Field of the invention:

The present invention relates to an improved process for the preparation of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-l}methanesulfonamide hydrochloride (commonly known as Dronedarone hydrochloride) represented by the formula-A,

Dronedarone is a class - III anti-arrythmic drug which is chemically related to benzofuran derivatives. Dronedarone is mainly used for the indication of cardiac arrhythmia (irregular heart beat) and it is also used for the treatment of atrial fibrillation and atrial flutter in patients whose hearts have either returned to normal rhythm or who undergo drug therapy or electric shock treatment to maintain normal rhythm. This medication was first developed and marketed by Sanofi-Aventis under the brand name Multaq®.

Background of the invention

Dronedarone hydrochloride and its process for the preparation was first disclosed in US 5,223,510 (here in after referred as '510' patent) which is as follows;

The synthesis of 2-n-butyl-5-nitrobenzofuran involves the condensation of (2-hydroxy-5-nitro-benzyl)triphenylphosphoniumbromide and pentanoylchloride in the presense of pyridine and chloroform. Wherein, the usage of pyridine and chloroform in industrial scale is practically not possible due to health matters, and further it requires organic bases like triethylamine for cyclisation to form 2-n-butyl-5-nitrobenzofuran. Moreover, this process will not produc sufficient yield.

Also, '510' patent disclosed the synthesis of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran involves the acylation of 2-n-butyl-5-nitrobenzofuran with anisoylchloride in presence of SnCl4 in dichloroethane. Wherein, the usage of dichloroethane as a solvent in commericial manufacturing is not preferrable due to its toxic nature. Also, this process involves the usage of costly reagents like SnCl4 , which leads to increase the cost of production. Moreover, it is a time consuming process.

'510' patent also disclosed the synthesis of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran involves the O-demethylation of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran by using reagents such as pyridine hydrochloride, borontribromide and aluminiumchloride in dichloroethane. Wherein, the O-demthylation step requires additional reagents and toxic solvents which leads to increases the cost of production and decreases the safety aspects.In addition to this, 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran showing mutagenic properties.

Also '510' patent disclosed the reduction of 5-nitrobenzofuran derivative to 5-aminobenzofuran derivative by using costly reagent like platinumoxide (Pt02), which proves to be expensive on the industrial scale.

Hence, there is a need in the art to develop an improved process for the preparation of dronedarone and its pharmaceutically acceptable salts, and its intermediates to minimize the disadvantages of all existing processes.

Brief Description of drawings:

Figure-1: Shows an illustrative example of X-ray powder diffraction pattern of
dronedarone hydrochloride prepared according to example-11 (using acetone as solvent)

Figure-2: Shows an illustrative example of X-ray powder diffraction pattern of
dronedarone hydrochloride prepared according to example-12 (using ethanol as solvent)

Figure-3: Shows an illustrative example of X-ray powder diffraction pattern of
dronedarone hydrochloride prepared according to example-13 (using acetonitrile as solvent)

Brief description of the invention:

The object of the present invention is to provide an improved process for the preparation of dronedarone and its pharmaceutically acceptable salts which overcomes the disadvantages of prior-art processes. Further, the process involves the usage of commercially available starting materials, simple reagents and low cost solvents which not only reduces the cost but also increaeses the yield and purity of the product.

The first aspect of the present invention relates to an improved process for the prepartion of 2-n-butyl-5-nitrobenzofuran comprises of, reacting the wittig salt i.e (2-hydroxy-5-nitro-benzyl)triphenylphosphoniumbromide compound of formula-2 with pentanoylchloride in presence of an inorganic base in a suitable solvent to give 2-n-butyl-5-nitrobenzofuran compound of formula-3.

The second aspect of the present invention relates to an improved process for the preparation of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran which comprises of reacting 2-n-butyl-5-nitrobenzofuran with p-hydroxybenzoicacid in presence of thionylchloride and Lewi's acid to give 2-n-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran compound of fonnula-4.

The third aspect of the present invention relates to an improved process for the preparation of 2-butyl-3-(4-[3-(dibutyl amino )propoxy] benzoyl)-5-aminobenzofuran which comprises of reducing 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran compound of formula-5 with reducing agents like Pd/C, NaBH4 or Fe/HC1 in a suitable solvent to give 2-butyl-3-(4-[3-(dibutylamino) propoxy]benzoyl)-5-aminobenzofuran compound of formula-6 which in turn converted into its organic acid salts or inorganic acid salts.

The fourth aspect of the present invention relates to an improved process for the preparation of dronedarone and its pharmaceutically acceptable salts thereof, preferably hydrochloride salt which involves, reacting 2-butyl-3-(4-[3-(dibutyl amino)propoxy]benzoyl)-5-aminobenzofuran or its acid addition salts with methanesulfonylchloride in presence or absence of a base in a suitable solvent to give dronedarone hydrochloride of formula-A.

The fifth aspect of the present invention relates to an improved process for the preparation of 2-n-butyl-5-aminobenzofuran which comprises of, reducing the 2-n-butyl-5-nitrobenzofuran with reducing agents like Pd/C, NaBH) or Fe/HC1 in a suitable solvent to give 2-n-butyl-5-aminobenzofuran compound of formula-8 which can be converted into stable salt form.

Sixth aspect of the present invention relates to an improved process for the preparation of Dronedarone hydrochloride compound of formula-A which comprises of the following steps,

a) Reacting the 4-nitrophenol with hydrobromic acid solution and formaldehyde solution in presence or absence of PBr3 to give 2-(bromomethyl)-4-nitrophenol compound of formula-1,

b) reacting the compound of formula-1 with triphenylphosphine (TPP) in a suitable solvent to give the wittig salt i.e (2-hydroxy-5-nitro-benzyl)triphenyl phosphoniumbromide compound of formula-2,

c) reacting the wittig salt compound of formula-2 with pentanoylchloride in presence of organic or inorganic base in a suitable solvent to give the 2-n-butyl-5-nitro benzofuran compound of formula-3,

d) reacting the compound of formula-3 with 4-hydroxybenzoicacid in presence of thionylchloride and Lewi's acid in a suitable solvent to give 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran compound of formula-4,

e) reacting the compound of formula-4 with l-chloro-3-di-n-butylaminopropane in presence of a base in a suitable solvent to give 2-butyl-3-(4-[3-(dibutyl amino)propoxy]benzoyl)-5-nitrobenzofuran compound of formula-5 and which in turn coverts into organic or inorganic acid salt,

f) reacting the compound of formula-5 with a reducing agents like Pd/C, NaBH4, and Fe/HC1 in a suitable solvent to give 2-butyI-3-(4-[3-(dibutylamino) propoxy]benzoyI)-5-aminobenzofuran compound of formula-6, which in turn reacts with corresponding organic or inorganic acids preferably organic acids like oxalic acid in a suitable solvent to give dioxalte salt of 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-aminobenzofuran compound of formula-7,

g) reacting the compound of formula-7 with methanesulfonylchloride in presence of a base in a suitable solvent and then followed by treatment with hydrochloric acid in a suitable solvent to give dronedarone hydrochloride compound of formula-A,

h) purifying the dronedarone hydrochloride in a suitable solvent followed by charcoal treatment and further isolation to give the pure dronedarone hydrochloride.

Seventh aspect of the present invention relates to a novel process for the preparation of 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran compound of formula-5 comprising of

a) Reacting the compound of formula-4 with chlorobromopropane in presence of an inorganic base in a suitable solvent to give 2-butyl-3-(4-(3-chloropropoxy)benzoyl)-5-nitrobenzofuran compound of formula-9,

b) reacting the compound of formula-9 with Di-n-butylamine at 130 - 135°C to give the compound of formula-5.

Eighth aspect of the present invention relates to an improved process for the preparation of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran compound of formula-4 which comprises of reacting 2-n-butyl-5-nitrobenzofuran compound of formula-3 with anisoylchloride in presense of a Lewi's acid in a suitable solvent to give 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran compound of formula-10 which insitu treated with excess amount of Lewi's acid to provide 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran.

Ninth aspect of the present invention relates to novel process for producing the crystalline polymorph of dronedarone hydrochloride from alcohol solvens,nitrile solvents and mixture thereof.

Tenth aspect of the present invention relates to novel impurities obtained in the process for the preparation of dronedarone hydrochlorde.

Detailed description of the invemtion:

As used herein, the term "alcohol solvents" refers to methanol, ethanol,!-propann ol,isopropanol and n-butanol and the like; "hydrocarbon solvents" refers to toluene, xylene, cyclohexane, hexane, heptane and the like; "polar aprotic solvents" refers to dimethylsulfoxide, dimethylacetamide, dimethyl formamide, tetrahydrofuran, acetonitrile and the like; "polar protic solvents" refers to water , formic acid and aceticacid and "chloro solvents" refers to methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform and the like; "nitrile solvents" refers to acetonitrile and the like; "ester solvents" refers to ethylacetate, ethylbutyrate, tert.butylacetate and the like; "keto solvents" refers to acetone , Methylethylketone and methylisobutylketone and the like; "ether solvents" refers to Diethylether, Diisopropylether and the like.

As used herein, the term "Lewi's acid" refers to AlCl3, SnCl4 and FeCl3 and the like; and "organic acids" refers to oxalic acid, maleic acid, malic acid, fumaric acid, succinic acid and the like; and "inorganic acids" refers to hydrochloric acid, sulfuric acid and the like; and "reducing agents" refers to Pd/C, NaBH4, LAH and Fe/HC1 and the like; and "organic bases" refers to pyridine, triethylamine. Dimethyl amino pyridine (DMAP) and the like; and "inorganic bases" refers to alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and bicarbonates such as sodium bicarbonate and potassium bicarbonate.

The present inventtion relates to an improved process for the preparation of dronedarone and its pharmaceutically acceptable salts preferably hydrochloride salt ofdronedarone.
According to first aspect of the prepsent invention relates to an improved process for the preparation of 2-n-butyl-5-nitrobenzofuran compound of formula-3, comprises of, reacting wittig salt i.e (2-hydroxy-5-nitro-benzyl) triphenyl phosphoniumbromide compound of formula-2, with pentanoylchloride in presence of an inorganic base selected from sodium carbonate, calcium carbonate, sodium hydroxide, sodium bicarbonate, potassium carbonate, magnesium carbonate and the like, preferably sodium carbonate and sodium hydroxide and more preferably sodium carbonate in a suitable solvent selected from alcohloic or chlorinated or keto or hydrocarbon solvents, preferably hydrocarbon solvents, more preferably toluene to provide the compound of formula-3. According to the first aspect of the present invention, the wittig salt can be prepared by reacting 4-nitrophenol with formaldehyde and hydrogenbromide in presence or absence of PBrs to give 2-(bromomethyl)-4-nitrophenol compound of formula-1,

which is then reacts with triphenylphosphine in presence of a hydrocarbon solvent preferably toluene to provide the wittig salt compound of formula-2.

The second aspect of the present invention relates to an improved process for the preparation of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of formula-4,

comprises of, reacting 2-n-butyl-5-nitrobenzofuran compound of formula-3 with p-hydroxybenzoic acid in presence of thionylchloride and Lewi's acid in a suitable solvent to provide 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran compound of formula-4.
In a prefered embodiment, the process for the preparation of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran comprises of , reacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran with p-hydroxybenzoic acid and thionylchloride in presence of AlCl3 in dichloromethane to provide 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran.

The third aspect of the present invention relates to an improved process for the preparation of 2-butyl-3-(4-[3-(dibutyl amino )propoxy] benzoyl)-5-aminobenzofuran compound of formula-6,

comprises of, reducing 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofiiran compound of formula-5,

with a suitable reducing agent in a suitable solvent or mixture thereof, provides 2-

butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-aminobenzofuran compound of formula-6 which in turn reacts with oxalicacid in a suitable solvent to give dioxalate salt of 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran compound of formula-7,

In a prefered embodiment, the process for the preparation of 2-butyl-3-(4-[3-(dibutyl amino )propoxy] benzoyl)-5-aminobenzofuran comprises of, reducing 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran with Fe/HCl in a mixture of ethanol and water to provide 2-butyl-3-(4-[3-(dibutyl amino )propoxy] benzoyl)-5-aminobenzofuran.

The fourth aspect of the present invention relates to an improved process for the preparation of dronedarone hydrochloride which involves, reacting 2-butyl-3-(4-[3-(dibutyl amino )propoxy] benzoyl)-5-aminobenzofuran or its dioxalte salt compound of formula-7 with methanesulfonylchloride in presence or absence of a base in a suitable solvent to provide dronedarone hydrochloride compound of formula-A.

In a prefered embodiment, an improved process for the preparation of dronedarone hydrochloride which comprises of, initially reacting the dioxalte salt of 2-butyl-3-(4-[3-(dibutyl amino )propoxy] benzoyl)-5-aminobenzofuran with ammonia solution in ethylacetate and then treated with methanesulfonylchloride in presence of triethylamine in acetonitrile and further reacted with HC1 in ethylacetate to provide dronedarone hydrochloride.

In an another embodiment, the improved process for the preparation of dronedarone hydrochloride which comprises of, initially reacting the dioxalte salt of 2-butyl-3-(4-[3-(dibutyl amino )propoxy] benzoyl)-5-aminobenzofuran with ammonia solution in ethylacetate and then treated with methanesulfonylchloride in methanol and further reacted with HC1 in ethylacetate to provide dronedarone hydrochloride.

In another embodiment, the improved process for the preparation of dronedarone hydrochloride which comprises of, initially reacting the 2-butyl-3-(4-[3-(dibutyl amino )propoxy] benzoyl)-5-aminobenzofuran compound of formula-6, with ammonia solution in ethylacetate and then treated with methanesulfonylchloride in methanol and further reacted with HC1 in ethylacetate to provide dronedarone hydrochloride.

The fifth aspect of the present invention relates to an improved process for the preparation of 2-n-butyl-5-aminobenzofuran compound of formula-8, involves, reducing the 2-n-butyl-5-nitrobenzofuran compound of formula-3, with a reducing agent in a suitable solvent to provide 2-n-butyl-5-aminobenzofuran which is converted into stable salt by treating it with an acid.

In a prefered embodiment, the process for the preparation of 2-n-butyl-5-aminobenzofuran comprises of, reducing 2-n-butyl-5-nitrobenzofuran with Fe/HC1 in mixture of ethanol and water provides 2-n-butyl-5-aminobenzofuran which is converted into stable salt by treating it with an acid.

According to sixth aspect of the present invention relates to an improved process for the preparation of Dronedarone and its pharmaceutically acceptable salts thereof , preferably hydrochloride salt of dronedarone compound of formula-A comprises of the following steps,

a) Reacting 4-nitrophenol with formaldehyde and hydrobromic acid solution in presence or absence of PBr3 provides 2-(bromomethyl)-4-nitrophenol compound of formula-1,

b) reacting the compound of formula-1 with triphenylphosphine (TPP) in a suitable solvent like toluene at 80-85°C provides the wittig salt i.e (2-hydroxy-5-nitro-benzyl)triphenylphosphoniumbromide compound of formula-2,

c) reacting the wittig salt compound of formula-2 with pentanoylchloride in presence of inorganic base like sodium carbonate in toluene provides the 2-n-butyI-5-nitrobenzofuran compound of formula-3,

d) reacting the compound of formula-3 with 4-hydroxybenzoicacid in presence of thionylchloride and AlCl3 in a suitable solvent like dichloromethane(DCM) provides 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of formula-4,

e) reacting the compound of formula-4 with l-Chloro-3-di-n-butylaminopropane in presence of a base, preferably inorganic base like potassium carbonate in a suitable solvent like acetone provides 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran compound of formula-5,
and which in turn converts into organic or inorganic acid salts like oxalate, maleate, malate, acetate, fumarate and hydrochloide salt and the like,

f) reacting the compound of formula-5 with a reducing agent like Fe/HC1 in a
suitable solvent selected from water, methanol, ethanol, isoprpylalcohol, 1-
propanol and mixture thereof more preferably ethanol and water provides 2-butyl-
3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-aminobenzofuran compound of
formula-6,

which in turn reacts with oxalic acid in a suitable solvent like isopropylalcohol to provide dioxalte salt of 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-aminobenzofuran compound of formula-7,

g) reacting the compound of formula-7 with methanesulfonylchloride in presence or
absense of an organic base like triethylamine(TEA) in a suitable solvent like
acetonitrile or methanol and then followed by treatment with hydrochloric acid in
a suitable solvent like ethylacetate provides dronedarone hydrochloride,

Dronedarone Hydrochloride

h) recrystallising the dronedarone hydrochloride in a suitable solvent selected from chloro, ester, hydrocarbon, keto, alcohol and nitrile solvents thereof preferably keto solvents like acetone, methylisobutylketone (MIBK) and methylethylketone (MEK) thereof, more preferably acetone followed by charcoal treatment and further isolation with acetone to give the pure dronedarone hydrochloride.

According to seventh aspect of the present invention relates to novel process for the preparation 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzo furan compound of formula-5 comprises of,

a) reacting compound of formula-4 with chlorobromopropane in presence of an
inorganic base like potassiumcarbonate in a suitable solvent like acetone to give the compound of formula-9,

b) reacting compound of formula-9 with di-n-butylamine in a suitable solvent selected from hydrocarbon solvents and more preferably toluene to give the compound of formula-5.

According to the seventh aspect, the novel process is schematically represented as follows:

Eighth aspect of the present invention relates to an improved process for the preparation of 2-n-butyl-3-(4-hydroxyben2oyl)-5-nitrobenzofuran compound of formula-4 which comprises of, reacting 2-n-butyl-5-nitrobenzofuran compound of formula-3 with anisoylchloride in presense of AICI3 in a suitable solvent like dichloromethane to provide 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran compound of formula-10,

which insitu treated with excess amount of AlCl3 provides 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran.

According to ninth aspect of the present invention relates to a novel process for producing pure crystalline form of dronedarone hydrochloide which involves purification of the dronedarone hydrochloride by using alcohol solvents like ethanol. The PXRD data completely matches with the prior-art form disclosed in '510' patent which was recrystallized from acetone. M.R: 137 - 141°C.

Similarly, crystalline form of dronedarone hydrochloide can also be produced by using nitrile solvents like acetonitrile and propionitrile, and more preferably acetontrile. The PXRD data was completely matches with the prior-art form disclosed in '510' patent which was recrystallized from acetone. M.R: 137 - 141°C.

The tenth aspect of the present invention relates to impurities obtined in the process for the preparation of dronedarone hydrochloride, which were identified, confirmed, charecterized and synthesized.

The process described in the present invention was demonstrated in examples as illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention:

Example-1: Preparation of 2-(bromomethyl)-4-nitrophenol compound of formula-1

Conc.sulfuricacid (15ml) was added to the mixture of p-nitrophenol (150 gm) and 50% HBr solution (1950ml) at 25 - 30°C, followed by 35% formalin solution (92.4gm) and PBr3 (72.9gm) The reaction mixture was heated to 70-75°C and then stirred for 6 hrs at 70-75°C. After completion of the reaction, the reaction mixture was poured into ice over a period of 30 min and then stirred for 1hr. The obtained solid was filtered, washed with chilled water and then dried to get the solid. Toluene (1275 ml) was added to the obtained solid. The reaction mixture was heated to 80-85°C and then stirred for 1 hr. The reaction mixture was cooled to 25-30°C, further to 0-5°C and then stirred for 1hr at 0-5°C. Filtered the obtained solid, washed with toluene and then dried to get the title compound. Yield: 200 gm

Example-2: Preparation of (2-hydroxy-5-nitro-benzyI) triphenyl phosphonium bromide compound of formula-2

Triphenylphosphine (192 gm) was added to a solution of 2-(bromomethyl)-4-nitrophenol compound of formula-1 (170 gm) in toluene (2040 ml) and then heated to 80-85°C . The recation mixture was stirred for 4 hrs and then cooled to 25-30°C. The reaction mixture was further stirred for 2 hr at 25-30°C. The obtaied solid was filtered, washed with toluene and then dried to get the title compound. Yield: 361.9 gm

Example-3: Preparation of 2-n-butyl-5-nitrobenzofuran compound of formula-3

Sodiumcarbonate (268 gm) was added to a solution of (2-hydroxy-5-nitro-benzyl)triphenyl phosphoniumbromide (250 gm) in toluene (2500 ml) at 25-30°C. Petanoylchloride (30.4 gm) was added to the reaction mixture for about 40 min at 20-25°C, the reaction mixture was heated to 60-65°C and then stirred for 5 hrs. After completion of the reaction, the reaction mixture was cooled to 25-30°C and water was added to it. The reaction mixture was stirred for 30 min at 25-30°C. Both the organic and aquoeus layers were separated and the organic layer was washed with water followed by ammonia solution (1250ml) and stirred for 1 hr at 25-30°C. Both the layers were separated and the aqueous layer was extracted with toluene (500ml) and combined the orgnic layers. Distilled off the solvent completely under reduced pressure to get the residue. Pet ether (750 ml) was added to the obtained residue at 25- 30°C. The reaction mixture was cooled to 0-5°C and then stirred for 2 hrs. Filtered the reaction mixture, washed with pet ether and distilled off the solvent from filtrate under reduced pressure to get the title compound. Yield: 170gm

Example-4: Preparation of 2-n-butyl-3-(4-hydroxybenzoyI)-5-nitrobenzofuran of formula-4

Dimethylformamide (0.5 ml) was added to a solution of p-hydroxybenzoicacid (4.4 gm) in dichloromethane (100 ml) at 25-30°C under nitrogen atmosphere. Thionylchloride (16.28 gm) was added dropwise to the reaction mixture for about 30min at 15-20°C. The reaction mixture was heated to reflux temperature and then stirred for 1 hr. After completion of the reaction, distilled off the solvent completely under reduced pressure and the reaction mixture was cooled to 25-30°C. Dichloromethane (100 ml) was added to the obtained residue at 25-30°C and then cooled to 0-5°C. 2-n-butyl-5-nitrobenzofuran (10 gm) was added to the above reaction mixture. Aluminium chloride (24.3 gm) was added to the reaction mixture lotwise for about 50 min and then stirred for 12 hrs at reflux temperature. After completion of the reaction, the reaction mixture was poured into ice and then stirred for 20 min. Filtered the reaction mixture and washed with dichloromethane. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Both the organic layers were combined, washed with water and the pH of reaction mixture was adjusted to 9.5 with 10% NaOH solution. Both the organic and aqueous layers were separated, the aqueous layer was cooled to 10-15°C and pH was adjusted to 1.5 using 50% hydrochloric acid solution. The reaction mixture was stirred for 1 hr. Filtered the obtained solid, washed with chilled water and then dried to get the title compound. Yield: 4 gm

Example-5: Preparation of 2-n-butyl-3-(4-hydroxybenzoyI)-5-nitrobenzofuran of formula-4

Anisoylchloride (250 gm) was added to the mixture of dichloromethane (2160 ml) and 2-n-butyl-5-nitrobenzofuran compound of formula-3 (215 gm) at 25-30°C. Stirred the reaction mixture for 5 minutes at 25-30°C. Aluminium chloride (392 gm) was added to the reaction mixture in lot-wise over a period of one hour at 25-30°C. Stirred the reaction mixture for 12 hours at 25-30°C . After completion of the reaction, the reaction mixture was poured into ice, stirred for 30 minutes and then 1000 ml of purified water was added to the reaction mixture and stirred for 20min.

The reaction mass was filterd and washed with 215 ml of purified water. Dichloromethane was added to the filtrate, and both the organic and aqueous layers were separated. The aqueous.layer was extracted with dichloromethane and the organic layer was washed with 5% sodiumhydroxide solution and distilled the organic layer completely under residue pressure. 1000 ml of Isopropylalcohol was added to the obtained residue and the reaction mixture was heated to 70°C and stirred for 30min.The reaction mixture was cooled to 30°C and further cooled to 0-5°C, and the reaction mixture was stirred for 3 hours at 0-5 °C. The obtained solid was filtered, washed with isopropyl alcohol and dried to give the compound of formula-4. yield: 80.2 grams

Example-6: Preparation of 2-butyl-3-(4-[3-(dibutyIamino)propoxy]benzoyI)-5-nitrobenzo furan compound of formula-5

35gm of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of formula-4 was dissolved in 350 ml of acetone at 25°C. 14.2 grams of potassium carbonate was added to the reaction mixture at 25-30°C followed by 21.2 gm of l-chloro-3-di-n-butylaminopropane was added to the reaction mixture at 25°C.The reaction mixture was heated to 55-60°C and stirred for 20 hrs at 55-60°C. The reaaction mixture was cooled to 25-30°C and further cooled to 0-5°C. Stirred the reaction mixture for 45 min at 0 - 5°C and the reaction mixture was filtered and washed with 35 ml of acetone. Distilled off the solvent from the filtrate completely under reduced pressure. 700ml of diisopropylether was added to the obtained residue at 25-30°C and stirred for 10-15 min at 25-30°C. 100 ml of 5% aqueous sodiumhydroxide solution was added to the reaction mixture at 25-30°C and stirred for 15 min at 25-30°C. Both the organic and aqueous were separated and the organic layer was dried with sodiumsulfate. Distilled off the solvent completely under vacuum to get the compound of formula-5. Yield:50gm

Example-7: Preparation of 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-aminobenzo furan compound of formula-6

A mixture of 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran (5 grams), 2.7 gm of Iron turnings, 20ml of etahnol and 10 ml of water was stirred at 25-30°C for 10 minutes. The reaction mixture was cooled to 15-20°C and 20ml of concentrated hydrochloride was added to the reaction mixture at 15-20°C. The reaction mixture was heated to 65°C and the reaction mixture was stirred for 3 hours at 65°C. After completion of the reaction, the reaction mixture was cooled to 25-30°C and 50ml of water was added to the reaction mixture at 25-30C and stirred for I5min.The reaction mixture was filtered and the filtrate was washed with water. 30ml of dichloromethane was added to the reaction mixture and stirred the reaction mixture for 15 min. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers and the pH of the organic layer was adjusted to 9,5 by using 10% sodium hydroxide solution The reaction mixture was filtered through high flow and washed with dichloromethane. The aqueous layer was separated from filtrate and extracted with dichloromethane. The organic layers were combined, dried with sodium sulfate and distilled off the solvent from the organic layer completely under reduced pressure and to get the title compound of formula-6 as residue. Yield: 4gm

Example-8: Preparation of dioxalte salt of 2-butyl-3-(4-[3-(dibutylamino) propoxy]benzoyl)-5-aminobenzo furan compound of formula-7.

The compound of formula-6 (4 grams) obtained in example-7 was dissolved in 30 ml of isopropylalcohol and the reaction mixture was heated to 55°C. The solution of oxalic acid (2.2 grams in 24 ml of isopropylalcohol) was added to the reaction mixture at 55°C over a period of 20 minutes and the reaction mixture was stirred for 30min at 50-55°C. The reaction mixture was cooled to 25°C, further cooled to 5-10°C and stirred the reaction mixture for 1.5hr at 5-10°C. The obtained solid was filtered, washed with chilled isopropylalcohol and dried to get the compound of formula-7. Yield: 2gm

Example-9: Preparation of Dronedarone hydrochloride compound of formula-A.
540 ml of aqueous ammonia was added to the mixture of compound of formula-7 (360 grams) in water (3600 ml), and then followed by the addition of 1800 ml of ethylacetate at 25-30°C.The reaction mixture was stirred for 30 min at 25-30°C. Both the organic and aqueous layers separated and the aqueous layer was extracted with ethylactate. The organic layer washed with water and dried with sodiumsulfate. The solvent distilled off from the organic layer completely under redused pressure. 1300 ml of acetonitrile was added to the obtained residue and stirred for 15 minutes at 25-30°C. The reaction mixture was cooled to 20-25°C and 116 grams of triethylamine was added to the reaction mixture at 20-25°C. 87.63 grams of methanesulfonylchloride in 500ml of acetonitrile was added to the reaction mixture at 25-30°C over a period of 60 minutes. Stirred the reaction mixture for 60 minutes at 25-35°C. After completion of the reaction, water followed by ethyl acetate was added to the reaction mixture at 25-30°C. Stirred the reaction mixture for 15 min and both the organic and aqueous layers were seperated and the aq.layer was extracted with ethylacetate. Combined the organic layers, washed with water and the organic layer was dried with sodiumsulfate. The solvent was distilled off from the organic layer under reduced pressure. 1800ml of ethylacetate was added to the obtained residue at 25-30°C and stirred for 15 minutes at 25-30°C. 360 ml of ethylacetate HCl was added to the reaction mixture at 25-30°C. The reaction miture was cooled to 0-5°C and stirred for 3hrs. Filtered the obtained solid, washed with chilled ethylacetate to get dronedarone hydrochloride compound of formula-A. Yield: 245gm

Example-10.'Preparation of Dronedarone hydrochloride compound of formula-A

540 ml of aqueous ammonia was added to the mixture of compound of formula-7 (360 grams) in water (3600 ml), and then followed by the addition of 1800 ml of ethylacetate at 25-30°C.The reaction mixture was stirred for 30 min at 25-30°C. Both the organic and aqueous layers separated and the aqueous layer was extracted with ethylactate. The organic layer washed with water and dried with sodiumsulfate. The solvent distilled off from the organic layer completely under redused pressure. 1300 ml of methanol was added to the obtained residue and stirred for 15 minutes at 25-30°C. The reaction mixture was cooled to 20-25°C. 87.63 grams of methanesulfonylchloride in 500ml of methanol was added to the reaction mixture at 25-30°C over a period of 60 minutes. Stirred the reaction mixture for 60 minutes at 25-35°C. After completion of the reaction, water followed by ethyl acetate was added to the reaction mixture at 25-30°C. Stirred the reaction mixture for 15 min and both the organic and aqueous layers were seperated and the aqlayer was extracted with ethylacetate. Combined the organic layers, washed with water and the organic layer was dried with sodiumsulfate. The solvent was distilled off from the organic layer under reduced pressure. 1800ml of ethylacetate was added to the obtained residue at 25-30°C and stirred for 15 minutes at 25-30°C. 360 ml of ethylacetate HC1 was added to the reaction mixture at 25-30°C. The reaction miture was cooled to 0-5°C and stirred for 3hrs. Filtered the obtained solid, washed with chilled ethylacetate to get dronedarone hydrochloride compound of formula-A. Yield: 245gm

Example-11: Purification of Dronedarone hydrochloride compound of formula-A

The mixture of 100 grams of dronedarone hydrochloride and 1700 ml of acetone was heated to 55-60°C and stirred the reaction mixture for 45min at 55-60°C. 10 grams of carbon was added to the reaction mixture at 55-60°C and stirred for 10min at 55-60°C. The reaction mixture was filtered through high-low bed and washed with 100ml of acetone. The filtrate was cooled to 25-30°C and stirred for 30 min at 25-30°C. Further the reaction mixture was cooled to 0-5°C and stirred for 3hrs at 0- 5°C. Filtered the solid, washed with chilled acetone and dried the material to get pure dronedarone hydrochloride. Yield: 91gm

Purity by HPLC : 99.69%, impurity at 1.15 RRT: 0.04%

Particle size distribution : D10: 3.792 μm; D50 : 17.843 μm; D90 : 81.262 μm; D1oo :
490.49 μm

Example-12: Purification of Dronedarone HC1 compound of formula-A.

The mixture of 10 grams of dronedarone hydrochloride and 150 ml of ethanol was heated to 55-60°C and stirred the reaction mixture for 45min at 55-60°C. 10 grams of carbon was added to the reaction mixture at 55-60°C and stirred for 10min at 55-60°C. The reaction mixture was filtered through hyflow bed and washed with ethanol. The filtrate was cooled to 25-30°C and stirred for 30 min at 25-30°C. Further the reaction mixture was cooled to 0-5°C and stirred for 3hrs at 0-5°C. Filtered the solid, washed with chilled ethanol and dried the material to get pure dronedarone hydrochloride. Yield:9.0gm

Example-13:Purification of Dronedarone hydrochloride compound of formula-A
The mixture of 10 grams of dronedarone hydrochloride and 150 ml of acetonitrile was heated to 55-60°C and stirred the reaction mixture for 45min at 55-60°C. 10 grams of carbon was added to the reaction mixture at 55-60°C and stirred for 10min at 55-60°C. The reaction mixture was filtered through hyflow bed and washed with acetonitrile. The filtrate was cooled to 25-30°C and stirred for 30 min at 25-30°C. Further the reaction mixture was cooled to 0-5°C and stirred for 3hrs at 0-5°C. Filtered the solid, washed with chilled acetonitrile and dried the material to get pure dronedarone hydrochloride. Yield:8.5gm

Example-14:Preparation of 2-butyl-5-aminobenzofuran compound of formula-8
A mixture of 2-butyl-5-nitrobenzofuran (10 grams), 2.8 gm of iron turnings, 40ml of etahnol and 20 ml of water was stirred at 25-30°C for 10 minutes. The reaction mixture was cooled to 15-20°C and 40ml of concentrated hydrochloride was added to the reaction mixture at 15-20°C. The temperature of the reaction mixture was raised to 25-30°C and then heated to 65°C. Stirred the reaction mixture was for 3 hours at 65 °C. After completion of the reaction, the reaction mixture was cooled to 25-30°C and the reaction mixture was poured into ice and stirred for 30min.The reaction mixture was filtered and washed with water. 30ml of dichloromethane was added to the filtrate and stirred the reaction mixture for 15 min at 25-30°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers and the pH of the organic layer was adjusted to 8 - 9 by using 10% sodium hydroxide solution .Both the organic and aqueous layers were seperated. Adjusted the pH of the aqueous layer to 1.2 with concentrated hydrochloric acid. The reaction mixture was extracted with dichloromethane and dried the dichloromethane layer with sodiumsulfate. Distilled off the solvent from the organic layer completely under reduced pressure and to get the title compound of formula-8. yield: 6.5 gm

Example-15:Preparation of 2-butyl-3-(4-[3-chloropropoxy]benzoyl)-5-nitrobenzo furan compound of formula-9

100gm of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of formula-4 was dissolved in 1000 ml of acetone at 25°C. 80.0 grams of potassium carbonate was added to the reaction mixture at 25-30°C followed by 136.14 gm of chlorobromopropane was added to the reaction mixture at 25°C.The reaction mixture was heated to 55-60°C and stirred for 20 hrs at 55-60°C. The reaaction mixture was cooled to 25-30°C and further cooled to 0-5°C. Stirred the reaction mixture for 45 min at 0 - 5°C and the reaction mixture was filtered and washed with 200 ml of acetone. Distilled off the solvent from the filtrate completely under reduced pressure to get the compound of formula-9. Yield: 186 gm

Example-16:Preparation of 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyI)-5-nitrobenzo furan compound of formula-5

A mixture of 184gm of 2-butyl-3-(4-[3-chloropropoxy]benzoyl)-5-nitrobenzo furan compound of formula-9 and 930ml of di-n-butylamine was heated to 130-135°C. The reaction mixture was stirred for 6hrs and then cooled to 25-30°C. Distill of the excess di-n-butylamine under reduced pressure. The pH of the reaction mixture was adjusted to pH 1 - 2 by using 950ml of 15% hydrochloric acid solution. 300 ml of toluene was added to the reaction mixture. Both the organic and aqueous layers were separated. The pH of the aqueous layer was adjusted to 8-9 with 500ml of 10% sodiumcarbonate solution .The aqueous layer was extracted with 1000ml of dichloromethane and distill off the organic layer under reduced pressure to give the compound of formula-5 as residue. Yield: 190gm
We claim:

1. An improved process for the preparation of dronedarone hydrochloride which comprises of,

a) Reacting 4-nitrophenol with hydrobromic acid solution and formaldehyde solution in presence of phosphorous tribromide (PBr3) to give 2-(bromomethyl)-4-nitrophenol compound of formula-1,

b) reacting the compound of formula-1 with triphenylphosphine (TPP) in a suitable solvent to provide the wittig salt i.e (2-hydroxy-5-nitro benzyl)triphenylphosphoniumbromide compound of formula-2,

c) reacting the wittig salt compound of formula-2 with pentanoylchloride in presence of organic or inorganic base in a suitable solvent provides the 2-n-butyl-5-nitrobenzofuran compound of formula-3,

d) reacting the compound of formula-3 with 4-hydroxybenzoicacid in presence of thionylchloride and Lewi's acid in a suitable solvent provides 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of formula-4,

e) reacting the compound of formula-4 with l-chloro-3-di-n-butylaminopropane in presence of a base in a suitable reagent to provide 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran compound of formula-5, and subsequent treatment with organic acid to give stable salts of formula-5,

f) reacting the compound of formula-5 with a reducing agent in a suitable solvent to give 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-aminobenzofuran compound of formula-6, and subsequent treatment with suitable organic or inorganic acid selected from oxalic acid, maleic acid, malic acid, succinic acid, acetic acid, hydrochloric acid, preferably oxalic acid to give dioxalate salt of 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-aminobenzofuran compound of formula-7,

g) reacting the compound of formula-7 with methanesulfonylchloride in presence or absence of a base in a suitable solvent and then followed by treatment with hydrochloric acid in a suitable solvent to give dronedarone hydrochloride compound of formula-A,

h) dissolving the dronedarone hydrochloride in a suitable solvent followed by treatment with charcoal and isolating the compound in a suitable solvent to provide pure dronedarone hydrochloride.

2. A process according to claim-1,

i) in step-b, the suitable solvent is selected from aromatic hydrocarbon solvents like toluene or xylene, preferably toluene;

ii) in step-c, the base is preferably an inorganic base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and magnesium carbonate and like, preferably sodium carbonate and the suitable solvent is selected from hydrocarbon solvents such as toluene, xylene ,n-butane, cyclohexane and n-hexane and the like, and the prefered solvent is toluene,

iii) in step-f, the prefered reducing agent is selected from Pd/C, NaBH4 or Fe/HC1, and more preferably Fe/HC1.

3. A process for producing compound of formula-3,

comprises of reacting (2-hydroxy-5-nitro-benzyl) triphenylphosphonium bromide compound of formula-2,

with pentanoylchloride in presence of an inorganic base like sodiumcarbonate in toluene to give the 2-n-butyl-5-nitrobenzofuran compound of formula-3.

4. A process for producing the compound of formula-4,

comprises of, reacting the compound of formula-3 with 4-hydroxy benzoic acid in presence of thionylchloride and Lewi's acid selected from AICI3 ,SnCL4 and FeCl3, preferably AlCl3 in a suitable solvent selected from chlorosolvents, alcohol solvents, ester solvents, nitrile solvents or mixture thereof, preferably chloro solvents and more preferably dichloromethane to give 2-n-butyI-3-(4-hydroxybenzoyl)-5-nitro benzo furan.

5. A process for the preparation of dronedarone hydrochloride of formula-A,

i) Treating 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran
compound of formula-5 with Fe/HC1 in a suitable solvent selected from
methanol, ethanol, isopropylalcohol, water and mixture thereof, preferably the
solvent is mixture of water and ethanol to give 2-butyl-3-(4-[3-(dibutylamino)
propoxy]benzoyl)-5-aminobenzofuran compound of formula-6,

ii) treating 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-aminobenzofuran compound of formula-6 with methanesulfonylchloride in methanol and
subsequent treatment with hydrochloric acid in ester solvents to give dronedarone hydrochloride of formula-A.

6. An improved process for producing dronedarone hydrochloride compound of formula-A comprises of, treating dioxalate salt of 2-butyl-3-(4-[3-dibutyl
amino)propoxy]benzoyl)-5-aminobenzofuran of formula-7.

with ammonia solution and then reacting with methanesulfonylchloride in a suitable solvent selected from alcohol solvents, preferably methanol, ethanol and isopropylalcohol and more preferably in methanol and then followed by treatment with hydrochloric acid in ethylacetate to give dronedarone hydrochloride compound of formula-A.

7. An improved process for preparaing dronedarone hydrochloride which comprises
of,

a) Reacting 4-nitrophenol with hydrobromic acid solution and formaldehyde solution in presence of PBr3 to give 2-(bromomethyl)-4-nitrophenol compound of formula-1,

b) reacting 2-(bromomethyl)-4-nitrophenol compound of formula-1 with triphenylphosphine (TPP) in toluene to give (2-hydroxy-5-nitro-benzyl) triphenylphosphoniumbromide compound of formula-2,

c) reacting (2-hydroxy-5-nitro-benzyl)triphenylphosphoniumbromide compound of formula-2 with pentanoylchloride in presence of sodiumcarbonate in a suitable solvent selected from chloro solvents, alcohol solvents, ester solvents, hydrocarbon solvents and mixture thereof, preferably hydrocarbon solvents and more preferably toluene to give the 2-n-butyl-5-nitrobenzofuran compound of formula-3,

d) reacting 2-n-butyl-5-nitrobenzofuran compound of formula-3 with 4-hydroxy
benzoic acid and thionylchloride in presence of a Lewi's acid selected from
SnCl4, AlCl3, FeCls and preferably A1C13 in a solvent selected from
chlorosolvents, alcohol solvents, ester solvents, nitrile solvents or mixture
thereof, preferably chloro solvents and more preferably dichloromethane to
give 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of formula-4,

e) reacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran compound of formula-4 with l-chloro-3-di-n-butylaminopropane in presence of potassium carbonate in keto solvents to give 2-butyl-3-(4-[3-(dibutylamino) propoxy]benzoyl)-5-nitrobenzofuran compound of formula-5 and, subsequent treatment with organic or inorganic acids to give stable salts of formula-5,

f) reacting 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran compound of formula-5 with Fe/HC1 in a mixture of ethanol and water to give 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-aminobenzofuran compound of formula-6, further reacting with oxalic acid in isopropylalcohol to give dioxalte salt of 2-butyl-3-(4-
[3-(dibutylamino) propoxy]benzoyl)-5-aminobenzofuran compound of formula-7,

g) reacting dioxalte salt of 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-aminobenzofuran compound of formula-7 with methanesulfonylchloride in presence of triethylamine in acetonitrile and then followed by treatment with hydrochloric acid in ethyl acetate to give dronedarone hydrochloride compound of formula-A,

h) dissolving the dronedarone hydrochloride in a suitable solvent selected from acetone, ethanol, acetonitrile or mixture thereof and followed by treatment with charcoal to give the pure dronedarone hydrochloride.

8. A novel process for preparing 2-butyl-3-(4-(3-chloropropoxy)benzoyl)-5- nitrobenzofuran compound of formula-9 comprises of, reacting 2-n- butyl-3-(4- hydroxybenzoyl)-5-nitrobenzofuran compound of formula-4 with chlorobromopropane in presence of an inorganic base like potassium carbonate in a suitable solvent, preferably acetone to give 2-butyl-3-(4-(3-chloropropoxy) benzoyl)-5-nitrobenzofuran compound of formula-9.

9. Benzofuran derivatives having the structural formula,
where, L- represents a leaving group which may be a halogen or -OTs or -OMs

10. Novel process for producing crystalline form of dronedarone hydrochloride
compound of formula-A comprises of,

a) Dissolving the dronedarone hydrochloride in ethanol, acetonitrile or mixture thereof,

b) heating the reaction mixture,

c) treating the reaction mixture with charcoal,

d) filtering the reaction mixture through hyflow,

e) cooling the filtrate to obtain the solid.