PREPARATION OF DRONEDARONE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

INTRODUCTION

Aspects of the present application relate to processes for the preparation of dronedarone, including intermediates and salts thereof. Particular aspects relate to solid forms of dronedarone and salts thereof.

The drug compound having the adopted name "dronedarone hydrochloride" has a chemical name N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl} methanesulfonamide, hydrochloride and is represented by structural Formula I.

Formula I

Dronedarone is a benzofuran derivative, having anti-arrhythmic properties. The dronedarone hydrochloride salt is the active ingredient in a commercially available product having the trademark MULTAQ, sold in the form of film coated tablets containing the equivalent of 400 mg of dronedarone.

U.S. Patent No. 5,223,510 ("US '510") discloses dronedarone and related compounds, along with their pharmaceutically acceptable salts. It also describes pharmaceutical compositions comprising dronedarone and their use in the treatment of arrhythmia. Further, it describes a process for the preparation of dronedarone hydrochloride.
The process described in US '510 has some disadvantages, such as use of platinum oxide for reduction, use of organic base in the methanesulfonyl chloride reaction, and involving chromatography for purifications. Platinum oxide is an expensive reagent. Removing residual organic bases from the reaction mixture is difficult and they are believed to be potentially genotoxic. Purification by chromatography is not desirable for commercial-scale manufacturing.

There is a continuing need to develop simplified processes for preparing dronedarone and its salts, which processes are suitable for commercial manufacturing in high purity and yield.

SUMMARY OF THE INVENTION

Aspects of the present application provide processes for preparing dronedarone and its salts, using common reagents and process conditions.

In an aspect, this application provides process for preparing 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n- butylbenzofuran of Formula VI, or a salt thereof, embodiments comprising:

a) reacting 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran of Formula II
with a Lewis acid reagent, in a solvent medium comprising chlorobenzene, to obtain
2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of Formula III,

b) reacting compound of Formula III with 1-chloro-3-di-n-butylaminopropane
of Formula IV, to obtain 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-
nitrobenzofuran of Formula V,

c) optionally, isolating the 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl]
5-nitrobenzofuran of Formula V; and

d) reducing 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-
nitrobenzofuran of Formula V, in the presence of a metal catalyst and ammonium
formate, to obtain 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-
butylbenzofuran of Formula VI;

In an aspect, the application provides process for preparing 1-chloro-3-di-n-butylaminopropane of Formula IV, embodiments comprising reacting 1-bromo-3-chloroDroDane of Formula VIII with di-n-butvlamine of Formula IX.

In an aspect, the application provides process for the preparation of dronedarone or a pharmaceutically acceptable salt thereof, embodiments comprising:

a) reacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of Formula III with 1-chloro-3-di-n-butylaminopropane of Formula IV, to obtain 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitrobenzofuran of Formula V,

b) optionally, isolating the 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitrobenzofuran of Formula V; and

c) reducing 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitrobenzofuran of Formula V, in the presence of a metal catalyst and ammonium formate, to obtain 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n- butylbenzofuran of Formula VI;

d) optionally, converting the compound of Formula VI into a suitable salt

e) reacting compound of Formula VI or its salt with methanesulfonyl chloride, in the presence of an inorganic base, to obtain dronedarone of Formula VII; and

f) optionally, converting dronedarone into a pharmaceutically acceptable salt.

In an aspect, the application relates to process for the preparation of dronedarone hydrochloride, comprising reacting dronedarone with hydrochloric acid, in the presence of a suitable solvent.

In an aspect, the application provides process for the preparation of 2-n-butyl-5-nitrobenzofuran of Formula XIII or a salt thereof, embodiments comprising:

a) reacting hexan-2-one oxime of Formula XI with 1-bromo-4-nitrobenzene of Formula X in presence of a base to obtain hexan-2-one -O-(4-nitrophenyl) oxime of Formula XII

b) cyclizing the compound of Formula XII to obtain 2-n-butyl-5-nitrobenzofuran of
Formula XIII,

In an aspect, the application provides process for the preparation of 2-n-butyl-5-nitrobenzofuran of Formula XIII or a salt thereof, embodiments comprising:

a) reacting 4-nitro phenol of Formula XIV with hexanoyl chloride of Formula XV in presence of a base to obtain 4-nitrophenyl hexanoate of Formula XVI,

b) by Fries rearrangement converting the compound of Formula XVI to 1-(2-hydroxy-5-nitrophenyl)hexan-1-one of Formula XVII,

c) methylating the compound of Formula XVII to obtain 1-(2-methoxy-5-
nitrophenyl)hexan-1-one of Formula XVIII

Formula XVIII

d) brominating the compound of Formula XVIII to obtain 2-bromo-1-(2-
methoxy-5-nitrophenyl)hexan-1-one of Formula XIX,

Formula XIX

e) demethylating the compound of Formula XIX to obtain 2-bromo-1-(2-
methoxy-5-nitrophenyl)hexan-1-one of Formula XX; and

Formula XX

f) cyclizing and reducing the compound of Formula XX to obtain 2-n-butyl-5-
nitrobenzofuran of Formula XIII,

Formula XIII

In an aspect, this application provides crystalline polymorphic Form A of dronedarone and processes for its preparation.

In an aspect, this application provides crystalline polymorphic Form I of dronedarone hydrochloride and processes for its preparation.

In an aspect, the application relates to an amorphous form of dronedarone hydrochloride and processes for its preparation.

In an aspect, this application provides dronedarone or a pharmaceutically acceptable salt thereof, prepared by the processes herein described above, having less than about 0.5 area % of total impurities as measured by high performance liquid chromatography (HPLC).
In an aspect, this application provides dronedarone or a pharmaceutically acceptable salt thereof, prepared by the processes herein described above, having less than about 0.15 area % of any individual impurity as measured by high performance liquid chromatography (HPLC).

In an aspect, this application provides dronedarone hydrochloride having a purity of greater than about 99.8 area % as measured by high performance liquid chromatography.
In an aspect, this application provides dronedarone hydrochloride having less than about 0.2 area % of total impurities as measured by high performance liquid chromatography.
In an aspect, this application provides dronedarone hydrochloride having less than about 0.15 area % of any individual impurity as measured by high performance liquid chromatography.

Aspects of the present application also relate to pharmaceutical compositions comprising dronedarone or a salt thereof, obtained by a process described in this application.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline dronedarone base, prepared according to Example 9.

Fig. 2 is an XRPD pattern of amorphous dronedarone hydrochloride, prepared according to Example 17.

Fig. 3 is an XRPD pattern of crystalline Form I of dronedarone hydrochloride, prepared according to Example 11.

Fig. 4 is a differential scanning calorimetry (DSC) pattern of dronedarone hydrochloride crystalline Form I, prepared according to Example 11.

DETAILED DESCRIPTION

In an aspect, this application provides processes for preparing 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n- butylbenzofuran of Formula VI, or a salt thereof, embodiments comprising:

a) reacting 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran of Formula II with a Lewis acid reagent, in a solvent medium comprising chlorobenzene, to obtain 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of Formula III,

b) reacting compond of Formula III with 1-chloro-3-di-n-butylaminopropane of Formula IV, to obtain 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitrobenzofuran of Formula V,

c) optionally, isolating the 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl]
5-nitrobenzofuran of Formula V; and

d) reducing 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-
nitrobenzofuran of Formula V, in the presence of a metal catalyst and ammonium
formate, to obtain 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-
butylbenzofuran of Formula VI;

Compound of Formula II may be obtained by any process including processes described in the art, or by a process described in this application.

Suitable Lewis acid reagents that may be used in the process of step a) include, for example, aluminum chloride, stannic chloride, and the like.

Quantities of Lewis acid reagent may range from about 1 to about 4 moles, or about 2 to about 3 moles, per mole of compound of Formula II.

Due to its high boiling temperature, a chlorobenzene solvent facilitates the reaction to be carried out at relatively high temperatures. Most of the chlorobenzene that is used in the reaction of step a) may be recovered and reused, as the solvent has low volatility.
Quantities of solvent used for the process may be from about 2 mL to about 20 mL, preferably about 3 mL to about 10 mL, per gram of compound of Formula II.

The process of step a) is suitably carried out at temperatures ranging from about 25°C to about 100°C, preferably about 75°C to about 85°C.

Step b) involves reaction of compound of Formula III with 1-chloro-3-di-n-butylaminopropane of Formula IV, to obtain compound of Formula V.

Suitably, the reaction of step b) is carried out in the presence of an inorganic base. Suitable inorganic bases that may be used include, but are not limited to: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, and the like; bicarbonates of alkali metals, such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and any mixtures thereof.

Suitable solvents that can be used for the reaction include, but are not limited to: alcohols such as methanol, ethanol, isopropanol (IPA), n-butanol, tert-butanol, and the like; halogenated hydrocarbons such as dichloromethane (DCM), ethylene dichloride, chloroform, and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; esters such as ethyl acetate, propyl acetate, and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone (MIBK), and the like; and any mixtures thereof.

The process of step b) is suitably carried out at temperatures ranging from about 50°C to about 100°C, preferably about 70°C to about 80°C.

After completion of the reaction, a salt by-product can be removed using techniques such as filtration. The organic layer containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.

Step c) involves reducing 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitrobenzofuran of Formula V, in the presence of a metal catalyst and ammonium formate, to obtain 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butylbenzofuran of Formula VI;

Suitable metal catalysts for use in step c) include palladium, nickel, and the like. The reaction may also be carried out in formic acid and ammonium formate.

The process of step c) may be carried out in a suitable solvent, such as methanol, ethanol, isopropanol, and the like.

The process of step c) is suitably carried out at temperatures ranging from about 30°C to about 100°C, preferably about 55°C to about 65°C.

After completion of the reaction, the catalyst may be removed using techniques such as filtration. The filtrate containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.

The product recovered may be further purified by a suitable technique before progressing to the next step. In embodiments, the product is converted to an acid addition salt such as an oxalate salt, and then is converted to free base.

In embodiments, the oxalate salt is a dioxalate and it is isolated in the form of a crystalline solid. The dioxalate salt of compound of Formula VI can be converted to free base by reacting with a suitable base.

In an aspect, the application provides processes for preparing 1-chloro-3-di-n-butylaminopropane of Formula IV, embodiments comprising reacting 1-bromo-3-chloropropane of Formula VIII with di-n-butylamine of Formula IX.

Suitably, the reaction may be conducted with or without addition of an external base. Suitable inorganic bases that may be used include, but are not limited to: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, and the like; bicarbonates of alkali metals, such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and any mixtures thereof.

The process is suitably carried out at temperatures ranging from about 25°C to about 60°C, or about 40°C to about 45°C.

After completion of the reaction, the product may be extracted into a suitable water immiscible solvent, such as, for example, toluene, ethyl acetate, methyl ethyl ketone, and the like.

The organic layer containing the product may be distilled completely to produce a residue, or it may be directly used in the next processing step.

In an aspect, the application provides processes for the preparation of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran of Formula II or a salt thereof, embodiments comprising:

a) reacting hexan-2-one oxime of Formula XI with 1-bromo-4-nitrobenzene of Formula X in presence of a base to obtain hexan-2-one -0-(4-nitrophenyl) oxime of Formula XII
b) cyclizing the compound of Formula XII to obtain 2-n-butyl-5-nitrobenzofuran of Formula XIII,

Compound of Formula XI may be obtained by any process including processes described in the art, or by a process described in this application.

Suitable base that may be used in the process of step a) include, but are not limited to, organic bases such as triethyl amine, tributyl amine, N-methylmorpholine, pyridine, 4-dimethylamino pyridine and the like; inorganic bases such as alkali metal hydrides like sodium hydride, lithium hydride, and the like; alkali metal alkoxides like sodium methoxide, sodium ethoxide, potassium t-butoxide and the like; alkali metal carbonates, such as sodium carbonate, potassium carbonate and the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. Of these the alkali metal hydrides and hydroxides are preferred. The amount of base employed is from about an equimolar amount to about 5 times the equimolar amount with respect to the compound of formula XI.

The reaction is effected in the presence of a solvent. The solvents that can be used include, but are not limited to, ethers such as diethyl ether, tetrahydrofuran (THF) and the like; halogenated solvent such as dichloromethane, ethylene dichloride, chloroform and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile and the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene and the like and mixtures thereof. Preferably the solvent is tetrahydrofuran.

The reaction is carried out at a temperature from about -10°C to about 70°C or reflux temperatures of the solvents used. Preferably from about 0°C to about 40°C.

The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period from about 30 minutes to about 10 hours, preferably from about 30 minutes to about 5 hours, is sufficient.

Step b) involves cyclization of the compound of Formula XII to obtain compound of Formula XIII. The process of cyclization is carried out in the presence of an acid and a weak lewis acid.

The acid used in the cyclization process includes, but are not limited to an organic acid such as acetic acid, formic acid, trifluoroacetic acid, propionic acid, para-toluenesulfonic acid, benzenesulfonic acid and the like. Preferably the organic acid is acetic acid. Inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like. Preferably the inorganic acid is hydrochloric acid.

The lewis acid that may be used in the cyclization process includes, but are not limited to, zinc chloride, zinc nitrate, magnesium chloride and the like. Preferably the lewis acid is zinc chloride. The amount of lewis acid employed is from about an equimolar amount to about 5 times the equimolar amount with respect to the compound of formula XII, preferably from about an equimolar amount to about 3 times the equimolar amount with respect to the compound of formula XII.

The reaction is carried out at a temperature from about 0°C to about 150°C. Preferably from about 30°C to about 80°C.

In an aspect, the application provides processes for the preparation of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran of Formula II or a salt thereof, embodiments comprising:

a) reacting 4-nitro phenol of Formula XIV with hexanoyl chloride of Formula XV in presence of a base to obtain 4-nitrophenyl hexanoate of Formula XVI,

b) by Fries rearrangement converting the compound of Formula XVI to 1-(2-hydroxy-5-nitrophenyl)hexan-1-one of Formula XVII,

c) methylating the compound of Formula XVII to obtain 1 -(2-methoxy-5-nitrophenyl)hexan-1-one of Formula XVIII

d) brominating the compound of Formula XVIII to obtain 2-bromo-1-(2-methoxy-5-nitrophenyl)hexan-1-one of Formula XIX,

e) demethylating the compound of Formula XIX to obtain 2-bromo-1-(2-methoxy-5-nitrophenyl)hexan-1-one of Formula XX; and

f) cyclizing the compound of Formula XX to obtain 2-n-butyl-5-nitrobenzofuran of Formula XIII,
ruiiiiuid AMI

In an aspect, the application provides processes for preparing dronedarone or any pharmaceutically acceptable salt thereof, embodiments comprising:

a) reacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of Formula III with 1-chloro-3-di-n-butylaminopropane of Formula IV, to obtain 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitrobenzofuran of Formula V,

b) optionally, isolating the 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitrobenzofuran of Formula V; and

c) reducing 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitrobenzofuran of Formula V, in the presence of a metal catalyst and ammonium formate, to obtain 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n- butylbenzofuran of Formula VI;

d) optionally, converting the compound of Formula VI into a suitable salt

e) reacting compound of Formula VI or its salt with methanesulfonyl chloride, in the presence of an inorganic base, to obtain dronedarone of Formula VII; and

f) optionally, converting dronedarone into a pharmaceutically acceptable salt.

Step a) involves reaction of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of
Formula III with 1-chloro-3-di-n-butylaminopropane of Formula IV, to obtain compound of Formula V.

Suitably, the reaction of step a) is carried out in the presence of an inorganic base. Suitable inorganic bases that may be used include, but are not limited to: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, and the like; bicarbonates of alkali metals, such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and any mixtures thereof.

Suitable solvents that can be used for the reaction include, but are not limited to: alcohols such as methanol, ethanol, isopropanol (IPA), n-butanol, tert-butanol, and the like; halogenated hydrocarbons such as dichloromethane (DCM), ethylene dichloride, chloroform, and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; esters such as ethyl acetate, propyl acetate, and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone (MIBK), and the like; and any mixtures thereof.

The process of step a) is suitably carried out at temperatures ranging from about 50°C to about 100°C, preferably about 70°C to about 80°C.

After completion of the reaction, a salt by-product can be removed using techniques such as filtration. The organic layer containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.

Suitable metal catalysts for use in step c) include palladium, nickel, and the like. The reaction may also be carried out in formic acid and ammonium formate.

The process of step c) may be carried out in a suitable solvent, such as methanol, ethanol, isopropanol, and the like.

The process of step c) is suitably carried out at temperatures ranging from about 30°C to about 100°C, or about 45°C to about 55°C.

After completion of the reaction, the catalyst may be removed using techniques such as filtration. The filtrate containing the product may be distilled completely to produce a residue, or it may be used directly in the next reaction step.

The product recovered may be further purified by a suitable technique before progressing to the next step. In embodiments, the product is converted to an acid addition salt such as an oxalate salt, and then is converted to free base.

In embodiments, the oxalate salt is a dioxalate and it is isolated in the form of a crystalline solid. The dioxalate salt of compound of Formula VI can be converted to free base by reacting with a suitable base.

Step e) involves reacting compound of Formula VI or its salt with methanesulfonyl chloride, in the presence of an inorganic base, to obtain dronedarone of Formula VII.

Suitable inorganic bases that may be used include: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, and the like; bicarbonates of alkali metals, such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and any mixtures thereof.

Suitable solvents that can be used for the reaction include, but are not limited to: halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; esters such as ethyl acetate, propyl acetate, and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and the like; and any mixtures thereof.
The process of step e) is suitably carried out at temperatures ranging from about 20°C to about 40°C, or about 25°C to about 35°C.

Inorganic bases are inexpensive and relatively easy to remove from the reaction mixture, as compared to organic amine bases.

After completion of the reaction, the formed salt by-product can be removed by filtration. The organic layer containing the product can be distilled completely to obtain a residue, or it may be used directly in the next reaction step.

In embodiments, dronedarone free base obtained by the above process may be purified, using suitable technique such as crystallization. Suitably, dronedarone is dissolved in solvent to obtain a solution and the solution is cooled to a lower temperature for crystallization of the product.

Suitable solvents that may be used for crystallization include, but are not limited to: aliphatic hydrocarbons such as n-hexane, n-heptane, cyclohexane, and the like; alcohols such as methanol, ethanol, isopropanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; ethers such as diethyl ether, diisopropyl ether, and the like; esters such as ethyl acetate, propyl acetate, and the like; nitriles such as acetonitrile, propionitrile, and the like; water; and any mixtures thereof.
The solid product obtained can be recovered from the reaction mixture using suitable techniques, such as decantation, filtration by gravity or by suction, centrifugation, and the like. The crystals so isolated can carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired, the crystals can be washed with a solvent to wash out residual mother liquor.

If desired, the obtained wet solid may be dried. Drying may be done in a tray dryer, air oven, vacuum dryer, spin flash dryer, fluidized bed dryer, flash dryer, etc. The drying may be carried out at temperatures ranging from about 50°C to about 75°C, with or without vacuum, and in the presence or absence of an inert atmosphere like nitrogen, argon, neon, and helium. The drying may be done for any desired times to get the desired product purity, such as from about 30 minutes to about 2 hours, or longer.

In an aspect, this application provides crystalline form A of dronedarone and processes for its preparation.

The crystalline form A of dronedarone obtained by processes described herein may be characterized by an XRPD pattern having peaks located at about 5.4, 8.1, 10.9, 19.1, 19.9, and 20.4 ± 0.2 degrees 2 theta.

The crystalline form A of dronedarone obtained by a process as in Example 5 hereof also may be characterized by its XRPD pattern having peaks located substantially as depicted in Fig. 1.

Optional step f) involves converting dronedarone into a pharmaceutically acceptable salt.
Some pharmaceutically acceptable acids that can be used for salt formation include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, and the like.

In embodiments, the acid is hydrochloric acid and the resulting acid addition salt is dronedarone hydrochloride.

Dronedarone used in the process may be obtained by a process described hereinabove, or from any other processes. Suitably, any polymorphic form of dronedarone may be used, e.g., crystalline, amorphous, or mixtures thereof.

Suitable solvents that may be used include, but are not limited to: aliphatic hydrocarbons such as n-hexane, n-heptane, cyclohexane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, chlorobenzene, and the like; alcohols such as methanol, ethanol, isopropanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; ethers such as diethyl ether, diisopropyl ether, and the like; esters such as ethyl acetate, propyl acetate, and the like; nitriles such as acetonitrile, propionitrile, and the like; water; and any mixtures thereof.

Dronedarone may be mixed with about 5 mL to about 30 mL of the solvent, per gram of dronedarone.

Quantities of acid may range from about 0.5 to about 3 moles, or about 1 to about 2 moles, per mole of dronedarone.

The reaction may be carried out at temperatures from about 20°C to about 40°C. The mixture may be stirred for any desired time periods to get the desired product, such as from about 30 minutes to about 2 hours, or longer.

The solid product obtained can be recovered from the reaction mixture using any suitable techniques such as decantation, filtration by gravity or by suction, centrifugation, and the like. The crystals so isolated can carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired, the crystals can be washed with a solvent to wash out residual mother liquor.

The obtained wet solid may be dried. Drying may be done using a tray dryer, air oven, vacuum dryer, spin flash dryer, fluidized bed dryer, flash dryer, etc. The drying may be carried out at temperatures from about 40°C to about 70°C, with or without vacuum, and in the presence or absence of an inert atmosphere like nitrogen, argon, neon, and helium. The drying may be done for any desired times to get the desired product purity, such as from about 30 minutes to about 2 hours, or longer.

In an aspect, the application relates to processes for the preparation of dronedarone hydrochloride, comprising reacting dronedarone with hydrochloric acid, in the presence of a suitable solvent.

Dronedarone used in the process may be obtained by a process described hereinabove, or from any other processes. Suitably, any polymorphic form of dronedarone may be used, e.g., crystalline, amorphous, or mixtures thereof.

Suitable solvents that may be used include, but are not limited to: aliphatic hydrocarbons such as n-hexane, n-heptane, cyclohexane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, chlorobenzene, and the like; alcohols such as methanol, ethanol, isopropanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; ethers such as diethyl ether, diisopropyl ether, and the like; esters such as ethyl acetate, propyl acetate, and the like; nitriles such as acetonitrile, propionitrile, and the like; water; and any mixtures thereof.

Suitable hydrochloric acid reagents for conversion of free base into the hydrochloride include but are not limited to methanolic hydrogen chloride in methanol, isopropanol, ethyl acetate, or an ether, aqueous hydrochloric acid, gaseous hydrogen chloride, and the like.

Dronedarone may be mixed with about 5 mL to about 30 mL of the solvent, per gram of dronedarone.

The reaction may be carried out at temperatures from about 20°C to about 40°C. The mixture may be stirred for any desired time periods, to get the desired product, such as from about 30 minutes to about 2 hours, or longer.

The solid product obtained is recovered from the reaction mixture using any suitable techniques such as decantation, filtration by gravity or by suction, centrifugation, and the like. The crystals so isolated can carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired, the crystals can be washed with a solvent to wash out residual mother liquor.
The obtained wet solid may be dried. Drying may be done using a tray dryer, air oven, vacuum dryer, spin flash dryer, fluidized bed dryer, flash dryer, etc. The drying may be carried out at temperatures from about 40°C to about 70°C, with or without vacuum, and in the presence or absence of an inert atmosphere like nitrogen, argon, neon, and helium. The drying may be done for any desired times to get the desired product purity, such as from about 30 minutes to about 2 hours, or longer.

Dronedarone hydrochloride obtained by a process described in this application is in the form of a crystalline solid (hereinafter designated as "crystalline Form I"), and can be characterized by an XRPD pattern substantially in accordance with the pattern of Fig. 3.
Crystalline Form I of dronedarone hydrochloride obtained by a process described in this application can also be characterized by an XRPD pattern having significant peaks located at about 7.7, 8.1, 13.1, 13.9, 15.8, 21.5, 21.7, and 26.1, ± 0.2 degrees 29.
Crystalline Form I of dronedarone hydrochloride can also be characterized by a differential scanning calorimetry curve substantially in accordance with the curve of Fig. 4. Crystalline Form I of dronedarone hydrochloride can also be characterized by a DSC curve having an endotherm at about 142°C.

Dronedarone and its salts, such as a hydrochloride salt, prepared in accordance with the present invention, contain less than about 0.2%, or less than about 0.1%, by weight of dronedarone-related impurities, as characterized using high performance liquid chromatography (HPLC) analysis techniques.

In an aspect, the application relates to an amorphous form of dronedarone hydrochloride, either alone or in combinations with pharmaceutically acceptable carriers, and processes for its preparation.

Amorphous dronedarone hydrochloride, either alone or in combination with a pharmaceutically acceptable carrier, can be characterized by its XRPD pattern. Amorphous dronedarone hydrochloride, either alone or in combination with a pharmaceutically acceptable carrier, can be characterized by its XRPD pattern being a halo with no sharp peaks, substantially in accordance with Fig. 2.

The amorphous dronedarone hydrochloride obtained by the process of present application is substantially free from a crystalline form.

In embodiments the amorphous form of dronedarone hydrochloride contains less than about 10%, or less than about 5%, or less than about 2%, by weight of a crystalline dronedarone hydrochloride.

Amorphous solid dronedarone hydrochloride may be prepared by processes comprising:

a) providing a solution comprising dronedarone hydrochloride and a volatile organic solvent; and

b) removing the solvent.

Step a) involves providing a solution of dronedarone hydrochloride, either alone or in combination with a pharmaceutically acceptable carrier, in a suitable solvent. The solution of dronedarone hydrochloride may be obtained by dissolving the compound in a suitable solvent, or such a solution may be obtained directly from a reaction in which the compound is formed. When the solution is prepared by dissolving dronedarone hydrochloride in a suitable solvent, any polymorphic form such as any crystalline form, including any solvates and hydrates, may be utilized for preparing the solution.

When the solution is prepared in combination with a pharmaceutically acceptable carrier, the order of charging the different ingredients is not critical for the product obtained. A specific order may be preferred with respect to the equipment actually used and will be easily determined by a person skilled in the art.

Solvents which are useful for dissolving dronedarone hydrochloride, either alone or in combination with a pharmaceutically acceptable carrier, include, but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, and n-propanol; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride; ketones such as acetone, ethyl methyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, and t-butyl acetate; ethers such as diethyl ether, dimethyl ether, and diisopropyl ether; hydrocarbons such as toluene, xylene, n-heptane, cyclohexane, and n-hexane; nitriles such as acetonitrile and propionitrile; and mixtures thereof or their combinations with water in various proportions.

Pharmaceutically acceptable carriers that are useful for the preparation of amorphous combinations with dronedarone hydrochloride include, but are not limited to, pharmaceutical hydrophilic carriers such as polyvinylpyrrolidones (homopolymers or copolymers of N-vinylpyrrolidone), gums, cellulose derivatives (including hydroxypropyl methylcelluloses, hydroxypropyl celluloses, and others), cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, polyethylene glycols, polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, and propylene glycol derivatives. The use of mixtures of more than one pharmaceutical carrier to provide desired drug release profiles, or for the enhancement of stability, is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are within the scope of this invention without limitation.

The solution may optionally be treated with materials such as carbon or other adsorbing agents like silica gel, or sodium sulfate, for clarification.

Step b) involves removing the solvent.

Removal of the solvent may be carried out suitably using techniques such as evaporation, atmospheric distillation, or distillation under vacuum.

Distillation of the solvent may be conducted under a vacuum, such as below about 100 mm Hg to below about 600 mm Hg, at elevated temperatures such as about 20°C to about 70°C.

Techniques which are useful for distillation include, without limitation thereto, distillation using a rotational evaporator device such as a Buchi Rotavapor, spray drying, and thin film drying.

The amorphous material obtained from step b) can be collected from the equipment using techniques such as by scraping, or by shaking the container or by adding a non-solvent liquid, as is appropriate for the device used.

The solid product may be dried. The drying can be carried out at reduced pressures, such as below about 200 mm Hg or below about 50 mm Hg, at temperatures such as about 35°C to about 70°C. The drying is carried out for any desired time period that achieves the desired purity, such as times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications.

The X-ray powder diffraction patterns described herein are generated using a Bruker AXS, DS Advance Powder X-ray powder diffractometer, with copper K-alpha radiation.
Differential scanning calorimetric analyses are carried out in a DSC Q1000 Model from TA Instruments with a ramp of 10°C/minute, the starting temperature being 40°C and the ending temperature being 200°C.

In an aspect, this application provides dronedarone hydrochloride, prepared by the processes herein described above, having each one or none of the following impurities, at amount determined by high performance liquid chromatography (HPLC), namely:

Formula A: N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)-N-(methylsulfonyl)methanesulfonamide.

Formula B: (5-amino-2-butylbenzofuran-3-yl)(4-hydroxyphenyl)methanone

Formulae: (5-amino-2-butylbenzofuran-3-yl)(4-methoxyphenyl)methanone

Formula D: N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)formamide

Formula E: (2-butyl-5-((3-(dibutylamino)propyl)amino)benzofuran-3-yl)(4-(3-(dibutylamino)propoxy)phenyl)methanone

Formula F: N1.N1.N3.N3-tetrabutvlDroDane-1.3-diamine dioxalate salt

In an aspect, this application provides dronedarone hydrochloride, prepared by the processes herein described above, having any or each one the above described impurities in an amount less than about 0.15%.

In an aspect, this application provides dronedarone hydrochloride, prepared by the processes herein described above, having a purity as measured by high performance liquid chromatography (HPLC) of at least about 98%, more preferably, at least about 99% and most preferably at least about 99.5%.

Preferably the chemical purity of the dronedarone hydrochloride is about 99% or more, more preferably about 99.5% or more, most preferably about 99.8% or more as measured by high performance liquid chromatography (HPLC).

In an aspect, this application provides dronedarone or a pharmaceutically acceptable salt thereof, prepared by the processes herein described above, having less than about 0.20% of any single impurity as measured by area under HPLC peaks. Preferably, the dronedarone or a pharmaceutically acceptable salt thereof, prepared by the processes herein described above, has less than about 0.15% of any single impurity as measured by area under HPLC peaks.

In an aspect, this application provides dronedarone or a pharmaceutically acceptable salt thereof, prepared by the processes herein described above, as analyzed chemical purity using high performance liquid chromatography (HPLC) with the conditions described below:

Column: Inertsil C8 - 3, 150mm x 4.6 mm ID, 3jam.

Column Temperature: 25°C.

Mobile phase: Mobile phase A=Buffer [Buffer: dissolved 1.36gms of KH2P04
and 3.39gms of Tetra butyl ammonium hydrogen sulfate in 1000ml_ of MQ water,
then sonicated, degassed and filtered through 0.22pm].
Mobile phase B: Mixed Acetonitrile and MQ water in the ratio 900:100 (v/v), then degassed and filtered through 0.22pm.

Diluent: Methanol: Buffer: Water in the ratio of 2:4:4 (v/v/v)

Flow Rate: 0.8mL per minute

Detection: 288 nm

Injection Volume: 10uL

In an aspect, this application provides dronedarone or a pharmaceutically acceptable salt thereof, prepared by the processes herein described above, has residual organic solvents or organic volatile impurities less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines, which are less than about 100 ppm of dichloromethane, less than about 100 ppm of n-hexane, less than about 50 ppm of diacetone alcohol and mesityl oxide, 500 ppm of acetone, ethyl acetate, isopropyl alcohol, tetrahydrofuran (THF) chlorobenzene.

In an aspect, this application provides dronedarone hydrochloride, prepared by the processes herein described above, can have a D50 and D90 particle size of less than about 400 microns, preferably less than about 100 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns and most preferably less than about 10 microns. The particle size can be determined by such techniques as, for example, Malvern light scattering, a laser light scattering technique, etc., using, e.g., a Malvern(R) Mastersizer 2000. It is noted the notation Dx means that X % of the particles have a diameter less than a specified diameter D. Thus, a D50 of about 250 urn means that 50% of the particles composition comprising of dronedarone or its pharmaceutically acceptable salts have a diameter less than about 250 urn.

The particle sizes of the dronedarone or its pharmaceutically acceptable salts obtained by, for example, milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state dronedarone or its pharmaceutically acceptable salts to the desired the foregoing desired particle size range.

Aspects of the present application also relate to pharmaceutical compositions comprising dronedarone or a salt thereof, obtained by a process described in this application.
Pharmaceutical compositions comprising dronedarone or a salt thereof, and their combinations with pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; and liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions. Formulations may be in the form of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using process steps such as direct blending, dry granulation, wet granulation, or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.

Pharmaceutical^ acceptable excipients that are useful for preparing formulations include, but are not limited to, any one or more of: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcellulosess, ethyl celluloses, methyl celluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES

Example 1: Preparation of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran (compound of Formula II)

2-Butyl-5-nitrobenzofuran (50 g) was charged into a 1 L round bottom flask containing DCM (500 ml_). 4-Methoxybenzoyl chloride (40.2 mL) and AICI3 (45.5 g) were added and stirring was continued for about 6 hours at 25-30°C. Then reaction massw as cooled to about 5°C and water (350 mL) was added slowly and stirred for about 15 minutes. The aqueous layer was separated and extracted with DCM (350 mL). The combined organic layer was washed with water (2x350 mL) and the organic layer was separated and then distilled completely under vacuum below 50°C. Isopropanol (100 mL) was charged to the residue and distilled completely under vacuum below 60°C. Isopropanol (150 mL) was charged to the residue and stirred for 15 minutes at 50-55°C and the mixture was cooled to 0-5°C and maintained for about 2 hours. The formed solid was filtered and the wet solid was washed with isopropanol (25 mL) and the solid was dried at 55-60°C for 5 hours, to produce 58 g of the title compound as a crystalline solid.

Purity by HPLC: 96.81%

Example 2: Preparation of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (compound of Formula III) using chlorobenzene solvent.

The compound prepared in Example 1 (58 g) was charged into a 1 L round bottom flask and chlorobenzene and aluminum chloride (65.6 g) were added and the mixture was heated to 75-80°C and stirred for about 5 hours at 70-75°C and then cooled to 60-65°C. Water (348 mL) was added and the mixture was cooled to 25-35°C. DCM (348 mL) was added and the mixture was stirred for about 30 minutes. The organic layer was separated and washed with water (2x348 mL). The organic layer was distilled completely under vacuum below 70°C. Chlorobenzene (116 mL) was charged to the residue and stirred for 15 minutes. The mixture was cooled to 0-5°C and stirred for about 2 hours at 0-5°C. The formed solid was filtered and the wet solid was washed with chlorobenzene (58 mL). The solid was dried at 55-60°C for 3 hours, to produce 42 g of the title compound as a crystalline solid.

Purity by HPLC: 98.72 % Example 3: Preparation of 2-n-butyl-3-(4-hydroxy benzoyl) 5-nitro benzofuran (compound of Formula III) using DCM solvent
The compound obtained in Example 1 (5 g) was charged into a 250 mL round bottom flask and DCM (35 mL) and aluminum chloride (4.33 g) were added and the mixture was heated to 40-45°C. The mixture was stirred for about 5 hours at 40-45°C and then cooled to 25-35°C. Water (35 mL) was added and the mixture was stirred for about 30 minutes. The aqueous layer was separated and extracted with DCM (35 mL). The combined organic layer was washed with saturated sodium bicarbonate solution (2x50 mL). The organic layer was distilled completely under vacuum below 60°C. n-Hexane (50 mL) was charged to the residue and stirred for 2 hours at 25-35°C. The solid was filtered and the wet solid was washed with n-hexane (25 mL) and the solid was dried at 55-60°C for 3 hours, to produce 3.4 g of the title compound as a crystalline solid.

Example 4: Preparation of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitrobenzofuran (compound of Formula V).

sodium carbonate (3.2 g)and DM water (60 mL) were charged into a 250 mL round bottom flask and N-butyl-N-(3-chloropropyl)butan-1 -amine oxalate (CDP oxalate) (5.2 g) added to the mixture. The mixture was heated to 35-40° and Toluene (25 mL) was added. Then layers were separated and the aqueous layer was extracted with Toluene (15ml_). Then organic layers were combined and concentrated under vacuum. Compound obtained in Example 2 (5 g) was charged into a and IPA (30 mL) and sodium carbonate (3.05 g) were added, followed by addition of N-butyl-N-(3-chloropropyl)butan-1-amine (CDP free base) (3.64 g) prepared above, and the mixture was heated to about 80°C. The mixture was stirred for about 2 hours at 80°C and then cooled to 25-35°C. The formed solid was filtered and washed with IPA (10 mL). The filtrate was concentrated under vacuum at below 50°C, to produce 7.5 g of the title compound as crude.

Purity by HPLC: 97.93 %

Example 5: Preparation of 5-amino-3-[4-(3-di-n-butylamino propoxy) benzoyl] 2-n-butyl benzofuran (compound of Formula VI) using platinum oxide

The compound obtained in Example 4 (4.5 g) was charged into an autoclave vessel and ethanol (67.5 mL) was added. Platinum oxide (0.18 g) was added and the mixture was stirred for 45 minutes under 4 kg/cm2 hydrogen gas pressure. The catalyst was removed by filtration and washed with ethanol (22.5 mL). The filtrate was distilled completely under vacuum below 60°C, to produce 3.8 g of the title compound as a residue.

Example 6: Preparation of 5-amino-3-[4-(3-di-n-butylamino propoxy) benzoyl] 2-n-butyl benzofuran (compound of Formula VI) using palladium

The compound obtained in Example 4 (10 g) was charged into 250 mL round bottom flask and IPA (100 mL) was added. Palladium on charcoal (5% w/w, 1.0 g) was added, followed by ammonium formate (7.5 g), and the mixture was heated to about 65°C and stirred for 3 hours. The mixture was cooled to 25-35°C and the catalyst was removed by filtration and washed with IPA (20 mL). The filtrate was distilled completely under vacuum below 60°C. DCM (60 mL) was charged to the residue and stirred to form a solution. The solution was washed with saturated

sodium bicarbonate solution (10 mL), and then distilled completely under vacuum below 40°C to produce 0.75 g of the title compound as a residue. Example 7: Preparation of 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butylbenzofuran (compound of Formula VI) dioxalate

The compound obtained by the process of Example 4 (9 g) was charged into a flask and IPA (54 mL) was added. Palladium on charcoal (5% w/w, 0.9 g) was added, followed by ammonium formate (6.7 g). The mixture was heated to 50°C and stirred for about 2 hours. The mixture was cooled to 25-35°C and the catalyst was removed by filtration and washed with IPA (18 mL). The filtrate was distilled completely under vacuum below 70°C. The residue was cooled to 25-35°C and dissolved in DCM (90 mL) to form a solution. The solution was washed with water (2x90 mL), and then distilled completely under vacuum below 50°C.

Isopropanol (45 mL) was charged to the residue and stirred for 5 minutes. A mixture of oxalic acid (4.46 g) and isopropanol (45 mL) were added and the mixture was heated to 75°C. The mixture was stirred for about 30 minutes at 70-75°C, then cooled to 0-5°C and stirred for 1 hour. The solid was filtered and washed with isopropanol (18 mL). The wet solid was dried at 50-55°C about 4 hours to obtain 9.4 g of the title compound as a crystalline solid.

The solid was dissolved in methanol (45 mL) at 60-65°C, cooled to 25-35°C and stirred for about 1 hour. The solid was filtered and washed with methanol (18 ml). The wet solid was dried at 50-55°C about 4 hours, to obtain 7.6 g of the title compound as a crystalline solid.

Purity by HPLC: 99.04 % Example 8: Preparation of 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butylbenzofuran (compound of Formula VI) dioxalate without isolating the compound of Formula V

DM water (600 mL) was charged into a 2000 mL round bottom flask and Sodium carbonate (31.2 g) was added, followed by 1-chloro-3-di-n-butylamino propane oxalate (52.3 g), and the mixture was heated to 40-45°C. Toluene (250mL) added to the mixture and the mixture was stirred for about 30 minutes at 40-45°C and layers were separated. Aqueous layer was extracted with Toluene (150mL). Combined the organic layers and distilled off completely under vacuum below 60°C to get residue mass. IPA (300 mL) was added to the residue mass, followed by the addition of the compound of Formula III (50 g) and Sodium carbonate (23.4 g) was added, and the mixture was heated to 75-80°C. The mixture was stirred for about 4 hours at 75-80°C and then cooled to 25-35°C. The formed solid was filtered and washed with IPA (100 mL). The filtrate was charged into another round bottom flask. Palladium on charcoal (10% w/w, 50% wet, 7.5 g) was added, followed by ammonium formate (55.7 g). The mixture was heated to 60-65°C and stirred for about 2 hours. The mixture was cooled to 25-35°C and the catalyst was removed by filtration and washed with IPA (150 mL). The filtrate was distilled completely under vacuum below 70°C. The residue was cooled to 25-35°C and dissolved in DCM (450 mL) to form a solution. The solution was washed with water (2x450 mL), and then distilled completely under vacuum below 50°C.
Isopropanol (750 mL) was charged to the residue and stirred for 5 minutes. A mixture of oxalic acid (41.83 g) and isopropanol (150 mL) were added and the mixture was heated to 75°C. The mixture was stirred for about 30 minutes at 70-75°C, then cooled to 25-35°C and stirred for 1 hour. The solid was filtered and washed with isopropanol (150 mL). The wet solid was dried at 50-55°C about 4 hours to obtain 61 g of the title compound as a crystalline solid. Purity by HPLC: 99.10%

Example 9: Preparation of dronedarone base from dioxalate salt of compound of Formula VI.

The compound obtained by the process of Example 8 (40 g) was charged into a round bottom flask and DCM (200 mL) and 10 % aqueous sodium bicarbonate solution (275 mL) were added and the mixture was stirred for 30 minutes. The organic layer was separated and washed with 10% aqueous sodium bicarbonate solution (296 mL) and then with water (296 mL).

The final organic layer containing the compound of Formula VI free base, and sodium bicarbonate (10.2 g) were charged into a flask and stirred for 10 minutes. A mixture of methanesulfonyl chloride (9.73 g) and DCM (70 mL) were added slowly over about 30 minutes and the mixture was stirred for about 2 hours at 25-35°C. Water (240 mL) was added and stirred for about 30 minutes. The organic layer was separated and washed with 10% aqueous sodium bicarbonate solution (2*370 mL) and then with water (370 mL). The organic layer was distilled completely under vacuum below 50°C, to produce the title compound as a residue.

The residue was dissolved in n-hexane (80 mL) in a 250 mL round bottom flask and distilled completely under vacuum below 50°C. n-Hexane (260 mL) was added to the residue and stirred for about 6 hours. The solid was filtered and washed with n-hexane (80 mL). The wet solid was dried at 30°C, to obtain 21.3 g of the solid title compound, having an XRPD pattern as shown in Fig. 1.

Purity by HPLC: 99.67% Example 10: Preparation of dronedarone hydrochloride.
Dronedarone (2.0 g) and ethyl acetate (20 mL) were charged into a 250 mL round bottom flask and the mixture was stirred for 10 minutes. 10% w/w HCI in diethyl ether (1.0 mL) was added and the mass was stirred for about 2 hours at 25-35°C. The solid was filtered and washed with ethyl acetate (5 mL). The wet solid was dried below 50°C, to produce 2.1 g of the title compound as a crystalline solid.

Purity by HPLC: 99.72% Example 11: Preparation of dronedarone hydrochloride in acetone.

Dronedarone (1.0 g) and acetone (10 mL) were charged into a 250 mL round bottom flask and the mixture was stirred for 10 minutes and cooled to 0-5°C. 10% w/w HCI in Ethyl acetate (1.0 mL) was added and the mass was stirred for about 2 hours at 0-5°C. The solid was filtered and washed with acetone (4 mL). The wet solid was dried below 50°C, to produce 1.2 g of the title compound as a crystalline solid.

The crystalline solid obtained in the above example has an XRPD pattern as shown in Fig. 3, and a DSC curve as shown in Fig. 4.

Purity by HPLC: 99.83 % Example 12: Preparation of dronedarone hydrochloride in acetonitrile.

Dronedarone (1.0 g) and acetonitrile (10 mL) were charged into a 250 mL round bottom flask and the mixture was stirred for 10 minutes. 10% w/w HCI in diethyl ether (0.5 mL) is added and the mass was stirred for about 2 hours at 25-35°C. The solid was filtered and washed with acetonitrile (4 mL). The wet solid was dried below 50°C, to produce 1.0 g of the title compound as a crystalline solid.

Purity by HPLC: 99.58 % Example 13: Preparation of dronedarone hydrochloride in ethyl acetate.

Dronedarone (1.0 g) and ethyl acetate (10 mL) are charged into a 250 mL round bottom flask and the mixture was stirred for 10 minutes. 10% w/w HCI in ethyl acetate (0.5 mL) was added and the mass was stirred for about 2 hours at 25-35°C. The solid was filtered and washed with acetonitrile (4 mL). The wet solid was dried below 50°C, to produce 1.0 g of the title compound as a crystalline solid.

Purity by HPLC: 99.48 %

Example 14: Preparation of dronedarone hydrochloride in MIBK.
Dronedarone (1.0 g) and MIBK (10 mL) were charged into a 250 mL round bottom flask and the mixture was stirred for 10 minutes. 10% w/w HCI in diethyl ether (0.5 mL) was added and the mass was stirred for about 2 hours at 25-35°C. The solid was filtered and washed with MIBK (5 mL). The wet solid was dried below 50°C to produce 1.0 g of the title compound as a crystalline solid.

Purity by HPLC: 99.45 % Example 15: Preparation of dronedarone hydrochloride using aqueous HCI

Dronedarone (2.0 g) and IPA (20 mL) are charged into a 250 mL round bottom flask and the mixture was stirred for 10 minutes. Aqueous HCI (36% w/w; 0.5 mL) was added and the mass was cooled and stirred for about 1 hour at -10°C to -15°C. Water (5.0mL) was added to the mass and stirring was continued. The solid was filtered and washed with IPA (10 mL). The wet solid was dried below 50°C, to produce 1.8 g of the title compound as a crystalline solid.

Purity by HPLC: 99.32% Example 16: Preparation of crystalline dronedarone hydrochloride from the amorphous form.

Amorphous dronedarone HCI (4.0 g) and acetone (40 mL) were charged into a 250 mL round bottom flask and the mixture was stirred for 10 minutes. The solution was cooled to about -15°C to -20°C stirred for about 2 hours. The solid was filtered and washed with acetone (10 mL). The wet solid was dried below 50°C, to produce 2.5 g of the title compound as a crystalline solid. HCI content: 6.21%.
Purity by HPLC: 99.52% Example 17: Preparation of dronedarone hydrochloride amorphous form.

Dronedarone (2 g) and DCM (20 mL) were charged into a 250 mL round bottom flask and the mixture was stirred for 15 minutes. 10% w/w HCI in diethyl ether (10 mL) was added and the mass was stirred for 1 hour at 25-35°C. The solvent was distilled completely under vacuum below 50°C. N-heptane (20 mL) was charged to the residue and the mixture was stirred for 30 minutes at 25-35°C. The solvent was distilled completely below 50°C under vacuum, to produce 1.8 g of the title compound as an amorphous solid, having an XRPD pattern as shown in Fig. 2.

Example 18: Preparation of Dronedarone oxalate

Dronedarone (9.0 g) and acetonitrile (27 mL) were charged into a 250 mL round bottom flask and the mixture was heated to 45-50°C for clear solution. A mixture was oxalic acid dihydrate(2 g) and acetonitrile (18 mL) was added to the reaction solution and stirred for about 15 minutes at 45-50°C. The mixture was cooled and stirred for about 1 hour at 25°C to 35°C. The solid was filtered and washed with acetonitrile (18 mL). The wet solid was dried below 50°C, to produce 8.5 g of the title compound as a crystalline solid. Purity by HPLC: 99.63% w/w.

The above obtained oxalate salt (8 g) and acetonitrile(40 mL) were charged into a 250 mL round bottom flask and the mixture was heated to 50-60°C for clear solution. The mixture was stirred for about 15 minutes at 50-60°C and then cooled and stirred for about 1 hour at 25°C to 35°C. The solid was filtered and washed with acetonitrile (16 mL). The wet solid was dried below 50°C, to produce 7.5 g of the title compound as a crystalline solid.

Purity by HPLC: 99.76% Example 19: Preparation of N-butyl-N-(3-chloropropyl)butan-1-amine, without base and solvent.

Di-N-butylamine (30 g) and 1-bromo-3-chloropropane (51.1 g) were charged into a round bottom flask and the mixture was heated to 45°C. The mixture was stirred for about 6 hours at 40-45°C. Toluene (105 mL) was added and the mixture was cooled to 0-5°C. The formed solid was filtered and washed with toluene (45 mL). The filtrate was mixed with water (180 mL) and the pH was adjusted to about 2 by adding 2N HCI solution (55 mL). The aqueous layer was separated and washed with toluene (75 mL). The aqueous layer was charged into a flask and toluene (150 mL) was added. The mixture pH was adjusted to about 9.5 by adding 20% aqueous NaOH solution (15 mL). The organic layer was separated and washed with water (2x90 mL). The organic layer was separated and distilled completely under vacuum below 60°C, to produce 22 g of the title compound as a residue. Example 20: Preparation of N-butyl-N-(3-chloropropyl)butan-1-amine using K2CO3

Di-N-butylamine (30 g), 1-bromo-3-chloropropane (51.1 g), and potassium carbonate (19.2 g) were charged into a round bottom flask and the mixture was heated to 45°C. The mixture was stirred for about 6 hours at 40-45°C. Toluene (105 mL) was added and the mixture was cooled to 0-5°C. The formed solid was filtered and washed with toluene (45 mL). The filtrate was charged into a flask and water (180 mL) was added. The mixture pH was adjusted to about 2 by adding 2N HCI solution (60 mL). The aqueous layer was separated and washed with toluene (75 mL). The aqueous layer was charged into a flask and toluene (150 mL) was added.

The mixture pH was adjusted to about 9.3 by adding 20 % aqueous NaOH solution (15 ml_). The organic layer was separated and washed with water (2x90 ml_). The organic layer was separated and distilled completely under vacuum below 60°C, to produce 23 g of the title compound as a residue. Example 21: Preparation of N-butyl-N-(3-chloropropyl)butan-1-amine using NaHCO3

Di-N-butylamine (30 g), 1-bromo-3-chloropropane (51.1 g), and sodium bicarbonate (21.7 g) were charged into a round bottom flask and the mixture was heated to 45°C. The mixture was stirred for about 6 hours at 40-45°C. Toluene (105 mL) was added and the mixture was cooled to 0-5°C. The formed solid was filtered and washed with toluene (45 mL). The filtrate was charged into a flask and water (180 mL) was added. The mixture pH was adjusted to about 2 by adding 2N HCI solution (60 mL). The aqueous layer was separated and washed with toluene (75 mL). The aqueous layer was charged into a flask and toluene (150 mL) was added. The mixture pH was adjusted to about 9.2 by adding 20% aqueous NaOH solution (15 mL). The organic layer was separated and washed with water (2x90 mL). The organic layer was distilled completely under vacuum below 60°C, to produce 22.3 g of the title compound as a residue. Example 22: Preparation of Hexan-2-one oxime (compound of Formula X)

Hexan-2-one (30.2 g), FeCI3.6H2O (15.5 g) and Hydroxylamine hydrochloride (20.0 g) were charged into a round bottom flask and stirred for 30 minutes. Toluene (100 mL) and DM water (100 mL) were added to the mixture and stirred for 15 minutes. Layers separated and the aqueous layer was extracted with Toluene (1x50 mL). Combined the organic layers and washed with DM water (1 x50 mL), followed by saturated NaHCO3 solution (1x100 mL) washing. Distilled off the organic layer under vacuum to produce 20.5 g of the title compound as a residue. Example 23: Preparation of Hexan-2-one-0-(4-nitrophenyl)oxime (compound of Formula XII)

THF (100 mL) and NaH (60%, 6.3 g) were charged into a round bottom flask and cooled to 10-15°C. Added slowly a solution of compound of Formula XI (10.0 g) and THF (30 mL) into the mixture and stirred for 30-45 minutes. Added slowly a solution of p-Chloronitrobenzene (13.7 g) in DMSO (30 mL) into the mixture and maintained the mixture for 3-4 hours at 25-30°C. The reaction mixture was poured into pre-cooled DM water (500 mL) and stirred for 15 minutes. Extracted the mixture with ethyl acetate (2x100 mL) and the ethyl acetate layer was washed with DM water

(100 ml_). Distilled off the organic layer under vacuum at 40-45°C to yield 10.5 g of the title compound as a residue.

Example 24: Preparation of Hexan-2-one-0-(4-nitrophenyl)oxime (compound of Formula XII)

THF (100 mL) and NaH (60%, 6.3 g) were charged into a round bottom flask and cooled to 10-15°C. Added slowly a solution of compound of Formula XI (10.0 g) and THF (30 mL) into the mixture and stirred for 30-45 minutes. Added slowly a solution of p-Bromonitrobenzene (13.7 g) in DMSO (30 mL) into the mixture and maintained the mixture for 3-4 hours at 25-30°C. The reaction mixture was poured into pre-cooled DM water (500 mL) and stirred for 15 minutes. Extracted the mixture with ethyl acetate (2x100 mL) and the ethyl acetate layer was washed with DM water (100 mL). Distilled off the organic layer under vacuum at 40-45°C to yield 10.0 g of the title compound as a residue. Example 25: Preparation of 2-n-butyl-5-nitrobenzofuran (compound of Formula XIII)

Compound of Formula XII (16.0 g) and 1.8N HCI in acetic acid (75 ml) were charged into a round bottom flask and stirred for 30 minutes. Hexane (2x160 mL) added to the reaction mixture and stirred for 30 minutes and the hexane layer was separated out. DM water (160 mL) and ethyl acetate (160 mL) were added to the mixture and stirred for 15 minutes and layers were separated. Aqueous layer was extracted with ethyl acetate (1x160 mL). Organic layers were combined and pH adjusted to 8.0 with 20% Na2C03 solution. Layers were separated and the organic layer was distilled of completely under vacuum to yield crude mass. The crude mass was dissolved in acetic acid (55 mL), ZnCI2 (13.8 g) was added to the solution and heated to 70-75°C and maintained for 2 hours. The reaction mixture was cooled to 25-30°C and DM water (160 mL) was slowly added to the reaction mixture and Toluene (80 mL) added and stirred for 30 minutes. Layers were separated and the organic layer was washed with 5% NaHC03 solution, followed by DM water (80 mL) washing. Organic layer was distilled out under vacuum to yield 3.2 g of the title compound as a residue. Example 26: Preparation of 4-nitrophenyl hexanoate (compound of Formula XVI)

p-Nitrophenol (100.0 g) and dichloromethane (1500 mL) were charged into a round bottom flask and stirred for 10 minutes and the reaction mixture was cooled to 10° C, followed by the addition of triethylamine (200 mL). Added slowly a solution of hexanoyl chloride (120.57 mL) into the reaction mixture and maintained the mixture for 1 hour. Added slowly DM water (500 ml_) to the mixture and stirred for 10-15 minutes and the layers were separated. Organic layer was washed with 5% HCI (200 mL), followed by washing with 5% NaHC03 (2 x 100 mL) and finally with 5% NaCI solution (100 mL). Organic layer was distilled off under vacuum to yield 167.8 g of the title compound as a residue.

Example 27: Preparation of 1-(2-hydroxy-5-nitrophenyl)hexan-1-one (compound of Formula XVII)

Compound of Formula XVI (25.0 g) and nitrobenzene (150 mL) were charged into a round bottom flask. Added AICI3 (15.45 g) in to the reaction mixture and heated to 140°C and maintained for 5-6 hours. The reaction mass was cooled to 25-30°C. Charged the reaction mass slowly into a beaker containing crushed ice (200 mL) and HCI (25 mL) and stirred for 10 minutes. Dichloromethane (200 mL) was charged into the reaction mass, filtered the reaction mass and washed with dichloromethane and water and the layers were separated. Extracted the aqueous layer with dichloromethane (100 mL) and washed the organic layer with DM water. The organic layer was distilled off. Charged toluene into the reaction mass and added slowly 10% NaOH (75 mL) into the reaction mass and heated to 80°C and maintained for 50 to 60 minutes. Layers were separated and the aqueous layer was washed with toluene and charged into a round bottom flask and cooled to 25-30°C. Charged toluene into the reaction mixture and adjusted the pH to 1.5-2.0 with HCI. Layers were separated and organic layer was washed with NaCI solution. Solvent from the organic layer was distilled off and to the residue n-Hexane was charged. Solvent was decanted and distilled off to yield 6.0 g of the title compound as solid.
Example 28: Preparation of 1-(2-methoxy-5-nitrophenyl)hexan-1-one (compound of Formula XVIII)

Compound of Formula XVII (5.0 g) and acetone (12.0 mL) were charged into a round bottom flask. Added methyl iodide (12.0 mL) into the reaction mixture, followed by slow addition of 1,8-Diazabicycloundec-7-ene (DBU) (12.0 mL) at 25-35°C. Stirred the reaction mixture at 25-35°C for 5 hours. DM water (50 mL) and dichloromethane (50 mL) were added to the reaction mixture and stirred for 30 minutes. Layers were separated and the organic layer was washed with dilute HCI, and the organic layer was concentrated under vacuum to yield 6.2 g of the title compound.

Example 29: Preparation of 2-bromo-1-(2-methoxy-5-nitrophenyl)hexan-1-one (compound of Formula XIX)

Compound of Formula XVIII (6.0 g) and diethyl ether (12.0 mL) were charged into a round bottom flask. Then bromine (12.0 mL) was added into the reaction mixture and stirred the reaction mixture at 25-35°C for 8 hours. Then ether was removed from the mixture under vacuum and DM water (50 mL) and dichloromethane (50 mL) were added to the reaction mixture and stirred for 30 minutes. Then the solution was filtered and the hexane layer was concentrated under vacuum to get 6.6 g of the title compound as oily mass. Example 30: Preparation of 2-bromo-1-(2-methoxy-5-nitrophenyl)hexan-1-one (compound of Formula XX)

Compound of Formula XIX (2.5 g) and dichloromethane (10.0 mL) were charged into a round bottom flask. Then aluminum chloride (3.0 g) was added into the reaction mixture and stirred the reaction mixture at 25-35°C for 2 hours. DM water (10.0 mL) and HCI (2.0mL) were charged into another round bottom flask and the reaction mixture was added slowly and stirred for 15 minutes. Then layers were separated and the organic layer was washed with DM water (10.0 mL) and concentrated under vacuum to obtain 2.0 g of title compound as crude. Example 31: Preparation of 2-n-butyl-5-nitrobenzofuran (compound of Formula XIII)

Compound of Formula XX (10.0 g) and dichloromethane (100 mL) were charged into a round bottom flask, and triethyl amine (6.4 g) was added and stirred the reaction mixture at 25-35°C for 2 hours. Then DM water (100 mL) was added to the reaction mixture and stirred for 15 minutes. Layers were separated and the organic layer was washed with 5% aqueous HCI (50 mL) followed by DM water (50 mL) washing. Distilled off organic layer completely under vacuum and dissolved the crude in methanol (50 mL) and the mixture is cooled to 0°C. then sodium borohydride (1.8 g) was added to the reaction mixture and stirred for 30 minutes. Temperature of the reaction mixture was raised to about 30°C and stirred for 1 hour. Then 36% aqueous HCI (50 mL) and DM water (50 mL) were added to the reaction mixture and heated to about 90°C and stirred for about 6 hours. Reaction mixture was cooled to about 30°C and extracted the reaction mixture with ethyl acetate (2x 50 mL). Combined the ethyl acetate layer and washed with DM water (50 mL) and concentrated the organic layer to obtain 5.5 g of the title compound as crude.

vve ciaim

1. A process for preparation of dronedarone or a pharmaceutically acceptable salt
thereof, comprising:

a) reacting 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran of Formula II
with a Lewis acid reagent, in a solvent medium comprising chlorobenzene, to obtain
2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of Formula III,

Formula II Formula III

b) reacting compound of Formula III with 1-chloro-3-di-n-butylaminopropane of Formula IV in presence of a base, to obtain 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-nitrobenzofuran of Formula V,

c) without isolating, reducing the compound of Formula V, in presence of a metal catalyst and ammonium formate, to obtain 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n- butylbenzofuran of Formula VI or a salt thereof.

Formula VI —

d) reacting compound of Formula VI or its salt with methanesulfonyl chloride,
in the presence of a base, to obtain dronedarone or a pharmaceutically acceptable
salt of Formula VII

Formula VII

2. The process according to claim 1, wherein the base used in step b) is selected
from the group consisting of sodium carbonate, potassium carbonate, sodium
hydroxide and potassium hydroxide.

3. The process according to claim 1, wherein the metal catalyst used in step c) is selected from the group consisting palladium, Platinum oxide and Raney Nickel.

4. The process according to claim 1, wherein the compound 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n- butylbenzofuran of Formula VI is isolated as dioxalate salt.
5. The process according to claim 1, wherein the base used in step d) is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.

6. The process according to claim 1, the pharmaceutically acceptable salt of dronedarone is dronedarone hydrochloride.

7. A process for the preparation of 2-n-butyl-5-nitrobenzofuran of Formula XIII or a salt thereof, comprising:

a) reacting hexan-2-one oxime of Formula X with 1-bromo-4-nitrobenzene of
Formula XI in presence of a base to obtain hexan-2-one -0-(4-nitrophenyl) oxime of
Formula XII

Formula X Formula XI Formula XII

b) cyclizing the compound of Formula XII to obtain 2-n-butyl-5-nitrobenzofuran
of Formula XIII,

Formula XIII

8. Use of 2-n-butyl-5-nitrobenzofuran of Formula XIII, obtained from the process of claim 7, in the preparation of dronedarone or a pharmaceutically acceptable salt thereof.
9. A process for the preparation of 2-n-butyl-5-nitrobenzofuran of Formula XIII or a salt thereof, comprising;
a) reacting 4-nitro phenol of Formula XIV with hexanoyl chloride of Formula XV in presence of a base to obtain 4-nitrophenyl hexanoate of Formula XVI,

Formula XVI

Formula XIV Formula XV

b) by Fries rearrangement converting the compound of Formula XVI to 1-(2-
hydroxy-5-nitrophenyl)hexan-1-one of Formula XVII,

Formula XVII
c) methylating the compound of Formula XVII to obtain 1-(2-methoxy-5-
nitrophenyl)hexan-1-one of Formula XVIII

Formula XVIII
d) brominating the compound of Formula XVIII to obtain 2-bromo-1-(2-
methoxy-5-nitrophenyl)hexan-1-one of Formula XIX,

Formula XIX

e) demethylating the compound of Formula XIX to obtain 2-bromo-1-(2-
methoxy-5-nitrophenyl)hexan-1-one of Formula XX; and

Formula XX

f) cyclizing and reducing the compound of Formula XX to obtain 2-n-butyl-5-
nitrobenzofuran of Formula XIII,

Formula XIII

10. Use of 2-n-butyl-5-nitrobenzofuran of Formula XIII, obtained from the process of claim 9, in the preparation of dronedarone or a pharmaceutically acceptable salt thereof