FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
Title
"AN IMPROVED PROCESS FOR THE PREPARATION OF DRONEDARONE"
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:

AN IMPROVED PROCESS FOR THE PREPARATION OF DRONEDARONE
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Dronedarone or its pharmaceutically acceptable salts having reduced content of ]-ch)oro-3(di-n-butylamino) propane (VI). The process comprises reduction of 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-5-nitro-l-benzofuran (II) to 5-amino-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-2-butyl-l-benzofuran of formula (III), which is a key intermediate for the preparation of Dronedarone using Raney nickel as a catalyst. The process of present invention is preferably carried out using single solvent system or "one-pot" synthesis. The present invention also relates to an amorphous polymorphic form of Dronedarone hydrochloride & their process for the preparation.
BACKGROUND OF THE INVENTION
Dronedarone is chemically known as N-[2-butyl-3-[4-[3-(di-n-
butylarnino)propoxy]benzoyl]-5-benzofuranyl]methane sulfonamide has the formula (I)

Dronedarone is a Class III anti-arrhythmic drug for the prevention of cardiac arrhythmias such as atrial fibrillation (AF). Dronedarone hydrochloride is marketed as Multaq® in the USA and Europe. Each tablet of Multaq® contains 400mg of Dronedarone (expressed as base).
Dronedarone and its pharmaceutically acceptable salts have been disclosed in patent U.S. Patent No. 5,223,510, as well as its therapeutic applications.

The preparation of said pharmaceutical agent can be obtained with different synthetic schemes. U.S. Patent No. 5.223,510 discloses process for the preparation of Dronedarone Hydrochloride as described according to the following scheme-1:
Scheme-1

As per scheme the synthesis of Dronedarone and its pharmaceutically acceptable salt by (a) reacting 2-butyl-5-nitrobenzofuran with anisoyl chloride in the presence of tin tetrachloride based on the Friedel-Crafts reaction conditions and hydrolysis to form 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran, (b) demethylation of the compound thus obtained in the presence of 2.25 molar equivalents of aluminum chloride and hydrolysis so as to form 2-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran, (c) condensation of the compound obtained with l-chloro-3-(di-n-butylamino)propane in the presence of potassium carbonate, to give 2-butyl-3-(4-[3-(di-n-butylamino] propoxylbenzoyl)-5-nitrobenzofuran, (d) hydrogenation of the compound thus formed, in the presence of platinum oxide, which gives 5-amino-2-butyl-3-(4-[3-di-n-butylamino) propoxy] benzoylbenzofuran, e) reaction of the 5-aminobenzofuran derivative thus obtained with methanesulfonyl chloride in the presence of triethylamine.
Repetition of the procedure described in US 5,223,510 results in crystalline Dronedarone Hydrochloride ( by Ethylacetate / ether HCI). Crystalline Dronedarone Hydrochloride is characterized by: an x-ray diffraction pattern with characteristic reflections at about 7.6°, 8.07°, 9.0°, 11.88°, 13.03°, 13.65°, 14.27°, 15.30°, 15.70°, 16.20°, 16.61°, 18.82°, 20.0°,

20.41°, 20.74°, 21.15°, 21.36°, 21.62°, 22.64°, 23.90°, 26.09°, 26.89°, 27.72°, 29.85° and 31.62° ±0.2°.
US 5,854,282 describes the process of preparation of 2-n-butyl-3-(3,5-diiodo-4-ethyl carboxymethoxybenzoyl)-5-trifluoromethylsulphonamidobenzofuran by condensation of 2-n-butyl-3-(4-hydroxybenzoyl)5-nitrobenzofuran with ethylbromoacetate in presence of potassium carbonate and acetone, followed by reduction in presence of Tin(II) chloride and mixture of ethylacetate with ethanol to give corresponding amine which is dissolved in methylene chloride, TEA and trifluoromethanesulphonyl anhydride to prepare the product.
J. methods in Enzymology, vol. 11, 1967 page-556 catalytic reduction of 2-butyl-5-
nitrobenzofuran (3.4 atm H2 / PtO2 / EtOH) gives 2-butyl-5-benzofuranamine free base,
which reacts with methanesulfonyl chloride in the presence of triethylamine as acid
scavenger and carbon tetrachloride as a solvent to give N-(2-butyl-5-benzofuranyl)-N-
(methylsulfonyl)methanesulfonamide instead of N-(2-butyl-5-
benzofuranyI)methanesulfonamide.
These prior art processes have many shortcoming such as-
(1) The process requires the costly metal catalyst like platinum and palladium for reduction and working under inert gas atmosphere, for which special production equipment is needed.
(2) The process require Dichloroethane and Triethyl amine for Mesylation wherein by-product is triethylamine hydrochloride which is difficult to remove from stage product when active ingredient is acid addition salt.
(3) Use of ether at commercial scale is not feasible and safe.
(4) Use of column chromatography for purification of product.
(5) Use of hazardous reagents in the reaction.
(6) Purification of intermediates after completion of each step, which is time consuming and require extra purification step which leads to increase in the cost of overall process.
(7) Presence of residue of genotoxic compound l-chloro-3(di-n-butylamino)propane (III) as impurity.

The Applicant has found simpler and cost-effective process for synthesizing Dronedarone, avoiding use of costly metal catalyst and time consuming extra purification step, which is industrially viable and gives better yields.
Thus, the present invention provides considerable benefits with respect to removing the technical problems associated with prior art as well being simpler and economical, while at the same time achieving high purity and yield of the product with convenience to operate on a commercial scale.
SUMMARY OF THE INVENTION
In one aspect, present invention provides the process of preparation of Dronedarone or its pharmaceutically acceptable salt thereof having less then 0.1% of the dimesyl impurity and having concentration of l-chloro-3(di-n-butylamino)propane (VI) less than 1.8 ppm, is optionally in a single solvent system which comprises;
a) condensation of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (V) with l-chloro-3(di-n-butylamino) propane (VI) to give compound 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl) -5-nitro-l-benzofuran (II).
b) removal of 1 -chloro-3(di-n-butylamino)propane (VI)
c) catalytic Hydrogenation of 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl) -5-nitro-I-benzofuran(II) to 5-amino-3-(4-(3-di-n-butyIamino-propoxy) benzoy])-2-butyl-l-benzofuran (III);
d) mesylation of 5-amino-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-2-butyl-1-benzofuran (III) to obtain 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-5-methyl sulfonamido-1-benzofuran (I) or its pharmaceutically acceptable salt;
e) optional formation of acid-addition salt of Compound of formula (I)
f) optional purification of compound of formula (I) or its pharmaceutically acceptable salt
In second aspect, the present invention provides a process for the preparation of compound of formula (III):


(III) Comprises, the catalytic hydrogenation of compound of formula (II)

(II)
using Raney nickel as a catalyst in presence of an inert solvent.
In further aspect, present invention provides an improved process for the preparation of Dronedarone and its pharmaceutically acceptable salts having low content of the dimesyl impurity (IV), preferably less than 0.12 % more preferably less then 0.1 %.
Yet another aspect of the present invention is to provide Amorphous polymorphic forms of Dronedarone hydrochloride
In another aspect, present invention provide a process for preparation of Amorphous polymorphic forms of Dronedarone and its pharmaceutically acceptable salts, which comprises: a) dissolving Dronedarone and its pharmaceutically acceptable salts in a solvent and optionally adding antisolvent after distilling the solvent or without distilling the solvent or b) using spray drying process.
In another embodiment, present invention provides preparation of crystalline Dronedarone and its pharmaceutically acceptable salts from the Amorphous Dronedarone and its pharmaceutically acceptable salts which comprises:

(a) providing a solution of Dronedarone and its pharmaceutically acceptable salts in a suitable solution
(b) optionally heating the solution of step (a)
(c) isolating crystalline Dronedarone and its pharmaceutically acceptable salts.
Another aspect of the instant invention is to provide a simpler and cost-effective and industrially viable process for synthesis of Dronedarone hydrochloride.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS:
Fig. 1: This figure indicates X-ray diffraction pattern of amorphous Form of Dronedarone
hydrochloride obtained according to the present invention.
Fig. 2: This figure indicates Infra red spectroscopy of amorphous Form of Dronedarone
hydrochloride obtained according to the present invention.
Fig. 3: This figure indicates X-ray diffraction pattern of Crystalline Dronedarone
Hydrochloride as per US 5,223,510 (Example-3(b)).
DETAILED DESCRIPTION:
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
The term "Single solvent system" or "One pot synthesis" as described herein signifies the use of single solvent during conversion of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran(V) to Dronedarone or its pharmaceutically acceptable salt (I).
2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl) -5-nitro-l-benzofuran (II) and 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (V) which can be prepared by any means

known to the skilled person, such as by method as disclosed in EP 0471609 and US 5223510.
The present invention provides an improved process for the preparation of 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-5-methyl sulfonamido-l-benzofuran known as Dronedarone and its pharmaceutically acceptable salts, which comprises catalytic hydrogenation of 2-butyl-3-(4-(3-di-n-butyIamino-propoxy) benzoyl) -5-nitro-l-benzofuran of formula (II) to 5-amino-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-2-butyl-l-benzofuran of formula (III) using Raney nickel as catalyst in presence of inert solvent followed by the mesylation of 5-amino-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-2-butyl-1-benzofuran of formula (III) to obtain 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-5-methyl sulfonamido-l-benzofuran of formula (1)
Following scheme- illustrates an exemplary process for the preparation of Dronedarone and its pharmaceutically acceptable salts in the accordance with the present invention.

In the preferred embodiment, the present invention provides the process of preparation of Dronedarone (I) or its pharmaceutically acceptable salt having less then 0.1% of the dimesyl impurity and having concentration of l-chloro-3(di-n-butylamino)propane (VI) less than 1.8 ppm in a single solvent system or "one-pot" comprises:

a) Condensation of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (V) with l-chioro-3(di-n-butylamino) propane (VI), in presence of organic solvent to give compound 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl) -5-nitro-l-benzofuran (II).
b) Removal of l-chloro-3(di-n-butylamino)propane (VI)
c) Catalytic Hydrogenation of 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl) -5-nitro-l-benzofuran(II) to 5-amino-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-2-butyl-l-benzofuran (III) using raney nickel as catalyst;
d) Mesylation of 5-amino-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-2-butyl-1-benzofuran (III), in presence of methane sulfonyl chloride with organic solvent and alkaline earth metal carbonate to obtain 2-buty1-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-5-methyl sulfonamide-1-benzofuran (I) or its pharmaceutically acceptable salt;
e) Optional formation of acid-addition salt of Compound of formula (I)
f) Optional purification of compound of formula (I) or its pharmaceutically acceptable salt
Following scheme- illustrates an exemplary process for the preparation of Dronedarone and its pharmaceutically acceptable salts in accordance with the present invention.

In one embodiment, the present invention provides Condensation of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran(V) with l-chloro-3(di-n-butylamino)propane(VI), in

presence of a suitable base and a solvent to give compound 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl) -5-nitro-l-benzofuran(II).
The condensation step according to present invention takes about 8-12 hours for completion.
One-pot synthesis according to present invention is advantageous over prior art process as reduces the time and cost of overall process. It eliminates the need of purification of compound at every step and only final product Dronedarone is purified and hence results in high yield.
Base used for the reaction is alkaline earth metal carbonates, bicarbonates, hydroxides selected from potassium carbonate, sodium carbonate, potassium hydroxide, Sodium hydroxide, Sodium bicarbonate and the like.
Solvent used for the reaction is non-polar solvent selected from Toluene. Xylene, pentane, cyclopentane, hexane, cyclohexane and the like.
Removal of l-chloro-3(di-n-butylamino) propane (VI), which is genotoxic in nature, as per step (b) is carried out by preparing its salt. The preferred salt includes salt of an acid selected from but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid and the like.
In another embodiment, the present invention provides the process of removal of residue of l-chloro-3(di-n-butylamino) propane (VI) by preparing its salt.
In another embodiment, the present invention provides the Dronedarone or its pharmaceutically acceptable salt comprising of l-chloro-3(di-n-butytamino) propane (VI) in concentration of less than 1.8 ppm.

In preferred embodiment, the present invention provides the Dronedarone or its pharmaceutically acceptable salt comprising of l-chloro-3(di-n-butylamino) propane (VI) in concentration of less than 1.4 ppm.
In preferred embodiment, present invention provides the Dronedarone or its pharmaceutically acceptable salt comprising of l-chloro-3(di-n-butylamino) propane (VI) in concentration of less than 1.0 ppm.
In most preferred embodiment, present invention provide Catalytic Hydrogenation of 2-butyl-3-(4-(3-di-n-butyIamino-propoxy) benzoyl) -5-nitro-l-benzofuran (II) to 5-amino-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-2-butyl-l-benzofuran (III) using raney nickel as catalyst
A reaction solvent for the catalytic hydrogenation is not particularly restricted as long as it is applicable to catalytic hydrogenation, but the examples include water, an alcohol, acetic acid, an acetic acid ester, ether, benzene, hexane, toluene, tetrahydrofurane, dioxane, or a mixed solvent thereof. Among them, preferred solvent is, for example, water, an alcohol, an acetic acid ester, toluene, tetrahydrofurane, or a mixed solvent thereof, or the like. Furthermore, preferred solvent is, for example, water, an alcohol, toluene, tetrahydrofurane, or a mixed solvent thereof, or the like, particularly, for example, water, tetrahydrofurane, toluene, methanol, or a mixed solvent thereof. Tetrahydrofurane, hydrated tetrahydrofurane, and a mixed solvent of tetrahydrofurane and toluene are most suitable. When the above described reaction solvents are specifically illustrated, "alcohol" means, for example, methanol, ethanol, isopropyl alcohol, or the like, "acetic acid ester" means, for example, methyl acetate, ethyl acetate, or the like, and "ether" means, for example, diethyl ether, diisopropyl ether, or the like.
The Raney nickel catalyst to be used in the reaction is not particularly restricted to any of the type for ex. example W-4, W-2.
Commercially available Raney nickel catalysts are provided in a hydrated state, and therefore a weight ratio can be usually determined including a weight of water.

The amount of the Raney nickel catalyst to be used in the reaction is not particularly restricted, but the weight ratio is. for example, in a range of 5 to 35 %, preferably in a range of 5 to 25%, and more preferably in a range of 5 to 20 % relative to the compound of the structural formula (II), which can be varied appropriately. The weight ratio is usually around 10%. The amount of the solvent to be used is not particularly restricted, but is, for example, 5 to 30 times, and preferably 5 to 10 times of the volume of the compound of the structural formula (II).
Hydrogen to be used in the reaction is not particularly restricted, but the hydrogen pressure is preferably 1 to 10 Kg/Cm2, 2 to 9 Kg/Cm2, and more preferably 2 to 8 Kg/Cm2.
The reaction can be carried out at a temperature ranging between 4 and 50°C, but preferably at 35°C. or lower, and particularly suitably at 25 to 30°C. A reaction time varies depending on reduction conditions, but usually the reaction often completes within 4 hours.
After completing the catalytic hydrogenation reaction, the catalyst is filtered out from the reaction solution, and the filtrate is concentrated under reduced pressure to get oily residue which can be taken as such for next step without purification.
In subsequent step, 5-amino-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-2-buty]-l-benzofuran of formula (III) undergoes Mesylation. For example compound (III) can be taken in suitable solvent in presence of reagents that include, but not limited to, sodium carbonate, sodium chloride. The Mesylation can be carried out over a period about 1-5 hour, in the range of temperature generally 25-30°C to obtain 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-5-methyl sulfonamido-1-benzofuran of formula (I). The compound of formula (1) can be optionally crystallized by using one or more suitable solvent at ambient temperature. The duration of the mesylation reaction may be from 15 minutes to 5 hours depending on reagents used and measuring end point of reaction by analytical method such as TLC, HPLC and the like.
The suitable solvent used in formation of solution of 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-5-methyl sulfonamido-1-benzofuran base includes but not limited to alcohols (methanol, ethanol, isopropanol, butanol, etc.), ketones ( acetone, methyl isopropyl ketone, etc.), aliphatic ethers (diethyl ether, di tert. butyl ether, etc.), cyclic ethers

( tetrahydrofurane, dioxane, etc.), aliphatic esters (ethyl acetate, etc.), hydrocarbons (toluene, heptane, hexane, etc.), chlorinated solvent (chloroform, dichloromethane, etc.), acetonitrile, polar aprotic solvents (DMF, DMAc, etc.) or mixture there of.
Base is optionally converted into its pharmaceutically acceptable salts by reaction between 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-5-methyl sulfonamido-1-benzofuran in presence of HC1 in ester, alcohol or mixture thereof. And crystallization in ketone solvent ( acetone, methyl isopropyl ketone, etc.)
In further aspect, present invention provides an improved process for the preparation of Dronedarone and its pharmaceutically acceptable salts having low content of the dimesyl impurity (IV), preferably less than 0.12 % more preferably less then 0.1 %.
Another aspect of the present invention provides Dronedarone hydrochloride with an improved yield by changing mole ratio of Methane sulphonyl chloride to keep the dimesyl impurity under limit, which is very difficult to remove from final product.
Methane sulphonyl chloride to be used in the mesylation reaction is not restricted, but the methane sulphonyl chloride is preferably used in a range of 1.2 to 2 mole and more preferably 1.3 tol.6 mole.

In preferred embodiment, Dronedarone (I) is converted to its acid addition salt by reacting it with suitable acid in presence of suitable solvent. Acid used for formation of salt of Dronedarone (I) is selected from hydrochloride and the like. Solvent used in preparation of acid addition salt is selected from toluene, ethyl acetate, ACN, THF and the like or alcohols selected from ethanol, methanol, isopropyl alcohol and the like.
In another embodiment, Crude Dronedarone or its pharmaceutically acceptable salt obtained can optionally be purified by heating the mixture with suitable solvent selected

from ketones including Acetone, methyl ethyl ketone, methyl isobutyl ketone and the like or alcohols including Isopropyl alcohol (IPA), butanol and the like or Toluene, ACN and the like.
In prior art process, after reduction of compound of formula TV, alcohol like methanol need to be removed completely from the reaction mixture before subjecting it to mesylation because methanol forms genotoxic impurity of methane sulfonates in presence of methane sulfonyl chloride. Use of non-polar solvent eliminates such risk and can be used in in-situ process of preparation of Dronedarone (I) or its pharmaceutically acceptable salts.
In yet another embodiment of the present invention there is provided a novel polymorphic form of Dronedarone hydrochloride e.g. amorphous form,
Polymorphism is the occurrence of distinct crystalline forms of a single compound, and has the same. molecular formula, but each polymorph may have distinct physical properties, A single compound may give rise to a variety of polymorphic forms, whose physical properties may be distinct and different, such as different solubility profiles, different melting point temperatures and different x-ray diffraction peaks. Due to differing solubility profiles of polymorphs, the identification of pharmaceutical polymorphs is essential for preparing pharmaceutical dosage forms with predictable solubility profiles. Polymorphic forms can be distinguished from each other by various analytical techniques, for example, by x-ray diffraction and infrared spectroscopic techniques.
Amorphous form of Dronedarone hydrochloride is obtained using different solvents / solvent combinations. In one embodiment of the invention, the reaction is carried out in an organic solvent or water or mixtures thereof. In another embodiment, the organic solvent is an alcohol; In another embodiment, the alcohol is selected from the group consisting of methanol, ethanol and isopropyl alcohol. In a further embodiment, the solvent used is methanol.
The polymorph of Dronedarone Hydrochloride in the present invention can be prepared either by a) dissolving Dronedarone Hydrochloride in a solvent and optionally adding antisolvent after distilling the solvent or without distilling the solvent or b) using spray drying process.

In another embodiment, present invention provides preparation of crystalline Dronedarone hydrochloride from the Amorphous Dronedarone hydrochloride, which comprises the following:
(a) Providing a solution of Dronedarone Hydrochloride in a suitable solution
(b) optionally heating the solution of step (a)
(c) isolating crystalline Dronedarone Hydrochloride.
The suitable solvent used in formation of solution of 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-5-methyl sulfonamido-1-benzofuran of formula (I) includes but not limited to ketones ( acetone, methyl isopropyl ketone, etc.), aliphatic ethers (diethyl ether, di tert, butyl ether, etc.), cyclic ethers ( tetrahydrofurane, dioxane, etc.), aliphatic esters (ethyl acetate, etc.), hydrocarbons (toluene, heptane, hexane, etc,), chlorinated solvent (chloroform, dichloromethane, etc.), acetonitrile, polar aprotic solvents (DMF, DMAc, etc.)
The solution can be optionally heated at a temperature ranging between 15° and 50°C, but preferably at 35°C. Or lower, and particularly suitably at 25 to 30°C. A crystallization time varies depending on conditions, but usually the crystallization often completes within 1 hour.
The different crystallization experiments carried out in the various solvent(s)/solvent combinations as described above yielded different polymorphic forms of Dronedarone hydrochloride, characterized by powder x-ray diffraction pattern, and infra-red spectrum.
While the present invention has been described in term of it's specific embodiments, certain modifications & equivalents will be apparent to scope of the instant invention.
In the following section, embodiments are described by way of examples to illustrate the process of invention; however this does not construe the limit of the present invention. Several variants of these examples would be evident to person's skill in the art.
Example-1 Preparation of 5-amino-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-2-butyl-1-benzofuran (HI):

5.0 gm of 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl) -5-nitro-l-benzofuran was added inlOO.O ml of hydrogenater charged methanol in presence of 2.0 gm of wet Raney nickel. The reaction mixture was stirred at 25-30° C at 8.0 Kg/Cm hydrogen gas pressure for 120 min. Then monitored the reaction mixture by TLC for 2.0 hrs. After completion of reaction, Nickel catalyst filtered through hi-flow bed and washed with 10.0 ml methanol. After that filtrate was distilled under vacuum at 40-45° C to get oily residue, which was taken as such for next stage without purification.
Example -2 Preparation of 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyI)-5-methyl sulfonamido-1-benzofuran hydrochloride (I):
To 1.0 lit. four neck round bottom flask , charged 40.0 gm of 5-amino-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-2-butyl-l-benzofuran, 320.0 ml toluene and 9.74 gm of sodium carbonate and stirred this reaction mass at 25-30°C for 15 min. Then added 11.48 gm of methanesulfonyl chloride in to the reaction mass at 25-30°C within 30 min. Stirred the reaction mass at 25-30°C for 2.0 hrs. After completion the reaction, 320 ml RO water added into reaction mass and stirred the reaction mass for 30 min. The layers were separated. The separated organic layer washed with 200.0 ml saturated sodium chloride solution. Then the organic layer distilled completely under vacuum at 40-45°Cto get oily syrup. Then the residue stripped with 40.0 ml Ethyl acetate. Oily residue was charged with 400.0 ml ethyl acetate in 250.0 ml three neck Round Bottom flask and stirred the reaction mass at 25-30°C for 10 min. Then added 18 ml of IPA.HC1 at 25-30°C up to pH= 2.0 to 3.0.Stirred the reaction mass at 25-30°C for 1.0 hrs. Then the separated solid was filtered and washed with 40 ml ethyl acetate. Dried the wet solid material at 40-45°C in air tray dryer to get Dronedarone hydrochloride and purity is <99%.
Example -3 Purification of crude Dronedarone hydrochloride
In round bottom flask charge crude Dronedarone hydrochloride (100 gm) and acetone
(1200 ml) at 25-30°C. Heat to 50-60 ° C in 20.0 min. and Stir at 50-60 ° C for 5.0 min to get clear solution. Filter the solution over hyflow bed (10 gm hyflow slurry prepared in 20 ml of acetone) and Wash with acetone (25 ml). Cool to 25-30°C and seed with Dronedarone hydrochloride (if solid not obtained) (0.2 gm) and stir at 5-10°C for 2 to 3 hrs. Filter the material and wash the bed with Chilled acetone (25ml, 0-5°C) and Suck dry the material for 1 hr. Dry the material in vacuum oven under vacuum at 30- 35°C for 6 hrs to get acetone below 3000 ppm by residual solvent test and purity is >99.5 %..

Example-4 Preparation of Amorphous Form of Dronedarone Hydrochloride
Charge Dronedarone hydrochloride (5.0 g) and Methanol (25.0 ml) at 25-30°C. and stir for
15.0 min to get clear solution. Filter the solution over hyflow bed (5.0 g of Hyfiow is prepared in 30.0 ml of Methanol). Distill out Methanol completely under vacuum at 25-35°C and keep the mass under vacuum at 40-45°C for 30.0 min to get amorphous Dronedarone hydrochloride and purity is >99.5 %.
Example-5 Preparation of crystalline form of Dronedarone Hydrochloride from amorphous Dronedarone hydrochloride
Mix amorphous Dronedarone hydrochloride (1.0 g) and Ethylacetate (10.0 ml) at 25-30°C.
and stir for 1 hour. Filter the material and wash the bed with ethylacetate (5ml) and Suck dry the material. Dry the material in vacuum oven under vacuum at 40- 45°C hrs to get crystalline Dronedarone hydrochloride
Example 6 Preparation of 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl) -5-nitro-1-benzofuran (compound of formula II)
100 g of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran is charged with 1000ml of toluene and 61.09g of K2C03 at room temperature followed by addition of 60.6g of 1-chloro-3(di-n-butylamino)propane. Reaction mixture is heated to reflux using Dean-stark apparatus for 8 hours. After cooling the reaction mixture to room temperature, 200 ml of water is added. Combined aqueous layer is extracted using 100ml of toluene. Organic layer is washed with 400 ml of 5% NaOH followed by washing with 1000 ml of 8% HCI solution two times and then with water which is treated by 10 g activated carbon. Reaction mixture is filtered through hyflo-bed and washed with toluene to obtain 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl) -5-nitro-l-benzofuran.
Example7 Preparation of 5-amino-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-2-butyl-1-benzofuran (compound III)
2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl) -5-nitro-l-benzofuran (as obtained from example 6) is charged with 100ml of toluene, 150ml of water and 45g of Raney Nickel at room temperature. Reaction mixture is stirred at 4.0-6.0 kg/cm2 H2 gas pressure for 3 hours. Reaction mixture is filtered and washed 2 times with toluene followed by washing with water. Separated organic layer is charged with 25g of sodium sulfate and washed with toluene to give 2-n-butyl-3-[4(3-dibutylaminopropoxy)benzoyl]-5-aminobenzofuran.

Example 8 Preparation of 2-butyI-3-(4-(3-di-n-burylamino-propoxy) benzoyl)-5-methyl sulfonamido-l-benzofuran (I)
2-n-butyI-3-[4(3-dibutylaminopropoxy)benzoyl]-5-aminobenzofuran as obtained from example 7 is charged with 43.73g of Na2C03 to the RBF at room temperature. Reaction mixture is cooled and added 45.57g of methane sulfonyl chloride slowly at 10-20 °C, followed by stirring for two hours maintaining the temperature. Distilled water is added to the mixture to separate the layers. Organic layer is washed with 200ml of toluene and then by 300ml of 15% NaCI solution. Organic layer is recovered under vacuum at 40-50 °C to form 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-5-methyl sulfonamido-1-benzofuran (I).
Example 9 In-situ synthesis of Dronedarone
100 g of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran is charged with 1000ml of toluene and 61.09g of K2C03 at room temperature followed by addition of 60.6g of 1-chloro-3(di-n-butylamino)propane. Reaction mixture is heated to reflux using Dean-stark apparatus for 8 hours. After cooling the reaction mixture to room temperature, 200 ml of water is added. Organic layer is washed with 400 ml of 5% NaOH followed by washing with 1000 ml of 8% HC1 solution two times and then with water which is treated by 10g activated carbon. After filtration, Mother liquor containing toluene is charged with 150ml of water and 45g of Raney Nickel at room temperature. Reaction mixture is stirred at 4.0-6.0 kg/cm2 H2 gas pressure for 3 hours. Reaction mixture is filtered and washed 2 times with toluene followed by washing with water. Separated organic layer is charged with 25g of sodium sulfate and washed with toluene. Mother liquor is charged with 43.73g of Na2CO3 to the RBF at room temperature. Reaction mixture is cooled and added 45.57g of methane sulfonyl chloride slowly at 10-20 °C, followed by stirring for two hours maintaining the temperature. Distilled water is added to the mixture to separate the layers. Organic layer is washed with 200ml of toluene and then by 300ml of 5% NaHCO3 solution followed by 15% NaCI solution (300ml). Organic layer is recovered under vacuum at 40-50 °C to give Dronedarone (I).
Example 10 Preparation of 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-5-methyl sulfonamido-l-benzofuran HC1
1500 ml of ethyl acetate is added to the 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-5-methyl sulfonamido-1-benzofuran, as obtained in example 8 or 9, at room

temperature, followed by addition of 80 ml of IPA-HC1. Stirring the reaction mixture for 3 hours at room temperature, followed by washing with 200ml of ethyl acetate and drying at 40-50 °C at vacuum gives HC1 salt of 2-buty!-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-5-methyl sulfonamido-1 -benzofuran.
Example 11 In-siru synthesis of Dronedarone (1) hydrochloride
100 g of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran is charged with 1000ml of toluene and 61.09g of K2CO3 at room temperature followed by addition of 60.6g of 1-chloro-3(di-n-butylamino)propane. Reaction mixture is heated to reflux using Dean-stark apparatus for 8 hours. After cooling the reaction mixture to room temperature, 200 ml of water is added. Organic layer is washed with 400 ml of 5% NaOH followed by washing with 1000 ml of 8% HC1 solution two times and then with water which is treated by 10g activated carbon. After filtration, Mother liquor containing toluene is charged with 150ml of water and 45g of Raney Nickel at room temperature. Reaction mixture is stirred at 4.0-6.0 kg/cm2 H2 gas pressure for 3 hours. Reaction mixture is filtered and washed 2 times with toluene followed by washing with water. Separated organic layer is charged with 25g of sodium sulfate and washed with toluene. Mother liquor is charged with 43.73g of Na2CO3 to the RBF at room temperature. Reaction mixture is cooled and added 45.57g of methane sulfonyl chloride slowly at 10-20 °C, followed by stirring for two hours maintaining the temperature. Distilled water is added to the mixture to separate the layers. Organic layer is washed with 200ml of toluene and then by 300ml of 5% NaHCO3 solution followed by 15% NaCl solution (300ml). Separated organic layer was dried over Na2SO4 and then filtered and washed with Toluene (100ml). TPA-HC1 (80ml)) was added to the Toluene layer at room temperature. Reaction mass was stirred for 3.0 hrs. Solid is filtered and washed with toluene (100ml) and dried under vacuum at 40-45°C to get Dronedarone Hydrochloride (Crude) (Purity: 99.1-99.3%)

Figure-1


Figure-2:


Figure-3:


We Claim:
1. A process for the preparation of Dronedarone of formula (1) or a pharmaceutically acceptable salt thereof which comprises :
a) condensation of 2-n-buty]-3-(4-hydroxybenzoyl)-5-nitrobenzofuran(V) with l-chloro-3(di-n-butylamino)propane(VI). in presence of organic solvent to give 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl) -5-nitro-l-benzofuran(II),
b) removel of l-chloro-3(di-n-butylamino) propane(VI).
c) catalytic hydrogenation of 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl) -5-nitro-l-benzofuran of formula (II) to 5-amino-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-2-butyl-l-benzofuran of formula (III) using raney nickel catalyst;
d) mesylation of 5-amino-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-2-butyl-1-benzofuran of formula (III), in presence of methane sulfonyl chloride with organic solvent and alkaline earth metal carbonate to obtain to 2-butyl-3-(4-(3-di-n-butylamino-propoxy) benzoyl)-5 -methyl sulfonamide-1-benzofuran of formula (I),
e) formation of acid-addition salt of Compound of formula (I),
f) optional purification of compound of formula (I) or its pharmaceutically acceptable salt.
Characterized in that the dronedarone so obtained has less then 0.1 % of the dimesyl impurity(IV) and having content of l-chloro-3(di-n-butylamino)propane(III) less than 1.8 ppm,
2. The process for the preparation of Dronedarone or its pharmaceutically acceptable salt according to claim 1, wherein the solvent system is polar or non-polar.
3. The process for the preparation of Dronedarone or its pharmaceutically acceptable salt according to claim 1, wherein the process is carried out in a single solvent.
4. The process of claim 1, wherein the organic solvent is methanol or Toluene.
5. The process of claim 1 step (b), wherein the removal of l-chloro-3(di-n-butylamino)

propane (VI) is carried out by preparing salt and such salt includes but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid.
6. Amorphous Dronedarone Hydrochloride.
7. A process for the preparation of amorphous polymorphic forms of Dronedarone hydrochloride, which comprises: a) dissolving Dronedarone Hydrochloride in a alcoholic solvent and optionally adding antisolvent after distilling the solvent or without distilling the solvent or b) using spray drying process.
8. A process for the preparation of crystalline Form of Dronedarone Hydrochloride,
comprising:
(a) providing a solution any form of Dronedarone Hydrochloride in a suitable solution
(b) optionally heating the solution of step(a)
(c) isolating crystalline Dronedarone Hydrochloride.
9. The process of claim 8, wherein the organic solvent is selected from the group includes
but not limited to ketones, aliphatic ethers, cyclic ethers, aliphatic esters, hydrocarbons, chlorinated solvent, acetonitrile, polar aprotic solvents.
10. A process for the preparation of Dronedarone substantially as herein described,
particularly with reference to the foregoing examples.