CN113121339B - Co-production process of 3-hydroxy-2-methyl benzoate and 3-methoxy-2-methyl benzoate - Google Patents
Co-production process of 3-hydroxy-2-methyl benzoate and 3-methoxy-2-methyl benzoate Download PDFInfo
- Publication number
- CN113121339B CN113121339B CN202110420811.7A CN202110420811A CN113121339B CN 113121339 B CN113121339 B CN 113121339B CN 202110420811 A CN202110420811 A CN 202110420811A CN 113121339 B CN113121339 B CN 113121339B
- Authority
- CN
- China
- Prior art keywords
- hydroxy
- methyl
- methoxy
- reaction
- methyl benzoate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/12—Formation of amino and carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/58—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a co-production process of 3-hydroxy-2-methylbenzoate and 3-methoxy-2-methylbenzoate, which comprises the following steps: (1) reduction hydrogenation reaction: preparing 3-amino-2-methylbenzoic acid by using 2-methyl-3-nitrobenzoic acid or 2-methyl-3-nitrobenzoic acid methyl ester as a raw material through hydrogenation reduction; (2) diazotization, hydrolysis and esterification one-pot reaction: diazotizing, hydrolyzing and esterifying in a one-pot reaction by taking a reduction product as a raw material and methanol as a solvent to prepare a mixture of 3-hydroxy-2-methylbenzoate and 3-methoxy-2-methylbenzoate; (3) And (3) carrying out reduced pressure distillation to respectively collect a finished product of the 3-hydroxy-2-methyl benzoate and a finished product of the 3-methoxy-2-methyl benzoate. The method adopts diazotization, hydrolysis and esterification one-pot reaction, has compact reaction steps and simple and convenient operation, and simultaneously has hydrolysis and methanolysis products in the diazotization hydrolysis process to realize the co-production of 3-hydroxy-2-methylbenzoate and 3-methoxy-2-methylbenzoate.
Description
Technical Field
The invention belongs to the technical field of synthesis of organic pesticides and medical intermediates, and particularly relates to a co-production process of 3-hydroxy-2-methyl benzoate and 3-methoxy-2-methyl benzoate.
Background
The 3-hydroxy-2-methyl benzoic acid methyl ester is an important pesticide and medicine intermediate, the hydrolysate 3-hydroxy-2-methyl benzoic acid is an important synthetic intermediate of nelfinavir, and the methylated product 2-methyl-3-methoxybenzoic acid is an important intermediate of the high-efficiency low-toxicity pesticide methoxyfenozide.
Nelfinavir was developed by agoron corporation, usa, and a nonpeptide HIV protease inhibitor marketed in 1997, which binds to HIV protease activity with reversible bond sites, prevents HIV protease, and affects the terminal formation of the virus. The strain is the most commonly used protease inhibitor, and is mainly used for patients with acquired immunodeficiency syndrome (AIDS) and HIV-1 infection.
Methoxyfenozide is one of insect growth regulators, mainly interferes with the normal growth and development of insects, even if insects exfoliate and die, and can inhibit feeding. The product has high safety, obvious insecticidal effect and very obvious killing effect on lepidoptera larvae.
The existing process of 3-hydroxy-2-methylbenzoic acid mainly comprises the following steps:
1) The method for preparing 3-hydroxy-2-methylbenzoic acid by using 2-naphthylamine-4,8-disulfonic acid sodium salt as a raw material and reacting the raw material in a strong alkaline aqueous solution at high temperature and high pressure, which is disclosed by Chinese patent CN 1130326C, has the harsh reaction conditions (pressure: 30-160 bar, temperature: 250-300 deg.C, which is not suitable for industrialization.
2) The method for preparing 3-hydroxy-2-methylbenzoic acid by using naphthalene-1,3,5-sodium trisulfonate as a raw material and performing high-temperature and high-pressure reaction in a strong alkaline aqueous solution, which is disclosed by Chinese patent CN 1642895A, has the harsh reaction conditions (temperature: 250-320 ℃) is not beneficial to industrialization.
3) Chinese patent CN 102040514A discloses that 2-methyl-3-aminobenzoic acid is used as a raw material, and is subjected to diazotization, hydrolysis, cooling, crystallization and filtration by sodium nitrite to obtain 3-hydroxy-2-methylbenzoic acid. The method has the advantages that the raw material of the 2-methyl-3-aminobenzoic acid is not easy to obtain, the use amount of sulfuric acid is large, the waste water and the waste salt are more, and the industrialization is not facilitated.
The 2-methyl-3-methoxybenzoic acid methyl ester (or 2-methyl-3-methoxybenzoic acid) is used as 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 methods are important:
1) 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.
2) 2-methyl-3-nitrobenzoic acid is taken as a raw material, and is synthesized into 3-methoxy-2-methyl benzoate through the steps of reduction, diazotization hydrolysis and methylation. (reference document: zhejiang chemical industry, no. 44 vol.1 of 2013, synthesis of 3-methoxy-2-methylbenzoic acid), the method has the characteristics of separation of all steps, multiple separation and purification steps, large wastewater amount and high toxicity of methylating reagents, and is not beneficial to industrialization.
3) O-xylene as a feedstock (patent application: CN 201710654959.0) is subjected to nitration and oxidation to prepare 3-nitro-2-methylbenzoic acid, and the product 2-methyl-3-methoxybenzoic acid methyl ester is synthesized through the steps of esterification, reduction, diazotization and methylation. The raw materials of the method are easy to obtain, but the method also has the defects of more reaction steps, complex separation and purification, large waste water amount and high toxicity of methylating agents, and is not beneficial to production.
In conclusion, the existing production process for preparing 2-methyl-3-methoxybenzoic acid (or 2-methyl-3-methoxybenzoic acid methyl ester) and 3-hydroxy-2-methylbenzoic acid (or 3-hydroxy-2-methylbenzoic acid methyl ester) has the defects of complex process, serious pollution and difficult industrialization, and is difficult to meet the market demand and the ecological environment development demand.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a co-production process of methyl 3-hydroxy-2-methylbenzoate and methyl 3-methoxy-2-methylbenzoate. The invention takes 2-methyl-3-nitrobenzoic acid or 2-methyl-3-nitrobenzoate as raw material, and the adopted technical scheme has compact reaction steps, less separation and purification and simple and convenient operation: the hydrogenation reducing solution simultaneously forms hydrolysis products and methanolysis products in the diazotization decomposition process, so that 3-hydroxy-2-methyl benzoate and 3-methoxy-2-methyl benzoate can be simultaneously obtained, and the co-production of the 3-hydroxy-2-methyl benzoate and the 3-methoxy-2-methyl benzoate is realized.
The invention is realized by the following technical scheme:
a co-production process of 3-hydroxy-2-methylbenzoate and 3-methoxy-2-methylbenzoate comprises the following steps:
(1) Reduction hydrogenation reaction: using 2-methyl-3-nitrobenzoic acid or 2-methyl-3-nitrobenzoate 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 by hydrogenation reduction;
(2) Diazotization, hydrolysis and esterification one-pot reaction: the mixture of 3-hydroxy-2-methyl benzoate and 3-methoxy-2-methyl benzoate is prepared by diazotizing, hydrolyzing and esterifying under the action of diazotizing reagent by taking 3-amino-2-methyl benzoic acid as a reducing substance as a raw material and methanol as a solvent;
(3) And (3) carrying out reduced pressure distillation to respectively collect a finished product of the 3-hydroxy-2-methyl benzoate and a finished product of the 3-methoxy-2-methyl benzoate.
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 0-5 ℃, 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; 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 to 15.
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, which is introduced via the aqueous sodium nitrite solution, or may be derived from the water produced by the hydrogenation reduction reaction. The further scheme of the invention is as follows:
when the reaction in step (2) is finished in one pot, the method comprises the following post-treatment steps: distilling under normal pressure or reduced pressure to recover solvent methanol, diluting the concentrated solution with water for layering, separating out water layer, collecting the oil layer, removing the water layer by organic solvent extraction, concentrating the organic layer, desolventizing, and performing 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 is carried out 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, the separated oil layer and organic layer after washing with concentrated water are a mixture of methyl 3-methoxy-2-methylbenzoate/methyl 3-hydroxy-2-methylbenzoate.
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, when the absolute pressure is 80-100Pa, the temperature of the methyl 3-hydroxy-2-methylbenzoate is 120-130 ℃, and the temperature of the methyl 3-methoxy-2-methylbenzoate is 106-110 ℃; the content of the 3-methoxy-2-methyl benzoate product can reach more than 99.5 percent, and the content of the 3-hydroxy-2-methyl benzoate product can reach 98.5 percent.
After the 3-methoxy-2-methyl benzoic acid methyl ester is purified by reduced pressure distillation, the 3-methoxy-2-methyl benzoic acid product obtained by hydrolysis and neutralization has higher purity, generally more than 99.8 percent, stable and controllable product quality, and is more suitable for industrialization of downstream products.
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 concentrating and recovering part of the solvent, cooling to 0-10 ℃, and filtering out insoluble 3-amino-2-methylbenzoic acid.
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 reduction hydrogenation and diazotization hydrolysis, so that the solvent can be conveniently recycled, and the ecological environment is protected.
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 realize the co-production of 3-hydroxy-2-methyl benzoate and 3-methoxy-2-methyl benzoate.
Detailed Description
Example 1
(1) Reductive hydrogenation
Adding 3-nitro-2-methylbenzoic acid (500 g), platinum carbon (platinum content is 2%,50 g) and methanol (2000 g) into a pressure kettle, replacing with nitrogen, introducing hydrogen pressure to 1.0-1.3MPa, heating to 70-80 ℃, controlling the reaction pressure until the reaction is complete (raw material is less than 0.5%), continuing stirring for 60min, filtering while hot, collecting catalyst for reuse, and directly performing diazotization hydrolysis on mother liquor.
(2) Diazotization hydrolysis
Cooling the reduction mother liquor obtained in the step (1) to 0-5 ℃, dropwise adding nitrosyl sulfuric acid 900g (weight percentage: 40%,1.02 eq.) under controlled temperature, heating to 50-60 ℃ after adding, heating for not less than 30min, stirring for 1 h, heating to 64-66 ℃ for reflux reaction for 4-8 h until the reaction is finished (HPLC: 3-hydroxy-2-methylbenzoic acid + 3-methoxy-2-methylbenzoic acid is less than 1%).
Heating the reaction solution to 85-100 ℃, distilling at normal pressure to recover methanol, recovering methanol 1400-1600g, adding water 1200g, standing for layering, separating out an oil layer, and collecting.
The water layer is extracted by 1000ml of MIBK, the separated organic layer is concentrated and then is combined with the oil layer to obtain a crude product of 3-hydroxy-2-methyl benzoate 425g (HPLC: 42.8 percent of 3-hydroxy-2-methyl benzoate and 51.4 percent of 3-methoxy-2-methyl benzoate) which is directly subjected to methylation reaction.
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, performing nitrogen replacement, introducing hydrogen pressure to 0.9-1.1 MPa, heating to 60-70 ℃, controlling the temperature and the reaction pressure until the reaction is complete (raw materials are 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 sulfuric acid 92.2 g (1.2 eq.) into the reduction mother liquor (1/3 of the amount) obtained in the step (1), cooling to 5-10 ℃, dropwise adding a sodium nitrite solution 126.6 g (sodium nitrite: 63.6 g,1.2 eq.; water: 63 g) 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%).
Raising the temperature to 85-100 ℃, distilling to recover methanol about 360 g, adding water 400 g, standing for layering, and separating out an oil layer 110g.
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 give crude methyl 3-hydroxy-2-methylbenzoate 135 g (HPLC: methyl 3-hydroxy-2-methylbenzoate: 56.25%, methyl 3-methoxy-2-methylbenzoate = 33.68%) which was directly subjected to methylation reaction.
Example 3
The reducing mother liquor (1/3 amount) obtained in the step (1) of the example 2 is added with sulfuric acid 150.6 g (2.0 eq.), cooled to 20-30 ℃, dropwise added with sodium nitrite solution 155.7 g (sodium nitrite: 55.7 g,1.05 eq.; water: 100 g) under controlled temperature, slowly heated to 50-60 ℃ after the addition, stirred for 1 hour, heated to 64-66 ℃ and refluxed for 8-16 hours till the reaction is finished (HPLC: 3-hydroxy-2-methylbenzoic acid + 3-methoxy-2-methylbenzoic acid < 1%).
Raising the temperature to 85-100 ℃, distilling at normal pressure to recover methanol about 360 g, adding water 400 g, standing for layering, and separating an oil layer 105 g.
The aqueous layer was extracted with 100ml of MIBK, the organic layer separated and concentrated, and then combined with the oil layer to give crude 3-hydroxy-2-methylbenzoate 138 g (HPLC: methyl 3-hydroxy-2-methylbenzoate: 49.3%; methyl 3-methoxy-2-methylbenzoate = 45.3%) which was directly subjected to methylation reaction.
Example 4
The reducing mother liquor (1/3 amount) obtained in the step (1) of the example 2 is added with sulfuric acid 263.6 g (3.5 eq.), cooled to 50-55 ℃, dropwise added with sodium nitrite solution 113.3 g (sodium nitrite: 58.3 g,1.1eq., water: 65 g) under controlled temperature, slowly heated to 50-60 ℃ after the addition, stirred for 1 hour, heated to 64-66 ℃ for reflux reaction for 8-16 hours until the reaction is completed (HPLC: 3-hydroxy-2-methylbenzoic acid + 3-methoxy-2-methylbenzoic acid < 1%).
After the temperature is raised and methanol is recovered by atmospheric distillation at about 360 g, 330 g is added into water, and the mixture is kept stand for layering, and 102g of an oil layer is separated.
The aqueous layer was extracted with 100ml of ethyl acetate, the organic layer was separated and concentrated, and the combined layer was combined with the oil layer to give crude methyl 3-hydroxy-2-methylbenzoate 136 g (HPLC: methyl 3-hydroxy-2-methylbenzoate: 48.05%; methyl 3-methoxy-2-methylbenzoate = 45.59%) which was directly subjected to methylation reaction.
Example 5
(1) Reductive hydrogenation
Adding 3-nitro-2-methylbenzoic acid (500 g), palladium carbon (palladium content is 10%, 10 g) and methanol (1500 g) into a pressure kettle, replacing nitrogen, introducing hydrogen pressure to 0.5-0.7 MPa, heating to 90 ℃, controlling the temperature to control the reaction pressure until the reaction is complete (raw material is less than 0.5%), continuing stirring for 60min, filtering while hot to recover the catalyst, concentrating the mother liquor to about residual 500-700 g methanol, cooling, filtering to obtain 3-amino-2-methylbenzoic acid 320-g, and performing diazotization hydrolysis on the solid.
(2) Diazotization hydrolysis
Adding 3000g of methanol into 300 g of the 3-amino-2-methylbenzoic acid obtained in the step (1), cooling to 20-30 ℃, dropwise adding 686 g of nitroso sulfuric acid (1.02 eq weight percentage: 40%) under controlled temperature, slowly heating to 50-60 ℃ after adding, 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 900g, standing for layering, and separating oil layer.
The aqueous layer was extracted with 300ml of n-butyl acetate, the organic layer was separated and concentrated, and the combined layer was combined with the oil layer to give crude methyl 3-hydroxy-2-methylbenzoate 301 g (HPLC: 33.3% methyl 3-hydroxy-2-methylbenzoate, 62.9% methyl 3-methoxy-2-methylbenzoate) which was directly subjected to methylation reaction.
Example 6
(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, replacing with nitrogen, introducing hydrogen pressure 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 performing 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 adding, slowly heating to 50-60 ℃, stirring for 1 hour, adding 10g 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 methanol about 200g, adding water 120 g, standing for layering, and separating oil layer 30 g.
The water layer was extracted with 100ml of ethyl acetate, the organic layer was separated and concentrated, and the combined with the oil layer to give crude methyl 3-hydroxy-2-methylbenzoate 40 g (HPLC: 40.1% methyl 3-hydroxy-2-methylbenzoate, 53.7% methyl 3-methoxy-2-methylbenzoate), which was directly subjected to methylation reaction.
Example 7
Crude methyl 3-hydroxy-2-methylbenzoate 315g (HPLC: methyl 3-hydroxy-2-methylbenzoate 42.8%, methyl 3-methoxy-2-methylbenzoate 55.4%) obtained in example 1 was distilled under reduced pressure, absolute pressure was controlled to 80-100Pa, steam temperature was controlled to 106-110 ℃, and methyl 3-methoxy-2-methylbenzoate 146g (GC: 99.7%) was collected. Continuing to heat until the steam temperature reaches 120-130 ℃, and starting to collect methyl 3-hydroxy-2-methylbenzoate 87g (GC: 98.5%); the mixture of methyl 3-hydroxy-2-methylbenzoate and methyl 3-methoxy-2-methylbenzoate collected during the temperature rise (110-120 ℃) was about 70g (GC: methyl 3-hydroxy-2-methylbenzoate 70.8%; methyl 3-methoxy-2-methylbenzoate 38.3%).
Example 8
The crude methyl 3-methoxy-2-methylbenzoate 100 g obtained in example 8 was added with sodium hydroxide solution 75.0 g (1.01 eq., concentration: 30%), water 200g, heated to 80-90 ℃ to complete the reaction, the reaction solution was cooled to 20-30 ℃, hydrochloric acid 103 g (concentration: 20%) was added to adjust the pH to 1-2, after the addition, stirring was carried out for 1 hour with heat preservation, filtration was carried out, and drying was carried out at 90-110 ℃ to obtain 87.8 g (HPLC: 99.8%, yield: 95.3%) of 3-methoxy-2-methylbenzoic acid.
Claims (1)
1. A co-production process of 3-hydroxy-2-methyl benzoate and 3-methoxy-2-methyl benzoate is characterized by comprising the following steps:
(1) Reductive hydrogenation
Adding 500g of 3-nitro-2-methylbenzoic acid, platinum and carbon, wherein the platinum content is 2%,50g and 2000g of methanol into a pressure kettle, replacing with nitrogen, introducing hydrogen to 1.0-1.3MPa, heating to 70-80 ℃, controlling the reaction pressure until the reaction is complete, continuing stirring for 60min after the raw material is less than 0.5%, filtering while hot, collecting and recycling the catalyst, and directly performing diazotization hydrolysis on the mother liquor;
(2) Diazotization hydrolysis
Cooling the reduction mother liquor obtained in the step (1) to 0-5 ℃, and dropwise adding 900g of nitroso-sulfuric acid at a controlled temperature, wherein the weight percentage is as follows: 40 percent, heating to 50-60 ℃ after adding, heating for not less than 30min, stirring for 1 hour, heating to 64-66 ℃, refluxing for 4-8 hours until the reaction is finished, and HPLC (high performance liquid chromatography) is performed, wherein the content of 3-hydroxy-2-methylbenzoic acid and 3-methoxy-2-methylbenzoic acid is less than 1 percent;
heating the reaction solution to 85-100 ℃, distilling at normal pressure to recover methanol, adding 1200g of water after 1400-1600g of methanol is recovered, standing for layering, separating out an oil layer and collecting;
extracting a water layer by using 1000ml of MIBK, separating an organic layer, concentrating, and then combining with an oil layer to obtain 425g of a crude product of 3-hydroxy-2-methyl benzoate, 42.8 percent of 3-hydroxy-2-methyl benzoate and 51.4 percent of 3-methoxy-2-methyl benzoate, and directly carrying out methylation reaction;
315g of the obtained crude 3-hydroxy-2-methyl benzoate, 42.8% of 3-hydroxy-2-methyl benzoate and 55.4% of 3-methoxy-2-methyl benzoate by HPLC, controlling the absolute pressure of 80-100Pa and the steam temperature of 106-110 ℃ by reduced pressure distillation, collecting 146g of 3-methoxy-2-methyl benzoate, and GC; continuously heating until the steam temperature reaches 120-130 ℃, and starting to collect 87g of methyl 3-hydroxy-2-methylbenzoate, wherein GC is as follows; 70g of a mixture of methyl 3-hydroxy-2-methylbenzoate and methyl 3-methoxy-2-methylbenzoate collected at 110-120 ℃ in the temperature rise process, and 70.8% of 3-hydroxy-2-methylbenzoate by GC; 38.3 percent of 3-methoxy-2-methyl benzoate.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110420811.7A CN113121339B (en) | 2021-04-19 | 2021-04-19 | Co-production process of 3-hydroxy-2-methyl benzoate and 3-methoxy-2-methyl benzoate |
| PCT/CN2021/104063 WO2022222271A1 (en) | 2021-04-19 | 2021-07-01 | Co-production process of methyl 3-hydroxy-2-methylbenzoate and methyl 3-methoxy-2-methylbenzoate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110420811.7A CN113121339B (en) | 2021-04-19 | 2021-04-19 | Co-production process of 3-hydroxy-2-methyl benzoate and 3-methoxy-2-methyl benzoate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113121339A CN113121339A (en) | 2021-07-16 |
| CN113121339B true CN113121339B (en) | 2022-10-11 |
Family
ID=76778060
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110420811.7A Active CN113121339B (en) | 2021-04-19 | 2021-04-19 | Co-production process of 3-hydroxy-2-methyl benzoate and 3-methoxy-2-methyl benzoate |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN113121339B (en) |
| WO (1) | WO2022222271A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114349627A (en) * | 2022-01-25 | 2022-04-15 | 山东友道化学有限公司 | Preparation method of 2-methyl-3-hydroxybenzoic acid |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5530028A (en) * | 1992-11-23 | 1996-06-25 | Rohm And Haas Company | Insecticidal N'-substituted-N,N'-diacylhydrazines |
| CN109384667A (en) * | 2017-08-02 | 2019-02-26 | 江苏永安化工有限公司 | A kind of synthesis technology of 2- methyl -3- methoxy benzoyl chloride |
-
2021
- 2021-04-19 CN CN202110420811.7A patent/CN113121339B/en active Active
- 2021-07-01 WO PCT/CN2021/104063 patent/WO2022222271A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| CN113121339A (en) | 2021-07-16 |
| WO2022222271A1 (en) | 2022-10-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8207354B2 (en) | Process for preparing alkyl 2-alkoxymethylene-4,4-difluoro-3-oxobutyrates | |
| CA1077057A (en) | Process for the preparation of acetic acid derivatives | |
| CN113121339B (en) | Co-production process of 3-hydroxy-2-methyl benzoate and 3-methoxy-2-methyl benzoate | |
| JPS6121211B2 (en) | ||
| CN112479938B (en) | Preparation method of N-cyclohexyl-2-aminoethanesulfonic acid | |
| JPS6232741B2 (en) | ||
| CN110734368B (en) | Preparation method of buparvaquone | |
| CN113511968A (en) | Synthesis process of 2-methyl-3-methoxybenzoic acid | |
| CN105198710B (en) | The synthetic method of one inter-species tert-butyl phenol | |
| CN105439837B (en) | Synthetic method of 6-bromoisovanillin | |
| CN113072441A (en) | Preparation method of 2-methoxy-6-methylbenzoic acid | |
| CN111116430B (en) | Preparation method of sodium taurate | |
| CN116410082A (en) | Preparation method of trans-p-methylcyclohexyl formic acid | |
| JPS6155902B2 (en) | ||
| CN107382885B (en) | Preparation method of 1H-1,2, 3-triazole | |
| CN116283500B (en) | Synthesis method of high-purity 2, 6-dihydroxytoluene | |
| CN116874360B (en) | Synthesis method of buparvaquone | |
| CN115368217B (en) | Synthesis method of 3,4, 5-trimethoxytoluene | |
| CN111484407B (en) | Preparation method of 1-halogenated-2-methyl-4-substituted carbonyloxy-2-butene | |
| JPH0662489B2 (en) | Valproic acid manufacturing method | |
| CN109867601B (en) | Preparation method of (R) -2- (4-hydroxyphenoxy) butyl propionate | |
| WO2023178538A1 (en) | Method for purifying levetiracetam intermediate | |
| EP0663394B1 (en) | Process for preparing 5-aminodihydropyrrole, intermediate thereof and process for preparing said intermediate | |
| CN114292229A (en) | Preparation method of 3-bromo-4-methoxypyridine | |
| JP4024919B2 (en) | Process for producing 1-amino-1-methyl-3 (4) -aminomethylcyclohexane |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |