Dabigatran etexilate 2-ketoglutarate as well as preparation method and application thereof

A technology of dabigatran etexilate and ketoglutarate, which is applied in the field of acid addition salts of dabigatran etexilate, can solve the problems of poor stability and low bioavailability, and achieves improved water solubility and rapid dissolution process , the effect of high stability and bioavailability

Inactive Publication Date: 2012-08-15
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Therefore, 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 etexilate with better stability, larger water solubility and higher bioavailability. Gatran etexilate 2-ketoglutaric acid salt and its hydrate and / or solvate, and their preparation method and application

Method used

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  • Dabigatran etexilate 2-ketoglutarate as well as preparation method and application thereof
  • Dabigatran etexilate 2-ketoglutarate as well as preparation method and application thereof
  • Dabigatran etexilate 2-ketoglutarate as well as 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 2-oxoglutarate of the present invention.

[0049] Add 1.6mmol of dabigatran etexilate and 1.6mmol of 2-oxoglutaric acid to 20ml of absolute ethanol at 20°C, mix and stir for 6 hours to form a salt, then crystallize at 20°C, filter, and use After washing with ethyl acetate and drying, ether was added for recrystallization to obtain 0.310 g of ether solvate of dabigatran etexilate 2-ketoglutarate. Measured ESI-MS (electrospray ionization-mass spectrometry) (m / z): 811[M+H] + .

[0050] The above-mentioned ether solvate is dried to obtain 0.296 g of dabigatran etexilate 2-ketoglutarate as a white solid. After calculation, in the above-mentioned ether solvate, the amount of dabigatran etexilate 2-ketoglutarate The content is 95.4wt%. The ether solvate contained 0.5 molecule of ether per molecule.

[0051] The above-mentioned dabigatran etexilate 2-oxoglutarate is measured:

[0052] ESI-MS(m / z): 7...

Embodiment 2

[0062] This example is used to illustrate the preparation of dabigatran etexilate 2-oxoglutarate of the present invention.

[0063] Add 3.2mmol of dabigatran etexilate and 1.6mmol of 2-oxoglutaric acid to 20ml of water at 30°C, mix and stir for 6 hours to form a salt, then crystallize at 30°C, filter, and wash with ethyl acetate , after drying, adding water for recrystallization, to obtain 0.450 g of dabigatran etexilate 2-oxoglutarate hydrate. Measured ESI-MS(m / z): 719[M+H] + .

[0064] The above-mentioned hydrate was dried to obtain 0.439 g of dabigatran etexilate 2-ketoglutarate as a white solid. After calculation, in the above-mentioned hydrate, the content of dabigatran etexilate 2-ketoglutarate was 97.5 wt%. Each molecule of the hydrate contains 1 molecule of water, that is, monohydrate.

[0065] The above-mentioned dabigatran etexilate 2-oxoglutarate is measured:

[0066] ESI-MS(m / z): 701[M+H] +

[0067] 1 H NMR (DMAO-d 6 , 400MHz) δ: 0.84 (t, J=9.0Hz, 3H, CH ...

Embodiment 3

[0076] This example is used to illustrate the preparation of dabigatran etexilate 2-oxoglutarate of the present invention.

[0077] Add 4.8mmol of dabigatran etexilate and 1.6mmol of 2-oxoglutaric acid to 20ml of absolute ethanol at 0°C, mix and stir for 6 hours to form a salt, then crystallize at 0°C, filter, and use acetic acid After washing with ethyl ester and drying, ethylene glycol dimethyl ether was added for recrystallization to obtain 0.420 g of dabigatran etexilate 2-ketoglutarate as a white solid.

[0078] The above-mentioned dabigatran etexilate 2-oxoglutarate is measured:

[0079] ESI-MS(m / z): 677[M+H] +

[0080] 1 H NMR (DMAO-d 6 , 400MHz) 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 ), 2.41-2.48 (m, 0.7H, CH 2 ), 2.66(t, J=14.4Hz, 0.7H, 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=14.4Hz, 2H, CH 2 ), 4.60 (d, J=5.6Hz, 2H, CH ...

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Abstract

The invention provides dabigatran etexilate 2-ketoglutarate shown in a general formula (I), hydrate and / or a solvate thereof. In the formula (I), n is 1, 2 or 3. The invention also provides a preparation method of dabigatran etexilate 2-ketoglutarate as well as hydrate and / or the solvate thereof 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 2-oxoglutarate 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", ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/4439A61P9/00A61P7/02A61P9/10
Inventor 蔡志强任晓文徐为人汤立达周植星
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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