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Dabigatran preparation method

A technology of dabigatran etexilate and molar ratio, applied in the field of preparation of dabigatran etexilate, can solve problems such as low yield, long reaction time, and incomplete reaction

Inactive Publication Date: 2014-05-21
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method takes a long time to react, and generally takes several days, and the reaction is not complete and the yield is low

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Embodiment 1: The ratio of the amount of Lewis acid to compound 1 is 0.4:1

[0020] Dissolve 80g (0.166mol) of the compound of formula 1 in freshly prepared saturated hydrochloric acid ethanol solution (1700ml), stir and dissolve at room temperature until the solution turns yellow-green and clear, then add 9.03g (0.066mol) zinc chloride solid. A white solid was precipitated after 3 hours of reaction, traced by thin-layer chromatography, and the reaction was complete after 10 hours. Concentrate with rotary evaporation at a heating temperature of 45-50° C., concentrate to 300 ml, add 1400 ml of ethyl acetate, stir for 3 hours, filter, and dry in air to obtain 115 g of a solid product of formula 2.

[0021] Dissolve the above solid with 1500ml of absolute ethanol, stir evenly and turn into pink turbidity, and slowly add 248ml of ammonia water dropwise in an ice-water bath. During the dropwise addition, the color of the reaction solution changed from pink turbidity to a co...

Embodiment 2

[0022] Embodiment 2: the ratio of the consumption of Lewis acid and formula 1 compound 0.2:1

[0023] Dissolve 80g (0.166mol) of the compound of formula 1 in freshly prepared saturated hydrochloric acid ethanol solution (1700ml), stir and dissolve at room temperature until the solution turns yellow-green and clear, then add 4.52g (0.033mol) zinc chloride solid. A white solid was precipitated after 3 hours of reaction, traced by thin-layer chromatography, and the reaction was complete after 10 hours. Concentrate by rotary evaporation and heating at a heating temperature of 45-50° C., concentrate to 300 ml, add 1400 ml of ethyl acetate, stir for 3 hours, filter, and dry in air to obtain 120 g of a solid product of formula 2.

[0024] Dissolve the above solid with 1565ml of absolute ethanol, stir evenly and turn into pink turbidity, and slowly add 258ml of ammonia water dropwise in an ice-water bath. During the dropwise addition, the color of the reaction solution changed from p...

Embodiment 3

[0025] Embodiment 3: the ratio of the consumption of Lewis acid and formula 1 compound 1.5:1

[0026] Dissolve 80g (0.166mol) of the compound of formula 1 in freshly prepared saturated hydrochloric acid ethanol solution (1700ml), stir and dissolve at room temperature until the solution turns yellow-green and clear, then add 33.94g (0.249mol) zinc chloride solid. A white solid was precipitated after 3 hours of reaction, traced by thin-layer chromatography, and the reaction was complete after 10 hours. Concentrate by rotary evaporation and heating at a heating temperature of 45-50°C, concentrate to 300ml, add 1400ml of ethyl acetate, stir for 3 hours, filter, and dry in air to obtain 118g of the compound of formula 2.

[0027] Dissolve the above solid with 1550ml of absolute ethanol, stir evenly and turn into pink turbidity, and slowly add 254ml of ammonia water dropwise in an ice-water bath. During the dropwise addition, the color of the reaction solution changed from pink tur...

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PUM

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Abstract

The present invention relates to a dabigatran preparation method, which is characterized in that in a saturated hydrochloric acid ethanol solution, a compound represented by a formula 1 is subjected to alcoholysis under catalysis of a Lewis acid to obtain a compound represented by a formula 2, the compound represented by a formula 2 reacts with ammonia to obtain a compound represented by a formula 3, and the compound represented by the formula 3 reacts with hexyl chloroformate in the presence of an alkali to obtain a compound represented by a formula 4, wherein the compound represented by the formula 4 is dabigatran.

Description

technical field [0001] The invention relates to a preparation method of dabigatran etexilate. [0002] Background technique [0003] Dabigatran etexilate (Dabigatran) is a new type of anticoagulant drug developed by Boehringer Ingelheim in Germany. In April 2008, it was first launched in Germany and the United Kingdom under the trade name of Pradaxa, which is used to prevent and treat acute venous thrombosis (VTE). [0004] Dabigatran etexilate is known in the prior art and was first disclosed in International Patent Application WO98 / 37075. Methods for the preparation of dabigatran etexilate are also known from WO 2006 / 000353 or from the article by Hauel et al. (J. Med. Chem., 2002, 45, 1757 ff). In addition to international patent applications WO 98 / 37075 and WO 2006 / 000353, WO 2007 / 071742 Al and WO 2007 / 071713 Al also disclose possible preparations of dabigatran etexilate. [0005] Known from above-mentioned patent, formula 3 compound 3-(2-(((4-carbamidinophenyl)amin...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 蔡志强孔维苓徐为人黄长江龚珉任晓文汤立达
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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