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Method for purifying dabigatran etexilate mesylate intermediate

A technology of dabigatran etexilate mesylate and purification method, which is applied in the field of purification of dabigatran etexilate mesylate intermediate, and can solve problems such as failure to meet quality standards

Inactive Publication Date: 2017-02-15
苏州正济药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The process adopted in the patent WO2012152855 of Spanish MEDICHEM SA company to prepare compound A is to prepare the p-toluenesulfonate of compound B, which is the intermediate of dabigatran etexilate methanesulfonate of the present invention. This process is suitable for large-scale industrial production, but the literature The HPLC of dabigatran etexilate mesylate intermediate in the middle is 83%, and the HPLC that uses dabigatran etexilate mesylate intermediate to continue to prepare dabigatran etexilate mesylate (compound A) to obtain is only 98.8%, far from reaching the requirements of Boehringer Ingelheim's quality standards for CFDA declaration in China

Method used

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  • Method for purifying dabigatran etexilate mesylate intermediate
  • Method for purifying dabigatran etexilate mesylate intermediate
  • Method for purifying dabigatran etexilate mesylate intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0048] Dabigatran etexilate mesylate intermediate (N-[[2-[[[(4-(aminoiminomethyl)phenyl]amino]methyl]-1-methyl-1H-5- Preparation of benzimidazole]carbonyl]-N-2-pyridyl-β-alanine ethyl ester p-toluenesulfonate)

[0049] Reference WO2012152855 Example 1, g step operation to prepare dabigatran etexilate mesylate intermediate.

[0050] To a 1000mL glass reaction flask, add 47.7g of compound C (3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-H-benzimidazole-5 -yl] carbonyl] pyridin-2-yl amino] ethyl propionate oxalate), 21.8g p-toluenesulfonic acid and 142g of 10mol / L hydrogen chloride ethanol solution. The reaction solution was incubated at room temperature for 24 hours, 400 mL of ethanol was added, the temperature was lowered to 0°C, ammonia gas was slowly introduced at 0°C until the precipitation was complete, and then the temperature was slowly raised to 10°C for 2 hours, and the temperature was raised to room temperature for overnight. The solvent was distilled off under redu...

Embodiment 2

[0052] Dabigatran etexilate mesylate intermediate (N-[[2-[[[(4-(aminoiminomethyl)phenyl]amino]methyl]-1-methyl-1H-5- Purification of benzimidazole]carbonyl]-N-2-pyridyl-β-alanine ethyl ester p-toluenesulfonate)

[0053]Add 34.0 g of the intermediate prepared in Example 1 into a 1000 mL glass reaction bottle, add 150 mL of ethanol and 200 mL of water in sequence, heat the reaction liquid in a water bath to 80-100° C. and keep it warm for 30 minutes, then heat filter and discard the filter cake. Transfer the filtrate into a 1000mL glass reaction bottle, raise the temperature until all the solids are dissolved, and perform gradient crystallization operation: control the rotation speed at 20-30 rpm, control the cooling rate at 5°C / min, and cool down to the time when solids start to precipitate (initial crystallization) Stop cooling and stir for 20 minutes; control the cooling rate to 5°C / min, add 200 mL of water dropwise at a rate of 5 mL / min, stop cooling at the same time when th...

Embodiment 3

[0056] Dabigatran etexilate mesylate intermediate (N-[[2-[[[(4-(ammonia results as attached figure 2 As shown, using analytical method 1, area normalized method: iminomethyl)phenyl]amino]methyl]-1-methyl-1H-5-benzimidazole]carbonyl]-N-2-pyridyl -Purification of β-alanine ethyl ester p-toluenesulfonate)

[0057] Add 34.0 g of the intermediate prepared in Example 1 into a 1000 mL glass reaction bottle, add 150 mL of methanol and 150 mL of water in sequence, heat the reaction liquid in a water bath to 75-100 ° C for 30 minutes, heat filter, and discard the filter cake. Transfer the filtrate into a 1000mL glass reaction bottle, raise the temperature until all the solids are dissolved, and perform gradient crystallization operation: control the rotation speed at 20-30 rpm, control the cooling rate at 5°C / min, and cool down to the time when solids start to precipitate (initial crystallization) Stop cooling and stir for 20 minutes; control the cooling rate to 5°C / min, add 200 mL of...

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Abstract

The invention relates to a method for purifying a dabigatran etexilate mesylate intermediate. The method comprises the following step: purifying the dabigatran etexilate mesylate intermediate in benign solvent through control of gradient crystallization. The purification method can make the purity of the dabigatran etexilate mesylate intermediate be more than 95%, and make other unknown single impurity be less than 0.15%; the intermediate can be used for preparing a dabigatran etexilate mesylate product which meets the quality requirement of a first-researching drug factory.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a method for purifying a dabigatran etexilate mesylate intermediate. Background technique [0002] Dabigatran etexilate mesylate (Compound A, English name Pradaxa) was developed by Boehringer Ingelheim of Germany and is currently on the market in 80 countries around the world. Dabigatran etexilate mesylate can significantly reduce the risk of stroke and systemic embolism by more than 35%, and significantly reduce the risk of ischemic stroke by 24%. At the same time, the risk of vascular death, intracranial hemorrhage, and fatal hemorrhage is also significantly reduced. The launch of this product is a major progress in the field of anticoagulant therapy and the prevention of potentially fatal thrombosis, which is a milestone. [0003] [0004] N-[[2-[[[(4-(aminoiminomethyl)phenyl]amino]methyl]-1-methyl-1H-5-benzimidazole]carbonyl]-N-2-pyridine The salt (compound B...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07C309/04C07C303/32C07C303/44
CPCC07D401/12C07B2200/13
Inventor 刘中华段世英张为成姚青钱超
Owner 苏州正济药业有限公司
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