CN112250562A - Synthetic method of 2-bromo-5-methoxybenzoic acid - Google Patents
Synthetic method of 2-bromo-5-methoxybenzoic acid Download PDFInfo
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- CN112250562A CN112250562A CN202011137321.8A CN202011137321A CN112250562A CN 112250562 A CN112250562 A CN 112250562A CN 202011137321 A CN202011137321 A CN 202011137321A CN 112250562 A CN112250562 A CN 112250562A
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- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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Abstract
The invention provides a synthetic method of 2-bromo-5-methoxybenzoic acid, which comprises the following steps: dissolving m-methoxybenzoic acid in a halogenated hydrocarbon solvent, and carrying out bromination reaction with a bromination reagent under the action of a bromination initiator, a cocatalyst and sulfuric acid to obtain a 2-bromo-5-methoxybenzoic acid reaction solution; and pouring the reaction liquid of the 2-bromo-5-methoxybenzoic acid into ice water for quenching, recovering the halogenated hydrocarbon solvent under reduced pressure, filtering, and recrystallizing by using the solvent to obtain a finished product of the 2-bromo-5-methoxybenzoic acid. The synthesis method of the 2-bromo-5-methoxybenzoic acid provided by the invention has the advantage that the yield of the prepared 2-bromo-5-methoxybenzoic acid is high.
Description
Technical Field
The invention relates to the technical field of biological pharmacy, in particular to a synthetic method of 2-bromo-5-methoxybenzoic acid.
Background
2-bromo-5-methoxybenzoic acid is a key intermediate in the synthesis of urolithin a, a potent intestinal metabolite that restores mitochondria and reverses muscle senescence, and oral administration of urolithin a can improve mitochondrial function by stimulating a process called mitochondrial autophagy. The urolithin A is also a raw material of anthraquinone drugs with good antitumor activity.
In the related technology, patent CN106831397A takes m-methoxybenzoic acid as raw material, glacial acetic acid as solvent, and reacts with bromine to generate 2-bromo-5-methoxybenzoic acid, when bromination is carried out, because of the common influence of carboxyl steric hindrance and electronic effect, bromination difficulty is large, long-time reaction is needed, and bromination directional selectivity is poor, C-2 substitution is accompanied by C-3 substitution, isomers are more, byproducts are more, purity is low, multiple refining is needed, and yield is only 72%; in the synthetic methods provided by the literature RSC Adv, 2017.7.17254-17263, the yield is 73%; the synthesis method provided by ChemMedChem,2011.6.2273-2286 is not high, but the yield is 82%.
Therefore, it is necessary to provide a novel 2-bromo-5-methoxybenzoic acid to solve the above problems.
Disclosure of Invention
The invention aims to overcome the technical problems and provide a method for synthesizing 2-bromo-5-methoxybenzoic acid with high yield.
In order to achieve the above object, the present invention provides a method for synthesizing 2-bromo-5-methoxybenzoic acid, comprising the following steps:
dissolving m-methoxybenzoic acid in a halogenated hydrocarbon solvent, and carrying out bromination reaction with a bromination reagent under the action of a bromination initiator, a cocatalyst and sulfuric acid to obtain a 2-bromo-5-methoxybenzoic acid reaction solution;
and pouring the reaction liquid of the 2-bromo-5-methoxybenzoic acid into ice water for quenching, recovering the halogenated hydrocarbon solvent under reduced pressure, filtering, and recrystallizing by using the solvent to obtain a finished product of the 2-bromo-5-methoxybenzoic acid.
Preferably, the halogenated hydrocarbon solvent comprises one or more of dichloromethane, chloroform and dichloroethane.
Preferably, the bromination initiator is red phosphorus; the cocatalyst is one or two of potassium bromide and potassium bromate; the brominating reagent comprises one or more of N-bromosuccinimide, dibromohydantoin and bromine.
Preferably, the mass ratio of the m-anisic acid to the halogenated hydrocarbon solvent is 1 (0.5-20).
Preferably, the molar ratio of the m-methoxybenzoic acid to the bromination initiator is 1 (0.01-0.2).
Preferably, the molar ratio of the m-anisic acid to the cocatalyst is 1 (0.01-0.2).
Preferably, the mass ratio of the m-anisic acid to the sulfuric acid is 1 (0.5-5).
Preferably, the molar ratio of the m-methoxybenzoic acid to the brominating reagent is 1 (0.6-3.0).
Preferably, the bromination reaction is carried out at the temperature of-10 ℃ to 80 ℃ for 1 to 24 hours.
Preferably, the solvent used for recrystallization comprises one or more of methanol, ethanol and isopropanol.
Compared with the related art, in the synthetic method of 2-bromo-5-methoxybenzoic acid, cheap and easily available m-methoxybenzoic acid is used as a raw material for synthesis, and the synthetic method has the characteristics of simplicity in operation, high purity, high yield and the like, and experimental results show that the yield of 2-bromo-5-methoxybenzoic acid obtained by the synthetic method is more than 92% and the purity is 98-99.6%; in the synthetic method, the bromine atom in the bromization reagent has high utilization rate, the using amount of sulfuric acid is small, three wastes are less, the product yield is high, the economic benefit is high, the environmental pollution can be reduced, the product production is clean and environment-friendly, and the method is suitable for mass production.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a synthetic method of 2-bromo-5-methoxybenzoic acid, which comprises the following steps:
dissolving m-methoxybenzoic acid in a halogenated hydrocarbon solvent, and carrying out bromination reaction with a bromination reagent under the action of a bromination initiator, a cocatalyst and sulfuric acid to obtain a 2-bromo-5-methoxybenzoic acid reaction solution;
and pouring the reaction liquid of the 2-bromo-5-methoxybenzoic acid into ice water for quenching, recovering the halogenated hydrocarbon solvent under reduced pressure, filtering, and recrystallizing by using the solvent to obtain a finished product of the 2-bromo-5-methoxybenzoic acid.
Preferably, the halogenated hydrocarbon solvent comprises one or more of dichloromethane, chloroform and dichloroethane; the bromination initiator is red phosphorus; the cocatalyst is one or two of potassium bromide and potassium bromate; the brominating reagent comprises one or more of N-bromosuccinimide, dibromohydantoin and bromine; the mass ratio of the m-methoxybenzoic acid to the halogenated hydrocarbon solvent is 1 (0.5-20); the molar ratio of the m-methoxybenzoic acid to the bromination initiator is 1 (0.01-0.2); the molar ratio of the m-methoxybenzoic acid to the cocatalyst is 1 (0.01-0.2); the mass ratio of the m-anisic acid to the sulfuric acid is 1 (0.5-5); the molar ratio of the m-methoxybenzoic acid to the brominating reagent is 1 (0.6-3.0); the temperature of the bromination reaction is-10 ℃ to 80 ℃, and the time is 1 to 24 hours. The solvent used for recrystallization comprises one or more of methanol, ethanol and isopropanol.
Example one
Adding 75g of dichloromethane, 15.2g (0.1mol) of m-methoxybenzoic acid, 30mL of concentrated sulfuric acid, 1.19g (0.01mol) of potassium bromide and 1.23g (0.01mol) of red phosphorus into a 500mL four-neck flask in sequence, starting stirring, adding 26.7g (0.15mol) of N-bromosuccinimide at 25 ℃, controlling the reaction temperature to be 25-30 ℃, reacting for 3h, monitoring the reaction of raw materials by High Performance Liquid Chromatography (HPLC), pouring the reaction Liquid into 200g of ice water for quenching, decompressing and recovering dichloromethane after quenching, filtering mother liquor, and recrystallizing by using 65mL of ethanol to obtain 21.57g of 2-bromo-5-methoxybenzoic acid. The yield of 2-bromo-5-methoxybenzoic acid is 93.4%, and the purity is 99.1%.
Example two
70g of chloroform, 15.2g (0.1mol) of m-methoxybenzoic acid, 30mL of concentrated sulfuric acid, 1.67g (0.01mol) of potassium bromate and 1.48g (0.012mol) of red phosphorus are sequentially added into a 500mL four-neck flask, stirring is started, 21.36g (0.12mol) of N-bromosuccinimide is added at 25 ℃, the reaction temperature is controlled to be 25-30 ℃, the reaction is carried out for 3h, after the reaction of the raw materials is monitored by HPLC, the reaction liquid is poured into 200g of ice water for quenching, the chloroform is recovered under reduced pressure after quenching, mother liquor is filtered, and is recrystallized by 60mL of methanol, so that 21.41g of 2-bromo-5-methoxybenzoic acid is obtained. The yield of the 2-bromo-5-methoxybenzoic acid is 92.7%, and the purity is 99.2%.
EXAMPLE III
80g of dichloromethane, 15.2g (0.1mol) of m-methoxybenzoic acid, 25mL of concentrated sulfuric acid, 1.67g (0.01mol) of potassium bromate and 1.23g (0.01mol) of red phosphorus are sequentially added into a 500mL four-neck flask, stirring is started, 42.9g (0.15mol) of dibromohydantoin is added at 25 ℃, the reaction temperature is controlled to be 25-30 ℃, the reaction is carried out for 3h, after the raw materials are monitored by HPLC to be reacted, the reaction liquid is poured into 200g of ice water for quenching, dichloromethane is recovered under reduced pressure after quenching, mother liquor is filtered, and is recrystallized by 70mL of ethanol, so that 21.62g of 2-bromo-5-methoxybenzoic acid is obtained. The yield of 2-bromo-5-methoxybenzoic acid is 93.6%, and the purity is 99.4%.
Example four
75g of dichloroethane, 15.2g (0.1mol) of m-methoxybenzoic acid, 25mL of concentrated sulfuric acid, 1.78g (0.015mol) of potassium bromide and 0.98g (0.008mol) of red phosphorus are sequentially added into a 500mL four-neck flask, stirring is started, 37.18g (0.13mol) of dibromohydantoin is added at 25 ℃, the reaction temperature is controlled to be 25-30 ℃, the reaction is performed for 3h, after the reaction of raw materials is monitored by HPLC, the reaction liquid is poured into 200g of ice water for quenching, dichloroethane is recovered under reduced pressure after quenching, mother liquor is filtered, and is recrystallized by 75mL of methanol, so that 21.43g of 2-bromo-5-methoxybenzoic acid is obtained. The yield is 92.8 percent, and the purity is 99.5 percent.
EXAMPLE five
Adding 90g of chloroform, 15.2g (0.1mol) of m-methoxybenzoic acid, 25mL of concentrated sulfuric acid, 1.78g (0.015mol) of potassium bromide and 0.98g (0.008mol) of red phosphorus into a 500mL four-neck flask in sequence, starting stirring, adding 34.32g (0.12mol) of dibromohydantoin at 25 ℃, controlling the reaction temperature to be 25-30 ℃, reacting for 3h, after the reaction of raw materials is monitored by HPLC, pouring the reaction liquid into 200g of ice water for quenching, recovering chloroform under reduced pressure after quenching, filtering mother liquor, recrystallizing by using 85mL of isopropanol to obtain 21.43g of 2-bromo-5-methoxybenzoic acid. The yield of the 2-bromo-5-methoxybenzoic acid is 92.8 percent, and the purity is 99.5 percent.
Comparative example
CN107531606A provides a synthesis method of 2-bromo-5-methoxybenzoic acid, which takes water as a solvent, uses bromine to carry out bromination reaction under the action of sodium hydroxide, and the yield of the 2-bromo-5-methoxybenzoic acid can reach 90.8 percent, and the synthesis method provided by the method is adopted for carrying out tests, and the specific process is as follows:
to a 500mL four-necked flask, 15.2g (0.1mol) of m-methoxybenzoic acid was added, and 80g of water was added and stirred to disperse the m-methoxybenzoic acid. Then 27.33g (0.205mol) of a 30% aqueous sodium hydroxide solution was added. Then, the liquid temperature was cooled to 0 ℃ and 16.78g (0.105mol) of bromine was added dropwise at a temperature of 0 to 5 ℃. After the dropwise addition, stirring is carried out for 1 hour at a liquid temperature of 0-5 ℃. After the reaction was completed, 0.128g of sodium sulfite was added, 10g of toluene was added, and the temperature was raised to 70 ℃. The organic phase was separated and removed, and 10.4g (0.1mol) of 35% hydrochloric acid was added dropwise to the aqueous phase, followed by stirring for 1 hour. The precipitated crystal is filtered and dried under reduced pressure to obtain 19.17g of 2-bromine-5-methoxybenzoic acid, which has poor product quality and more impurities. The actual yield of 2-bromo-5-methoxybenzoic acid was 83%, and the purity was 98.5%.
Compared with the comparative example, the yield of the first to fifth examples is obviously higher than the actual yield of the comparative example, and the purity is improved relative to the comparative example.
Compared with the related art, in the synthetic method of 2-bromo-5-methoxybenzoic acid, cheap and easily available m-methoxybenzoic acid is used as a raw material for synthesis, and the synthetic method has the characteristics of simplicity in operation, high purity, high yield and the like, and experimental results show that the yield of 2-bromo-5-methoxybenzoic acid obtained by the synthetic method is more than 92% and the purity is 98-99.6%; in the synthetic method, the bromine atom in the bromization reagent has high utilization rate, the using amount of sulfuric acid is small, three wastes are less, the product yield is high, the economic benefit is high, the environmental pollution can be reduced, the product production is clean and environment-friendly, and the method is suitable for mass production.
While the foregoing is directed to embodiments of the present invention, it will be understood by those skilled in the art that various changes may be made without departing from the spirit and scope of the invention.
Claims (10)
1. A synthetic method of 2-bromo-5-methoxybenzoic acid is characterized by comprising the following steps:
dissolving m-methoxybenzoic acid in a halogenated hydrocarbon solvent, and carrying out bromination reaction with a bromination reagent under the action of a bromination initiator, a cocatalyst and sulfuric acid to obtain a 2-bromo-5-methoxybenzoic acid reaction solution;
and pouring the reaction liquid of the 2-bromo-5-methoxybenzoic acid into ice water for quenching, recovering the halogenated hydrocarbon solvent under reduced pressure, filtering, and recrystallizing by using the solvent to obtain a finished product of the 2-bromo-5-methoxybenzoic acid.
2. The method of synthesis according to claim 1, wherein the halogenated hydrocarbon solvent comprises one or more of dichloromethane, chloroform, dichloroethane.
3. The method of synthesis of claim 1, wherein the bromination initiator is red phosphorus; the cocatalyst is one or two of potassium bromide and potassium bromate; the brominating reagent comprises one or more of N-bromosuccinimide, dibromohydantoin and bromine.
4. The synthesis method according to claim 1, wherein the mass ratio of the m-anisic acid to the halogenated hydrocarbon solvent is 1 (0.5-20).
5. The synthesis method of claim 1, wherein the molar ratio of the m-anisic acid to the bromination initiator is 1 (0.01-0.2).
6. The synthesis method of claim 1, wherein the molar ratio of the m-anisic acid to the cocatalyst is 1 (0.01-0.2).
7. The synthesis method of claim 1, wherein the mass ratio of the m-anisic acid to the sulfuric acid is 1 (0.5-5).
8. The synthesis method of claim 1, wherein the molar ratio of the m-anisic acid to the brominating reagent is 1 (0.6-3.0).
9. The synthesis method according to claim 1, wherein the bromination reaction is carried out at-10 ℃ to 80 ℃ for 1 hour to 24 hours.
10. The synthesis method according to claim 1, wherein the solvent used for recrystallization comprises one or more of methanol, ethanol and isopropanol.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IN190435B (en) * | 1996-06-20 | 2003-07-26 | Council Scient Ind Res | |
| CN101172953A (en) * | 2007-12-04 | 2008-05-07 | 王俊华 | Method of preparing telmisartan midbody of angiotensin medicament for treating hypertension |
| CN102295572A (en) * | 2011-08-24 | 2011-12-28 | 信永中达（北京）科技发展中心 | Design method for industrial process of 2-bromine-4-fluoroacetanilide |
| CN102795993A (en) * | 2012-07-11 | 2012-11-28 | 常州大学 | Preparation method of 2-bromo-6-fluorobenzoic acid |
| CN106831397A (en) * | 2016-12-12 | 2017-06-13 | 东北师范大学 | A kind of anthraquinone analog compound and preparation method thereof and medical application |
| CN110002989A (en) * | 2019-03-15 | 2019-07-12 | 河北合佳医药科技集团股份有限公司 | A kind of preparation method of the bromo- 2- chlorobenzoic acid of highly selective 5- |
| CN110105193A (en) * | 2019-05-31 | 2019-08-09 | 杭州科耀医药科技有限公司 | A kind of synthetic method of 2- halogen -5- bromobenzoic acid |
-
2020
- 2020-10-22 CN CN202011137321.8A patent/CN112250562A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IN190435B (en) * | 1996-06-20 | 2003-07-26 | Council Scient Ind Res | |
| CN101172953A (en) * | 2007-12-04 | 2008-05-07 | 王俊华 | Method of preparing telmisartan midbody of angiotensin medicament for treating hypertension |
| CN102295572A (en) * | 2011-08-24 | 2011-12-28 | 信永中达（北京）科技发展中心 | Design method for industrial process of 2-bromine-4-fluoroacetanilide |
| CN102795993A (en) * | 2012-07-11 | 2012-11-28 | 常州大学 | Preparation method of 2-bromo-6-fluorobenzoic acid |
| CN106831397A (en) * | 2016-12-12 | 2017-06-13 | 东北师范大学 | A kind of anthraquinone analog compound and preparation method thereof and medical application |
| CN110002989A (en) * | 2019-03-15 | 2019-07-12 | 河北合佳医药科技集团股份有限公司 | A kind of preparation method of the bromo- 2- chlorobenzoic acid of highly selective 5- |
| CN110105193A (en) * | 2019-05-31 | 2019-08-09 | 杭州科耀医药科技有限公司 | A kind of synthetic method of 2- halogen -5- bromobenzoic acid |
Non-Patent Citations (1)
| Title |
|---|
| WU, YONG-QI ET AL: "A convenient and efficient H2SO4-promoted regioselective monobromination of phenol derivatives using N-bromosuccinimide" * |
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