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Preparation method of dabigatran intermediate

A compound and reaction technology, applied in new preparation fields, can solve problems such as incomplete reaction of raw materials, high operation risk, and low product yield, and achieve the effect of short steps, mild conditions, and high total yield

Active Publication Date: 2019-12-06
江苏阿尔法集团盛基药业(宿迁)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] This route uses highly corrosive bromoacetic acid as a raw material, and the operation risk is high, and the raw material reaction is not complete during the STEP3 step reaction, and the product yield is low. The key is that the prepared final product formula [I] has many impurities and is not suitable Purification, not suitable for industrial production

Method used

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  • Preparation method of dabigatran intermediate
  • Preparation method of dabigatran intermediate
  • Preparation method of dabigatran intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Preparation of Embodiment 1 Formula III Compound (-X=-Cl)

[0033] Dissolve 37.2g of the compound of formula V in 200ml of dichloromethane, add 15g of triethylamine, control the temperature in an ice-water bath at 0-5 degrees, slowly add 13.8g of chloroacetyl chloride dropwise, and drop it in about 20 minutes. After the drop is completed, remove the ice bath , naturally warming up to room temperature and stirring for 3 to 4 hours. After the reaction, 100ml of water was added, and the layers were separated after stirring. The aqueous layer was extracted twice with 100ml of dichloromethane*2. Dry with 8 g of anhydrous sodium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and recrystallize the residue with 115 ml of ethyl acetate to obtain 40.2 g of the product.

Embodiment 2

[0034] The preparation of embodiment 2 formula II compound

[0035] Dissolve 22.4 g of the compound of formula III (-X=-Cl) prepared in Example 1 in 120 ml of acetonitrile, add 6.3 g of p-aminobenzonitrile and 10 g of potassium carbonate, and slowly raise the temperature to about 35 degrees under stirring and react for 5 hours Left and right, TLC showed that after the reaction was completed, the acetonitrile was concentrated under reduced pressure to dryness, 120ml of water was added, extracted with 150ml of ethyl acetate*2, the organic layers were combined, washed with 50ml of saturated saline, dried with 10g of anhydrous sodium sulfate, filtered with suction, and the filtrate was reduced Concentrate to dryness under pressure, add 70ml of ethanol to the residue, heat, cool and crystallize, filter and dry to obtain 23.8g of the product.

Embodiment 3

[0036] The preparation of embodiment 3 formula I compound

[0037] Put 20 g of the compound of formula II prepared in Example 2 and 200 ml of ethyl acetate into a hydrogenation tank, stir and dissolve, add 0.4 g of 5% palladium hydroxide, add 1 ml of glacial acetic acid, replace N2 three times with hydrogen, and then pass in hydrogen Control the pressure around 1kg / cm2 to react for 4-6 hours. After the reaction was completed, hydrogen was replaced by nitrogen, the material was discharged, suction filtered, the filtrate was concentrated to dryness under reduced pressure, 95 ml of ethanol was added to the residue, heated to dissolve, and then cooled to crystallize to obtain 14.9 g of the product.

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PUM

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Abstract

The invention discloses a dabigatran intermediate preparation method which is as follows: a formula V compound as a raw material reacts with a formula VI compound to prepare a formula III compound, the formula III compound reacts with 4-amino cyanobenzene under the effect of an alkali to obtain a formula II compound, and then a target product formula I compound is obtained by transfer hydrogenation. The dabigatran intermediate preparation method is short and simple in steps, mild in conditions, high in total reaction yield, and suitable for industrial production.

Description

technical field [0001] The invention provides a new preparation method of a dabigatran intermediate (compound of formula [I]), which belongs to the field of medicine and chemical industry. Background technique [0002] Dabigatran etexilate is a new type of synthetic direct thrombin inhibitor, which is the prodrug of dabigatran and is a non-peptide thrombin inhibitor. After oral administration and gastrointestinal absorption, it is transformed into dabigatran with direct anticoagulant activity in vivo. Dabigatran binds to the fibrin-specific binding site of thrombin, preventing fibrinogen from being cleaved into fibrin, thereby blocking the final step of the coagulation cascade network and thrombus formation. Dabigatran dissociates from the fibrin-thrombin complex and exerts a reversible anticoagulant effect. [0003] Patent US6087380 reports a kind of preparation method of dabigatran etexilate, wherein relates to the synthetic method of dabigatran intermediate (formula [I]...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 漆志文叶银梅万新强罗威秦闯陈立芳
Owner 江苏阿尔法集团盛基药业(宿迁)有限公司
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