Novel method for synthesizing dronedarone key intermediate

Abstract

The invention relates to a novel method for synthesizing 2-butyl-3-(4-hydroxybenzene formoxyl)-5-nitryl benzfuran. An intermediate is a key intermediate of dronedarone serving as a novel medicament for treating atrial fibrillation. The method comprises the following steps of: undergoing a Fourier acylation reaction on 2-butyl-5-nitryl benzfuran serving as an initial raw material and p-acetoxyl benzoyl chloride to obtain 2-butyl-3-(4-hydroxybenzene formoxyl)-5-nitryl benzfuran; and hydrolyzing with sodium hydrate to obtain a target product.

Description

Technical field:

[0001] The invention relates to a method for preparing a key intermediate of dronedarone for treating atrial fibrillation. The method can obtain dronedarone intermediate 2-butyl-3-(4-hydroxybenzoyl) with low cost and low pollution. )-5-nitrobenzofuran, used for the synthesis of drug dronedarone. Background technique:

[0002] Dronedarone (international common name: Dronedarone, trade name: Multaq) is a new drug for the treatment of atrial fibrillation that has been successfully developed by Sanofi-Aventis for nearly 20 years. Its chemical structure is similar to the standard drug amiodarone for the treatment of atrial fibrillation, and its mechanism of action is the same, both of which are potassium ion channel blockers. Dronedarone is currently the only antiarrhythmic drug that has been shown to significantly reduce the morbidity and mortality of patients with atrial fibrillation / atrial flutter through clinical trials. It is a milestone in the field of ant...

Examples

Embodiment 1

[0027] Embodiment 1: the synthesis of p-acetoxybenzoic acid A

[0028] Put 138g of p-hydroxybenzoic acid into a 2L three-necked flask, add 200ml of acetic anhydride dropwise and stir thoroughly, then slowly add 1ml of concentrated sulfuric acid, heat up vigorously, continue stirring for 10min, and the solid gradually dissolves. Then heat up to 85-90°C, react for 1h, TLC (chloroform:methanol 15:1) monitors the completion of the reaction of raw materials, remove the oil bath, cool and crystallize to 40-50°C, add 700ml of water, cool to room temperature, then ice-water bath (5-15°C) cool, stir for 1 hour, filter, and wash with water until neutral. Air-dried at 55°C for more than 6 hours to obtain 175 g of white solid with a yield of 97%. Melting point: 190~192℃

Embodiment 2

[0029] Embodiment 2: the synthesis of acetoxybenzoyl chloride B by oxalyl chloride method

[0030] At 10-20°C, suspend 90g of p-acetoxybenzoic acid (A) in 130ml of dichloromethane (insoluble state), then add dropwise a mixed solution of 50ml of oxalyl chloride and 20ml of dichloromethane (if bubbles are generated Slowly add 20 drops of DMF (1ml), the temperature is basically kept at 10-20°C, after the drop is completed, the temperature is raised to 25-30°C, and the reaction is until the solution becomes clear (note that adding CaCl 2 Drying tube, waterproof and let the CO, CO produced by the reaction 2 , HCl discharged in time) about 40 ~ 60min. The completion of the reaction was monitored by TLC, and the solvent was evaporated to dryness at 40° C. to obtain 98 g of light yellow oil, which was directly used in the next reaction.

Embodiment 3

[0031] Embodiment 3: Thionyl chloride method synthesizes p-acetoxybenzoyl chloride B

[0032] At 10-20°C, suspend 90g of p-acetoxybenzoic acid (A) in 130ml of dichloromethane (insoluble state), then dropwise add a mixed solution of 43ml of thionyl chloride and 20ml of dichloromethane (if any There are less air bubbles, you can speed up), slowly add 20 drops of DMF (1ml), the temperature is basically maintained at 10-20 ° C, after the drop, the temperature is raised to reflux reaction (note that CaCl is added to the reflux tube) 2 Drying tube, waterproof while letting the SO produced by the reaction 2 , HCl discharged in time), reacted for 3h until the solution became clear. The completion of the reaction was monitored by TLC, and the solvent was distilled off at 40° C. to obtain 99 g of light yellow oil, which was directly used in the next reaction.

Technical field:

[0001] The invention relates to a method for preparing a key intermediate of dronedarone for treating atrial fibrillation. The method can obtain dronedarone intermediate 2-butyl-3-(4-hydroxybenzoyl) with low cost and low pollution. )-5-nitrobenzofuran, used for the synthesis of drug dronedarone. Background technique:

[0002] Dronedarone (international common name: Dronedarone, trade name: Multaq) is a new drug for the treatment of atrial fibrillation that has been successfully developed by Sanofi-Aventis for nearly 20 years. Its chemical structure is similar to the standard drug amiodarone for the treatment of atrial fibrillation, and its mechanism of action is the same, both of which are potassium ion channel blockers. Dronedarone is currently the only antiarrhythmic drug that has been shown to significantly reduce the morbidity and mortality of patients with atrial fibrillation / atrial flutter through clinical trials. It is a milestone in the field of ant...

Examples

Embodiment 1

[0027] Embodiment 1: the synthesis of p-acetoxybenzoic acid A

[0028] Put 138g of p-hydroxybenzoic acid into a 2L three-necked flask, add 200ml of acetic anhydride dropwise and stir thoroughly, then slowly add 1ml of concentrated sulfuric acid, heat up vigorously, continue stirring for 10min, and the solid gradually dissolves. Then heat up to 85-90°C, react for 1h, TLC (chloroform:methanol 15:1) monitors the completion of the reaction of raw materials, remove the oil bath, cool and crystallize to 40-50°C, add 700ml of water, cool to room temperature, then ice-water bath (5-15°C) cool, stir for 1 hour, filter, and wash with water until neutral. Air-dried at 55°C for more than 6 hours to obtain 175 g of white solid with a yield of 97%. Melting point: 190~192℃

Embodiment 2

[0029] Embodiment 2: the synthesis of acetoxybenzoyl chloride B by oxalyl chloride method

[0030] At 10-20°C, suspend 90g of p-acetoxybenzoic acid (A) in 130ml of dichloromethane (insoluble state), then add dropwise a mixed solution of 50ml of oxalyl chloride and 20ml of dichloromethane (if bubbles are generated Slowly add 20 drops of DMF (1ml), the temperature is basically kept at 10-20°C, after the drop is completed, the temperature is raised to 25-30°C, and the reaction is until the solution becomes clear (note that adding CaCl 2 Drying tube, waterproof and let the CO, CO produced by the reaction 2 , HCl discharged in time) about 40 ~ 60min. The completion of the reaction was monitored by TLC, and the solvent was evaporated to dryness at 40° C. to obtain 98 g of light yellow oil, which was directly used in the next reaction.

Embodiment 3

[0031] Embodiment 3: Thionyl chloride method synthesizes p-acetoxybenzoyl chloride B

[0032] At 10-20°C, suspend 90g of p-acetoxybenzoic acid (A) in 130ml of dichloromethane (insoluble state), then dropwise add a mixed solution of 43ml of thionyl chloride and 20ml of dichloromethane (if any There are less air bubbles, you can speed up), slowly add 20 drops of DMF (1ml), the temperature is basically maintained at 10-20 ° C, after the drop, the temperature is raised to reflux reaction (note that CaCl is added to the reflux tube) 2 Drying tube, waterproof while letting the SO produced by the reaction 2 , HCl discharged in time), reacted for 3h until the solution became clear. The completion of the reaction was monitored by TLC, and the solvent was distilled off at 40° C. to obtain 99 g of light yellow oil, which was directly used in the next reaction.

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