FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
AN IMPROVED PROCESS FOR THE PREPARATION
OF DRONEDARONE AND IT'S
PHARMACEUTICALLY ACCEPTABLE SALTS
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANY ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM
BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI
(WEST), MUMBAI - 400 102, MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS FOR THE PREPARATION OF DRONEDARONE AND IT'S PHARMACEUTICAL ACCEPTABLE SALTS.
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Dronedarone
and its pharmaceutically acceptable salts, particularly hydrochloride, chemically known
as 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-5-methyl sulfonamido
benzofuran hyrochloride.
BACKGROUND OF THE INVENTION
Dronedarone and its pharmaceutically acceptable salts is a Class III anti-arrhythmic drug used for the prevention of cardiac arrhythmias such as atrial fibrillation or atrial flutter and is marketed as Multaq by Sanofi Aventis in USA. Dronedarone is represented as formula (I).

US 5,223,510 (Jean Gubin; Jul., 1991) discloses a process for the preparation of Dronedarone hydrochloride by using 2-butyl-5-nitrobenzofuran as a key starting raw material. In the said process, the 2-n-butyl-5-nitrobenzofuran is acylated with p-anisoyl chloride by using tin (IV) chloride as Friedel Craft catalyst, followed by de-methylation using aluminium chloride in dichloroethane. Further the 2-n-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran thus obtained was O-alkylated by using l-chloro-3-di-n-butylamino propane and potassium carbonate in methyl ethyl ketone to obtain 2-n-butyl-3-[4-(3-di-n-butylamino)propoxy]-5-nitrobenzofuran, which was reduced with platinum

oxide to obtain amino derivative. The amino compound, 5-amino-2-butyl-3-[4-(3-dibutylamino) propoxy] benzoyl benzofuran was further mesylated with methanesulfonyl chloride in the presence of triethylamine in dichloroethane to obtain Dronedarone, which was purified by using column chromatography. Further its hydrochloride was prepared in dry ethyl acetate by using solution of hydrogen chloride ether.
The above mentioned process suffers from several disadvantages like the use of tin (IV) chloride, which is a fuming chemical and also react very rapidly when in contact with water, thus creates problem while handling at commercial scale; use of expensive homogenous catalyst like platinum oxide; use of dichloroethane, which is a Class 1 solvent, for demethylation and further purification by column chromatography.
WO2007/140989 (Cambrex K., June 2007) covers synthesis of 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofurane via Friedel-Craft acylation of 2-butyl-5-nitrobenzofuran using FeCl3 in the presence of a non halogenated solvent like ortho-nitrotoluene, para-nitrotoluene and meta- nitrotoluene. The disadvantage of these solvent is that they are expensive and relatively not safe in larger quantity at commercial scale.
WO2003040120 (Gutman Arie., et. al., Nov., 2002) describes a process for the preparation of Dronedarone or its salts by using p-phenitidine or p-anisidine as starting raw material. In said process, the p-anisidine was acetylated with acetic anhydride and the product obtained was reacted with 2-bromohexanoyl halide in presence of AICI3 or AlBr3 to obtain N-[3-(2-bromohexanoyl)-4-hydroxyphenyl] acetamide. The compound thus obtained was converted into 2-butyl-5-benzofuranamine hydrochloride and it was subsequently converted into Dronedarone in several steps or its pharmaceutically acceptable salts. The process used involves large number of steps including protection and de-protection chemistry, which reduces the through of the process.
In the light of above cited prior art, there was a need for the development of an improved process for the preparation of Dronedarone or its hydrochloride thereof, which will avoid the disadvantages associated with known methods.

OBJECT OF INVENTION
The object of the present invention is to provide an efficient process for the synthesis of Dronedarone or its pharmaceutical salts thereof.
Another object of present invention is to provide a process with increased through-put at industrial scale and is also cost efficient.
Still another object of the present invention is to avoid the use of hazardous chemicals and column chromatography.
Another object of the present invention is to provide a Dronedarone or its salts, particularly hydrochloride, with a good yield and purity.
SUMMARY OF INVENTION
The present invention relates to an improved process for the preparation of (N-[2-(n-butyl)-3-[4-[3-(dibutylamino) propoxy] benzoyl]-5-benzofuranyl] methane-sulphonamide), Dronedarone of formula (I) or pharmaceutically acceptable salts thereof

comprising the steps of
a. Friedel-Craft acylation of 2-n-butyl-5-nitrobenzofuran of formula (II) with p-anisoyl chloride of formula (III) in presence of a Lewis acid and solvent


to obtain 2-n-butyl 3-(4-methoxy benzoyl) 5-nitro benzofuran of formula (IV);

b. De-methylation of 2-n-butyl 3-(4-methoxy benzoyl)-5-nitro benzofuran of formula (IV) in presence of a Lewis acid and an organic solvent to obtain 2-n-butyl 3-(4-hydroxy benzoyl) 5-nitro benzofuran of formula (V);
c. O-alkylation of 2-n-butyl 3-(4-hydroxy benzoyl) - 5-nitro benzofuran of formula
(V) with l-chloro-3-di-n-butylamino propane of formula (VI) in an organic
solvent, in presence of an inorganic base and metal iodide catalyst to obtain 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitro-benzofuran of formula (VII);


d. Reduction of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitro
benzofuran of formula (VII) with a heterogeneous metal catalyst in an organic
solvent to obtain 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl
benzofuran of formula (VIII).
e. Purification of 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl
benzofuran of formula (VIII) of step d) by forming its acidic salt in an organic
solvent.
f. Neutralization of the acidic salt formed in step e) with a base to obtain pure 5-
amino 3- [4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl benzofuran of
formula (VIII).

g. Mesylation of 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl benzofuran of formula (VIII) in presence of mesyl chloride and base in an organic

solvent to obtain Dronedarone of fonnula (I) and its conversion into pharmaceutically acceptable salt.

h. Purification of the salt of Dronedarone
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved, efficient, and high through put process for producing Dronedarone and its pharmaceutically acceptable salts particularly hydrochloride salt by employing non-hazardous and environment friendly chemicals.
The process according to the present invention, wherein preparation o f Dronedarone involves Friedel-Crafts acylation of 2-n-butyl-5-nitrobenzofuran of formula (II) with p-anisoyl chloride of formula (III) in presence of Lewis acid and solvent to form 2-n-butyl 3-(4-methoxy-benzoyl) 5-nitro-benzofuran of formula (IV).



The process according to the present invention, wherein the said Lewis acid used in Friedel-Craft acylation comprises of FeCl3, InCl3, ZnCl2, preferably it is FeCl3; and the solvent used in the said reaction comprises of methylene chloride, ethylene chloride, preferably it is methylene chloride.
The said Friedel Craft's acylation reaction according to present invention can be carried out at 25-30°C to the refluxing temperature of the solvent used, preferably it is carried out at the refluxing temperature of the solvent used, and this reaction is completed in approximately 2 hours.
The process according to present invention, wherein the process further comprises of demethylation of 2-n-butyl 3-(4-methoxy-benzoyl) 5-nitro-benzofuran of formula (IV) using Lewis acid in an organic solvent to form 2-n-butyl 3-(4-hydroxy benzoyl) 5-nitro-benzofuran of formula (V).

The process according to the present invention, wherein the said Lewis acid used in the demethylation step is aluminium chloride and the solvent used comprises of monochlorobenzene, 1,2-dichlorobenzene or 1,4-dichlorobenzene, preferably the solvent used is monochlorobenzene.

The said demethylation reaction according to the present invention is carried out at 50 -100°C, preferably at 60 - 85°C, more preferably at 75-78°C. Reaction time for this reaction is depend on the temperature of the reaction and takes approximately 24.0 hrs for completion if carried out at 75-78°C.
The demethylation step according to present invention is followed by O-alkylation of 2-n-butyl 3-(4-hydroxy benzoyl) 5-nitro-benzofuran of formula (V) obtained with 1-chloro-3-di-n-butylaminopropane of formula (VI) in an organic solvent in the presence of an inorganic base and metal iodide catalyst to form 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy)benzoyl] 5-nitro benzofuran of formula (VII).

The process according to present invention, wherein the O-alkylation is carried out in presence of inorganic base comprising of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate, preferably it is potassium carbonate and metal iodide comprising of sodium iodide, potassium iodide, copper iodide, preferably it is potassium iodide.
The said O-alkylation reaction can be conducted in presence of an organic solvent comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone or mixture thereof, preferably it is acetone.

The said O-alkylation is carried out at 25-30°C to 75°C, preferably at 50 to 65°C, more preferably at 55 to 57°C. The reaction is completed approximately in 45-50 hrs.
The process according to present invention further involves the step of reduction of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitro benzofuran of formula (VII) in the presence of heterogeneous metal catalyst and under hydrogen pressure in an organic solvent to form 5-amino 3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-2-n-butylbenzofuran of formula (VIII).

The said heterogeneous metal catalyst comprises of Palladium on carbon, Raney nickel, Platinum on carbon, Rhodium on carbon, preferably it is Palladium on carbon.
The hydrogen pressure at which the reaction is carried out varied from 2.0 to 8.0 kg, preferably 4.0 to 5.0 kg, more preferably at 5.0 kg and the said organic solvent used in reduction step comprises of methanol, ethanol, n-propanol, isopropyl alcohol, tert-butanol or n-butanol, preferably it is methanol.
The said reduction reaction is carried out at 25°C to refluxing temperature of the solvent used; preferably the reaction is carried at 50°C and it completes in 3 - 5 hrs.
The amino compound thus obtained can be purified by making its acidic salts by treatment with an acid in an organic solvent. The acid which can be used for making acidic salts comprises of hydrochloric acid, sulphuric acid, hydrobromic acid, oxalic acid, tartaric acid, para-toluene sulphonic acid, methane sulphonic acid or mandelic acid. Preferably oxalate salt is formed for the purpose of purification.

The said organic solvent used for the acidic salt formation comprises of methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone or mixture thereof, preferably the solvent used is acetone.
In a specific embodiment of the present invention, the oxalate salt of 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl benzofuran of formula (VIII) is prepared by adding the oxalic acid solution in acetone and stirring for 2 hrs for precipitation. The salt formation can be carried out at a 25°C to refluxing temperature of the solvent. Preferably for the purpose of the formation of salt, refluxing temperature of the solvent is used. To precipitate the salt the solution was cooied to 25-30°C and the precipitated oxalate salt was collected by filtration.
The process according to present invention, wherein the acidic salt formation step further involves neutralization of the said acidic salt formed. The said acidic salt can be neutralized by treatment with a base to form pure amine, wherein the said base can be an inorganic or organic base. The said inorganic base comprises of aqueous ammonia, methanolic ammonia, sodium carbonate, sodium bi-carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, preferably it is sodium bicarbonate or aqueous ammonia, more preferably it is sodium carbonate; or the organic base comprises of triethyl amine, diisopropyl amine, diisopropyl ethyl amine, methyl amine, preferably triethylamine.
When aqueous solution of inorganic bases are used for the neutralization of acidic salts, the amino compound obtained is extracted in water immiscible solvent comprising of dichloromethane, ethylene chloride, toluene, ethyl acetate, preferably it is methylene chloride and is recovered by distillation of the solvent used.
The pure amine i.e. 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl] 2-n-butyl benzofuran of formula (VIII) thus obtained is further mesylated using mesyl chloride in presence of base and an organic solvent to form Dronedarone of formula (I)


The process according to the present invention, wherein the base used in the said mesylation step comprises of triethyl amine, di-isopropylethylamine, sodium carbonate, potassium carbonate, preferably it is triethyl amine; and the solvent used in the said mesylation step comprises of methylene chloride, ethylene chloride, and toluene, preferably it is methylene chloride. This mesylation process is carried out at 25-30°Cfor 24-28 hrs.
Dronedarone thus obtained can be converted into its acid addition salts by treating with acids, preferably with hydrochloric acid.
The hydrochloride salt of Dronedarone can be prepared by treating the solution of Dronedarone in solvents like ethylacetate, methylacetate, isopropyl acetate, diethyl ether or di-isopropyl ether, preferably in ethylacetate with the hydrochloric acid absorbed in solvent like diethylether, di-isopropyl ether, tetrahydrofuran, methanol, ethanol, isopropyl alcohol, preferably tetrahydrofuran at -10 to 25°C, preferably at -5 to 0°C. After addition of hydrochloric acid is completed, the resulting solution can be stirred to get the precipitation of Dronedarone hydrochloride, which can be obtained by filtration.
Further the Dronedarone hydrochloride can be purified by crystallization to meet the purity criteria of ICH guidelines. The solvent which can be used for purification comprise of acetone, methyl ethyl ketone, methyl isobutyl ketone, ethanol, isopropanol or tetrahydrofuran and 1,4-dioxane preferably the solvent is acetone. The Dronedarone obtained meets the- criteria of ICH guideline purity wherein all impurities present are below 0.1%.

The process according to present invention is represented as Scheme 1. Scheme-1:


The following non-limiting examples illustrate specific embodiments of the present invention. They are, however, not intended to be limiting the scope of present invention in any way.
Example 1
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims
a) Preparation of anisoyl chloride (Formula III)
In a four neck round bottom flask equipped with overhead stirrer and refluxing condenser 143 gm (0.93 mol) of p-anisic acid and 137 ml (1.87 mol) of thionyl chloride were charged. The resulting mixture was heated at 65°C for two hours and the progress of the reaction was monitored by TLC. After the completion of the reaction the thionyl chloride was distilled off completely to get oil.
b) Preparation of 2-n-butyl 3-(4-methoxy benzoyl) 5-nitro benzofuran (Formula IV)
In a four neck round bottom flask equipped with overhead stirrer and refluxing condenser, 150 gm (0.68 mol) of 2-n-butyl 5-nitro benzofuran and 1200 ml of dichloromethane were charged. To the resulting mixture above prepared anisoyl chloride was added and solution was stirred. To this 144.27 gm (0.88 mol) of FeCl3 was added lot-wise. After the addition was over the temperature was raised to 40°C and stirred for 2 hours. The progress of the reaction was monitored by TLC. After the reaction was over the reaction mass was poured on 900 ml of water at RT and layer obtained was separated. The organic layer was washed with water. The organic layer was separated and washed with 5% sodium hydrogen carbonate solution and finally with water. The organic layer thus obtained was distilled off to get oil. To the oil, 750 ml of isopropyl alcohol (IPA) was added at 25-30°C and then heated to 45-50°C to get the clear solution. The clear solution was cooled to RT to precipitate the product; stirred for 1 hour at room temperature and filtered to get 200 g of 2-n-butyl 3-(4-methoxy benzoyl) 5-nitro benzofuran. Yield: 82% HPLC Purity: 98.0 %

Example 2
Preparation of 2-n-butyl 3-(4-hydroxy benzoyl) 5-nitro benzofuran (Formula V)
In a four neck round bottom flask equipped with overhead stirrer and refluxing condenser, 50 gm (0.14 mol) of 2-n-butyl 3-(4-methoxy benzoyl) 5-nitro benzofuran and 400 ml of monochlorobenzene were charged. To the mixture thus obtained, 50 g (0.37 mol) of aluminum chloride was added and reaction was heated to 75-78°C. The temperature was maintained for 24.0 hrs and progress of the reaction was monitored by TLC. After reaction was over, the mixture was cooled to RT and poured in 1000 ml of dilute HC1. The organic phase was separated and washed with water till neutral. The organic layer was distilled off to obtain 65 gm oil. To the oil thus obtained, 100 ml ethyl acetate was added and heated at 60-65°C. In the mixture, 700 ml n-Hexanes was added and the solution was cooled to RT. The precipitated product was filtered and dried in a vacuum at 50° C to obtain 41 g of 2-n-butyl 3-(4-hydroxy benzoyl) 5-nitrobenzofuran. Yield: 85 % HPLC Purity: 96.5.0 %
Example 3
Preparation of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitro benzofuran (Formula VII)
In a four neck round bottom flask equipped with overhead stirrer and refluxing condenser 100 gm (0.2946 mol) of 2-n-butyl 3-(4-hydroxy benzoyl) 5-nitro benzofuran and 800ml of acetone were charged. The mixture was stirred and 45g (0.324 mol) of anhydrous Potassium carbonate and Potassium iodide l.Og (0.0060 mol) were added thereto. The mixture was stirred for 0.5 hour at RT and 66.69 g (0.324 mol) of l-chloro-3-di-n-butylamino propane was then added and the mixture was heated at 55-57°C - for 48 hours. The reaction was monitored by TLC. After the reaction was over, it was cooled to RT and the inorganic salts were filtered off and washed with 100 ml acetone. The filtrate was evaporated to dryness and the residue was dissolved in 500 ml of dichloromethane. The solution was washed twice with 500 ml 5% sodium hydroxide solution and finally washed with water. It was dried over sodium sulphate, filtered and distilled off to obtain

145 g of the 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitro benzofuran as yellow oil. Yield: 96 % HPLC Purity: 95.0 %
Example 4
Preparation of 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl benzofuran (Formula VIII)
In a 2.0 liter autoclave, 113gm (0.22 mol) of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitro benzofuran and 1360 ml of methanol were charged. To this 2.82 g of 5% Pd/C was added. The temperature of reaction mass was raised to 45-48°C. In the autoclave hydrogen gas was charged and pressure of 4 to 5 Kg/cm2 of hydrogen was maintained for 5 hours. The progress of the reaction was monitored with TLC. After the reduction was over, the hydrogen gas was released and the catalyst was filtered and washed with methanol. The filtrate was distilled off to obtain 96.0 gm of 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl benzofuran as an oil. Yield: 93% HPLC Purity: 95.0 %
Example-5
Preparation of 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl benzofuran oxalate
In a four neck round bottom flask equipped with overhead stirrer and refluxing condenser, a solution of oxalic acid 97.50 gm (0.773 mol) in 555 ml of acetone was added to a solution of 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl benzofuran 185 gm (0.386 mol) in 370 ml of acetone and the mixture was heated at 65 °C for 2 hours. The reaction mixture was allowed to cool to room temperature; the product was filtered off and washed with acetone. Yield: 79.6 % HPLC Purity: 97.5 %
Example-6
Preparation of 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl benzofuran
In a four neck round bottom flask equipped with overhead stirrer, 200 ml of water and 100 gm 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl benzofuran

oxalate salt were charged at room temperature. Followed by addition of 500 ml of dichloromethane and adjust pH to 7-8 by using 10 % sodium carbonate solution. Separate layers and dry organic layer over anhydrous sodium sulphate. Distill off dichloromethane completely to obtain 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl benzofuran 73.0 gm (Oil)
Example-7:
Preparation of 2-n-butyl 3- [4-(3-di-n-butylamino-propoxy)-benzoyl] -5-methyl-sulfonamido benzofuran (Formula I)(Dronedarone)
In a four neck round bottom flask equipped with overhead stirrer and refluxing condenser, 54.0 gm (0.1128 mol) of 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl benzofuran and 1080 ml of dichloromethane were charged. To the solution thus obtained 23.5 ml (0.169 mol) of triethylamine was added. A solution of 10.91ml (0.141 mol) of methanesulfonyl chloride in 810 ml of dichloromethane was added drop wise at 25-30°C. The mixture was stirred for 24 hrs at 25-30° C and poured into 432 ml of water. The organic layers was separated and washed with water. The organic layer was distilled off to obtain 58.97 gm Dronedarone as oil. Yield: 93%
Example 8
Preparation of Dronedarone Hydrochloride (Formula I A).
In a four neck round bottom flask equipped with overhead stirrer and refluxing condenser, 58.97 gm of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-methyl sulfonamido benzofuran (Dronedarone) oil) was dissolved in 320 ml of ethyl acetate. To the solution thus obtained, pH was adjusted to 3 with a solution of Hydrogen chloride in THF at -5 to 0°C. It was stirred for 3.0 hrs at -5 to 0°C and filtered to obtain 50 gm of Dronedarone hydrochloride. Yield: 80 % HPLC Purity: 95 %
Example -9:
Purification of Dronedarone Hydrochloride:

In a four neck round bottom flask equipped with overhead stirrer and refluxing condenser, 50 gm of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy)benzoyl] 5-methyl sulfonamido benzofuran was dissolved in 750 ml of acetone at 55°C. The clear solution thus obtained was cooled to RT and filtered to get 33g of pure Dronedarone hydrochloride. Yield: 66% HPLC Purity: 99.86 % with single maximum impurity <0.1%
Example -10
Purification of Dronedarone Hydrochloride:
In a four neck round bottom flask equipped with overhead stirrer and refiuxing condenser, 7 gm of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-methyl sulfonamido benzofuran hydrochloride and 35 ml of isopropanol were charged and was heated to 65°C to obtain clear solution. The reaction mass was then cooled to 28-30 °C to obtain solid, which was filtered to get 6.3 gm of Dronedarone hydrochloride. Yield: 90 % HPLC Purity: 98.86 %
Example -11
Purification of Dronedarone Hydrochloride:
In a four neck round bottom flask equipped with overhead stirrer and refiuxing condenser 7.0 gm of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-methyl sulfonamido benzofuran hydrochloride and 35 ml of ethanol were charged and heated to 45°C to obtain a clear solution. Clear reaction mass was cooled to 28 - 30°C, solid precipitate out. The solid was filtered to obtain 5.73 gm of Dronedarone hydrochloride. Yield: 81.8 % HPLC Purity: 99.26 %
Example -12:
Purification of Dronedarone Hydrochloride:
In a four neck round bottom flask equipped with overhead stirrer and refiuxing condenser 10 g of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-methyl sulfonamido benzofuran hydrochloride and 230 ml of methyl isobutyl ketone were charged and

heated to 85 - 90 °C to get the clear solution. It was cooled to 25-28°C, solid precipitated out. The solid was filtered to get 9.01 gm of Dronedarone hydrochloride. Yield: 90.1 % HPLC Purity: 98.05 %
Example -13:
Purification of Dronedarone Hydrochloride:
In a four neck round bottom flask equipped with overhead stirrer and refluxing
condenser, 10.0 gm of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-methyl
sulfonamido benzofuran hydrochloride and 50 ml of tetrahyrofuran were charged and
heated at 58- 60°C to obtain clear solution. The clear solution was cooled to 25-28 °C and
solid precipitated out. The solid was filtered to get 5.24 gm of Dronedarone
hydrochloride.
Yield: 52.4 % HPLC Purity: 99.17 %
Example -14:
Purification of Dronedarone Hydrochloride:
In a four neck round bottom flask equipped with overhead stirrer and refluxing
condenser, 10.0 gm of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-methyl
sulfonamido benzofuran hydrochloride and 60 ml of 1,4 dioxane were charged and
heated at 58- 60°C to obtain clear solution. The clear solution was cooled to 25-28°C and
solid precipitated out. The solid was filtered to get 5.41 gm of Dronedarone
hydrochloride.
Yield: 54.1 % HPLC Purity: 99.06 %

We Claim
1. An improved process for the preparation of (N-[2-(n-butyl)-3-[4-[3-(dibutylamino) propoxy] benzoyl]-5-benzofuranyl] methane-sulphonamide), Dronedarone of formula (I) or pharmaceutically acceptable salts thereof

comprising the steps of
a. Friedel-Craft acylation of 2-n-butyl-5-nitrobenzofuran of formula (II) with p-anisoyl chloride of formula (III) in presence of a Lewis acid and solvent

to obtain 2-n-butyl 3-(4-methoxy benzoyl) 5-nitro benzofuran of formula (IV);

b. De-methylation of 2-n-butyI 3-(4-methoxy benzoyI)-5-nitro benzofuran of formula (IV) in presence of a Lewis acid and an organic solvent to obtain 2-n-butyl 3-(4-hydroxy benzoyl) 5-nitro benzofuran of formula (V);

c. O-alkylation of 2-n-butyl 3-(4-hydroxy benzoyl)- 5-nitro benzofuran of formula (V) with l-chloro-3-di-n-butylamino propane of formula (VI) in an organic solvent, in presence of an inorganic base and metal iodide catalyst to obtain 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitro-benzofuran of formula
(VII);

d. Reduction of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitro
benzofuran of formula (VII) with a heterogeneous metal catalyst in an organic
solvent to obtain 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl
benzofuran of formula (VIII).
e. Purification of 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl
benzofuran of formula (VIII) of step d) by forming its acidic salt in an organic
solvent.
f. Neutralization of the acidic salt formed in step e) with a base to obtain pure 5-
amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl benzofuran of
formula (VIII).

g. Mesylation of 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl benzofuran of formula (VIII) in presence of mesyl chloride and base in an organic solvent to obtain Dronedarone of formula (I) and its conversion into pharmaceutically acceptable salt.


h. Purification of the salt of Dronedarone
2. An improved process according to Claim la), wherein the Lewis acid comprises of FeCl3, InCl3 and ZnCl2; preferably FeCl3, and solvent comprises of methylene chloride, ethylene chloride, preferably methylene chloride.
3. An improved process according to Claim lb), wherein the said Lewis acid comprises of aluminium chloride and organic solvent comprises of monochlorobenzene, 1, 2-dichlorobenzene or 1,4-dichlorobenzene, preferably monochlorobenzene.
4. An improved process according to claim lc), wherein the said inorganic bases comprises of sodium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate or potassium carbonate, preferably potassium carbonate.
5. An improved process according to Claim lc), wherein metal iodide comprises of potassium iodide, sodium iodide, copper iodide, preferably potassium iodide.
6. An improved process according to claim lc), wherein the said solvent comprises of acetone, methylethyl ketone, methylisobutyl ketone or mixture thereof; preferably acetone.
7. An improved process according to claim Id), wherein the heterogeneous metal catalyst comprises of Palladium on carbon, Raney nickel, Platinum on carbon, Rhodium on carbon; preferably Palladium on carbon.

8. An improved process according to claim Id), wherein the said organic solvent
comprises of methanol, ethanol, isopropanol, n-propanol, tert-butanol or n-butanol;
preferably methanol.
9. An improved process according to claim Id), wherein the hydrogen pressure used for
the reduction is 2.0 to 8.0 kg, preferably 4.0 to 5.0 kg, most preferably 5.0 kg.
10. An improved process according to claim le), wherein the said acidic salt comprises of hydrochloride, hydrobromide, hydrogen sulphate, tartrate, oxalate, mandelate, mesylate, para toluene sulphonate; preferably oxalate salt; and organic solvent comprises of methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone or mixture thereof, preferably acetone.
11. An improved process according to claim If), wherein the said base is an organic base comprising of triethyl amine, diisopropyl ethyl amine, diisopropyl amine, methyl amine preferably triethylamine or an inorganic base comprising of aqueous ammonia, methanolic ammonia, sodium carbonate, sodium bi-carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide; preferably sodium carbonate.
12. An improved process according to claim 11), wherein the said neutralization step follows extraction with water immiscible solvent comprising of methylene chloride, ethylene chloride, toluene, ethyl acetate, preferably methylene chloride.
13. An improved process according to claim lg), wherein the base comprises of triethyl amine, di-isopropyl ethyl amine, potassium carbonate , sodium carbonate, preferably triethyl amine, and solvent comprises of methylene chloride, ethylene chloride, toluene; preferably methylene chloride.
14. An improved process according to claim lg), wherein preferably the
pharmaceutically acceptable is hydrochloride salt of Dronedarone.

15. An improved process according to claim 14, wherein hydrochloride salt of
Dronedarone obtained by treating the solution of Dronedarone in solvent like
ethylacetate, methyl acetate, isopropylacetate, diisopropyl ether, diethyl ether, preferably
ethylacetate, with a hydrochloric acid solution in tetrahydrofuran, ether, diisopropylether,
methanol, ethanol and isopropanol, preferably tetrahydrofuran; and isolated by filtration.
16. An improved process according to claim lh), wherein the Dronedarone hydrochloride purified from the solvents comprising of acetone, methyl ethyl ketone, methylisobutyl ketone, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane preferably acetone.
17. An improved process according to claim 16, wherein the purified Dronedarone hydrochloride obtained meets the criteria of ICH guideline wherein all the impurities present in Dronedarone are than 0.1 %.
18. An improved process according to any of the preceding claims substantially as herein described with reference to the examples.