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Preparing method of dabigatran etexilate mesylate crystal form I

A technology of dabigatran etexilate mesylate and dabigatran etexilate mesylate, applied in the field of preparation of dabigatran etexilate mesylate I crystal form, can solve the problem of unstable preparation of dabigatran etexilate mesylate Ⅰ crystal form and other issues, to achieve the effect of suitable process conditions

Inactive Publication Date: 2015-06-24
CHONGQING TOPTECH PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the prior art, for example, the patent CN1845917B prepares dabigatran etexilate mesylate I crystalline form by reacting dabigatran etexilate with methanesulfonic acid in acetone at 30-35°C. When the temperature deviates, or the reaction system Dabigatran etexilate mesylate Ⅰ crystal form cannot be prepared stably when it contains a certain amount of water, and the obtained product contains a small part of Ⅱ crystal form or hemihydrate

Method used

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  • Preparing method of dabigatran etexilate mesylate crystal form I
  • Preparing method of dabigatran etexilate mesylate crystal form I
  • Preparing method of dabigatran etexilate mesylate crystal form I

Examples

Experimental program
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Effect test

Embodiment 1

[0044] (1) at room temperature, dabigatran etexilate is joined in acetone, wherein, acetone volume consumption is 20 times of dabigatran etexilate quality; be warming up to 30 ℃ and make dabigatran etexilate fully dissolve; then cool down to 25 ℃, keep temperature 25 ℃, add methanesulfonic acid acetone solution, wherein, the amount of methanesulfonic acid substance is 0.98 times of the amount of dabigatran etexilate substance, and the volume consumption of acetone is 15 times of methanesulfonic acid quality; Mix well , making dabigatran etexilate mesylate solution;

[0045] (2) Cool the mixture obtained in step (1) to 10°C, stir and crystallize for 1.5 hours;

[0046] (3) filter step (2) gained mixture, filter cake is joined in the ethyl acetate solvent, wherein, the ethyl acetate solvent volume consumption is 30 times of dabigatran etexilate quality described in the step (1); Warming up to 45°C, keep the temperature at 45°C, and stir for 5 hours;

[0047] (4) cooling the mi...

Embodiment 2

[0052] (1) at room temperature, dabigatran etexilate is joined in acetone, wherein, acetone volume consumption is 20 times of dabigatran etexilate quality; be warming up to 56 ℃ and make dabigatran etexilate dissolve completely; then cool down to 40 ℃, keep temperature 40 ℃, add methanesulfonic acid acetone solution, wherein, the amount of methanesulfonic acid substance is 0.98 times of the amount of dabigatran etexilate substance, and the volume consumption of acetone is 15 times of methanesulfonic acid quality; Mix well , making dabigatran etexilate mesylate solution;

[0053] (2) Cool the mixture obtained in step (1) to 15°C, stir and crystallize for 1.5 hours;

[0054] (3) filter step (2) gained mixture, filter cake is joined in the ethyl acetate solvent, wherein, the ethyl acetate solvent volume consumption is 15 times of dabigatran etexilate quality described in the step (1); Warming up to 55°C, keep the temperature at 55°C, and stir for 1 hour;

[0055] (4) cooling th...

Embodiment 3

[0061] (1) at room temperature, dabigatran etexilate is joined in acetone, wherein, acetone volume consumption is 20 times of dabigatran etexilate quality; be warming up to 40 ℃ and make dabigatran etexilate dissolve completely; then cool down to 30 ℃, keep temperature 30 ℃, add methanesulfonic acid acetone solution, wherein, the amount of methanesulfonic acid substance is 0.98 times of the amount of dabigatran etexilate substance, and the volume consumption of acetone is 15 times of methanesulfonic acid quality; Mix well , making dabigatran etexilate mesylate solution;

[0062] (2) Cool the mixture obtained in step (1) to 12°C, stir and crystallize for 1.5 hours;

[0063] (3) filter step (2) gained mixture, filter cake is joined in the methyl propionate solvent, wherein, the methyl propionate solvent volume consumption is 5 times of dabigatran etexilate solid mass described in step (1) ;Heat up to 78°C, keep the temperature at 78°C, and stir for 2 hours;

[0064] (4) Cool t...

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Abstract

An embodiment of the invention discloses a preparing method of dabigatran etexilate mesylate crystal form I. The method includes the steps of adding dabigatran etexilate into acetone solution before heating for solution, and adding methylsulfonic acid to generate dabigatran etexilate mesylate; stirring the dabigatran etexilate mesylate in ester solvent or ether solvent under heating so that the dabigatran etexilate mesylate with low crystal form I (containing little crystal form II or part of semihydrate) is converted into the dabigatran etexilate mesylate with high content of the crystal form I. The dabigatran etexilate mesylate crystal form I prepared by the method is high in purity, lower in water content and more stable in quality.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a preparation method of dabigatran etexilate mesylate I crystal form. Background technique [0002] Dabigatran etexilate mesylate was originally developed by Boehringer Ingelheim for the prevention of stroke and systemic embolism (SEE) in adult patients with non-valvular atrial fibrillation with one or more risk factors. This is the first new class of oral anticoagulant drugs to be marketed in 50 years after warfarin. 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] The structural formula of dabigatran etexilate mesylate is as follows: [0004] [0005] Boehringer Ingelheim applied for patent CN1845917B in 2004, reporting the I crystal form, II crystal form and hemihydrate of dabigatran etexilate mesylate. Powder X-ray dif...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12C07B2200/13
Inventor 黄钦军沈君伟刘学国夏吉虎袁亮
Owner CHONGQING TOPTECH PHARMA TECH
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