Claims:We claim:
1. A process for the preparation of benzofuran compound of Formula 1a or its salts,

Formula 1a

wherein R represents an alkyl group, aralkyl group, which involves:
i) reacting 5-aminobenzo[b]furan-2-carboxylate of Formula 4a

Formula 4a

with diethylamine compound of Formula 5 or its salts in presence of solvent

X-CH3-CH2-NH-CH2-CH3-X
Formula 5

wherein X represents halogen,
ii) optional purification of compound of Formula 1a,
iii) basifying of compound of Formula 1a using a base in a solvent.

2. A process for the preparation of benzofuran derivative of Formula 1a or its salts,


Formula 1a

wherein R represents alkyl group, aralkyl group, which involves:
i) reduction of 5-nitrobenzo[b]furan-2-carboxylate of Formula 3a

Formula 3a

using a catalyst in solvent to obtain compound of Formula 4a or its salts,

Formula 4a
wherein R is as defined above,
ii) reacting the product obtained in step i) above with diethylamine compound of Formula 5 or its salts in presence of solvent to obtain compound of Formula 1a,
iii) basifying compound of Formula 1a using a base, solvent.

3. A process for the preparation of a mixture of nitrobenzo[b]furan carboxylate, which involves:
i) nitrating salicylaldehyde to obtain a mixture of 3-nitro salicylaldehyde and 5-nitro salicylaldehyde,
ii) cyclizing the mixture obtained in step i) without purification with dialkyl malonate of Formula 6

Formula 6

wherein R represents alkyl group, aralkyl group and X represents halogen, using a base in a solvent to obtain mixture of nitrobenzo[b]furan-2-carboxylate as a mixture of 5-nitro and 3-nitro isomer.

4. A process for the preparation of benzofuran derivative of Formula 1a or its salts,

Formula 1a

wherein R represents alkyl group, aralkyl group, which involves:
i) nitrating salicylaldehyde to obtain a mixture of 3-nitro salicylaldehyde and 5-nitro salicylaldehyde,
ii) cyclizing the mixture obtained in step i) without purification with dialkyl malonate of Formula 6

Formula 6
wherein R represents alkyl group, aralkyl group and X represents halogen, using a base in a solvent to obtain mixture of nitrobenzo[b]furan-2-carboxylate as a mixture of 5-nitro and 3-nitro isomer,
iii) reduction of 5-nitrobenzo[b]furan-2-carboxylate

Formula 3a

using a catalyst in solvent to obtain compound of Formula 4a or its salts,

Formula 4a
wherein R is as defined above,
iv) reacting product obtained in step i) above with diethylamine compound of Formula 5 or its salts in presence of solvent to obtain compound of Formula 1a,
v) basifying compound of Formula 1a using a base, solvent.

5. A process for the purification of nitrobenzo[b]furan carboxylate, which involves:

i) dissolving mixture of 5-nitrobenzo[b]furan carboxylate and 3-nitrobenzo[b]furan carboxylate in a solvent,
ii) optionally adding anti-solvent,
iii) filtering and drying to obtain 5-nitrobenzo[b]furan carboxylate.

6. A process for the conversion of nitrosalicylaldehyde prepared according to the process claimed in 3 & 4 without purification to Benzofuran derivative.

7. A process for the conversion of benzofuran derivative of Formula 1a prepared to according to the process claimed in any of the above claims to Vilazodone.

8. The process according to claims 1, 2, 3 & 4 wherein the base is selected from inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate, sodium bicarbonate and potassium bicarbonate and organic bases such as triethylamine, triethanolaminetributylamine, N-methylmorpholine, N,N-diisopropylethyl amine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, 1,4-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-octane (DABCO).

9. The process according to claims 1, 2, 3 & 4, wherein solvent is selected from water, "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone or "glycol ethyl ethers" such as Ethylene glycol monomethyl ether, Ethylene glycol monoethyl ether Ethylene glycol monopropyl ether, Ethylene glycol monoisopropyl ether, Ethylene glycol monobutyl ether , Ethylene glycol monophenyl ether, Ethylene glycol monobenzyl ether, Diethylene glycol monomethyl ether, Diethylene glycol mono-n-butyl ether or "halogenated solvents" such as CCl4, dichloroethane, hexafluoro-2-propanol, trichloroethane, dichloromethane, diiodomethane, tetrachloroethane, chlorobenzene, tetrabromomethane and/or mixtures thereof.

10. The process according to claim 2 and 4 wherein catalysts is selected from Raney nickel, palladium on carbon, platinum on carbon, palladium acetate, Borane dimethylsulfide, platinum dioxide, Ni(PPh3)3Cl2/NaBH4, sodium cyanoborohydride, Tin(II) chloride, Nickel (II) chloride, LiAlH4, Fe/HCl, LiBH4, NaBH4, NaBH3CN, KBH4. sodium triacetoxy borohydride, alkyl and dialkyl cyanoborohydrides, potassium borohydride, zinc borohydride, and lithium tri-sec-butyl borohydride.

11. The process according to claim 3 and 4 wherein nitrating agent is selected from nitric acid, NaNO3, KNO3, t-butyl nitrite, ethyl nitrite, methyl nitrite, mixtures of nitric acid and sulfuric acid, mixtures of nitric acid with inorganic and organic anhydrides, dinitrogen pentoxide, mixture of acetic acid and nitric acid.

Dated this Thirtieth (30th) day of December 2016.
________________________________¬¬__________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883 , Description:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)
&
THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF BENZOFURAN DERIVATIVE

We, ONEKEM PHARMA PVT. LTD,
a company incorporated under the companies act, 1956 having address at 5-9-262/2/1A, Rajeev Gandhi Nagar, Prashanth Nagar, IDA Kukatpally, Kukatpally, Hyderabad, Telangana 500072, India

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of an intermediate used in the preparation of selective serotonin reuptake inhibitor and 5-HT1 receptor agonist.

The present invention specifically relates to an improved process for the preparation of Benzofuran derivative which is used as an intermediate in the preparation of Vilazodone.

The present invention further relates to commercially feasible process for the preparation of Benzofuran derivative of Formula 1a.

Formula 1a

BACKGROUND OF THE INVENTION
Vilazodone hydrochloride is marketed under the trade name VIIBRYD®. It is an orally administered selective serotonin reuptake inhibitor and a 5HT1A receptor partial agonist. It is used for the treatment of major depressive disorder (MDD).

Vilazodone HCl is 2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-hydrochloride (1:1). Its molecular weight is 477.99. The structural Formula is:

Vilazodone is first disclosed generically in US 5,532,241 A. No specific process for the preparation of Vilazodone is disclosed in this patent and the process is disclosed for an analogous compound.

US 4,226,792 discloses a process for the preparation of 3-nitrosalicyaldehyde, which involves nitration reaction of salicylaldehyde in presence of nitric acid and acetic acid followed by separation of isomers by fractional recrystallization in water. The process is shown in the scheme given below:

Scheme-I

IN 1187/MUM/2012 discloses a process for the preparation of ethyl 5-nitrobenzo[b] furan-2-carboxylate, which involves the reaction of 5-nitro salicylaldehyde with 2-bromo-diethylmalonate in presence of cyclohexane. The process is shown in the scheme given below:

Scheme-II

IN `1187 also discloses a process for the preparation of Benzofuran derivative of Formula 1, which is shown below:

Scheme-III

Purification of ethyl 5-nitrobenzo[b]furan-2-carboxylate using methanol is disclosed in International Journal of Universal Pharmacy and Life sciences, 2011, Vol 1(2), pg 127-134.

CN 102108070 B discloses a process for the preparation of ethyl 5-aminobenzo [b]furan-2-carboxylate, which is shown in the scheme given below:

Scheme-IV

The purification of mixture of nitrosalicyaldehyde is a tedious process and requires a lot of work up through fractional crystallization. Fractional crystallization is not industrial suitable process and hence is not feasible on commercial scale. Accordingly, the present application discloses a process which is simple, industrially feasible and economical.

None of the prior art references disclose a process for the preparation of benzofuran derivative of Formula 1 which is industrially scalable and yields the intermediate in pharmaceutically acceptable purity.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of an intermediate used in the preparation of 5-HT1 receptor agonist.

In a preferred objective of the present invention is to provide an improved process for the preparation of benzofuran derivative which is used in the preparation of Vilazodone.

In a more preferred objective of the present invention is to provide an improved process for the preparation of benzofuran derivative, which is commercially feasible.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides the process for the preparation of benzofuran derivative of Formula 1a or its salts,

Formula 1a

wherein R represents an alkyl, aralkyl group, which involves:
i) reacting 5-aminobenzo[b]furan-2-carboxylate of Formula 4a

Formula 4a

with diethylamine compound of Formula 5 or its salts in presence of a suitable solvent

X-CH3-CH2-NH-CH2-CH3-X
Formula 5

wherein X represents halogen,
ii) optional purification of compound of Formula 1a,
iii) basifying of compound of Formula 1a using a base in a suitable solvent.

Another embodiment of the present invention involves the preparation of Benzofuran derivative of Formula 1a or its salts,


Formula 1a

wherein R represents alkyl, aralkyl group, which involves:
i) reduction of 5-nitrobenzo[b]furan-2-carboxylate of Formula 3a

Formula 3a

using a catalyst in a suitable solvent to obtain compound of Formula 4a or its salts,

Formula 4a
wherein R is as defined above,
ii) reacting the product obtained in step i) above with diethylamine compound of Formula 5 or its salts in presence of solvent to obtain compound of Formula 1a,
iii) basifying compound of Formula 1a using a base in a suitable solvent.

Another embodiment of the present invention involves the preparation of mixture of nitrobenzo[b]furan carboxylate, which involves :
i) nitrating salicylaldehyde to obtain a mixture of 3-nitro salicylaldehyde and 5-nitro salicylaldehyde,
ii) cyclizing the mixture obtained in step i) without purification with dialkyl malonate of Formula 6

Formula 6

wherein R represents alkyl, aralkyl group and X represents halogen, using a base in a sutiable solvent to obtain mixture of nitrobenzo[b]furan-2-carboxylate as a mixture of 5-nitro and 3-nitro isomer.

Yet another embodiment of the present invention provides the purification of nitrobenzo[b]furan carboxylate (a mixture of 5-nitro and 3-nitro isomer), which involves:
i) dissolving mixture of 5-nitrobenzo[b]furan carboxylate and 3-nitrobenzo[b]furan carboxylate in a suitable solvent,
ii) optionally adding an anti-solvent,
iii) filtering and drying to obtain 5-nitrobenzo[b]furan carboxylate.

Another preferred embodiment of the present invention involves the preparation of benzofuran derivative of Formula 1a or its salts,

Formula 1a

wherein R represents alkyl, aralkyl group, which involves:
i) nitrating salicylaldehyde to obtain a mixture of 3-nitro salicylaldehyde and 5-nitro salicylaldehyde,
ii) cyclizing the mixture obtained in step i) without purification with dialkyl malonate of Formula 6

Formula 6
wherein R represents alkyl group, aralkyl group and X represents halogen, using a base in a suitable solvent to obtain mixture of nitrobenzo[b]furan-2-carboxylate as a mixture of 5-nitro and 3-nitro isomer,
iii) reduction of 5-nitrobenzo[b]furan-2-carboxylate

Formula 3a

using a catalyst in a suitable solvent to obtain compound of Formula 4a or its salts,

Formula 4a
wherein R is as defined above,
iv) reacting product obtained in step i) above with diethylamine compound of Formula 5 or its salts in a suitable solvent to obtain compound of Formula 1a,
v) basifying compound of Formula 1a using a base in a suitable solvent.

Another embodiment involves the use of nitro salicylaldehyde without purification in the preparation of Benzofuran derivative.

Another embodiment involves the use of benzofuran derivative of Formula 1a in the preparation of Vilazodone.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of benzofuran derivative which is commercially, economically and industrially feasible.

Accordingly in a preferred embodiment the present invention involves the preparation of Formula 1a or its salts,

Formula 1a

wherein R represents an alkyl, aralkyl group, which involves:
i) reacting 5-aminobenzo[b]furan-2-carboxylate of Formula 4a

Formula 4a

wherein R is as defined above, with Bis-(2-chloroethyl)amine or its salts in a suitable solvent,
ii) optional purification of compound of Formula 1a,
iii) basification of compound of Formula 1a using base in a suitable solvent.

Another preferred embodiment of the present invention involves the preparation of benzofuran derivative of Formula 1a or its salts,

Formula 1a

wherein R represents alkyl, aralkyl group, which involves:
i) reduction of 5-nitrobenzo[b]furan-2-carboxylate of Formula 3a

Formula 3a

using Raney nickel in a suitable solvent to obtain compound of Formula 4a or its salts,

Formula 4a
wherein R is as defined above,
ii) reacting the product obtained in step i) above with Bis-(2-chloroethyl)amine or its salts in a suitable solvent to obtain compound of Formula 1a,
iii) basifying compound of Formula 1a using a base in a suitable solvent.

Another preferred embodiment of the present invention involves the preparation of mixture of nitrobenzo[b]furan carboxylate, which involves :
i) nitrating salicylaldehyde to obtain a mixture of 3-nitro salicylaldehyde and 5-nitro salicylaldehyde,
ii) cyclizing the mixture obtained in step i) without purification with 2-bromo diethylmalonate using a base in a suitable solvent to obtain mixture of 5-nitro and 3-nitro isomer.

Another preferred embodiment of the present invention is the purification of nitrobenzo[b]furan carboxylate, which involves:
i) dissolving mixture of 5-nitrobenzo[b]furan carboxylate and 3- nitrobenzo[b]furan carboxylate in alcohol and water,
ii) optionally adding anti-solvent,
iii) filtering and drying to obtain 5-nitrobenzo[b]furan carboxylate.

Another preferred embodiment of the present invention involves the preparation of Benzofuran derivative of Formula 1a or its salts,

Formula 1a

wherein R represents alkyl group, aralkyl group, which involves:
i) nitrating salicylaldehyde to obtain a mixture of 3-nitro salicylaldehyde and 5-nitro salicylaldehyde,
ii) cyclizing the mixture obtained in step i) without purification with 2-bromo diethylmalonate using a base in a suitable solvent to obtain mixture of 5-nitro and 3-nitro isomer,
iii) reduction of 5-nitrobenzo[b]furan-2-carboxylate

Formula 3a

using Raney nickel in a suitable solvent to obtain compound of Formula 4a or its salts,

Formula 4a
wherein R is as defined above,
iv) reacting product obtained in step i) above with Bis-(2-chloroethyl)amine or its salts in a suitable solvent to obtain compound of Formula 1a,
v) basifying compound of Formula 1a using a base in a suitable solvent.

Another preferred embodiment involves the use of nitro salicylaldehyde without purification in the preparation of benzofuran derivative.

Another more preferred embodiment involves the conversion of benzofuran derivative of Formula 1a to Vilazodone by methods known in the art.

“Alkyl” as used herein refers to but not limited to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, octyl, isopentyl and t-butyl.

“Aralkyl” as used herein refers to but are not limited to benzyl, 2-phenylethyl, diphenylmethyl, triphenylmethyl, naphthalene methyl, 3- phenyl propyl, l-phenyl-2-propyl, 4-tert-butylbenzyl, 2- and 3-paratolylpropyl, p-tolylmethyl group, p-nitro benzyl group, p-amino benzyl group and p-chlorobenzyl group.

Halogens as used herein refers to fluorine, chlorine, bromine, iodine.

The term “salts” as used herein refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, beta-hydroxybutyrate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, mesylate, nitrate, oxalate, phthalate, phosphate, monohydro genphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propionate, phenylpropionate, salicylate, succinate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like. A preferred salt is the hydrochloride salt.

“Solvent” as defined in the presence invention is selected from water, "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone or "glycol ethyl ethers" such as Ethylene glycol monomethyl ether, Ethylene glycol monoethyl ether Ethylene glycol monopropyl ether, Ethylene glycol monoisopropyl ether, Ethylene glycol monobutyl ether , Ethylene glycol monophenyl ether, Ethylene glycol monobenzyl ether, Diethylene glycol monomethyl ether, Diethylene glycol mono-n-butyl ether or "halogenated solvents" such as CCl4, dichloroethane, hexafluoro-2-propanol, trichloroethane, dichloromethane, diiodomethane, tetrachloroethane, chlorobenzene, tetrabromomethane and the like and/or mixtures thereof. The percentage of different solvents when a mixture of solvents are used vary from 10 : 90 to 90: 10. Specifically, the percentage of water in solvents can be used in the range of 10-30%.

Anti-solvent as used herein is same as the solvent defined herein.

Base as used herein in the present invention is selected from either inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof or organic bases such as triethylamine, triethanolaminetributylamine, N-methylmorpholine, N,N-diisopropylethyl amine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, 1,4-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-octane (DABCO) and the like.

Basification of compound of Formula 1a is carried out preferably using carbonates and bicarbonates like sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate, sodium bicarbonate and potassium bicarbonate, more preferably using sodium and potassium carbonates.

Catalysts as used in the present invention is selected from Raney nickel, palladium on carbon, platinum on carbon, palladium acetate, Borane dimethylsulfide, platinum dioxide, Ni(PPh3)3Cl2/NaBH4, sodium cyanoborohydride, Tin(II) chloride, Nickel (II) chloride, LiAlH4, Fe/HCl, LiBH4, NaBH4, NaBH3CN, KBH4. sodium triacetoxyborohydride, alkyl and dialkyl cyanoborohydrides, potassium borohydride, zinc borohydride, and lithium tri-sec-butyl borohydride.

The nitration can be carried out using but are not limiting nitric acid, NaN03, KN03, t-butyl nitrite, ethyl nitrite, methyl nitrite, mixtures of nitric acid and sulfuric acid, mixtures of nitric acid with inorganic and organic anhydrides, dinitrogen pentoxide, mixture of acetic acid and nitric acid.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to 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:
Synthesis of 5-nitro salicylaldehyde:
To a mixture of salicylaldehyde (300 g) and acetic acid (1260g) fuming nitric acid (5 gm) was added at room temperature. The mixture was stirred for 30 minutes and then the reaction mass was cooled to 18-200C. The reaction mixture was continued for few more minutes and remaining fuming nitric acid (283 grams) was added drop wise for 1hr 30 min to 2 hours below 25°C. After completing the addition of nitric acid, the temperature was increased gradually to 40oC. The reaction mass was stirred for further for 1 hour and checked the TLC. After completing the reaction as monitored by TLC, the reaction mass was poured into ice cooled water (1500 grams) and continued stirring for 3-4 hrs. The compound was filtered and washed with water (500ml).
Wet weight :-( 650g), dry weight :-( 290g).
(5-nitro salicylaldehyde to 3 nitro salicylaldehyde ratio = 60:40 to 70:20).

This reaction can also be done by using sulfuric acid in place of acetic acid. Similar results obtained.

Example-2:
Stage-2: Synthesis of ethyl-5-nitrobenzofuran-2-carboxylate:
The reaction flask was charged with example-1 product (mixture of 5-nitro & 3-nitro salicylaldehyde) (200 grams) and DMF (400 grams) and stirred for 15 minutes at room temperature. Diethyl-2-bromo malonate (314 grams) was added drop wise to the reaction mixture followed by addition of anhydrous K2CO3 (410 grams) portion wise below 40oC in 30 minutes to 1 hour. The reaction temperature was raised to 100°C and maintained for 4-6 hrs. After completion of the reaction as monitored by TLC, reaction mass was poured into ice cooled water (1500g) and stirred for 30min. Solid obtained was separated, filtered and washed with water (400ml).
Wet weight :-( 400g), dry weight :-( 230g)

Example-3:
Stage-3: Purification of ethyl-5-nitrobenzofuran-2-carboxylate:
To the crude ethyl-5-nitro benzofuran-2-carboxylate (1 Kg) was dissolved in 3 lit isopropyl alcohol and 1 lit water at room temperature. Stirred for 15 minutes and then raised the temperature to 60oC to 65oC. The reaction was further stirred for 4 to 6 hours and filtered to obtain pure ethyl-5-nitro benzofuran-2-carboxylate. The product was dried below 60oC.
Dry weight: 500 gr to 550 gr.
HPLC purity: >99%, 7-nitro isomer below 0.15 %.

Example-4:
Stage-4: Synthesis of ethyl-5-amino benzofuran-2-carboxylate:
Suspension of Stage-III product (1 Kg) and Raney nickel (50 grams) in DMF (4 Lit), the mixture was stirred under hydrogen gas pressure (8 kg) at 80°C for 8-10 hrs. After completion of the reaction as monitored by TLC, reaction mass was cooled to room temperature. The Raney nickel was filtered over celite and distilled of 3 Lit DMF under reduced pressure below 80oC. Pour the reaction mass into ice cool water and stir for 3 hours. The solid was filtered and dried below 45oC.
Wet weight :-( 950 g), dry weight: - (800 g).

Example-5:
Stage-5: Synthesis of ethyl-5-piperazinyl-benzofuran-2-carboxylate:
i) The reaction flask was charged with Ethyl-5-amino benzofuran-2-carboxylate (380 grams) and Bis-(2-chloroethyl) amine hydrochloride (330 grams) in diglyme (1500 mL) at room temperature. The reaction mass was heated to reflux (170°C) for 20 hrs. After completion of the reaction as monitored by TLC, reaction mass was cooled to 0°C and stirred further for 1-3 hours. The product obtained was separated, filtered and washed with pre-cooled diglyme (200ml).

ii) Purification:
The crude product (600 g) was suspended in diglyme (800ml) and stirred for 30 min at 80°C. Solid obtained was separated and filtered at the same temperature and washed with hot diglyme (200ml). The obtained compound was hydrochloride salt of ethyl-5-piperazinyl-benzofuran-2-carboxylate.
Wet weight (490g), dry weight (440g)

iii) Basification of hydrochloride salt:
The above obtained hydrochloride salt (440g), DCM (1320ml) and water (300 ml) was charged in a reaction flask and cooled to 10-15°C. The pH (10-10.5) was adjusted by drop wise addition of aqueous K2CO3 solution (250g in 900ml water) at same temperature. The organic layer and aqueous layer were separated and again extracted with DCM (500ml, 250ml). The combined DCM layers were washed with brain (400ml) and water (400ml) and the organic layer was treated with activated carbon and dried using sodium sulphate. DCM was distilled out completely under vacuum below 50°C to obtain semi solid product. To the above obtained semi solid, heptane (500ml) was added and stirred further for 1 hr at 0°C. Solid obtained was separated, filtered and washed with chilled heptane (100ml) to get free base.
Wet compound:-360g, dry compound: - 330g.