FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
AN IMPROVED PROCESS FOR THE PREPARATION OF DRONEDARONE ACID ADDITION 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 ACID ADDITION SALTS
FIELD OF THE INVENTION
The present invention relates to an improved efficient process.for the preparation of pharmaceutically acceptable acid addition salts of Dronedarone, chemically known as 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-5-methylsulfonamido benzofuran in a single organic solvent.
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 hydrochloride is represented as formula (I).

US 5,223,510 (Jean Gubin; Jul., 1991) discloses a process for the preparation of Dronedarone hydrochloride by Oralkylation of 2-n-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran with l-chIoro-3-di-n-butylamino propane using 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 said amino derivative was mesylated with methanesulfonyl chloride in the presence of triethylamine in dichloroethane to obtain Dronedarone, which was purified by 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 expensive homogenous catalyst like platinum oxide and purification by column chromatography.
Various other methods are known in the literature for the synthesis of Dronedarone hydrochloride, few of them are described below.
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, which was converted into 2-butyl-5-benzofuranamine hydrochloride and it was subsequently converted into Dronedarone in several steps or its pharmaceutically acceptable salts. The said process involves large number of steps involving protection and de-protection chemistry, which reduces the throughput of the process.
The process described in the patent US6846936 (Michel Biard., et. al., Dec 2001) involves the Fridel Craft reaction of 2-h-butyl-5-nitro-benzofuran with 4-[3-(dibutylamino)-propoxy] benzoyl chloride to obtain 2-n-butyl-3-[4-(3-(di-n-butyIamino)propoxy]benzoyl]-5-mtrobenzofuran, which is reduced in the presence of platinum oxide catalyst to form 5-amino-2-butyl-3-[4-(3-dibutylamino) propoxy] benzoyl benzofuran. The said compound is further reacted with methanesulfonyl chloride or methanesulfonic anhydride in presence of acid acceptor to form Dronedarone, which is optionally converted into its salt. It is known in the art that during the mesylation reaction a double mesylated derivative is also formed, making the process low yielding and • involving column chromatographic methods for the purification. The industrial application of the method is therefore not economical.
WO2011070380 (Friesz, Antal, et. al., June, 2011) describes the synthesis of Dronedarone' involving the step of reaction of 2-n-butyl-3-(4-hydroxybenzoyI)-5-nitro-

benzofuran with l-bromo-3-chloropropane to obtain (2-n-butyl-5-nitro-l-benzofuran-3-yl)-[4-(3-chloropropoxy)phenyl] methanone; reduction in the presence of palladium catalyst to form 5-amino-2-n-butyl- benzofuran -3-yl-[4-(3-chloropropoxy)phenyl] methanone; its mesylation with methanesulfonyl chloride or with methanesulfonic anhydride in the presence of base to obtain N-(2-n-butyl-3-[4-(3-chloropropoxy)benzoyl] • •. benzofuran-5-yl) methanesulfonamide. The halo derivative thus obtained was reacted with dibutylamine to obtain Dronedarone followed by treatment with isopropanol and 37 % HC1 to obtain Dronedarone hydrochloride. salt. The process used involves large number of steps of condensation, which reduces the throughput of the process.
The process disclosed in the patent application WO2011104591 (Sada, Mara, et. Al, Sep
2011.) involves O-alkylation of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro-benzofuran with
3-chloro-l-propanol to obtain 3-{4-[(2-butyl-5-nitro-l-benzofuran-3-yl) carbonyl]
phenoxy}propan-l-ol, which is reduced in the presence of 10 % Pd/C in methanol to
form 3-{4-[(5-amino-2-butyl-l-benzofuran-3-yl)carbonyl]phenoxy}propan-l-ol. Its
mesylation with methanesulfonyl chloride in the presence of base, pyridine is carried out
to obtain 3-{4-[(2-butyl-5-methanesulfonamide-l-benzofuran-3-
yl)carbonyl]phenoxy} propyl methanesulfonate, which is further reacted with .dibutylamine to obtain Dronedarone, followed by treatment with acetone and 37 % hydrochloric .acid to obtain Dronedarone hydrochloride salt. The process used involves large number of steps of condensation, which reduces the throughput of the process.
Patent application WO2011158050 (Friesz, Antal, et. al, Dec, 2011) also discloses a method for the preparation of Dronedarone. In this method 2-n-butyl-5-bis-(methylsulfonamido)-benzofuran is reacted with anisoyl chloride under Friedel Craft conditions to obtain 2-n-butyl-5-bis-(methylsulfonamido)-3-(4-methoxy-benzoyl)-benzofuran, which is demethylated using aluminum chloride in Chlorobenzene to obtain 2-n-butyl-5-bis-(methylsulfonamido)-3-(4-hydroxy-benzoyl)-benzofuran. O-alkylation of the same with 3-di-n-butyl amino-propyl chloride to obtain 2-n-butyl-3-[(di-n-butylamino-3~propoxy)-benzoyl]-5-bis-(methylsulfonamido) benzofuran, is further treated with alkali alcoholate to obtain N-[2-(n-butyl)-3-[4-[3-(dibutylamino) propoxy]

benzoyl]-5-benzofuranyl] methane-sulphonamide. The process described involved the use of sodium metal, which is pyrophoric and difficult to handle at commercial scale.
In the light of above cited prior art, there was a need for the development of an improved and high throughput process for the preparation of Dronedarone acid addition salts, • particularly its hydrochloride and which can avoid the disadvantages associated with known methods.
OBJECT OF INVENTION
The object of the present invention is to provide high throughput process for the synthesis of pharmaceutically acceptable acid addition salts of Dronedarone .
Another object of present invention is to provide an in-situ, simple and economical and industrially feasible method for preparing pharmaceutically acceptable acid addition salts of Dronedarone in a single organic solvent.
Still another object of the present invention is to avoid the use of hazardous chemicals and column chromatography for preparation of pharmaceutically acceptable acid addition salts of Dronedarone.
Another object of the present invention is to provide pharmaceutically acceptable acid addition salts of Dronedarone with, a good yield and purity.
SUMMARY OF INVENTION
The present invention relates to an improved process for the preparation of pharmaceutically acceptable acid addition salts of (2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-5-methylsulfonamido benzofuran, Dronedarone comprising the steps of
a) O-alkylation of 2-n-butyl-3-(4-hydroxy benzoyl) 5-nitro benzofuran (Formula II) " with l-chloro-3-di-n-butylamino propane (Formula III) in presence of inorganic

base and phase transfer catalyst in a water immiscible organic

solvent to get 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitro benzofuranof formula (IV);

b) In-situ reduction of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitro benzofuran of formula (IV) using heterogeneous metal catalyst under H2 pressure to get 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl benzofuran of forniula (V);

c) in-situ mesylation of 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl benzofuran of formula (V) by using mesyl chloride in presence of an inorganic base to obtain 3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-5-methyl-sulfonamide benzofuran of formula (VI);


d) in-situ conversion of Dronedarone free base of formula (VI) into its acid addition salts of Formula I, by treating it with acids
e) Purification of the obtained pharmaceutically acceptable acid addition salts of Dronedarone.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved, efficient, one pot and high through put process for producing pharmaceutically acceptable acid addition salts of Dronedarone, particularly hydrochloride salt, in a single organic solvent. According to present invention the intermediates formed during the process are not isolated as solids or liquids; rather they are carried forward to next step in same solvent.
The process according to present invention involves the steps of O-alkylation of 2-n-
butyl-3-(4-hydroxybenzoyi)-5-nitro benzofuran with l-chloro-3-di-n-butylamino
propane to form 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy)benzoyl]-5-nitro
benzofuran; in-situ reduction of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy)benzoyl]-5-
i nitro benzofuran to form 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl] 2-n-butyl
benzofuran; and in-situ mesylation of 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl]
2-n-butyl benzofuran to form Dronedarone; conversion of in-situ formed Dronedarone

base into its pharmaceutically acceptable acid addition salt; and purification of Drondarone acid addition salts formed.
The process according to present invention, wherein said O-alkylation of 2-n-butyl 3-(4- ' hydroxy benzoyl) 5-nitro-benzofuran of formula (II) with l-chloro-3-di-n-butylaminopropane of formula (III) is carried out in a water! immiscible organic solvent and water in the presence of an inorganic base and phase transfar catalyst to form 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy)benzoyl] 5-nitro benzofuran of formula (IV).

The process according to present invention, wherein the said inorganic base used in the O-alkylation steps is comprised of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate, preferably it is potassium carbonate and the said -phase transfer catalyst comprises of quaternary ammonium salts like tetra butyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium chloride, preferably it is tetra butyl ammonium bromide. The said water immiscible organic

solvent, which can be used during the reaction is comprised of toluene, o-xylene, p-xylene, m-xylene, methylene chloride, ethylene chloride, monochlorobenzene or mixture thereof, preferably it is toluene.
The temperature, at which O-alkylation is carried, varies from 25°C to 100°C, preferably at 50 to 85°C, more preferably at 80 to 85°C. The reaction is completed approximately in 28-30 hrs. The O-alkylated product remains in toluene layer while lower aqueous layer is discarded. The toluene layer containing O-alkylated product i.e. 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy)benzoyl] 5-nitro benzofuran of formula (IV) is further reduced with a heterogeneous metal catalyst and under hydrogen pressure to obtain 5-amino 3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-2-n-butylbenzofuran of formula (V).

The said heterogeneous metal catalyst comprises of Palladium on' carbon, Raney nickel, Platinum on carbon, Rhodium on carbon, preferably it is Raney nickel.
The hydrogen pressure at which the reaction is carried out varied from 2.0 to 7.0 kg, preferably 4.0 to 5.0 kg.
The said reduction reaction is carried out at 25°C to refluxing temperature of the solvent used; preferably the reaction is carried at 50-55 °C and it completes in 5 - 6 hrs.
After reduction is over the catalyst used is removed by filtration and toluene layer containing reduced product i.e. 5-amino 3-[4-(3-di-n-butylamiino-propoxy)-benzoyl]-2-n--butylbenzofuran of formula (V) is mesylated by using mesyl chloride in presence of inorganic base to obtain Dronedarone free base (VI).

The process according to present invention, wherein the said mesylation reaction is carried out at 25-30°C for 01-02 Irrs. The inorganic bases that can be utilized in the mesylation reaction are comprising of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate. Particularly sodium bicarbonate is used as base.
The Dronedarone free base (VI) thus formed, is converted into its pharmaceutical^ acceptable acid addition salts by treating with acids. The said acids are comprising of hydrochloric acid, sulphuric acid, hydrobromic acid, methane sulphonic acid, preferably it is hydrochloric acid.
Particularly the Dronedarone free base in toluene is treated with concentrated hydrochloric acid. The toluene layer is removed by distillation and the hydrochloride thus formed is precipitated by adding ethyl acetate.
The Dronedarone acid addition salts, preferably hydrochloride thus formed are purified in an organic solvent to obtain pure Dronedarone acid addition salts, preferably Dronedarone hydrochloride of formula (I). The process is very environmentally friendly since it utilizes only one organic solvent to form Dronedarone hydrochloride.

The solvent which can be used for purification comprised of acetone, methyl ethyl ketone, methyl isobutyl ketone, ethanol, isopropanol or tetrahydrofuran; preferably
acetone. The. Dronedarone hydrochloride obtained meets the criteria of ICH guideline
i
purity wherein all impurities present are below 0.1%.


The process according to present invention, wherein the said process is advantageous since it is carried in a one pot and in a single solvent, without isolation of any intermediate formed therein, and hence avoiding intermediates filtration, drying and purification steps. Further the process according to present invention is environmentally friendly as the solvent used can be recovered and recycled. The said process avoids use of alcoholic solvents in the process and further eliminates the chance of formation of sulfonates of alcohols which are the genotoxic alerts. The process according to present .invention provides pharmaceutically acceptable acid addition salts of Dronedarone, preferably Dronedarone hydrochloride of a very high purity without any chromatographic purification; and it is simple, inexpensive, good yielding, can be adopted for commercial production with high degree of consistency and reproducibility.
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.
Preparation of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-5-methyl-
sulfonamido benzofuran hydrochloride (Formula I) (Drohedarone hydrochloride)
i
In a four neck round bottom flask equipped with overhead stirrer and refluxing condenser 100 g (0.29 mol) of 2-n-butyl 3-(4-hydroxy benzoyl) 5-nitro benzofuran and 700ml of toluene were charged. The mixture was stirred and solution of potassium carbonate (dissolve 44.8 gm (0.32mol) of K2CO3 in 300 ml water), and tetrabutylammonium bromide (TBAB) 2.0 g were added thereto. The mixture was stirred for 15 min at RT and 63.66 g (0.30 mol) of l-chloro-3-di-n-butylamino propane was then added and the mixture was heated at 80-85°G for 30 hours. The reaction was monitored by HPLC. After the reaction was over, it was cooled to RT and washed with water to obtain 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitro benzofuran.
In a 2.0 liter pressure reactor, reaction mass of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitro benzofuran (900 ml approx.) was charged. To this 5.0 g of 5 % Raney Ni was added. The temperature of reaction mass was raised to 53-55°C. In the reactor hydrogen gas was charged and pressure of 4.5 to 5 Kg/cm2 of hydrogen was maintained for 6 hours. The progress of the reaction was monitored with HPLC. After the reduction was over, the hydrogen gas was released and the catalyst was filtered and washed with toluene (100 ml) to obtain 5-amino 3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-2-n-butylbenzofuran of formula (V).

In a four neck round bottom flask equipped with overhead stirrer and refluxing condenser, toluene layer containing 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl]-2-n-butyl benzofuran (1000 ml) and sodium bicarbonate (30 gm) were charged. A solution of 33.22 gm (0.29 mol) of methanesulfonyl chloride in 100 ml of toluene was added in a single lot at 25-30°C. The mixture was stirred for 2 hrs at 25-30° C. Charged water (500 ml) and separated layers. Charged 40 ml of 37 % hydrochloride acid in organic layer at 25°C and stirred at 25-30°C for two hours. Reaction mass is concentrated and taken up in 500 ml of ethylacetate and stirred at 25-30°C for six hours. Filtered solid and washed with 300 ml of acetone to obtain 127 gm of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-5-methyl- sulfonamide benzofuran hydrochloride. Yield: 72.69 % HPLC Purity: 98.5 %
Example 2
Purification of Dronedarone Hydrochloride:
In a four neck round bottom flask equipped with overhead stirrer and refluxing. condenser, 127 gm of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy)benzoyl] 5-methyl sulfonamido benzofuran hydrochloride was dissolved in 2159 ml of acetone at 55°C. The clear solution thus obtained was cooled to Q-5°C and filtered to get 105 g of pure Dronedarone hydrochloride. Yield: 82.67 % HPLC Purity: 99.86 % with single maximum impurity <0.1%.

We Claim
1. An improved process for the preparation of pharmaceutically acceptable acid addition salts of (2-n-butyl-3-[4-(3-di-n-butylarnino-propoxy) benzoyl]-5-methylsulfonamido benzofuran, Dronedarone comprising the steps of
a) O-alkylation of 2-n-butyl-3-(4-hydroxy benzoyl) 5-nitro benzofuran (Formula II) with l-chloro-3-di-n-butylamino propane (Formula III) in presence of inorganic base and phase transfer catalyst in a water immiscible organic

solvent to get 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitro benzofuran of formula (IV);

b) In-situ reduction of 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitro benzofuran of formula (IV) using heterogeneous metal catalyst under FI2 pressure to get 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl benzofuran of formula (V);

c) in-situ mesylation of 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl benzofuran of formula (V) by using mesyl chloride in presence of an inorganic base to obtain 3-[4-(3-di-n-butylamino-propoxy)-benzoyl]-5-methyl-sulfonamide benzofuran of formula (VI);

d) in-situ conversion of Dronedarone free base of formula (VI) into its acid addition
salts of Formula I, by treating it with acids
e) Purification of the obtained pharmaceutically acceptable acid addition salts of
Dronedarone.
2. An improved process according to claim la), wherein the said inorganic bases comprises of sodium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate or potassium carbonate, preferably potassium carbonate.

3. An improved process according to claim la), wherein the said phase transfer catalyst comprises of tetra butyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium chloride, preferably tetra butyl ammonium bromide.
4. An improved process according to claim la), wherein'the said water immiscible organic! solvent comprises of toluene, o-xylene, p-xylene, m-xylerle, methylene chloride, ethylene chloride, monochlorobenzene , preferably toluene.
5. An improved process, according to claim lb), wherein the heterogeneous metal catalyst comprises of Palladium on carbon, Raney nickel, Platinum on carbon, Rhodium on carbon; preferably Raney nickel.
6. An improved process according to claim lb), wherein the!hydrogen pressure used for the reduction is 2.0 to 7.0 kg, preferably 4.0 to 5.0.
7. An. improved process according to claim lc) wherein the said inorganic base'
comprises of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium
carbonate, cesium carbonate; preferably sodium bicarbonate.
8. An improved process according to claim Id), wherein the said acids comprises of
hydrochloric acid, sulphuric acid, hydrobromic acid, methane jsulphonic acid, preferably
hydrochloric acid is used to obtain Dronedarone Hydrochloride.
9. An improved process according to claim le) and claim 8, wherein the obtained
Dronedarone hydrochloride is purified from the solvents comprising of acetone, methyl
ethyl ketone,- methyliso butyl ketone, ethanol , isopropanol, tetrahydrofuran , preferably acetone.
10. An improved process according to claim 9, wherein the purified Dronedarone
hydrochloride obtained meets the criteria of ICH guideline wherein all the impurity
present in Dronedarone Hydrochloride is less than 0.1%.

11. An improved process according to any of the preceding claims substantially as herein described with reference to the examples.