FORM 2
THE PATENT ACT, 1970 (39 of 1970)
&
The Patents Rules, 2003 COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"A NOVEL PROCESS FOR THE PREPARATION OF MILNACIPRAN HYDROCHLORIDE"
Centaur Pharmaceutical Private Limited, an Indian Company, having its Registered Office at Centaur House, Near Grand Hyatt, Shanti Nagar, Vakola, Santacruz (East), Mumbai- Maharashtra, 400055, India
1. The following specification describes the invention.

A NOVEL PROCESS FOR THE PREPARATION OF MILNACIPRAN HYDROCHLORIDE
FIELD OF THE INVENTION:
The present invention relates to novel intermediate compounds represented by structural formula I and their uses for the preparation of Milnacipran hydrochloride compound represented by structural formula II,

BACKGROUND OF THE INVENTION:
Milnacipran hydrochloride is a selective norepinephrine and serotonin reuptake inhibitor; it inhibits norepinephrine uptake with greater potency than serotonin.
Milnacipran hydrochloride is a racemic mixture with the chemical name: (±)-[lR(S), 2S(R)]-2-(aminomethyl)-N, N-diethyl-lphenylcyclopropanecarboxamide hydrochloride and is known from U.S. Patent No. 4,478,836 and is represented by compound of structural formula II.


Milnacipran hydrochloride has been approved in USA and sold in market under the proprietary name SAVELLA. It is indicated for the management of fibromyalgia.
U.S. Patent No. 4,478,836 ("the 836 patent") described a process for the preparation of Milnacipran hydrochloride compound of structural formula II by the reaction of an acid chloride compound of structural formula III with diethylamine followed by salifying with hydrochloric acid as described below in scheme I:

European Patent No. 0200638 ("the 638 patent") described a process for the preparation of Milnacipran hydrochloride compound of structural formula II by employing an intermediate compound of formula IV as described below in scheme II:


PCT Publication nos. 2010086394, 2011158249 and 2012046247 also described the processes for the preparation of Milnacipran hydrochloride compound of structural formula II by employing an intermediate compound of formula IV.
lapanese Patent no. G4354436B2 described a process for the Preparation of Milnacipran hydrochloride compound of structural formula II by employs an intermediate compound of formula V as described below in scheme III:

Wherein Z is sulphonate functional group.
The prior art processes yields Milnacipran hydrochloride compound of structural formula II with substantial amount of an impurities of structural formula IV and VI, which are often removed by recrystallization step or by purification through column chromatograPhy technique, which results

into low yield of pure Milnacipran hydrochloride accordingly there is a need in the art to develop novel process of preparing Milnacipran hydrochloride compound of structural formula II.

SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a process of preparing Milnacipran hydrochloride compound represented by structural formula II comprising the steps of:
a. hydrolyzing compounds represented by structural formula I into Milnacipran compound represented by structural formula VII and

b. converting Milnacipran compound represented by structural formula VII into Milnacipran hydrochloride compound represented by structural formula II.


A second aspect of the present invention is to provide novel compounds represented by structural formula I:

A third aspect of the present invention is to provide process of preparing novel compounds represented by structural formula 1 comprising reacting compound represented by structural formula VIII with a compound represented by structural formula IX.

Wherein X is halogen atom selected from the group comprising of F, CI, Br or I.
Another aspect of the present invention is to provide substantially pure Milnacipran hydrochloride compound of structural formula II comprising reacting a compound of structural

formula VII with a solution of hydrochloric acid in an ether solvent in the presence of an alkyl acetate or ketone solvents.

DETAIL DESCRIPTION OF THE INVENTION:
The compound of structural formula I may be prepared by reacting compound represented by structural formula VIII with compound represented by structural formula IX in the presence of an organic solvent.

Wherein X is halogen atom selected from the group comprising of F, CI, Br or I.
The examples of organic solvent may include but not limited to aromatic hydrocarbon, alkyl amide solvent or mixture(s) thereof.
The examples of aromatic hydrocarbon solvent may include but not limited to benzene toluene or
xylene.
The examples of alkyl amide solvent may include but not limited to N, N-dimethylformamide
(DMF), N, N-dimethylacetamide (DMA), N, N-diethylacetamide (DEA), and N, N-
dimethylpropanamide (DMP).

The reaction of compound represented by structural formula VIII with compound represented by structural formula IX may be carrying out at a temperature in the range of 30°C to 120°C for a period of 2hours to 8hours.
The compounds represented by structural formula I may be purified in aliphatic hydrocarbon solvents.
The examples of aliphatic hydrocarbon solvents may be selected from the group comprising of hexane, cyclohexane, heptane or octane.
The compounds represented by structural formula I may be hydrolyzed into Milnacipran compound represented by structural formula VII in the presence of hydrochloric acid in an alcoholic solvent.
The examples of an alcoholic solvent may include but not limited to methanol, ethanol. n-propanol, isopropanol, n-butanol, isobutanol, pentanol, hexanol or mixture(s) thereof.
A compound of structural formula VII may be reacted with a solution of hydrochloric acid in an ether solvent in the presence of alkyl acetate or ketone solvents to get substantially pure Milnacipran hydrochloride compound represented by structural formula II.
The examples of alkyl acetate solvent may include but not limited to ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tertiary butyl acetate or mixture (s) thereof.
The examples of ketone solvent may include but not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone or mixture (s) thereof.

The examples of ether solvent may include but not limited to diethyl ether, methyl ethyl ether, dibutyl ether, diisopropyl ethyl, methyl tertiary butyl ether or mixture (s) thereof.
The substantially pure Milnacipran hydrochloride compound represented by structural formula II may contain less than 0.10% weight / weight of impurities represented by compounds of structural formula IV and VI.

The limit of detection and limit of quantification of compounds of structural formula IV and VI is 0.001 and 0.01 respectively as determined by HPLC method.
The Milnacipran compound represented by structural formula VII may be converted into Milnacipran hydrochloride compound represented by structural formula II by methods known in the art such as those described in U.S Patent nos. 4,478,836; 7,592,485; 7,943,785; U.S Patent Publication nos. 2010274050; 2010145099: PCT Publication nos. 2011/158249; 2012/046247 and European Patent no,200638.
EXAMPLES:
In the following example, the preferred embodiment of the present invention is described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.

EXAMPLE 1: PREPARATION OF (1R, 2S)-2-DIFORMYLAMINOMETHYL-N-N-DIETHYL-1-PHENYL CYCLOPROPANE CARBOXAMIDE
The 1 -phenyl-l-diethylaminocarbinyl-2-chloromethyl-cyclopropane (26.8gm) was reacted with sodium diformylamide (25gm) in a mixture of toluene (200ml) and dimethyl formamide (100ml) at 110-115°C for 3 hours. The progress of reaction was checked by TLC technique. The resulting reaction mixture was cooled to 30°C and then it was diluted with water (125ml). The organic layer separated, washed twice with aqueous sodium hydroxide solution (5%, 2 x 50ml) and water (75ml). The organic layer was dried over anhydrous sodium sulfate (20gm) and concentrated under reduced pressure at 50°C. The resulting crude product was crystallized in cyclohexane (50ml) to get title compound. Yield: 27.5gm Purity: 99.9% (By HPLC method)
EXAMPLE 2: PREPARATION OF MILNACIPRAN HYDROCHLORIDE
(1R, 2S)-2-diformylaminomethyl-N-N-diethyl-l-phenyl cyclopropane carboxamide (20gm) was treated with hydrochloric acid solution in methanol (12%, 160ml) and then resulting solution was co-distilled with stripping of ethyl acetate (40ml) under reduced pressure at 40°C. The resulting thick slurry was treated with ethyl acetate (80ml) and resulting solution was stirred at 50°C for 30 minutes and then resulting reaction mixture was cooled to 25°C and then again it was stirred for 1 hour. The resulting solids were filtered, washed with ethyl acetate (40ml) and dried at 50°C under reduced pressure to get title compound. Yield: 18gm Purity: 99.87% (By HPLC method)
EXAMPLE 3: PREPARATION OF MILNACIPRAN HYDROCHLORIDE
A solution of (1R, 2S)-2-diformylaminomethyl-N-N-diethyl-l-phenyl cyclopropane carboxamide (20gm) in methanol (40ml) was treated with hydrochloric acid (12%, 80ml)

solution in diisopropyl ether and then resulting solution was co-distilled with stripping of ethyl acetate (40ml) under reduced pressure at 40°C. The resulting thick slurry was treated with ethyl acetate (80ml) and resulting solution was stirred at 50°C for 45 minutes and then resulting reaction mixture was cooled to 25°C and then again it was stirred for 2 hours. The resulting solids were filtered, washed with ethyl acetate (50ml) and dried at 45°C under reduced pressure to get title compound. Yield: 18.8gm Purity; 99.97% (By HPLC method)
EXAMPLE 4: PREPARATION OF MILNACIPRAN HYDROCHLORIDE
A solution of Milnacipran base (20gm) in ethyl acetate (60ml) was treated with hydrochloric acid
(12%, 80ml) solution in diisopropyl ether and then resulting solution was stirred for 30 minutes
at MTC.The resulting solution was cooled to25X and then jigainYt was stirred for Tnours. Trie
resulting solids were filtered, washed with ethyl acetate (50ml) and dried at 45 °C under reduced
pressure to get title compound.
Yield: 17gm
Purity: 99.91% (By HPLC method)
EXAMPLE 5: PREPARATION OF MILNACIPRAN HYDROCHLORIDE
A solution of Milnacipran base (20gm) in acetone (5Oral) \vas treated with hydrochloric acid
(12%, 75ml) solution in diisopropyl ether and then resulting solution was stirred for 30 minutes
at 50°C. The resulting solution was cooled to 25°C and then £gain it was stirred for 3 hours. The
resulting solids were filtered, washed with ethyl acetate (45ml) and dried at 50°C under reduced
pressure to get title compound.
Yield: 18gm
Purity: 99.95% (By HPLC method)

WE CLAIM:
1. A process of preparing Milnacipran hydrochloride compound represented by structural formula II comprising the steps of:
a. hydrolyzing compounds represented by structural formula I into Milnacipran compound represented by structural formula VII and

b. converting Milnacipran compound represented by structural formula VII into Milnacipran hydrochloride compound represented by structural formula II.

2. The process according to claim no. 1. wherein compounds represented by structural formula I is hydrolyzed in the presence of hydrochloride acid in alcoholic solvents selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, pentanol, hexanol or mixture(s) thereof.
3. A novel compounds represented by structural formula I:


4. Use of novel compounds represented by structural formula I for the preparation of Milnacipran compound represented by structural formula VII.

5. A process of preparing novel compounds represented by structural formula I comprising reacting compound represented by structural formula VIII with a compound represented by structural formula I in the presence of an organic solvent.

Wherein X is halogen atom selected from the group comprising of F, CI, Br or I.
6. The process according to claim no. 5 wherein organic solvent is selected from the group comprising of aromatic hydrocarbon, alkyl amide solvent or mixture(s) thereof.

7. The process according to claim no. 6, wherein aromatic hydrocarbon is selected from the group comprising of benzene toluene or xylene and alkyl amide solvent is selected from the group comprising of N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N, N-diethylacetamide (DEA), and N, N-dimethylpropanamide (DMP).
Substantially pure Milnacipran hydrochloride compound of structural formula II prepared by process comprising reacting compound of structural formula VII with a solution i hydrochloric acid in an ether solvent in the presence of alkyl acetate or ketone solve

9. The process according to claim no. 8 wherein alkyl acetate solvent is selected from the group comprising of ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tertiary butyl acetate or mixture (s) thereof; ketone solvent is selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone or mixture (s) thereof and ether solvent is selected from the group comprising of diethyl ether, methyl ethyl ether, dibutyl ether, diisopropyl ethyl, methyl tertiary butyl ether or mixture (s) thereof.
10. The process according to claim no. 8, wherein substantially pure Milnacipran hydrochloride compound represented by structural formula II contain less than 0.10% weight / weight of impurities represented by compounds of structural formula IV and VI as determined by HPLC method.