Preparation method of amiodarone hydrochloride

Abstract

The invention discloses a preparation method of amiodarone hydrochloride, which comprises the following steps: carrying out substitution reaction on (2-butyl-3-benzofuryl) (4-hydroxy-3, 5-diiodophenyl) ketone and 2-chloroethanol, then carrying out chlorination, carrying out amination reaction with diethylamine to obtain free amiodarone, salifying and crystallizing in a hydrochloric acid ethanol solution, and purifying to obtain the amiodarone hydrochloride. The amiodarone hydrochloride is obtained. According to the method, use of 2-chloro-N, N-diethyl ethylamine hydrochloride in a traditional route is avoided, the process conditions are mild, the total yield of the route is high, and the method is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and particularly to a preparation method of amiodarone hydrochloride. Background Art

[0002] Amiodarone hydrochloride is a classic antiarrhythmic drug, and its chemical structure is (2-butyl-1-benzofuran-3-yl){4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl}methanone hydrochloride. Amiodarone hydrochloride is generally classified as a class III antiarrhythmic drug and has the properties of mild class I and class IV antiarrhythmic drugs.

[0003] Many synthesis methods of amiodarone hydrochloride have been reported in the prior art, but these methods still have some deficiencies. A common method is to carry out a Friedel-Crafts reaction between p-methoxybenzoyl chloride and butylbenzofuran in the presence of a Lewis acid to form the main skeleton of amiodarone and remove the methoxy protection, and then carry out iodination and use 2-chloro-N,N-diethylamine hydrochloride for O-substitution to obtain amiodarone. This method is currently widely used, but it still has some defects. For example, 2-chloro-N,N-diethylamine hydrochloride used in the process is a strictly controlled compound, and the acquisition procedures are relatively complex, bringing additional production costs.

[0004] Chinese Patent Document CN109988131A discloses a method for preparing 2-butylbenzofuran by Sonogashira coupling cyclization of 2-iodophenol with 1-hexyne and preparing amiodarone. The yield of 2-butylbenzofuran in this method is relatively high, but multiple metal catalysts such as copper and nickel need to be used in the reaction, and aluminum chloride is still used for coupling subsequently, which may cause the problem of metal residues in the product, and the treatment difficulty of reaction sewage and waste also increases accordingly.

[0005] Chinese Patent Document CN 109988132 B discloses a route for preparing amiodarone hydrochloride. This document uses 3,5-diiodo-4-(2-hydroxyethoxy)-benzoic acid to carry out a chlorination reaction with thionyl chloride to generate 3,5-diiodo-4-(2-chloroethoxy)-benzoyl chloride, and then carry out a Friedel-Crafts reaction under the catalysis of aluminum trichloride to obtain (2-butyl-1-benzofuran-3-yl)[4-(2-chloroethoxy)-3,5-diiodophenyl]methanone, and finally aminate with diethylamine to obtain amiodarone. Although this route avoids the use of 2-chloro-N,N-diethylamine hydrochloride, it may cause side reactions of Friedel-Crafts alkylation, resulting in a decrease in yield and product purity, and the whole process has many reaction steps and is cumbersome. Summary of the Invention

[0006] Based on the deficiencies of the existing methods for preparing amiodarone, the present invention proposes a new method for preparing amiodarone. Compared with the prior art, this method avoids the use of the controlled substance 2-chloro-N,N-diethyl-ethylamine hydrochloride, has simple operations, fewer engineering steps, and significant advantages in terms of production cost and efficiency.

[0007] (2-Butyl-1-benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone is an intermediate for preparing amiodarone with a mature process, sufficient and stable supply, and easy availability. Therefore, this scheme selects to start the preparation from the intermediate (2-butyl-1-benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone, and the overall route is as follows:

[0008] The specific reaction process is as follows: (2-Butyl-1-benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone undergoes a substitution reaction with 1 - 1.2 equivalents of 2-chloroethanol in an organic solvent to form (2-butyl-1-benzofuran-3-yl)[4-(2-hydroxyethoxy)-3,5-diiodophenyl]methanone. The organic solvents used are selected from solvents such as toluene and chloroform that have good solubility for the raw materials. Inorganic bases such as potassium carbonate and sodium bicarbonate need to be added as acid-binding agents in the reaction, and the reaction temperature is 50 - 70 °C, preferably 70 °C. The post-treatment method is to add water to the reaction solution for washing, and after refining and separating layers, the organic phase is taken and evaporated to dryness.

[0009] (2-Butyl-1-benzofuran-3-yl)[4-(2-hydroxyethoxy)-3,5-diiodophenyl]methanone undergoes a chlorination reaction under the condition of 1.2 - 2 equivalents of thionyl chloride to form (2-butyl-1-benzofuran-3-yl)[4-(2-chloroethoxy)-3,5-diiodophenyl]methanone. The reaction temperature is 25 °C, and the organic solvents used are selected from toluene or dichloromethane. The post-treatment method is to add water to the reaction flask, add sodium carbonate under stirring to adjust the pH to neutral, separate the liquid, and the organic phase is washed with drinking water and then evaporated to dryness.

[0010] (2-Butyl-1-benzofuran-3-yl)[4-(2-chloroethoxy)-3,5-diiodophenyl]methanone undergoes a substitution amination reaction with 1 - 2 equivalents of diethylamine to form amiodarone. Inorganic bases can be added as acid-binding agents in the reaction. The organic solvents used in the reaction are selected from toluene or chloroform, and the reaction temperature is 30 - 85 °C. The post-treatment method is to add water to the reaction flask, separate the liquid, take the organic phase and add water, dropwise add hydrochloric acid to adjust the pH to 1 - 2, shake and separate the liquid, remove the organic phase, take the aqueous phase and wash it with toluene, collect the aqueous phase, add toluene, adjust the pH to 8 - 9 with sodium hydroxide solution, separate the liquid, the aqueous phase is extracted with toluene and then combined, and the organic phase is evaporated to dryness under reduced pressure to obtain the product.

[0011] Dissolve the obtained amiodarone above in absolute ethanol, add hydrochloric acid ethanol solution under stirring to adjust the pH to 1 - 2, keep stirring at 25 °C for 1 hour, then cool down to 0 - 10 °C for crystallization for 2 hours, perform suction filtration, and wash the filter cake with cold ethanol to obtain the finished product of amiodarone hydrochloride. The dosage of absolute ethanol in milliliters is 3 - 5 times the grams of amiodarone.

[0012] In the above process, the chlorination reaction and the amination reaction can also be completed by a one - pot method, and no additional separation and purification are required in the middle. The method is as follows: Dissolve (2 - butyl - 1 - benzofuran - 3 - yl)[4 - (2 - hydroxyethoxy)-3,5 - diiodophenyl]methanone in toluene, add 1 - 1.5 equivalents of thionyl chloride and react at 25 °C. After the reaction is completed, add an aqueous solution of inorganic bases such as sodium carbonate and potassium carbonate for neutralization, and then add 2 - 3 equivalents of diethylamine to the reaction solution and react at 40 - 80 °C to obtain amiodarone.

[0013]

[0014] This synthetic route method avoids the use of 2 - chloro - N,N - diethylethylamine hydrochloride in the traditional route. The synthetic raw materials used are all cheap and easily available. The whole - route synthesis has few steps, and a one - pot method can be used for combined reactions, which has a significant effect on improving production efficiency and reducing production costs. Embodiment Example 1

[0015] Add 50 g of (2 - butyl - 1 - benzofuran - 3 - yl)(4 - hydroxy - 3,5 - diiodophenyl)methanone, 8.5 g of 2 - chloroethanol, 31.6 g of potassium carbonate and 200 ml of toluene into the reaction flask, stir and heat up to 70 °C for reaction for 4 h. After the reaction is completed, add 100 ml of water, separate the layers, wash the organic phase with water and then concentrate under reduced pressure to obtain 51.8 g of (2 - butyl - 1 - benzofuran - 3 - yl)[4 - (2 - hydroxyethoxy)-3,5 - diiodophenyl]methanone, with a yield of 96%. Example 2

[0016] Take 51.8 g of (2 - butyl - 1 - benzofuran - 3 - yl)[4 - (2 - hydroxyethoxy)-3,5 - diiodophenyl]methanone and dissolve it in 200 ml of dichloromethane. Dropwise add 18 g of thionyl chloride at 25 °C, maintain stirring at 25 °C for reaction for 2 h. After the reaction is completed, add 100 ml of water to the reaction flask, add sodium carbonate under stirring to adjust the pH to neutral, separate the layers, wash the organic phase with drinking water and then concentrate to obtain 49.8 g of (2 - butyl - 1 - benzofuran - 3 - yl)[4 - (2 - chloroethoxy)-3,5 - diiodophenyl]methanone, with a yield of 93%. Example 3

[0017] Add 49.8 g of ((2-butyl-1-benzofuran-3-yl)[4-(2-chloroethoxy)-3,5-diiodophenyl]methanone), 9 g of diethylamine, 11.5 g of potassium carbonate, and 200 ml of toluene into a reaction flask. Stir and heat up to 80 °C for reaction for 4 h. After the reaction is completed, cool down to 25 °C. Add 100 g of water into the reaction flask, separate the layers. Add 200 ml of water to the organic phase, adjust the pH to 1 - 2 by dropping hydrochloric acid, separate the layers, remove the organic phase. Wash the aqueous phase with toluene, collect the aqueous phase, add toluene, adjust the pH to 8 - 9 with sodium hydroxide solution, separate the layers. Extract the aqueous phase with toluene and combine them, concentrate to obtain 50.7 g of amiodarone, with a yield of 96%. Example 4

[0018] Dissolve 50.7 g of amiodarone in 200 ml of ethanol. Add hydrochloric acid ethanol solution with stirring, adjust the pH = 2, stir at 25 °C for 1 h, cool down to 5 °C for crystallization for 2 h, filter by suction, wash the filter cake with cold ethanol to obtain 45.0 g of amiodarone hydrochloride finished product, with a yield of 84%. Example 5

[0019] Dissolve 5.9 g of ((2-butyl-1-benzofuran-3-yl)[4-(2-hydroxyethoxy)-3,5-diiodophenyl]methanone) in 70 ml of toluene. Add 1.78 g of thionyl chloride and react at 25 °C. After the reaction is completed, slowly add saturated sodium carbonate aqueous solution for neutralization until no obvious bubbles are generated. Then remove the aqueous phase. Add 1.6 g of diethylamine into the reactor and heat to 80 °C for reaction. After the reaction is completed, cool to 25 °C. Wash the reaction solution with water, then add 100 ml of water to the reaction solution, adjust the pH to 1 - 2 by dropping hydrochloric acid, separate the layers, remove the organic phase. Wash the aqueous phase with toluene, collect the aqueous phase, add toluene, adjust the pH to 8 - 9 with sodium hydroxide solution, separate the layers. Extract the aqueous phase with toluene and combine them, concentrate to obtain 6.1 g of amiodarone, with a yield of 95%. Example 6

[0020] Dissolve 5.9 g of ((2-butyl-1-benzofuran-3-yl)[4-(2-hydroxyethoxy)-3,5-diiodophenyl]methanone) in 70 ml of toluene. Add 1.78 g of thionyl chloride and react at 25 °C. After the reaction is completed, slowly add saturated sodium carbonate aqueous solution for neutralization until no obvious bubbles are generated. Then directly add 2.2 g of diethylamine into the reactor and heat to 40 °C for reaction. After the reaction is completed, cool to 25 °C. Wash the reaction solution with water, then add 100 ml of water to the reaction solution, adjust the pH to 1 - 2 by dropping hydrochloric acid, separate the layers, remove the organic phase. Wash the aqueous phase with toluene, collect the aqueous phase, add toluene, adjust the pH to 8 - 9 with sodium hydroxide solution, separate the layers. Extract the aqueous phase with toluene and combine them, concentrate to obtain 4.6 g of amiodarone, with a yield of 71%.

Claims

1. A method for synthesizing amiodarone hydrochloride, characterized in that, it is carried out according to the following steps: ； Step 1: Take (2-butyl-1-benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone and 2-chloroethanol to carry out a substitution reaction in a toluene solvent. After the reaction is completed, wash with water and separate the liquid. Take the organic layer and evaporate it to dryness under reduced pressure to obtain (2-butyl-1-benzofuran-3-yl)[4-(2-hydroxyethoxy)-3,5-diiodophenyl]methanone; Step 2: Dissolve (2-butyl-1-benzofuran-3-yl)[4-(2-hydroxyethoxy)-3,5-diiodophenyl]methanone in toluene, add thionyl chloride and react at 25 °C. After the reaction is completed, neutralize the reaction solution with an aqueous sodium carbonate solution, and add diethylamine to the reaction solution and react at 40 °C - 80 °C to obtain amiodarone; Step 3: Dissolve amiodarone in 3 - 5 times the mass of absolute ethanol, add a hydrochloric acid ethanol solution under stirring to adjust the pH to 1 - 2, keep stirring at 25 °C for 1 hour, then cool down to 0 - 10 °C for crystallization for 2 hours, filter by suction, and wash the filter cake with ethanol to obtain the finished product of amiodarone hydrochloride.

2. The method according to claim 1, wherein in step 1, the molar ratio of (2-butyl-1-benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone to 2-chloroethanol is 1:1 - 1:1.2, and the reaction temperature is 50 - 70 °C.

3. The method according to claim 1, wherein in step 2, the molar ratio of (2-butyl-1-benzofuran-3-yl)[4-(2-hydroxyethoxy)-3,5-diiodophenyl]methanone to thionyl chloride is 1:1 - 1:1.

5.

4. The method according to claim 1, wherein in step 2, the molar ratio of (2-butyl-1-benzofuran-3-yl)[4-(2-hydroxyethoxy)-3,5-diiodophenyl]methanone to diethylamine is 1:2 - 1:3.

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