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Dabigatran compound and preparation method and medicinal composition thereof

A technology of dabigatran etexilate and dabigatran etexilate mesylate, which is applied in the field of medicine, can solve the problems of many interfering factors, large individual differences in dosage, and narrow treatment window, and achieve easy operation, few types of use, Conducive to the effect of production and storage

Active Publication Date: 2012-03-28
CSPC OUYI PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, warfarin is the only oral antithrombotic drug approved by the FDA to prevent VTE and atrial fibrillation after surgery, but it has a narrow therapeutic window, large individual differences in dosage, many interfering factors, and frequent monitoring of coagulation indicators (INR) and other defects, so safe and effective oral anticoagulant has become a research and development hotspot in this field

Method used

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  • Dabigatran compound and preparation method and medicinal composition thereof
  • Dabigatran compound and preparation method and medicinal composition thereof
  • Dabigatran compound and preparation method and medicinal composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1: the preparation of dabigatran etexilate mesylate:

[0032] With 6.278g (0.01mol) dabigatran etexilate (method as described in WO 98 / 37075), be dissolved in 400ml ethyl acetate, add the acetic acid that dissolves methanesulfonic acid 0.961g (0.01mol) while stirring at room temperature 40ml of ethyl ester solution, continue to stir for 60 minutes after the addition, then put it in an ice bath and stir for 40 minutes, filter, wash the filter cake with 80ml of ethyl acetate, dry in a circulating air drier at 55°C for 3h, and obtain 6.85g of Bigatran etexilate mesylate anhydrate, yield 94.6%. Melting point: 178-179°C.

[0033] Elemental analysis:

[0034] Elemental analysis Actual value% Theoretical value% C 58.02 58.09 H 6.32 6.22 N 13.60 13.55 O 17.24 17.27 S 4.47 4.43

Embodiment 2

[0035] . Embodiment 2: the preparation of dabigatran etexilate compound of the present invention:

[0036] Take 2 g of dabigatran etexilate methanesulfonate in Example 1, add 100 ml of hot water at 60°C to dissolve, cool to 15-20°C and stir for 1 hour, then cool to 5-10°C and stir for 1 hour, and finally cool to -5 Stirring at -0°C for 10 hours, crystals were precipitated, filtered, and the filter cake was dried at 35°C and 65% relative humidity for 6 hours to obtain 1.68 g of the dabigatran etexilate compound of the present invention, with a yield of 82%.

[0037] Elemental analysis:

[0038] Elemental analysis Actual value% Theoretical value% C 56.56 56.68 H 6.38 6.34 N 13.25 13.22 O 19.46 19.43 S 4.27 4.32

[0039] The moisture in the dabigatran etexilate compound of the present invention measured by Karl Fischer method is 2.2% (theory: 2.4%); the thermogravimetric analysis result shows that it is the characteristic of monohy...

Embodiment 3

[0040] Embodiment 3: the preparation of dabigatran etexilate compound of the present invention:

[0041] Take 2g of dabigatran etexilate methanesulfonate in Example 1, add 100ml of hot water at 60°C to dissolve, cool to 15-20°C and stir for 1 hour, then cool to 5-10°C and stir for 1 hour, and finally cool to - Stir at 5-0°C for 10 hours to precipitate crystals, filter, and dry the filter cake at 30°C and 60% relative humidity for 8 hours to obtain 1.63 g of the dabigatran etexilate compound of the present invention, with a yield of 80%.

[0042] Elemental analysis:

[0043] Elemental analysis Actual value% Theoretical value% C 56.61 56.68 H 6.29 6.34 N 13.28 13.22 O 19.51 19.43 S 4.26 4.32

[0044]The moisture in the dabigatran etexilate compound of the present invention measured by Karl Fischer method is 2.5% (theory: 2.4%); the thermogravimetric analysis result shows that it is the characteristic of monohydrate.

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Abstract

The invention discloses a dabigatran compound and a preparation method and a medicinal composition thereof. The dabigatran compound is mesylate-hydrate of 3-[(2-{[4-(carbethoxyl amino-imino-methyl)-phenyl amino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridine-2-radical-amino-ethyl propionate. The invention further relates to a preparation method of the compound and a medicinal composition taking the compound as an active ingredient. Compared with dabigatran mesylate, the compound has higher stability and is more suitable for preparing, storing and using medicinal preparations of various forms.

Description

technical field [0001] The present invention relates to a kind of new dabigatran etexilate compound, specifically relate to 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}- 1-Methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester i.e. the mesylate hydrate of dabigatran etexilate, its preparation method and its The pharmaceutical composition belongs to the technical field of medicine. Background technique [0002] Atrial fibrillation, referred to as atrial fibrillation, is the most common clinical arrhythmia. The survey shows that the total prevalence of atrial fibrillation in my country is about 0.6%, and it shows an upward trend with age. The age group over 80 years old reaches 7.5%, which is significantly higher than other age groups. The proportions of valvular, non-valvular and isolated atrial fibrillation in all patients with AF were 12.9%, 65.2% and 21.9%, respectively, and the non-valvular type was significantly higher...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/4439A61P9/06A61P9/10
Inventor 张育齐新英郑雪清张文静刘聪敏李瑞建孔海花
Owner CSPC OUYI PHARM CO LTD
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