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A kind of preparation method of amiodarone hydrochloride

A technology of amiodarone hydrochloride and an acid-binding agent, which is applied in the field of preparation of amiodarone hydrochloride, can solve the problems of increasing aluminum-containing wastewater, complicated steps, unfriendly environment, etc., and achieves low pollution, simple process, and shortened synthesis route Effect

Active Publication Date: 2020-12-01
ZHEJIANG SANMEN HYGECON PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] It can be seen from formula 1 that the steps of the traditional synthetic method are complex and must include the step of demethoxylation with anhydrous aluminum trichloride, which increases the aluminum-containing wastewater and is not environmentally friendly.

Method used

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  • A kind of preparation method of amiodarone hydrochloride
  • A kind of preparation method of amiodarone hydrochloride
  • A kind of preparation method of amiodarone hydrochloride

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preparation example Construction

[0030] The invention provides a kind of preparation method of amiodarone hydrochloride, comprising the following steps:

[0031] (1) Under the action of sodium acetate, methyl p-hydroxybenzoate and iodine are subjected to a substitution reaction to obtain methyl 3,5-diiodo-4-hydroxybenzoate;

[0032] (2) Under the action of an acid-binding agent, the 3,5-diiodo-4-hydroxybenzoic acid methyl ester is etherified with a halogenated alkanol to obtain 3,5-diiodo-4-(2-hydroxyethyl Oxy)-methyl benzoate;

[0033] (3) The 3,5-diiodo-4-(2-hydroxyethoxy)-methyl benzoate is hydrolyzed in an alkaline aqueous solution to obtain 3,5-diiodo-4-(2- hydroxyethoxy)-benzoic acid;

[0034] (4) Under the action of DMF, the 3,5-diiodo-4-(2-hydroxyethoxy)-benzoic acid is chlorinated with thionyl chloride to obtain 3,5-diiodo-4 -(2-Chloroethoxy)-benzoyl chloride;

[0035] (5) Under the action of anhydrous aluminum chloride, the 3,5-diiodo-4-(2-chloroethoxy)-benzoyl chloride and 2-butylbenzofuran wer...

Embodiment 1

[0076] Preparation of methyl 3,5-diiodo-4-hydroxybenzoate (Ⅰ)

[0077] Add 10g (65.7mmol) of methyl p-hydroxybenzoate and 80ml of methanol at room temperature, stir to dissolve, add 11.3g of sodium acetate, 7g of water, stir to dissolve, add 30g of iodine (118.3mmol), heat up to 70°C, and react for 2 hours , add sodium hydroxide solution (sodium hydroxide 5.5g (137.5mmol) and water 200ml), keep 70 ℃, react for 2 hours, slowly cool down to room temperature, dropwise add 10g of 25% sodium bisulfite solution until the color of the material liquid fades , then stirred for 1 hour to crystallize, filtered, and the wet product was dried in hot air at 50° C. for 8 hours to obtain 26.2 g of off-white crystalline powder with a yield of 98.8%.

Embodiment 2

[0079] Preparation of 3,5-diiodo-4-(2-hydroxyethoxy)-benzoic acid methyl ester (Ⅱ)

[0080] At room temperature, add 24.24g (60mmol) of methyl 3,5-diiodo-4-hydroxybenzoate (I), 100ml of DMF, stir to dissolve, add 24.9g (180mmol) of potassium carbonate, raise the temperature to 75°C, within 2 hours Add 30g (240mmol) of 2-bromoethanol dropwise, continue to keep warm for 1 hour, remove potassium carbonate by hot filtration, evaporate DMF under reduced pressure in a water bath at 75°C, add 200ml of toluene and 150ml of water, stir, let stand to separate and discard Water layer; add 150ml of 1% potassium carbonate solution to the toluene layer, wash 3 times at 50°C, discard the potassium carbonate lotion; add 150ml of water to the toluene layer, wash twice at 50°C, discard the water layer; evaporate in a water bath at 55°C under reduced pressure Remove toluene, the concentrate is solidified, add 80ml of methanol, dissolve at 50°C, add dropwise 120ml of water, crystallize, stir and ...

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Abstract

The invention provides a preparation method of amiodarone hydrochloride, and relates to the technical field of drug synthesis. According to the invention, methyl p-hydroxybenzoate is used as a main raw material to carry out a substitution reaction, an etherification reaction, a hydrolysis reaction, a chlorination reaction, a Friedel-Crafts reaction, an amination reaction and acidification in sequence to obtain the amiodarone hydrochloride. According to the preparation method provided by the invention, a process of removing methoxy groups under the action of anhydrous aluminum trichloride is not needed, and then the use of anhydrous aluminum trichloride in one step is reduced, so that environmental pollution is greatly reduced; and meanwhile, when acylating chlorination is carried out on carboxyl of 3,5-diiodo-4-(2-hydroxyethoxy)-benzoic acid by using thionyl chloride, hydroxyl at the end position is chlorinated, and the synthetic route is shortened. The preparation method provided by the invention is simple in process, low in cost, small in pollution and high in yield.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of amiodarone hydrochloride. Background technique [0002] Amiodarone hydrochloride is currently one of the most commonly used antiarrhythmic drugs. It was synthesized by Marly Nitrogen and Chemical Products Company in Belgium. It was applied for production in West Germany in 1961. It was originally released as a coronary artery dilator. In 1976, Rosenbam took the lead in introducing it For antiarrhythmic treatment. First launched in Italy in 1984, it is currently the most clinically used and most widely used antiarrhythmic drug. [0003] With the increasingly fierce social competition, the pace of life is gradually accelerating, and people are facing increasing pressure, which directly leads to a sharp increase in the number of patients with cardiovascular diseases, and the demand for such drugs is also increasing. Based on stable efficacy and low s...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/80
CPCC07D307/80
Inventor 陈文斌王涛盛景新黄锋方国华
Owner ZHEJIANG SANMEN HYGECON PHARMA CO LTD
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