This application claims priority to Indian patent application numbered 1690/CHE/2011 filed on May 18, 2011, the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Milnacipran hydrochloride. The present invention also relates to process for the purification of Milnacipran hydrochloride.

BACKGROUND OF THE INVENTION:

Milnacipran hydrochloride is chemically known as (±)-[1R(S), 2S(R)]-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride, having structural formula-l is shown in figure-l.

Milnacipran hydrochloride is a Norepinephrine Serotonin Reuptake Inhibitor (NSRI) and it is useful in the treatment of depression and chronic pain conditions like fibromyalgia and Lupus. Milnacipran hydrochloride is sold under the brand name SAVELLA® which is indicated for the management of fibromyalgia.

Milnacipran hydrochloride is first disclosed in US 4,478,836. This patent also discloses process for the preparation of Milnacipran hydrochloride.

EP 0200638 discloses a process for the preparation of Milnacipran hydrochloride comprising reacting 2-oxo-1-phenyl-3-oxabicyclo[3.1.0]-hexane with potassium phthalimide and the resulting phthalimide intermediate is chlorinated in the presence of chlorinated agent. The resulted chlorinated intermediate is reacted with diethylamine to get corresponding amide intermediate, which is further converted into Milnacipran hydrochloride.

US 5,034,541 disclose a similar process for the preparation of Milnacipran phthalimide intermediate comprising reacting 2-oxo-1-phenyl-3-oxabicyclo[3.1.0]-hexane with a Lewis acid-amine complex in presence of diethylamine to get 2-hydroxymethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide, which is converted into its chloro derivative by reacting thionyl chloride. The resulting chloro intermediate is reacted with phthalimide salt in the presence of dimethylformamide to yield Milnacipran phthalimide intermediate, cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-N, N-diethyl-1-phenylcyclopropanecarboxamide.

The yields obtained in the above mentioned processes are low. Therefore the present invention provides commercially viable process for the preparation of Milnacipran hydrochloride.

OBJECT AND SUMMARY OF THE INVENTION:

The main object of the present invention is to provide an improved process for the preparation of Milnacipran hydrochloride.

Another object of the present invention is to provide a purification process for the preparation of Milnacipran hydrochloride.

The schematic representation of the present invention for the preparation of Milnacipran hydrochloride is given in the following scheme-l.

SCHEME-I In one aspect the present invention provides, an improved process for the preparation of Milnacipran hydrochloride comprising the steps of:

a) reacting 2-hydroxymethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide (compound-1) with chlorinating agent to give chloro derivative characterized in that after completion of the reaction, reaction mass is treated with a base,

b) reacting 2-chloromethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide (compound-2) with phthalide salt in solvent to get phthalimide intermediate, cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-N, N-diethyl-1-phenyl -cyclopropanecarboxamide (compound-3),

c) optionally purifying the phthalimide intermediate ( compound-3) using organic solvents,

d) converting phthalimide intermediate (compound-3) into Milnacipran hydrochloride.

In another aspect the present invention provides, an improved process for the preparation of (Z)-1-phenyl-2-(phthalimidomethyl) cyclopropanecarboxylic acid, which is an intermediate in the preparation of Milnacipran hydrochloride comprising reacting 2-oxo-1-phenyl-3-oxabicyclo [3.1.0]-hexane with Phthalimide salt in presence of ionic liquid.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of Milnacipran
hydrochloride wherein, 2-hydroxymethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide is reacted with chlorinating agent to give chloro derivative characterized in that after completion of the reaction, reaction mass is treated with a base to get chloro intermediate of compound of formula 2. It is reacted with phthalimide salt in the presence of solvent to yield Milnacipran phthalimide intermediate of compound of formula 3. It is further converted into Milnacipran hydrochloride by conventional method.

The main aspect of the present invention is to provide an improved process for the preparation of Milnacipran hydrochloride comprising the steps of:

a) reacting 2-hydroxymethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide (compound-1) with chlorinating agent to give chloro derivative characterized in that after completion of the reaction, reaction mass is treated with a base,

b) reacting 2-chloromethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide (compound-2) with phthalimide salt in a solvent to yield cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl)methyl-N,N-diethyl-1 -phenylcyclopropane carboxamide (compound-3),

c) optionally purifying compound-3 in a solvent,

d) converting phthalimide intermediate of compound of formula 3 into Milnacipran hydrochloride.

In step a) process, 2-hydroxymethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide (compound-1) is converted into its chloro derivative of 2-chloromethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide (compound-2). The compound of formula 1 is reacted with chlorinating agent and then after completion of the reaction, it is treated with a base. Chlorinating agent is selected from thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, preferable chlorinating agent is thionyl chloride. The reaction is carried out in inert solvent such as dichloroethane or dichloromethane.

As per the present invention, 2-hydroxymethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide is suspended/ dissolved in methylene chloride and reaction mass is cooled to -10-5°C. To this thionyl chloride is added and reaction mixture. After completion of the reaction, a base such as imidazole is added and the resulting reaction mixture is concentrated under reduced pressure. Toluene is added to this and concentrated under reduced pressure. Methylene chloride and water mixture is added and organic layer is separated. The organic layer is concentrated under reduced pressure to give 2-chloromethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide.

Prior art process does not involve the usage of base in chlorination stage. The usage of base is enhancing the yield and purity of the reaction. The yield of the reaction is drastically changed by using the base after completion of the reaction. If the base is not used after completion of the chlorination 2-oxo-1-phenyl-3-oxabicyclo[3.1.0]-hexane is formed as an impurity. Therefore, usage of base reduces the formation of impurity 2-oxo-1-phenyl-3-oxabicyclo[3.1.0]-hexane. The base used in this chlorination reaction is selected from imidazole, morpholine, N-methyl morpholine, pyridine, piperazine, triethylamine, preferably imidazole. If the base is not used ~ 4 % of 2-oxo-1 -phenyl-3-oxabicyclo[3.1.0]-hexane is formed as an impurity, by using the base the impurity is reduced to ~ 1- 0.5 %.

In the second step, the chlorinated derivative of compound of formula 2 is reacted with a phthalimide salt, preferably the potassium phthalimide, in an organic solvent. The organic solvent used in this reaction is inert organic solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene or dichloroethane, preferably dimethylformamide.

Alternatively, in the second step the chlorinated derivative of compound of formula 2 is reacted with a phthalimide salt, preferably the potassium phthalimide, in an ionic liquid as solvent. The ionic liquids used in this process are such as 1-butyl-3-methylimidazolium chloride and 1 -butyl-3-methylimidizolium tetrafluoroborate. The usage of ionic liquid in this reaction enhance the yield and purity of the phthalimide intermediate Cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-N, N-diethyl-1-phenylcyclopropane -carboxamide. In this process the reaction is maintained at a temperature 30-160 °C, preferably 65-90 °C. The ionic liquid is recovered from the mother liquor and reused.

In the third step, the phthalimide intermediate Cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-N, N-diethyl-1-phenylcyclopropanecarboxamide (compound of formula 3) formed in the second step is optionally purified. The organic solvent used in the purification is alcoholic solvent selected from ethanol, methanol and isopropanol, preferably methanol. The purification reaction yields pure phthalimide intermediate cis-2-[(1, 3-Dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-N, N-diethyl-1-phenylcyclopropanecarboxamide having less impurities and high yield. The phthalimide impurity is reduced from -12% to ~ 0.01- 0.05 % after purification with organic solvent.
In the fourth step, phthalimide intermediate cis-2-[(1, 3-Dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-N, N-diethyl-1-phenylcyclopropanecarboxamide (compound of formula 3) is converted into Milnacipran hydrochloride in presence of hydrazine hydrate without using the solvent. This is the cost effective process when compared with the prior art processes. In this process 80% Hydrazine hydrate is used.

In one embodiment of the present invention, starting material 2-hydroxymethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide is prepared by conventional methods as disclosed in US 5034541. Alternatively the compound 2-hydroxymethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide is prepared by reacting 2-oxo-1-phenyl-3-oxabicyclo [3.1.0]-hexane with diethylamine in presence of Lewis acids and ionic liquids. The Lewis acid used in this process is aluminium chloride. The ionic liquids used in this process are such as 1 -butyl-3-methylimidazolium chloride and 1-butyl-3-methylimidizolium tetrafluoroborate. The reaction is carried out in inert solvent such as dichloroethane or dichloromethane.

Another aspect of the present invention is to provide novel process for the purification of Milnacipran hydrochloride comprising the steps of treating the Milnacipran hydrochloride with polar solvent or a mixture of polar and non polar solvents; and isolating pure Milnacipran hydrochloride.

As per the present invention, Milnacipran hydrochloride is taken in a polar solvent or a mixture of polar and non polar solvents. Polar solvent is selected from ethyl acetate, tert- butyl acetate, methanol, ethanol, isopropyl alcohol and butanol. Non polar solvent is selected from toluene, hexane heptane, preferably toluene. The reaction mixture is heated to 45 to 120 °C, preferably 55 to 70 °C. After dissolution the reaction mixture, clear solution is cooled to -10 to 20 °C preferably -5 to 10 °C. The obtained solid is filtered to isolate pure Milnacipran hydrochloride.

One more aspect of the present invention is to provide an improved process for the purification of Milnacipran hydrochloride comprising the steps of

a) dissolving Milnacipran hydrochloride in an ester solvent,

b) cooling the reaction mixture, and

c) isolating pure Milnacipran hydrochloride.

In one embodiment of the present invention, ester solvent is selected from ethyl acetate, isopropyl acetate or tert- butyl acetate.

Another aspect the present invention is to provide an improved process for the preparation of (Z)-1-Phenyl-2-(phthalimidomethyl) cyclopropanecarboxylic acid, which is an intermediate in the preparation of Milnacipran hydrochloride comprising reacting 2-oxo-1-phenyl-3-oxabicyclo [3.1.0]-hexane with phthalimide salt in presence of ionic liquid. The ionic liquids used in this process are such as 1-butyl-3-methylimidazolium chloride and 1-butyl-3-methylimidizolium tetrafluoroborate. The compound (Z)-1-phenyl-2-(phthalimidomethyl) cyclopropanecarboxylic acid is further converted into Milnacipran hydrochloride by the conventional methods as disclosed in EP 200638. The compound (Z)-1-phenyl-2-(phthalimidomethyl) cyclopropanecarboxylic acid is converted into Milnacipran hydrochloride by the process disclosed in scheme-ll.

The following examples are provided to illustrate the process of the present invention. They, are however, not intended to limiting the scope of the present invention in any way and several variants of these examples would be evident to person ordinarily skilled in the art.

Examples

Example-1: Process for the Preparation of 2-hydroxymethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide
Aluminum chloride (8.4 g) was stirred with methylene dichloride (50 ml), and the reaction mixture was cooled to 0-5 °C. To this a mixture of diethyl amine (12 g) and 1-butyl-3-methylimi- dazolium chloride (50 ml) with added. To the reaction mass 2-oxo-1-phenyl-3-oxabicyclo [3.1.0]-hexane (10 g) was added and reaction mixture stirred at same temperature for 2 hours. To the reaction mixture ice (50 g) and DM water (200 ml) was added slowly under stirring. The organic layer was separated and washed with 25% sodium chloride (50 ml) solution. The organic layer was concentrated under reduced pressure to give 2-hydroxymethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide (13 g, Yield 91.0 %) HPLC purity -99 %.

Example-2: Process for the Preparation of 2-chloromethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide 2-Hydroxymethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide (100 g) was stirred with methylene dichloride (500 ml), reaction mixture was cooled to -10-5 °C, and thionyl chloride (53 g in 100ml of MDC) was added with stirring at -10-0°C about one hour. Reaction mixture stirred at same temperature for 1 hour. After completion of the reaction imidazole (13.7 g) was added and the reaction mixture was concentrated under reduced pressure to give crude, and to this toluene (2 x 50 ml) was added and concentrated under reduced pressure twice, methylene dichloride and DM water was added to crude and stirred. The organic layer was separated and washed with 5% sodium bicarbonate solution and finally washed with DM water, the organic layer was concentrated under reduced pressure to give 2-chloromethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide (92 g). HPLC purity - 99.68 %.

Example-3: Process for the Preparation of 2-Chloromethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide 2-Hydroxymethyl-1-phenyl-cyc!opropanecarboxylic acid diethylamide (100g) was stirred with methylene dichloride (250 ml), reaction mixture was cooled to -15-0 °C, and thionyl chloride (53 g) was added with stirring at -15-0°C about one hour. After completion of the reaction imidazole (13.7 g) was added and the reaction mixture was concentrated under reduced pressure to give crude, and to this toluene (2 x 50 ml) was added and concentrated under reduced pressure twice.

methylene dichloride and DM water was added to crude and stirred. The organic layer was separated and washed with 0.5% sodium bicarbonate solution and finally washed with DM water, the organic layer was concentrated under reduced pressure to give 2-chloromethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide (98 g). HPLC purity - 99.68 %.

Example-4: Preparation of Cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl)-methyl-N, N-diethyl-1-phenylcyclopropanecarboxamide 2-Chloromethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide (100 gm) was stirred with dimethyl formamide (200 ml) at 30-40 °C. To this potassium phthalimide (87.1 gm) was added heated to 140-160°C. The reaction mass was cooled and DM water was added. The reaction mass was filtered and dried to yield crude cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-N, N-diethyl-1-phenylcyclopropane carboxamide (110 g). HPLC purity 95%

Example-5: Preparation of cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl)-methyl-N, N-diethyl-1-phenylcyclopropanecarboxamide 2-Chloromethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide (10 gm) was stirred with 1-butyl-3-methylimidazolium chloride (70 ml) at 20-40 °C. To this potassium phthalimide (9 gm) was added heated to 70-85 °C. The reaction mass was extracted with ethyl acetate. The remaining ionic liquid was reused after drying in vacuum. The extracted compound was dried to yield crude cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-N, N-diethyl-1-phenylcyclopropane carboxamide (11 g).

Example-6: Preparation of cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-N, N-diethyl-1-phenylcyclopropanecarboxamide

2-Chloromethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide (10 gm) was stirred with 1-butyl-3-methylimidazolium chloride (70 ml) at 20-40 °C. To this mixture of potassium phthalimide (9 gm) & potassium hydroxide (1g) was added and heated to 70-85°C. The reaction mass was extracted with ethyl acetate. The remaining ionic liquid was reused after drying in vacuum. The extracted compound was dried to yield crude cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-N, N-diethyl-1-phenylcyclopropane carboxamide (11 g).

Example-7: Preparation of cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl)-methyl-N, N-diethyl-1-phenylcyclopropanecarboxamide

2-Chloromethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide (10 gm) was stirred with 1-butyl-3-methylimidazolium chloride (70 ml) at 20-40 °C. To this potassium phthalimide (9 gm) was added and heated to 70-85°C. To this reaction mass water was added and stirred. The reaction mass was filtered and dried to yield crude cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-N, N-diethyl-1-phenylcyclopropane- carboxamide (11g).

The ionic liquid was extracted by adding solvent in aqueous mother liquor & reused after evaporation of solvent drying in vacuum.

Example-8: Preparation of cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl)-methyl-N, N-diethyl-1-phenylcyclopropanecarboxamide

2-Chloromethyl-1-phenyl-cyclopropapecarboxylic acid diethylamide (10 gm) was stirred with 1-butyl-3-methylimidizolium tetrafluoroborate (75 ml) at 20-40 °C. To this potassium phthalimide (9 gm) was added heated to 70-85°C. To this reaction mass water was added and stirred. The reaction mass was filtered and dried to yield crude cis-2-[(1, 3-Dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-N, N-diethyl-1-phenylcyclopropane carboxamide (11g).

The ionic liquid was extracted by adding solvent in aqueous mother liquor & reused after evaporation of solvent drying in vacuum.

Example-9: Purification of crude cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-N, N-diethyl-1-phenylcyclopropanecarboxamide

Crude cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-N, N-diethyl-1-phenylcyclopropane carboxamide taken from any of examples 2-6 was stirred with methanol and the reaction mixture was heat to reflux. The reaction mixture was cooled to 0-50 °C and the resulted reaction mixture filtered, washed with methanol and dried to yield pure cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-N, N-diethyl-1-phenyl cyclopropane carboxamide. HPLC purity-99.93%.

Example-10: Preparation of Milnacipran hydrochloride Cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-N, N-diethyl-1-phenylcyclo -propanecarboxamide(100g) and hydrazine hydrate 80 % (33 g) was taken in DM water (1000 ml) and the reaction mixture was refluxed for 1-2 hours. The reaction mixture was cooled to room temperature and toluene (1000 ml) was added. pH of the reaction mixture was adjusted with sodium hydroxide solution. The reaction mixture was separated and the aqueous layer was extracted with toluene twice. Three organic layers were combined and water (300 ml) was added. The reaction mixture was cooled to 10-15°C and a pH was adjusted to below 2.0 with hydrochloric acid. The reaction mixture was separated and aqueous layer pH was adjusted to 11-13 with the addition of sodium hydroxide solution. The aqueous layer was extracted with toluene and the organic layer was concentrated under reduced pressure to yield the oily crude. The crude was diluted with ethyl acetate (500 ml) and IPA (100 ml). The pH of the reaction mixture was adjusted below 2.0 with ethanolic.HCI (50 ml). The reaction mass was heat to reflux and cool to 0-10°C, filtered, washed with ethyl acetate (500 ml) and dried to yield (1R, 2S)-2-(aminomethyl)-N, N-diethyl-1-phenylcyclo propanecarboxamide hydrochloride (65 g).

Example-11: Purification of Milnacipran hydrochloride Milnacipran hydrochloride crude (100 g) was stirred with ethyl acetate (500 ml) and the reaction mixture was heated to reflux. The reaction mixture was cooled to 0-5°C and the resulted reaction mixture filtered, washed with ethyl acetate (200 ml) and dried to yield pure Milnacipran hydrochloride (98 g). HPLC purity-99.98%.

Example-12: Purification of Milnacipran hydrochloride Milnacipran hydrochloride crude (100 g) was stirred with mixture of ethyl acetate (500 ml) and isopropyl alcohol (100 ml) and the reaction mixture was heated to reflux. The reaction mixture was cooled to 0-5 °C and the resulted reaction mixture filtered, washed with ethyl acetate (200 ml) and dried to yield pure Milnacipran hydrochloride (94 g). HPLC purity-99.99%.

Example-13: Purification of Milnacipran Hydrochloride Milnacipran hydrochloride crude (100 g) was stirred with mixture of toluene (500 ml) and isopropyl alcohol (100 ml) and the reaction mixture was heated to reflux. The reaction mixture was cooled to 0-5 °C and the resulted reaction mixture filtered, washed with toluene and dried to yield pure Milnacipran hydrochloride (85 g). HPLC purity - 99.99%.

Example-14: Purification of Milnacipran Hydrochloride Milnacipran hydrochloride Crude (10 g) was stirred with ethanol (25 ml) and the reaction mixture was heated to reflux. The reaction mixture was cooled to 0-5 °C and the resulted reaction mixture was filtered, washed with ethanol (10 ml) and dried to yield pure Milnacipran hydrochloride (7 g).

Example-15: Purification of Milnacfpran Hydrochloride Milnacipran hydrochloride crude (10 g) was stirred with butanol (25 ml) and the reaction mixture was heated to reflux. The reaction mixture was cooled to 0-5 °C and the resulted reaction mixture was filtered, washed with butanol (10 ml) and dried to yield pure Milnacipran hydrochloride (7.5 g).
Example-16: Purification of Milnacipran Hydrochloride Milnacipran hydrochloride crude (10 g) was stirred with tert- butyl acetate (30 ml) and the reaction mixture was heated to reflux. The reaction mixture was cooled to 0-5 °C and the resulted reaction mixture was filtered, washed with tert- butyl acetate (10 ml) and dried to yield pure Milnacipran hydrochloride (9 g).

Example-17: Preparation of (Z)-1-phenyl-2-(phthalimidomethyl) cyclopropane carboxylic acid 2-Oxo-1-phenyl-3-oxabicyclo [3.1.0]-hexane (5 g) was added to a mixture of potassium phthalimide (6 g) and 1-butyl-3-methylimidazolium chloride (25 ml). The reaction mixture was heated for 2 hours. The reaction mixture was cooled to 30 °C and water (100 ml) was added. The reaction mass was filtered and washed with water (3 x10 ml). The crude was crystallized in methanol (50 ml) to give (Z)-1-phenyl-2-(phthalimidomethyl) cyclopropane carboxylic acid. (7 g, Yield 76 %) HPLC purity -99 %.

We Claim:

1. An improved process for the preparation of Milnacipran hydrochloride comprising the steps of;

a) reacting 2-hydroxymethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide with chlorinating agent to give chloro derivative characterized in that after completion of the reaction, reaction mass is treated with a base;

b) reacting 2-chloromethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide (compound-2) with phthalimide salt in a solvent to yield cis-2-[(1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl)methyl-N,N-diethyl-1-phenylcyclopropane carboxamide (compound-3),

c) optionally purifying compound-3 in a solvent,

d) converting the Phthalimide intermediate into Milnacipran hydrochloride.

2. The process according to claim 1, wherein the chlorinating agent is selected from thionyl chloride, phosphorus oxychloride or phosphorus pentachloride.

3. The process according to claim 1, wherein the base is selected from imidazole, morpholine, N-methyl morpholine, pyridine, piperazine or triethylamine.

4. An improved process for the preparation of phthalimide intermediate, cis-2-[(1, 3 dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-N, N-diethyl-1-phenylcyclo -propanecarboxamide comprising condensing 2-chloromethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide with phthalimide Salt in presence of ionic liquid.

5. The process according to claim 4, wherein ionic liquid is selected from 1-butyl-3-methylimidazolium chloride or 1-butyl-3-methylimidizolium tetrafluoroborate.

6. The process according to claim 4, wherein phthalimide salt is potassium phthalimide.

7. An improved process for the purification of phthalimide intermediate cis-2-[(1, 3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl-N,N-diethyl-1-phenylcyclopropane carboxamide comprising treating cis-2-[(1, 3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl-N,N-diethyl-1-phenylcyclopropane carboxamide with organic solvents.

8. The process according to claim 7, wherein the organic solvent is alcoholic solvent selected from ethanol, methanol or isopropanol.

9. The process according to claim 7, wherein phthalimide intermediate cis-2-[(1, 3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl-N,N-diethyl-1-phenylcyclopropane carboxamide is further converted into Milnacipran hydrochloride.

10. A process for the preparation of Milnacipran comprising reacting phthalimide intermediate cis-2-[(1, 3-Dihydro-1, 3-dioxo-2H-isoindol-2-yl) methyl-N, N-diethyl-1-phenylcyclopropanecarboxamide with hydrazine hydrate without using the solvent.

11. The process according to claim 10, wherein 80% hydrazine hydrate is used in the preparation of Milnacipran hydrochloride.

12. An improved process for the preparation of 2-hydroxymethyl-1-phenyl-cyclopropanecarboxylic acid diethylamide comprising reacting 2-oxo-1-phenyl-3-oxabicyclo [3.1.0]-hexane with diethylamine in presence of Lewis acids and ionic liquids.

13. The process according to claim 12, wherein the Lewis acid is aluminium chloride.

14. The process according to claim 12, wherein ionic liquid is 1-butyl-3-methylimidazolium chloride or 1-butyl-3-methylimidizolium tetrafluoroborate.

15. An improved process for the purification of Milnacipran hydrochloride comprising the steps of

a) dissolving Milnacipran hydrochloride in an ester solvent,

b) cooling the reaction mixture, and

c) isolating pure Milnacipran hydrochloride.

16. The process according to claim 15, wherein ester solvent is selected from ethyl acetate, isopropyl acetate or tert- butyl acetate.

17. An improved process for the preparation of (Z)-1-phenyl-2-(phthalimidomethyl) cyclopropanecarboxylic acid comprising reacting 2-oxo-1-phenyl-3-oxabicyclo [3.1.0]-hexane with phthalimide salt in presence of ionic liquid.

18. The process according to claim 17, wherein ionic liquid is 1-butyl-3-methylimidazolium chloride or 1-butyl-3-methylimidizolium tetrafluoroborate.

19. The process according to claim 17, wherein Phthalimide salt is potassium phthalimide.

20. The process according to claim 17, wherein the compound (Z)-1-2-(phthalimidomethyl) cyclopropanecarboxylic acid is further converted into Milnacipran
hydrochloride.