Preparation method of amiodarone hydrochloride intermediate

A technology of hexanoic acid and potassium carbonate, which is applied in the field of medicine and chemical industry, can solve the problem of less discharge of three wastes, achieve the effects of less discharge of three wastes, facilitate large-scale industrial production, and improve the process

Pending Publication Date: 2022-05-27
HAINAN PULIN PHARMA +2
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Aiming at the deficiencies in the prior art, the object of the present invention is to provide amiodine hydrochloride which is simple in reaction operation, does not require operations such as rectification, has less discharge of three wastes, is environmentally friendly and sustainable, has high yield and purity, and is more suitable for industrialization. The new preparation method of ketone intermediate 2-butylbenzofuran solves the problems existing in the existing preparation method of amiodarone hydrochloride intermediate 2-butylbenzofuran

Method used

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  • Preparation method of amiodarone hydrochloride intermediate
  • Preparation method of amiodarone hydrochloride intermediate
  • Preparation method of amiodarone hydrochloride intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Example 1 Preparation of 2-butylbenzofuran

[0065] 1) Preparation of 2-(2-formylphenoxy)hexanoic acid

[0066]

[0067] In stainless steel reactor, add successively 1.000kg salicylaldehyde, 1.800kg 2-bromohexanoic acid methyl ester, 2.00kg N, N-dimethylformamide, 2.830kg salt of wormwood, stir, heat up, and reaction solution is warming up to 55 ℃ , keep the reaction for 2h, start sampling to detect salicylaldehyde ≤ 0.5%, stop the reaction.

[0068] The reaction solution was filtered into a glass-lined reactor through a corrosion-resistant filter, washed twice with 0.50kg N,N-dimethylformamide respectively, and the filtrates were combined; distilled at 72.3°C under reduced pressure to steam out ≥50% of the input amount. N,N-dimethylformamide, after the distillation is completed, the temperature is lowered to 20~30°C, 3.047kg sodium hydroxide solution is added and the temperature is raised to 36.7°C, and the reaction is kept for 2h; the temperature is lowered to 20~...

Embodiment 2

[0073] Example 2 Preparation of 2-butylbenzofuran

[0074] 1) Preparation of 2-(2-formylphenoxy)hexanoic acid

[0075]

[0076] In stainless steel reactor, add 1.500kg salicylaldehyde successively, 2.560kg 2-bromohexanoic acid methyl ester, 3.00kg N, N-dimethylformamide, 4.230kg salt of wormwood, stir, heat up, and reaction solution is warming up to 60 ℃, Incubate the reaction for 2h, start sampling and detect when salicylaldehyde is less than or equal to 0.5%, and stop the reaction.

[0077] The reaction solution was filtered into a glass-lined reactor through a corrosion-resistant filter, washed twice with 0.75kg of N,N-dimethylformamide, and the filtrates were combined; distilled at 76.9°C under reduced pressure to steam out ≥50% of the input amount. N,N-dimethylformamide, after the distillation is completed, the temperature is lowered to 20~30°C, 4.87kg of sodium hydroxide solution is added and the temperature is raised to 31.6°C, the reaction is kept for 1.5h, and sam...

Embodiment 3

[0082] Example 3 Preparation of 2-butylbenzofuran

[0083] 1) Preparation of 2-(2-formylphenoxy)hexanoic acid

[0084]

[0085] In stainless steel reactor, add successively 1.500kg salicylaldehyde, 2.700kg 2-bromohexanoic acid methyl ester, 3.00kg N, N-dimethylformamide, 4.230kg salt of wormwood, stir, heat up, and reaction solution is warming up to 50 ℃ , heat preservation reaction for 3h, start sampling to detect salicylaldehyde ≤ 0.5%, stop the reaction.

[0086] The reaction solution was filtered into a glass-lined reactor through a corrosion-resistant filter, washed twice with 0.75kg of N,N-dimethylformamide, and the filtrates were combined; distilled at 81.7°C under reduced pressure to steam out ≥50% of the input amount. N,N-dimethylformamide, after the distillation is completed, the temperature is lowered to 20~30°C, 4.88kg sodium hydroxide solution is added and the temperature is raised to 30.5~33.4°C, the reaction is kept for 1h, and sampling is performed for dete...

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Abstract

The invention provides a preparation method of an amiodarone hydrochloride key intermediate, in particular to a preparation method of 2-butylbenzofuran, which is prepared by cyclization reaction of 2-(2-formylphenoxy) hexanoic acid, acetic anhydride and potassium carbonate. The provided preparation method has the advantages of simple reaction operation, no need of rectification and other operations, less discharge of three wastes, greenness, environmental protection and sustainability, the purity of the prepared 2-butylbenzofuran is more than 98%, the yield is more than 88%, compared with the prior art, the purity and yield are obviously improved, and the preparation method is more suitable for industrialization.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and particularly relates to a preparation method of an amiodarone hydrochloride intermediate. Background technique [0002] 2-Butylbenzofuran is a key intermediate in the synthesis of the anti-angina drug amiodarone hydrochloride. The molecular formula is as follows: [0003] [0004] Amiodarone hydrochloride is an antianginal drug that selectively dilates coronary blood flow, while reducing myocardial oxygen consumption, slowing heart rate, and reducing atrioventricular conduction velocity similar to the effects of beta-blockers. For supraventricular and ventricular tachycardia, paroxysmal atrial flutter and fibrillation, pre-excitation syndrome, but also for refractory paroxysmal tachycardia, chronic coronary insufficiency and angina pectoris. Its chemical name is: 2-butyl-3-benzofuranyl-4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl ketone hydrochloride, and its molecular structu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/79C07D307/80A61K31/343A61P9/06
CPCC07D307/79C07D307/80A61K31/343A61P9/06Y02P20/584
Inventor 朱逸凡范敏华施海峰郭卫革邢小静蒋秀丽梁欢欢陆翠军周胜军
Owner HAINAN PULIN PHARMA
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