FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patent Rules, 2006
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. TITLE OF THE INVENTION: "An improved process for preparation of Dronedarone intermediate, Dronedarone and pharmaceutically acceptable salts thereof "
2. Applicant

(a) NAME: Arch Pharmalabs Limited
(b) NATIONALITY: Indian
(c) ADDRESS: 541-A, Arch House, Marol-Maroshi Road, Marol,
Andheri (East), Mumbai - 400 059, India
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

TITLE
An improved process for preparation of Dronedarone intermediate, Dronedarone and pharmaceutically acceptable salts thereof.
FIELD OF TECHNOLOGY:
The present invention relates to an efficient, economic, and in-situ process using single solvent also referred as solo solvent starting from easily available key raw materials rather than using the advanced intermediates for the preparation of substantially pure Dronedarone base of formula I A and its salt of formula I. Solo solvent used for the process plays a vital role in carrying the reaction directly to Dronedarone HO salt without the formation of base avoiding adding HC1 externally as a reactant or to Dronedarone base which can be isolated as a product or in-situ converted into the corresponding salt by adding the desired acid into the reaction mixture. The solo solvent used for the preparation of Dronedarone intermediate, Dronedarone base and Dronedarone HC1 is characterized by its protic or non protic nature, polarity and solubility characteristics.
The key features of the instant invention are; that the process uses a single solvent, does not comprise the use of advanced intermediate as a starting material and it neither requires removal of solvent that is used for the entire process at any intermediate stage nor require the purification at any intermediate stage, which not only avoids the isolation of any intermediate but also minimizes the unit operations at

plant scale that reduces handling loss thereby resulting in to higher yield and productivity. More over, by choosing the right solo solvent. Nitrobenzofuran of formula II is directly converted into Dronedarone intermediate of formula IV, dronedarone base of formula IA and Dronedarone hydrochloride of formula I; wherein X is CI thereby reducing the processing steps. In case wherein the solo solvent halts reaction at Dronedarone base by not using HC1 generated as a byproduct to directly prepare Dronedarone HC1, in such cases also there are options either to isolate Dronedarone base or without isolating base convert it in-situ into in the same solvent into corresponding acid by adding the desired acid into the reaction mixture.

BACKGROUND OF THE INVENTION:
Dronedarone coded as (SR33589) chemically known as 2-n-butyl-3-[4-
(3-di-n-butylaminopropoxy)benzoyl] 5-methanesulfonamido benzofuran
hydrochloride is a drug mainly used for the indication of cardiac
arrhythmias. Dronedarone hydrochloride is marketed under the brand
name MULTAQ™ in the US.
There are various chemical methods disclosed therein the prior art for
the synthesis of Dronedarone and its pharmaceutically acceptable salts as
well as for the various intermediates thereof.
Process for preparation of Dronedarone and its hydrochloride salt was
first disclosed in US 5,223,510 hereinafter referred as '510. The process
disclosed in '510 patent is illustrated below in scheme 1:

The said process comprises;

a) contacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran with 1-chloro-3-di-tt-butylaminopropane in presence of potassium carbonate to produce 2-w-butyl-3-[4-[3-(di-/7-butylamino)propoxy]benzoyl-5-nitrobenzofuran;
b) nitrobenzofuran derivative is then hydrogenated in presence of platinum oxide to produce 5-amino-2-n-butyl-3-[4-[3-(di-/7-butylamino) propoxy]benzoyl] benzofuran;
c) aminobenzofuran derivative is then reacted with methanesulfonyl chloride in presence of triethylamine to produce crude Dronedarone base isolated as oily residue;
d) this oily residue is then further purified by column chromatography
to produce pure Dronedarone base;
e) Dronedarone base is then converted to its hydrochloride salt by
addition of hydrochloric acid using ether as a solvent.
The disadvantages associated with process mentioned hereinabove comprises the multiple number of individual steps, isolation of intermediates at the various stages, use of multiple solvents, use of column chromatographic purification thereby limiting at plant scale. Moreover, all the intermediates are isolated as liquids that require solvent removal first by distilling and finally by degassing. These operations are not only time consuming but also contributes for extra energy consumption, thereby increasing the overheads making it noneconomical and not feasible at plant scale.

Furthermore, mesylation step comprising reaction of aminobenzofuran derivative with methanesulfonyl chloride in presence of triethylamine to obtain Dronedarone base results in the formation product containing disulfonamide impurity of formula X which is difficult to be removed. Therefore, column chromatography becomes a necessary tool for purification and is inevitable for the process disclosed therein in '510. Furthermore, inspite of column chromatographic purification the purity of Dronedarone base obtained based on the process disclosed therein '510 is only 96% by HPLC. The base so obtained is then converted into Dronedarone hydrochloride.

WO 2011/153923 (hereinafter referred as '923) discloses a process for the preparation of Dronedarone hydrochloride as illustrated below in scheme 2:
The said process disclosed therein '923 comprises:
Scheme 2


reaction of penultimate advanced intermediate aminobenzofuran
derivative of formula IV with methanesulfonyl chloride using
acetonitrile as a solvent to produce crude Dronedarone hydrochloride
with 89% yield and 99.5% of HPLC purity.
This crude salt is then further purified by crystallization using acetone
and water to produce pure Dronedarone hydrochloride with 83% yield
and 99.8% purity.'923 does not discloses the process for preparing
compound of formula IV which is a penultimate compound for the
preparation of Dronedarone molecule and requires only a single reaction
step.
WO 2012/004658 (hereinafter referred as '658) discloses the process for
preparation of Dronedarone hydrochloride as illustrated below in scheme
3:

The process disclosed in '658 comprises:
a) hydrogenation of advanced intermediate nitrobenzofuran derivative of formula III using transfer hydrogenation reagent ammonium formate in presence of palladium catalyst using methanol as a solvent to produce aminobenzofuran derivative of formula IV as oily mass;

b) reacting aminobenzofuran derivative of formula IV with methanesulfonyl chloride in presence of water to produce Dronedarone hydrochloride with purity 99%. However, it has been observed by the inventors of the instant present invention that the reaction of mesylation when conducted in water does not go to the completion even after prolonged time leaving behind unreacted staring material as an impurity and is validated by the chromatograph illustrated herein below in figure-I. Moreover, '658 does not disclose any process for the preparation of compound of formula III.

WO 2012/007959 (hereinafter referred as '959) discloses a process for preparation of Dronedarone hydrochloride as illustrated below in scheme 4:


The process disclosed in scheme 4 comprises:.
a) reacting nitrobenzofuran of formula II with l-chloro-3-di-w-
butylaminopropane in presence of potassium carbonate using methyl
ethyl ketone as solvent to produce 2-butyl-3-[4-[3-(di-n-butylamino)
propoxy]benzoyl]-5-nitrobenzofuran of formula III as a pale brown
thick oil
b) hydrogenating compound of formula III by hydrogen in presence of palladium carbon using ethyl acetate as solvent to produce crude aminobenzofuran derivative of formula IV having purity 96.76%;
c) compound of formula IV is then purified by preparing its oxalate salt and again converting the oxalate salt back in to base by using aqueous ammonia. Purity after this purification is enhanced to 98.34%;
d) mesylation of 98% pure compound of formula IV is carried out using methanesulfonyl chloride and triethylamine using dichloroethane as solvent to produce Dronedarone base of 93.39% purity having 4.57% disulfonamide impurity;

e) disulfonamide impurity is then eliminated by reacting dronedarone base with sodium hydroxide in presence of ethanol. At this stage the purity of Dronedarone base is enhanced to 97.67%;
f) dronedarone base is further purified using hexane to produce 98.15% of Dronedarone base as a solid;
g) dronedarone base obtained in step f is contacted with hydrochloric
acid in presence of acetone to obtain dronedarone hydrochloride with
99% purity.
The disadvantages associated with the process disclosed in '959 are:
1. Multiple numbers of processing steps.
2. Isolation of intermediates at the various stages.
3. Use of multiple solvents as for each step a new solvent system is used.
4. Additional purification step for each intermediate.
5. Additional operational steps viz preparation of oxalate salt of amino compound is used as a purification tool and later after purification hydrolysis of oxalate salt to obtain corresponding free base.
6. Despite purification by additional operational steps formation of 4.57% disulfonamide impurity in the subsequent operational step of mesylation.
7. Use of hexane as purification solvent for Dronedarone base on plant scale is not favorable owing to its highly inflammable nature and a risk of electrostatic charge initiated fire.

WO 2012/010788 (hereinafter referred as '788) discloses a process for the preparation of Dronedarone hydrochloride as illustrated below in scheme 5:

The process disclosed in the '788 patent describes preparation of Dronedarone hydrochloride without isolating the intermediate. In particular the '788 discloses mode of reduction for the preparation of amino compound of formula IV by the catalytic transfer hydrogenation of advanced intermediate nitro compound of formula III using ethereal solvents replacing alcohol as reported in prior art, which is then further taken for the mesylation. However only one example disclosed in the said application uses multiple solvents i.e. methyl tertiary butyl ether, tetrahydrofuran and IP A. Although the said patent application mentions about ether as solo solvent or mixture thereof, but in fact it has been observed by the inventors of the present invention that in this case the polarity of the ether plays a vital role in carrying out the reaction. It has been observed that when the set of the said reaction is conducted in methyl tert. butyl ether as solo solvent, it does not go to the completion and leaves about 54% of unreacted starting material of formula III as confirmed by the chromatograph given herein below as figure II:


FIGURE II
But when the same reaction is carried out in 50% mixture of tetrahydrofuran and methyl tertiary butyl ether as a means for increasing the polarity of the reaction mass, the reaction gets completed as indicated in the chromatograph herein below as figure III. This indicates that the non polar ethereal solvent cannot be used as solo solvent. Moreover, '788 discloses the use of advanced intermediate of formula III as starting material without any indication for its preparation and the said process forms Dronedarone base as an intermediate which is further subjected to distillation of ethereal solvent mixture (THF-MTBE) followed by subsequent addition of isopropanol and again distillation of IP A for stripping the solvent and the Dronedarone hydrochloride is prepared by addition of isopropanol and hydrochloric acid.


FIGURE III
WO2012/052448 (hereinafter referred as '448) discloses a process for
the preparation of dronedarone base of formula IA comprising
contacting 2-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]-5-
nitrobenzofuran of formula III with mesylchloride in non polar aprotic solvent in absence of a base at reflux for at least three hours.

Drawback of the said reaction is insufficiency of the polarity of the solvent and the mesylation reaction requires high energy content as the said reaction is conducted at a temperature of 110°C (reflux temperature of toluene). In spite of using the non polar aprotic solvent and no base; final product is Dronedarone base and not the Dronedarone hydrochloride as expected. The reason for this is the escape of hydrogen

chloride at the temperature of 110°C making unavailable for the interaction with Dronedarone base.
Processes disclosed therein the prior art for the preparation of Dronedarone and salt thereof comprises multiple steps using multiple solvents, the intermediates formed are needed to be isolated at various steps and purified to get the desired purity of the final product. Isolation of intermediates at various stages makes the process tedious, time consuming, increasing the number of unit operations that leads to lesser yield and increase in over head costs making the process for preparation of Dronedarone and Dronedarone hydrochloride industrially not viable and uneconomical.
This necessitates the development of an improved process which minimizes the unit operations, provides better yield and higher purity of product, minimizes effluent load and solvent usage in comparison with the processes disclosed therein in the prior art. Hence there is a dire need to develop an efficient and economical process suitable at industrial scale.
Inventors of the present invention disclose herein a process for the preparation of substantially pure Dronedarone intermediate, Dronedarone base and Dronedarone hydrochloride comprising using cheaply available key raw materials and a solo solvent without isolating any intermediate. The proposed process avoids unit operations like distillation/ removal of solvent at every stage, isolation and purifications

of the intermediates thereby making the process simpler, economical and user friendly at plant scale.
Technical problems associated with the prior art processes are mainly the use of multiple solvents, isolation and purification of the intermediates, purification technique like column chromatography, isolation of intermediates as liquid oily compounds incorporating operations like distillation and degassing of solvent, and use of advanced intermediate as key raw material for the formation of dronedarone hydrochloride.
Solution to the technical problems associated with prior arts is the object of the present invention. Keeping the said object in view, the present invention provides an industrially viable and economical process thereby eliminating all the above-mentioned shortcomings associated with the processes disclosed therein the prior art for the preparation of dronedarone base and salts thereof.
Disclosed herein is an industrially viable, safe and economical process for the preparation of substantially pure Dronedarone intermediate of formula IV, Dronedarone base of formula IA and Dronedarone acid salt of formula I in good yield; bridging all the shortcomings of the prior art comprising use of cheap and readily available key raw materials rather than using advanced key intermediates, using single also referred as solo solvent selected from a group of solvents suitable for all the reaction steps without isolating and purifying any intermediate. The key features of the said group of solvents are their physical parameters like protic or

aprotic nature, polarity, solubility and reflux temperature suitable for all the reactants used in the various reaction steps to ensure clean reactions at all the intermediate stages. During these reactions the solo solvent that is selected need not to be removed by distillation after the completion of the reaction and resulting reaction mass of the preceeding reaction step can be used as such for the next reaction step. This results in minimization of many unit operations like distillation, degassing, isolation, and purification and the like at all the intermediate stages thereby making the process user friendly and economical. Selectivity of the. solo solvent for the preparation of Dronedarone intermediate of formula IV, Dronedarone base of formula IA and Dronedarone acid addition salt of formula I is dependent upon physical parameters like protic or aprotic nature of solvent, polarity and solubility which decides the solvency factor of intermediates and accordingly further reaction steps. For example solo solvent for the preparation of Dronedarone hydrochloride without the formation and isolation of Dronedarone base; it has been found that the solvent has to be aprotic and polar. Examples of the solvents are ethyl acetate, 1,2-dimethoxy ethane, methyl ethyl ketone and the like. When aprotic solvent is used as a solo solvent then for mesylation step.use of base is optional depending upon the polarity of the solvent. When polar aprotic solvent is used as a solo solvent then it is not necessary to use base for the said mesylation reaction step and the reaction gets completed at ambient temperature. HC1 generated as a byproduct is instantly captured by the Dronedarone

base to directly form Dronedarone HC1 salt. In case of non polar aprotic solvent owing to solvency factor it is desirable to use base for the mesylation step, even at elevated temperature. As disclosed in WO2012/052448 wherein reaction comprising toluene as a non polar solvent without base proceeds at high reflux temperature for longer duration resulting into Dronedarone base and not its HC1 salt. Inventors of the present invention have observed that when protic solvent is used then it is necessary to use base for the mesylation reaction step and the reaction has to be carried out at elevated temperature and the product obtained is Dronedarone base of formula IA and not its HC1 salt. The possible reason is that the HC1 produced as a byproduct is captured by the base used as an acid scavenger and is not available to Dronedarone base to form HC1 salt. In such case the Dronedarone base is isolated as a product and converted into corresponding inorganic or organic salt by reacting with respective acid optionally in-situ without isolating base.
OBJECT AND SUMMARY OF THE INVENTION:
First aspect of the present invention is to provide an improved in-situ process for the preparation of Dronedarone intermediate of formula IV, Dronedarone base of formula IA and Dronedarone acid addition salt of formula I comprising using easily available key raw materials, a set of solo solvents to obtain the desired product in a higher yield and better

purity and overcoming all the shortcomings of prior arts as described
hereinabove.
Second aspect of the invention is to provide an improved, economical
and plant viable in-situ process for the preparation of Dronedarone
hydrochloride without isolating any intermediate comprising using polar
aprotic solvent as solo solvent comprising steps of:
a) contacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of
formula II with l-chloro-3-di-n-butylaminopropane in the presence of
a base to obtain a reaction mixture containing advanced intermediate
2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]-5-
nitrobenzofuran of formula III;
b) reaction mixture containing compound of formula III from step a is subjected to reduction to obtain a reaction mixture containing advanced intermediate 5-amino-2-n-buty 1-3-[4-[3-(di-n-butylamino) propoxy]benzoyl] benzofuran of formula IV;
c) reaction mixture containing compound of formula IV from step b is contacted with metanesulfonyl chloride optionally in the presence of a base to obtain Dronedarone hydrochloride of formula I as illustrated herein below:


Third aspect of the invention is to provide an improved, economical and plant viable in-situ process for the preparation of Dronedarone base comprising using readily available key raw materials and polar protic solo solvent comprising no isolation and purification of the intermediates at any stage of the process comprising steps of:
a) contacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of
formula II with l-chloro-3-di-n-butylaminopropane using a solo
solvent in the presence of a base to obtain a reaction mixture
containing 2-n-butyl-3-[4-[3-(di-n.-butylamino)propoxy]benzoyl]-5-
nitrobenzofuran of formula III;
b) reaction mixture containing compound of formula III from step a is
subjected to reduction to obtain a reaction mixture containing 5-
amino-2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]
benzofuran of formula IV;
c) reaction mixture containing compound of formula IV from step b is
further contacted with metanesulfonyl chloride in the presence of a
base to obtain Dronedarone base of formula IA as illustrated
hereinbelow:


In accordance with this embodiment the Dronedarone free base is optionally isolated at step c or reaction mass containing Dronedarone base of formula IA which is further contacted with an organic or inorganic acid to obtain corresponding pharmaceutically acceptable salt of Dronedarone of formula I.

Forth aspect of the present invention is to provide an in-situ process for
the preparation of an intermediate 5-amino-2-n-butyl-3-[4-[3-(di-77-
butylamino)propoxy] benzoyljbenzofuran of formula IV using key raw
materials and set of solo solvents characterized by its protic or aprotic
nature and polarity characteristics comprising steps of:
a) contacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of
formula II with l-chloro-3-di-n-butylaminopropane using a solo
solvent in the presence of a base to obtain 2-n-butyl-3-[4-[3-(di-n-
. butylamino)propoxy]benzoyl]-5-nitrobenzofuran of formula III;

b) reaction mixture containing compound of formula III from step a is subjected to reduction to obtain 5-amino-2-/2-butyl-3-[4-[3-(di-n-butylamino) propoxy] benzoyl]benzofuran of formula IV.
The process is illustrated hereinbelow:

In accordance with this embodiment the intermediate of formula IV is optionally isolated at step b.
Fifth aspect of the present invention is to use solo solvent through out the entire process that need not be distilled off during the intermediate stages thereby reducing the unit operations at plant scale.
Sixth aspect of the invention is to avoid the isolation of intermediates and further purification as additional operational steps thereof thereby again reducing the unit operations.
Seventh aspect of the invention is to use easily and cheaply available raw materials rather than using advanced intermediate as starting materials.

ADVANTAGES OF THE PRESENT INVENTION:
1. Use of cheap and easily available key raw materials rather than using advanced intermediate as starting material.
2. Use of solo solvent throughout the process, which need not be removed during the entire process till the isolation of desired product.
3. Elimination of unit operations like distillation, degassing of solvent at intermediate stages, isolation and purification at intermediate stages and in-situ preparation of substantially pure dronedarone hydrochloride directly from compound of formula II without isolation of dronedarone base as intermediate thereby making the process more economical, operational friendly on plant scale and the product obtained is on good yield and is substantially pure.
4. Elimination of unit operations like distillation, degassing of solvent at intermediate stages, isolation and purification at intermediate stages and in-situ preparation of dronedarone base directly from compound of formula II.
5. Elimination of unit operations like distillation, degassing of solvent at intermediate stages, isolation and purification at intermediate stages and in-situ preparation of amino compound of formula IV directly from compound of formula II.

6. Clean reaction at every intermediate stage as indicated by the chromatographs under preferred embodiments, thereby resulting into substantially pure final product.
SUMMARY OF THE INVENTION:
The process disclosed herein is an efficient, economical and industrially viable eco friendly process for the preparation of substantially pure Dronedarone intermediates, Dronedarone base and Dronedarone acid addition salt comprising use of cheap and easily available key raw materials and solo solvent for all operational steps that need not to be removed at any stage throughout the process till the isolation of desired product.
Inventors of the present invention have successfully identified a set of solvents which can be used solo for all the irrational steps without isolating intermediate at any stage and also without any need for removal and recharging of solvent at operational stage for the preparation of Dronedarone intermediate, Dronedarone base or Dronedarone salt from readily available key raw materials rather than using the advanced key intermediates. The key features of the said group of solvents are their physical parameters like protic/aprotic characteristics, polarity, solubility and reflux temperature suitable for all the reactants used in the various reaction steps to ensure clean reactions at all the intermediate stages. During these reactions the solo solvent that is selected need not to be

removed by distillation after the completion of the reaction and resulting reaction mixture of preceeding reaction step can be used as such for the next reaction step. This results in minimization of many unit operations like distillation, degassing, isolation, and purification etc. at all the intermediate stages thereby making the process user friendly and economical and in-situ process.
DETAILED DESCRIPTION OF THE INVENTION:
The words contacting or contacted used hereinabove and hereinbelow mean reacting, mixing, heating, refluxing, treating, stirring, condensing and the like.
The invention will now be described in detail in connection with certain general and preferred embodiments, so that various aspects thereof may be more fully understood and appreciated without limiting the scope of the invention.
In a general embodiment of the present invention, there is provided an in-situ process using cheap and readily available key raw materials and solo solvent for the preparation of Dronedarone hydrochloride comprising the steps of:
a) contacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of formula II with l-chloro-3-di-n-butylaminopropane in a solo solvent in the presence of a base to obtain 2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]-5-nitrobenzofuran of formula III;

b) reaction mixture containing compound of formula III from step a is reduced to obtain 5-amino-2-n-butyl-3-[4-[3-(di-n-butylamino) propoxy]benzoyl]benzofuran of formula IV;
c) reaction mixture containing compound of formula IV from step b is further contacted with methanesulfonyl chloride optionally in the presence of a base to obtain Dronedarone hydrochloride of formula I; wherein X is CI.
The said process from the general embodiment of the present invention is illustrated in the following scheme 6.

The reaction sequence in the manufacturing process of the present invention involves condensation, reduction, mesylation, and purification, wherein the entire process is carried out without removing the solvent at any intermediate stage and hence no isolation of the intermediates at each stage, thus making the overall process facile and convenient at plant scale.
The invention provide the Dronedarone hydrochloride of pharmaceutical purity after recrystallization of crude dronedarone hydrochloride and the present process does not require the purification of Dronedarone base for

the removal of disulfonamide impurity of formula X by column
chromatography or any purification at intermediate stages.
The invention also eliminate the formation of disulfonamide impurity of
formula X, which gets inevitably formed during the manufacture of
Dronedarone during mesylation reaction step based on processes
disclosed therein in the prior art and thereby avoiding the purification by
column chromatography.
The key raw material of formula II used as starting material of said
process for the present invention is commercially available or prepared
according the process well known in the prior art.
The suitable solo solvent used in the entire said process for the
preparation of Dronedarone hydrochloride salt of the present invention is
an aprotic polar solvent selected from the group comprising esters,
ethers, ketones and the like.
Ester solvent is selected from the group comprising ethyl acetate, methyl
acetate, propyl acetate, butyl acetate and the like. Preferably ester
solvent is ethyl acetate.
Ether solvent is selected from the group comprising tetrahydrofuran,
1,2-dimethoxy ethane, methyl tertiary butylether and the like. Preferably
ether solvent is 1,2-dimethoxyethane.
ketonic solvent is selected from the group comprising methyl ethyl
ketone, acetone, methyl isobutyl ketone and the like. Preferably ketonic
solvent is methyl ethyl ketone.

Base used for step a comprising contacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of formula II with l-chloro-3-di-n-butylaminopropane using a solo solvent is selected from the group of inorganic base and organic bases preferably inorganic base. The inorganic base is selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal hydroxides. Preferably base is potassium carbonate.
Reduction of compound of formula III to obtain compound of formula IV as disclosed hereinabove in step b comprises catalytic hydrogenation or by catalytic transfer hydrogenation preferably catalytic hydrogenation.
The catalyst is selected from the list but not limited to platinum oxide, palladium on carbon, Raney Nickel, Zinc dust, mixture of Zinc and hydrochloric acid, stannous chloride, mixture of tin and hydrochloric acid, rhodium and platinum. Preferably catalyst is noble metal catalyst. The hydrogen transfer reagent is selected from the list but not limited to hydrogen gas, aliphatic alcohol, alkali metal and amine esters of fatty acids for example sodium acetate, ammonium formate, sodium formate and potassium formate or mixture thereof.
The suitable metal catalyst for the heterogeneous catalytic hydrogenation of compound of formula III is selected from the list but not limited to platinum oxide, palladium oxide, palladium on carbon, raney nickel. Preferably hydrogenation catalyst selected is palladium on carbon.

The hydrogenation reaction is carried out at a hydrogen pressure in the range of about 2-10 Kg/cm2 preferably at about 3-5 Kg/cm2 at a temperature in the range of about 20-100°C preferably at about 50-55°C.
Base used optionally for step c to obtain Dronedarone hydrochloride of formula I; wherein X is CI is selected from organic bases. Preferably base is aromatic organic base selected from the group comprising pyridine, imidazole, N,N-dimethylaniline and the like. Optionally the Dronedarone hydrochloride crude having the purity of about 98% is further purified from organic solvents. Preferably solvent is selected from alcoholic solvents. More preferably solvent is isopropanol. The Dronedarone hydrochloride obtained after purification has HPLC purity about > 99.5%.
In another general embodiment disclosed herein is the process for the preparation of Dronedarone base and pharmaceutically acceptable salt thereof comprising the steps of;
a) contacting 2-/7-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of
formula II with l-chloro-3-di-«-butylaminopropane in a solo solvent
in the presence of a base to obtain reaction mixture containing 2-n-
butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]-5-nitrobenzofuran
of formula III;
b) reaction mixture containing compound of formula III from step a is
reduced to obtain reaction mixture containing 5-amino-2-7i-butyl-3-
[4-[3-(di-n-butylamino)propoxy]benzoyl]benzofuran of formula IV;

c) reaction mixture containing compound of formula IV from step b is further contacted with methanesulfonyl chloride in the presence of a base to obtain Dronedarone base of formula IA;
d) reaction mixture containing Dronedarone base of formula IA is optionally contacted with an organic or inorganic acid to obtain corresponding pharmaceutically acceptable salt of Dronedarone of formula I.
In accordance with this embodiment the Dronedarone free base is optionally isolated in step c.
The solo solvent is selected from protic solvents like aliphatic alcohols comprising ethanol, methanol, propanol, butanol, isopropanol and the like. Preferably solvent is isopropanol.
The base for step a, reduction catalysts for step b and base for step c are same as disclosed hereinabove in earlier embodiment. During mesylation in reaction step c the Dronedarone base formed is either isolated as an oily liquid product or is in-situ converted into corresponding pharmaceutically acceptable salt by adding acid solution in the same solvent into the reaction mixture and after standard work up isolating the corresponding salt. The reaction scheme is illustrated in scheme-7


Wherein X is the acid moiety
The said acid comprises inorganic acid selected from hydrochloric acid,
hydrobromic acid, phosphoric acid and the like. Organic acid is selected
from the group comprising fumaric acid, malic acid, tartaric acid, oxalic
acid, salicylic acid and the like.
Preferably the pharmaceutically acceptable salt is hydrochloride salt.
In another general embodiment disclosed herein is a process for the preparation of Dronedarone intermediate of formula IV directly from compound of formula II comprising the steps of:
a) contacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of
formula II with l-chloro-3-di-n-butylaminopropane using solo
solvent in the presence of a base to obtain reaction mixture containing
2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]-5-
nitrobenzofuran of formula III;
b) reaction mixture containing compound of formula III from step a is
reduced to obtain reaction mass containing 5-amino-2-n-butyl-3-[4-
[3-(di-n-butylamino)propoxy]benzoyl]benzofuran of formula IV.


The solo solvent used is selected from the group of aprotic and protic
solvents described hereinabove for preceeding embodiments.
The reduction for step b is performed either by catalytic hydrogenation
reaction or transfer hydrogen reaction as described in preceeding
embodiments.
In accordance with embodiment the intermediate 5-amino-2-n-butyl-3-
[4-[3-(di-n-butylamino)propoxy]benzoyl]benzofuran of formula IV is
isolated from the reaction mixture of step b.
In a preferred embodiment of the present invention, there is provided an
in-situ process using solo solvent for the preparation of Dronedarone
hydrochloride comprising the steps of:
a) contacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of formula II in ethyl acetate with l-chloro-3-di-n-butylaminopropane in the presence of potassium carbonate to obtain reaction mixture containing 2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]-5-nitrobenzofuran of formula III;

b) reaction mass containing compound of formula III from step a is in-situ hydrogenated to obtain reaction mass containing substantially pure 5-amino-2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl] benzofuran of formula IV used in-situ as very clean reaction product as confirmed by the online monitoring HPLC chromatograph as illustrated in figure IV;

FIGURE IV
c) reaction mass containing compound of formula IV from step b is further contacted with methanesulfonyl chloride in presence of an aromatic base to obtain Dronedarone hydrochloride of formula I; (wherein X is CI) as crude with purity of 98.32% as depicted in figure V.


FIGURE V
Crude Dronedarone HC1 obtained in step c may be further purified by any standard purification step preferably crystalisation to obtain the pharmaceutical purity of at least 99% as illustrated in figure VI.

FIGURE VI
In yet another preferred embodiment of the present invention disclosed herein is an in-situ process using solo solvent for the preparation of Dronedarone hydrochloride comprising
a) contacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of formula II in ethyl acetate with l-chloro-3-di-n-butylaminopropane in

the presence of a potassium carbonate to obtain reaction mixture containing 2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]-5-nitrobenzofuran of formula III; b) reaction mass containing compound of formula III from step a is hydrogenated to obtain reaction mixture containing substantially pure 5-amino-2-/7-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl] benzofuran of formula IV used in-situ as very clean reaction product as confirmed by the online monitoring HPLC chromatograph as illustrated in figure VII;

FIGURE VII
c) reaction mass containing compound of formula IV from step b is further contacted with methanesulfonyl chloride without using a base to obtain substantially pure Dronedarone hydrochloride of formula I as very clean reaction product as confirmed by the HPLC chromatograph of crude as illustrated in figure VIII.


FIGURE VIII
Crude Dronedarone HO obtained in step c may be further purified by any standard purification step preferably crystalisation to obtain the pharmaceutical purity of at least 99%.
In a preferred embodiment disclosed herein is an in-situ process for the preparation of Dronedarone base of formula IA and Dronedarone HC1 salt comprising the steps of:
a) contacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of
formula II with l-chloro-3-di-n-butylaminopropane using isopropanol
as a solo solvent in the presence of a base to obtain reaction mixture
containing 2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyI]-5-
nitrobenzofuran of formula III;
b) reaction mixture containing compound of formula III from step a is
reduced to obtain reaction mixture containing substantially pure 5-
amino-2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]

benzofurau of formula IV as indicated by the online HPLC chtomatogtapti as illustrated in figure IX given herein below;

FIGURE IX
c) reaction mixture containing compound of formula IV from step b is further contacted with methanesulfonyl chloride in the presence of an organic base to obtain substantially pure Dronedarone base of formula IA as illustrated in figure X given herein below;


d) reaction mixture of step c containing Dronedarone base of formula IA is optionally in-situ contacted with hydrochloric acid to obtain salt of Dronedarone hydrochloride of formula I. In accordance with this embodiment substantially pure Dronedarone free base is optionally isolated from the reaction mixture of step c. The base for step a, reduction catalysts for step b and base for step c are same as disclosed hereinabove in preceedingembodiments.
In a preferred embodiment disclosed herein is an in-situ process for the preparation of Dronedarone intermediate of formula IV, comprising the steps of:
a) contacting 2-«-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of
formula III with l-chloro-3-di-n-butylaminopropane using
isopropanol as single solvent and potassium carbonate as a base to
obtain reaction mixture containing 2-n-butyl-3-[4-[3-(di-n-
butylamino)propoxy] benzoyl]-5-nitrobenzofuran of formula III used
in-situ as very clean reaction product as confirmed by the
chromatograph of the final amino compound of formula IV given
herein below in Figure XI;
b) reaction mass containing compound of formula III from step a is
reduced using hydrogen gas and Pd/C to obtain reaction mass
containing 5-amino-2-n-butyl-3-[4-[3-(di-«-butylamino)propoxy]
benzoyl]benzofuran of formula IV as very clean reaction product as

confirmed by the HPLC chromatograph of the amino compound of formula IV illustrated in figure XI given herein below:

FIGURE XI
The amino product thus obtained is isolated by standard means known in the literature.
The details of the invention provided in the following examples are given by the way of illustration only and should not be construed to limit the scope of the present invention.
EXAMPLES:
Example 1: To the stirred solution of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (7.5 g) in ethyl acetate (23 ml) at room temperature is charged potassium carbonate (6.1 g) and heated to reflux for four hours. Then l-chloro-3-di-n-butylaminopropane (5.0 g) is added through addition funnel in 15-20 minutes and refluxed for 22-24 hours. After completion of reaction (as monitored on HPLC), the reaction mass is stirred at 10-15°C for 30 minutes. The inorganic material is filtered off.

The filtrate is charged in autoclave flask for hydrogenation and 10% Pd-C (0.37 g) is added under inert atmosphere. The reaction mass is hydrogenated at 50-55°C at hydrogen pressure of 4-5 Kg/cm for 8-10 hours. After completion of reaction (as monitored on HPLC), the catalyst is filtered off and filtrate is charged with N, N-dimethylaniline (2 g) at room temperature followed by the addition of methane sulphonyl chloride (3 ml) in 20-30 minutes maintaining temperature at 25-30°C. The reaction mass is stirred at 25-30°C for 28-30 hours and after completion of reaction (as monitored on HPLC), the solid appeared is filtered and dried under vacuum at 50-55°C to get crude Dronedarone hydrochloride (9.8 g). Yield: 75.1%; HPLC purity: 98.32%. This crude Dronedarone hydrochloride is further purified from isopropanol to get pure Dronedarone hydrochlorides with purity of 99.77% and yield of 87%.
Example 2: To the stirred solution of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (7.5 g) in 1,2-dimethoxy ethane (23 ml) at room temperature is charged potassium carbonate (6.1 g) and heated to reflux for four hours. Then l-chloro-3-di-n-butylaminopropane (5.0 g) is added through addition funnel in 15-20 minutes and refluxed for overnight. After completion of reaction (as monitored on HPLC), the reaction mass is stirred at 10-15°C for 30 minutes. The inorganic material is filtered on hyflo bed and wash with 1,2-DME (7.5 ml). The filtrate is charged in autoclave flask for hydrogenation and 10% Pd-C (0.3 g) is added under

inert atmosphere. The reaction mass is hydrogenated at 50-55°C at hydrogen pressure of 4-5 Kg/cm for 8-10 hours. After completion of reaction (as monitored on HPLC), catalyst is removed by filtration and filtrate is charged with iV,jV-dimethylaniline (2 g) followed by the addition of methane sulphonyl chloride (3 ml) in 20-30 minutes maintaining temperature at 25-30°C. The reaction mass is stirred at 25-30°C for 28-30 hours and after completion of reaction (as monitored on HPLC), the solid appeared is filtered, washed with 1,2-dimethoxy ethane and dried under vacuum at 50-55°C to get crude Dronedarone hydrochloride with HPLC purity: 98.43%.
Example 3: To the stirred solution of 2-rc-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (3.8 g) in ethyl acetate (12 ml) at room temperature is charged potassium carbonate (3.0 g) and heated to reflux for four hours. Then l-chloro-3-di-n-butylaminopropane (2.5 g) is added through addition funnel in 15-20 minutes and refluxed for 22-24 hours. After completion of reaction (as monitored on HPLC), the reaction mass is stirred at 10-15°C for 30 minutes. The inorganic material is filtered on hyflo bed and wash with ethyl acetate (4 ml). The filtrate is charged in autoclave flask for hydrogenation and 10% Pd-C (0.18 g) is added under inert atmosphere. The reaction mass is hydrogenated at 50-55°C at hydrogen pressure of 4-5 Kg/cm2 for 8-10 hours. After completion of reaction (as monitored on HPLC), the reaction mass is cooled to room temperature and catalyst is filtered off and to the filtrate is charged

methane sulphonyl chloride (1.2 ml) slowly through addition funnel in 20-30 minutes maintaining temperature at 25-30°C. The reaction mass is stirred at 25-30°C for 22-24 hours. After completion of reaction (as monitored on HPLC), the solid appeared is filtered off dried under vacuum at 50-55°C to get crude Dronedarone hydrochloride (5.1 g). Yield: 77.1%; HPLC purity: 98.28%.
Example 4: To the stirred solution of 2-«-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (50 g) in isopropyl alcohol (150 ml) at room temperature is charged potassium carbonate (40.7 g) and heated to reflux for four hours. Then l-chloro-3-di-77-butylaminopropane (31.82 g) is added in 15-20 minutes and refluxed for 10-12 hours until the completion of reaction, as monitored on HPLC. The inorganic material is filtered on hyflo bed and wash with IPA (25 ml). The filtrate is charged in autoclave flask for hydrogenation and 10% Pd-C (2 g) is added under inert atmosphere. The reaction mass is hydrogenated at 50-55°C at hydrogen pressure of 4-5 Kg/cm for 8-10 hours. After completion of reaction (as monitored on HPLC), and filtrate obtained is added with pyridine (20.8 ml) at room temperature under stirring followed by the addition of methane sulphonyl chloride (15.0 ml) in 20-30 minutes. Then reaction mass is refluxed for 14-15 hours. After completion of reaction (as monitored on HPLC), the reaction mass is cooled to room temperature and is added with (14% w/w) IPA-HC1 (60.5 g) maintaining temperature at 25-30°C. Then Cool the reaction mass at 0

to -5°C and stirred at 0 to -5°C for 5 hours, the solid appeared is filtered off, and dried under vacuum at 50-55°C to get crude Dronedarone hydrochloride (67.0 g) Yield: 77.1%. This crude Dronedarone hydrochloride is further purified from isopropanol to get pure Dronedarone hydrochlorides with purity of 99.5%, and yield of 88 %.
Example 5: To the stirred solution of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (7.5 g) in isopropyl alcohol (23 ml) at room temperature is charged potassium carbonate (6.1 g) and heated to reflux for four hours. Then l-chloro-3-di-n-butylaminopropane (5 g) is added through addition funnel in 15-20 minutes and refluxed for 10-12 hours until the completion of reaction, as monitored on HPLC. Then the reaction mass is cooled to 10-15°C and stir for 30 minutes. The inorganic material is filtered on hyflo bed and wash with IPA. The filtrate is charged in autoclave flask for hydrogenation and 10% Pd-C (0.3 g) is added under inert atmosphere. The reaction mass is hydrogenated at 50-55°C at hydrogen pressure of 4-5 Kg/cm2 for 8-10 hours. After completion of reaction (as monitored on HPLC), the reaction mass is filtered on hyflo bed under nitrogen atmosphere at room temperature. Hyflo bed is washed with IPA and filtrate is transferred in another round bottom flask. Then pyridine (3.2 ml) is charged at room temperature under stirring followed by the addition of methane sulphonyl chloride (2.4 ml) through addition funnel maintaining temperature at 25-30°C in 20-30 minutes. Then reaction mass is refluxed for 14-15 hours. After

completion of reaction (as monitored on HPLC), the reaction mass is cooled to room temperature. Then distilled off the IPA to get crude Dronedarone base as an oily liquid (10.3 g). Yield: 84%; HPLC purity: 97.8%
Example 6: To the stirred solution of 2-n-butyl-3-(4-hydroxybenzoyl)-
5-nitrobenzofuran (50 g) in IPA (150 ml) at room temperature is charged
potassium carbonate (40.7 g) and heated to reflux for four hours. Then 1-
chloro-3-di-tt-butylaminopropane (33.3 g) is added through addition
funnel in 15-20 minutes and refluxed for 10-12 hours. After completion
of reaction (as monitored on HPLC), the reaction mass is stirred at 10-
15°C for 30 minutes. The inorganic material is filtered off and the filtrate
is charged in autoclave flask for hydrogenation and 10% Pd-C (2 g) is
added under inert atmosphere. The reaction mass is hydrogenated at 50-
55°C at hydrogen pressure of 4-5 Kg/cm for 8-10 hours. After
completion of reaction (as monitored on HPLC), catalyst is filtered off
and filtrate is evaporated under reduced pressure to get oily mass (65.5
g) as product 5-amino-2-«-butyl-3-[4-[3-(di-«-
butylamino)propoxy]benzoyl] benzofuran. Yield: 93%; HPLC purity: 98.8 %.
Example 7: To the stirred solution of 2-/7-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (7.5 g) in IPA (23 ml) at room temperature is charged potassium carbonate (6.1 g) and heated to reflux for four hours. Then 1-chloro-3-di-/7-butylaminopropane (5 g) is added through addition funnel

in 15-20 minutes and re fluxed for 10-12 hours. After completion of reaction (as monitored on HPLC), the reaction mass is stirred at 10-15°C for 30 minutes. The inorganic material is filtered off, washed with IP A and filtrate containing 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-5-nitrobenzofuran is charged with 10% Pd-C (1.0 g) under inert atmosphere. Then ammonium formate (6.2 g) is added and reaction mass is stirred at 40-45°C for 8-10 hours. After completion of reaction (as monitored on HPLC), the reaction mass is filtered off and filtrate is distilled-off under vacuum at 35-40°C to get 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butylbenzofuran (9.2 g) as greenish yellow colored oil. Yield: 87%; HPLC purity: 96.0%.
Example 8: To the stirred solution of Dronedarone base prepared by in-situ process using solo solvent is taken (20.5 g) in isopropyl alcohol and is added (14% w/w) IPA-HC1 (19.3 g) maintaining temperature at 25-30°C. Cool the reaction mass at 0 to -5°C and stirred at 0 to -5°C for 5 hours. The solid appeared is filtered, washed with chilled isopropyl alcohol and dried under vacuum at 50-55°C till LOD of material is below 1% w/w to get crude Dronedarone hydrochloride (19.6 g). Yield: 90.0 %; HPLC purity: 98.47% .This crude Dronedarone hydrochloride is further purified from isopropanol to get pure Dronedarone hydrochlorides with purity of 99.7% and yield of 88 %.

Example 9: 5-Amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-
butylbenzofuran (2.0 g) is taken in DM water (50 ml) and mesyl chloride
(0.32 ml) is added slowly in 15-20 minutes. Then reaction mass is stirred
at room temperature for 40-44 hours but reaction could not go to
completion. No solid material is observed at room temperature then
reaction mass is cooled to 0-5°C and stirred at 0-5°C for 3 hours but no
precipitation of solid material is observed. Then extracted with
methylene dichloride (20 ml) the evaporation of solvent under reduced
pressure gave oily mass (1.2 g) as mixture of Dronedarone and 5-amino-
3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butylbenzofuran as
shown by HPLC result. HPLC: Dronedarone 70%; Starting Material: 27.7%.
Example 10: 2-77-Butyl-3-[4-(3-di-/2-butylaminopropoxy)benzoyl]-5-
nitrobenzofuran (10 g) is charged in methyl tertiary butyl ether (50 ml)
under stirring and 10% Pd-C (1.0 g) is added under inert atmosphere.
Then ammonium formate (6.2 g) is added and reaction mass is stirred at
40-45°C for 22-24 hours. Reaction did not go to completion even for
stirring at 40-45°C for 24 hours. Then reaction mass is filtered on hyflo
bed under nitrogen atmosphere at room temperature. Hyflo bed is
washed with methyl tertiary butyl ether and filtrate is washed with water
(15X2 ml) and organic layer is distilled off completely under vacuum at
40-45°C to get mixture of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)
benzoyl]-5-nitrobenzofuran and 5-amino-3-[4-(3-di-n-

butylaminopropoxy)benzoyl]-2-/z-butyl benzofuran as oil. HPLC purity: Product: 44.6%; Starting material: 54.3%.

CLAIMS:
We claim:
1. A process for the preparation of Dronedarone hydrochloride of formula 1

comprising steps of:
a) contacting 2-w-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of formula II with l-chloro-3-di-n-butylaminopropane in a solo solvent in the presence of a base to obtain 2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]-5-nitrobenzofuran of formula III;
b) reaction mixture containing compound of formula HI from step a is reduced to obtain 5-amino-2-n-butyl-3-[4-[3-(di-n-butylamino) propoxy]benzoyl]benzofuran of formula IV;
c) reaction mixture containing compound of formula IV from step b is further contacted with methanesulfonyl chloride optionally adding a base to obtain Dronedarone hydrochloride of formula I; wherein X is CI.
2. A process for the preparation of Dronedarone base of formula IA and pharmaceutically acceptable salts thereof of formula I


comprising steps of;
a) contacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of formula II with l-chloro-3-di-n-butylaminopropane in a solo solvent in the presence of a base to obtain reaction mixture containing 2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]-5-nitrobenzofuran of formula III;
b) reaction mixture containing compound of formula III from step a is reduced to obtain reaction mixture containing 5-amino-2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]benzofuran of formula IV;
c) reaction mixture containing compound of formula IV from step b is
further contacted with methanesulfonyl chloride in the presence of a base to obtain Dronedarone base of formula I A;
d) isolated compound of formula IA from the reaction mixture of step
c;
e) reaction mixture from step c containing Dronedarone base of
formula IA is contacted with an acid to obtain corresponding
pharmaceutically acceptable salt of Dronedarone of formula I.
3. A process for the preparation of Dronedarone base of formula IA


comprising the steps of:
a) contacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of formula II with l-chloro-3-di-n-butylaminopropane in a solo solvent in the presence of a base to obtain reaction mixture containing 2-n-butyl-3-[4-[3-(d-n-butylamino)propoxy]benzoyl]-5-nitrobenzofuran of formula III;
b) reaction mixture containing compound of formula III from step a is reduced to obtain reaction mixture containing 5-amino-2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]benzofuran of formula IV;
c) reaction mixture containing compound of formula IV from step b is further contacted with methanesulfonyl chloride in the presence of a base to obtain Dronedarone base of formula IA;
d) isolated compound of formula IA from the reaction mixture of step c.
4. A process for the preparation of 5-amino-2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]benzofuran of formula IV


comprising steps of:
a) contacting 2-w-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of formula II with l-chloro-3-di-n-butylaminopropane in a solo solvent in the presence of a base to obtain reaction mixture containing 2-n-butyl-3-[4-[3-(di-«-butylamino)propoxy]benzoyl]-5-nitrobenzofuran of formula III;
b) reaction mixture containing compound of formula III from step a is reduced to obtain reaction mass containing 5-amino-2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]benzofuran of formula IV;
c) isolating the compound of Formula IV from the reaction mixture of step b.

5. The process of claim 1 wherein solo solvent is selected from the group comprising esters, ethers, ketones.
6. The process of claim 5 wherein the solo solvent is selected from a group comprising ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, tetrahydrofuran, 1,2-dimethoxy ethane, 1,4-dioxane, methyl tertiary butyl ether, methyl ethyl ketone, acetone, methyl isobutyl ketone and the like.
7. The process of claim 6 wherein solo solvent is selected from a group comprising ethyl acetate, 1,2-dimethoxyethane, methyl ethyl ketone.
8. The process of preceeding claims 1- 4 wherein base for step a is selected from the group comprising inorganic bases selected from

alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides.
9. The process of claim 8 wherein base is potassium carbonate.
10. The process of preceeding claims 2 and 3 wherein solo solvent is
protic selected from aliphatic alcohols comprising ethanol, methanol, propanol, butanol, tertiary butanol, isopropanol.
11. The process of claim 10 wherein solo solvent is isopropanol.
12. The process of claim 4 wherein the solo solvent is protic, aprotic
selected from the group of solvents described in claims 6 and 10.
13. The process of preceeding claims 1 - 4 wherein reduction for step b to prepare compound of formula IV comprising catalytic hydrogenation, catalytic transfer hydrogen reaction.
14. The process of preceeding claims 2 and 3 for step c the base is organic aromatic base.
15. The process of claim 14 wherein base is selected from the group
comprising N,N- dimethyl aniline, pyridine, imidazole and mixture thereof.