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Synthesis method of 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester

A technology of methyl methoxybenzoate and methylenedioxy, applied in the field of chemical pharmacy, can solve problems such as restricting industrial production, incomplete protection, difficult treatment, etc., so as to solve the problem of waste water, facilitate operation, and reduce the cost of treatment. Effect

Active Publication Date: 2020-04-17
苏州诚和医药化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The method uses borax to protect the methylation process, the protection is incomplete, polymethylated impurities are produced, the yield is low, and a large amount of borax-containing wastewater is produced, which is difficult to handle. Because the method mainly has the following shortcomings, it seriously restricts industrial production

Method used

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  • Synthesis method of 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester
  • Synthesis method of 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester
  • Synthesis method of 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester

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Effect test

Embodiment 1

[0026] A kind of synthetic method of 2-bromo-3,4-methylenedioxy-5-methoxybenzoic acid methyl ester, such as figure 2 shown, including the following steps:

[0027] 1. Synthesis of compound 1:

[0028] Add 20g (117.6mmol) of gallic acid (117.6mmol), 100ml of toluene, 30g (202.7mmol) of triethyl formate, and 0.1g of p-toluenesulfonic acid into the reaction flask, heat up to 100°C under the protection of nitrogen for 8 hours, cool to 0°C, After filtration, 25.5 g of phenyl orthoformate (compound 1) was obtained, with a yield of 96%.

[0029] 2. Synthesis of methyl compound (compound 2):

[0030] Add 25g (110.6mmol) of compound 1, 100ml of acetone, and 31g (224.6mmol) of potassium carbonate to the reaction flask, and add 28.3g (224.6mmol) of dimethyl sulfate dropwise at a controlled temperature of 20°C. After the addition, keep the temperature at 20°C for 4 hours. Concentrate acetone under negative pressure, add 150ml of water, heat up to 50±2°C for 2 hours, cool to 5°C for 1 ...

Embodiment 2

[0039] A kind of synthetic method of 2-bromo-3,4-methylenedioxy-5-methoxybenzoic acid methyl ester, such as image 3 shown, including the following steps:

[0040] 1. Synthesis of Compound 3:

[0041] Add 20g (117.6mmol) of gallic acid (117.6mmol), 100ml of toluene, 25g (235.2mmol) of trimethyl formate and 0.1g of p-toluenesulfonic acid into the reaction flask, heat up to 105°C under the protection of nitrogen, keep it under reflux for 8-10 hours, and cool to 5 °C, 20.5 g of phenyl orthoformate (compound 3) was obtained by filtration, with a yield of 97%.

[0042] 2. Synthesis of methyl compound (compound 4):

[0043] Add 20g (106.1mmol) of compound 3, 100ml of acetone, and 29.3g (212.2mmol) of potassium carbonate to the reaction flask, add 26.7g (212.2mmol) of dimethyl sulfate dropwise at a controlled temperature of 25°C, and keep warm at 25°C for 5 hours , concentrated acetone under negative pressure, added 150ml of water, raised the temperature to 50±2°C for 3 hours, coo...

Embodiment 3

[0052] A kind of synthetic method of 2-bromo-3,4-methylenedioxy-5-methoxybenzoic acid methyl ester, such as figure 2 shown, including the following steps:

[0053] 1. Synthesis of compound 1:

[0054] Add 20g (117.6mmol) of gallic acid (117.6mmol), 100ml of toluene, 26.5g (178.9mmol) of triethyl formate and 0.1g of p-toluenesulfonic acid into the reaction flask, heat up to 103°C under the protection of nitrogen, keep the temperature at reflux for 9 hours, and cool to 4°C , and filtered to obtain 25.8 g of phenyl orthoformate (compound 1), with a yield of 97%.

[0055] 2. Synthesis of methyl compound (compound 2):

[0056] Add 25g (110.6mmol) of compound 1, 100ml of acetone, and 31g (224.6mmol) of potassium carbonate to the reaction flask, and add 28.3g (224.6mmol) of dimethyl sulfate dropwise at a controlled temperature of 20-25°C. After 1 hour, concentrate the acetone under negative pressure, add 150ml of water, heat up to 50±2°C for 2.5 hours, cool to 7°C for 1 hour, fil...

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Abstract

The invention belongs to the field of chemical pharmacy, and specifically discloses a preparation method of 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester. The preparation method comprises the following steps: by taking gallic acid as a raw material, carrying out esterification reaction with triethyl orthoformate or trimethyl orthoformate to protect o-diphenolic hydroxyl, then carrying out dimethylation and deprotection, and then carrying out bromination and methylenization to obtain the 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester. According to the synthesismethod of 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester, trimethyl orthoformate or triethyl orthoformate is adopted to protect o-diphenolic hydroxyl, protection is complete, reactionconditions are mild, the process is simple, and operation is convenient. By exploring and optimizing conditions, the product yield and purity are high, the wastewater problem in a borax protection method is solved, the environment is not damaged, the later industrial wastewater treatment is reduced, the production cost of the whole process is reduced to the maximum extent, and the method has extremely high application value.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a method for synthesizing methyl 2-bromo-3,4-methylenedioxy-5-methoxybenzoate. Background technique [0002] Biphenyldicarboxylate (Biphenyldicarboxylate, DDB) is an intermediate product of artificial synthesis of Schisandra C, a new drug discovered in the process of researching the traditional Chinese medicine Schisandra, clinically used for chronic persistent hepatitis with elevated alanine aminotransferase (ALT), It can also be used for ALT elevation caused by chemical poisons and drugs. [0003] CN86107486A discloses a synthetic method of biphenyl diester, the key intermediate of which is 2-bromo-3,4-methylenedioxy-5-methoxybenzoic acid methyl ester. The current industrial production process uses gallic acid as raw material , first esterify in methanol to obtain the methyl ester, then methylate under the protection of borax, and then obtain the target intermediat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D317/68
CPCC07D317/68
Inventor 陈晓强
Owner 苏州诚和医药化学有限公司