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Preparation method of dronedarone hydrochloride and intermediate of dronedarone hydrochloride

A technology for dronedarone hydrochloride and intermediates, which is applied in the field of pharmaceutical preparation, can solve the problems of complex operation, cumbersome reaction, and long process time, and achieve the effects of simple preparation process, simple purification process, and easy removal process

Inactive Publication Date: 2012-09-19
山东富创医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The defect of this method is that the 2-butyl-5-methanesulfonamidobenzofuran generated by the reaction of 2-butyl-5-aminobenzofuran and methanesulfonyl chloride is not easy to purify, and the operation is complicated, and the Friedel-Crafts reaction is not easy to purify. Raw material requirements are relatively high, which inevitably leads to a reduction in yield and purity
[0014] The main defect of this method is that the reaction is cumbersome, and the generation of intermediates requires 2 steps of reaction, which inevitably leads to a reduction in yield and an increase in cost.
The resulting intermediates with protective groups are not easy to purify
It needs to be purified by column chromatography before the next reaction, so that the whole process takes a very long time, and the stationary phase and mobile phase used in column chromatography also increase the cost and environmental pollution

Method used

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  • Preparation method of dronedarone hydrochloride and intermediate of dronedarone hydrochloride
  • Preparation method of dronedarone hydrochloride and intermediate of dronedarone hydrochloride
  • Preparation method of dronedarone hydrochloride and intermediate of dronedarone hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Take 225.7g (1mol) of 2-butyl-5-aminobenzofuran hydrochloride, add it into 2257ml of dichloromethane, stir and cool down to below 10°C, add 404g (4mol) of triethylamine within 20min, and then Add 331.8g (3 mol) of methanesulfonyl chloride dropwise at a temperature of 10-20°C, and the dropwise addition is completed in about 30 minutes. After the dropping is completed, stir for 30 minutes, filter with suction, wash the filter cake with 200ml of dichloromethane, combine the filtrates, and evaporate to dryness to obtain a solid. The solid was beaten with 1000ml of 5wt% hydrochloric acid for 30min, suction filtered, the filter cake was washed with 50ml of water, and dried to obtain 350g of crude product. Add the crude product to 1750ml of absolute ethanol, heat to reflux for 30min, then cool down to 0°C and stir for 30min, then suction filter, wash the filter cake with 20ml of absolute ethanol, dry the filter cake to obtain 2-butyl-5-[( N,N-Dimethylsulfonyl)amino]benzofuran ...

Embodiment 2

[0064] Take 1mol of 2-butyl-5-aminobenzofuran hydrochloride, add it to 2500ml of chloroform, stir and cool down to below 10°C, add 5mol of sodium carbonate within 20min, and then add formaldehyde dropwise at a temperature of 10-20°C Add 4 mol of sulfonyl chloride in about 30 minutes. After the dropping, stir for 30 minutes, filter with suction, wash the filter cake with 250 ml of chloroform, combine the filtrates, and evaporate to dryness to obtain a solid. Slurry the solid with 1000ml of 5wt% hydrochloric acid for 30min, filter with suction, wash the filter cake with 50ml of water, and dry to obtain the crude product. Add the crude product to 1750ml of absolute ethanol, heat to reflux for 30min, then cool down to 0°C and stir for 30min, then suction filter, wash the filter cake with 20ml of absolute ethanol, dry the filter cake to obtain 2-butyl-5-[( N,N-Dimethylsulfonyl)amino]benzofuran, the yield was 87%.

Embodiment 3

[0066] Take 1mol of 2-butyl-5-aminobenzofuran hydrochloride, add it to 2000ml of benzene, stir and cool down to 0-10°C, add 3mol of potassium carbonate within 20min, then add methanesulfonate dropwise at a temperature of 10-20°C Acyl chloride 2mol, about 30 minutes to complete the dropwise addition, stirring for 30 minutes after the completion of the dropping, suction filtration, the filter cake was washed with 200ml of benzene, the combined filtrates were evaporated to dryness to obtain a solid. Slurry the solid with 950ml of 5wt% hydrochloric acid for 30min, filter with suction, wash the filter cake with 50ml of water, and dry to obtain the crude product. Add the crude product to 1700ml of absolute ethanol, heat to reflux for 30min, then cool down to 0°C and stir for 30min, then suction filter, wash the filter cake with 20ml of absolute ethanol, dry the filter cake to obtain 2-butyl-5-[( N,N-Dimethylsulfonyl)amino]benzofuran, the yield was 86%.

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Abstract

The invention discloses a preparation method of an intermediate of dronedarone hydrochloride, which comprises the step of reacting 2-butyl-5-amino benzofuran hydrochloride serving as a starting material with methylsulfonyl chloride in the presence of a basic catalyst and an organic solvent to produce the intermediate of dronedarone hydrochloride, wherein the intermediate is 2-butyl-5-((N, N-dimethyl sulfonyl) amido) benzofuran. The invention also discloses a method for preparing dronedarone hydrochloride by using the intermediate. The preparation of the intermediate is simple and easy to operate; amino is protected by methylsulfonyl, so that the side reaction possibly generated in the reaction for preparing the dronedarone hydrochloride at the later period can be avoided, and the difficulty in purification at the later period can be simplified; the dronedarone hydrochloride yield is high; the problems in the prior art that the preparation of dronedarone hydrochloride is complicated with high cost, the intermediate is difficult to purify and aftertreatment is complicated can be solved; and the preparation difficulty of dronedarone hydrochloride is greatly reduced.

Description

technical field [0001] The invention relates to a preparation method of dronedarone hydrochloride, a medicine for treating arrhythmia, and also relates to a preparation method of a key intermediate in the synthesis process of dronedarone hydrochloride, belonging to the technical field of medicine preparation. Background technique [0002] Dronedarone hydrochloride, the chemical name is 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methanesulfonamidobenzofuran Hydrochloride, a polarization inhibitor developed by Sanofi-Aventis in France, was first launched in the United States in July 2009 and is mainly used clinically to treat arrhythmias. This product can effectively reduce the risk of hospitalization for cardiovascular events in patients with atrial fibrillation or atrial flutter, and is suitable for cardiac rhythm control, maintenance of sinus rhythm and slowing of ventricular rhythm in patients with atrial fibrillation and atrial flutter. Dronedarone and amiodaron...

Claims

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Application Information

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IPC IPC(8): C07D307/80C07C217/22C07C213/08
Inventor 宫庆创司志现
Owner 山东富创医药科技有限公司
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