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Dabigatran etexilate malate, and preparation method and application thereof

A technology of dabigatran etexilate and malate, which is applied in the field of acid addition salt of dabigatran etexilate, can solve the problems of poor stability and low bioavailability, and achieve improved water solubility, good solubility or The effects of compressibility, high stability and bioavailability

Inactive Publication Date: 2013-09-18
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 malate and its hydrate and / or solvate, and their preparation method and application

Method used

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  • Dabigatran etexilate malate, and preparation method and application thereof
  • Dabigatran etexilate malate, and preparation method and application thereof
  • Dabigatran etexilate malate, and preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

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

[0049] Add 1.6mmol of dabigatran etexilate and 1.6mmol of malic 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 wash with ethyl acetate , after drying, ether was added for recrystallization to obtain 0.310 g of ether solvate of dabigatran etexilate malate. Measured ESI-MS (electrospray ionization-mass spectrometry) (m / z): 799[M+H] + .

[0050] The ether solvate was dried to obtain 0.300 g of dabigatran etexilate malate as a white solid. According to calculation, in the ether solvate, the content of dabigatran etexilate malate was 95.4wt%. The ether solvate contained 0.5 molecule of ether per molecule.

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

[0052] ESI-MS(m / z): 762[M+H] +

[0053] 1 H NMR (DMAO-d 6 , 400MHz) δ: 0.88 (t, J=9.0Hz, 3H, CH 3 ), (t, J=...

Embodiment 2

[0062] This embodiment is used to illustrate the preparation of dabigatran etexilate malate of the present invention.

[0063] Add 3.2mmol of dabigatran etexilate and 1.6mmol of malic acid into 20ml 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 , Add water to carry out recrystallization, obtain the hydrate of the dabigatran etexilate malate of 0.450g. Measured ESI-MS(m / z): 713[M+H] + .

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

[0065] Determination of above-mentioned dabigatran etexilate malate:

[0066] ESI-MS(m / z): 695[M+H] +

[0067] 1 H NMR (DMAO-d 6 , 400MHz) δ: 0.88 (t, J=9.0Hz, 3H, CH 3 ), (t, J=8.4Hz, 3H, CH 3 ), 1.27...

Embodiment 3

[0076] This embodiment is used to illustrate the preparation of dabigatran etexilate malate of the present invention.

[0077] Add 4.8mmol of dabigatran etexilate and 1.6mmol of malic 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, wash with ethyl acetate, After drying, ethylene glycol dimethyl ether was added for recrystallization to obtain 0.420 g of dabigatran etexilate malate as a white solid.

[0078] Determination of above-mentioned dabigatran etexilate malate:

[0079] ESI-MS(m / z): 673[M+H] +

[0080] 1 H NMR (DMAO-d 6 , 400MHz) δ: 0.88 (t, J=9.0Hz, 3H, CH 3 ), (t, J=8.4Hz, 3H, CH 3 ), 1.27-1.37 (m, 6H, CH 2 CH 2 CH 2 ), 1.57-1.61 (m, 2H, CH 2 ), 2.55-2.60 (m, 0.7H, CH 2 ), 2.68(t, J=14.4Hz, 2H, CH 2 ), 2.85(s, 0.3H, OH), 3.77(s, 3H, CH 3 ), 3.95-4.01 (m, 4H, 2CH 2 ), 4.22(t, J=14.4Hz, 2H, CH 2 ), 4.35-4.39 (m, 0.3H, CH), 4.61 (d, J=5.6Hz, 2H, CH 2 ), 6.76(d, J=8.8Hz, 2H, ArH), 6.89(d, J=...

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Abstract

The invention provides a dabigatran etexilate malate having a general formula shown in the specification, and a hydrate and / or solvate thereof. In the formula, n is 1, 2 or 3. The invention also provides a preparation method of the dabigatran etexilate malate, the hydrate and / or solvate thereof, and an application in the preparation of medicines 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 malate 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", while th...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07C59/245C07C51/41A61K31/4439A61P9/10
Inventor 蔡志强任晓文黄长江龚珉徐为人刘洪强张伟光汤立达
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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