solid acid is dried in an oven at 95-105°C for 1-3 hours to obtain the solid acid; S2, cooling the reaction solution, adding anhydrous aluminum chloride, and stirring to close the ring to obtain 7-methylisatin; S3, continue to pass chlorine gas, after the reaction is completed, filter and recover the solid acid, add water to quench, filter and dry to obtain 5-chloro-7-methylisatin.

2. The method according to claim 1, wherein Ethyl orthosilicate, water and hydrochloric acid are mixed in a molar ratio of 1:6-10:0.05-0.

2.

3. The method according to claim 1, wherein The solvent is selected from one of dichlorobenzene, 1,2,4-trichlorobenzene, nitrobenzene and carbon disulfide.

4. The method according to claim 1, wherein The solvent is dichlorobenzene.

5. The method according to claim 1, wherein The reaction temperature for dropwise addition of oxalyl chloride in step S1 is 0-50°C.

6. The method according to claim 1, wherein The amount of oxalyl chloride used is 1.0 to 3.0 times the molar amount of o-toluidine used.

7. The method according to claim 1, wherein The amount of anhydrous aluminum chloride used is 1.0 to 3.0 times the molar amount of o-toluidine.

8. The method according to claim 1, wherein The amount of chlorine used is 1.0 to 3.0 times the molar amount of o-toluidine.

9. The method according to claim 1, wherein The chlorination reaction temperature in step S3 is 0-50°C.

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