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Purification method of benzimidazole derivative

A purification method and technology of benzimidazole, which is applied in the field of purification of key intermediate benzimidazole derivatives, can solve problems such as difficulty in realization, difficulty in salt formation and precipitation of crude compound A, and inability to obtain solid samples, etc.

Active Publication Date: 2014-09-17
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In WO98 / 37075, it is proposed that a high-purity product can be obtained by column chromatography purification, but in large-scale production, the solution of silica gel column chromatography purification product is difficult to realize, not only the amount of solvent that needs to be used is large, but also The scale of purification is also difficult to scale up
Patent document CN101600709 provides a method for preparing compound A of formula (1) on a large scale. Its salt-forming and crystallization scheme is effective for relatively high purity compound A crude product, but when the obtained compound A crude product is not high in purity, it becomes The salt crystallization method cannot obtain a solid sample because the crude product of compound A is precipitated in oil, and because other acids need to be introduced into the compound to form a salt, it may affect the product purity of the subsequent reaction or due to the influence of impurities, even if it is salted, the compound A crude product is also difficult to form salt and precipitate out

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Add hydrogen chloride ethanol solution (30% w / w, 300mL) to a 500mL reaction flask equipped with a thermometer, add compound B (30.0g, 62.2mmol) in batches under stirring at room temperature, stir until the solid is completely dissolved, and heat the reaction solution to 30°C Stir for 20 hours. Thin-layer chromatography detected that compound B disappeared, and the reaction solution was concentrated to 1 / 3 of its original volume by rotary evaporation under reduced pressure. Add 200 mL of ethanol to the concentrated solution to dissolve, slowly add ammonia water (25%) under stirring to adjust the pH value to 9-10, and stir at room temperature for 12 h. Thin layer chromatography showed that the stirring was stopped after the end of the reaction. The insoluble matter was removed by filtration, and the filtrate was spin-dried to obtain 35.2 g of the crude product of Compound A as a viscous light yellow oil.

[0044]The crude product of Compound A was mixed with 70 g of sil...

Embodiment 2

[0048] Add hydrogen chloride ethanol solution (35% w / w, 3000mL) to a 5000mL reaction flask equipped with a thermometer, add compound B (301g, 622mmol) in batches under stirring at room temperature, stir until the solid is completely dissolved, and heat the reaction solution to 30°C and stir for 20 Hour. Thin-layer chromatography detected that compound B disappeared, and the reaction solution was concentrated to 1 / 3 of its original volume by rotary evaporation under reduced pressure. Add 2000 mL of ethanol to the concentrated solution to dissolve, slowly add ammonia water (25%) under stirring to adjust the pH value to 9-10, and stir at room temperature for 12 h. Thin layer chromatography showed that the stirring was stopped after the end of the reaction. The insoluble matter was removed by filtration, and the filtrate was spin-dried to obtain 354 g of the crude product of Compound A as a viscous pale yellow oil.

[0049] Add 1000mL ethanol to the crude product of Compound A, ...

Embodiment 3

[0053] Add hydrogen chloride ethanol solution (30% w / w, 60L) in the 100L glass reactor that thermometer is equipped with, add compound B (8.57Kg, 17.78mol) in batches under stirring at room temperature, stir until the solid dissolves completely, control the reaction liquid temperature not to If the temperature is higher than 30°C, after the addition, the reaction solution is heated to 30°C and stirred for 20 hours. Thin-layer chromatography detected that compound B disappeared, and the reaction solution was concentrated to 1 / 3 of its original volume by distillation under reduced pressure. Add 20L of ethanol to the concentrated solution to mix and dissolve, slowly add ammonia water (25%) under stirring to adjust the pH value to 9-10 (control the temperature of the reaction solution not to exceed 35°C during the process), and stir at room temperature for 12h. Thin layer chromatography showed that the stirring was stopped after the end of the reaction. The insoluble matter was r...

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PUM

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Abstract

The invention relates to a purification method of a benzimidazole derivative. The benzimidazole derivative is a compound A shown in a formula (1), prepared from a compound B shown in a formula (2). The purification method is characterized by comprising the steps of (1) mixing a prepared compound A crude product with a porous medium to form an adsorption mixture; (2) washing the adsorption mixture by using a poor solvent or a mixed solution of the poor solvent and a good solvent of the compound A; (3) washing the adsorption mixture by using the good solvent of the compound A, concentrating obtained washing liquid, and performing re-crystallization by using a solvent to obtain a purified product.

Description

technical field [0001] The invention relates to a purification method of benzimidazole derivatives, in particular to a purification method of benzimidazole derivatives which are key intermediates for preparing dabigatran etexilate. Background technique [0002] Dabigatran etexilate is a new generation of oral anticoagulant direct thrombin inhibitors (DTIs), which can be used for the prevention and treatment of acute and chronic thromboembolic diseases. WO98 / 37075 first disclosed the preparation method of dabigatran etexilate, and the preparation methods are also involved in patent documents such as WO2006 / 000353, WO2007 / 071742A1 and WO2007 / 071743A1. [0003] In patent document WO98 / 37075, dabigatran etexilate is reacted with ethanol to obtain intermediate by the compound B of following formula (2) and ethanol and then reacts with ammonia to obtain the compound A of following formula (1), then through Reaction with n-hexyl chloroformate to obtain dabigatran etexilate, and th...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 刘飞孟方奕华刘建马亚平袁建成
Owner HYBIO PHARMA
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