Preparation method of amisulpride

An amisulpride and amino technology, which is applied in the field of chemical and chemical raw materials synthesis and preparation, can solve problems such as difficult operation in industrial production, need for wastewater treatment, need to be recycled, etc., and achieves low production cost, low impurity content, and reduced addition amount. Effect

Pending Publication Date: 2021-12-03
深圳市新浩瑞医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Due to the use of strong bases such as sodium alkoxide and potassium alkoxide as catalysts, neutralization treatment is required after the reaction; this patent also uses solvents, which need to be recycled, the process is complicated, industrial production is not easy to operate, and wastewater treatment is required, which is costly

Method used

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  • Preparation method of amisulpride
  • Preparation method of amisulpride
  • Preparation method of amisulpride

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preparation example Construction

[0021] The present invention provides a kind of preparation method of amisulpride, and concrete synthetic route is as follows:

[0022]

[0023] The principle is: use 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid methyl ester (A-4) as raw material, directly carry out transesterification reaction with N-ethyl-2-aminomethylpyrrole, Get amisulpride. Specifically, it can be divided into two methods for transesterification without adding water and adding water, as follows:

[0024] (Without adding water) Method 1: In an atmospheric distillation device, add 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid methyl ester (A-4) and N-ethyl-2-aminomethyl Base pyrrole, carry out transesterification reaction at 70-90°C, and distill methanol while reacting. When the distillate methanol is no longer distilled out, stop the reaction and carry out vacuum distillation to distill the excess N-ethyl-2-aminomethylpyrrole under reduced pressure at 3-5mmHg pressure and 60-70°C. The N-ethyl-2-amin...

Embodiment 1

[0027] In a 5L three-necked flask, first add 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid methyl ester (A-4) 500g, then add N-ethyl-2-aminomethylpyrrole 2000g ( The mass ratio of 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid methyl ester to N-ethyl-2-aminomethylpyrrole is 1:4), and the outlet is equipped with an atmospheric distillation device. The transesterification reaction was carried out at 80°C, and the methanol was distilled off during the reaction. After 10 hours, the reaction was stopped when distilled methanol no longer distilled off. Distillation under reduced pressure was carried out again, and excess N-ethyl-2-aminomethylpyrrole was distilled out under reduced pressure at 3 mmHg pressure and 60°C. The N-ethyl-2-aminomethylpyrrole recovered by distillation under reduced pressure can be used in the next reaction. After vacuum distillation, the crude product of amisulpride was obtained in the three-necked flask, and 2000g of acetone was added to obtain the solutio...

Embodiment 2

[0029] In a 100L stainless steel reaction kettle bottle, add 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid methyl ester (A-4) 10kg, then add N-ethyl-2-aminomethylpyrrole 50Kg (The mass ratio of 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid methyl ester to N-ethyl-2-aminomethylpyrrole is 1:5), and the transesterification reaction was carried out at 70°C, Methanol was distilled off during the reaction. After 12 hours, the reaction was stopped when distilled methanol no longer distilled off. Change to vacuum distillation, and excess N-ethyl-2-aminomethylpyrrole was distilled out under reduced pressure at 5 mmHg pressure and 70°C. The N-ethyl-2-aminomethylpyrrole recovered by distillation under reduced pressure can be used in the next reaction. After distillation under reduced pressure, the crude product of amisulpride was obtained in the reaction kettle, and 40kg of acetone was added to obtain the solution, and then the recrystallization operation was carried out, specifically:...

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Abstract

The invention discloses a preparation method of amisulpride, which comprises the following steps: carrying out ester exchange reaction on methyl 4-amino-2-methoxy-5-ethylsulfonylbenzoate and N-ethyl-2-aminomethyl pyrrole at 70-90 DEG C, and distilling out methanol while reacting; and when the methanol is not distilled out, stopping the reaction, carrying out reduced pressure distillation to obtain an amisulpride crude product, and conducting recrystallizing to obtain the amisulpride. The preparation method is low in production cost, simple in process, free of wastewater production in the preparation process and environmentally friendly. When the preparation method provided by the invention is used for producing amisulpride, the side reaction is few, the impurity amount is small, the product yield is high, the molar yield reaches 95% or above, and the purity of the obtained amisulpride is high.

Description

technical field [0001] The invention relates to the field of synthesis and preparation of chemical and chemical raw materials, in particular to a preparation method of amisulpride. Background technique [0002] Amisulpride Tablets are used for the treatment of acute or chronic schizophrenia with positive symptoms (such as delirium, hallucinations, cognitive impairment) and / or negative symptoms (such as slow response, apathy, and social decline), including negative symptoms characteristic schizophrenia. Its chemical name is: 4-amino-N-[(1-ethyl-2-pyrrolidine)methyl]-5-ethylsulfonyl-2-methoxybenzamide. The specific structural formula is: [0003] [0004] Chinese patent CN103819383A discloses a synthetic method of amisulpride comprising: step a: 2-methoxy-4-amino-5-ethanesulfonylbenzoic acid (amic acid) and lower alcohol, in dichloromethylene Esterification under sulfone catalysis gives 4-amino-2-methoxy-5-ethylsulfonylbenzoate (A-4); step b: the 4-amino-2-methoxy- Cond...

Claims

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Application Information

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IPC IPC(8): C07D207/09
CPCC07D207/09
Inventor 金鹏
Owner 深圳市新浩瑞医药科技有限公司
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