Crystalline form I of acotiamide hydrochloride hydrate, preparation method therefor and use thereof

A technology of acotiamide hydrochloride and acotiamide, applied in the field of chemical synthesis

Inactive Publication Date: 2016-01-13
WATERSTONE PHARMA WUHAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the current method for preparing the crystal form of acotiamide still needs to be improved.

Method used

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  • Crystalline form I of acotiamide hydrochloride hydrate, preparation method therefor and use thereof
  • Crystalline form I of acotiamide hydrochloride hydrate, preparation method therefor and use thereof
  • Crystalline form I of acotiamide hydrochloride hydrate, preparation method therefor and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1 Synthesis of Acotinamide Hydrochloride Monohydrate

[0032] Step (1) Preparation of Acotamide Hydrochloride

[0033] Take 3.0 g of free acotiamide, add 30 ml of isopropanol, and heat to 50°C to dissolve. At this temperature, add 4g of 35% hydrochloric acid aqueous solution, stir for 5h, and cool to 15°C naturally. Filter and wash the filter cake with 20 ml isopropanol. It was dried at 50°C to obtain 2.6g crude acotiamine hydrochloride.

[0034] Step (2) Refining of Acotamide Hydrochloride Monohydrate

[0035] Take 2.6 g of the crude acotiamine hydrochloride prepared above, add 25 ml of a 70% isopropanol aqueous solution by volume, and heat to 70° C. to dissolve. Stir for 4h. Filter and wash the filter cake with 10 ml isopropanol. Then dry at 50°C for 6h. Finally, 2.36 g of acotiamide hydrochloric acid hydrate was obtained with a yield of 88.0%. The purity was 99.6% by HPLC, and the moisture value was 3.33% by the moisture analyzer. After thermal weight loss and...

Embodiment 2

[0037] Example 2 Synthesis of Acotinamide Hydrochloride Monohydrate

[0038] Step (1) Preparation of Acotamide Hydrochloride

[0039] Take 30g of free acotiamine, add 300ml of methanol, and heat to 70°C to dissolve. At this temperature, add 40g of 20% hydrochloric acid aqueous solution, stir for 5h, and cool to 15°C naturally. Filter and wash the filter cake with 50 ml methanol. Dry at 70℃. Finally, 29.2 g of crude acotiamine hydrochloride was obtained.

[0040] Step (2) Preparation of Acotamide Hydrochloride Hydrate

[0041] Take 29.2 g of the crude acotiamine hydrochloride prepared above, add 300 ml of an 80% isopropanol aqueous solution by volume, and heat to 70°C to dissolve. Stir for 4h. Filter and wash the filter cake with 100 ml isopropanol. Then dry at 60°C for 4h. Finally, 27.06 g of acotiamide hydrochloride hydrate was obtained, with a total yield of 89.7%. The purity was 99.5% by HPLC, and the moisture value was 3.33% by a moisture analyzer. After thermal weight los...

Embodiment 3

[0043] Example 3 Synthesis of Acotinamide Hydrochloride Monohydrate

[0044] Step (1) Preparation of Acotamide Hydrochloride

[0045] Take 130g of free acotiamine, add 450ml of methanol, and heat to 30°C to dissolve. At this temperature, 75g of 35% hydrochloric acid aqueous solution was added, stirred for 5h, and naturally cooled to 15°C. Filter and wash the filter cake with 100 ml methanol. Dry at 70℃. Finally, 110 g of crude acotiamine hydrochloride was obtained.

[0046] Step (2) Preparation of Acotamide Hydrochloride Hydrate

[0047] Take 110 g of the crude acotiamine hydrochloride prepared above, add 770 ml of an 80% isopropanol aqueous solution by volume, and heat to 70°C to dissolve. Stir for 4h. Filter and wash the filter cake with 100 ml isopropanol. Then dry at 60°C for 4h. Finally, 104.7 g of acotiamide hydrochloride hydrate was obtained with a yield of 92.1%. The purity was 99.7% by HPLC, and the moisture value was 3.33% by a moisture analyzer. After thermal weight...

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Abstract

The present invention relates to a crystalline form I of an acotiamide hydrochloride hydrate, a preparation method therefor and use thereof. The preparation method comprises: mixing acotiamide with an organic solvent so as to obtain a first mixture containing the acotiamide and the organic solvent; adding a salt-forming solvent into the first mixture to carry out a salt-forming reaction so as to obtain a second mixture containing an acotiamide hydrochloride; filtering the second mixture, and washing and drying a filter cake by an organic solvent so as to obtain a third mixture containing a crude product of the acotiamide hydrochloride; dissolving the third mixture in an aqueous organic solvent and performing slowly cooling crystallization after heating dissolution, so as to obtain a fourth mixture of an acotiamide hydrochloride hydrate crystal; and separating the crystal from the fourth mixture, and heating the separated crystal at 50-90 DEG C so as to obtain the acotiamide hydrochloride hydrate. The method is mild in reaction condition and simple in process and can be used for efficiently obtaining a highly pure acotiamide hydrochloride hydrate and a stable crystalline form thereof.

Description

Technical field [0001] The present invention belongs to the field of chemical synthesis. Specifically, the present invention relates to the I crystal form of acotiamine hydrochloride hydrate and its preparation method and application. Background technique [0002] Acotamide (a compound represented by formula I) is the world's first functional dyspepsia treatment drug, developed by Japan Zari New Pharmaceutical Co., Ltd., and approved for marketing in Japan in February 2013. It is suitable for the treatment of postprandial fullness, functional indigestion, upper abdomen fullness and early fullness. [0003] [0004] However, the current method for preparing acotiamine crystal form still needs to be improved. Summary of the invention [0005] The present invention aims to solve one of the above technical problems at least to a certain extent or at least provide a useful business option. To this end, an object of the present invention is to propose a method for preparing the crystall...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56A61K31/426A61P1/14
Inventor 陈继伟秦志平王火箭何伟崔健钱丽娜
Owner WATERSTONE PHARMA WUHAN
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