DESCRIPTION

The present invention provides a process for the preparation of 2-n-butyl-3-[4-(3-di-n-butylamino-propxy) benzoyl]-5-nitro benzofuran, an intermediate for the preparation of Dronedarone HCl. The process comprises reacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran and 1-chloro-3-di-n-butylaminopropane in the presence of a base and a solvent excepting the ketonic solvent, methyl ethyl ketone or optionally in presence a phase transfer catalyst to produce 2-n-butyl-3-[4-(3-di-n-butylamino-propxy) benzoyl]-5-nitro benzofuran.

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 preparation of 2-n-butyl-3-[4-(3-di-n-butylamino-propxy) benzoyl]-5-nitro benzofuran (Formula IV), an intermediate for the preparation of Dronedarone HCl (Formula I), which include of reacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (Formula II) and 1-chloro-3-di-n-butylaminopropane (Formula III) in solvent where solvent is not methyl ethyl ketone and presence of base the process is characterized that it complete in less than 12 hour time.

Formula II Formula III Formula IV

The intermediate of Formula II and III are reacting in presence of base in a solvent and reflux temperature. After completion of reaction the reaction mixture is concentrated to get syrupy mass, which is then dissolved in halogenated solvent and washed with the aqueous solution of base. Concentration of reaction mixture yields the intermediate of Formula IV in good yield and purity. Inventor observed the reaction goes to completion much faster in less than 12 hours with higher yield and purity.

In one of the aspect of the invention the reaction proceed in much faster way about 5 hours time when the reaction carried out with a mixture of bases.

In another aspect when reaction is carried out in solvent like water or a mixture of water and tetrahydrofuran, the reaction proceed in 10 hours in presence of a phase transfer catalyst such as tetra butyl ammonium bromide.

The terminologies used in the instant invention solvent comprises protic polar solvent, an aprotic polar solvent, or a mixture of a protic polar solvent , an aprotic polar and non polar solvent.

For example polar protic solvent, polar aprotic, protic solvent, non polar solvent which may include of Formic acid, acetic acid, water, methanol, ethanol, isopropanol , n-propanol , Acetone, Dimethyl sulphoxide, Dimethyl acetamide, Dimethyl formamide, Tetrahydrofuran, acetonitrile, ethyl acetate, acetone, dichloromethane, hexane, benzene toluene, N-methyl pyrrolidone and the like may be used as single or in mixture of to carry out the reaction.

The term “base” as used herein refers to hydroxide, carbonate, bicarbonate, sulphates of an alkaline earth metal or a mixture of one or more of them.

In one of the aspects of the invention of 2-n-butyl-3-[4-(3-di-n-butylamino-propxy) benzoyl]-5-nitro benzofuran (Formula IV) is produced by reacting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (Formula II) and 1-chloro-3-di-n-butylaminopropane (Formula III) in the presence of a base and a solvent excepting the ketonic solvent methyl ethyl ketone.

A base or a mixture of any two bases comprising hydroxides, carbonates, bicarbonates and sulphates of an alkaline earth metal may be added to a solution obtained by dissolution of 2-n-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran (Formula II) in suitable solvents. After stirring, 1-chloro-3-di-n-butylamino propane (Formula III) may be added and the reaction mixture may be heated at reflux temperature for its completion. The reaction may be completed in about 1 to 12 hours depending on the solvent and base employed. A summary of reaction parameters such as time and temperature for reaction completion vis a vis the base and solvent employed is summarized in Table 1. The reaction temperature varies between 700C to 1100C depending on the solvent. The reaction mass may be cooled to room temperature, filtered and filtrate evaporated to obtain syrupy mass. The syrupy mass may be dissolved in polar protic or aprotic solvent and washed with an alkaline base followed by water. The organic layer may be concentrated to obtain pure syrupy mass of 2-n-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran of purity of 96% or more.

In yet another aspect of the invention the reaction of 2-n-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran (Formula II) and 1-chloro-3-di-n-butylamino propane (Formula III) to produce 2-n-butyl-3-[4-(3-di-n-butylamino-propxy) benzoyl]-5-nitro benzofuran (Formula IV) is biphasic when the solvent is either water or a mixture of water and tetrahydrofuran. The reaction is accelerated by using phase transfer catalyst such as tetra butyl ammonium bromide and the reaction is completed in about 7 to 10 hours.
Table 1

Reaction parameters vis a vis solvents in the preparation of 2-n-butyl-3-[4-(3-di-n-butylamino-propxy) benzoyl]-5-nitro benzofuran

Sl No Base Solvent Reaction parameters Remarks
Time (Hrs) Temperature(0 C)
1 Potassium carbonate DMF 5 80 -
2 Potassium carbonate Toluene 110 -
3 Potassium carbonate Dimethyl sulfoxide 1 80 -85 -
4 Potassium carbonate Dimethyl sulfoxide and Toluene 7 80 -85 -
5 Potassium carbonate Water 7 80 -85 TBAB used
6 Potassium carbonate Water and Tetrahydrofuran 10 80 -100 TBAB used
7 Potassium carbonate Acetonitrile 5 80 -85 -
8 Sodium carbonate Acetonitrile 2 80 -85 -
9 Potassium bi carbonate Acetonitrile 3 80 -85 -
10 Sodium bi carbonate Acetonitrile 7 80 -85 -
11 Sodium carbonate Acetonitrile 4 80 -85 -
12 Potassium carbonate N-Methyl pyrrolidine 3 80-85 -
13 Potassium carbonate Dimethyl acetamide 11 80-85 -
14 Potassium carbonate Isopropanol 4 80 -85 -

The molar ratio of the base and 1-chloro-3-di-n-butylamino propane would be in the range 1: 1.1 to 1: 1.5.

The 2-n-butyl-3-[4-(3-di-n-butylamino-propxy) benzoyl]-5-nitro 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 1
2-n-butyl-3-[4-(3-di-n-butylamino-propxy) benzoyl]-5-nitro benzofuran

2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (5 gm) was dissolved in acetonitrile (35 ml) followed by anhydrous potassium carbonate (2.64 gm) was added. After stirring for 30 minutes 1-chloro-3-di-n-butylamino propane is added and reaction mixture is heated at reflux temperature for 5 hours for reaction completion. Then reaction mass is cooled to room temperature and filtered. The filtrate is concentrated to get syrupy mass. Syrupy mass was taken into dichloromethane (100 ml) and washed with 5 % aq. sodium hydroxide solution (50 ml) followed by water (50 ml). The separated dichloromethane layer was concentrated get syrupy mass.
Yield: 7.2 gm
Purity: 96%
We claim:

1. A process for the preparation of 2-n-butyl-3-[4-(3-di-n-butylamino-propxy) benzoyl]-5-nitro benzofuran (Formula IV) from the reactants 2-n-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran (Formula II) and 1-chloro-3-di-n-butylamino propane (Formula III); in the presence of a base and a solvent other than methyl ethyl ketone optionally in presence of phase transfer catalyst.

(Formula II) (Formula III) (Formula IV)

2. The process of claim 1 wherein, solvent is protic polar solvent, an aprotic polar solvent, or a mixture of a protic polar solvent, non polar solvent or a mixture of aprotic solvent or a mixture of protic polar solvent, an aprotic polar solvent and halogenated solvent.
3. The process of claim 1, wherein the solvent water or a mixture of water and tetrahydrofuran reaction carried in presence of phase transfer catalyst.
4. The process of claim 3, wherein phase transfer catalyst is tetra butyl ammonium bromide.
5. The process of claim 2 wherein the protic polar solvent is methanol, n propanol or iso propanol.
6. The process of claim 2, wherein the aprotic polar solvent are dimethylacetamide, dimethyl formamide and Dimethylsulfoxide.
7. The process of claim 2, wherein the non-polar solvent comprises hexane, benzene and toluene.
8. The process of claim 1, wherein the intermediate used to make Dronedarone hydrochloride.
9. The process of claim 1, wherein the base comprises hydroxide, carbonate, bicarbonates, sulphates of an alkaline earth metal and a mixture of one or more of them.
10. The process of claim 9 wherein the carbonate of alkaline earth metal is potassium carbonate.

Dated this 10th day of November 2010
For Wockhardt Limited

(Dr Mandar Kodgule)
Authorized Signatory