A kind of preparation method of dronedarone hydrochloride

A technology of dronedarone hydrochloride and hydrochloric acid, applied in the field of pharmaceutical synthesis, can solve problems such as difficulty in large-scale industrial production, increase in production cost, etc., and achieve the effects of less product impurities, high liquid phase purity, and fewer operation steps

Active Publication Date: 2020-06-09
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] Although the reaction steps are greatly reduced in this invention, column chromatography is required to remove impurities in actual industrial production, and because noble metal catalysts are used in the reduction process of nitro, the production cost is greatly increased, and it is difficult to carry out industrial production on a large scale

Method used

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  • A kind of preparation method of dronedarone hydrochloride
  • A kind of preparation method of dronedarone hydrochloride
  • A kind of preparation method of dronedarone hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0071] A preparation method of dronedarone hydrochloride (I), comprising the following steps:

[0072] Add 1500 g of 1,2-dichloroethane, 112.0 g (1.0 mol) of 1,4-cyclohexanedione, and 3.0 g of 30% hydrochloric acid aqueous solution into a 5-liter four-neck flask, cool and keep the internal temperature at 10-15°C In between, 156.0 g (2.2 mol) of chlorine gas was slowly introduced, and the reaction was stirred at 15-25° C. for 3 h until the reaction was complete. Then nitrogen was bubbled for 2 hours to blow off the generated hydrogen chloride and excess chlorine. Thereafter, 390 grams (1.0 mol) of 1-[4-(3-dibutylamino-propoxy)-phenyl]-heptane-1,3-dione (VI) was added to the resulting reaction liquid, 152 gram of potassium carbonate, stirred and reacted at 55-60°C for 5 hours, cooled to 20°C, filtered, layered, added 30 grams of 10% hydrochloric acid aqueous solution to the gained organic layer, stirred and reacted at 40-50°C for 4 hours, divided layer, the aqueous layer was e...

Embodiment 2

[0078] A preparation method of dronedarone hydrochloride (I), comprising the following steps:

[0079] Add 1500 grams of 1,2-dichloroethane, 112.0 grams (1.0mol) of 1,4-cyclohexanedione, 5.0 grams of 40% hydrobromic acid aqueous solution to a 5-liter four-neck flask, cool, and keep the inner temperature at 10- 322.0 g (2.0 mol) of liquid bromine was slowly added dropwise at 15°C, and the reaction was stirred at 15-25°C for 2 hours until the reaction was complete. Then nitrogen gas was bubbled for 2 hours to blow off the generated hydrogen bromide gas. Thereafter, 390 grams (1.0 mol) of 1-[4-(3-dibutylamino-propoxy)-phenyl]-heptane-1,3-dione (VI) was added to the resulting reaction liquid, 152 gram of potassium carbonate, stirred and reacted at 55-60°C for 5 hours, cooled to 20°C, filtered, layered, added 30 grams of 10% hydrochloric acid aqueous solution to the gained organic layer, stirred and reacted at 40-50°C for 4 hours, divided layer, the aqueous layer was extracted tw...

Embodiment 3

[0081] A preparation method of dronedarone hydrochloride (I), comprising the following steps:

[0082]Add 1500 grams of 1,2-dichloroethane, 112.0 grams (1.0mol) of 1,4-cyclohexanedione, and 4.0 grams of anhydrous ferric chloride to a 5-liter four-neck flask, cool and keep the inner temperature at 10- Between 15°C, 156.0 g (2.2 mol) of chlorine gas was slowly introduced, and the reaction was stirred at 15-25°C for 5 hours until the reaction was complete. Then nitrogen was bubbled for 2 hours to blow off the generated hydrogen chloride and excess chlorine. Thereafter, 390 grams (1.0 mol) of 1-[4-(3-dibutylamino-propoxy)-phenyl]-heptane-1,3-dione (VI) was added to the resulting reaction liquid, 152 gram of potassium carbonate, stirred and reacted at 55-60°C for 5 hours, cooled to 20°C, filtered, layered, added 30 grams of 10% hydrochloric acid aqueous solution to the gained organic layer, stirred and reacted at 40-50°C for 4 hours, divided layer, the aqueous layer was extracted...

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Abstract

The invention relates to a preparation method for dronedarone hydrochloride. The preparation method includes utilizing 1,4-cyclohexanedione as a raw material to generate dihalogenated-1,4-cyclohexanedione through halogenation reaction with chlorine or bromine; generating a compound V and a compound V' through nucleophilic substitution reaction, elimination reaction and dehydration annulation with1-[4-(3-di-n-butylamino-propoxy)-phenyl]-heptane-1,3-dione; and obtaining a product through the ammonification of ammonia gas to generate dronedarone through the mesylation of methanesulfonyl chloride, and generating dronedarone hydrochloride by salting with hydrochloric acid. The preparation method is simple in process flow, less in operation step, low in production cost, high in yield and purity, less in waste water generation amount and green and environmentally friendly, and therefore, the industrial production and application of the dronedarone hydrochloride can be realized.

Description

technical field [0001] The invention relates to a preparation method of dronedarone hydrochloride, which belongs to the technical field of medicine synthesis. Background technique [0002] With the rapid development of my country's modern society, human beings are under increasing social pressure, leading to an increasing incidence of cardiovascular diseases, and arrhythmia is a common and frequently-occurring disease in cardiovascular diseases, and atrial fibrous Atrial fibrillation (AF) is a common clinical arrhythmia, and it is one of the important factors causing stroke. Dronedarone is a new drug for the treatment of atrial fibrillation (AF) developed by Sanofi-Aventis in France. Its chemical name is 2-n-butyl-3-[4-(3-di-n-butyl Aminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran, which was approved by the U.S. FDA in July 2009. Its structure is similar to iodominone, which retains its effectiveness. base, reducing iodine toxicity and creating good social benefits, its ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/80
CPCC07D307/80
Inventor 刘红亮戚聿新鞠立柱周立山
Owner XINFA PHARMA
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