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Dabigatran etexilate levulinic acid salt, preparation method and application thereof

A technology of dabigatran etexilate and fructonate, applied in the field of acid addition salts of dabigatran etexilate, can solve the problems of poor stability, low bioavailability and the like

Inactive Publication Date: 2014-02-12
天津拓飞科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The object of the present invention is to overcome the defects such as poor stability and low bioavailability of dabigatran etexilate and its existing compounds, and provide a kind of dabigatran with better stability, greater water solubility and higher bioavailability Ester fructonates and their hydrates and / or solvates, and their preparation methods and applications

Method used

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  • Dabigatran etexilate levulinic acid salt, preparation method and application thereof
  • Dabigatran etexilate levulinic acid salt, preparation method and application thereof
  • Dabigatran etexilate levulinic acid salt, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] This example is used to illustrate the preparation of dabigatran etexilate fructonate of the present invention.

[0049] Add 1.6 mmol of dabigatran etexilate and 1.6 mmol of fructose to 20 ml of absolute ethanol at 20°C, mix and stir for 6 hours to form a salt, then crystallize at 20°C, filter, and use ethyl acetate After washing and drying, diethyl ether was added for recrystallization to obtain 0.310 g of diethyl ether solvate of dabigatran etexilate fructonate. Measured ESI-MS (electrospray ionization-mass spectrometry) (m / z): 781[M+H] + .

[0050] The above ether solvate was dried to obtain 0.296 g of dabigatran etexilate fructose as a white solid. According to calculation, in the above ether solvate, the content of dabigatran etexilate fructose was 95.4wt%. The ether solvate contained 0.5 molecule of ether per molecule.

[0051] Determination of above-mentioned dabigatran etexilate fructoate:

[0052] ESI-MS(m / z): 744 [M+H] +

[0053] 1 H NMR (DMAO- d 6 ,4...

Embodiment 2

[0061] This example is used to illustrate the preparation of dabigatran etexilate fructonate of the present invention.

[0062] Add 3.2 mmol of dabigatran etexilate and 1.6 mmol of fructoic acid to 20 ml of water at 30°C, mix and stir for 6 hours to form a salt, then crystallize at 30°C, filter, wash with ethyl acetate, and dry Afterwards, add water and carry out recrystallization, obtain the hydrate of the dabigatran etexilate fructose salt of 0.450 g. Measured ESI-MS(m / z): 714[M+H] + .

[0063] The above-mentioned hydrate was dried to obtain 0.439 g of dabigatran etexilate fructonate as a white solid. According to calculation, the content of dabigatran etexilate fructose in the above-mentioned hydrate was 97.5wt%. Each molecule of the hydrate contains 1 molecule of water, that is, monohydrate.

[0064] Determination of above-mentioned dabigatran etexilate fructoate:

[0065] ESI-MS(m / z): 696[M+H] +

[0066] 1 H NMR (DMAO- d 6 ,400 MHz)δ: 0.84(t, J =9.0Hz, 3H,CH 3 ...

Embodiment 3

[0074] This example is used to illustrate the preparation of dabigatran etexilate fructonate of the present invention.

[0075] Add 4.8 mmol of dabigatran etexilate and 1.6 mmol of fructose to 20 ml of absolute ethanol at 0°C, mix and stir for 6 hours to form a salt, then crystallize at 0°C, filter, and wash with ethyl acetate , after drying, ethylene glycol dimethyl ether was added for recrystallization, and 0.420 g of dabigatran etexilate fructose salt was obtained as a white solid.

[0076] Determination of above-mentioned dabigatran etexilate fructoate:

[0077] ESI-MS(m / z): 668[M+H] +

[0078] 1 H NMR (DMAO- d 6 ,400 MHz)δ: 0.84(t, J =9.0Hz, 3H,CH 3 ), 1.09(t, J =8.4Hz, 3H,CH 3 ), 1.28-1.32(m, 6H,CH 2 CH 2 CH 2 ), 1.55-1.60(m, 2H, CH 2 ), 2.88-2.92(m, 2H,CH 2 ),3.76(s, 3H,CH 3 ), 3.94-4.04(m, 4H,2CH 2 ), 4.20(t, J =14.4 Hz, 2H, CH 2 ),4.60(d, J =5.6 Hz, 2H,CH 2 ), 6.76(d, J =8.8 Hz, 2H,ArH), 6.87(d, J =7.6 Hz, 1H,ArH), 7.01-7.16(m, 3H,ArH), 7.38(d, ...

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Abstract

The invention provides a dabigatran etexilate levulinic acid salt with a general formula shown as the following, its hydrate and / or solvate, a preparation method and application thereof. Specifically, n is 1, 2 or 3. The invention also provides the preparation method for the dabigatran etexilate levulinic acid salt, its hydrate and / or solvate, and application in preparation of medicaments for treating or preventing cardiovascular diseases.

Description

technical field [0001] The invention relates to an acid addition salt of dabigatran etexilate, in particular to a dabigatran etexilate fructose salt and a preparation method and application thereof. Background technique [0002] Dabigatran (Dabigatran) is an innovative anticoagulant, a new generation of blood-thinning drugs, which belongs to "Direct Thrombin Inhibitors (DTI)" in drug classification. At present, the medical community has confirmed the role of "dabigatran" in many clinical indications. It may replace "warfarin", which is an old blood-thinning drug, and become the drug used in most cases. Drug of choice for anticoagulation. [0003] "Dabigatran" enters the human body orally in the form of its prodrug "dabigatran etexilate". "Dabigatran etexilate" was developed by Boehringer Ingelheim of Germany and launched in Europe in 2008 under the trade name "Pradaxa" and in Canada under the trade name "Pradax". The Hong Kong Chinese product name of "Pradaxa" is "百达生", w...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/4439A61P9/10
CPCC07D401/12
Inventor 许辉
Owner 天津拓飞科技有限公司