Patent of addition to our earlier co-pending application no: 629/CHE/2011 filed on 3rd March 2011

Field of the invention:

The present invention provides a process for the preparation of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methanesulfonamide compound represented by the following structural formula-1 and its pharmaceutically acceptable salts.

Formula-1 Background of the invention:
N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl} methanesulfonamide (development codename SR33589 and marketed as Multaq) is a drug by Sanofi-Aventis, mainly for the indication of cardiac arrhythmias. It was approved by the FDA on 1st July 2009. It was recommended as an alternative to amiodarone for the treatment of atrial fibrillation and atrial flutter in people whose hearts have either returned to normal rhythm or who undergo drug therapy or electric shock treatment to maintain normal rhythm.

Alkylaminoalkyl derivatives of benzofuran and process for their preparation is first disclosed in US5223510A, which is herein referred as '510' patent.

The above said '510' patent discloses the synthesis of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methanesulfonamide, which involves refluxing a mixture of 2-hydroxy-5-nitro benzylbromide and triphenyl phosphine in chloroform to provide 2-hydroxy-5-nitro benzyl triphenyl phosphonium bromide, which on reaction with n-pentanoyl chloride in presence of pyridine in chloroform provides 2-n-butyl-5-nitro benzofuran. The obtained benzofuran compound on freidel crafts acylation with anisoyl chloride in presence of tin tetrachloride in dichloroethane provides 2-n-butyl-3-(4-methoxybenzoyl)-5-nitro benzofuran, which on demethylation with AlCl3 in dichloroethane provides 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro benzofuran. The hydroxy compound on condensation with l-chloro-3-di-n-butylamino propane in presence of K2CO3 provides 2-n-butyl 3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran, which on reduction with platinum oxide in ethanol provides 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran. This amine on mesylation with methane sulfonyl chloride in presence of triethylamine in dichloroethane provides N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl] benzofuran-5-yl}methanesulfonamide.

The process disclosed in '510' patent involves the reduction of 5-nitro benzofuran derivatives using platinum oxide, which is an expensive reagent. The said process also involves the usage of pyridine as a base for the reaction of 2-hydroxy-5-nitro benzyl triphenyl phosphonium bromide with n-pentanoyl chloride and dichloroethane as a solvent for Freidel craft acylation, demethylation and mesylation steps. As pyridine and dichloroethane are toxic in nature, their usage is not suggestible on industrial scale. The said process also involves the usage of costly reagents like SnCl2, which leads to increase in the cost of production. Moreover, it is a time consuming process.

In view of all these points, there is a need in the art to develop a process which involves safer and cost-effective reagents.

WO2012032545A1 disclosed the usage of Fe-HCl for the reduction of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran to the corresponding amine. The above said application didn't provide any process for this reduction step.

We found that the usage of Fe-HCl for the above reduction step leading to tedious work-up procedure which is not recommendable on commercial scale. When Fe-HCl is used as a reducing agent in the above reduction step, the separation of amine from the reaction mixture is found to be problematic as the organic layer containing the amine compound forms emulsion with the aqueous layer. Due to the formation of such emulsion, the layer separation is very difficult to perform.

Hence there is a significant need in the art to develop an industrially viable process for the reduction of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran by adopting suitable reducing agents.

Brief description of the invention:
The first aspect of the preset invention is to provide a process for the preparation of 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran compound of formula-5, comprising of reducing the 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4 with Fe-acetic acid in a suitable solvent to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran compound of formula-5.

The second aspect of the present invention is to provide a process for the preparation of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methanesulfonamide hydrochloride salt compound of formula-la, comprising of;

a) Reacting the di-n-butylamine with l-bromo-3-chloro propane in the presence or absence of a solvent to provide 1-chloro 3-di-n-butylamino propane compound of formula-2,

b) condensing the compound of formula-2 in-situ with 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro benzofuran compound of formula-3 in presence of a suitable base in a suitable solvent to provide 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4,

c) reducing the compound of formula-4 in-situ with Fe-acetic acid in a suitable solvent to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran compound of formula-5,

d) optionally converting the compound of formula-5 into its dioxalate salt compound of formula-5a by treating it in-situ with oxalic acid in a suitable solvent,

e) mesylation of compound of formula-5 or its dioxalate salt compound of formula-5a by treating it with methane sulfonyl chloride in presence of a suitable base in a suitable solvent to provide N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methanesulfonamide compound of formula-1,

f) converting the compound of formula-1 into its hydrochloride salt compound of formula-la by treating it with a suitable HC1 source in a suitable solvent.

The third aspect of the present invention is to provide a process for the preparation of 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran dioxalate salt compound of formula-5a, comprising of; a) Reacting the di-n-butylamine with l-bromo-3-chloro propane to provide 1-chloro 3-di-n-
butylamino propane compound of formula-2,

b) condensing the compound of formula-2 in-situ with 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro benzofuran compound of formula-3 in presence of a suitable base in a suitable solvent to provide 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4,

c) reducing the compound of formula-4 in-situ with Fe-acetic acid in a suitable solvent to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran compound of formula-5,

d) treating the compound of formula-5 in-situ with oxalic acid in a suitable solvent to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran dioxalate salt compound of formula-5a.

Detailed description of the invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethylether, diethylether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, dioxane, acetonitrile and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, t-butanol and the like; "polar solvents" such as water; and/or their mixtures thereof.

As used herein the present invention the term "suitable base" refers to "alkali metal carbonates" such as sodium carbonate, potassium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium tert.butoxide and the like; "alkali metal phosphates" such as disodium hydrogen phosphate, dipotassium hydrogen phosphate and "organic bases" like diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine and the like.

The first aspect of the preset invention provides a process for the preparation of 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran compound of formula-5,
Formula-5 comprising of reducing the 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4 Formula-4 with Fe-acetic acid in a suitable solvent selected from hydrocarbon solvents, alcoholic solvents, ester solvents, ether solvents, chloro solvents, polar solvents and/or their mixtures thereof to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran compound of formula-5.

Wherein, the amount of Iron used is 2-8 mole ratio, preferably 3-7 mole ratio, more preferably 4-6 mole ratio per one mole ratio of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4 and the amount of acetic acid used is 1-4 ml, preferably 2-3 ml, more preferably 1 ml per one gram of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4.

A preferred embodiment of the present invention provides a process for the preparation of 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran compound of formula-5, comprising of reducing the 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4 with Fe-acetic acid in a mixture of toluene and water to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran compound of formula-5.

The second aspect of the present invention provides a process for the preparation of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methanesulfonamide hydrochloride salt compound of formula-la, comprising of;

a) Reacting the di-n-butylamine with l-bromo-3-chloro propane in the presence or absence of a solvent to provide 1-chloro 3-di-n-butylamino propane compound of formula-2,
Formula-2

b) condensing the compound of formula-2 in-situ with 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro benzofuran compound of formula-3

Formula-3 in presence of a suitable base in a suitable solvent to provide 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4,

c) reducing the compound of formula-4 in-situ with Fe-acetic acid in a suitable solvent to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran compound of formula-5,

d) optionally converting the compound of formula-5 into its dioxalate salt compound of formula-5a

Formula-5a by treating it in-situ with oxalic acid in a suitable solvent,

e) mesylation of compound of formula-5 or its dioxalate salt compound of formula-5a by treating it with methane sulfonyl chloride in presence of a suitable base in a suitable solvent to provide N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl} methanesulfonamide compound of formula-1,

f) converting the compound of formula-1 into its hydrochloride salt compound of formula-la by treating it with a suitable HC1 source in a suitable solvent.

Wherein, in step-a) the suitable solvent can be selected from ketone solvents, hydrocarbon solvent, ether solvents, ester solvents and/or their mixtures thereof;

in step-b) the suitable base is selected from hydroxides, alkoxides, carbonates and bicarbonates of alkali metals and organic bases; the suitable solvent is selected from hydrocarbon solvents, ketone solvents, ether solvents, ester solvents, polar-aprotic solvents and/or their mixtures thereof;

in step-c) the suitable the suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, chloro solvents, hydrocarbon solvents, polar solvents and/or their mixtures thereof;

in step-d) the suitable solvent is selected from alcoholic solvents, polar-aprotic solvents, ester solvents, ether solvents, ketone solvents and/or their mixtures thereof;

in step-e) the suitable base is selected from carbonates and bicarbonates of alkali metals and organic bases; the suitable solvent is selected from ketone solvents, hydrocarbon solvents, chloro solvents, polar solvents and/or their mixtures thereof;

in step-f) the suitable HC1 source is selected from dry HC1, aq.HCl, HC1 gas, ethyl acetate-HCl and isopropyl alcohol-HCl; and the suitable solvent is selected from alcoholic solvents, hydrocarbon solvents, ketone solvents, ester solvents and/or their mixtures thereof.

A preferred embodiment of the present invention provides a process for the preparation of N- {2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl} methanesulfonamide hydrochloride salt compound of formula-la, comprising of;

a) Reacting the di-n-butylamine with l-bromo-3-chloro propane to provide 1-chloro 3-di-n-butylamino propane compound of formula-2,

b) condensing the compound of formula-2 in-situ with 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro benzofuran compound of formula-3 in presence of potassium carbonate in toluene to provide 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4,

c) reducing the compound of formula-4 in-situ with Fe-acetic acid in a mixture of toluene and water to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran compound of formula-5,

d) converting the compound of formula-5 into its dioxalate salt compound of formula-5a by treating it in-situ with oxalic acid in isopropyl alcohol,

e) mesylation of compound of formula-5 or its dioxalate salt compound of formula-5a by treating with methane sulfonyl chloride in presence of sodium bicarbonate in a mixture of acetone and water to provide N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl] benzofuran-5-yl}methanesulfonamide compound of formula-1,

f) converting the compound of formula-1 into its hydrochloride salt compound of formula-la by treating it with HC1 in isopropyl alcohol to provide N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl} methanesulfonamide hydrochloride salt compound of formula-la.

Another preferred embodiment of the present invention provides a process for the preparation of N- {2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl} methanesulfonamide hydrochloride salt compound of formula-la, comprising of;

a) Reacting the di-n-butylamine with l-bromo-3-chloro propane to provide 1-chloro 3-di-n-butylamino propane compound of formula-2,

b) condensing the compound of formula-2 in-situ with 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro benzofuran compound of formula-3 in presence of potassium carbonate in toluene to provide 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4,

c) reducing the compound of formula-4 with Fe-acetic acid in a mixture of toluene and water to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran compound of formula-5,

d) converting the compound of formula-5 into its dioxalate salt compound of formula-5a by treating it with oxalic acid in isopropyl alcohol,

e) mesylation of compound of formula-5 or its dioxalate salt compound of formula-5a by treating with methane sulfonyl chloride in presence of sodium bicarbonate in a mixture of acetone and water to provide N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl] benzofuran-5-yl}methanesulfonamide compound of formula-1,

f) converting the compound of formula-1 into its hydrochloride salt compound of formula-la by treating it with HC1 in isopropyl alcohol to provide N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl} methanesulfonamide hydrochloride salt compound of formula-1a.

The 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro benzofuran compound of formula-3 utilized in step-a) of the first aspect of the present invention can be synthesized as follows;

a) Reaction of p-nitro phenol with formaldehyde and hydrobromic acid in presence of conc.sulfuric acid and phosphorous tribromide provides 2-(bromomethyl)-4-nitrophenol,

b) treating the 2-(bromomethyl)-4-nitrophenol with triphenyl phosphine in toluene provides (2-hydroxy-5-nitro-benzyl)triphenyl phosphonium bromide,

c) cyclization of (2-hydroxy-5-nitro-benzyl)triphenyl phosphonium bromide on reacting with n-pentanoyl chloride in presence of sodium carbonate in toluene provides 2-n-butyl-5-nitrobenzofuran,

d) Freidel craft acylation of 2-n-butyl-5-nitrobenzofuran with p-methoxy benzoyl chloride in presence of aluminium chloride in chloroform provides 2-n-butyl-3-(4-methoxybenzoyl)-5-nitro benzofuran,

e) demethylation of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitro benzofuran in presence of aluminium chloride in dichloromethane provides 2-n-butyl-3-(4-hydroxy benzoyl)-5-nitro benzofuran compound of formula-3.

The 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro benzofuran compound of formula-3 utilized in the present invention can also be prepared by the Freidel craft acylation of 2-n-butyl-5-nitrobenzofuran with p-hydroxy benzoyl chloride in presence of aluminium chloride in a suitable solvent.

The third aspect of the present invention is to provide a process for the preparation of 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran dioxalate salt compound of formula-5a, comprising of;

a) Reacting the di-n-butylamine with l-bromo-3-chloro propane to provide 1-chloro 3-di-n-butylamino propane compound of formula-2,

b) condensing the compound of formula-2 in-situ with 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro benzofuran compound of formula-3 in presence of a suitable base in a suitable solvent to provide 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4,

c) reducing the compound of formula-4 in-situ with Fe-acetic acid in a suitable solvent to provide 5 -amino-3 - [4-(3 -di-n-butylaminopropoxy)benzoyl] -2-n-butyl benzofuran compound of formula-5,

d) treating the compound of formula-5 in-situ with oxalic acid in a suitable solvent to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran dioxalate salt compound of formula-5a.

Wherein, the suitable reagents, bases and solvents used from step-a) to step-d) of the third aspect are same as defined for step-a) to step-d) respectively of the second aspect of the present invention.

A preferred embodiment of the present invention provides a process for the preparation of 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran dioxalate salt compound of formula-5 a, comprising of;

a) Reacting the di-n-butylamine with l-bromo-3-chloro propane to provide 1-chloro 3-di-n-butylamino propane compound of formula-2,

b) condensing the compound of formula-2 in-situ with 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro benzofuran compound of formula-3 in presence of potassium carbonate in toluene provide 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4,

c) reducing the compound of formula-4 in-situ with Fe-acetic acid in a mixture of toluene and water to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran compound of formula-5,

d) treating the compound of formula-5 in-situ with oxalic acid in isopropyl alcohol to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran dioxalate salt compound of formula-5a.

The present invention is schematically represented as follows. Synthetic scheme:

The best mode of carrying out the present invention is illustrated by the below mentioned examples.

These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

Examples:
Example-1: Preparation of 2-(bromomethyl)-4-nitrophenol
Conc.sulfuric acid (25 ml) was dropwise added to a mixture of p-nitro phenol (250 gm) and 50% HBr solution (500 ml) at 25-30°C. 35% Formaldehyde solution (154 gm) followed by phosphorous tribromide (242.8 gm) were slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 5 hrs at the same temperature. After the completion of the reaction, slowly added the reaction mixture to chilled water (2500 ml) at 5-10°C and stirred the reaction mixture for 60 min at 15-20°C. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 332.0 gm.

Example-2: Preparation of (2-hydroxy-5-nitro-benzyl)triphenyl phosphonium bromide
Triphenyl phosphine (113 gm) was added to a solution of 2-(bromomethyl)-4-nitrophenol (100 gm) in toluene (1000 ml) at 25-30°C. Heated the reaction mixture to 80- 85°C and stirred for 3 hrs at the same temperature. After the completion of the reaction, cooled the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with toluene and dried to get the title compound. Yield: 198 gm.

Example-3: Preparation of 2-n-butyl-5-nitrobenzofuran
(2-Hydroxy-5-nitro-benzyl)triphenyl phosphonium bromide (100 gm) was added to a solution of n-pentanoyl chloride (108.5 gm) in toluene (1000 ml) at 10-15°C and stirred for 15 min at the same temperature. Slowly added sodium carbonate (95.5 gm) followed by water (10 ml) to the reaction mixture at 10-15°C and stirred for 15 min at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 4 hrs at the same temperature. After the completion of the reaction, water (500 ml) was slowly added to the reaction mixture at 45-50°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated, ammonia solution (500 ml) was added to the organic layer at 25-30°C and stirred for 90 min at the same temperature. Both the organic and aqueous layers were separated, washed the organic layer with water and distilled off the solvent completely under reduced pressure. Pet ether (300 ml) was added to the obtained residue, cooled the reaction mixture to 0-5 °C and stirred for 2 hrs at the same temperature. Filtered the reaction mixture and distilled off the solvent completely from the filtrate under reduced pressure to get the tilte compound. Yield: 45.0 gm.

Example-4: Preparation of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitro benzofuran
Thionyl chloride (24 ml) was added to a solution of p-methoxy benzoic acid (40.5 gm) in chloroform (225 ml) and N,N-diemthyl formammide (2.5 ml) at 25-35°C under N2 atmosphere and stirred for 60 min at the same temperature. Afetr the completion of the reaction, 2-n-butyl-5-nitrobenzofuran (45 gm) obtained in example-3 followed by aluminium chloride (41 gm) were slowly added to the reaction mixture under N2 atmosphere at 10-15°C and stirred for 15 min at the same temperature. Stirred the reaction mixture for 4 hrs at 25-30°C under N2 atmosphere. After the completion of the reaction, the reaction mixture was slowly added to aq.hydrochloric acid at 5-10°C and distilled off chloroform completely under reduced pressure. Ethyl acetate (450 ml) was added to the reaction mixture at 25-3 0°C and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated, washed the organic layer with 20% sodium carbonate solution. Distilled off the solvent from the organic layer under reduced pressure and co-distilled with isopropyl alcohol. Isopropyl alcohol (180 ml) was added to the obtained compound at 25-30°C, heated the reaction mixture to 60-65°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 5-10°C and stirred for 60 min at the same temperature.

Filtered the precipitated solid, washed with isopropyl alcohol and dried to get the title compound. Yield: 41.0 gm.

Example-5: Preparation of 2-n-butyl-3-(4-hydroxybenzoyI)-5-nitro benzofuran (FormuIa-3)
Aluminium chloride (46 gm) was slowly added to a solution of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitro benzofuran (35 gm) in dichloromethane (245 ml) under N2 atmosphere at 25-30°C and stirred for 15 min at the same temperature. Heated the reaction miture to reflux temperature and stirred for 32 hrs at the same temperature. Another 20 gm of aluminium chloride was slowly added to the reaction mixture at 25-3 5°C, heated the reaction mixture to reflux temperature and stirred for 23 hrs at the same temperature. After the completion of the reaction, distilled off the solvent completely under reduced pressure. Cooled the residue to 0-5°C, water (350 ml) followed by dichloromethane (245 ml) were added at 25-30°C and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated, distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with toluene. Toluene (125 ml) was added to the obtaine dresidue at 25-30°C. Heated the reaction mixture to 65-75°C, carbon (2 gm) was added and stirred for 15 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with toluene. Cooled the filtrate to 10-15°C and stirred for 90 min. Filtered the precipitated solid, washed with toluene and dried to get title compound. Yield: 26.0 gm.

Example-6: Preparation of 2-n-butyl-3-(4-hydroxybenzoyi)-5-nitro benzofuran (Formula-3)
Dimethylformamide (0.5 ml) was added to a solution of p-hydroxybenzoicacid (4.4 gm) in dichloromethane (100 ml) at 25-30°C under nitrogen atmosphere. Thionyl chloride (16.28 gm) was added dropwise to the reaction mixture at 15-20° C. Heated the reaction mixture to reflux temperature and stirred for 1 hr at the same temperature. After completion of the reaction, distilled off the solvent completely from the reaction mixture under reduced pressure. Dichloromethane (100 ml) was added to the obtained residue at 25-30°C and then cooled to 0-5°C. 2-n-butyl-5-nitrobenzofuran (10 gm) followed by aluminium chloride (24.3 gm) were slowly added to the reaction mixture and then stirred for 12 hrs at reflux temperature. After completion of the reaction, the reaction mixture was poured into ice and stirred for 20 min. Filtered the reaction mixture and washed with dichloromethane. Both the organic and aqueous layers were separated, washed the organic layer with water. Adjusted the pH of the reaction mixture to 9.5 with 10% NaOH solution. Both the organic and aqueous layers were separated. Adjusted the pH of the aqueous layer to 1.5 using 50% hydrochloric acid solution at 10-15 °C and stirred for 1 hr at the same temperature. Filtered the precipitated solid, washed with chilled water and dried to get the title compound. Yield: 4.0 gm.

Example-7: Preparation of 1-chloro 3-di-n-butylamino propane (Formula-2)
A mixture of di-n-butylamine (32.5 gm) and l-bromo-3-chloro propane (20 gm) was heated to 40-50°C and stirred for 22 hrs at the same temperature. Cooled the reaction mixture to 20-30°C, pet ether (40 ml) followed by water (80 ml) were added and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated, water (20 ml) was added to the organic layer and stirred for 15 min. Adjusted the pH of the reaction mixture to 1.0 using dil.HCl solution at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated, adjusted the pH of the aqueous layer to 12 using sodium hydroxide solution. Both the aqueous and product layers were separated.

Example-8: Preparation of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran (Formula-4)

A solution of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro benzofuran (25 gm) in toluene (175 ml) was heated to 70-80°C and stirred for 15 min at the same temperature. Potassium carbonate (13.5 gm) was slowly added to the reaction mixture at 70-80°C and l-chloro-3-di-n-butylamino propane layer obtained in example-7 was added. Heated the reaction mixture to reflux temperature and stirred for 10 hrs at the same temperature. After the completion of the reaction, cooled the reaction mixture to 30-40°C. Filtered the reaction mixture and washed with dil.HCl solution. Washed the organic layer with sodium carbonate solution followed by water. The resulting organic layer containing 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-5-nitro benzofuran was utilized in the next step without isolating the compound from the reaction mixture.

Example-9: Preparation of 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran (Formula-5)
The organic layer containing 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran obtained in example-8 was added to a mixture of water (54 ml) and Iron powder (20 gm) at 25-30°C and heated the reaction mixture to 70-80°C. Acetic acid (54 ml) was slowly added to the reaction mixture at 70-80°C and stirred for 4 hrs at the same temperature. After the completion of the reaction, water (75 ml) was added to the reaction mixture at 30-40°C and stirred for 15 min at the same temperature. Filtered the reaction mixture and washed with toluene. Taken the filtrate and both the organic and aqueous layers were separated. Washed the organic layer with water and distilled off the solvent completely from the organic layer to get the title compound as a residue.

Example-10: Preparation of 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran dioxalate (Formula-5a)
Isopropyl alcohol (125 ml) was added to the residue obtained in example-9 and heated the reaction mixture to 60-70°C. A solution of oxalic acid (20.5 gm) in isopropyl alcohol (125 ml) was slowly added to the reaction mixture at 60-70°C. Heated the reaction mixture to reflux temperature and stirred for 15 min at the same temperature. Cooled the reaction mixture to 20-3 0°C and stirred for 90 min at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and dried to get the title compound. Yield: 36.5 gm.

Example-11: Preparation of 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran dioxalate (Formula-5a)
A mixture of di-n-butylamine (32.5 gm) and l-bromo-3-chloro propane (20 gm) was heated to 40-50°C and stirred for 22 hrs at the same temperature. Pet ether (40 ml) followed by water (80 ml) were added to the reaction mixture at 20-30°C and stirred for 15 min at the same temperature. Both organic and aqueous layers were separated, water (20 ml) was added to the organic layer and stirred for 15 min. Adjusted the pH of the reaction mixture to 1.0 using dil.HCl solution at 25-3 0°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated, adjusted the pH of the aqueous layer to 12 using sodium hydroxide solution. Both the aqueous and product layers were separated, and the
product layer was slowly added to a mixture of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro benzofuran (25 gm), toluene (175 ml) and potassium carbonate (13.5 gm) at 70-80°C. Heated the reaction mixture to reflux temperature and stirred for 10 hrs at the same temperature. After the completion of the reaction, filtered the reaction mixture and washed the filtrate with dil.HCl solution. Washed the organic layer with sodium carbonate solution followed by water and added to a mixture of water (54 ml) and Iron powder (20 gm) at 25-30°C. Heated the reaction mixture to 70-80°C, acetic acid (54 ml) was slowly added and stirred for 4 hrs at the same temperature. After the completion of the reaction, water (75 ml) was added to the reaction mixture at 30-40°C and stirred for 15 min at the same temperature. Filtered the reaction mixture and washed with toluene. Taken the filtrate, both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer. Isopropyl alcohol (125 ml) was added to the obtained residue and heated the reaction mixture to 60-70°C. A solution of oxalic acid (20.5 gm) in isopropyl alcohol (125 ml) was slowly added to the reaction mixture at 60-70°C. Heated the reaction mixture to reflux temperature and stirred for 15 min at the same temperature. Cooled the reaction mixture to 20-30°C and stirred for 90 min at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and dried to get the title compound. Yield: 36.5 gm.

Example-12: Preparation of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl] benzofuran-5-yl}methanesulfonamide (Formula-1)
5-Amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran dioxalate (35 gm), water (350 ml) and ethyl acetate (175 ml) were charged into a clean and dry RBF at 25-30°C and stirred for 10 min at the same temperature. Adjusted the pH of the reaction mixture to 10.0 with aq.ammonia solution and stirred for 30 min. Both the organic and aqueous layers were separated, distilled off the solvent completely from the organic layer under reduced pressure. Acetone (18 ml) and water (18 ml) were added to the obtained residue at 25-3 5°C and stirred for 10 min at the same temperature. Sodium bicarbonate (18 gm) followed by methane sulfonyl chloride (18.2 gm) were added to the reaction mixture at 25-35°C and stirred for 3 hrs at the same temperature. After the completion of the reaction, distilled off the solvent completely from the reaction mixture under reduced pressure. Water (175 ml) followed by ethyl acetate (175 ml) were added to the reaction mixture at 25-35°C and stirred for 10 min at the same temperature. Adjusted the pH of the aqueous layer to 10.5 using 10% sodium carbonate solution. Both the organic and aqueous layers were separated and washed the organic layer with water. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with isopropyl alcohol to get the title compound as a residue. Yield: 31.5 gm.

Example-13: Preparation of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl] benzofuran-5-yl}methanesulfonamide hydrochloride (Formula-la)
Isopropyl alcohol (185 ml) was added to the residue obtained in example-12 at 25-35°C and stirred for 10 min at the same temperature. Adjusted the pH of the reaction mixture to 2.0 with isopropyl alcohol-HCl at 25-30°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid and isopropyl alcohol (120 ml) was added. Heated the reaction mixture to 60-70°C and stirred for 15 min at the same temperature. Carbon (3.0 gm) was added to the reaction mixture at 60-70°C and stirred for 15 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with isopropyl alcohol. Cooled the filtrate to 25-3 0°C and stirred for 90 min at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and dried to get the title compound. Yield: 23.5 gm.

Example-14: Purification of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl] benzofuran-5-yl}methanesulfonamide hydrochloride (Formula-la)
A solution of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methanesulfonamide hydrochloride (10 gm) in acetone (170 ml) was heated to reflux temperature and stirred for 30 min at the same temperature. Carbon (1.0 gm) was added to the reaction mixture at 55-60°C and stirred for 10 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with hot acetone. Cooled the reaction mixture to 0-5 °C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with chilled acetone and dried to get the pure title compound. Yield: 8.3 gm; Purity by HPLC: 99.69%. Particle size distribution: Di0: 3.792 μm; D50: 17.843μm; D90: 81.262μm; D100: 490.49 μrn.

We Claim:

1. A process for the preparation of 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-
butyl benzofuran compound of formula-5, Formula-5 comprising of reducing the 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4

Formula-4 with Fe-acetic acid in a suitable solvent selected from hydrocarbon solvents, alcoholic
solvents, ester solvents, ether solvents, chloro solvents, polar solvents and/or their
mixtures thereof to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl
benzofuran compound of formula-5.

2. A process according to claim 1, wherein the reduction is carried out by the usage of Iron in an amount of 2-8 moles, preferably 3-7 moles, more preferably 4-6 moles per one mole of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4.

3. A process according to claim 1, wherein the amount of acetic acid used is 0.5-4.0 ml, preferably 1.0-3.0 ml, more preferably 1.5-2.5 ml per one gram of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4.

4. A process for the preparation of 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran compound of formula-5, comprising of reducing the 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4 with Fe-acetic acid in toluene or in a mixture of toluene and water to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran compound of formula-5.

5. A process for the preparation of N-{2-butyl-3-[4-(3-dibutylaminopropoxy) benzoyl]benzofuran-5-yl}methanesulfonamide HC1 salt compound of formula-la, comprising of; a) Reacting the di-n-butylamine with l-bromo-3-chloro propane in the presence or absence of a solvent to provide 1-chloro 3-di-n-butylamino propane compound of formula-2

b) condensing the compound of formula-2 in-situ with 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro benzofuran compound of formula-3

Formula-3 in presence of a suitable base in a suitable solvent to provide 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4,

c) reducing the compound of formula-4 in-situ with Fe-acetic acid in a suitable solvent to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran compound of formula-5,

d) optionally converting the compound of formula-5 into its dioxalate salt compound of formula-5 a
Formula-5a by treating it in-situ with oxalic acid in a suitable solvent, e) mesylation of compound of formula-5 or its dioxalate salt compound of formula-5a by treating it with methane sulfonyl chloride in presence of a suitable base in a suitable solvent to provide N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl] benzofuran-5-yl}methanesulfonamide compound of formula-1,

Formula-1 f) converting the compound of formula-1 into its hydrochloride salt compound of formula-la by treating it with a suitable HC1 source selected from dry HC1, aq.HCl, HC1 gas, ethyl acetate-HCl and isopropyl alcohol-HCl in a suitable solvent.

Formula-la
6. A process according to claim 5, wherein;

step-a) is carried out in the absence of solvent, in step-b) the suitable base is selected from carbonates and bicarbonates of alkali metals and organic bases; the suitable solvent is selected from hydrocarbon solvents, ketone solvents, ether solvents, ester solvents, polar-aprotic solvents and/or their mixtures thereof;

in step-c) the suitable solvent is selected from hydrocarbon solvents, alcoholic solvents, ester solvents, ether solvents, chloro solvents, polar solvents and/or their mixtures thereof;

in step-d) the suitable solvent is selected from alcoholic solvents, polar-aprotic solvents, ester solvents, ether solvents, ketone solvents and/or their mixtures thereof;

in step-e) the suitable base is selected from carbonates and bicarbonates of alkali metals and organic bases; the suitable solvent is selected from ketone solvents, hydrocarbon solvents, chloro solvents, polar solvents and/or their mixtures thereof;

in step-f) the suitable solvent is selected from alcoholic solvents, hydrocarbon solvents, ketone solvents, ester solvents and/or their mixtures thereof.

7. A process for the preparation of N-{2-butyl-3-[4-(3-dibutylaminopropoxy) benzoyl]benzofuran-5-yl}methanesulfonamide HC1 salt compound of formula-la, comprising of;

a) Reacting the di-n-butylamine with l-bromo-3-chloro propane to provide 1-chloro 3-di-n-butylamino propane compound of formula-2,

b) condensing the compound of formula-2 in-situ with 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro benzofuran compound of formula-3 in presence of potassium carbonate in toluene to provide 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4,

c) reducing the compound of formula-4 in-situ with Fe-acetic acid in a mixture of toluene and water to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran compound of formula-5,

d) converting the compound of formula-5 into its dioxalate salt compound of formula-5a by treating it in-situ with oxalic acid in isopropyl alcohol,

e) mesylation of compound of formula-5 or its dioxalate salt compound of formula-5a by treating with
methane sulfonyl chloride in presence of sodium bicarbonate in a mixture of acetone and water to provide N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methanesulfonamide compound of formula-1,

f) converting the compound of formula-1 into its hydrochloride salt compound of formula-la by treating it with HC1 in isopropyl alcohol to provide N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methanesulfonamide hydrochloride salt compound of formula-la.

8. A process for the preparation of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl] benzofuran-5-yl} methanesulfonamide hydrochloride salt compound of formula-la, comprising of;

a) Reacting the di-n-butylamine with l-bromo-3-chloro propane to provide 1-chloro 3-di-n-butylamino propane compound of formula-2,

b) condensing the compound of formula-2 in-situ with 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro benzofuran compound of formula-3 in presence of potassium carbonate in toluene to provide 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4,

c) reducing the compound of formula-4 with Fe-acetic acid in a mixture of toluene and water to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran compound of formula-5,

d) converting the compound of formula-5 into its dioxalate salt compound of formula-5a

by treating it with oxalic acid in isopropyl alcohol,

e) mesylation of compound of formula-5 or its dioxalate salt compound of formula-5a by treating with methane sulfonyl chloride in presence of sodium bicarbonate in a mixture of acetone and water to provide N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl] benzofuran-5-yl}methanesulfonamide compound of formula-1,

f) converting the compound of formula-1 into its hydrochloride salt compound of formula-la by treating it with HC1 in isopropyl alcohol to provide N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methanesulfonamide hydrochloride salt compound of formula-la.

9. A process for the preparation of 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-
butyl benzofuran dioxalate salt compound of formula-5a, comprising of;

a) Reacting the di-n-butylamine with l-bromo-3-chloro propane to provide 1-chloro 3-di-n-butylamino propane compound of formula-2,

b) condensing the compound of formula-2 in-situ with 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro benzofuran compound of formula-3 in presence of potassium carbonate in toluene provide 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-nitro benzofuran compound of formula-4,

c) reducing the compound of formula-4 in-situ with Fe-acetic acid in a mixture of toluene and water to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran compound of formula-5,

d) treating the compound of formula-5 in-situ with oxalic acid in isopropyl alcohol to provide 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butyl benzofuran dioxalate salt compound of formula-5 a.

10. Usage of Fe-acetic acid for the reduction of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)
benzoyl]-5-nitro benzofuran compound of formula-4.