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Preparation method of amisulpride

An amisulpride and amino technology, applied in the field of drug synthesis, can solve the problems of affecting the quality of amisulpride finished products, high viscosity, inconvenient use and the like

Active Publication Date: 2021-04-09
JIANGSU ALPHA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Adopt glycerol as solvent when preparing amisulpride, because the fusing point of glycerol is at 17.8 ℃, and viscosity is bigger, it is very inconvenient to use, and in reaction process glycerol will be mixed with 2-methoxy Base-4-amino-5-ethanesulfonylbenzoic acid methyl ester is carried out alcohol transesterification, can produce by-product 2-methoxy-4-amino-5-ethanesulfonylbenzoic acid glycerol ester, in subsequent treatment This by-product is difficult to remove in the process, seriously affects the quality of amisulpride finished product

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035]With 106.5g 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid methyl ester (methyl amiate), 99.8g N-ethyl-2-aminomethylpyrrolidine, 156.0g concentration is Add 30%wt sodium methoxide methanol solution into 1065ml of methanol, after stirring evenly, raise the temperature to 65°C and keep it warm for 20h. After the reaction is completed, concentrate the reaction solution until the solvent no longer drips out, and then add 530ml of water, stirred at 10-20°C for 4h, precipitated a white solid, filtered, added 530ml of water to the obtained white solid for beating for 1h, filtered, washed, and air-dried at 50°C for 15h to obtain White solid amisulpride 136.1g, HPLC purity 99.91%, yield 94.5%, 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid methyl ester (methyl amiate) residue 0.07%, The total amount of other impurities is 0.02%.

Embodiment 2

[0037] With 27.5g 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid methyl ester, 39.0g N-ethyl-2-aminomethylpyrrolidine, 50.0g concentration is 20% wt sodium ethylate ethanol solution Add it into 275ml of ethanol, after stirring evenly, raise the temperature to 75°C and keep it warm for 24 hours. After the reaction is completed, concentrate the reaction solution until the solvent no longer drips out, then add 140ml of water to the concentrated reaction solution. Stir at 20°C for 4h, a white solid precipitates, filter, add 140ml of water to the obtained white solid for beating for 1h, filter, wash, and blow dry at 50°C for 15h to obtain a white solid, amisulpride 35.5 g, HPLC purity 99.84%, yield 95.6%, residual methyl amiate 0.06%, other impurities total 0.10%.

Embodiment 3

[0039] Add 136.6g methyl 4-amino-2-methoxy-5-ethylsulfonylbenzoate, 64.2g N-ethyl-2-aminomethylpyrrolidine, 96.1g sodium tert-butoxide to 956.2ml tert In butanol, after stirring evenly, raise the temperature to 83°C and keep it warm for 18 hours. After the reaction is completed, concentrate the reaction solution until the solvent no longer drips out, then add 820ml of water to the concentrated reaction solution, and heat it at 10-20°C Stirred under the conditions of 4h, white solid precipitated, filtered, 820ml of water was added to the obtained white solid for beating for 1h, filtered, washed, and air-dried at 50°C for 15h to obtain 172.6g of white solid amisulpride, The HPLC purity is 99.86%, the yield is 93.7%, the residue of methyl amiate is 0.05%, and the total amount of other impurities is 0.09%.

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Abstract

The invention relates to a preparation method of amisulpride, which comprises the steps of carrying out condensation reaction on 4-amino-2-methoxy-5-ethyl sulfonyl methyl benzoate, N-ethyl-2-aminomethylpyrrolidine and a solvent at the temperature of 50-100 DEG C under the condition of taking organic alkali as a catalyst, and after the reaction is finished, concentrating the reaction liquid to remove the solvent, and filtering and drying to obtain the amisulpride. The organic alkali is sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, potassium tert-butoxide or sodium tert-butoxide, and the specific synthetic route is shown in the description. By adopting the preparation method disclosed by the invention, a catalyst harmful to the environment is not used in the reaction process, the post-treatment is simple, the solvent is a common recyclable solvent, the yield reaches 90% or above, the purity can reach 99.7%, the single impurity content is less than 0.1%, the requirements of medicinal preparations are met, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of amisulpride. Background technique [0002] Amisulpride is a new type of atypical antipsychotic drug developed by Sanofi-Synthelabo in France. It belongs to benzamide derivatives. It can selectively act on dopamine D2 and D3 receptors and competitively antagonize 5-HT receptors. In particular, it can eliminate the side effects of most drugs on D2 receptor blockade, and has the advantages of less adverse reactions and no increase in blood sugar. It has obvious effect on the treatment of positive and negative symptoms of schizophrenia in patients with acute or chronic need for long-term maintenance treatment. Its chemical name: 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide, its structural formula is as follows: [0003] [0004] Chinese patent CN102838520A discloses a preparation method of amisulpride,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/09
CPCC07D207/09Y02P20/584
Inventor 陈本顺石利平郭炳华刘春河李大伟叶金星钱若灿靳学健朱小亮孟祥杰
Owner JIANGSU ALPHA PHARM CO LTD
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