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Preparation method of 3-[[[2-[[4-cyanophenyl) amino] methyl]-1-methyl-1H-benzimidazole-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate

A technology of cyanophenyl and ethyl propionate, applied in the direction of organic chemistry, can solve the problems of difficult crystallization and purification of products, and achieve the effects of low cost, mild operation and less by-products

Inactive Publication Date: 2013-11-13
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In the existing method, by-products such as imidazole and hydroxybenzotriazole are unavoidable in the reaction system, and the product is difficult to purify by simple crystallization. In the literature, column chromatography or salt formation and then freeing are used to obtain relatively pure products.

Method used

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  • Preparation method of 3-[[[2-[[4-cyanophenyl) amino] methyl]-1-methyl-1H-benzimidazole-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate
  • Preparation method of 3-[[[2-[[4-cyanophenyl) amino] methyl]-1-methyl-1H-benzimidazole-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate
  • Preparation method of 3-[[[2-[[4-cyanophenyl) amino] methyl]-1-methyl-1H-benzimidazole-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate

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Experimental program
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Effect test

Embodiment 1

[0042] Dissolve compound 3 (3.4g, 0.0193mol) in dichloromethane (150ml), add bis(trichloromethyl)carbonate (2.3g / 0.0077mol), pyridine (1.82g, 0.0231mol), at 20°C Stir for 3h. Dichloromethane was evaporated to dryness, the residue was dissolved in dichloromethane (75ml), transferred to a four-necked flask, compound 4 (6g, 0.0175mol) was dissolved in dichloromethane (75ml), and added to the above solution, Heated to reflux and reacted for 15-20h. Dichloromethane was evaporated to dryness, and acetic acid (80ml) was added to the residue to reflux for 1.5h. Evaporate acetic acid to dryness, dissolve with dichloromethane, wash with water 3-4 times, and dry the dichloromethane layer with anhydrous magnesium sulfate. Evaporate to dryness to obtain 7.8 g of slightly yellow amorphous substance. Ethyl acetate (25ml) was added for crystallization to obtain 6g of a yellowish solid, which was recrystallized by adding ethanol (30ml) to obtain 5.87g of a white solid. Yield: 70%, m.p.: 14...

Embodiment 2

[0044] Dissolve compound 3 (12.g, 0.0679mol) in 600ml of dichloromethane, add bis(trichloromethyl)carbonate (8.1g, 0.0272mol), pyridine (6.45g, 0.0816mol), and stir at 24°C 3h. Evaporate dichloromethane to dryness, dissolve the residue in dichloromethane (300ml), transfer to a four-necked flask, dissolve compound 4 (21.1g, 0.0617mol) in dichloromethane (300ml), add to the above solution , heated to reflux, and reacted for 15-20h. Dichloromethane was evaporated to dryness, and acetic acid (350ml) was added to the residue to reflux for 1.5h. Evaporate acetic acid to dryness, dissolve with dichloromethane, wash with water 3-4 times, and dry the dichloromethane layer with anhydrous magnesium sulfate. Evaporate to dryness to obtain 38.8 g of slightly yellow amorphous substance. Ethyl acetate (150ml) was added for crystallization to obtain 25g of a yellowish solid, which was recrystallized by adding ethanol (120ml) to obtain 22g of a white solid. Yield 74%, m.p.: 141-142°C. Pur...

Embodiment 3

[0046]Dissolve compound 3 (24.7g, 0.140mol) in 1300ml of dichloromethane, add bis(trichloromethyl)carbonate (16.6g / 0.056mol), pyridine (13.3g, 0.168mol), and stir at 25°C for 3h . Evaporate dichloromethane to dryness, dissolve the residue in 600ml dichloromethane, transfer to a four-necked flask, dissolve compound 4 (40g / 0.117mol) in dichloromethane (700m) 1, add in the above solution, heat To reflux, react for 15-20h. Dichloromethane was evaporated to dryness, and 80ml of acetic acid was added to the residue to reflux for 1.5h. Evaporate acetic acid to dryness, dissolve in dichloromethane, wash with water three times, and dry the dichloromethane layer with anhydrous magnesium sulfate. Evaporate to dryness to obtain 66 g of slightly yellow amorphous substance. Ethyl acetate (260ml) was added for crystallization to obtain 46g of yellowish solid, which was recrystallized by adding ethanol (230ml) to obtain 43g of white solid, yield: 76% m.p.: 141-142°C. Purity: 99.5% (measur...

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Abstract

The invention discloses a preparation method of 3-[[[2-[[4-cyanophenyl) amino] methyl]-1-methyl-1H-benzimidazole-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate. The preparation method is characterized by comprising reaction steps as follows: a first reaction of [(4-cyanophenyl) amino] acetic acid and bis(trichloromethyl) carbonate, and then a reaction of 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-yl) amino] ethyl propionate and a product of the first reaction. The preparation method is simple, easy to operation and low-cost.

Description

technical field [0001] The present invention belongs to the field of drug synthesis, specifically, relates to a method for preparing 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazole-5 -yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester. Background technique [0002] Thrombosis is mainly divided into arterial thrombosis and venous thrombosis. Venous thromboembolism (VET) can be induced by various reasons in venous vessels, and its main clinical manifestations are deep venous thrombosis (DVT) and pulmonary embolism (PE). A disease that seriously endangers human health. Pulmonary embolism is one of the common respiratory and cardiovascular diseases. Deep vein thrombosis mainly occurs after major orthopedic surgery. Anticoagulant drug treatment is the basic method to control thrombosis, which can effectively reduce mortality , to prevent recurrence. [0003] Dabigatran etexilate (Dabigatran etexilate, formula 1 below) is a new type of oral direct thromb...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 马明霞霍韶伟宋永刚郭晔堃钟静芬时惠麟
Owner SHANGHAI INST OF PHARMA IND
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