Preparation method for dabigatran etexilate

A technology of dabigatran etexilate and molar ratio, applied in the field of drug synthesis, can solve the problems of easy water absorption and deterioration of CDI, dazzling acid chloride compounds, unfavorable large-scale production, etc., and achieves the effects of low production cost, easy preparation, and simplified production operation.

Inactive Publication Date: 2017-02-15
JIANGSU KANION PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the price of the compound of formula II' used in the first step reaction is relatively high, and the CDI used is easy to absorb water and deteriorate, and is not easy to preserve
Later, some researchers improved its synthesis. For example, in patent applications CN104003977A, CN102633713A, and CN102850325A, acid halides and diamino compounds were used to synthesize benzimidazole structures. Because acid chloride compounds are dazzling, highly toxic, and costly, it is not conducive to industrialized production
In the CN104987323A patent application, a slight improvement is made, and an acid anhydride and a diamine compound are used to synthesize the acid anhydride, but the acid anhydride needs to be prepared with acid chloride and II' compound, so it still has the defect of high production cost

Method used

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  • Preparation method for dabigatran etexilate
  • Preparation method for dabigatran etexilate
  • Preparation method for dabigatran etexilate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1 prepares N-(4-cyanophenyl) aminoacetate ethyl ester (II)

[0035] At room temperature, add p-aminobenzonitrile (11.8g, 0.1mol) and potassium carbonate (10.0g, 0.1mol) into acetonitrile (100ml), add ethyl bromoacetate (16.7g, 0.1mol) dropwise under stirring, and heat up to reflux , after reacting for 16h, cooled to room temperature, filtered, concentrated to remove the solvent, the residue was stirred with water, filtered, washed twice with water, and recrystallized from toluene to obtain II (17.9g, 88%).

Embodiment 2

[0036] Example 2 Preparation of 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl ) amino] ethyl propionate (III) method (one)

[0037] In a 500mL reaction flask, add ethyl 3-[N-(4-methylamino-3-aminobenzoyl)-N-(pyridin-2-yl)amino]propionate (I) (16.4g, 0.048mol ), ethyl N-(4-cyanophenyl)aminoacetate (II) (11.2g, 0.055mol) and 300mL DMF (N,N-dimethylformamide), stirred for 1h, heated to 120℃ and stirred for reaction 10h. After cooling down to room temperature, the reaction solution was poured into 1000ml of ice water to precipitate a solid, which was suction filtered, and the filter cake was washed 3 times with water to obtain the crude product III, which was recrystallized with ethyl acetate to obtain the pure product (18.3 g, 79%).

[0038] Preparation of 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino] The method of ethyl propionate (III) (two)

[0039] In a 500mL reaction flask, a...

Embodiment 3

[0044] Example 3 Preparation of 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl )amino] ethyl propionate (IV)

[0045] 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propane Ethyl acetate (III) (10.0 g, 0.021 mol) was added to 6 M ethanol solution of hydrogen chloride (50 ml), and stirred overnight at room temperature. The excess solvent was distilled off, the residue was dissolved in 40ml ethanol solution, ammonium carbonate (19.2g, 0.2mol) was added, and stirred overnight at room temperature. Filter to remove insoluble matter, and the filtrate is concentrated to dryness under reduced pressure. The residue was dissolved in 60 ml of a mixed solution of ethyl acetate and ethanol (5:1), and stirred at room temperature for 2 h. Suction filtration and drying gave compound IV hydrochloride (10.2 g, 92%).

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Abstract

The invention provides a method for preparing dabigatran etexilate. The method comprises the following steps: A) subjecting a compound as shown in a formula I and a compound as shown in a formula II to a reaction in an inert solvent so as to obtain a compound as shown in a formula III, wherein the compound as shown in the formula II comprises an R which is one selected from the group consisting of methyl, ethyl, propyl or isopropyl; B) subjecting the compound as shown in the formula III to activation through a hydrogen chloride solution in an inert solvent, and carrying out a reaction of the activated material and an ammonium salt so as to obtain a product IV; and C) subjecting a compound as shown in a formula IV and a compound as shown in a formula V to a reaction under the action of an acid-binding agent so as to obtain dabigatran etexilate VI. The method provided by the invention has the advantages of low cost, high yield, mild reaction conditions, avoidance of using unstable reagents, etc.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of dabigatran etexilate. Background technique [0002] Dabigatran etexilate, chemical name: 3-[[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl] -1-Methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester, chemical structural formula: [0003] [0004] It is a new oral anticoagulant drug developed by Boehringer Ingelheim, Germany, and belongs to non-peptide thrombin inhibitors. It was first launched in Germany and the United Kingdom in April 2008, and dabigatran etexilate was approved in Europe and Canada in 2008 for the prevention and treatment of acute venous thrombosis. The US Food and Drug Administration approved the oral anticoagulant dabigatran etexilate for stroke prevention in patients with atrial fibrillation in September 2010. In February 2011, the Japanese Ministry of Health and Welfare ap...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 萧伟赵士魁郭庆明李瑛光刘永友贾根光张伟昌兴龙王振中
Owner JIANGSU KANION PHARMA CO LTD
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