This application claims priority to this Indian patent application number 3660/CHE/2012 filed on September 05, 2012.

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Vilazodone intermediates and further conversion to Vilazodone or its pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION:

Vilazodone Hydrochloride, 5-[4-[4-(5-cyano-1 H-indol-3-yl)butyl]-1 -piperazinyl]-2-benzofurancarboxamide hydrochloride, having the Formula-I is approved, under the trade name VIIBRYD®, by the United States Food and Drug Administration. VIIBRYD® is indicated for the treatment of major depressive disorder.

Vilazodone hydrochloride was first disclosed in United States patent number US
5532241.

US 5723614 discloses 5-Piperazin-l-yl-benzofuran-2-carboxylic acid alkyl ester or its pharmaceutically acceptable salt of Formula-II, which is one of the important intermediate in the preparation of Vilazodone hydrochloride.

US 5723614 also discloses process for the preparation of compound of Formula-H as given in the following scheme-I.

There is still need in the art to prepare 5-Piperazin-l-yl-benzofuran-2-carboxylic acid alkyl ester. Thus the present invention provides an improved process for the preparation of 5-Piperazin-l-yl-benzofuran-2-carboxylic acid alkyl ester or its salts of Formula-H and further conversion into Vilazodone or its pharmaceutically acceptable salts thereof.

OBJECT AND SUMMARY OF THE INVENTION:

Principle object of the present invention is to provide an improved process for the preparation of 5-Piperazin-l-yl-benzofiiran-2-carboxylic acid alkyl ester or its salts.

Another object of the present invention is to provide further conversion of 5-Piperazin-l-yl-benzofuran-2-carboxylic acid alkyl ester or its salts into Vilazodone or its pharmaceutically acceptable salts thereof.

One aspect of the present invention provides an improved process for the preparation of Vilazodone or its pharmaceutically acceptable salts comprises;

a) nitrating (2-formylphenoxy) acetic acid alkyl ester to get (2-Formyl-4-nitro-phenoxy)-acetic acid alkyl ester,

b) converting (2-Formyl-4-nitro-phenoxy)-acetic acid alkyl ester into alkyl -5- nitrobenzofuran-2-carboxylate,

c) reducing alkyl-5-nitrobenzofuran-2-carboxylate to get alkyl-5- aminobenzofuran-2-carboxylate,

d) reacting the alkyl-5-aminobenzofuran-2-carboxylate with Bis(2-haloethyl)amine or its salt to get 5- Piperazin-l-yl-benzofuran-2-carboxylic acid alkyl ester or its salts thereof,

e) reacting 5- Piperazin-l-yl-benzofuran-2-carboxylic acid alkyl ester or its salts with compound of Formula-Ill get 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]-piperazin-l-yl}-benzofuran-2-carboxylic acid alkyl ester or its salts thereof, and wherein L is a leaving group.

f) converting 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]-piperazin-l-yl}-benzofuran-2-carboxylic acid alkyl ester or its salts into Vilazodone or its pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides an improved process for the preparation of 5-Piperazin-l- yl-benzofuran-2-carboxylic acid alkyl ester or its salts and further conversion to Vilazodone or its pharmaceutically acceptable salts thereof.

Accordingly, the present invention provides an improved process for the preparation of Vilazodone or its pharmaceutically acceptable salts comprises;

a) nitrating (2-formylphenoxy) acetic acid alkyl ester to get (2-Formyl-4-nitro-phenoxy)-acetic acid alkyl ester,

b) converting (2-Formyl-4-nitro-phenoxy)-acetic acid alkyl ester into alkyl -5- nitrobenzofuran-2-carboxylate,

c) reducing alkyl-5-nitrobenzofuran-2-carboxylate to get alkyl-5- aminobenzofuran-2-carboxylate,

d) reacting the alkyl-5-aminobenzofuran-2-carboxylate with Bis(2-haloethyl)amine or its salt to get 5- Piperazin-l-yl-benzofuran-2-carboxylic acid alkyl ester or its salts thereof,

e) reacting 5- Piperazin-l-yl-benzofuran-2-carboxylic acid alkyl ester or its salts with compound of Formula-Ill get 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]-piperazin-l-yl}-benzofuran-2-carboxylic acid alkyl ester or its salts thereof, and wherein L is a leaving group.

f) converting 5- {4-[4-(5-Cyano-1 H-indol-3-yl)-buty 1]-piperazin-1 -y 1} -benzofuran-2-carboxylic acid alkyl ester or its salts into Vilazodone or its pharmaceutically acceptable salts thereof.

In one embodiment of the present invention, Nitration of (2-formylphenoxy) acetic acid alkyl ester is carried out in presence of nitrating agent such as fuming nitric acid, NaNO2 in presence of acid in an organic solvent. Organic solvent can be halogenated solvent such as dichloromethane.

In one more embodiment of the present invention, (2-Formyl-4-nitro-phenoxy)-acetic acid alkyl ester is cyclised to give alkyl-5-nitrobenzofuran-2-carboxylate in presence of a base such as inorganic base such as KOH, NaOH, or organic base such as l,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) in an organic solvent. Organic solvent can be alcoholic solvent such as ethanol.

In one more embodiment of the present invention, alkyl-5-nitrobenzofuran-2-carboxylate is reduced in presence of reducing agents such as Iron powder and ammonium chloride or raney nickel catalyst, SnC^, Zn in presence of acid to get alkyl-5-aminobenzofuran-2-carboxylate.

In one more embodiment of the present invention, alkyl-5-aminobenzofuran-2- carboxylate or its salts is reacted with Bis(2-haloethyl)amine or its salt, preferably Bis(2-chloroethyl)amine or its salt optionally in presence of dehydrating agents such as organic sulphonic acid like p-Toluene sulphonic acid to get 5- Piperazin-l-yl-benzofuran-2-carboxylic acid alkyl ester or its pharmaceutically acceptable salts thereof.

In one more embodiment of the present invention, 5-{4-[4-(5-Cyano-lH-indol-3-yl)- butyl]-piperazin-l-yl}-benzofuran-2-carboxylic acid alkyl ester or its salts is prepared by reacting 5- Piperazin-l-yl-benzofuran-2-carboxylic acid alkyl ester or its salts with compound of Formula-Ill wherein L is leaving group such as halogen, alkylsulphonyloxy, or arylsulphonyloxy; optionally in presence of alkali metal iodides such as sodium iodide, potassium iodide, preferably sodium iodide; and a base in presence of a suitable polar aprotic solvent such as N-Methyl-2-pyrrolidone.

Base is selected from inorganic base such as sodium bicarbonate, potassium carbonate, potassium bicarbonate, preferably potassium bicarbonate or organic base such as DBU. After completion of the reaction the reaction mass containing organic layer is washed with buffering agents such as potassium dihydrogen phosphate to remove any unreacted 5-Piperazin-l-yl-benzofuran-2-carboxylic acid alkyl ester or its salts. The organic layer is dried and distilled off to get 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]-piperazin-l-yl}-benzofuran-2-carboxylic acid alkyl ester or its salts.

In one more embodiment of the present invention, Vilazodone or its pharmaceutically acceptable salts, is prepared from 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]-piperazin-l-yl}-benzofuran-2-carboxylic acid alkyl ester or its salts by following processes disclosed in US 5532241.

Another aspect of the present invention provides, an improved process for the preparation of Vilazodone or its pharmaceutically acceptable salts comprises reacting 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]-piperazin-l-yl}-benzofuran-2-carboxylic acid alkyl ester or its salts with ammonia source such as alcoholic ammonia.

In one embodiment, alcoholic ammonia is methanolic ammonia. As per the present invention, 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]-piperazin-l-yl}-benzofuran-2- carboxylic acid alkyl ester or its salt is taken in autoclave and alcoholic ammonia such as methanolic ammonia is added at 50-90 °C, preferably at 60-70 °C for about 30 hours. The obtained solid is filtered, washed with water and dried. The obtained solid is treated with mixture of sodium hydroxide, dimethylformamide followed by water. The reaction mass is filtered and dried to get Vilazodone.

One more aspect of the present invention provides an improved process for the preparation of Vilazodone or its pharmaceutically acceptable salts comprises;

a) reacting 5- Piperazin-l-yl-benzofuran-2-carboxylic acid ethyl ester or its salts with compound of Formula-Ill get 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]-piperazin-l-yl}-benzofuran-2-carboxylic acid alkyl ester or its salts thereof, wherein L is a leaving group, and

b) converting 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]-piperazin-l-yl}-benzofliran-2-carboxylic acid ethyl ester or its salts into Vilazodone or its pharmaceutically acceptable salts thereof.

In one embodiment of the present invention, 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]-piperazin-l-yl}-benzofuran-2-carboxylic acid ethyl ester or its salts is prepared by reacting 5- Piperazin-l-yl-benzofuran-2-carboxylic acid ethyl ester or its salts with compound of Formula-IH optionally in presence of alkali metal iodides such as sodium iodide, potassium iodide, preferably sodium iodide; and a base in presence of a suitable polar aprotic solvent such as N-Methyl-2-pyrrolidone.

Base is selected from inorganic base such as sodium bicarbonate, potassium carbonate, potassium bicarbonate, preferably potassium bicarbonate or organic base such as DBU. After completion of the reaction the reaction mass containing organic layer is washed with buffering agents such as potassium dihydrogen phosphate to remove any unreacted 5- Piperazin-l-yl-benzofuran-2-carboxylic acid ethyl ester or its salts. The organic layer is dried and distilled off to get 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]-piperazin-l-yl}-benzofuran-2-carboxylic acid ethyl ester or its salts.

In one more embodiment, Vilazodone or its pharmaceutically acceptable salts thereof is prepared by reacting 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]-piperazin-l-yl}-benzofuran-2-carboxylic acid ethyl ester or its salts with ammonia source such as methanolic ammonia.

In one aspect of the present invention, Vilazodone obtained in the above processes, is further converted into its pharmaceutically acceptable salts by following the prior art procedures disclosed in US 5532241.

Experimental procedure:

Example-1: Process for the preparation of (2-Formyl-4-nitro-phenoxy)-acetic acid
ethyl ester A mixture of acetone (1000 ml) and potassium carbonate (362.1 g) and Tetra-n-butylammonium bromide (5.3 g) was taken and to this a mixture of salicylaldehyde (200.0 g) and ethyl bromoacetate (190.2 ml) was added drop wise. The reaction mass was filtered to separate the salts and salts were washed with dichloromethane and to this concentrated acetone layer was added. To this water was added and dichloromethane layer was separated.

The aqueous layer was extracted with dichloromethane and both dichloromethane layers were combined and washed with brine solution. Dichloromethane was distilled out atmosphererically as much as possible and then under vacuum to obtain wet compound. Fuming nitric acid (682.4 ml) was taken in another reactor and cooled to 10 °C. To this the obtained wet compound solution (340.99 g in 682.4 ml dichloromethane) was added and the temperature was raised to 20 °C. To this water and dichloromethane was added.

Dichloromethane layer was separated, the aqueous layer was extracted with dichloromethane and both dichloromethane layers were combined. Dichloromethane was distilled out atmospherically and Isopropyl ether was added to the crude product.

The product was filtered and washed with Isopropyl ether to yield (2-Formyl-4-nitro-phenoxy)-acetic acid ethyl ester.

Example-2: Process for the preparation of Ethyl-5-nitrobenzofuran-2-carboxylate A mixture of ethanol (3750 ml) (2-Formyl-4-nitrophenoxy) acetic acid ethyl ester (250 g) and l,8-Diazabicyclo[5.4.0]undec-7-ene (165.3 g) was stirred for 20 hours at 25-30 °C. The reaction mass was stirred at 0-5 °C for ten hours. The product was filtered, washed with ethanol and dried to yield Ethyl-5-nitrobenzofuran-2-carboxylate.

Example-3: Process for the preparation of EthyI-5-aminobenzofuran-2-carboxylate A mixture of Ethyl-5-nitrobenzofuran-2-carboxylate (32.0 g), methanol (640 ml), DM water (235 ml), ammonium chloride (52.96 g) and iron powder (40.16 g) was stirred for six hours at 25-30 °C.

The inorganic salts were filtered though hyflow and washed with methanol. The filtrate was concentrated under vacuum at 40-45 °C and ethyl acetate (320 ml) was added at 25-30 °C. To this DM water was added and layers were separated. The aqueous layer was extracted with ethyl acetate and the layers were separated. Both ethyl acetate layers were combined and washed with brine solution. The ethyl acetate containing product was dried with anhydrous sodium sulphate and ethyl acetate is distilled under vacuum to yield Ethyl-5-aminobenzofuran-2-carboxylate.

Example-4: Process for the preparation of Ethyl-5-aminobenzofuran-2-carboxylate A mixture of Ethyl-5-nitrobenzofuran-2-carboxylate (100.0 g), ethanol (1500 ml), and raney nickel (10 g) was taken and hydrogenation chamber and maintained for 10 hours at 50 °C. The reaction mass was cooled to room temperature filtered over hyflow and with ethanol. The aqueous HC1 was added to the filtrate and stirred for 1-2 h. The solid was filtered, washed with ethanol and dried to yield Ethyl-5-aminobenzofuran-2-carboxylate hydrochloride.

Example-5: Process for the preparation of 5- Piperazin-l-yl-benzofuran-2-carboxylic acid ethyl ester hydrochloride A mixture of Xylene (900 ml), Ethyl-5-aminobenzofuran-2-carboxylate (75.0 g), Bis(2-chloroethyl)amine hydrochloride (71.7 g) and p-Toluene sulphonic acid monohydrate (2.08 g) was heated to 140 °C and maintained for 85 hours. The reaction mixture was cooled to room temperature. The compound was filtered, washed with acetone.

The wet solid was slurried in acetone and added hydrochloric acid and filtered the solid and dried to yield 5- Piperazin-l-yl-benzofuran-2-carboxylic acid ethyl ester hydrochloride.

Example-6: Process for the purification of 5- Piperazin-l-yl-benzofuran-2-car boxy lic acid ethyl ester hydrochloride To the compound 5- Piperazin-l-yl-benzofuran-2- carboxylic acid ethyl ester hydrochloride (114 g), methanol (436 ml) was added and heated to 65 C. The reaction mixture was cooled to room temperature.

The compound was filtered, washed with methanol and dried to yield pure 5- Piperazin-l-yl-benzofuran-2-carboxylic acid ethyl ester hydrochloride.

Example-7: Process for the Preparation of 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]- piperazin-l-yl}-benzofuran-2-carboxylic acid ethyl ester dihydrochloride A mixture of 5- Piperazin-l-yl-benzofuran-2-carboxylic acid ethyl ester hydrochloride (76.8 g), 3-(4-Chlorobutyl)-lH-indol-5-carbonitrile (50 g), N-Methyl-2-pyrrolidone (1000 ml), sodium carbonate (64.5 g) and sodium iodide (48.3 g) stirred at 60 °C for 24 hours. To this ethyl acetate (1000 ml) and water (2250 ml) was added.

The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined and washed with water. The ethyl acetate layer was washed with 5% KH2PO4 and brine solution. Ethyl acetate layer was dried and distilled under vacuum completely to get viscous liquid product. The oily residue was dissolved in acetone and ethanolic HC1 was added. The product was filtered, washed with acetone and dried to yield 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]-piperazin-l-yl}-benzofuran-2-carboxylic acid ethyl ester dihydrochloride.

Example-8: Process for the Preparation 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]- piperazin-l-yl}-benzofuran-2-carboxy!ic acid amide (Vilazodone) 5-{4-[4-(5-Cyano-1 H-indol-3-yl)-butyl]-piperazin-1 -yl }-benzofuran-2-carboxylic acid ethyl ester dihydrochloride (100 g) was taken in autoclave and methanolic ammonia (1000 ml) was added at 60-70 °C for 30 h.

The obtained solid was fileted and washed with water (100 ml) and the solid was dried at 60°C. The obtained solid was treated with mixture of NaOH and DMF (750 ml) followed by water (500 ml) and filtered the solid and further washed with water (400 ml). The solid was dried at 60°C to get 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]-piperazin-l-yl}-benzofuran-2-carboxylic acid amide (Vilazodone).

We claim:

1. An improved process for the preparation of Vilazodone or its pharmaceutically acceptable salts comprises, reacting 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]-piperazin-l-yl}-benzofuran-2-carboxylic acid alkyl ester or its salts with alcoholic ammonia.

2. The process according to claim 1, alcoholic ammonia is methanolic ammonia.

3. An improved process for the preparation of Vilazodone or its pharmaceutically acceptable salts comprises;

a) nitrating (2-formylphenoxy) acetic acid alkyl ester to get (2-Formyl-4-nitro- phenoxy)-acetic acid alkyl ester,

b) converting (2-Formyl-4-nitro-phenoxy)-acetic acid alkyl ester into alkyl -5- nitrobenzofuran-2-carboxylate,

c) reducing alkyl-5-nitrobenzofuran-2-carboxylate to get alkyl-5-aminobenzofuran-2-carboxylate,

d) reacting the alkyl-5-aminobenzofuran-2-carboxylate with Bis(2-haloethyl)amine or its salt to get 5- Piperazin-l-yl-benzofuran-2-carboxylic acid alkyl ester or its salts thereof,

e) reacting 5- Piperazin-l-yl-benzofuran-2-carboxylic acid alkyl ester or its salts with compound of Formula-Ill get 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]-piperazin-l-yl}-benzofuran-2-carboxylic acid alkyl ester or its salts thereof, and wherein L is a leaving group.

f) converting 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]-piperazin-l-yl}- benzofuran-2-carboxylic acid alkyl ester or its salts into Vilazodone or its pharmaceutically acceptable salts thereof.

4. The process according to claim 3, wherein nitration of (2-formylphenoxy) acetic acid alkyl ester is carried out in presence of nitrating agent such as fuming nitric acid and NaNO2.

5. The process according to claim 3, wherein cyclization of (2-Formyl-4-nitro- phenoxy)-acetic acid alkyl ester is carried in presence of a base.

6. The process according to claim 5, wherein base is selected from inorganic base such as KOH, NaOH, or organic base such as 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).

7. The process according to claim 3, wherein reduction of alkyl-5-nitrobenzofuran-2-carboxylate is carried out in presence of reducing agents such as Iron powder and ammonium chloride or raney nickel catalyst, SnCl2 and Zn in presence of acid.

8. The process according to claim 3, wherein reaction of alky 1-5-aminobenzofuran-2-carboxylate with Bis(2-haloethyl)amine or its salt is carried out optionally in presence of dehydrating agents.

9. The process according to claim 8, wherein dehydrating agent is p-Toluene sulphonic acid.

10. An improved process for the preparation of Vilazodone or its pharmaceutically acceptable salts comprises;

a) reacting 5- Piperazin-l-yl-benzofuran-2-carboxylic acid ethyl ester or its salts with compound of Formula-Ill get 5-{4-[4-(5-Cyano-lH-indol-3-yl)-butyl]-piperazin-l-yl}-benzofuran-2-carboxylic acid alkyl ester or its salts thereof wherein L is a leaving group, and

b) converting 5- {4-[4-(5-Cyano-1 H-indol-3-yl)-butyl]-piperazin-1 -yl} - benzofuran-2-carboxylic acid ethyl ester or its salts into Vilazodone or its pharmaceutically acceptable salts thereof.