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Acotiamide hydrochloride trihydrate refining method and acotiamide hydrochloride trihydrate preparation method

A technology for acotiamide hydrochloride and acotiamide hydrochloride sodium salt, which is applied in the field of refining and preparation of acotiamide hydrochloride trihydrate, and can solve problems such as difficulty in removal, impact on product quality, and poor removal of impurities , achieve the effect of reducing cost and improving the purity of liquid phase

Active Publication Date: 2016-07-13
浙江新赛科药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The shortcoming of this method is that the removal effect of the impurity before the main peak is not good, especially to the impurity that the relative retention time (RRT) is 0.802 before the main peak, there is almost no removal ability, and the impurity polarity before the main peak is relatively large, which is different from that of acotiamide Similar in nature, difficult to remove, seriously affecting product quality, the impurities of the crude product of acotiamide hydrochloride obtained by the synthetic method of acotiamide hydrochloride reported in the literature are mainly the impurities before the main peak

Method used

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  • Acotiamide hydrochloride trihydrate refining method and acotiamide hydrochloride trihydrate preparation method
  • Acotiamide hydrochloride trihydrate refining method and acotiamide hydrochloride trihydrate preparation method
  • Acotiamide hydrochloride trihydrate refining method and acotiamide hydrochloride trihydrate preparation method

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preparation example Construction

[0035] The preparation method of acotiamide and acotiamide hydrochloride:

[0036] (1) The preparation method of acotiamide:

[0037] 2-[(2,4,5-trimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid methyl ester was prepared by prior art, and then 2-[(2,4,5- Methyl trimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylate was suspended in DMAC (dimethylacetamide), N,N-diisopropylethylenediamine was added, under nitrogen protection , heat up to 130-135°C, start timing when the reaction liquid is fully dissolved, turn off the heating after reacting for about 20 hours, drop to 20-30°C, add drinking water to dilute, then add ethyl acetate to wash 3 times, combine ethyl acetate and drinking water Back-extract twice, combine the water layers and evaporate to dryness under reduced pressure at 75-80°C, add drinking water, stir at 20-30°C for 16 hours, filter, and dry under reduced pressure at 50°C for 20 hours to obtain off-white solid N-[2-(diisopropyl Amino)ethyl]-2-[(2-hydroxy-4,5-dim...

Embodiment 1

[0059] Preparation of acotiamide:

[0060] Suspend 20g of 2-[(2,4,5-trimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid methyl ester (ACTM-02 for short) in 40ml of DMAC (dimethylacetamide) , add 18.8g N,N-diisopropylethylenediamine (ACTS-03 for short), under the protection of nitrogen, heat up to 130-135°C, start timing when the reaction solution is completely dissolved, turn off the heating after about 20 hours of reaction, and drop to 20- 30°C, add 200ml of water to dilute, add 70ml of ethyl acetate to wash 3 times, combine ethyl acetate and 70ml of water for stripping twice, combine the water layer and evaporate to dryness under reduced pressure at 75-80°C, add 60g of water and stir at 20-30°C for 16h , filtered, and dried under reduced pressure at 50° C. for 20 h to obtain 18.4 g of an off-white solid (ie, the crude product of acotiamide), with a yield of 72%.

[0061] Refined (acotiamide into acotiamide sodium salt):

[0062] Add 15.0g of crude acotiamide to a 250ml...

Embodiment 2

[0066] Preparation of acotiamide:

[0067] Suspend 20g of 2-[(2,4,5-trimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid methyl ester (ACTM-02 for short) in 40ml of DMAC (dimethylacetamide) , add 18.8g N,N-diisopropylethylenediamine (ACTS-03 for short), under the protection of nitrogen, heat up to 130-135°C, start timing when the reaction solution is completely dissolved, turn off the heating after about 20 hours of reaction, and drop to 20- 30°C, add 200ml of water to dilute, add 70ml of ethyl acetate to wash 3 times, combine ethyl acetate and 70ml of water for stripping twice, combine the water layer and evaporate to dryness under reduced pressure at 75-80°C, add 60g of water and stir at 20-30°C for 16h , filtered, and dried under reduced pressure at 50° C. for 20 h to obtain 19.6 g of off-white solid with a yield of 77%.

[0068] Refined (acotiamide into acotiamide sodium salt):

[0069] Add 15.0g crude acotiamide to a 250ml three-neck flask, stir 90ml0.5mol / L potassiu...

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Abstract

The invention discloses an acotiamide hydrochloride trihydrate refining method and an acotiamide hydrochloride trihydrate preparation method.The acotiamide hydrochloride trihydrate refining method includes adding crude acotiamide into an inorganic base aqueous solution with uniformly mixing, adding an organic solvent with stirring to crystallize, filtering and drying to obtain acotiamide hydrochloride sodium salt or acotiamide hydrochloride potassium salt, wherein inorganic base refers to sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate; adding the acotiamide hydrochloride sodium salt or acotiamide hydrochloride potassium salt into a hydrous isopropanol solution with uniformly mixing, adding hydrochloric acid to acidize a mixture to a pH value being 1-2, stirring to crystallize, heating to dissolve, decreasing the temperature to crystallize, and performing decompression drying so as to obtain acotiamide hydrochloride trihydrate.The acotiamide hydrochloride trihydrate refining method has the advantages that the acotiamide is prepared into the sodium salt or potassium salt, the sodium salt or potassium salt is refined, and accordingly impurities before and after a main peak can be removed effectively, and the final product, namely the acotiamide hydrochloride trihydrate, is above 99.8% in purity and below 0.10% in individual impurities.

Description

technical field [0001] The invention relates to the technical field of refining acotiamide, in particular to a method for refining and preparing acotiamide hydrochloride trihydrate. Background technique [0002] Acotiamide is the world's first approved drug for the treatment of functional dyspepsia. Dyspepsia symptoms are prevalent and significantly reduce the quality of life of patients, most of whom have functional dyspepsia (FD). [0003] Acotiamide was first developed by Zeria Shinyaku Kogyo Co., Ltd. in Japan, and later jointly launched by Astellas Pharmaceuticals and Zeria Pharmaceuticals in Japan. Acotiamide oral tablet acts mainly through the mechanism of inhibiting acetylcholinesterase in the digestive tract, which can promote gastric motility, improve gastric accommodation disorders, and enhance gastric fundus expansion. [0004] The structural formula of acotiamide hydrochloride trihydrate: [0005] [0006] The Chinese invention patent application whose app...

Claims

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Application Information

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IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 杨玲玲杨和军李洪武张海玲郭拥政蒋栋
Owner 浙江新赛科药业有限公司
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