Method for preparing dronedarone hydrochloride

A technology for dronedarone hydrochloride and hydrochloric acid solution, which is applied in the field of preparation of dronedarone hydrochloride, can solve the problems of being unsuitable for industrial production, high preparation cost, and high price, and achieves the elimination of high-pressure hydrogenation reaction, simple operation, Less toxic and polluting effects

Inactive Publication Date: 2012-03-21
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The raw material 1,3-dibromopropane used in this patented method is expensive, and requires the use of expensive metal reducing agents and high-pressure hydrogenation reaction conditions, the preparation cost is high, and it is not suitable for industrial production

Method used

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  • Method for preparing dronedarone hydrochloride
  • Method for preparing dronedarone hydrochloride
  • Method for preparing dronedarone hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0033] (1). Preparation of 2-n-butyl-3-[4-(3-chloropropoxy)benzoyl]-5-nitrobenzofuran

[0034] 72g of 1-bromo-3-chloropropane was added to 300ml of acetone, and 21g of anhydrous potassium carbonate was added. Heating to reflux at 56°C, while slowly adding a mixed solution of 51g of 2-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran and 200ml of acetone dropwise. After the dropwise addition, the reaction was refluxed for 4h. After the reaction is complete, cool to 25°C, filter with suction, wash the filter cake with acetone, combine the filtrates, evaporate the solvent acetone and excess 1-bromo-3-chloropropane to obtain 2-n-butyl-3-[4-(3 -Chloropropoxy)benzoyl]-5-nitrobenzofuran 59g, yield 94.4%. HPLC purity 98.1%.

[0035] (2). Preparation of 2-n-butyl-3-[4-(3-chloropropoxy)benzoyl]-5-aminobenzofuran

[0036] Get 2-n-butyl-3-[4-(3-chloropropoxy)benzoyl]-5-nitrobenzofuran 65g obtained in (1), ammonium chloride 17g, reduced iron powder 44g and 75% (volume fraction) ethanol was m...

Embodiment 2

[0044] (1). Preparation of 2-n-butyl-3-[4-(3-chloropropoxy)benzoyl]-5-nitrobenzofuran

[0045] 236g of 1-bromo-3-chloropropane was added to 600ml of toluene, and 25.5g of sodium bicarbonate was added. Heat at 110°C to reflux, and slowly add dropwise a mixed solution of 51g of 2-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran and 300ml of toluene. After the dropwise addition was completed, the reaction was refluxed for 2.5 hours. After the reaction is complete, cool to 25°C, filter with suction, wash the filter cake with toluene, combine the filtrates, evaporate the solvent toluene and excess 1-bromo-3-chloropropane to obtain 2-n-butyl-3-[4-(3 -Chloropropoxy)benzoyl]-5-nitrobenzofuran 58g, yield 92.8%. HPLC purity 98.0%.

[0046] (2). Preparation of 2-n-butyl-3-[4-(3-chloropropoxy)benzoyl]-5-aminobenzofuran

[0047] Get 91g of 2-n-butyl-3-[4-(3-chloropropoxy)benzoyl]-5-nitrobenzofuran obtained in (1), 150ml of 6mol / L hydrochloric acid solution, reduce zinc powder 43g and 1200...

Embodiment 3

[0055] (1). Preparation of 2-n-butyl-3-[4-(3-chloropropoxy)benzoyl]-5-nitrobenzofuran

[0056] 29g of 1-bromo-3-chloropropane was added to 400ml of ethyl acetate, and 24g of anhydrous sodium carbonate was added. Heat at 77°C to reflux, and slowly add a mixed solution of 77g of 2-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran and 300ml of ethyl acetate dropwise. After the dropwise addition was completed, the reaction was refluxed for 6 hours. After the reaction is complete, cool to 25°C, filter with suction, wash the filter cake with ethyl acetate, combine the filtrates, evaporate the solvent ethyl acetate to obtain 2-n-butyl-3-[4-(3-chloropropoxy)benzene Formyl]-5-nitrobenzofuran 78g, yield 83.2%. HPLC purity 97.5%.

[0057] (2). Preparation of 2-n-butyl-3-[4-(3-chloropropoxy)benzoyl]-5-aminobenzofuran

[0058] Get 130g of 2-n-butyl-3-[4-(3-chloropropoxy)benzoyl]-5-nitrobenzofuran obtained in (1), 90ml of glacial acetic acid, 175g of reduced iron powder and 50 % (volume fra...

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Abstract

The invention relates to a method for preparing dronedarone hydrochloride, comprising the following concrete steps of: (1) carrying out etherification reaction on 2-butyl-3-(4-hydroxy benzoyl)-5-nitro benzofuran and 1-bromine-3-chloropropane in an organic solvent so as to obtain 2-n-butyl-3-[4-(3-chlorine propoxy) benzoyl]-5-nitro benzofuran; (2) reducing to 2-n-butyl-3-[4-(3-chlorine propoxy) benzoyl]-5-amido benzofuran by utilizing a reductant; (3) carrying out sulfamide reaction with methyl sulfonyl chloride in the organic solvent so as to obtain 2-n-butyl-3-[4-(3-chlorine propoxy) benzoyl]-5-methyl sulfonamide benzofuran; (4) carrying out N-hydrocarbon reaction with di-n-butylamine so as to obtain the dronedarone; and (5) salifying the dronedarone hydrochloride and obtaining the dronedarone hydrochloride. The method provided by the invention has the advantages that the reaction route is simple, the raw material is cheap and easy to obtain and the reaction condition is mild and easy to control and is suitable for industrialized production.

Description

Technical field: [0001] The invention relates to a preparation method of dronedarone hydrochloride. Background technique: [0002] Dronedarone, the chemical name is N-[2-n-butyl-3-[4-3-(di-n-butylamino)propoxy]benzoyl]-5-phenylpropanyl] Methylsulfonamide, developed by Sanofi-Aventis in France, can effectively reduce atrial fibrillation or atrial flutter. It is an antiarrhythmic drug and is suitable for patients with paroxysmal or persistent atrial fibrillation or atrial flutter. In July 2009, it was approved for marketing by the US Food and Drug Administration (FDA). [0003] [0004] Atrial fibrillation is a very complex disease that can increase the risk of stroke by 5 times, worsen the prognosis and triple the mortality rate of patients with cardiovascular risk factors. Atrial flutter is another type of atrial arrhythmia that can develop into atrial fibrillation. Atrial fibrillation is the main cause of arrhythmia hospitalization. Since the hospitalization history c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/80
Inventor 王德才宋俊松刘华全朱海溪韦萍欧阳平凯
Owner NANJING UNIV OF TECH
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