DESCRIPTION :

The present invention provides a process for the preparation of dronedarone intermediate 5-amino-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-2-n-butyl benzofuran in high yield and purity, using hydrogen pressure 50 psi or less with catalyst palladium /carbon or raney nickel, optionally use of hydrogen donor such as hydrazinium monoformate and /or ammonium formate in absence of hydrogen pressure.

Dronedarone HCl is a benzofuran derivative which is represented by Formula I. It is also known by chemical name N-{2-butyl-3-[4-(3-dibutylaminopropoxy) benzoyl] benzofuran-5-yl} 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.

The present inventors while developing a process for the preparation of Dronedarone developed the process which involves the conversion of 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)benzoyl-5-nitro benzofuran to 5-Amino-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-2-n-butyl benzofuran in hydrogen pressure 50 psi or less and with safe readily available and inexpensive catalyst such as palladium/carbon (Pd/C) and Raney nickel. The inventors also develop the process, which can be carried out without hydrogen pressure wherein hydrazinium monoformate and or ammonium formate used as hydrogen donor. The intermediate obtained by the process of invention in high yield (92%) and purity (98% or more).

In one of the aspect of the invention a process for the preparation of Dronedarone Hydrochloride which includes the step of:
a) contacting 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl-5-nitro benzofuran with catalyst in alcoholic solvent at 50 psi hydrogen pressure,
b) isolating the 5-Amino-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-2-n-butyl benzofuran from the reaction mixture thereof,
c) converting 5-Amino-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-2-n-butyl benzofuran to N-{2-butyl-3-[4-(3-dibutylaminopropoxy) benzoyl] benzofuran-5-yl} methane sulfonamide hydrochloride.

The reaction of 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl-5-nitro benzofuran carry out in presence of catalyst such as palladium/carbon (Pd/C) and Raney nickel and alcohol solvents such as methanol, ethanol, propanol and isopropanol reduces to 5-Amino-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-2-n-butyl benzofuran. The reaction takes place less than 2 hours to reach on completion at temperature between 20°C to 40°C, after completion the catalyst is filtered and solvent is removed under reduced pressure to obtain step b) product which is further converted to dronedarone hydrochloride by the process known though the art via US 5,223,510.

In another aspect of the invention a process for the preparation of dronedarone hydrochloride includes the steps of;
a) contacting 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl-5-nitro benzofuran with catalyst in alcoholic solvent in presence of hydrogen donor,
b) isolating the 5-Amino-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-2-n-butyl benzofuran from the reaction mixture thereof,
c) converting 5-Amino-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-2-n-butyl benzofuran to N-{2-butyl-3-[4-(3-dibutylaminopropoxy) benzoyl] benzofuran-5-yl} methane sulfonamide hydrochloride.

The process involves the reduction of 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl-5-nitro benzofuran to 5-Amino-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-2-n-butyl benzofuran in presence of catalyst such as palladium/carbon (Pd/C) and Raney nickel and in alcoholic solvents such as methanol, ethanol, propanol and isopropanol. The process is characterized in that, wherein when no hydrogen pressure is used the reaction is carried out in presence of hydrogen donors such as hydrazinium monoformate or ammonium formate.

The reaction may be carried out at temperature range 20°C to 40°C and it takes less than 2 hours to reach to completion. After the completion of reaction the catalyst is filtered and the solvent is removed to obtain the residue, which is dissolved in dichloromethane and the dichloromethane layer washed with water. The dichloromethane is concentrated to obtain 5-amino-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-2-n-butyl benzofuran in HPLC purity > 98%, and the mother liquor is concentrated to obtain 5-Amino-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-2-n-butyl benzofuran.

The 5-Amino-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-2-n-butyl benzofuran obtained by the process of invention is converted to dronedarone by the process known to skilled artisan via US patent 5,223,510.

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 1A: Preparation of 5-amino-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-2-n-butyl benzofuran:
Charged 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)benzoyl-5-nitro benzofuran (80 g) and methanol (800 ml) in hydrogenator under stirring then added 5% Pd/C (4 g). Applied hydrogen pressure (50 psi) and continued stirring for1 hr at 25-35 0C. After completion of the reaction, filtered the catalyst and concentrated the reaction mass to obtain the title product.
Yield:70 gm
HPLC: 98.3%

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

Charged 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl-5-nitro benzofuran ( 5 g) and methanol (20 ml) in hydrogenator under stirring. Added 10% Pd/C (1.0 gm) and hydrazinium monoformate (5 ml) and continued stirring for 30 minutes at 25-30°C. After completion of the reaction, the reaction mixture is filtered and filtrate was concentrated to obtain the residue. The residue was dissolved in Dichloromethane (50 ml), washed dichloromethane with water. Dichloromethane was concentrated to yield the title product
Yield: 5.1 gm.
HPLC purity: 99.2 %

We Claim:

1. A process for the preparation of Dronedarone Hydrochloride, the process comprising:
a) contacting 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl-5-nitro benzofuran with catalyst in alcoholic solvent at 50 psi hydrogen pressure,
b) isolating the 5-Amino-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-2-n-butyl benzofuran from the reaction mixture thereof,
c) converting 5-Amino-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-2-n-butyl benzofuran to N-{2-butyl-3-[4-(3-dibutylaminopropoxy) benzoyl] benzofuran-5-yl} methane sulfonamide hydrochloride.
2. The process of Claim 1, wherein catalyst use in step a) is 5%Pd/C or Raney Nickel.
3. The process of Claim 2, wherein catalyst is Raney Nickel.
4. The process of claim 1, wherein alcoholic solvent used in step a) is selected from methanol, ethanol, propanol, and isopropanol.
5. The process of claim 1, wherein step a) is carried out at temperature 25°C -35°C.
6. A process for the preparation of Dronedarone Hydrochloride comprising;
a) contacting 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy) benzoyl-5-nitro benzofuran with catalyst in alcoholic solvent in presence of hydrogen donor,
b) isolating the 5-Amino-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-2-n-butyl benzofuran from the reaction mixture thereof,
c) converting 5-Amino-3-[4-(3-di-n-butylamino-propoxy) benzoyl]-2-n-butyl benzofuran to N-{2-butyl-3-[4-(3-dibutylaminopropoxy) benzoyl] benzofuran-5-yl} methane sulfonamide hydrochloride.
7. The process of claim 6, wherein catalyst used in step a) is 5% Pd/C or Raney Nickel.
8. The process of claim 1, wherein alcoholic solvent used in step a) is selected from methanol, ethanol, propanol, and isopropanol.
9. The process of claim 1, wherein hydrogen donor is selected from hydrazinium monoformate or ammonium formate.
10. The process of claim 6, wherein isolation process comprises of removal of alcoholic solvent, dissolution of residue in dichloromethane and washing the layer with water and further removal of dichloromethane.

Dated this 8th day of February 2011 For Wockhardt Limited

(Dr Mandar Kodgule)
Authorized Signatory