DESCRIPTION

The present invention provides a process for the preparation of Dronedarone. The process includes conversion of (i) 2-n-butyl-3-(4-hydroxy benzoyl)-5-nitro benzofuran to 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-5-nitro benzofuran mono oxalate by reaction with 1-chloro-3-di-n-butylamino propane and oxalic acid in the presence of a base and solvent. (ii) Hydrogenation of 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-5-nitro benzofuran mono oxalate to 5-amino-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran mono oxalate in the presence of palladium/carbon catalyst and a solvent and its further conversion to 5-amino-3- [4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran dioxalate by reacting it with oxalic acid in the presence of a solvent.(iii) Conversion of 5-amino-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran di oxalate to 2-n-butyl-3- [4-(3-di-n-butylamino-propoxy) benzoyl]-5-methylsulfonamidobenzofuran by reacting with methane sulfonyl chloride in suitable solvent and isolating dronedarone base in high purity. It is further converted into its pharmaceutically acceptable salts.
Dronedarone HCl is a benzofuran derivative which is represented by Formula I. It is chemically known as N-{2-butyl-3-[4-(3-dibutylaminopropoxy) benzoyl] benzofuran-5yl} methane sulfonamide, hydrochloride.

Formula I
US patent No 5,223,510 discloses benzofuran, benzo thiophene, indole or indolizine compounds and their process of preparation.

US patent No 6,846,936 relates to 2-butyl-3-(4-[3-(dibutylamino) propoxy] benzoyl-5-nitrobenzofuran hydrochloride, to its preparation and to its use as synthetic intermediate.

Further US 5,223,510 discloses mesylation of oily 5-amino-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran by drop wise addition of methane sulfonyl chloride in the presence of a mixture of triethylamine and dichloroethane. The reaction takes almost 20 hours to reach on completion. The dronedarone base obtained by this process has the features of long reaction time, poor quality purity of around 83.85%, higher dimesyl dronedarone impurity (Formula II) more than 5%, disadvantage associated are handling of oily intermediate, toxic ethyl dichloroethane on a commercial scale and use of column chromatography for isolation.

Formula II
The present inventors while developing a process for the preparation of Dronedarone have developed a process where in 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)benzoyl]-5-nitro benzofuran is isolated as oxalate salt which is further reduced and converted to 5-amino-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran diocxalate salt. The mesylation of dioxalate salt suitable solvent to yield dronedarone base. The process has many advantages such as getting high purity dronedarone base with lower level less than 0.5% unreacted starting material. The handling of 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-5-nitro benzofuran oxalate salt is very convenient due to its solid nature further it is hydrogenated and isolated as novel dioxalate salt of 5-amino-3- [4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran. The isolation of above intermediate as solid oxalate salt makes process easier, faster with an end result of high purity intermediate. This in subsequent step the dioxalate salt is mesylated in suitable solvent and converted into dronedarone and its salt thereof having dimesyl impurity less than 0.1% and unreacted starting material 5-amino-3- [4-(3-di-n-butyl amino propoxy) benzoyl]-2-n-butyl benzofuran is less than 0.5% when measured by HPLC.

In one of the aspect of the invention a process for the preparation of dronedarone hydrochloride wherein dimesyl dronedarone is less than 0.1%, the process includes steps of;
a) contacting 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-5-nitro benzofuran with oxalic acid in a solvent,
b) hydrogenation of step a) product in alcohol solvent with 5% Pd/C and,
c) treating step b) product with oxalic acid and isolating di oxalate salt as solid,
d) mesylating step c) product with methane sulfomnyl chloride in suitable solvent and presence of base,
e) isolating dronedarone base and converting it to hydrochloride salt thereof.

The 2-n-butyl-3-(4-hydroxy benzoyl)-5-nitro benzofuran may be reacted with 1-chloro-3-di-n-butylamino propane and a base in the presence of a solvent at 80-85°C for 2 hrs to obtain 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)benzoyl]-5-nitro benzofuran which is an oily liquid, which is treated with oxalic acid in the presence of solvents acetone and di isopropyl ether to obtain 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)benzoyl]-5-nitro benzofuran oxalate.

2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-5-nitro benzofuran oxalate may be hydrogenated in presence of catalyst 5% Pd/C in methanol maintaining a temperature of 20-400C for about 2-6 hours. After completion of the hydrogenation reaction catalyst may be filtered and filtrate may be distilled under vacuum. Residue obtained may be further treated with oxalic acid in alcohol solvent at temperature of 20-350C for 2-6 hours to obtain 5-amino-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran di oxalate as a solid.

The 5-amino-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran di oxalate is suspended in a mixture of water and 2-methyl tetrahydrofuran in presence of organic base such as tri ethylamine at a temperature of 05-200C, the reaction mixture subjected to mesylation reaction with methane sulfonyl chloride in suitable solvent. The reaction may proceed in one or more mixture of suitable solvent. After completion of the reaction suitable solvent layer may be separated and distilled to obtain 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-5-methylsulfonamidobenzofuran. The purity of 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-5-methylsulfonamidobenzofuran is more than 96% when measured by HPLC and it may be converted to dronedarone hydrochloride salt in the presence of solvent acetone and diisopropyl ether by reaction with isopropanolic hydro chloric acid.

The term isolating includes the concentration of reaction mixture and isolating solid by using suitable techniques such as slurry in a solvent, adding antisolvents technique and the like.

The term solvent may comprise one or more of methanol, isopropyl alcohol, acetone, dichloromethane, toluene, diisopropyl ester, methyl isobutyl ketone and hexane.

The suitable solvent for step d) mesylation reaction includes one or more of water, 2-methyl tetrahydrofuran, methylene chloride, tetrahydrofuran, toluene, ethyl acetate and mixture thereof.

The term “base” as used herein refers to inorganic and organic bases. The inorganic bases include of hydroxide, carbonate, and bicarbonate, sulphates of an alkali metal or a mixture of one or more of them. The alkali metals may be one or more of lithium, sodium and potassium.

The organic bases include of one or more mixture of triethyl amine, dimethyl amine, dicyclohexyl amine, diisopropyl amine, pyridine or a mixture of one or more of them.

In another embodiment of the invention wherein 5-amino-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran oxalate and di oxalate salt having purity more than 97% when measured by HPLC, is converted to dronedarone base and then to dronedarone hydrochloride.

In another embodiment of the invention the invention is related to the compound 5-amino-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran oxalate and di oxalate and is salts.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1
Preparation of 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-5-nitro benzofuran oxalate

A mixture of 2-n-butyl-3-(4-hydroxy benzoyl)-5-nitro benzofuran (100 gm) , 1-chloro-3-di-n-butylamino propane (72 gm) and potassium carbonate (53 gm) in isopropyl alcohol are refluxed for 4 hr. After completion of the reaction isopropyl alcohol was distilled out to get 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-5-nitro benzofuran.
Oxalic acid (40 gm) was added to solution of 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-5-nitro benzofuran in acetone (300 ml) and diisopropyl ether 1200 ml) at 35-40°C. The reaction mixture was cooled to 20-30°C and precipitated solid was filtered to get title compound.
Yield : 166 gm
HPLC Purity: 99.39%

Example 2
Preparation of 5-amino-3- [4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran dioxalate
A mixture of 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-5-nitro benzofuran oxalate (85 gm) and 5% Pd/C (50% wet 4.25 gm) was hydrogenated in methanol (600 ml) for 2 hrs at 20-40°C. After completion of the reaction catalyst was filtered and filtrate was concentrated and treated with oxalic acid (16.5gm) in isopropyl alcohol (150ml) and methanol (40 ml) at 25-35°C for 2 hr. The precipitated material is filtered to obtain title compound.
Yield: 77 gm
HPLC Purity: 97.36%
Example 3
Preparation of 2-n-Butyl-3- [4-(3-di-n-butylamino-propoxy) benzoyl]-5-methylsulfonamidobenzofuran
To a suspension of 5-amino-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran di oxalate (70 gm) in water (350ml) and methylene chloride (280 ml) Triethyl amine (43 g) was charged at 15-20°C. The solution of Methane sulfonyl chloride (36 gm) in methylene chloride was added slowly at 15-20°C in 1 hr. After completion of the reaction methylene chloride layer was separated and washed with water. After concentration of methylene chloride yields 2-n-Butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-5-methylsulfonamidobenzofuran.
Yield : 69 gm
Purity: 98.35%
Dimesyl dronedarone: 0.09% by HPLC
Dronedarone Base: 0.48% by HPLC

We claim:

1. A process for the preparation of dronedarone hydrochloride wherein dimesyl dronedarone is less than 0.1%, the process comprises of;
a) contacting 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-5-nitro benzofuran with oxalic acid in a solvent,
b) hydrogenation of step a) product in alcohol solvent with 5 % Pd/C and,
c) treating step b) product in alcohol with oxalic acid and isolating di oxalate salt as solid,
d) mesylating step c) product with methane sulfonyl chloride in suitable solvent and presence of base,
e) isolating dronedarone base and converting it to hydrochloride salt thereof.

2. The process of claim 1, wherein the solvent used in the steps (a) is selected from methanol, isopropyl alcohol, acetone, dichloromethane, toluene, diisopropyl ester, methyl isobutyl ketone and hexane.

3. The process of claim 1, wherein suitable solvent used in step d) selected from one or more mixture of water, 2-methyl tetrahydrofuran, methylene chloride, tetrahydrofuran, toluene, ethyl acetate.

4. The process of claim 3, wherein step d) reaction is carried out in water.

5. The process of claim 3, wherein suitable solvent comprises of water with mixture of one of the solvent selected from 2-methyl tetrahydrofuran, methylene chloride, tetrahydrofuran, toluene and ethyl acetate.

6. The process of claim 1, wherein in step d) mesylated product has less than 0.5% unreacted 5-amino-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran, when measured by HPLC.

7. The process of claim 1, wherein isolation steps includes suitable techniques such as the concentration of solvents, slurry in a solvent and adding antisolvents technique.

8. A compound 5-amino-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran dioxalate salt.

9. The compound of Claim 8, wherein the purity of 5-amino-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-2-n-butyl benzofuran dioxalate is 97% or more when measured by HPLC.

10. The purity of dronedarone base obtained by the process of the invention is 96% or more when measured by HPLC.

Dated this 9th day of March 2011
For Wockhardt Limited

(Dr Mandar Kodgule)
Authorized Signatory