A process for the synthesis of 2-amino-3-methyl-5-substituted benzoic acids

Abstract

This invention relates to a method for synthesizing 2-amino-3-methyl-5-substituted benzoic acid. Compound IV is protected with an amino group to synthesize compound III, followed by oxidation to synthesize compound II, and then the protecting group is removed to obtain compound I. This invention can shorten the reaction steps, improve product selectivity, reduce operational difficulty, and achieve safe and environmentally friendly industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for synthesizing 2-amino-3-methyl-5-substituted benzoic acid. Background Technology

[0002] The core intermediate of the insecticides chlorantraniliprole and bromocyanamide is K-amine. The main synthetic route uses m-xylene as a raw material and involves five reaction steps: catalytic oxidation, nitration, catalytic hydrogenation, chlorination, and amidation. Among these, the nitration and hydrogenation reduction reactions in the preparation of the intermediate 3-methyl-2-aminobenzoic acid are highly hazardous, and the nitration reaction has side reactions, requiring sophisticated equipment, generating a large amount of waste, and presenting significant challenges in post-treatment.

[0003] Patent application CN119431187A uses o-methylaniline to acylate aniline substrate via Boc anhydride, followed by ortho-lithiation of n-butyllithium with carbon dioxide gas, and acid hydrolysis to obtain 2-amino-3-methylbenzoic acid. This process requires harsh conditions such as -78°C and an anhydrous environment, resulting in low reaction safety and poor process controllability.

[0004] Patent application CN106458843A uses 1,3-dimethyl-2-nitrobenzene as a raw material to prepare 3-methyl-2-aminobenzoic acid through air oxidation and reduction reactions. This synthetic route is simple and avoids the explosion risk of nitration. However, the conversion rate of the air oxidation reaction is low, and the selectivity of the target product is only 70% at most. The industrial implementation is costly and difficult.

[0005] Therefore, there is an urgent need to develop a new synthetic method for 2-amino-3-methyl-5-substituted benzoic acid that is simple in route, highly selective, and environmentally friendly, in order to meet the rapidly growing demand in the pesticide intermediate market. Summary of the Invention

[0006] The purpose of this invention is to address the shortcomings of existing technologies by providing a method for synthesizing 2-amino-3-methyl-5-substituted benzoic acid, thereby shortening the reaction steps, reducing operational difficulty, improving product selectivity, avoiding the risk of nitration explosion, and achieving safe and environmentally friendly industrial production.

[0007] A method for synthesizing 2-amino-3-methyl-5-substituted benzoic acid, comprising the following steps:

[0008]

[0009] Compound IV is synthesized into compound III through amino protection, then into compound II through oxidation, and finally compound I is obtained by removing the protecting group.

[0010] Where X is selected from hydrogen, fluorine, chlorine, bromine, iodine or cyano; R is an amino protecting group.

[0011] Wherein, R is an acetyl, propionyl, pivaloyl, or tert-butoxycarbonyl protecting group.

[0012] In the process of synthesizing compound (III) from compound (IV) through amino protection,

[0013] The amino-protecting agent used is selected from one or more of acetyl chloride, propionyl chloride, acetic anhydride, propionic anhydride, tert-valerate chloride, and di-tert-butyl dicarbonate.

[0014] The solvent used is selected from one of acetonitrile, acetic acid, methanol, ethanol, ethyl acetate, isopropyl acetate, acetone, butanone, tetrahydrofuran, dioxane, diethyl ether, cyclopentyl methyl ether, DMF, DMAC, DMSO, sulfolane, or any mixture thereof in any ratio.

[0015] The reaction temperature is 0~180℃, preferably 70~100℃.

[0016] The reaction time is 2 to 24 hours, preferably 5 to 12 hours.

[0017] In the process of synthesizing compound (II) from compound (III) by oxidation reaction, the oxidation reaction is carried out in the presence of an oxygen source, an oxidation catalyst and a co-catalyst.

[0018] The oxygen source used is selected from oxygen or air.

[0019] The oxidation catalyst used is selected from one or more of N,N'-dihydroxyphthalimide (hereinafter referred to as NDHPI), N-hydroxyphthalimide (hereinafter referred to as NHPI), N-hydroxytetrachlorophthalimide (hereinafter referred to as TCNHPI), and N,N',N”-trihydroxyisocyanuric acid (hereinafter referred to as THICA).

[0020] The cocatalyst used is selected from manganese, cobalt, and iron-doped nitrogen-doped carbon materials, such as Mn / Co / Fe-BNC, Mn / Co-BNC, Co / Fe-BNC, and Mn / Fe-BNC.

[0021] The solvent used is selected from acetonitrile, acetic acid, propionic acid, methanol, ethanol, ethyl acetate, isopropyl acetate, acetone, butanone, tetrahydrofuran, dioxane, diethyl ether, cyclopentyl methyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, or any mixture thereof in any ratio.

[0022] The oxidation catalyst used is present in a weight ratio of 0.005 to 0.5 relative to the compound of formula (III); preferably 0.01 to 0.3 by weight.

[0023] The co-catalyst used is present in a weight ratio of 0.005 to 0.1 relative to the compound of formula (III); preferably 0.005 to 0.05 by weight.

[0024] The oxygen source used is present in an amount of 1 to 10 equivalents relative to the compound of formula (III); preferably 1 to 3 equivalents.

[0025] The reaction temperature is 0~180℃, preferably 20~80℃.

[0026] The reaction time is 2-24 hours, preferably 3-12 hours.

[0027] In the process of synthesizing compound (I) from compound (II) by removing the protecting group, when the process is carried out in an alkaline environment,

[0028] The alkaline reagent used is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and lithium hydroxide.

[0029] In the process of synthesizing compound (I) from compound (II) by removing the protecting group, when carried out in an acidic environment,

[0030] The acidic reagent used is selected from one of sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, and methanesulfonic acid.

[0031] The solvent used is selected from acetonitrile, acetic acid, propionic acid, methanol, ethanol, ethyl acetate, isopropyl acetate, acetone, butanone, tetrahydrofuran, dioxane, diethyl ether, cyclopentyl methyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, or any mixture thereof in any ratio.

[0032] The reaction temperature is 0~100℃, preferably 10~50℃.

[0033] The reaction time is 1 to 6 hours, preferably 1 to 4 hours.

[0034] Furthermore, the present invention also provides a method for synthesizing the intermediate 2-amino-5-chloro-N,3-dimethylbenzamide, wherein when X is chlorine, it is obtained by esterification of a compound of formula I with methanol.

[0035] Furthermore, the present invention also provides a method for synthesizing the intermediate 2-amino-5-bromo-N,3-dimethylbenzamide, wherein when X is bromine, it is obtained by esterification of a compound of formula I with methanol.

[0036] Furthermore, the present invention also provides a method for synthesizing the intermediate 2-amino-5-cyano-N,3-dimethylbenzamide, wherein when X is bromine, 2-amino-5-bromo-N,3-dimethylbenzamide is obtained by esterification of a compound of formula I with methanol, followed by cyanidation; or when X is cyano, it is obtained by esterification of a compound of formula I with methanol.

[0037] The core working principle of this invention is as follows: With amino protection as a prerequisite, a synergistic catalytic system constructed from N-hydroxyphthalimide and its analogues and transition metal compounds is used to selectively catalyze the oxidation of the substrate to prepare 2-amino-3-methyl-5-substituted benzoic acid. The specific mechanism is as follows:

[0038] 1) Necessity of amino protection: The amino group in the substrate (IV) compound of this invention is modified by a protecting agent to form a stable amide bond or carbamate bond, which can effectively prevent the amino group from being oxidized and destroyed in subsequent oxidation reactions, while not affecting the reactivity of the target methyl group on the benzene ring, thus providing a structural basis for selective oxidation. If amino protection is not performed, the reaction selectivity is not ideal.

[0039] 2) Initiation and propagation of free radical chain reactions: N-hydroxyphthalimide and its analogues, as highly efficient electron carriers in electrochemical oxidation, have weak OH bonds in their molecules, which readily undergo homolytic cleavage under reaction conditions to generate N-oxyphthalimide free radicals (PINO radicals). These free radicals are highly reactive and can specifically abstract the CH bond hydrogen atom from the target methyl group attached to the benzene ring in compounds of formula (III) (amino-protected substrates), causing homolytic cleavage of the substrate to generate carbon free radicals, thereby initiating a continuous free radical chain oxidation reaction, providing the core reaction motive force for the conversion of methyl to carboxyl groups.

[0040] 3) Synergistic effect of transition metal compounds: Transition metals such as Co and Mn have empty d orbitals, possessing both electron-donating and electron-accepting capabilities, and their oxidation state and coordination number can undergo reversible changes. During the reaction, transition metal ions can, on the one hand, transfer electrons with PINO radicals, maintaining the continuous progress of the radical chain reaction; on the other hand, metal ions can form weak coordination with protecting groups or benzene rings in the substrate, regulating the electron cloud density of the substrate molecule through special electronic effects, and simultaneously defining the reaction site through steric effects, thereby significantly improving the selectivity of methyl oxidation and reducing side reactions of benzene rings and other substituents.

[0041] Compared with the prior art, the beneficial technical effects of the present invention are as follows:

[0042] 1. Significantly improved selectivity: This invention creatively introduces an amino protecting group to avoid the destruction of amino groups during the oxidation reaction. At the same time, by synergistically selecting a specific combination of oxidation catalyst and co-catalyst, the selective oxidation rate of methyl can reach more than 93%, which is far higher than the prior art, and the content of by-products is less than 2%.

[0043] 2. Short reaction process: The present invention can obtain the target product through only three steps: amino protection, selective oxidation and deprotection. Compared with the multi-step reaction route of the prior art, the process is significantly shortened and the production efficiency is greatly improved.

[0044] 3. Simple reaction operation: The equipment requirements of this invention are low, the post-processing operation is simple, the explosion risk of nitration reaction is avoided, and the operation is highly safe.

[0045] 4. High industrial feasibility: This invention has a short reaction time, a comprehensive yield of over 88%, cheap and readily available raw materials, and strong process controllability, making it suitable for large-scale industrial production. The production cost is reduced by 30-40% compared to existing technologies. Attached Figure Description

[0046] Figure 1 Example 2: Product NMR spectrum Detailed Implementation

[0047] Example 1 Preparation of co-catalyst

[0048] 0.588 g of Co(NO3)2·6H2O and 0.4 g of MnCl2·4H2O were dissolved in 40 mL of deionized water and reacted with stirring for 15 min to obtain solution A. Solution B was prepared by adding 2 mL (2.627 g) of NaBH4 and 0.234 g of Co(NO3)2·6H2O to 40 mL of deionized water and mixing for 15 min. Solution B was then poured into solution A with stirring, and the reaction was continued for 2 h. When no more bubbles were generated, the reaction was transferred to a sealed reaction system and continued. The resulting product was collected by centrifugation, washed three times with deionized water, and then dried at 70 °C for 12 h. The prepared Mn / Co-ZIF was encapsulated in a tube furnace and heated to 900 °C in a 5% H2 / Ar gas stream at a rate of 5 °C / min for 2 h. Finally, after cooling to room temperature until the reaction stopped, Mn / Co-BNC was obtained.

[0049] Similar to the preparation of co-catalysts: replace the type of metal salt, and keep other process parameters, such as ligand dosage and calcination conditions, the same as above.

[0050] Example 2 Synthesis of 2-amino-3-methyl-5-chlorobenzoic acid

[0051] The specific reaction equation is shown below:

[0052]

[0053] Step A: Add 100 g of 4-chloro-2,6-dimethylaniline to a 500 mL four-necked flask, add 300 g of dichloroethane and 98 g of triethylamine, start stirring, and then slowly add 56 g of acetyl chloride dropwise into the flask. Maintain the temperature at 20-30°C and continue the reaction for 6 hours. When GC detection shows that the starting material has completely disappeared, the reaction is complete. Add 1 kg of n-hexane to the reaction flask. A large amount of solid precipitates in the reaction flask. Continue stirring for 1 hour, filter, and use 2 M hydrochloric acid to slurry the filter cake to remove triethylamine. Then wash with water until no hydrochloric acid residue is left, to obtain 125.1 g of 4-chloro-2,6-dimethylacetaniline, with a yield of 98.5%.

[0054] Step B: 125.1 g of 2,6-dimethylacetanilide was added to the reactor, followed by 15 g of NDHPI, 2.3 g of Mn / Co-BNC catalyst, and 600 g of acetonitrile. The mixture was purged with nitrogen three times and oxygen three times. Stirring was started, and the mixture was kept at 80°C for 10 hours. The reaction was considered complete when GC analysis showed complete disappearance of the starting material. The Mn / Co-BNC catalyst was recovered by filtration, and acetonitrile was removed by rotary evaporation. The mixture was then extracted with water and ethyl acetate. The organic phases were combined and concentrated to obtain 135.3 g of 2-acetamido-3-methylbenzoic acid, with a yield of 93.9%.

[0055] Step C: Add 135.3 g of 2-acetamido-3-methylbenzoic acid to a four-necked flask, add 334 g of methanol, start stirring, and slowly add 97 g of liquid alkali (30%) dropwise into the reaction flask. After the addition is complete, slowly raise the temperature to 50°C and keep the reaction at this temperature for 4 hours. When GC detection shows that the starting material has completely disappeared, the reaction is complete. While stirring, add 1500 g of water to the flask, continue stirring for 1 hour, filter, and dry the filter cake to obtain 104.9 g of 2-amino-3-methylbenzoic acid, with a yield of 95.1%.

[0056] 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 2.5 Hz, 1H), 7.34 (d, J = 2.5Hz, 1H), 2.11 (s, 3H).

[0057] Example 3

[0058]

[0059] Step A: Add 100 g of 4-chloro-2,6-dimethylaniline to a 500 mL four-necked flask, add 318 g of dichloroethane and 97 g of triethylamine, start stirring, and then slowly add 154 g of di-tert-butyl dicarbonate to the flask. Maintain the temperature at 20-30°C and continue the reaction for 6 hours. When GC detection shows that the starting material has completely disappeared, the reaction is complete. Add 1 kg of n-hexane to the reaction flask. A large amount of solid precipitates in the reaction flask. Continue stirring for 1 hour, filter, and use 2 M hydrochloric acid to slurry the filter cake to remove triethylamine. Then wash with water until no hydrochloric acid residue is left, to obtain 157.7 g of [(4-chloro-2,6-dimethylphenyl)amino]methane-2-methylpropyl-2-yl ester, with a yield of 96.0%.

[0060] Step B: 157.7 g of ((4-chloro-2,6-dimethylphenyl)amino)methane-2-methylpropyl-2-yl ester was added to the reactor, followed by 15 g of NDHPI, 3.1 g of Mn / Co-BNC catalyst, and 760 g of acetonitrile. The mixture was purged with nitrogen three times and oxygen three times. Stirring was started, and the mixture was kept at 80°C for 12 hours. The reaction was considered complete when GC analysis showed complete disappearance of the starting material. The Mn / Co-BNC catalyst was recovered by filtration, and acetonitrile was removed by rotary evaporation. The mixture was then extracted with water and ethyl acetate. The organic phases were combined and concentrated to obtain 163.5 g of 5-chloro-3-methyl-2-((((2-methylpropyl-2-yl)oxy)carbonyl)amino)benzoic acid, with a yield of 92.8%.

[0061] Step C: 163.5 g of 5-chloro-3-methyl-2-((((2-methylprop-2-yl)oxy)carbonyl)amino)benzoic acid was added to a four-necked flask, along with 384 g of DCE. Stirring was started, and 243 g of dilute hydrochloric acid (10%) was slowly added dropwise to the reaction flask. After the addition was complete, the temperature was slowly raised to 50°C and the reaction was maintained at this temperature for 4 hours. GC detection showed that the starting material had completely disappeared, indicating the end of the reaction. While stirring, liquid alkali was added to adjust the pH to 8-9, and stirring was continued for 1 hour. The mixture was filtered, and the filter cake was dried to obtain 98.3 g of 2-amino-5-chloro-3-methylbenzoic acid, with a yield of 92.6%.

[0062] Example 4

[0063]

[0064] Step A: Add 100 g of 4-bromo-2,6-dimethylaniline to a 500 mL four-necked flask, add 320 g of dichloroethane and 98 g of triethylamine, start stirring, and then slowly add 140 g of di-tert-butyl dicarbonate dropwise into the flask. Maintain the temperature at 20-30°C and continue the reaction for 6 hours. When GC detection shows that the starting material has completely disappeared, the reaction is complete. Add 1 kg of n-hexane to the reaction flask. A large amount of solid precipitates in the reaction flask. Continue stirring for 1 hour, filter, and use 2 M hydrochloric acid to slurry the filter cake to remove triethylamine. Then wash with water until no hydrochloric acid residue remains, to obtain 147.1 g of [(4-bromo-2,6-dimethylphenyl)amino]methane-2-methylpropyl-2-yl ester, with a yield of 98.0%.

[0065] Step B: 147.1 g of ((4-bromo-2,6-dimethylphenyl)amino)methane-2-methylpropyl-2-yl ester was added to the reactor, followed by 15 g of NDHPI, 3.1 g of Mn / Co-BNC catalyst, and 760 g of acetonitrile. The mixture was purged with nitrogen three times and oxygen three times. Stirring was started, and the mixture was kept at 80°C for 12 hours. The reaction was considered complete when GC analysis showed complete disappearance of the starting material. The Mn / Co-BNC catalyst was recovered by filtration, and acetonitrile was removed by rotary evaporation. The mixture was then extracted with water and ethyl acetate. The organic phases were combined and concentrated to obtain 151.8 g of 5-bromo-3-methyl-2-((((2-methylpropyl-2-yl)oxy)carbonyl)amino)benzoic acid, with a yield of 93.8%.

[0066] Step C: Add 151.8 g of 5-bromo-3-methyl-2-((((2-methylprop-2-yl)oxy)carbonyl)amino)benzoic acid to a four-necked flask, add 386 g of DCE, start stirring, and slowly add 244 g of dilute hydrochloric acid (10%) dropwise into the reaction flask. After the addition is complete, slowly raise the temperature to 50°C and keep the reaction at this temperature for 4 hours. When GC detection shows that the starting material has completely disappeared, the reaction is complete. While stirring, add liquid alkali to adjust the pH to 8-9, continue stirring for 1 hour, filter, and dry the filter cake to obtain 100.1 g of 2-amino-5-bromo-3-methylbenzoic acid, with a yield of 94.6%.

[0067] Example 5

[0068]

[0069] Step A: Add 100 g of 4-cyano-2,6-dimethylaniline to a 500 mL four-necked flask, add 317 g of dichloroethane and 98 g of triethylamine, start stirring, and then slowly add 56 g of acetyl chloride dropwise into the flask. Maintain the temperature at 20-30 °C and continue the reaction for 6 hours. When GC detection shows that the starting material has completely disappeared, the reaction is complete. Add 1 kg of n-hexane to the reaction flask. A large amount of solid precipitates in the reaction flask. Continue stirring for 1 hour, filter, and use 2 M hydrochloric acid to slurry the filter cake to remove triethylamine. Then wash with water until no hydrochloric acid residue is left, to obtain 122.9 g of N-(4-cyano-2,6-dimethylphenyl)acetamide, with a yield of 95.4%.

[0070] Step B: 122.9 g of N-(4-cyano-2,6-dimethylphenyl)acetamide was added to the reactor, followed by 15 g of NDHPI, 2.4 g of Mn / Co-BNC catalyst, and 590 g of acetonitrile. The mixture was purged with nitrogen three times and oxygen three times. Stirring was started, and the reaction was maintained at 80°C for 12 hours. The reaction ended when GC analysis showed complete disappearance of the starting material. The Mn / Co-BNC catalyst was recovered by filtration, and acetonitrile was removed by rotary evaporation. The mixture was extracted with water and ethyl acetate, and the organic phases were combined and concentrated to obtain 129.6 g of 2-(acetylamino)-5-cyano-3-methylbenzoic acid, with a yield of 91.0%.

[0071] Step C: Add 129.6 g of 2-(acetylamino)-5-cyano-3-methylbenzoic acid to a four-necked flask, add 334 g of methanol, start stirring, and slowly add 97 g of liquid alkali (30%) dropwise into the reaction flask. After the addition is complete, slowly raise the temperature to 50°C and keep the reaction at this temperature for 4 hours. When GC detection shows that the starting material has completely disappeared, the reaction is complete. While stirring, add 1500 g of water to the flask, continue stirring for 1 hour, filter, and dry the filter cake to obtain 95.5 g of 2-amino-3-methylbenzoic acid, with a yield of 91.3%.

[0072] Example 6

[0073] Step B: 118 g of 2,6-dimethylacetanilide was added to the reactor, followed by 14 g of NDHPI, 3.2 g of Co / Fe-BNC catalyst, and 600 g of acetonitrile. The mixture was purged with nitrogen three times and oxygen three times. Stirring was started, and the mixture was kept at 80°C for 12 hours. The reaction was considered complete when GC analysis showed complete disappearance of the starting material. The Mn / Co-BNC catalyst was recovered by filtration, and acetonitrile was removed by rotary evaporation. The mixture was then extracted with water and ethyl acetate. The organic phases were combined and concentrated to obtain 130.7 g of 2-acetamido-3-methylbenzoic acid, with a yield of 96.2%.

[0074] Example 7

[0075] Step B: 118 g of 2,6-dimethylacetanilide was added to the reactor, followed by 9 g of NHPI, 2.3 g of Mn / Co-BNC catalyst, and 600 g of acetonitrile. The mixture was purged with nitrogen three times and oxygen three times. Stirring was started, and the mixture was kept at 80°C for 12 hours. The reaction was considered complete when GC analysis showed complete disappearance of the starting material. The Mn / Co-BNC catalyst was recovered by filtration, and acetonitrile was removed by rotary evaporation. The mixture was then extracted with water and ethyl acetate. The organic phases were combined and concentrated to obtain 118.6 g of 2-acetamido-3-methylbenzoic acid, with a yield of 87.3%.

[0076] Comparative Example 1

[0077] 100 g of 2,6-dimethylaniline was added to a reactor, followed by 14 g of NDHPI, 2.3 g of Mn / Co-BNC catalyst, and 600 g of acetonitrile. The reactor was purged with nitrogen three times and oxygen three times. Stirring was started, and the reactor was kept at 80°C for 12 hours. A large number of complex byproducts were produced that could not be separated.

[0078] Comparative Example 2

[0079] 118 g of 2,6-dimethylacetanilide was added to a reaction vessel, followed by 600 g of water. Stirring was started, and 260 g of potassium permanganate was added to the reaction solution. The mixture was kept at 80°C and reacted for 12 hours. GC analysis showed that the starting material had completely disappeared, and a large number of byproducts were produced. The products were complex and could not be separated.

[0080] Comparative Example 3

[0081] 118 g of 2,6-dimethylacetanilide was added to the reactor, followed by 2.6 g of Mn / Co-BNC catalyst and 600 g of acetonitrile. The mixture was purged with nitrogen three times and oxygen three times. Stirring was started, and the mixture was kept at 80°C for 12 hours. GC analysis showed that the starting material was essentially unreacted.

[0082] The comparison results of the comprehensive examples and comparative examples show that: amino protection is a necessary prerequisite for the effective advancement of the synthesis reaction in this invention. Without amino protection, the raw materials cannot effectively yield the target product (Comparative Example 1). However, after modification with protective agents such as acetyl chloride and di-tert-butyl dicarbonate, the amino group can be prevented from being oxidized and destroyed, and the reactivity of the target methyl group can be preserved. Moreover, acetyl chloride has higher reactivity and is more advantageous in terms of yield and reaction efficiency (Examples 2 and 3). The synergistic effect of the oxidation catalyst and the transition metal-doped BNC co-catalyst is the core of achieving high selective oxidation. The reaction cannot be initiated by using the co-catalyst alone (Comparative Example 3). However, the combination of oxidation catalysts such as NDHPI and NHPI with co-catalysts such as Mn / Co-BNC and Co / Fe-BNC can achieve a methyl selective oxidation rate of 93% through a free radical chain reaction. The above methods are far superior to conventional oxidants such as potassium permanganate and avoid the problem of complex and difficult-to-separate products (Example 2, Comparative Example 2). The method of the present invention has good compatibility with various substituents such as fluorine, chlorine, bromine, iodine, and cyano (Examples 2, 3, 4, 5). Furthermore, by adjusting the types of oxidation catalyst and co-catalyst (such as Co / Fe-BNC compared to Mn / Co-BNC, NDHPI compared to NHPI), a flexible balance between yield and cost can be achieved (Examples 2, 6, 7).

[0083] In summary, this invention, through the core design of "amino protection + synergistic catalysis system", solves the defects of existing technologies such as poor selectivity, lengthy process and harsh conditions. It has the advantages of high yield, high selectivity and industrial feasibility, and the production cost is reduced by 30-40% compared with existing technologies. It provides a reliable solution for the efficient and environmentally friendly production of 2-amino-3-methyl-5-substituted benzoic acid and downstream pesticide intermediates.

[0084] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A process for the synthesis of 2-amino-3-methyl-5-substituted benzoic acids, characterized in that, Includes the following steps: Compound IV is synthesized into compound III through amino protection, then into compound II through oxidation, and finally compound I is obtained by removing the protecting group. Where X is selected from hydrogen, fluorine, chlorine, bromine, iodine or cyano; R is an amino protecting group.

2. The method of synthesis of claim 1, wherein, R is an acetyl, propionyl, tert-valeryl, or tert-butoxycarbonyl protecting group.

3. The method of synthesis of claim 1, wherein, The amino-protecting agent is selected from one or more of acetyl chloride, propionyl chloride, acetic anhydride, propionic anhydride, tert-valerate chloride, and di-tert-butyl dicarbonate.

4. The method of synthesis of claim 1, wherein, The oxidation reaction is carried out in the presence of an oxygen source, an oxidation catalyst, and a co-catalyst.

5. The method of synthesis of claim 3, wherein, The oxygen source is selected from oxygen or air; the oxidation catalyst is selected from one or more of N,N'-dihydroxyphthalimide, N-hydroxyphthalimide, N-hydroxytetrachlorophthalimide, and N,N',N”-trihydroxyisocyanuric acid; the co-catalyst is selected from one of Mn / Co / Fe-BNC, Mn / Co-BNC, Co / Fe-BNC, and Mn / Fe-BNC.

6. The method of synthesis of claim 1, wherein, The process of removing the protecting group to synthesize compound (I) is carried out in an alkaline or acidic environment.

7. The method of synthesis of claim 5, wherein, When the alkaline environment is used, the alkaline reagent is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, or lithium hydroxide.

8. The method of synthesis of claim 5, wherein, When the acidic environment is used, the acidic reagent is selected from sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, or methanesulfonic acid.

9. A process for the preparation of 2-amino-5-chloro-N,3-dimethylbenzamide, characterized in that, Use a compound of formula I prepared as described in claim 1.

10. A process for the preparation of 2-amino-5-bromo-N,3-dimethylbenzamide, characterized in that, Use a compound of formula I prepared as described in claim 1.

11. A method for preparing 2-amino-5-cyano-N,3-dimethylbenzamide, characterized in that, Use a compound of formula I prepared as described in claim 1.

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