TWI516483B - Preparation process of dronedarone and its salts - Google Patents

Description

Method for preparing dronedarone and its salt

The present invention relates to 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzylidene)-5-methylsulfonylamino-benzofuran (Dreondarone) And a novel preparation method of the salt thereof for treating diseases of the cardiovascular system.

Dronedarone (SR33589) is a benzofuran derivative and is a newly developed treatment for arrhythmia. The structure and characteristics are similar to those of the cardiovascular drug amiodarone, which is iodine-free and has low lipophilicity. Dronedarone has not only maintained the efficacy of amiodarone, but also has no extracardiac adverse reactions of amiodarone, so it is hopeful to become safer and better patient tolerant. As one of the drugs to treat arrhythmia instead of amiodarone . With the continuous acceleration of social modernization, people are under increasing social pressure. The number of cardiovascular diseases in China is also increasing. Cardiovascular diseases are listed as one of the top ten causes of death. Therefore, the development of Dronedarone will bring better economic and social benefits. The chemical structure of dronedarone is shown in Formula I:

As described in Scheme 1, the patent document US 5,223,510 A uses 2-butyl-5-nitrobenzofuran as a starting material, and is subjected to deuteration, hydrolysis, O-alkylation and reduction to obtain 5-amino-2- Butyl-3-(4-[3-(dibutylamino)propoxy]benzylidene)benzofuran (referred to herein as Compound A), Compound A under the catalysis of triethylamine with methotrexate Chlorine is subjected to a deuteration reaction, and dronedarone is purified by column chromatography. Then, it was made into a salt with hydrogen chloride-diethyl ether in ethyl acetate to obtain dronedarone hydrochloride.

plan 1:

In this method, compound A is subjected to a deuteration reaction with methanesulfonium chloride, which is liable to form a bis-methanesulfonate by-product (referred to herein as a compound of formula Ia), which requires purification by a complicated operation of column chromatography. It is very uneconomical for industrial production. In addition, the preparation of dronedarone hydrochloride requires a salt formation process, which requires the use of more reaction equipment, while reducing the yield of the entire route and increasing the production cost.

There are many studies on the deuteration of amines. It is also reported in the patent document US 5,223,510 A that 5-amino-2-butyl-benzofuran is catalyzed by triethylamine with methanesulfonate in carbon tetrachloride. The reaction produces bis-methanesulfonate, ie, compound IIa, instead of obtaining monomethanesulfonate, compound II. Compound IIa can be reconverted to compound II after being depurinated, but the process of depurination is increased, which also increases the production cost. Not conducive to industrial production. As shown in scenario 2:

Scenario 2:

The patent document WO 03/048144 A2 reports the ratio of compound IIa to compound II of 2-butyl-5-benzofuranamine under different catalysts, giving a method for preparing compound II between 5 < Pka < 10.

Subsequent patent document US2005049302 discloses a process for the preparation of compound II from 5-amino-2-butyl-benzofuran without obtaining compound IIa. The invention synthesizes dronedarone by reacting compound II with compound III under the condition of tin tetrachloride (see scheme 3). The method has low yield and still undergoes complicated operation steps such as purification by column chromatography, which is not favorable for industrialization. produce.

Option 3:

Therefore, the research operation is simple, the yield is high, the cost is low, and the synthesis method of dronedarone and its salt suitable for industrial production is undoubtedly very meaningful.

In order to overcome the deficiencies of the prior art, the object of the present invention is to provide a new synthetic method suitable for industrial production of dronedarone and its salt with less steps, high yield and simple operation.

One aspect of the invention relates to a process for the preparation of dronedarone hydrochloride, which comprises 5-amino-2-butyl-3-(4-[3-(dibutylamino)propoxy]benzene a step of directly synthesizing dronedarone hydrochloride by reacting mercaptofuran (compound A) with methanesulfonyl chloride, which is carried out without adding a catalyst; preferably, the reaction is carried out in a solvent or a mixed solvent of a plurality of solvents. Preferably, after the crude dronedarone hydrochloride is obtained, the step of further refining to obtain the pure product is further included.

Another aspect of the invention relates to a novel process for the preparation of dronedarone and a salt thereof which is not a hydrochloride salt. The method comprises: first 5-amino-2-butyl-3-(4-[3-(dibutylamino)propoxy]benzylidene)benzofuran (Compound A) with methotrexate The chlorine reaction is used to synthesize dronedarone hydrochloride, and then the high-purity dronedarone is prepared by treatment with an alkaline solution or converted to other pharmaceutically acceptable salts as needed. See route 4 for the route:

Option 4:

More specifically, the method of preparing dronedarone and its salt comprises the following steps:

a) 5-Amino-2-butyl-3-(4-[3-(dibutylamino)propoxy]benzylidene)benzofuran (Compound A) with methanesulfonium chloride The reaction is carried out to synthesize crude dronedarone hydrochloride, and the reaction is carried out without adding any catalyst; preferably, the reaction is carried out in a solvent or a mixed solvent of a plurality of solvents.

b) The crude dronedarone hydrochloride is treated with a refined or alkaline solution to prepare high purity dronedarone or its hydrochloride or converted to other pharmaceutically acceptable salts.

The inventors have unexpectedly found in the study of the deuteration reaction that the compound A and the methanesulfonium chloride can smoothly carry out the deuteration reaction without adding any catalyst, and the by-product of the methanesulfonate (the compound Ia) is greatly inhibited. The formation of high-purity dronedarone hydrochloride can be directly obtained, thereby obtaining a new synthesis method for preparing dronedarone and its salt.

The present inventors have found that in a solvent of a nitrile, a ketone, a halogenated hydrocarbon, an ether or an aromatic hydrocarbon or a mixed solvent composed of two or more of the above solvents, Compound A and A are added without adding a catalyst. The sulfonium chloride can be smoothly subjected to the oximation reaction, and the high-purity dronedarone hydrochloride can be directly obtained through the complicated purification step of the column chromatography and the salt formation process, or the ruthenium can be prepared as needed. Dalon hydrochloride is converted to other pharmaceutically acceptable salts.

The catalyst referred to in the present invention refers to 5-amino-2-butyl-3-(4-[3-(dibutylamino)propoxy]benzylidene)benzofuran and methanesulfonate. Catalysts which are catalytically active in the ruthenium chloride reaction, such as acid adsorbents, including organic bases such as alkylamines such as triethylamine, dipropylamine, etc.; inorganic bases such as alkali metals and their alkaline earth metal salts such as sodium carbonate, potassium carbonate, carbonic acid Sodium hydrogen, sodium hydroxide, calcium hydroxide, barium hydroxide, and the like.

The nitrile solvent used in the present invention is selected from a C ₂ to C ₆ fatty nitrile such as acetonitrile, propionitrile, butyronitrile, etc., preferably acetonitrile.

5-Amino-2-butyl-3-(4-[3-(dibutylamine) of the invention in 0 to 10 times, preferably 1 to 8 times, more preferably 3 to 6 times the amount of acetonitrile Propyl]benzhydryl)benzofuran with 1 to 5 equivalents, preferably 1.1 to 3 equivalents, more preferably 1.2 to 2.5 equivalents of methanesulfonate chloride at room temperature to reflux temperature, preferably at reflux Temperature reaction. After completion of the reaction, crystallization is carried out at -30 to 50 ° C, preferably -20 to 35 ° C, more preferably -15 to 25 ° C, to obtain crude dronedarone hydrochloride, which is then prepared by treatment with a refined or aqueous alkali solution. Purity of dronedarone or its hydrochloride, or converted to other pharmaceutically acceptable salts as needed.

The ketone solvent used in the present invention is selected from the group consisting of C ₃ to C ₆ aliphatic ketones, preferably acetone.

5-Amino-2-butyl-3-(4-[3-(dibutylamine) of the invention in 0 to 15 times, preferably 4 to 10 times, more preferably 5 to 8 times the amount of acetone Propyl]benzhydryl)benzofuran with 1 to 5 equivalents, preferably 1.5 to 3.5 equivalents, more preferably 2 to 2.5 equivalents of methanesulfonate chloride at room temperature to reflux temperature, preferably at reflux Temperature reaction. After completion of the reaction, crystallization is carried out at -30 to 55 ° C, preferably -15 at 40 ° C, more preferably at -10 to 25 ° C, to obtain crude dronedarone hydrochloride, and then high by treatment with a refined or aqueous alkali solution. Purity of dronedarone or its hydrochloride, or converted to other pharmaceutically acceptable salts as needed.

The halogenated hydrocarbon solvent used in the present invention is selected from the group consisting of C ₁ to C ₆ aliphatic halogenated hydrocarbons, and is usually dichloromethane, chloroform, carbon tetrachloride or the like, preferably dichloromethane.

5-Amino-2-butyl-3-(4-[3-(dibutylamino) group in 0 to 30 times, preferably 10 to 25 times, more preferably 15 to 20 times the amount of dichloromethane Propyloxy]benzhydryl)benzofuran with 1 to 15 equivalents, preferably 5 to 10 equivalents, more preferably 6 to 9 equivalents of methanesulfonate chloride at room temperature to reflux temperature, preferably at reflux temperature reaction. After completion of the reaction, treatment with an alkaline reagent gives dronedarone, such as an alkali metal hydroxide (such as sodium hydroxide), an alkali metal carbonate or an alkali metal hydrogencarbonate such as sodium hydrogencarbonate, preferably. It is sodium bicarbonate. The obtained dronedarone is salted and crystallized with hydrochloric acid in acetone to obtain crude dronedarone hydrochloride, and then purified or purified by an aqueous alkali solution to prepare high-purity dronedarone or its hydrochloride, or as needed Converted to other pharmaceutically acceptable salts.

In the ether solvent used in the present invention, the linear ether is selected from a C ₁ to C ₆ fatty ether, preferably ethylene glycol dimethyl ether; and the cyclic ether is selected from a C ₂ to C ₄ aliphatic cyclic ether, preferably It is tetrahydrofuran.

5-Amino-2-butyl-3-(4-[3-(dibutylamine) of the present invention in 0 to 15 times, preferably 3 to 12 times, more preferably 5 to 10 times the amount of tetrahydrofuran Propyl]benzhydryl)benzofuran with 1 to 8 equivalents, preferably 1.5 to 5 equivalents, more preferably 2 to 3 equivalents of methanesulfonate chloride at room temperature to reflux temperature, preferably at reflux Temperature reaction. After completion of the reaction, crystallization is carried out at -25 to 50 ° C, preferably -15 to 40 ° C, more preferably at -10 to 35 ° C to obtain crude dronedarone hydrochloride. High purity dronedarone or its hydrochloride is then prepared via treatment with a refinery or aqueous base, or converted to other pharmaceutically acceptable salts as needed.

The aromatic hydrocarbon solvent employed in the present invention is selected from the group consisting of substituted or unsubstituted C ₆ to C ₁₀ aromatic hydrocarbons commonly used in the art, such as toluene, ethylbenzene, cumene, preferably toluene.

The mixed solvent selected in the present invention is a mixed solvent of two or more solvents of the same or different types of solvents in a nitrile, a ketone, a halogenated hydrocarbon, an ether or an aromatic hydrocarbon solvent, preferably an acetone-acetonitrile mixed solvent.

The ratio of acetone/acetonitrile of the present invention is from 0 to 5:1, preferably from 0.2 to 3:1, more preferably from 0.5 to 1:1, of 5-amino-2-butyl-3-(4- [3-(Dibutylamino)propoxy]benzylidene)benzofuran with 1 to 5 equivalents, preferably 1.5 to 4 equivalents, more preferably 2 to 3 equivalents of methanesulfonium chloride at room temperature The reaction is carried out at reflux temperature, preferably at reflux temperature. After the completion of the reaction, crystallization is carried out at -40 to 50 ° C, preferably -15 to 40 ° C, more preferably at -10 to 35 ° C to obtain crude dronedarone hydrochloride. High purity dronedarone or its hydrochloride can then be prepared via treatment with a refinery or aqueous base, or converted to other pharmaceutically acceptable salts as needed.

The solvent used for the purification of dronedarone hydrochloride of the present invention is acetone-water, preferably 30 to 5:1 (V/V).

The selected alkaline solution is prepared by subjecting the dronedarone hydrochloride to a purified or alkaline solution to prepare a pure product of dronedarone or a hydrochloride thereof, or converted into a pharmaceutically acceptable other salt. The base is an inorganic base such as sodium hydroxide, sodium carbonate and sodium hydrogencarbonate, preferably sodium hydrogencarbonate.

In summary, the present invention is in a solvent such as a nitrile solvent of acetonitrile, such as a ketone solvent of acetone, such as a halogenated hydrocarbon of methylene chloride in a single solvent or a mixed solvent, without adding any catalyst, Compound A and methylsulfonate. The ruthenium chloride is subjected to a oximation reaction, and high-purity dronedarone or its hydrochloride can be prepared by a treatment of a refined or alkaline solution without complicated operation such as column chromatography and salt formation, or conversion. It is a pharmaceutically acceptable other salt.

The method of the invention has the advantages of less steps, high yield, simple operation, low cost, suitable for industrial production and the like, and has significant social and economic benefits.

The invention will be explained in detail below with reference to specific examples, which are intended to provide a more complete understanding of the invention.

Unless stated to the contrary, in these examples, the English abbreviations used have the following meanings:

HPLC: high pressure liquid chromatography

¹ H-NMR: Hydrogen nuclear magnetic resonance spectroscopy

MS: Mass Spectrometry

Synthesis of starting material compound A of the invention

The synthesis of 5-amino-2-butyl-3-(4-[3-(dibutylamino)propoxy]benzylidene)benzofuran (Compound A) is described in the patent document US 5,223,510 A. Prepared by the method described.

Example 1

Step 1) Preparation of crude dronedarone hydrochloride

In a 5 L reaction flask, 480 g (1 mol) of Compound A, 1.7 L of acetonitrile were added, and the mixture was heated under reflux, and 100 mL (1.29 mol) of methanesulfonium chloride / 800 mL of acetonitrile solution was added dropwise thereto, and the mixture was refluxed for about 25 to 30 minutes, and refluxed for 8 hours. The temperature was lowered, and the solid was precipitated the next day, and 530 g of crude dronedarone hydrochloride was obtained by filtration. The yield was 89.2%, and the HPLC purity was 99.5%.

Step 2) Preparation of dronedarone hydrochloride

In a 5 L reaction flask, 530 g of crude dronedarone hydrochloride, 3.0 L of acetone and 100 mL of water were added, and the mixture was heated to reflux to dissolve, mechanically stirred, and cooled in a water bath for about 30 minutes to precipitate a solid, which was filtered, washed with acetone and dried. 440 g of the title product, yield 83%, m.p. 141.5 to 143 ° C, HPLC purity: 99.8%, MS: [M+H] ⁺ m/e 557.50.

Example 2

Step 1) Preparation of crude dronedarone hydrochloride

The method was the same as the step 1) in the first embodiment, the reaction temperature was 55 to 60 ° C, the reaction was carried out for 15 hours, the yield was 85.3%, and the HPLC purity was 99.0%.

Step 2) Preparation of dronedarone hydrochloride

The procedure was the same as in Step 2) of Example 1, the yield was 81%, the melting point was 141 to 143 ° C, and the HPLC purity was 99.5%.

Example 3

Step 1) Preparation of crude dronedarone hydrochloride

The method was the same as the step 1) in the first embodiment, the reaction temperature was 40 to 45 ° C, the reaction was carried out for 41 hours, the yield was 82.1%, and the HPLC purity was 98.3%.

Step 2) Preparation of dronedarone hydrochloride

The procedure was the same as in Step 2) of Example 1, the yield was 80%, the melting point was 141 to 143 ° C, and the HPLC purity was 99.1%.

Example 4

Step 1) Preparation of crude dronedarone hydrochloride

In a 5 L reaction flask, 530 g (1.1 mol) of Compound A and 3 L of acetone were added, and 200 mL (2.58 mol) of methanesulfonium chloride/1 L of acetone solution was added dropwise under reflux, and the mixture was refluxed for 20 minutes, refluxed for 6 hours, and stirred overnight to precipitate a white solid. . Drying gave 473 g of crude dronedarone hydrochloride in a yield of 72%. The HPLC purity was 99.3%.

Step 2) Preparation of dronedarone hydrochloride

In a 5 L reaction flask, 470 g of crude dronedarone hydrochloride, 1550 mL of acetone and 310 mL of water were added, and the mixture was heated to reflux to dissolve, mechanically stirred, and decanted in an ice water bath for about 1.5 hours to precipitate a solid, which was filtered, washed with acetone and dried to give the title product. 399.5 g, yield 84%, melting point 141.5 to 143.5 ° C, HPLC purity 99.5%.

Example 5

Step 1) Preparation of crude dronedarone hydrochloride

The method was the same as in the step 1) of Example 4, the reaction temperature was 40 to 45 ° C, the reaction was carried out for 48 hours, the yield was 69%, and the HPLC purity was 98.8%.

Step 2) Preparation of dronedarone hydrochloride

The procedure was the same as in Step 2) of Example 1, the yield was 83%, the melting point was 141 to 143 ° C, and the HPLC purity was 99.0%.

Example 6

Step 1) Preparation of crude dronedarone hydrochloride

2.4 g (5 mmol) of Compound A was added to 30 mL of dichloromethane, and the mixture was heated under reflux, and 3 mL (38.8 mmol) of methanesulfonium chloride / 10 mL of dichloromethane solution was added dropwise thereto, and the mixture was refluxed for 20 minutes, and refluxed for 26 hours, and the purity was 95%. . Washed with saturated sodium bicarbonate solution until neutral, dried, filtered, reduced to dryness, added 6 mL of acetone, 1 mL hydrochloric acid, stirred and crystallized, filtered and dried to give 2.1 g of crude dronedarone hydrochloride, yield 70.8%, The HPLC purity was 99%.

Step 2) Preparation of dronedarone hydrochloride

The procedure was the same as in Step 2) of Example 1, the yield was 81%, the melting point was 141.5 to 143.5 ° C, and the HPLC purity was 99.5%.

Example 7

Step 1) Preparation of crude dronedarone hydrochloride

In a 500 mL reaction flask, 53 g (0.11 mol) of Compound A and 350 mL of tetrahydrofuran were added, and 20 mL (0.26 mol) of methanesulfonium chloride / 40 mL of tetrahydrofuran solution was added dropwise under reflux, and the mixture was refluxed for 20 minutes, refluxed for 9 hours, and stirred for white solid. . Drying gave 56.4 g of crude dronedarone hydrochloride in a yield of 86%. HPLC purity was 98.8%.

Step 2) Preparation of dronedarone hydrochloride

In a 500 mL reaction flask, 55 g of crude dronedarone hydrochloride, 225 mL of acetone and 22.5 mL of water were added, dissolved by heating under reflux, mechanically stirred, and decanted in an ice water bath for about 1 hour to precipitate a solid, filtered, washed with acetone, and dried to obtain 45.1. g title product, yield 82%, melting point 141.5 to 143.5 ° C, HPLC purity 99.1%.

Example 8

Step 1) Preparation of crude dronedarone hydrochloride

In a 5 L reaction flask, 64 g (0.13 mol) of Compound A, 1 L of acetone and 1 L of acetonitrile were added, and the mixture was heated under reflux, and 26 mL (0.34 mol) of methanesulfonium chloride / 104 mL of acetonitrile solution was added dropwise thereto, and the mixture was refluxed for about 25 to 30 minutes. After an hour, the temperature was naturally lowered, and the solid was precipitated the next day, and filtered to obtain 68 g of crude dronedarone hydrochloride. The yield was 88.3%, and the HPLC purity was 99.1%.

Step 2) Preparation of dronedarone hydrochloride

The procedure was the same as in Step 2) of Example 1, the yield was 82.5%, the melting point was 141.5 to 143 ° C, and the HPLC purity was 99.4%.

Example 9

Step 1) Preparation of crude dronedarone hydrochloride

The method was the same as Step 1) in Example 7, the reaction temperature was 40 to 45 ° C, the yield was 86.1% in 36 hours, and the HPLC purity was 98.8%.

Step 2) Preparation of dronedarone hydrochloride

The method was the same as the step 2) in the first embodiment, the yield was 82.5%, the melting point was 141.5 to 143 ° C, and the HPLC purity was 99.2%.

Example 10

Step 1) Preparation of dronedarone

5.93 g (0.01 mol) of dronedarone hydrochloride obtained in Example 1 was dissolved in 40 mL of dichloromethane, and the pH was adjusted to neutral by adding a saturated sodium hydrogencarbonate solution, and the organic phase was separated, using saturated sodium hydrogencarbonate. The solution was washed with 10 mL×2, dried over anhydrous sodium sulfate, filtered, and evaporated.

Step 2) Preparation of dronedarone sulfate

The oil obtained in the step 1) was dissolved in 12 mL of acetone, 2 mL of water was added, and 1.1 mL of a concentrated solution of concentrated sulfuric acid in 3 mL of acetone was slowly added dropwise at 10 to 15 ° C for about 20 minutes, and the mixture was stirred at 52 ° C for 1 hour. The mixture was stirred and crystallized under a water bath for 3.5 hours, filtered, and dried under vacuum at 50 ° C to give 5.5 g of product (yield: 84%). The HPLC purity was 99.85%.

Example 11

Step 1) Preparation of dronedarone

The method is the same as step 1) in Example 10.

Step 2) Preparation of dronedarone mesylate

The procedure was identical to step 2) in the examples except that 1.5 g of methanesulfonic acid (99%) was used in a yield of 76% and the HPLC purity was 99.83%.

Example 12

Step 1) Preparation of crude dronedarone hydrochloride

In a 100 mL reaction flask, 15 g (0.03 mol) of Compound A, 15 mL (0.19 mol) of methanesulfonium chloride was added, the temperature was raised to 80 ° C, and the reaction was incubated for 5.5 hours. The unreacted methanesulfonium chloride was distilled off under reduced pressure, and acetonitrile was added thereto. 100 mL was dissolved, and the temperature was naturally lowered. The solid was precipitated the next day, and filtered to obtain 13.5 g of crude dronedarone hydrochloride. The yield was 72.5% and the HPLC purity was 97.5%.

Step 2) Preparation of dronedarone hydrochloride

The procedure was the same as in the step 2) of Example 1, the yield was 78.5%, the melting point was 140.5 to 142.5 ° C, and the HPLC purity was 98.9%.

Claims (23)

A method for preparing dronedarone hydrochloride, the method comprising the steps of 5-amino-2-butyl-3-(4-[3-(dibutylamino)propoxy The reaction of the benzhydryl-based benzofuran with methanesulfonyl chloride gives dronedarone hydrochloride without the addition of a catalyst. A method for producing dronedarone hydrochloride according to claim 1, wherein the 5-amino-2-butyl-3-(4-[3-(dibutylamino)propyl group The reaction of oxy]benzhydryl)benzofuran with methanesulfonyl chloride is carried out in a solvent or a mixed solvent of a plurality of solvents. The method for producing dronedarone hydrochloride according to claim 2, wherein the solvent is selected from the group consisting of a nitrile, a ketone, a halogenated hydrocarbon, an ether or an aromatic hydrocarbon solvent. The method for preparing dronedarone hydrochloride according to claim 2, wherein the mixed solvent is composed of a solvent of the same type or a different type of solvent in a nitrile, a ketone, a halogenated hydrocarbon, an ether or an aromatic hydrocarbon solvent. More or more solvent composition. The method for producing dronedarone hydrochloride according to claim 3 or 4, wherein the nitrile solvent is selected from the group consisting of C ₂ to C ₆ fatty nitriles. The method for producing dronedarone hydrochloride according to claim 5, wherein the nitrile solvent is acetonitrile. The method for producing dronedarone hydrochloride according to claim 3, wherein the ketone solvent is selected from the group consisting of C ₃ to C ₆ fatty ketones. Preparation of dronedarone hydrochloride as described in claim 7 The method wherein the ketone solvent is acetone. The method for producing dronedarone hydrochloride according to claim 3 or 4, wherein the halogenated hydrocarbon solvent is selected from the group consisting of C ₁ to C ₆ aliphatic halogenated hydrocarbons. The method for producing dronedarone hydrochloride according to claim 9, wherein the halogenated hydrocarbon solvent is dichloromethane. The method for producing dronedarone hydrochloride according to claim 3 or 4, wherein the ether is selected from a linear ether or a cyclic ether. The method for producing dronedarone hydrochloride according to claim 11, wherein the linear ether is selected from the group consisting of C ₁ to C ₆ fatty ethers; and the cyclic ether is selected from the group consisting of C ₂ to C ₄ fats. Cyclic ether. The method for producing dronedarone hydrochloride according to claim 12, wherein the linear ether is ethylene glycol dimethyl ether; and the cyclic ether is tetrahydrofuran. The method for producing dronedarone hydrochloride according to claim 3 or 4, wherein the aromatic hydrocarbon solvent is selected from the group consisting of substituted or unsubstituted C ₆ to C ₁₀ aromatic hydrocarbons. The method for producing dronedarone hydrochloride according to claim 14, wherein the aromatic hydrocarbon solvent is toluene. The method for producing dronedarone hydrochloride according to claim 3 or 4, wherein the method further comprises the step of refining the dronedarone hydrochloride. The method for preparing dronedarone hydrochloride according to claim 16, wherein the solvent used for the purification of the dronedarone hydrochloride is C. Ketone-water. The method for producing dronedarone hydrochloride according to claim 17, wherein the acetone-water is from 30:1 to 5:1 (V/V). A process for the preparation of dronedarone and a salt thereof, which comprises the step of preparing dronedarone hydrochloride according to any one of claims 1 to 18. The method for preparing dronedarone and a salt thereof according to claim 19, which further comprises preparing dronedarone or further converting into pharmaceutically acceptable by treating dronedarone hydrochloride through an alkaline solution. The steps to accept other salts. The method for producing dronedarone and a salt thereof according to claim 20, wherein the base in the alkaline solution is an inorganic base. The method for producing dronedarone and a salt thereof according to claim 21, wherein the inorganic base is selected from the group consisting of sodium hydroxide, sodium carbonate or sodium hydrogencarbonate. The method for producing dronedarone and a salt thereof according to claim 22, wherein the inorganic base is sodium hydrogencarbonate.