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Preparation method for novel antiarrhythmic medicament of dronedarone

An anti-arrhythmic and dronedarone technology, applied in the direction of organic chemistry and the like, can solve the problems of high preparation cost and no effective solution, and achieve the effects of low cost, good therapeutic effect and high yield

Inactive Publication Date: 2011-09-14
江苏万全特创医药生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The preparation cost of the two raw materials in this method is relatively high, and in the published reports on the preparation method of dronedarone, there is no effective method to solve the above problems

Method used

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  • Preparation method for novel antiarrhythmic medicament of dronedarone
  • Preparation method for novel antiarrhythmic medicament of dronedarone
  • Preparation method for novel antiarrhythmic medicament of dronedarone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] (1) Preparation of 2-butyl-3-{4-[3-(dibutylamino)propoxy]benzoyl-5-nitro}benzofuran (compound Ⅴ)

[0032]

[0033] In a 3000ml three-neck flask, add 1500ml toluene, 475g (1.0mol) 2-butyl-3-{4-[3-(methylsulfonyl)propoxy]benzoyl-5-nitro}benzofuran (Compound IV) was added to the reaction system, 5g (6.0mol) of di-n-butylamine was added, and reacted at 72°C for 30h; the solvent was evaporated to dryness, and the theoretical yield was 508g, which was directly used in the next reaction;

[0034] (2) Preparation of 2-butyl-3-{4-[3-(dibutylamino)propoxy]benzoyl-5-nitro}benzofuran (compound VI)

[0035]

[0036] In a 20 L autoclave, add 4800 ml of ethanol, 2.5 g (2.3 mmol) of 10% Pd / C, and react at 1.0 Mpa, and the concentrated solution of the previous step 2-butyl-3-{4-[3-( Dibutylamino)propoxy]benzoyl-5-nitro}benzofuran (compound V) was added to the reaction system, and reacted at 78°C for 8h; filtered with suction, evaporated part of the solvent under reduced pressure,...

Embodiment 2

[0040] (1) Preparation of 2-butyl-3-{4-[3-(dibutylamino)propoxy]benzoyl-5-nitro}benzofuran (compound V)

[0041]

[0042] In a 3000ml three-neck flask, add 1500ml tetrahydrofuran, 475 g (1.0mol) 2-butyl-3-{4-[3-(methylsulfonyl)propoxy]benzoyl-5-nitro}benzo Add furan (compound IV) to the reaction system, add 4g (1.5mol) of di-n-butylamine, and react under reflux at 65°C for 45 hours; evaporate the solvent to dryness, and the theoretical yield is 508g, which is directly used in the next reaction;

[0043] (2) Preparation of 2-butyl-3-{4-[3-(dibutylamino)propoxy]benzoyl-5-nitro}benzofuran (compound VI)

[0044]

[0045] In a 3000ml three-necked flask, add 2400ml of methanol, 5.0g (4.6mmol) of 10% Pd / C, and react at 0.1Mpa, and the concentrated solution of the previous step 2-butyl-3-{4-[3-(di Butylamino)propoxy]benzoyl-5-nitro}benzofuran (Compound Ⅴ) was added to the reaction system, and reacted at 65°C for 20h; Gas, after obtaining solid filtration, desalination, toluene...

Embodiment 3

[0050] (1) Preparation of 2-butyl-3-{4-[3-(dibutylamino)propoxy]benzoyl-5-nitro}benzofuran (compound V)

[0051]

[0052] In a 10000ml three-necked flask, add 4750ml of dichloromethane, 475 g (1.0mol) of 2-butyl-3-{4-[3-(methylsulfonyl)propoxy]benzoyl-5-nitro} Benzofuran (compound IV) was added to the reaction system, 1030g (8.0mol) of di-n-butylamine was reacted at 39°C for 80h; the solvent was evaporated to dryness, and the theoretical yield was 508g, which was directly used in the next reaction;

[0053] (2) Preparation of 2-butyl-3-{4-[3-(dibutylamino)propoxy]benzoyl-5-nitro}benzofuran (compound VI)

[0054]

[0055] In a 20L autoclave, add 3500 ml of dichloroethane, 1 g (0.92 mmol) of 10% Pd / C, and react at 2.0 Mpa, and the concentrated solution of the previous step 2-butyl-3-{4-[3 -(dibutylamino)propoxy]benzoyl-5-nitro}benzofuran (compound V) was added to the reaction system, and reacted at 85°C for 8h; suction filtered, and part of the solvent was evaporated unde...

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Abstract

The invention discloses a preparation method for a novel antiarrhythmic medicament of dronedarone. The preparation method comprises the following steps of: (1) performing substitution reaction on a compound IV and dibutylamine in an organic solvent to obtain an intermediate compound V; (2) performing reduction reaction on the compound V in the organic solvent under the action of a catalyst to obtain an intermediate VI; and (3) performing sulfonylation reaction on the compound VI and methanesulfonyl chloride in the organic solvent to obtain the final product of dronedarone. The product prepared by the method has high purity, an operation method is simple, production cost is low, and the method has strong competitive power in markets, and is more suitable for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of N-(2-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)benzofuran-5-yl)methanesulfonamide i.e. nedarone , a new antiarrhythmic drug for the treatment of atrial fibrillation. Background technique [0002] Dronedarone, the chemical name is N-(2-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)benzofuran-5-yl)methanesulfonamide , a new type of antiarrhythmic drug developed by Sanofi-Aventis (French: Sanofi-Aventis), the third largest pharmaceutical company in the world, for the treatment of atrial fibrillation. [0003] Dronedarone is a multi-channel blocker, which, like amiodarone, has the characteristics of class Ⅰ~Ⅳ antiarrhythmic drugs (Vaughan-Williams classification). In pharmacological studies, the electrophysiological and hemodynamic properties of dronedarone are similar to those of amiodarone. Amiodarone is one of the most effective antiarrhythmic drugs, especially in the treatment of atrial fibrillation, with ...

Claims

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Application Information

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IPC IPC(8): C07D307/80
Inventor 翟富民陈拥军胡全
Owner 江苏万全特创医药生物技术有限公司
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