Method for synthesizing 2-methoxy-4-amino-5-ethylsulfone methyl benzoate by halogenation

A technology of methyl ethyl sulfone benzoate and methyl acetaminobenzoate, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of low yield, difficult to remove, and poor quality, and achieve high product yield and good product quality , The effect of simple process route

Active Publication Date: 2016-01-20
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

[0004] The route is to obtain the target product through deacetylation, thiocyanation, ethylation and oxidation of 2-methoxy-4-aminobenzoic acid methyl ester. After 5 steps of reaction, the yield of each step is low and the quality is relatively low. Poor, according to the author's verification, the total yield is about 50%. The by-products produced in the thiocyanation process have been carried into the finished product, which is difficult to remove, and its appearance is light yellow, which cannot be turned into white after repeated purification.

Method used

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  • Method for synthesizing 2-methoxy-4-amino-5-ethylsulfone methyl benzoate by halogenation
  • Method for synthesizing 2-methoxy-4-amino-5-ethylsulfone methyl benzoate by halogenation

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Experimental program
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Effect test

Embodiment approach 1

[0018] Add 300g of dichloromethane and (1) 200g (0.89mol) of methyl 2-methoxy-4-acetamidobenzoate into a reaction flask equipped with a hydrogen chloride absorption device, cool to below 10°C, and stir Maintain 10-15°C and slowly feed chlorine gas, when the gas flow reaches 69.5g (0.98mol), stop the chlorine gas flow, continue to stir and react for 1 hour, then concentrate the reaction solution under negative pressure to dryness to obtain solid (2) 2-methoxy Base-4-acetylamino-5-chlorobenzoic acid methyl ester, add 400 grams of DMF, 155 g (1.33 mol) of sodium ethyl sulfinate, 6 g (0.04 mol) of cuprous oxide in the same reaction flask, after the addition is completed, slowly Raise the temperature to 65-70°C and keep it at this temperature for 8 hours. After the heat preservation is over, cool it down to below 10°C and filter to get (3) methyl 2-methoxy-4-acetamido-5-ethylsulfonylbenzoate , add (3) into the reaction flask with a stirring reflux device, add 300ml of methanol and ...

Embodiment approach 2

[0020] Add 225g of dichloromethane and (1) 150g (0.67mol) of methyl 2-methoxy-4-acetamidobenzoate into a reaction flask equipped with a hydrogen bromide absorption device, cool to below 10°C, and stir Slowly add bromine 112.4g (0.70mol) dropwise at 10-15°C, keep the temperature at 10-15°C for 4 hours at the end of the dropwise addition, and concentrate the reaction solution under negative pressure to dryness to obtain solid (2) 2-methoxy -4-Acetamido-5-bromobenzoic acid methyl ester, add 300 grams of DMF, 124.5g (1.07mol) sodium ethyl sulfinate, 5g (0.05mol) cuprous chloride in the same reaction flask, the addition is complete, Slowly raise the temperature to 75-80°C, and keep it warm at this temperature for 8 hours. After the heat preservation is over, cool it down to below 10°C, and filter to get (3) 2-methoxy-4-acetamido-5-ethylsulfonylbenzoic acid methyl ester, add (3) into a reaction flask with a stirring reflux device, add 250ml of methanol and 4 grams of concentrated su...

Embodiment approach 3

[0022] Add 600g of dichloromethane, (1) 300g (1.34mol) of methyl 2-methoxy-4-acetamidobenzoate, and 390g (1.54mol) of iodine into a 1000ml reaction bottle. After the addition is complete, heat up to 35-40°C , and kept at this temperature for 10 hours, after the end of the heat preservation, the reaction solution was concentrated to dryness under negative pressure to obtain a solid (2) 2-methoxy-4-acetamido-5-chlorobenzoic acid methyl ester, added 600 grams of DMF, 417g (2.68mol) of sodium ethyl sulfinate and 8g (0.04mol) of cuprous iodide, after feeding, slowly raise the temperature to 65-70°C, and keep it at this temperature for 10 hours, after the end of the heat preservation, cool To below 10°C, filter to obtain (3) methyl 2-methoxy-4-acetamido-5-ethylsulfonylbenzoate, add (3) to a reaction flask with a stirring reflux device, and add 450ml of methanol and 8 grams of concentrated sulfuric acid, heat up to reflux and keep warm for 5 hours under reflux conditions. After the h...

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Abstract

The present invention relates to a method for synthesizing 2-methoxy-4-amino-5-ethylsulfone methyl benzoate by halogenation with halogen. In the present invention, the target product is condensed with sodium ethyl sulfinate by halogenation (chlorination, bromination, iodination) of 2-methoxy-4-acetylaminobenzoic acid methyl ester with halogen, and its advantage is that the process route is simple, The product yield is high, the total yield reaches 80%, the product quality is good, the purity reaches 99.5%, and the appearance is white.

Description

technical field [0001] The invention relates to the technical field of preparation of pharmaceutical intermediates, in particular to a method for synthesizing 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid methyl ester by halogenation. Background technique [0002] Psychosis refers to a serious psychological disorder, in which there may be persistent and obvious abnormalities in the mental activities of patients such as cognition, emotion, will, action and behavior; they cannot study, work, and live normally; their actions and behaviors are difficult to be understood by ordinary people; Under the control of morbid psychology, there are actions of suicide or attacking or hurting others. 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid is an important intermediate of the antipsychotic drug amisulpride. There are many related reports on its synthetic route, and the main routes used in industrial production are as follows: [0003] [0004] The route is to obtain the target pro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C317/48C07C315/04
Inventor 王利明夏秋景陈洁
Owner 苏州诚和医药化学有限公司
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