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Preparation method of amiodarone hydrochloride

A technology of amiodarone hydrochloride and amiodarone hydrochloride, which is applied in the field of preparation of amiodarone hydrochloride, can solve the problems of complex steps, numerous operations, reduced yield and purity of amiodarone hydrochloride, etc., and achieves the improvement of purity and yield, Improved productivity and improved convenience

Pending Publication Date: 2019-07-09
ZHEJIANG POLY PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] This process has the following problems: 1. The route is long, the steps are complicated, and the operation is numerous; 2. The yield is low and the cost is high; 3. There are many three wastes and the waste liquid treatment cost is high
[0012] This method has been greatly improved compared to the earlier technology, but the yield and purity of 2-butylbenzofuran prepared by the route method are low, thereby causing the yield and purity of amiodarone hydrochloride to be greatly reduced
CN107382925 continues to improve the above process, and the purity and yield have all increased, but it needs to be purified by column chromatography, which is not suitable for large-scale industrial production

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] 1. Preparation of intermediate 2-butylbenzofuran:

[0024]

[0025] 5.5 g K 2 CO 3 , 076 gram of CuI and 0.74 gram of TBAI are added in the 100 milliliter reaction bottle that 30 milliliters of toluene are housed, continue to add 4.4 gram of 2-iodophenols, 2.5 milliliters of 1-hexynes and 60 milligrams of nickel catalysts, replace 3 with nitrogen Second, under the protection of nitrogen, keep warm at 50°C and stir for 18-22 hours. The reaction liquid was filtered, the filtrate was washed with 40 ml of 5% NaOH aqueous solution, and washed twice with 40 ml of water, and the filtrate was concentrated under reduced pressure to obtain 3.12 g of a dark yellow solid, namely 2-butylbenzofuran, with a yield of 89.7%.

[0026] 2. Synthesis of intermediate 2-butyl-(4-methoxybenzoyl)benzofuran:

[0027]

[0028] Add 5.50 g of aluminum trichloride and 24 ml of dichloromethane into a 100 ml reaction bottle, stir and cool down to 0°C, add 7.0 g of p-methoxybenzoyl chloride dr...

Embodiment 2

[0040] 1. Preparation of intermediate 2-butylbenzofuran:

[0041] 5.5 g K 2 CO 3 , 0.76 gram of CuI and 0.74 gram of TBAI added in the 100 milliliter reaction bottle that 30 milliliters of toluene are housed, continue to add 4.4 gram of 2-iodophenols, 2.5 milliliters of 1-hexynes and 190 milligrams of ruthenium catalysts, replace 3 with nitrogen Second, under the protection of nitrogen, keep warm at 50° C. and stir for 22 to 28 hours. The reaction solution was filtered, the filtrate was washed with 40 ml of 5% NaOH aqueous solution, and 40 ml of water twice, and the filtrate was concentrated under reduced pressure to obtain 3.25 g of a dark yellow solid, namely 2-butylbenzofuran, with a yield of 93.4%.

[0042] All the other steps are the same as in Example 1.

Embodiment 3

[0044] 1. Preparation of intermediate 2-butylbenzofuran:

[0045] 5.5 g K 2 CO 3 , 0.76 gram of CuI and 0.74 gram of TBAI are added in the 100 milliliter reaction bottle that 30 milliliters of toluene are housed, continue to add 4.4 gram of 2-iodophenols, 2.5 milliliters of 1-hexynes and 89 milligrams of palladium catalysts, replace 3 with nitrogen Second, under the protection of nitrogen, keep warm at 40°C and stir for 26-30 hours. The reaction solution was filtered, the filtrate was washed with 40 ml of 5% NaOH aqueous solution, and 40 ml of water twice, and the filtrate was concentrated under reduced pressure to obtain 3.36 g of a dark yellow solid, namely 2-butylbenzofuran, with a yield of 96.6%.

[0046] All the other steps are the same as in Example 1.

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Abstract

The invention relates to a preparation method of amiodarone hydrochloride. According to the preparation method, synthesis of intermediate 2-butylbenzofuran is realized under effect of a catalyst, a cocatalyst, and an acid binding agent, through Sonogashira coupling cyclization reaction of 2-iodo phenol and 1-acetylene in an organic solvent at a 2-iodo phenol to 1-acetylene molar ratio of 1:09-1.3,wherein reaction temperature ranges from 30 to 60 DEG C, and reaction time ranges from 12 to 38h. Compared with the prior art, the advantages are that: operation is simplified; operation convenienceand product stability are improved; controlling of the ratio of the catalyst to the materials is capable of increasing the purities and yields of intermediates; no column chromatography purifying is needed; cost is reduced; production efficiency is increased at the same time; and convenience is provided for industrial large scale production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of amiodarone hydrochloride. Background technique [0002] Amiodarone, also known as amiodarone, was originally developed as a coronary artery dilator. In 1976, Rosenbanm took the lead in applying it to the treatment of antiarrhythmia. The toxicity of amiodarone is very small, the lethal dose of intravenous injection is 10 times of the therapeutic dose, the lethal dose of oral administration is negligible, and the long-term use of large doses is safe. Amiodarone hydrochloride (ADHC) is the hydrochloride salt of amiodarone, which was first listed in Italy in 1984. Its structure is as follows: [0003] [0004] Amiodarone hydrochloride is a class III antiarrhythmic drug. It is mainly used clinically for supraventricular and ventricular tachyarrhythmias. It is also used for various structural heart diseases and acute coronary syndrome. It can be used as a ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/80
CPCC07D307/80
Inventor 范敏华施海峰周胜军
Owner ZHEJIANG POLY PHARMA
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