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Dabigatran etexilate benzene sulfonate as well as preparation method and application thereof

A technology of dabigatran etexilate and besylate, applied in the field of medicine, can solve the problems of poor absorption, large distribution coefficient, difficult transport and the like, and achieve the effects of improving drug efficacy and broad prospects

Active Publication Date: 2013-09-11
HUAREN PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The oil / water partition coefficient of the drug is too large, and sometimes the absorption is not good. This is because the drug may be strongly combined with the lipid after penetrating into the plasma layer, and it is not easy to transport to the systemic circulation system

Method used

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  • Dabigatran etexilate benzene sulfonate as well as preparation method and application thereof
  • Dabigatran etexilate benzene sulfonate as well as preparation method and application thereof
  • Dabigatran etexilate benzene sulfonate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 13

[0024] Example 13-[(2-{4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1Hbenzimidazole-5-carbonyl)-pyridine- Preparation of 2-yl-amino]-propionate ethyl benzenesulfonate

[0025] Include steps:

[0026] 3-[(2-{4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1Hbenzimidazole-5-carbonyl)-pyridine-2 -Base-amino]-propionic acid ethyl ester 5g (0.008mol) was dissolved in 350ml of acetone, at room temperature, stirred and added 1.56g (0.0096mol) benzenesulfonic acid solid, after stirring at room temperature for 5h, the ice bath cooled to 0 Stir at -4°C for 24h. The precipitated solid was filtered, washed with an appropriate amount of acetone, and the product was vacuum-dried at a maximum temperature of 50° C. for 4 hours to obtain 5.10 g (81%) of a light yellow powder. HPLC determined that the light yellow powder was the target product with a purity of 99.6%.

Embodiment 23

[0027] Example 23-[(2-{4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1Hbenzimidazole-5-carbonyl)-pyridine- Preparation of 2-yl-amino]-propionate ethyl benzenesulfonate

[0028] Include steps:

[0029] 3-[(2-{4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1Hbenzimidazole-5-carbonyl)-pyridine-2 5 g (0.008 mol) of ethyl propionate was dissolved in 500 ml of tetrahydrofuran, and 1.3 g (0.008 mol) of benzenesulfonic acid solid was added with stirring at 45 ° C. After stirring at room temperature for 4 h, the temperature was cooled to Stir at 0-4°C for 28h. 500ml of ether was added to the reaction solution to precipitate a solid. The precipitated solid was filtered, washed with an appropriate amount of acetone, and the product was vacuum-dried at a maximum temperature of 50° C. for at least 4 hours to obtain 5.04 g (80%) of a light yellow powder. HPLC determined that the light yellow powder was the target product with a purity of 99.5%...

Embodiment 33

[0030] Example 33-[(2-{4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1Hbenzimidazole-5-carbonyl)-pyridine- Preparation of 2-yl-amino]-propionate ethyl benzenesulfonate

[0031] Include steps:

[0032] 3-[(2-{4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1Hbenzimidazole-5-carbonyl)-pyridine-2 -Base-amino]-propionic acid ethyl ester 5g (0.008mol) was dissolved in 350ml of methanol, and at 50-60°C, 2.6g (0.016mol) of benzenesulfonic acid solid was added with stirring, and after stirring at room temperature for 3h, the ice bath Cool down to 0-4°C and stir for 32h. The precipitated solid was filtered, washed with an appropriate amount of acetone, and the product was vacuum-dried at a maximum temperature of 50° C. for at least 4 hours to obtain 4.9 g (78%) of a light yellow powder. HPLC confirmed that the light yellow powder was the target product with a purity of 99.3%. .

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Abstract

The invention discloses Dabigatran etexilate benzene sulfonate as well as a preparation method and application thereof. The Dabigatran etexilate benzene sulfonate has a structure shown in a formula I in the specification. According to the Dabigatran etexilate benzene sulfonate, the active substance Dabigatran etexilate is salified to change the physical and chemical properties of the active substance, and then effect of a medicament is significantly improved under the condition without pharmacokinetic differences, so that the Dabigatran etexilate benzene sulfonate has a wide prospect in the aspect of preparing an anticoagulant medicament.

Description

technical field [0001] The invention belongs to the field of medicines, more specifically, the invention relates to dabigatran etexilate besylate (3-[(2-{4-(hexyloxycarbonylamino-imino-methyl)-phenylamino] -methyl}-1-methyl-1Hbenzimidazole-5-carbonyl)-pyridin-2-yl-amino]-ethyl propionate-benzenesulfonate) and its preparation method and application. Background technique [0002] WO98 / 37075 discloses a compound with the effect of inhibiting thrombin and prolonging the action time of thrombin, its name is 1-methyl-2-[N-[4-(N-n-hexyloxycarbonyl-amidino)benzene Base]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide, a compound of formula A (up to Bigatran etexilate, molecular weight is the prodrug of 628.84). [0003] [0004] The compound of formula A is first converted in vivo to the actual effective compound (ie the compound of formula B). The main scope of indications of the compound of formula A is postoperative prevention o...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07C309/29C07C303/32A61K31/4439A61P7/02
Inventor 李继仁孙玮
Owner HUAREN PHARMACEUTICAL CO LTD
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