Synthesis method of 2-bromo-5-methoxybenzoic acid

Abstract

The invention provides a synthesis method of 2-bromo-5-methoxybenzoic acid, which comprises the following steps: dissolving m-methoxybenzoic acid in a halogenated hydrocarbon solvent, and carrying outbromination reaction with a bromination reagent under the actions of a bromination initiator, a cocatalyst and sulfuric acid to obtain a 2-bromo-5-methoxybenzoic acid reaction solution; and pouring the 2-bromo-5-methoxybenzoic acid reaction solution into ice water for quenching, recovering the halogenated hydrocarbon solvent under reduced pressure, performing filtering, and performing recrystallizing with a solvent to obtain a 2-bromo-5-methoxybenzoic acid finished product. According to the synthesis method of the 2-bromo-5-methoxy benzoic acid, provided by the invention, the yield of the prepared 2-bromo-5-methoxy benzoic acid is high.

Description

technical field

[0001] The invention relates to the technical field of biopharmaceuticals, in particular to a method for synthesizing 2-bromo-5-methoxybenzoic acid. Background technique

[0002] 2-Bromo-5-methoxybenzoic acid is a key intermediate in the synthesis of urolithin A, a powerful intestinal metabolite that can restore mitochondria and reverse muscle aging. Oral urolithin A can Improves mitochondrial function by stimulating a process called mitophagy. Urolithin A is also a raw material of anthraquinone drugs with good antitumor activity.

[0003] In the related technology, the patent CN106831397A uses m-methoxybenzoic acid as a raw material, and glacial acetic acid as a solvent reacts with bromine to generate 2-bromo-5-methoxybenzoic acid. Due to the common influence of the bromination effect, the bromination is more difficult and requires a long time to react, and the directional selectivity of the bromination is poor, and the substitution at the C-2 position is ...

Examples

preparation example Construction

[0020] The invention provides a kind of synthetic method of 2-bromo-5-methoxybenzoic acid, comprises the steps:

[0021] Dissolve m-methoxybenzoic acid in a halogenated hydrocarbon solvent, and carry out a bromination reaction with a brominating reagent under the action of a brominated initiator, a cocatalyst, and sulfuric acid to obtain 2-bromo-5-methoxybenzoic acid. liquid;

[0022] Pour the 2-bromo-5-methoxybenzoic acid reaction solution into ice water to quench, recover the halogenated hydrocarbon solvent under reduced pressure, filter, and recrystallize with the solvent to obtain 2-bromo-5-methoxybenzene Formic acid products.

[0023] Preferably, the halogenated hydrocarbon solvent includes one or more of methylene chloride, chloroform, and ethylene dichloride; the brominated initiator is red phosphorus; the cocatalyst is potassium bromide, potassium bromate One or both of them; the brominated reagent includes one or more of N-bromosuccinimide, dibromohydantoin, and bro...

Embodiment 1

[0025] Into a 500mL four-necked flask, add 75g of dichloromethane, 15.2g (0.1mol) of m-methoxybenzoic acid, concentrated sulfuric acid (30mL), 1.19g (0.01mol) of potassium bromide, and 1.23g (0.01mol) of red phosphorus ), start stirring, add N-bromosuccinimide 26.7g (0.15mol) at 25°C, control the reaction temperature at 25-30°C, react for 3h, and monitor the raw materials by HPLC (High Performance Liquid Chromatography, high pressure liquid chromatography) After the reaction was completed, the reaction solution was poured into 200 g of ice water for quenching. After quenching, dichloromethane was recovered under reduced pressure, the mother liquor was filtered, and 65 ml of ethanol was used for recrystallization to obtain 21.57 g of 2-bromo-5-methoxybenzoic acid. The yield of 2-bromo-5-methoxybenzoic acid was 93.4%, and the purity was 99.1%.

Embodiment 2

[0027] Into a 500mL four-neck flask, add chloroform 70g, m-methoxybenzoic acid 15.2g (0.1mol), concentrated sulfuric acid (30mL), potassium bromate 1.67g (0.01mol), red phosphorus 1.48g (0.012mol), and start stirring , add 21.36g (0.12mol) of N-bromosuccinimide at 25°C, control the reaction temperature at 25-30°C, and react for 3h. After the reaction of the raw materials is monitored by HPLC, the reaction solution is poured into 200g of ice water for quenching After quenching, the chloroform was recovered under reduced pressure, the mother liquor was filtered, and recrystallized with 60ml of methanol to obtain 21.41g of 2-bromo-5-methoxybenzoic acid. The yield of 2-bromo-5-methoxybenzoic acid was 92.7%, and the purity was 99.2%.

technical field

[0001] The invention relates to the technical field of biopharmaceuticals, in particular to a method for synthesizing 2-bromo-5-methoxybenzoic acid. Background technique

[0002] 2-Bromo-5-methoxybenzoic acid is a key intermediate in the synthesis of urolithin A, a powerful intestinal metabolite that can restore mitochondria and reverse muscle aging. Oral urolithin A can Improves mitochondrial function by stimulating a process called mitophagy. Urolithin A is also a raw material of anthraquinone drugs with good antitumor activity.

[0003] In the related technology, the patent CN106831397A uses m-methoxybenzoic acid as a raw material, and glacial acetic acid as a solvent reacts with bromine to generate 2-bromo-5-methoxybenzoic acid. Due to the common influence of the bromination effect, the bromination is more difficult and requires a long time to react, and the directional selectivity of the bromination is poor, and the substitution at the C-2 position is ...

Examples

preparation example Construction

[0020] The invention provides a kind of synthetic method of 2-bromo-5-methoxybenzoic acid, comprises the steps:

[0021] Dissolve m-methoxybenzoic acid in a halogenated hydrocarbon solvent, and carry out a bromination reaction with a brominating reagent under the action of a brominated initiator, a cocatalyst, and sulfuric acid to obtain 2-bromo-5-methoxybenzoic acid. liquid;

[0022] Pour the 2-bromo-5-methoxybenzoic acid reaction solution into ice water to quench, recover the halogenated hydrocarbon solvent under reduced pressure, filter, and recrystallize with the solvent to obtain 2-bromo-5-methoxybenzene Formic acid products.

[0023] Preferably, the halogenated hydrocarbon solvent includes one or more of methylene chloride, chloroform, and ethylene dichloride; the brominated initiator is red phosphorus; the cocatalyst is potassium bromide, potassium bromate One or both of them; the brominated reagent includes one or more of N-bromosuccinimide, dibromohydantoin, and bro...

Embodiment 1

[0025] Into a 500mL four-necked flask, add 75g of dichloromethane, 15.2g (0.1mol) of m-methoxybenzoic acid, concentrated sulfuric acid (30mL), 1.19g (0.01mol) of potassium bromide, and 1.23g (0.01mol) of red phosphorus ), start stirring, add N-bromosuccinimide 26.7g (0.15mol) at 25°C, control the reaction temperature at 25-30°C, react for 3h, and monitor the raw materials by HPLC (High Performance Liquid Chromatography, high pressure liquid chromatography) After the reaction was completed, the reaction solution was poured into 200 g of ice water for quenching. After quenching, dichloromethane was recovered under reduced pressure, the mother liquor was filtered, and 65 ml of ethanol was used for recrystallization to obtain 21.57 g of 2-bromo-5-methoxybenzoic acid. The yield of 2-bromo-5-methoxybenzoic acid was 93.4%, and the purity was 99.1%.

Embodiment 2

[0027] Into a 500mL four-neck flask, add chloroform 70g, m-methoxybenzoic acid 15.2g (0.1mol), concentrated sulfuric acid (30mL), potassium bromate 1.67g (0.01mol), red phosphorus 1.48g (0.012mol), and start stirring , add 21.36g (0.12mol) of N-bromosuccinimide at 25°C, control the reaction temperature at 25-30°C, and react for 3h. After the reaction of the raw materials is monitored by HPLC, the reaction solution is poured into 200g of ice water for quenching After quenching, the chloroform was recovered under reduced pressure, the mother liquor was filtered, and recrystallized with 60ml of methanol to obtain 21.41g of 2-bromo-5-methoxybenzoic acid. The yield of 2-bromo-5-methoxybenzoic acid was 92.7%, and the purity was 99.2%.