阅读说明：本技术 一种2-甲基-3-甲氧基苯甲酸的合成工艺 (Synthesis process of 2-methyl-3-methoxybenzoic acid ) 是由 耿敬坤 方浙能 姚林夕 季品俊 张燕超 苗君慧 王博涛 于 2021-04-19 设计创作，主要内容包括：本发明公开了一种2-甲基-3-甲氧基苯甲酸合成工艺,包括以下步骤：(1)还原加氢反应：以2-甲基-3-硝基苯甲酸或2-甲基-3-硝基苯甲酸甲酯为原料,甲醇为溶剂、氢气为氢源,以钯碳或铂碳为催化剂,氢化还原制备3-氨基-2-甲基苯甲酸或3-氨基-2-甲基苯甲酸甲酯；(2)重氮化、水解以及酯化一锅反应：以还原产物为原料,甲醇为溶剂,重氮化试剂作用下,进行重氮化、水解以及酯化反应制备3-羟基-2-甲基苯甲酸甲酯；(3)甲基化反应：以3-羟基-2-甲基苯甲酸甲酯为原料,以硫酸二甲酯为甲基化试剂,在碱存在下甲基化反应制备3-甲氧基-2-甲基苯甲酸甲酯；(4)水解反应：3-甲氧基-2-甲基苯甲酸甲酯与碱、水混合,加热水解,反应完成,降温以酸调节PH至1～3析出产品,过滤、干燥得3-甲氧基-2-甲基苯甲酸。(The invention discloses a synthesis process of 2-methyl-3-methoxybenzoic acid, which comprises the following steps: (1) reduction hydrogenation reaction: using 2-methyl-3-nitrobenzoic acid or 2-methyl-3-nitrobenzoic acid methyl ester as a raw material, methanol as a solvent, hydrogen as a hydrogen source, palladium carbon or platinum carbon as a catalyst, and preparing 3-amino-2-methylbenzoic acid or 3-amino-2-methylbenzoic acid methyl ester by hydrogenation reduction; (2) diazotization, hydrolysis and esterification one-pot reaction: carrying out diazotization, hydrolysis and esterification reaction under the action of a diazotization reagent by taking a reduction product as a raw material and methanol as a solvent to prepare 3-hydroxy-2-methyl benzoate; (3) methylation reaction: taking 3-hydroxy-2-methyl benzoate as a raw material, taking dimethyl sulfate as a methylating agent, and carrying out methylation reaction in the presence of alkali to prepare 3-methoxy-2-methyl benzoate; (4) and (3) hydrolysis reaction: mixing 3-methoxy-2-methyl benzoic acid methyl ester with alkali and water, heating for hydrolysis, cooling to adjust the PH value to 1-3 by acid after the reaction is finished, separating out a product, filtering, and drying to obtain the 3-methoxy-2-methyl benzoic acid.)

1. A synthesis process of 2-methyl-3-methoxybenzoic acid is characterized by comprising the following steps:

reduction hydrogenation reaction: using 2-methyl-3-nitrobenzoic acid or 2-methyl-3-nitrobenzoic acid methyl ester as a raw material, methanol as a solvent, hydrogen as a hydrogen source, palladium carbon or platinum carbon as a catalyst, and preparing a 3-amino-2-methylbenzoic acid or 2-methyl-3-nitrobenzoic acid methyl ester reducing substance by hydrogenation reduction;

diazotization, hydrolysis and esterification one-pot reaction: carrying out diazotization, hydrolysis and esterification reaction under the action of a diazotization reagent by taking a reduced substance as a raw material and methanol as a solvent to prepare 3-hydroxy-2-methyl benzoate;

methylation reaction: using the obtained 3-hydroxy-2-methyl benzoate as a raw material, using dimethyl sulfate as a methylation reagent, and carrying out methylation reaction in the presence of alkali to prepare 3-methoxy-2-methyl benzoate;

(4) and (3) hydrolysis reaction: mixing and stirring 3-methoxy-2-methyl benzoic acid methyl ester, alkali and water, heating to react until hydrolysis reaction is completed, adjusting pH to 1-3 with acid to separate out a product, filtering, and drying to obtain 3-methoxy-2-methyl benzoic acid;

the reaction equation is as follows:

the diazotization reagent in the step (2) is sodium nitrite, nitroso sulfuric acid or nitrous acid ester.

2. The process for synthesizing 2-methyl-3-methoxybenzoic acid according to claim 1, which comprises the following steps: in the one-pot reaction in the step (2), when sodium nitrite is used as a diazotization reagent, sulfuric acid is used for providing an acidic condition to carry out diazotization, hydrolysis and esterification reactions so as to prepare the 3-hydroxy-2-methyl benzoate.

3. The process for synthesizing 2-methyl-3-methoxybenzoic acid according to claim 1, which comprises the following steps: in the one-pot reaction in the step (2), the nitrite ester is nitrite ester formed by alcohol with 1-5 carbon atoms.

4. The process for synthesizing 2-methyl-3-methoxybenzoic acid according to claim 1, which comprises the following steps: the reduction hydrogenation reaction in the step (1) is carried out at the temperature of 60-90 ℃ and under the hydrogen pressure of 0.5-1.5 MPa, and the reaction is stopped until the content of the raw material is less than 0.5%.

5. The process for synthesizing 2-methyl-3-methoxybenzoic acid according to claim 1, which comprises the following steps: and (3) carrying out one-pot reaction in the step (2), wherein the temperature of the diazotization reagent dropwise added is 0-15 ℃, and after the dropwise addition is finished, the reaction is carried out for 4-16 h at the temperature of 50-66 ℃.

6. The process for synthesizing 2-methyl-3-methoxybenzoic acid according to claim 1, which comprises the following steps: the reaction temperature of the methylation reaction in the step (3) is 30-45 ℃, and the reaction time is 1-2 hours; the temperature of the hydrolysis reaction in the step (4) is 80-100 ℃.

7. The process for synthesizing 2-methyl-3-methoxybenzoic acid according to claim 1, which comprises the following steps: in the reduction hydrogenation reaction in the step (1), the weight ratio of the raw material to the catalyst is 1: 0.02 to 0.2; the weight ratio of the raw materials to the methanol is 1: 3 to 15.

8. The process for synthesizing 2-methyl-3-methoxybenzoic acid according to claim 1, which comprises the following steps: in the step (2), in one-pot reaction, the molar ratio of the reducing substance to the diazotization reagent is 1: 1.02-1.5.

9. The process for synthesizing 2-methyl-3-methoxybenzoic acid according to claim 1, which comprises the following steps: in the methylation reaction in the step (3), the molar ratio of the raw material to the dimethyl sulfate is 1: 1.3-2.20, and the molar weight of the alkali is 1.5-1.8 times of that of the dimethyl sulfate.

10. The process for synthesizing 2-methyl-3-methoxybenzoic acid according to claim 1, which comprises the following steps: in the hydrolysis reaction in the step (4), the molar ratio of the methyl 3-methoxy-2-methylbenzoate to the alkali is 1: 1.01-1.05.

11. The process for synthesizing 2-methyl-3-methoxybenzoic acid according to claim 1, which comprises the following steps: after the one-pot reaction in the step (2) is finished, distilling the reaction liquid to recover the solvent, washing with water and layering to obtain a 3-hydroxy-2-methyl benzoate crude product which is a mixture of 3-hydroxy-2-methyl benzoate and 3-methoxy-2-methyl benzoate;

the mixture of the methyl 3-hydroxy-2-methylbenzoate and the methyl 3-methoxy-2-methylbenzoate can be directly subjected to the next methylation reaction, and the methyl 3-methoxy-2-methylbenzoate and the methyl 3-hydroxy-2-methylbenzoate can also be separated by reduced pressure distillation.

12. The process for synthesizing 2-methyl-3-methoxybenzoic acid according to claim 11, which comprises the following steps: distilling and separating 3-methoxy-2-methyl benzoic acid methyl ester to directly remove the hydrolysis step to prepare 3-methoxy-2-methyl benzoic acid;

the methyl 3-hydroxy-2-methylbenzoate separated by distillation is subjected to demethylation and then hydrolysis to prepare the 3-methoxy-2-methylbenzoic acid.

13. The process for synthesizing 2-methyl-3-methoxybenzoic acid according to claim 1, which comprises the following steps: in the step (3) or (4), the alkali is one or a mixture of more than two of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; in the step (4), the acid is sulfuric acid or hydrochloric acid, and the mass concentration of the acid is 10-30%.

14. The process for synthesizing 2-methyl-3-methoxybenzoic acid according to claim 1, which comprises the following steps: the steps (1) to (4) further comprise a post-treatment step.

Technical Field

The invention belongs to the technical field of synthesis of organic pesticide intermediates, and particularly relates to a synthesis process of 2-methyl-3-methoxybenzoic acid.

Background

The 2-methyl-3-methoxybenzoic acid is an important intermediate of the high-efficiency low-toxicity pesticide methoxyfenozide, and the traditional preparation process is different according to the starting raw materials, and the following three methods are important:

the method comprises the following steps: the 3-methoxy-2-methylbenzoic acid is obtained by taking 2, 6-dichlorotoluene as a raw material and carrying out etherification, Grignard reaction and hydrolysis, or Grignard reaction, hydrolysis and etherification. The method adopts virulent reagent sodium cyanide and Grignard reaction, has high safety risk, unstable yield and product quality, and is not beneficial to industrialization.

The second method comprises the following steps: 2-methyl-3-nitrobenzoic acid is taken as a raw material, and the 3-methoxy-2-methylbenzoic acid is synthesized through the steps of reduction, diazotization hydrolysis, methylation and the like. (reference document: Zhejiang chemical industry, No. 44, vol.1, 2013, synthesis of 3-methoxy-2-methylbenzoic acid), the total yield of the method can reach 85%, but the method has the characteristics that all steps need to be separated, the separation and purification steps are multiple, raw materials are not easy to obtain, and the content of the obtained product is low (about 96.0%), so that the method cannot meet the production requirement of methoxyfenozide.

And thirdly, taking o-xylene as a raw material (patent application: CN 201710654959.0), preparing 3-nitro-2-methyl benzoic acid through nitration and oxidation, and synthesizing the product 2-methyl-3-methoxy benzoic acid through esterification, reduction, diazotization and methylation. The method has easily obtained raw materials and total yield controlled at above 65%. However, this method also has the disadvantages of many reaction steps and complicated separation and purification. In addition, in the process of preparing methoxyfenozide from the 3-methoxy-2-methylbenzoic acid obtained by the method, the reduced pressure distillation operation of the intermediate 3-methoxy-2-methylbenzoyl chloride is required, and the acyl chloride seriously corrodes the equipment pipeline in the distillation process, so that the equipment cost is high, and the production is not facilitated.

In conclusion, the existing production process for preparing 2-methyl-3-methoxybenzoic acid has the defects of complex process, high production cost and unstable product quality, and the production requirement of pesticide methoxyfenozide is difficult to meet.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a synthesis process of 2-methyl-3-methoxybenzoic acid, which has the characteristics of simple and convenient process method, continuity and controllable quality.

The invention is realized by the following technical scheme:

a synthesis process of 2-methyl-3-methoxybenzoic acid comprises the following steps:

(1) reduction hydrogenation reaction: using 2-methyl-3-nitrobenzoic acid or 2-methyl-3-nitrobenzoic acid methyl ester as a raw material, methanol as a solvent, hydrogen as a hydrogen source, palladium carbon or platinum carbon as a catalyst, and preparing 3-amino-2-methylbenzoic acid or 3-amino-2-methylbenzoic acid methyl ester by hydrogenation reduction;

(2) diazotization, hydrolysis and esterification one-pot reaction: carrying out diazotization, hydrolysis and esterification reaction under the action of a diazotization reagent by taking a reduced substance as a raw material and methanol as a solvent to prepare 3-hydroxy-2-methyl benzoate;

(3) methylation reaction: using the obtained 3-hydroxy-2-methyl benzoate as a raw material, using dimethyl sulfate as a methylation reagent, and carrying out methylation reaction in the presence of alkali to prepare 3-methoxy-2-methyl benzoate;

(4) and (3) hydrolysis reaction: mixing and stirring 3-methoxy-2-methyl benzoic acid methyl ester, alkali and water, heating to react until hydrolysis reaction is completed, cooling, adjusting pH to 1-3 with acid to precipitate a product, filtering, and drying to obtain 3-methoxy-2-methyl benzoic acid;

the reaction equation is as follows:

the further scheme of the invention is as follows:

the reduction hydrogenation reaction in the step (1) is carried out at the temperature of 60-90 ℃ and the hydrogen pressure of 0.5-1.5 MPa; in the one-pot reaction in the step (2), a diazotization reagent is dropwise added at 0-15 ℃, after the dropwise addition is finished, the temperature is raised to 50-66 ℃, the reaction is kept at the temperature until the reaction is finished, and the required reaction time is 4-16 h; the reaction temperature of the methylation reaction in the step (3) is 30-45 ℃, and the reaction time is 1-2 hours; the temperature of the hydrolysis reaction in the step (4) is 80-100 ℃. And (3) after the reduction hydrogenation reaction in the step (1) is finished, filtering and recovering the catalyst, and directly carrying out diazotization reaction on the filtrate in the step (2).

Further, in the reduction hydrogenation reaction of the step (1), the weight ratio of the 2-methyl-3-nitrobenzoic acid to the catalyst is 1: 0.02 to 0.2; the methanol is used as a reaction solvent, the solvent amount can meet the reaction requirement, and the weight ratio of the 2-methyl-3-nitrobenzoic acid or the methyl ester thereof to the methanol is 1: 3-15; in the methylation reaction in the step (3), the mass ratio of methyl 3-hydroxy-2-methylbenzoate to dimethyl sulfate is 1: 1.3-2.20, the alkali is used for adjusting the pH value of a reaction system and neutralizing phenolic hydroxyl to increase the methylation reaction activity, and the required amount of the alkali is related to the usage amount of dimethyl sulfate and is usually 1.5-1.8 times of the mass amount of dimethyl sulfate; during the hydrolysis reaction in the step (4), the mass ratio of the methyl 3-methoxy-2-methylbenzoate to the alkali is 1: 1.01-1.05.

Further, in the one-pot reaction in the step (2), sulfuric acid is used for providing an acidic condition, and sodium nitrite is used as a diazotization reagent to carry out diazotization, hydrolysis and esterification reactions to prepare the methyl 3-hydroxy-2-methylbenzoate.

Further, in the one-pot reaction of the step (2), diazotization, hydrolysis and esterification reactions are carried out to prepare the methyl 3-hydroxy-2-methylbenzoate by using a sulfuric acid solution of nitroso sulfuric acid or nitrite ester as a diazotization reagent. The nitroso sulfuric acid is a sulfuric acid solution of nitroso sulfuric acid with a mass concentration of 40%, and the nitrite is nitrite formed by alcohol with 1-5 carbon atoms, such as methyl nitrite, ethyl nitrite, propyl nitrite, butyl nitrite, amyl nitrite and the like.

In the one-pot reaction in the step (2), the molar ratio of the 3-amino-2-methylbenzoic acid to the diazotization reagent is 1: 1.02-1.5; the diazotization reaction solution may contain a portion of water derived from the aqueous sodium nitrite solution and a portion of water generated by the hydrogenation reduction reaction.

Further, the alkali in the step (3) or (4) is one or more of inorganic alkali which is conventionally used, such as sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide; the acid in the step (4) is a conventionally used inorganic acid such as sulfuric acid, hydrochloric acid, etc., and the preferred acid is sulfuric acid with a mass concentration of 10-30% or hydrochloric acid with a mass concentration of 10-30%.

The further scheme of the invention is as follows:

when the reaction in the step (2) is finished in one pot, recovering the solvent methanol by atmospheric or reduced pressure distillation, diluting and layering the concentrated solution by adding water, separating out a water layer, directly carrying out methylation on an oil layer in the step (3), extracting the water layer by using an organic solvent, then removing the water layer, concentrating and desolventizing the organic layer obtained by extraction, and carrying out methylation in the step (3);

in the step, methanol is used as a solvent to carry out diazotization and diazonium salt decomposition reaction, so that hydrolysis and alcoholysis reaction can simultaneously occur to obtain a mixture of 3-methoxy-2-methylbenzoic acid/3-hydroxy-2-methylbenzoic acid; in addition, because the reaction is carried out under sulfuric acid, the esterification reaction under a sulfuric acid catalyst can be carried out simultaneously while the hydrolysis reaction is carried out, so that a mixture of 3-methoxy-2-methyl benzoate/3-hydroxy-2-methyl benzoate can be obtained after hydrolysis/alcoholysis, separation and purification. Therefore, after the one-pot reaction in the step (2) is completed, an oil layer obtained after the solvent is concentrated and recovered and an organic layer separated by the post-treatment are a mixture of methyl 3-methoxy-2-methylbenzoate/methyl 3-hydroxy-2-methylbenzoate.

During the methylation reaction in the step (3), after the reaction is finished, washing and layering reaction liquid to obtain a crude product of methyl 3-methoxy-2-methylbenzoate, purifying by reduced pressure distillation to obtain a refined product of methyl 3-methoxy-2-methylbenzoate, and hydrolyzing the refined product serving as a raw material in the step (4); the distillation temperature of the reduced pressure distillation process in the step (3) is related to the vacuum degree of the reduced pressure distillation process, and when the absolute pressure is 100Pa, the distillation temperature is 106-110 ℃; the content of the methyl 3-methoxy-2-methylbenzoate obtained by reduced pressure distillation is more than 99.5%.

After the methyl 3-methoxy-2-methylbenzoate is purified by reduced pressure distillation, the purity of the 3-methoxy-2-methylbenzoic acid product obtained by hydrolysis and neutralization in the step (4) is higher, and generally more than 99.7 percent. And recrystallization is not needed for further controlling the product quality, the operation steps are simple, convenient and clean, the product quality is stable and controllable, and the method is more suitable for industrialization.

The invention further improves the scheme as follows:

and (3) after the one-pot reaction in the step (2) is finished, carrying out reduced pressure distillation on the crude product of the methyl 3-hydroxy-2-methylbenzoate to separate methyl 3-methoxy-2-methylbenzoate and a mixture of methyl 3-hydroxy-2-methylbenzoate and methyl 3-hydroxy-2-methylbenzoate/methyl 3-methoxy-2-methylbenzoate. The methyl 3-methoxy-2-methylbenzoate can directly enter the step (4) to carry out hydrolysis reaction to prepare 3-methoxy-2-methylbenzoic acid; the reduced pressure distillation separation of methyl 3-hydroxy-2-methylbenzoate or methyl 3-hydroxy-2-methylbenzoate/methyl 3-methoxy-2-methylbenzoate mixture can be used for preparing 3-methoxy-2-methylbenzoic acid after methylation in the step (3). When the improved scheme is adopted, the method can separate the 3-hydroxy-2-methyl benzoate intermediate after the post-treatment in the step (2) is finished, reduce the impurity amount of raw materials entering the methylation step and finally control the product quality.

Another embodiment of the present invention is:

in the reduction hydrogenation reaction in the step (1), when the raw material is 3-amino-2-methylbenzoic acid, after the reaction is completed, the catalyst is filtered and recovered when the reaction is completed, the filtrate is filtered by a conventional crystallization method to obtain 3-amino-2-methylbenzoic acid, and the obtained 3-amino-2-methylbenzoic acid and methanol are fed into the step (2) together to carry out diazotization reaction. The crystallization can be realized by reducing the temperature to 0-10 ℃ after concentrating and recovering part of the solvent and filtering out insoluble substances.

Still further variations of the present invention are:

after the methylation reaction in the step (3) is finished, directly taking the obtained 3-methoxy-2-methyl benzoate reaction liquid as a raw material to perform hydrolysis in the step (4); and after the hydrolysis reaction is finished, adjusting the pH value to 1-3 by using acid to separate out a product, filtering and drying to obtain the 3-methoxy-2-methylbenzoic acid. In order to control the quality of the product 3-methoxy-2-methylbenzoic acid, the 3-methoxy-2-methylbenzoic acid obtained in the step can be recrystallized by using alcohol as a solvent to obtain a product with the content of over 99.0 percent.

The invention has the beneficial effects that:

the post-treatment process of the invention has less purification steps: from hydrogenation reduction to methylation, each step can be reacted in a crude product form, so that unnecessary purification operation is reduced, and the production cost is reduced;

hydrolysis and methanolysis products exist simultaneously in the diazotization process, and partial methylation of materials is realized in the hydrolysis process, so that the use amount of a methylation reagent can be reduced, and the waste salt amount caused by the methylation process is reduced. The method has favorable influence on the ecological environment while reducing the material loss and the production cost.

During the diazotization hydrolysis process, the esterification reaction of acid and methanol under the catalysis of excessive sulfuric acid can be carried out simultaneously, so that the reaction steps are simplified, and the effect of reducing the production cost can be achieved.

Methanol is adopted as a solvent in the steps of hydrogenation and diazotization hydrolysis, and a methanol byproduct is generated in the steps of methylation and hydrolysis, so that the solvent can be conveniently recycled, and the ecological environment is protected.

The invention can purify the 3-methoxy-2-methyl benzoate crude product by reduced pressure distillation, and has more convenient operation while the product quality is stable and controllable.

In conclusion, compared with the prior art, the technical scheme adopted by the invention has the characteristics of compact reaction steps, less separation and purification, simple and convenient operation and easy separation and purification. Meanwhile, the obtained product has high purity and controllable quality, and can meet the quality requirement of methoxyfenozide production.

Detailed Description

Example 1

(1) Reductive hydrogenation

Adding 500 g of 3-nitro-2-methylbenzoic acid, 50 g of platinum carbon (with platinum content being 2 percent) and 2000 g of methanol into a pressure kettle, replacing with nitrogen, introducing hydrogen to 1.0-1.3 MPa, heating to 70-80 ℃, controlling the reaction pressure until the reaction is complete (raw materials are less than 0.5 percent), continuing stirring for 60 min, filtering while hot, collecting and recycling the catalyst, and directly performing diazotization hydrolysis on the mother liquor.

(2) Diazotization hydrolysis

And (2) cooling the reduction mother liquor obtained in the step (1) to 0-5 ℃, dropwise adding 900 g (weight percentage: 40%,1.02 eq.) of nitroso sulfuric acid at a controlled temperature, heating to 50-60 ℃ after adding, heating for not less than 30min, stirring for 1 hour, heating to 64-66 ℃, and carrying out reflux reaction for 4-8 hours until the reaction is finished (HPLC: 3-hydroxy-2-methylbenzoic acid + 3-methoxy-2-methylbenzoic acid is less than 1%).

Heating the reaction liquid to 85-100 ℃, distilling at normal pressure to recover methanol, adding 1200 g of water after recovering 1400-1600 g of methanol, standing for layering, separating an oil layer and collecting.

The aqueous layer was extracted with 1000ml of MIBK, the separated organic layer was concentrated and combined with the oil layer to give 425 g of crude methyl 3-hydroxy-2-methylbenzoate (HPLC: 42.8% methyl 3-hydroxy-2-methylbenzoate, 51.4% methyl 3-methoxy-2-methylbenzoate), which was directly subjected to methylation reaction.

(3) Methylation of

100 g of the 3-hydroxy-2-methyl benzoate crude product obtained in the step (2), adding dimethyl sulfate (58.5 g, 1.8 eq.), heating to 30-35 ℃, dropwise adding 30% sodium hydroxide solution (103.0 g, 3.0 eq.), controlling the temperature not to exceed 40 ℃, and continuing stirring for 1 hour after the addition is finished until the reaction is finished.

Standing for layering, separating an oil layer, and washing with water to obtain 101 g of a crude product of the 3-methoxy-2-methyl benzoic acid methyl ester. Vacuum distillation is carried out, the vacuum degree is controlled to be less than 100Pa, the gas phase temperature is controlled to be 106-

(4) Neutralization by hydrolysis

50 g of the crude 3-methoxy-2-methylbenzoic acid methyl ester obtained in the step (3), 37.8 g of sodium hydroxide solution (1.02 eq., concentration: 30%) and 100 g of water are added, the mixture is heated to 80-90 ℃ to react until the reaction is finished, the reaction liquid is cooled to 50-60 ℃, 69.7 g of sulfuric acid (concentration: 20%) is added to adjust the pH to 2-3, after the addition is finished, the mixture is stirred for 1 hour under heat preservation, and the mixture is filtered and dried to obtain 44.3 g of the crude 3-methoxy-2-methylbenzoic acid (HPLC: 99.5%, yield: 96.0%).

Example 2

(1) Reductive hydrogenation

Adding 3-nitro-2-methylbenzoic acid (450 g), platinum carbon (platinum content is 2%, 9.0 g) and methanol (1350 g) into a pressure kettle, replacing with nitrogen, introducing hydrogen pressure to 0.9-1.1 MPa, heating to 60-70 ℃, controlling the reaction pressure until the reaction is complete (raw material is less than 0.5%), continuing stirring for 30min, filtering while hot, dividing the mother liquor into three parts while hot, and directly performing diazotization hydrolysis.

(2) Diazotization hydrolysis

Adding 92.2 g (1.2 eq.) of sulfuric acid into the reduction mother liquor (1/3 wt%) obtained in the step (1), cooling to 5-10 ℃, dropwise adding 126.6 g of sodium nitrite solution (63.6 g of sodium nitrite, 1.2 eq.; 63 g of water) at controlled temperature, slowly heating to 50-60 ℃ after adding, controlling the heating time to be not less than 30min, stirring for 1 hour, heating to 64-66 ℃ and carrying out reflux reaction for 8-12 hours until the reaction is finished (HPLC: 3-hydroxy-2-methylbenzoic acid + 3-methoxy-2-methylbenzoic acid is less than 1%).

Heating to 85-100 ℃, distilling to recover about 360 g of methanol, adding 400 g of water, standing for layering, and separating out 110g of an oil layer.

The aqueous layer was extracted with 100ml of MTBE, the organic layer was separated and concentrated, and the resulting mixture was combined with the oil layer to obtain 135 g of crude methyl 3-hydroxy-2-methylbenzoate (HPLC: methyl 3-hydroxy-2-methylbenzoate: 56.25%, methyl 3-methoxy-2-methylbenzoate = 33.68%) which was directly subjected to methylation reaction.

(3) Methylation of

135 g of the 3-hydroxy-2-methyl benzoate crude product obtained in the step (2), adding dimethyl sulfate (74.9 g, 1.3 eq.), heating to 35-40 ℃, dropwise adding 30% sodium hydroxide solution (121.8 g, 2.0 eq.), controlling the temperature not to exceed 40 ℃, and continuing stirring for 1 hour after the addition is finished until the reaction is finished. Standing for layering, separating an oil layer, and washing with water to obtain 138g (HPLC: 91.5%) of crude methyl 3-methoxy-2-methylbenzoate.

Example 3

Diazotization hydrolysis

150.6 g (2.0 eq.) of sulfuric acid was added to the reducing mother liquor (1/3 wt%) obtained in step (1) of example 2, the temperature was reduced to 20-30 ℃, 155.7 g of sodium nitrite solution (55.7 g, 1.05 eq.; water: 100 g) was added dropwise under controlled temperature, after the addition, the temperature was slowly increased to 50-60 ℃, after stirring for 1 hour, the temperature was increased to 64-66 ℃ and reflux reaction was carried out for 8-16 hours until the reaction was completed (HPLC: 3-hydroxy-2-methylbenzoic acid + 3-methoxy-2-methylbenzoic acid < 1%).

Heating to 85-100 ℃, distilling at normal pressure to recover about 360 g of methanol, adding 400 g of water, standing for layering, and separating out 105 g of oil layer.

The aqueous layer was extracted with 100ml of MIBK, the separated organic layer was concentrated and combined with the oil layer to give 138g of crude methyl 3-hydroxy-2-methylbenzoate (HPLC: methyl 3-hydroxy-2-methylbenzoate: 49.3%; methyl 3-methoxy-2-methylbenzoate = 45.3%) which was directly subjected to methylation reaction.

Methylation of

Adding 38g of the crude product of the methyl 3-hydroxy-2-methylbenzoate in the step, adding dimethyl sulfate (21.3 g,1.5 eq.), heating to 40-45 ℃, dropwise adding 30% sodium hydroxide solution (34.6 g, 2.3 eq.), controlling the temperature not to exceed 40 ℃, and continuing stirring for 1 hour after the addition is finished until the reaction is finished. The reaction solution is directly subjected to hydrolysis reaction.

Standing for layering, separating an oil layer, and washing with water to obtain 38g (HPLC: 95.7%) of crude methyl 3-methoxy-2-methylbenzoate.

Example 4

Diazotization hydrolysis

263.6 g (3.5 eq.) of sulfuric acid (in 1/3 wt.) is added to the reduction mother liquor obtained in step (1) of example 2, the temperature is reduced to 50-55 ℃, 113.3 g of sodium nitrite solution (58.3 g of sodium nitrite, 1.1 eq., water, 65 g) is dropwise added at a controlled temperature, after the addition is finished, the temperature is slowly increased to 50-60 ℃, the mixture is stirred for 1 hour, and then the temperature is increased to 64-66 ℃ for reflux reaction for 8-16 hours until the reaction is finished (HPLC: 3-hydroxy-2-methylbenzoic acid + 3-methoxy-2-methylbenzoic acid < 1%).

After the temperature was raised and about 360 g of methanol was recovered by atmospheric distillation, 330 g of water was added, and the mixture was allowed to stand for layering, thereby separating 102g of an oil layer.

The aqueous layer was extracted with 100ml of ethyl acetate, the organic layer was separated and concentrated, and the resulting mixture was combined with the oil layer to give 136 g of crude methyl 3-hydroxy-2-methylbenzoate (HPLC: methyl 3-hydroxy-2-methylbenzoate: 48.05%; methyl 3-methoxy-2-methylbenzoate = 45.59%) which was directly subjected to methylation reaction.

Methylation of

Adding 36 g of the crude product of the methyl 3-hydroxy-2-methylbenzoate obtained in the step into dimethyl sulfate (28.9 g, 2.2 eq.), heating to 30-40 ℃, dropwise adding 30% sodium hydroxide solution (55.5 g, 4.0 eq.), controlling the temperature not to exceed 40 ℃, and continuing stirring for 1 hour after the addition is finished until the reaction is finished.

Standing for layering, separating an oil layer, and washing with water to obtain 35g (HPLC:95.8%) of crude methyl 3-methoxy-2-methylbenzoate.

Example 5

Distillation under reduced pressure

The crude methyl 3-methoxy-2-methylbenzoate obtained in example 2, example 3 and example 4 are combined (about 211 g), vacuum distillation is carried out, the vacuum degree is controlled to be less than 100Pa, the steam temperature is controlled to be 106 ℃ and 110 ℃, and 168 g of product (GC:99.5 percent) is collected

Neutralization by hydrolysis

Adding 74.7 g (1.01 eq., concentration: 30%) of sodium hydroxide solution and 200 g of water into 100 g of the crude 3-methoxy-2-methylbenzoic acid methyl ester obtained in the above steps, heating to 90-100 ℃ for reaction until the reaction is finished, cooling to 50-60 ℃, adding 136.3 g (concentration: 20%) of sulfuric acid at the controlled temperature to adjust the pH to 1-2, cooling to 20-30 ℃ after the addition is finished, keeping the temperature and stirring for 1 hour, filtering and drying to obtain 89.1 g (HPLC: 99.6%, yield: 96.6%) of the crude 3-methoxy-2-methylbenzoic acid.

Example 6

(1) Reductive hydrogenation

Adding 3-nitro-2-methylbenzoic acid (500 g), palladium carbon (10 percent of palladium content and 10 g) and methanol (1500 g) into a pressure kettle, replacing with nitrogen, introducing hydrogen pressure to 0.5-0.7 MPa, heating to 90 ℃, controlling the temperature, controlling the reaction pressure until the reaction is complete (raw material is less than 0.5 percent), continuing stirring for 60 min, filtering while hot to recover the catalyst, concentrating the mother liquor to about 700 g of residual methanol, cooling, filtering to obtain 320 g of 3-amino-2-methylbenzoic acid, and performing diazotization hydrolysis on the solid.

(2) Diazotization hydrolysis

Adding 3000g of methanol into 300 g of 3-amino-2-methylbenzoic acid obtained in the step (1), cooling to 20-30 ℃, dropwise adding 686 g of nitrososulfuric acid (1.02 eq. weight percentage: 40%) under controlled temperature, slowly heating to 50-60 ℃, stirring for 1 hour, heating to 64-66 ℃, and carrying out reflux reaction for 8-16 hours until the reaction is finished (HPLC: 3-hydroxy-2-methylbenzoic acid + 3-methoxy-2-methylbenzoic acid is less than 1%). .

Heating to 85-100 deg.C, distilling under normal pressure to recover methanol about 2700 g, adding water 900 g, standing for layering, and separating oil layer.

The aqueous layer was extracted with 300ml of n-butyl acetate, the organic layer separated was concentrated and then combined with the oil layer to obtain 301 g of crude methyl 3-hydroxy-2-methylbenzoate (HPLC: 33.3% for methyl 3-hydroxy-2-methylbenzoate and 62.9% for methyl 3-methoxy-2-methylbenzoate) which was directly subjected to methylation reaction.

(3) Methylation of

Adding 250 g of crude methyl 3-hydroxy-2-methylbenzoate obtained in the step (2), adding dimethyl sulfate (101.1 g, 1.6 eq.), heating to 35-40 ℃, dropwise adding 30% sodium hydroxide solution (187.0 g, 2.8 eq.), controlling the temperature not to exceed 40 ℃, and continuing stirring for 1 hour after the addition is finished until the reaction is finished.

Standing for layering, separating an oil layer, and washing with water to obtain 255 g of crude 3-methoxy-2-methyl benzoate.

The obtained crude product is subjected to reduced pressure distillation under the conditions that the vacuum degree is controlled to be less than 100Pa, the steam temperature is controlled to be 106-

(4) Neutralization by hydrolysis

100 g of the crude 3-methoxy-2-methylbenzoic acid methyl ester obtained in the step (3), 77.7 g of sodium hydroxide solution (1.05 eq., concentration: 30%) and 100 g of water are added, the mixture is heated to 80-90 ℃ to react until the reaction is finished, the temperature is reduced to 50-60 ℃, 278.6 g of sulfuric acid (with the concentration of 10%) is added to regulate the pH to 1-2 under the condition of controlling the temperature, after the addition is finished, the temperature is reduced to 20-30 ℃, the mixture is kept and stirred for 1 hour, and the mixture is filtered and dried to obtain 89.0 g of the crude 3-methoxy-2-methylbenzoic acid (HPLC: 99.8%, yield: 96.6%).

Example 7

(1) Reductive hydrogenation

Adding 3-nitro-2-methyl benzoate (50 g), platinum carbon (platinum content is 2%, 10 g) and methanol (250 g) into a pressure kettle, displacing with nitrogen, introducing hydrogen gas to 1.3-1.5 MPa, heating to 80-90 ℃, controlling the reaction pressure until the reaction is complete (raw material is less than 0.5%), continuing stirring for 30min, filtering while hot to recover the catalyst, and directly carrying out diazotization hydrolysis on the mother liquor.

(2) Diazotization hydrolysis

And (2) cooling the reduction mother liquor obtained in the step (1) to 10-15 ℃, dropwise adding nitroso-tert-butyl ester (39.6 g,1.5 eq.) under controlled temperature, continuously stirring for 30min after the addition is finished, slowly heating to 50-60 ℃, stirring for 1 hour, adding 10g of sulfuric acid, heating to 64-66 ℃, and carrying out reflux reaction for 8-16 hours until the reaction is finished (HPLC: 3-hydroxy-2-methylbenzoic acid + 3-methoxy-2-methylbenzoic acid is less than 1%).

Heating to 85-100 ℃, distilling at normal pressure to recover about 200 g of methanol, adding 120 g of water, standing for layering, and separating out an oil layer of 30 g.

The aqueous layer was extracted with 100ml of ethyl acetate, the organic layer was separated and concentrated, and then the resulting mixture was combined with the oil layer to obtain 40 g of a crude methyl 3-hydroxy-2-methylbenzoate (HPLC: 40.1% for methyl 3-hydroxy-2-methylbenzoate and 53.7% for methyl 3-methoxy-2-methylbenzoate) which was directly subjected to methylation reaction.

(3) Methylation of

35g of the crude 3-hydroxy-2-methyl benzoate obtained in the step (2), adding dimethyl sulfate (15.9 g,1.5 eq.), heating to 35-40 ℃, dropwise adding 30% sodium hydroxide solution (25.3 g, 2.25 eq.), controlling the temperature not to exceed 40 ℃, and continuing stirring for 1 hour after the addition is finished until the reaction is finished.

Standing for layering, separating an oil layer, and washing with water to obtain 34 g (HPLC: 95.2%) of crude methyl 3-methoxy-2-methylbenzoate.

(4) Neutralization by hydrolysis

34 g of crude 3-methoxy-2-methylbenzoic acid methyl ester obtained in the step (3), 25.6 g of sodium hydroxide solution (1.02 eq., concentration: 30%) and 100 g of water are added, the mixture is heated to 80-90 ℃ to react until the reaction is completed, the temperature of a reaction solution is reduced, 47.1 g of sulfuric acid (concentration: 20%) is added to adjust the pH value to 1-2, the mixture is stirred for 1 hour under the condition of heat preservation after the addition is completed, and the mixture is filtered and dried to obtain 30 g of crude 3-methoxy-2-methylbenzoic acid (HPLC: 96.5%, total yield: 85%).

Recrystallization

30 g of the crude 3-methoxy-2-methylbenzoic acid obtained above was recrystallized by adding ethanol (80%) to obtain 20 g of 3-methoxy-2-methylbenzoic acid (HPLC: 99.4%).

Example 8

315 g of crude methyl 3-hydroxy-2-methylbenzoate (HPLC: methyl 3-hydroxy-2-methylbenzoate 42.8%, methyl 3-methoxy-2-methylbenzoate 55.4%) obtained in example 1 was subjected to distillation under reduced pressure, and 146 g of methyl 3-methoxy-2-methylbenzoate (GC:99.5%) was collected at an absolute pressure of 80-100 Pa and a vapor temperature of 106-. Continuing to heat until the steam temperature reaches 120-130 ℃, and starting to collect 87 g (GC: >95%) of methyl 3-hydroxy-2-methylbenzoate; about 70 g of the mixture of methyl 3-hydroxy-2-methylbenzoate and methyl 3-methoxy-2-methylbenzoate collected during the temperature rise (110 ℃ C. and 120 ℃ C.) (GC: 70.8% of methyl 3-hydroxy-2-methylbenzoate; 28.3% of methyl 3-methoxy-2-methylbenzoate).

Example 9

100 g of the crude methyl 3-methoxy-2-methylbenzoate obtained in example 8 was added with 75.0 g of a sodium hydroxide solution (1.01 eq., concentration: 30%) and 200 g of water, heated to 80-90 ℃ to complete the reaction, the reaction solution was cooled to 20-30 ℃, 103 g of hydrochloric acid (concentration: 20%) was added to adjust the pH to 1-2, and after the addition was completed, stirring was carried out under constant temperature for 1 hour, followed by filtration and drying at 90-110 ℃ to obtain 87.8 g of 3-methoxy-2-methylbenzoic acid (HPLC: 99.8%, yield: 95.3%).

Example 10

50 g of a mixture of methyl 3-hydroxy-2-methylbenzoate and methyl 3-methoxy-2-methylbenzoate (GC: 70.8% of methyl 3-hydroxy-2-methylbenzoate; 28.3% of methyl 3-methoxy-2-methylbenzoate), dimethyl sulfate (43.0 g, 1.6 eq.), 30% liquid alkali (79.5 g) added dropwise at a temperature of 30-40 ℃ with stirring for about 0.5-1.5 h, and stirring was continued until the amount of methyl 3-hydroxy-2-methylbenzoate was less than 1%.

Standing for layering, separating an oil layer, washing with water to obtain 48 g (HPLC:95.6%) of crude methyl 3-methoxy-2-methylbenzoate, and distilling under reduced pressure to obtain 35g (GC:99.6%) of methyl 3-methoxy-2-methylbenzoate.