A method for preparing 3-hydroxy-2-methylbenzoic acid

Abstract

This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing 3-hydroxy-2-methylbenzoic acid. The method comprises the following steps: mixing 3-amino-2-methylbenzoic acid, an inorganic acid, a catalyst, and water for hydrolysis to obtain crude 3-hydroxy-2-methylbenzoic acid; extracting the crude 3-hydroxy-2-methylbenzoic acid to obtain an extract phase and a raffinate phase; and sequentially washing and concentrating the extract phase to obtain the 3-hydroxy-2-methylbenzoic acid. The method provided by this invention is simple, generates no waste, and has a relatively simple ammonium salt recovery process, making it a green and environmentally friendly synthesis process. As shown in the example data, the yield of 3-hydroxy-2-methylbenzoic acid synthesized by this invention can reach over 94%, and the purity can reach up to 98%, demonstrating good industrial value.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing 3-hydroxy-2-methylbenzoic acid. Background Technology

[0002] 3-Hydroxy-2-methylbenzoic acid is an important pesticide and pharmaceutical intermediate, often used in the synthesis of substances such as methoxyfenozide and HIV protease inhibitors.

[0003] Currently, the purity of 3-hydroxy-2-methylbenzoic acid in industrial production is relatively low, requiring further purification before it can be used for downstream product preparation. Chinese patent CN1264358A discloses a method for preparing 3-hydroxy-2-methylbenzoic acid, using 3-amino-1,5-naphthalenedisulfonic acid and potassium hydroxide aqueous solution at 250–300°C and at least 100 bar. While this method yields high product purity, the high-temperature, high-pressure reaction is not suitable for industrial production due to high energy consumption and safety concerns. Chinese patent CN102040514A discloses a method using 3-amino-2-methylbenzoic acid as a raw material, undergoing diazotization with sodium nitrite, followed by hydrolysis, cooling, crystallization, and filtration to obtain 3-hydroxy-2-methylbenzoic acid. This method employs a traditional diazotization reaction, which is relatively complex and also carries significant risks. The large amount of sulfuric acid used results in substantial wastewater and waste salt production, which is unfavorable for industrial production. Summary of the Invention

[0004] In view of this, the purpose of this invention is to provide a method for preparing 3-hydroxy-2-methylbenzoic acid. The preparation method provided by this invention can achieve the safe production of 3-hydroxy-2-methylbenzoic acid and is environmentally friendly.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] This invention provides a method for preparing 3-hydroxy-2-methylbenzoic acid, comprising the following steps:

[0007] 3-Amino-2-methylbenzoic acid, inorganic acid, catalyst and water were mixed and hydrolyzed to obtain crude 3-hydroxy-2-methylbenzoic acid;

[0008] The crude 3-hydroxy-2-methylbenzoic acid was extracted to obtain an extract phase and a raffinate phase;

[0009] The extract phase was sequentially washed with water and concentrated to obtain the 3-hydroxy-2-methylbenzoic acid.

[0010] Preferably, the inorganic acid includes phosphoric acid, sulfuric acid, or hydrochloric acid.

[0011] Preferably, the molar ratio of 3-amino-2-methylbenzoic acid to the inorganic acid is 1:1 to 5.

[0012] Preferably, the catalyst is a copper-based catalyst.

[0013] Preferably, the mass ratio of the catalyst to 3-amino-2-methylbenzoic acid is 0.1% to 1%.

[0014] Preferably, the molar ratio of 3-amino-2-methylbenzoic acid to water is 1:50 to 150.

[0015] Preferably, the hydrolysis reaction includes a first stage and a second stage performed sequentially;

[0016] The temperature of the first stage is 60-70℃, and the time is 1-3 hours;

[0017] The second stage has a temperature of 180–220℃, a pressure of 1.0–2.5 MPa, and a time of 6–12 hours.

[0018] Preferably, the extractant used in the extraction is ethyl acetate, methyl isopropyl ketone, methyl isobutyl ketone, or toluene.

[0019] Preferably, the concentration is achieved by vacuum distillation.

[0020] Preferably, after obtaining the raffinate phase, the method further includes neutralizing and concentrating the raffinate phase sequentially to obtain an ammonium salt.

[0021] This invention provides a method for preparing 3-hydroxy-2-methylbenzoic acid, comprising the following steps: mixing 3-amino-2-methylbenzoic acid, an inorganic acid, a catalyst, and water for hydrolysis to obtain crude 3-hydroxy-2-methylbenzoic acid; extracting the crude 3-hydroxy-2-methylbenzoic acid to obtain an extract phase and a raffinate phase; and sequentially washing and concentrating the extract phase to obtain the 3-hydroxy-2-methylbenzoic acid. The method provided by this invention uses 3-amino-2-methylbenzoic acid as a raw material and directly hydrolyzes it to synthesize 3-hydroxy-2-methylbenzoic acid under the action of acid and a catalyst. The process is simple, generates no waste, and compared with existing technologies, avoids the dangers of diazotization reactions and does not produce difficult-to-recover sodium salts. The ammonium salt recovery process generated by this method is relatively simple, making it a green and environmentally friendly synthesis process. As shown in the example data, the yield of 3-hydroxy-2-methylbenzoic acid synthesized by this invention can reach over 94%, and the purity can reach up to 98%, demonstrating good industrial value.

[0022] Meanwhile, the preparation method provided by this invention has mild reaction conditions, relatively low temperature and pressure, and low equipment requirements, making it suitable for large-scale industrial production. Detailed Implementation

[0023] This invention provides a method for preparing 3-hydroxy-2-methylbenzoic acid, comprising the following steps:

[0024] 3-Amino-2-methylbenzoic acid, inorganic acid, catalyst and water were mixed and hydrolyzed to obtain crude 3-hydroxy-2-methylbenzoic acid;

[0025] The crude 3-hydroxy-2-methylbenzoic acid was extracted to obtain an extract phase and a raffinate phase;

[0026] The extract phase was sequentially washed with water and concentrated to obtain the 3-hydroxy-2-methylbenzoic acid.

[0027] In this invention, unless otherwise specified, all raw material components are commercially available products well known to those skilled in the art.

[0028] The present invention involves mixing 3-amino-2-methylbenzoic acid, an inorganic acid, a catalyst, and water to carry out a hydrolysis reaction to obtain crude 3-hydroxy-2-methylbenzoic acid.

[0029] In this invention, the inorganic acid preferably includes phosphoric acid, sulfuric acid, or hydrochloric acid, more preferably phosphoric acid or sulfuric acid, and most preferably phosphoric acid; the molar ratio of 3-amino-2-methylbenzoic acid to the inorganic acid is preferably 1:1 to 5, more preferably 1:1 to 4, and most preferably 1:1 to 2.5; this invention does not have a special limitation on the concentration of the inorganic acid, and conventional concentrations known to those skilled in the art can be used.

[0030] In this invention, the catalyst is preferably a copper-based catalyst; the copper-based catalyst is preferably copper powder, cuprous chloride, or copper oxide, more preferably copper powder or cuprous chloride; the mass ratio of the catalyst to 3-amino-2-methylbenzoic acid is preferably 0.1-1%, more preferably 0.1-0.5%, and most preferably 0.1-0.3%.

[0031] In this invention, the molar ratio of 3-amino-2-methylbenzoic acid to water is preferably 1:50 to 150, more preferably 1:80 to 150, and most preferably 1:100 to 150.

[0032] In this invention, the preferred order of adding the hydrolysis reaction materials is water, inorganic acid, 3-amino-2-methylbenzoic acid, and catalyst in sequence.

[0033] In this invention, the hydrolysis reaction preferably includes a first stage and a second stage carried out sequentially; the temperature of the first stage is preferably 60-70°C, more preferably 65-70°C; the time is preferably 1-3 hours, more preferably 1-2 hours; the temperature of the second stage is preferably 180-220°C, more preferably 190-210°C; the pressure is preferably 1.0-2.5 MPa, more preferably 1.5-2.0 MPa; the time is preferably 6-12 hours, more preferably 8-10 hours.

[0034] In this invention, the reaction atmosphere of the hydrolysis reaction is preferably an inert atmosphere; the inert atmosphere is preferably nitrogen; the inert atmosphere is preferably provided by inert atmosphere replacement; the number of inert atmosphere replacements is preferably 3 to 5 times, more preferably 3 to 4 times.

[0035] In this invention, the reactor lining material for the hydrolysis reaction is preferably zirconium, tantalum, zirconium alloy or Monel alloy, more preferably zirconium, tantalum or zirconium alloy, and most preferably zirconium or zirconium alloy.

[0036] In this invention, the use of the above-mentioned types of reactor lining materials for the hydrolysis reaction serves two purposes: firstly, it can solve the corrosion of the reactor lining material by inorganic acids under high-temperature conditions; and secondly, it can reduce the generation of tar.

[0037] In this invention, the chemical equation for the hydrolysis reaction is:

[0038]

[0039] After obtaining the crude 3-hydroxy-2-methylbenzoic acid, the present invention extracts the crude 3-hydroxy-2-methylbenzoic acid to obtain an extract phase and a raffinate phase.

[0040] In this invention, the extractant used for extraction is preferably ethyl acetate, methyl isopropyl ketone, methyl isobutyl ketone, or toluene, more preferably ethyl acetate, methyl isopropyl ketone, or toluene, and most preferably ethyl acetate or toluene; the number of extractions is preferably 1 to 4 times, more preferably 2 times; the mass ratio of the extractant to water is preferably 1:1 to 20, more preferably 1:1 to 10, and most preferably 1:1 to 5; the extraction temperature is preferably 20 to 60°C, more preferably 20 to 40°C, and most preferably 30°C.

[0041] In this invention, the extraction process preferably includes a periodic separation.

[0042] After obtaining the extract phase, the present invention sequentially washes and concentrates the extract phase with water to obtain the 3-hydroxy-2-methylbenzoic acid.

[0043] In this invention, the number of water washings is preferably 1 to 3 times, more preferably 2 times; the water washing process also includes static stratification.

[0044] In this invention, the concentration is preferably carried out by vacuum distillation; this invention does not impose any special limitations on the vacuum distillation process, and the solvent of the extract phase can be removed by means well known to those skilled in the art.

[0045] After obtaining the raffinate phase, the present invention preferably neutralizes and concentrates the raffinate phase sequentially to obtain an ammonium salt.

[0046] In this invention, the neutralizing reagent is preferably liquid ammonia; the mass ratio of the raffinate phase to liquid ammonia is preferably 50-400:1, more preferably 50-300:1, and most preferably 50-200:1; this invention does not impose any special limitations on the concentration process, and the ammonium salt in the raffinate phase can be crystallized out using a method known to those skilled in the art.

[0047] The method provided by this invention uses 3-amino-2-methylbenzoic acid as a raw material to directly hydrolyze and synthesize 3-hydroxy-2-methylbenzoic acid under the action of acid and catalyst. The process is simple, generates no waste, and avoids the dangers of diazotization reactions compared to existing technologies. It also avoids the production of difficult-to-recover sodium salts. The recovery process for the ammonium salts produced by this method is relatively simple, making it a green and environmentally friendly synthesis process. As shown in the example data, the yield of 3-hydroxy-2-methylbenzoic acid synthesized by this invention can reach over 94%, and the purity can reach up to 98%, demonstrating good industrial value. Furthermore, the preparation method provided by this invention uses mild reaction conditions with relatively low temperature and pressure, requiring less sophisticated equipment and making it suitable for large-scale industrial production.

[0048] To further illustrate the present invention, the preparation method of 3-hydroxy-2-methylbenzoic acid provided by the present invention will be described in detail below with reference to the embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0049] Example 1

[0050] In a 1L high-pressure reactor containing zirconium, 360g of water, 40g (0.4mol) of 98.5% sulfuric acid, 30.6g (0.2mol) of 3-amino-2-methylbenzoic acid, and 0.1g of copper powder were added sequentially. The reactor was purged with nitrogen three times and then sealed. The temperature was raised to 70℃ and maintained for 1 hour. The temperature was then raised again to 180℃, the pressure was 1.0 MPa, and the reaction was maintained for 12 hours. After the hydrolysis reaction, the temperature was lowered to 30℃, and the reaction solution was extracted twice with 100g of methyl isobutyl ketone. The extract and raffinate phases were combined to obtain 390g of raffinate phase and 135g of extract phase. The raffinate was neutralized with 3.4g of liquid ammonia, concentrated, and crystallized to obtain 42.7g of ammonium bisulfate as a byproduct. The extract phase was washed twice with water and the solvent was removed by vacuum distillation to obtain 29.6g of crude 3-hydroxy-2-methylbenzoic acid. The purity of the crude product was determined by high performance liquid chromatography (HPLC) to be 96.0%, with a yield of 93.5%.

[0051] Example 2

[0052] In a 1L high-pressure reactor containing zirconium, 353g of water, 46.1g (0.4mol) of 85% phosphoric acid, 30.6g (0.2mol) of 3-amino-2-methylbenzoic acid, and 0.1g of copper powder were added sequentially. The reactor was purged with nitrogen three times and then sealed. The temperature was raised to 70℃ and maintained for 1 hour. The temperature was then raised again to 180℃, the pressure was 1.0 MPa, and the reaction was maintained for 12 hours. After the hydrolysis reaction, the temperature was lowered to 30℃, and the reaction solution was extracted twice with 100g of methyl isobutyl ketone. The extract and raffinate phases were combined to obtain 395g of raffinate phase and 132.5g of extract phase. The raffinate was neutralized with 3.4 g of liquid ammonia, concentrated, and crystallized to obtain 42.0 g of ammonium dihydrogen phosphate as a byproduct. The extract phase was washed twice with water and the solvent was removed by vacuum distillation to obtain 29.5 g of 3-hydroxy-2-methylbenzoic acid. The purity of the product was determined by high performance liquid chromatography (HPLC) to be 97.5%, and the yield was 94.5%.

[0053] Example 3

[0054] In a 1L high-pressure reactor containing zirconium, 345g of water, 40g (0.4mol) of 36.5% hydrochloric acid, 30.6g (0.2mol) of 3-amino-2-methylbenzoic acid, and 0.1g of copper powder were added sequentially. The reactor was purged with nitrogen three times and then sealed. The temperature was raised to 70℃ and maintained for 1 hour. The temperature was then raised again to 180℃, the pressure was 1.0MPa, and the reaction was maintained for 12 hours. After the hydrolysis reaction was completed, the temperature was lowered to approximately 30℃, and the reaction solution was extracted twice with 100g of methyl isobutyl ketone. The extract and raffinate phases were combined to obtain 380.5g of raffinate phase and 131g of extract phase. The raffinate was neutralized with 3.4g of liquid ammonia, concentrated, and crystallized to obtain 19.5g of ammonium chloride as a byproduct. The extract phase was washed twice with water and the solvent was removed by vacuum distillation to obtain 29.5g of 3-hydroxy-2-methylbenzoic acid. The purity of the product was determined by high performance liquid chromatography (HPLC) to be 97.0%, with a yield of 94.1%.

[0055] Example 4

[0056] In a 1L high-pressure reactor containing zirconium, 353g of water, 46.1g (0.4mol) of 85% phosphoric acid, 30.6g (0.2mol) of 3-amino-2-methylbenzoic acid, and 0.1g of copper powder were added sequentially. The reactor was purged with nitrogen three times and then sealed. The temperature was raised to 70℃ and maintained for 1 hour. The temperature was then raised again to 220℃ and the pressure to 2.5MPa, and the reaction was maintained for 6 hours. After the hydrolysis reaction, the temperature was lowered to approximately 30℃, and the reaction solution was extracted twice with 100g of methyl isobutyl ketone. The extract and raffinate phases were combined to obtain 392g of raffinate phase and 133g of extract phase. The raffinate was neutralized with 3.4g of liquid ammonia and then concentrated and crystallized to obtain 41.8g of ammonium dihydrogen phosphate as a byproduct. The extract phase was washed twice with water and the solvent was removed by vacuum distillation to obtain 29.5g of 3-hydroxy-2-methylbenzoic acid. The purity of the product was determined by high performance liquid chromatography (HPLC) to be 97.3%, and the yield was 94.4%.

[0057] Example 5

[0058] In a 1L high-pressure reactor containing zirconium, 173g of water, 46.1g (0.4mol) of 85% phosphoric acid, 30.6g (0.2mol) of 3-amino-2-methylbenzoic acid, and 0.1g of copper powder were added sequentially. The reactor was purged with nitrogen three times and then sealed. The temperature was raised to 70℃ and maintained for 1 hour. The temperature was then raised again to 220℃ and the pressure to 2.5 MPa, and the reaction was maintained for 6 hours. After the hydrolysis reaction, the temperature was lowered to approximately 30℃, and the reaction solution was extracted twice with 50g of methyl isobutyl ketone. The extracted phase and raffinate were combined to obtain 215g of raffinate and 80g of extracted phase. The raffinate was neutralized with 3.4g of liquid ammonia and then concentrated and crystallized to obtain 43.1g of ammonium dihydrogen phosphate as a byproduct. The extract phase was washed twice with water and the solvent was removed by vacuum distillation to obtain 29.4g of 3-hydroxy-2-methylbenzoic acid. The purity of the product was determined by high performance liquid chromatography (HPLC) to be 96.3%, and the yield was 92.2%.

[0059] Example 6

[0060] In a 1L high-pressure reactor containing zirconium, 533g of water, 46.1g (0.4mol) of 85% phosphoric acid, 24.4g (0.2mol) of 3-amino-2-methylbenzoic acid, and 0.1g of copper powder were added sequentially. The reactor was purged with nitrogen three times and then sealed. The temperature was raised to 70℃ and maintained for 1 hour. The temperature was then raised again to 220℃ and the pressure to 2.5MPa, and the reaction was maintained for 6 hours. After the hydrolysis reaction was completed, the temperature was lowered to 30℃, and the reaction solution was extracted twice with 120g of methyl isopropyl ketone. The extract and raffinate phases were combined to obtain 447g of raffinate phase and 151g of extract phase. The raffinate was neutralized with 3.4g of liquid ammonia, concentrated, and crystallized to obtain 40.8g of ammonium dihydrogen phosphate as a byproduct. The extract phase was washed twice with water and the solvent was removed by vacuum distillation to obtain 29.8g of 3-hydroxy-2-methylbenzoic acid. The purity of the product was determined by high performance liquid chromatography (HPLC) to be 98.0%, with a yield of 96.0%.

[0061] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A process for the preparation of 3-hydroxy-2-methylbenzoic acid, characterized in that, Includes the following steps: 3-Amino-2-methylbenzoic acid, inorganic acid, catalyst and water were mixed and hydrolyzed to obtain crude 3-hydroxy-2-methylbenzoic acid; The crude 3-hydroxy-2-methylbenzoic acid was extracted to obtain an extract phase and a raffinate phase; The extract phase was sequentially washed with water and concentrated to obtain the 3-hydroxy-2-methylbenzoic acid; The catalyst is copper powder.

2. The production method according to claim 1, characterized by, The inorganic acid includes phosphoric acid, sulfuric acid, or hydrochloric acid.

3. The preparation method according to claim 1 or 2, characterized in that, The molar ratio of 3-amino-2-methylbenzoic acid to inorganic acid is 1:1 to 5.

4. The preparation method according to claim 1, characterized in that, The mass ratio of the catalyst to 3-amino-2-methylbenzoic acid is 0.1% to 1%.

5. The preparation method according to claim 1, characterized in that, The molar ratio of 3-amino-2-methylbenzoic acid to water is 1:50 to 150.

6. The preparation method according to claim 1, characterized in that, The hydrolysis reaction includes a first stage and a second stage that proceed sequentially. The temperature of the first stage is 60-70℃, and the time is 1-3 hours; The second stage has a temperature of 180–220℃, a pressure of 1.0–2.5 MPa, and a time of 6–12 hours.

7. The preparation method according to claim 1, characterized in that, The extraction solvent used is ethyl acetate, methyl isopropyl ketone, methyl isobutyl ketone, or toluene.

8. The preparation method according to claim 1, characterized in that, The concentration is achieved through vacuum distillation.

9. The preparation method according to claim 1, characterized in that, After obtaining the raffinate phase, the process further includes neutralizing and concentrating the raffinate phase sequentially to obtain an ammonium salt.

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