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Reductive amination process for preparation of dronedarone using amine intermediary compound

A technology of compounds and reducing agents, applied in the fields of organic chemistry, drug combination, cardiovascular system diseases, etc., can solve the problem that the steps cannot be purified.

Inactive Publication Date: 2014-02-05
SANOFI SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the components used in the Friedel-Crafts reaction and the resulting products and by-products are all insoluble in water, and the step of washing with water does not give any purification except removal of inorganic salts

Method used

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  • Reductive amination process for preparation of dronedarone using amine intermediary compound
  • Reductive amination process for preparation of dronedarone using amine intermediary compound
  • Reductive amination process for preparation of dronedarone using amine intermediary compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0168] N-[2-Butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl]methanesulfonamide (I)

[0169] Dissolve 1 g of N-[2-butyl-3-{4-[(3-amino)propoxy]benzoyl}-1-benzofuran-5-yl]-methanesulfonamide in 30 ml of dichloromethane middle. 0.5 g of butyraldehyde and 1.8 g of triacetoxyborohydride were added, and the reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was evaporated and the residue was dissolved in isopropyl acetate. Dilute the solution with 20ml water, 10ml5%NaHCO 3 solution and washed with 10ml of water. The solvent was evaporated.

[0170] Yield: 1.21g (94.5%).

[0171] The product was purified by forming its oxalate salt as follows: 6 ml methyl ethyl ketone was added to the residue and the mixture was heated to 70°C. To this solution was added 0.26 g of oxalic acid dissolved in 2.5 ml of methyl ethyl ketone at 70°C. Cool to 20°C over 6 hours, then stir the mixture at 10°C for 1 hour and filter. To the resulting oxalate was adde...

Embodiment 2

[0176] N-[2-Butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl]methanesulfonamide (I)

[0177] 1 g of N-[2-butyl-3-{4-[(3-amino)propoxy]benzoyl}-1-benzofuran-5-yl]methanesulfonamide was dissolved in 12 ml of butyric acid. 0.2 g of butyraldehyde and 0.26 g of sodium borohydride were added. The mixture was stirred at 55°C for 8 hours. Cool to 0°C and add 20ml of water. The mixture was made strongly basic with solid potassium hydroxide and extracted with 2x20ml dichloromethane. Dilute the solution with 25ml of water, 15ml of 5%NaHCO 3 Washed with 10ml of water and evaporated.

[0178] Yield: 1.10g (85.9%)

[0179] The product was purified according to Example 1 by its oxalate salt (87%).

[0180] Product purity: 99.6% (HPLC). The product was identical to the compound prepared in Example 1.

Embodiment 3

[0182] N-[2-Butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl]methanesulfonamide (I)

[0183] 1 g of N-[2-butyl-3-{4-[(3-amino)propoxy]benzoyl}-1-benzofuran-5-yl]methanesulfonamide was dissolved in 12 ml of butyric acid and 0.39 g sodium borohydride was added. The mixture was stirred at 55°C for 8 hours. Cool to 0°C and add 20ml of water. The mixture was made strongly basic with solid potassium hydroxide and extracted with 2x20ml dichloromethane. Dilute the solution with 25ml of water, 15ml of 5%NaHCO 3 Washed with 10ml of water and evaporated.

[0184] Yield: 0.88g (69%)

[0185] The product was purified according to Example 1 by its oxalate salt (81%).

[0186] Product purity: 99.4% (HPLC). The product was identical to the compound prepared in Example 1.

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Abstract

The invention relates to a novel process for preparation of drohedarone of formula (I) and pharmaceutically acceptable salts thereof characterized in that a compound of formula (II) is reacted in the presence of a reductive agent with butyraldehyde and / or butanoic acid, and isolating the obtained product and, if desired, converting it into a pharmaceutically acceptable salt thereof. The invention also relates to some hovel intermediary compounds and the preparation thereof.

Description

technical field [0001] The present invention relates to a new process for the preparation of dronedarone and pharmaceutically acceptable salts thereof, new intermediate compounds used in the process and their preparation. Background technique [0002] Dronedarone is a known drug used in the treatment of cardiac arrhythmias and has the chemical name N-[2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzidine Acyl]benzofuran-5-yl]methanesulfonamide [see also formula (I) below]. Several methods of preparing dronedarone are known, as follows: [0003] In EP0471609 the following scheme for the preparation of dronedarone is disclosed [Method A] [0004] [0005] The above patent specification also discloses some new intermediate compounds. [0006] In WO02 / 48078, the following scheme [Method B] for the preparation of dronedarone is disclosed: [0007] [0008] The novelty of the method is based on a modification using the Friedel-Crafts reaction in the first step. Also dis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/81
CPCC07D307/81C07D307/80A61P9/06C07D307/83C07D307/85Y02P20/55
Inventor A.弗里兹C.胡斯扎
Owner SANOFI SA
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