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A kind of synthetic method of biphenyl diester intermediate

The technology of a kind of bifendate and synthetic method is applied in the field of synthesis of bifendate intermediate, which can solve the problems of restricting industrial production, incomplete protection, low yield, etc.

Active Publication Date: 2021-05-11
苏州诚和医药化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • A kind of synthetic method of biphenyl diester intermediate
  • A kind of synthetic method of biphenyl diester intermediate
  • A kind of synthetic method of biphenyl diester intermediate

Examples

Experimental program
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Embodiment 1

[0026] A kind of synthetic method of bifendate intermediate, such as figure 2 shown, including the following steps:

[0027] 1. Synthesis of carbonate:

[0028] Add 20g (117.6mmol) of gallic acid (117.6mmol), 100ml of dichloromethane, 1g of triethylamine, 15g (141.1mmol) of sodium carbonate, and 30ml of water into the reaction flask, and add 14g (47.2mmol) of solid phosgene dropwise under stirring at a temperature of 15°C. After adding dichloromethane solution, keep warm at 15°C for 1 hour, let stand to separate the upper aqueous layer, concentrate the organic layer to dryness, add 100ml of toluene, stir for 30 minutes, filter, and dry to obtain 21.9g of carbonate, yield: 95%.

[0029] 2. Synthesis of methyl compounds:

[0030] Add 20g (102.0mmol) of carbonate, 100ml of acetone, and 31g (224.6mmol) of potassium carbonate into the reaction flask, add 28.3g (224.6mmol) of dimethyl sulfate dropwise at a controlled temperature of 25°C, and keep the temperature at 25°C for 5 ho...

Embodiment 2

[0037] A kind of synthetic method of bifendate intermediate, such as figure 2 shown, including the following steps:

[0038] 1. Synthesis of carbonate:

[0039] Add 20g (117.6mmol) of gallic acid (117.6mmol), 100ml of dichloromethane, 1g of triethylamine, 15g (141.1mmol) of sodium carbonate, and 30ml of water into the reaction bottle, and add 11.2g (37.8mmol) of solid phosgene dropwise under stirring at a temperature of 10°C Dichloromethane solution, after adding, keep warm at 10°C for 1 hour, let stand to separate the upper aqueous layer, concentrate the organic layer to dryness, add 100ml of toluene, stir for 30 minutes, filter, and dry to obtain 22.0g of carbonate, the yield : 95.5%.

[0040] 2. Synthesis of methyl compounds:

[0041] Add 20g (102.0mmol) of carbonate, 100ml of acetone, and 35.2g (255.2mmol) of potassium carbonate into the reaction flask, add 32.2g (255.2mmol) of dimethyl sulfate dropwise at a controlled temperature of 20°C, and keep warm at 20°C for 4 h...

Embodiment 3

[0048] A kind of synthetic method of bifendate intermediate, such as figure 2 shown, including the following steps:

[0049] 1. Synthesis of carbonate:

[0050]Add 20g (117.6mmol) of gallic acid (117.6mmol), 100ml of dichloromethane, 1g of triethylamine, 15g (141.1mmol) of sodium carbonate, and 30ml of water into the reaction bottle, and add 16.8g (56.6mmol) of solid phosgene dropwise under stirring at a temperature of 12°C After adding dichloromethane solution, heat it at 12°C for 1 hour, let it stand to separate the upper aqueous layer, concentrate the organic layer to dryness, add 100ml of toluene, stir for 30 minutes, filter, and dry to obtain 22.2g of carbonate, the yield : 96%.

[0051] 2. Synthesis of methyl compounds:

[0052] Add 20g (102.0mmol) of carbonate, 100ml of acetone, and 28.2g (204.2mmol) of potassium carbonate to the reaction flask, add 25.7g (204.2mmol) of dimethyl sulfate dropwise at a controlled temperature of 22°C, and keep warm at 22°C for 4.5 hour...

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Abstract

The invention belongs to the field of chemical pharmacy, and specifically discloses a method for synthesizing a biphenyl diester intermediate. Using gallic acid as a raw material, it undergoes an esterification reaction with solid phosgene to protect the o-diphenol hydroxyl group, followed by dimethylation and deprotection. Then, the biphenyl diester intermediate is obtained through bromination and methylation. The synthesis method of the bifendate intermediate of the present invention adopts phosgene to protect the ortho-diphenol hydroxyl group, the protection is complete, the reaction condition is mild, the process is simple, and the operation is convenient. Through the exploration and optimization of conditions, the product yield and purity are high, and the waste water problem in the borax protection method is solved, without damaging the environment, and it reduces the treatment of industrial waste water in the later stage, and reduces the production cost of the overall process to the greatest extent. high application.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a method for synthesizing a bifendate intermediate. 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 intermediate through bromination and c...

Claims

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Application Information

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Patent Type & Authority Patents(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
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