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Dabigatran etexilate novel intermediate, and preparation method and application thereof

A technology of dabigatran etexilate and catalytic reaction, applied in the direction of organic chemistry, etc., can solve the problems of unsuitability for industrial production, high price, and odor, and achieve high yield and low cost preparation, short reaction time, and mild conditions Effect

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

The condensing agents used in the synthesis of the benzimidazole ring include carbonyldiimidazole, pivaloyl chloride, and propane phosphoric anhydride. Among them, carbonyldiimidazole and propane phosphoric anhydride are expensive, and pivaloyl chloride has a foul smell, which is not suitable for industrial production.

Method used

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  • Dabigatran etexilate novel intermediate, and preparation method and application thereof
  • Dabigatran etexilate novel intermediate, and preparation method and application thereof
  • Dabigatran etexilate novel intermediate, and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1: the preparation of formula 4 compound (method 1)

[0035] Heat 4.3g (0.0292mol) of compound of formula 3, 5.0g (0.0146mol) of compound of formula 2, 0.5g of ammonium chloride, and 30ml of ethanol to 65-70°C under nitrogen protection and stir for two hours. Chloromethane 100ml, water 100ml×2 washed, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, added 30ml ethyl acetate, stirred to precipitate solid, filtered, and dried to obtain 4.8g of product, yield 86.0%.

[0036] Melting point: 140-143℃ESI-MS(m):383[M+H] +

Embodiment 2

[0037] Embodiment 2: the preparation of formula 4 compound (method 2)

[0038] The compound of formula 2 (5.0g, 0.146mol), the compound of formula 5 (3.8g, 0.161mol), 0.5g of ammonium chloride, and 30ml of absolute ethanol were stirred and reacted at 65-70°C under nitrogen protection for 3h. Add 1.0 g of palladium-carbon catalyst with a content of 5%, and stir the reaction under normal pressure with hydrogen reflux, monitor by TLC until the reaction of the raw materials is complete, filter to remove the catalyst and inorganic salt, concentrate to dryness, add 20 ml of ethyl acetate and stir, filter to precipitate a solid, After drying, 5.0 g of the target product was obtained, with a yield of 89.6%.

Embodiment 3

[0039] Embodiment 3: the preparation of formula 7 compound, R is methyl

[0040] Add the compound of formula 4 (5.0g, 0.0131mol) and triethylamine (3.3g, 0.0327mol) into 100ml of dichloromethane, add methanesulfonyl chloride (3.0g, 0.0262mol) dropwise within 2min at 5-10°C, and stir After reacting for 2 minutes, add 100ml of ice water and 2ml of ammonia water, stir for 5min, and separate the layers. The organic layer is washed with 100ml of saturated sodium bicarbonate and 100ml of saturated sodium chloride.

[0041] ESI-MS(m / z):461[M+H] +

[0042] Embodiment: 4: the preparation of dabigatran etexilate

[0043] Add formula 8 hydrochloride (4.0g, 0.0133mol) into a 100ml single-necked flask, add 20ml of 10% sodium hydroxide solution, 90ml of butyl acetate, add 50°C and stir for 30min, separate the layers, and extract the water layer once with 10ml of butyl acetate , the combined organic layers were washed once with 50 ml of saturated sodium bicarbonate and once with 100 ml of...

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Abstract

The invention belongs to the technical field of Dabigatran etexilate preparation method. The invention provides a novel compound represented by the formula 4. A preparation method of the compound is simple, and reaction conditions are mild. With the compound represented by the formula 4, a target compound Dabigatran etexilate can be obtained with two-step reactions and with high yield. Compared with prior arts, the prices of reagents adopted by the preparation method are cheap, reaction times in the steps are short, the yield is high, the conditions are mild, and intermediate purification is convenient. The method provided by the invention is a good method for preparing Dabigatran etexilate with high yield and low cost.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis method of oral anticoagulant dabigatran etexilate. 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] Boehringer Ingelheim reported the first synthetic route in patent WO9837075, and its synthetic method is as follows: [0005] [0006] This synthetic route is a linear synthesis with low yield, difficult separation and purification of intermediates and final products, and the step of synthesizing amidine uses a large amount of hydrochloric acid gas, causing serious pollution and serious corrosion to equipment; [0007] In 2006, Boehringer Ingelheim reported another synthetic route of dabigatran etexilate, as follows: [0008] [0009] The total yield...

Claims

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Application Information

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