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Preparation method of Dabigatran etexilate key intermediate

A compound and catalyst technology, applied in the field of chemical synthesis of oral anticoagulant dabigatran etexilate intermediates, can solve the problems of unsuitability for industrial production, increase of production cost, high preparation cost, etc., and achieve short reaction time and high yield The effect of low cost and convenient purification

Active Publication Date: 2013-01-02
SHANXI WEIQIDA PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When using chloroacetic acid, the reaction yield is only 30%; when using chloroacetyl chloride cyclization, it is easy to produce diacylated impurities, and the yield is only 71%; chloroacetic anhydride is more expensive, which increases the production cost to a large extent; Ethoxychloroethane is not commercialized, it needs to be self-made, the synthesis is more complicated, and the preparation cost is also higher
Therefore, the four cyclization reagents are not suitable for the industrial production of intermediate 3

Method used

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  • Preparation method of Dabigatran etexilate key intermediate
  • Preparation method of Dabigatran etexilate key intermediate
  • Preparation method of Dabigatran etexilate key intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0018]

[0019] Compound 2 (10.0g, 0.029mol) was added to a 250mL three-neck flask, 100mL of ethanol was added, compound 7 (5.3g, 0.032mol), ammonium chloride 1.0g, stirred and reacted at 65-70°C for 2h under nitrogen protection, the solvent was evaporated, and added Ethyl acetate 100mL, wash the organic layer with 100mL×2, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate to about 50mL, solid precipitates, add 50mL petroleum ether, stir, ice bath for one hour, filter, 50℃ 9.5 g of white solid dried under reduced pressure, yield 81%.

Embodiment 2

[0021] Compound 2 (10.0g, 0.029mol) was added to a 250mL three-necked flask, 100mL of ethanol was added, compound 7 (5.3g, 0.032mol), methanesulfonic acid 1.0g, stirred and reacted at 65-70°C for 2h under nitrogen protection, the solvent was evaporated, added Ethyl acetate 100mL, wash the organic layer with 100mL×2, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate to about 50mL, solid precipitates, add 50mL petroleum ether, stir, ice bath for one hour, filter, 50℃ 9.8 g of white solid dried under reduced pressure, yield 84%.

Embodiment 3

[0023]

[0024] Compound 2 (10.0g, 0.029mol) was added to a 250mL three-necked flask, 100mL of ethanol was added, compound 8 (7.6g, 0.032mol), ammonium chloride 1.0g, stirred and reacted at 65-70°C for 2h under nitrogen protection, the solvent was evaporated, and added Ethyl acetate 100mL, wash the organic layer with 100mL×2, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate to about 50mL, solid precipitates, add 50mL petroleum ether, stir, ice bath for one hour, filter, 50℃ 9.4 g of white solid dried under reduced pressure, yield 80%.

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Abstract

The invention belongs to the technical field of chemical synthesis of an oral anticoagulant Dabigatran etexilate intermediate (a compound represented by a formula 3). Compared with prior arts, a method provided by the invention assists in solving various problems. The prices of adopted reagents are cheap, a reaction time is short, a yield is high, conditions are mild, and intermediate purification is convenient. With the method provided by the invention, the Dabigatran etexilate key intermediate 3 can be prepared with high yield and low cost. The method is suitable for industrialized productions.

Description

technical field [0001] The invention belongs to the field of synthesis, and relates to a chemical synthesis method of an oral anticoagulant dabigatran etexilate intermediate. Background technique [0002] Dabigatran etexilate is a new oral anticoagulant drug developed by Boehringer Ingelheim, Germany. In April 2008, it was first launched in Germany and the UK under the trade name of Pradaxa, and its chemical structure is as follows: [0003] [0004] The synthetic route of dabigatran etexilate reported by Boehringer Ingelheim in patent WO2011061080 is as follows: [0005] [0006] The cyclization reagent used in the preparation of key intermediate 3 in the above route is chloroacetic acid, chloroacetyl chloride, chloroacetic anhydride or triethoxychloroethane. When using chloroacetic acid, the reaction yield is only 30%; when using chloroacetyl chloride cyclization, it is easy to produce diacylated impurities, and the yield is only 71%; chloroacetic anhydride is more...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 万会玲邹强王国平侯建
Owner SHANXI WEIQIDA PHARMA IND
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