Preparation method of amiodarone hydrochloride intermediate 2-butylbenzofuran

A technology of amiodarone hydrochloride and intermediates, which is applied in the field of preparation of pharmaceutical compound intermediates, can solve the problems of many reaction steps, cumbersome post-processing, cumbersome processes and the like, and achieves the effects of simple operation, simple post-processing, and simple reaction steps.

Active Publication Date: 2018-10-19
BEIJING JIALIN PHARM INC
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] In the patent CN201710595820.3, regarding the preparation process of 2-butylbenzofuran, methyl 2-(2-formylphenoxy)hexanoate needs to be protected with reagents such as trimethyl orthoformate, and there are many reaction steps , the process is cumbersome and the yield is low, and the product prepared according to the method needs to be distilled or column chromatographed to obtain the 2-butylbenzofuran intermediate with high purity
[0008] Chinese patent CN1858042A mentions a preparation method of 2-butylbenzofuran, according to its Example 1, it is found that the yield is about 20%, and the post-treatment is relatively cumbersome, and the purification process needs to be distilled

Method used

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  • Preparation method of amiodarone hydrochloride intermediate 2-butylbenzofuran

Examples

Experimental program
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Effect test

Embodiment 1

[0046] Embodiment 1: the preparation of 2-butylbenzofuran

[0047] Add 6.67g of potassium carbonate, 2.17g of KI, and 30ml of DMF to 15g of methyl 2-(2-formylphenoxy)hexanoate, heat up and reflux for 1.5h, the TLC reaction is complete, stop the reaction, cool the reaction solution to room temperature, add 100g of water , 100g of n-hexane, fully stirred, extracted and separated the organic phase, concentrated under reduced pressure (T=40-60°C, pressure 0.095Mpa) and evaporated to dryness of n-hexane to obtain a yellow transparent liquid weight: 6.3g, yield 60.3%

Embodiment 2

[0048] Embodiment 2: Preparation of 2-butylbenzofuran

[0049] Add 667g potassium carbonate, 217g KI, 3Kg DMF to 1500g 2-(2-formylphenoxy) methyl hexanoate, heat up and reflux for 5h, TLC reaction is complete, stop the reaction, the reaction solution is cooled to room temperature, add 10kg water, 10kg n-hexane Alkanes, stir well, extract and separate the organic phase, concentrate under reduced pressure (T=40-60°C, pressure 0.095Mpa) and evaporate to dryness of n-hexane to obtain a yellow transparent liquid Weight: 680g, yield 65.1%

Embodiment 3

[0050] Embodiment 3: One-pot method prepares 2-butylbenzofuran

[0051] Add 8kg salicylaldehyde, 16kg2-bromohexanoic acid methyl ester, 22.9kg DMF in the reaction kettle, stir, then add 10.88kg anhydrous potassium carbonate, exothermic when adding potassium carbonate, add, and anhydrous potassium carbonate is incompletely dissolved, slowly Slowly heat to 85°C, control the temperature at 85-90°C, stir for 3 hours, then raise the temperature and reflux for 5 hours, stop the reaction, cool the reaction solution to room temperature, add 130kg of water, 130kg of n-hexane, stir well, extract and separate the organic phase, and concentrate under reduced pressure ( T=40-60 ℃, pressure is 0.095Mpa) After evaporating to dry n-hexane, obtain yellow transparent liquid weight 8.88kg, total yield 77.7%

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Abstract

The invention relates to a preparation method of an amiodarone hydrochloride intermediate 2-butylbenzofuran. The preparation method comprises the following steps: A, with methyl 2-(2-aldehydephenoxy)hexanoate as a reaction substrate, under the action of potassium carbonate and potassium iodide, reacting in an organic solvent until a raw material disappears; B, adding water and an organic solvent into a reaction solution obtained in the step A, thoroughly stirring for extracting, separating out an organic phase, drying and then concentrating under reduced pressure to obtain yellow transparent liquid 2-butylbenzofuran. The 2-butylbenzofuran prepared by the preparation method is high in purity; the operation is simple; use of cumbersome column chromatography is avoided; the preparation methodis suitable for large-scale industrial production.

Description

Technical field: [0001] The invention relates to a preparation method of a pharmaceutical compound intermediate, in particular to a preparation method of amiodarone hydrochloride intermediate 2-butylbenzofuran. Background technique: [0002] Amiodarone hydrochloride has the following structural formula: [0003] [0004] Amiodarone hydrochloride, also known as amiodarone, is a commonly used antiarrhythmic drug in clinic with a high therapeutic index. The clinical research of this drug has been carried out extensively, such as: maintaining sinus rhythm, preventing arrhythmia after myocardial infarction, and prolonging the Survival of patients with congestive heart failure, etc. Especially in recent years, with the development of large-scale clinical trials, its beneficial role in preventing and treating malignant ventricular arrhythmia and atrial fibrillation and improving clinical prognosis has attracted more and more people's attention. [0005] There are many public r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/79
CPCC07D307/79
Inventor 杨亮吕建伟杨爽李文轩王瑛李振杰
Owner BEIJING JIALIN PHARM INC
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