This application claims priority to Indian patent application numbered 1442/CHE/2011 filed on Apr 26, 2011 the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Dronedarone or its pharmaceutically acceptable salt.

BACK GROUND OF THE INVENTION:

Dronedarone is an anti arrhythmia drug for the prevention of cardiac arrhythmias such as Atrial Fibration (AF). AF is a condition characterized by an irregular heart beat. This occurs the lower chambers of the heart, the ventricles, to contract chaotically so that blood is inefficiently pumped to the body, which can lead to tissue damage and even death.

Dronedarone chemically known as N-{2-butyl-3-[4-(3-dibutylaminopropoxy) benzoyl] benzofuran-5-yl} methanesulfonamide having the structure of formula I and is marketed as hydrochloride salt.US patent 5223510, disclosed Dronedarone and its salts, wherein Dronedarone is prepared by the condensation of 2-n-butyl 3-(4-hydroxy benzoyl)-5-nitrobenzofuran with l-chloro,3-di-n-butylamino propane, in the presence of potassium carbonate in methylethylketone, followed by nitro reduction in the presence of platinum oxide in ethanol and finally sulfonation in the presence of triethylamine in dichloromethane to get crude Dronedarone, which is purified by column chromatography to obtain pure Dronedarone. The Dronedarone free base is converted to hydrochloride salt by conventional methods as shown in scheme-I.

US patent 6828448, disclosed Dronedarone process, according to this patent condensation of 2-butyl-5-(methanesulfonamido) benzofuran with 4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride in the presence of Lewis acid and dichloromethane to obtain Dronedarone hydrochloride, which is basified with aqueous sodium hydroxide to get Dronedarone free base and further converted to Dronedarone hydrochloride by conventional methods, which is illustrated in scheme-H.

According to US patent 7312345, Dronedarone is prepared by condensation of 2-butyl-5-(methanesulfonamido)benzofuran with 4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride in the presence of Lewis acid and dichloromethane to obtain Dronedarone and further converted to Dronedarone hydrochloride as shown scheme-Ill.The prior art process involves organic base during the sulfonation and the compound is isolated by column chromatography, which leads to poor yield and time consuming. Thus there is a need of an alternative simple, less time consuming cost effective and commercially feasible process for the preparation of dronedarone with substantially free of impurities. The present process does not involve any base during the sulfonation step and the product is directly isolated without any column chromatography purification.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide a process for the preparation of dronedarone hydrochloride of formula I, which comprising the steps of:

a) reacting a compound of formula IV with l-chloro-3-di-n-butyl propane in the presence of a base in a solvent to get compound of formula III,

b) reducing the compound of formula III to get compound of formula II,

c) reacting the compound of formula II or its salts with methanesulfonylchloride in the presence of a solvent and absence of a base, and

d) isolating the dronedarone hydrochloride.

Another aspect of the present invention is to provide a process for the preparation of dronedarone hydrochloride , which comprises:

a) reacting the compound of formula II or its salts with methanesulfonylchloride in the presence of a solvent and absence of a base, and

b) isolating the crude dronedarone Hydrochloride, and

c) optionally purifying the crude dronedarone Hydrochloride

Yet another aspect of the present invention is to provide Dronedarone hydrochloride having the particle size dgo is less than 100 microns, preferably less than 50 microns, d50 is less than 50 microns, preferably less than 20 microns and dio is less than 15 microns. The entire process for the preparation of dronedarone is depicted in scheme-IV below:

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of dronedarone or its pharmaceutically acceptable salts.

In one embodiment, the present invention provides an improved process for the preparation of Dronedarone hydrochloride comprising the steps of;

a) reacting a compound of formula IV with l-chloro-3-di-n-butyl propane in the presence of a base in a solvent to get compound of formula III,

b) reducing the compound of formula III to get compound of formula II,

c) reacting the compound of formula II or its salts with methanesulfonylchloride in the presence of a solvent and absence of a base, and

d) isolating the dronedarone hydrochloride.

According to the present invention 2-n-butyl-3-(4-hydroxy benzoyl)-5-nitro benzofuran of formula IV is suspended in a solvent or mixture of solvents at ambient temperature, base is added followed by l-chloro-3-di-n-butylamino propane. The resulting mixture is heated to 80-120°C, preferably 90-95°C for about 10-20hours. After the work-up to get 2-n-Butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran of formula III, reducing the compound of the formula III with reducing agent under hydrogen pressure for 5-10 hours in alcoholic solvent to get 5-Amino-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran of the formula II. Sulfonation of the compound of 5-Amino-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran of formula II, added mixture of solvents and followed by methane sulfonyl chloride for one to one and half hours at ambient temperature and maintained 3-8 hrs to get dronedarone or its salts, purification of the compound of Dronedarone hydrochloride crude in acetone to get pure dronedarone hydrochloride.

According to the present invention the solvent used for condensation reaction is selected from water, acetonitrile, acetone, methyl ethyl ketone, toluene or mixture thereof. The base in the present invention is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide preferably potassium carbonate.

According to the present invention reducing agent is selected from platinum oxide, Raney nickel, palladium carbon preferably palladium carbon.

According to the present invention solvents used in sulfonation reaction is selected from water, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, acetone, ethyl acetate or mixture of solvents, preferably water and dichloromethane.

According to the present invention purification of crude dronedarone hydrochloride in a solvent is selected from acetone, ethyl acetate, isopropyl ether or di isopropyl ether, acetonitrile, water preferably acetone.

Another embodiment of the present invention is to provide a process for the preparation of dronedarone hydrochloride, which comprises:

a) reacting the compound of formula II or its salts with methanesulfonylchloride in the presence of a solvent and absence of a base, and

b) isolating the crude dronedarone Hydrochloride, and

c) optionally purifying the crude dronedarone Hydrochloride.

According to the present invention sulfonation of the compound of 5-Amino-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran of formula II, added mixture of solvents and followed by methane sulfonyl chloride for one to one and half hours at ambient temperature and maintained 3-8 hrs to get dronedarone or its salts, purification of the dronedarone hydrochloride crude in acetone to get pure dronedarone hydrochloride.

According to the present invention solvents used in sulfonation reaction is selected from water, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, acetone, ethyl acetate or mixture of solvents, preferably water and dichloromethane.

According to the present invention purification of crude dronedarone hydrochloride in a solvent is selected from acetone, ethyl acetate, isopropyl ether or di isopropyl ether, acetonitrile, water, preferably acetone.

Yet embodiment of the present invention is to provide Dronedarone hydrochloride having the particle size d9o is less than 100 microns, preferably less than 50 microns, dso is less than 50 microns, preferably less than 20 microns and dio is less than 15 microns.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

Example- 1) Preparation of 2-n-Butyl-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-5- nitro benzofuran

Example-A)

A mixture consisting 2-n-butyl-3-(4-hydroxy benzoyl)-5-nitro benzofuran (166gms), Potassium carbonate (81.1gms) in 1500ml of toluene was stirred for 30minutes. L0lgms of 1-chloro, 3-di-n-butylaminopropane was added, then slowly raised the temperature to 90 - 95°C, maintained stirring for 12-14 hours at same temperature. After completion of the reaction, purified water (830ml) was added to the reaction mass. Separated the Toluene layer, and washed with brine solution (500ml).Organic layer was distilled out completely to obtained 244gms of title compound.

Example - B)

A mixture consisting 2-n-butyl-3-(4-hydroxy benzoyl)-5-nitro benzofuran (50gms),Potassium carbonate (24.4gm) in 250ml of toluene, purified water (250ml) and TBAB (0.1 gm) were stirred for 30minutes. Slowly raised the temperat ure to 70 -75°C, 1-chloro, 3-di-n-butylamino propane ( 32gm) was added slowly over 30minutes, then slowly raised the temperature to 90 - 95°C, maintained 10-12 hours at same temperature. After completion of reaction cool to 25 - 30°C, separated the organic layer, purified water (250ml) was added and stirred for 30minutes. Separated the Toluene layer, and washed with brine solution (l00ml).Organic layer was distilled out completely to obtained the 75gms of 2-n-Butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran (Yield - 98% ) ,It was directly taken to next stage with out further purification.

Example - 2) Preparation of Dronedarone hydrochloride

240gms of 2-n-Butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran was stirred in 1440ml of methanol in the presence of 10% Palladium carbon (8.3gm) in a hydrogenation apparatus under a pressure of 5kg/cm2 for 5hours. After completion of reaction, filtered the reaction mass, then distilled off methanol completely to obtain the residue, residue was dissolved in 500ml of methylene dichloride and washed with 5% sodium bicarbonate solution (500ml), finally washed with brine solution (300ml). The above solution containing 208.8gm of 5-Amino-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran, to this solution methylene dichloride (540ml), purified water (625ml) and methanesulfonylchloride (120gm) were added slowly over 60 minutes at 25 - 30°C, maintain 4-6 hours at 25-30°C. After completion of reaction separated the MDC layer, aqueous layer was extracted with 210ml of MDC, combined the organic layers and distilled off organic layer completely under vacuum to obtained the residue, to this residue acetone (420ml) was added at 40°C, stirred the reaction mass 30minutes at 40-45°C, Cooled to 25-30°C, and stirred for 2hours at 25-30°C, further cooled to 5-10°C, maintained lhour at 5 - 10°C, filtered the reaction mass and washed with 100ml of acetone.

Methane sulfonyl chloride reactions conducted in different solvents:

The above reaction is conducted in different solvents and with base and without base, the results are depicted below.

Example - 3) Purification of Dronedarone hydrochloride

Crude Dronedarone hydrochloride (50gms) was dissolved in acetone (750ml) at 55 -60°C, charcolisation treatment was given to this solution and filtrated the solution , distilled off acetone up to inside volume ~400ml, cooled to 5-10°C, maintain 60 minutes at 5-10°C, filtered the reaction mass and washed with acetone (25ml). It gives 45gms of Pure Dronedarone hydrochloride.

We Claim:

1. An improved process for the preparation of Dronedarone hydrochloride comprising the steps of

a) reacting a compound of formula IV with l-chloro-3-di-n-butyl propane in the presence of a base and a solvent to get compound of formula III,

b) reducing the compound of formula III to get compound of formula II,

c) reacting the compound of formula II or its salts with methanesulfonylchloride in the presence of a solvent and absence of a base,

and

d) isolating the dronedarone hydrochloride.

The process according to claim 1, wherein the solvent is selected from water, acetonitrile, acetone, methyl ethyl ketone, toluene or mixture thereof. The process according to claim 1, wherein the base is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide.

4. The process according to claim 1, reducing agent is selected from platinum oxide, Raney nickel, palladium carbon.

5. Process for the preparation of Dronedarone hydrochloride, which comprises

a) reacting the compound of formula II or its salts with methanesulfonylchloride in the presence of a solvent and absence of a base,

b) isolating the crude dronedarone Hydrochloride, and

c) optionally purifying the crude dronedarone Hydrochloride.

6. The process according to claim 1 & 5, solvent used for sulfonation is selected from water, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, acetone, ethyl acetate or mixture thereof.

7. The process according to clam 5, crude dronedarone hydrochloride is purified in a solvent selected from acetone, ethyl acetate, isopropyl ether or di-isopropyl ether, acetonitrile, water or mixture thereof.

8. The process according to claim 1 & 5, dronedarone hydrochloride having the particle size 100 microns, d5o is less than 50 microns, and d10 is less than 15 microns.