FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
AN IMPROVED PROCESS FOR THE PREPARATION OF MILNACIPRAN
AND SALTS THEREOF
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road,
Near Dinesh Hall,
Ahmadabad 380 009.
Gujarat, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to a process for preparation milnacipran and salts thereof. The process involved for the preparation of milnacipran and salt thereof is cost effective, commercially viable and industrially feasible.
BACKGROUND OF THE INVENTION
Milnacipran is marketed in United States by Cypress Bioscience as film-coated tablets containing 12.5 mg, 25 mg, 50 mg, and 100 mg milnacipran hydrochloride under the brand name Savella®. Milnacipran hydrochloride is a racemic mixture with chemical name (1R,,2S)-rel-2~(amino methyl)-N,N-diethyl-l-phenyl-cyclopropane carboxamide hydrochloride and is represented by following chemical structure (Formula-I).

FORMULA-I
Milnacipran hydrochloride is a selective norepinephrine and serotonin reuptake inhibitor; it inhibits norepinephrine uptake with greater potency than serotonin. It is useful in the treatment of depression of and chronic pain conditions like Fibromyalgia and Lupus.
U.S. Patent No. 4,478,836 discloses about Milnacipran and its hydrochloride salt. The '836 patent also discloses process of its preparation by hydrolyzing the hydrochloride of (±)-1 -phenyl-1 -ethoxycarbony1-2-aminomethylcyclopropane and then treatment of resulting intermediate acid chloride with diethylamine followed by salifying it with hydrochloric acid. However, the solvents involved in this salification step are not disclosed in this patent. European Patent No. 0200638 B1 provides a process of preparation of milnacipran hydrochloride by the addition of ethanolic hydrochloric acid

to milnacipran base. Japanese patent application. No. 2006008569A2 discloses process of preparation of milnacipran hydrochloride by the treatment of milnacipran base with hydrochloric acid-ethyl acetate followed by addition of ethyl acetate and isopropyl alcohol and concentration of solvent from reaction mixture. WO2010086394 discloses use of toluene, and mixture of isopropyl acetate and isopropanol in the salification step. WO2006001493 and its equivalents EP1770084 Al and US7592485 discloses use of toluene as co-solvent in the reaction of (1R, 2S)-rel-2-[(1, 3-dihydro-l,3 didxo-2H-isoindol-2-yl) methyl]-N,N-diethyl-l-phenyl.Cyclopropane carboxamide and monomethylamine to produce (1R,2S)-rel-2-(amino methyl)-N,N-diethyl-l-phenyl -cyclopropane carboxamide. In this process the solvent is evaporated completely and to resulting residue hydrogen chloride-ethyl acetate and isopropanol mixture is added to obtain milnacipran hydrochloride.
Use of non-polar antisolvent in the isolation of milnacipran hydrochloride is known in the art. The process of the present invention is cost effective, commercially viable and industrially feasible which involves single or same solvent to prepare milnacipran hydrochloride from milnacipran free base and no antisolvent such as ether or ethyl acetate is used in the process.
SUMMARY OF INVENTION
FORMULA-II
In one aspect of present invention there is provided a process for preparation of salts of (lR,2S)-rel-2-(amino methyl)-N,N-diethyl-l--phenyl-cyclopropane carboxamide Formula-II).


In another aspect of present invention there is provided process for preparation of salt of (1R,2S)-rel-2-(amino methyl)-N,N-diethyl-1 -phenyl-cyclopropane carboxamide which comprises the steps of;
a) treating (1R, 2S)-rel-2-[(1, 3-dihydro-1,3 dioxo-2H-isoindol-2-yl) methyl]-N,N-diethyl-1-phenyl-cyclopropane carboxamide with monomethylamine,
b) extracting reaction mass by organic solvent,
c) optionally removing the solvent,
d) treating reaction mass with acid and
e) recovering salt of (1R,2S)-rel-2-(amino methyl)-N,N-diethyl-1 -phenyl-cyclopropane carboxamide.
In yet another aspect, acids employed to form salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids. Pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, P-hydroxybutyrate, glycollate, maleate, tartrate, methanesulfonate, propanesulfonates, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandeiate and the like salts. Preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such oxalic acid and maleic acid. Acid used for salt formation is preferably inorganic acid, more preferably hydrochloric acid.

In yet another aspect of the present invention the process for the preparation of salt of compound of Formula-II, no antisolvent such as ether or ester is used.
In yet another aspect of the present invention Milnacipran Hydrochloride (Formula-I) obtained by this process is having purity at least about 98 % preferably 99% and more preferably 99.9% when measured by HPLC.
In yet another aspect of the present invention Milnacipran Hydrochloride (Formula-I) obtained by this process is having total impurities is equal to or less than 0.1% equal to or less than 0.08% and more preferably equal to or less than 0.05 when measured by HPLC.
In yet another aspect of the present invention Milnacipran Hydrochloride (Formula-I) obtained by this process is having 0.035% impurity at 1.060 RRT, 0.009 at 1.328 RRT and 0.013 at 1.699 RRT when measured by HPLC.
In yet another aspect of the present invention Milnacipran Hydrochloride (Formula-I) obtained by this process is having particle size D 90 less than 150 μm, D 50 less than 100 μm and D 10 less than 50 μm.
In yet another aspect of the present invention Milnacipran Hydrochloride (Formula-I) obtained by this process is having toluene content less than 600 ppm preferably less than 550 ppm.
In yet another aspect of the present invention the process for the preparation of salt of compound of Formula-II, preferably hydrochloric acid salt of compound of Formula-II is cost effective, commercially viable and industrially feasible. Further salt of compound of Formula-II, preferably hydrochloric acid salt of compound of Formula-II obtained by above process is having higher yield and purity.

DESCRIPTION OF THE DRAWINGS:
Figure 1: X-ray powder diffraction pattern of milnacipran hydrochloride (Formula-I).
Figure 2: DSC of milnacipran hydrochloride (Formula-I).
DETAILED DESCRIPTION OF THE INVENTION
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
The present invention relates to a process for preparation of salts of (1R,2S)-rel-2-(amino methyl)-N,N-diethyl-l -phenyl-cyclopropane carboxamide (Formula-II).
In another aspect of present invention there is provided process for preparation of salt of (1R,2S)-rel-2-(amino methyl)-N,N-diethyl-l -phenyl-cyclopropane carboxamide which comprises the steps of;
a) treating (1R,2S)-rel-2-[(l, 3-dihydro-l,3 dioxo-2H-isoindol-2-yl) methyl]-N,N-diethyl-1-phenyl-cyclopropane carboxamide with monomethylamine,
b) extracting reaction mass by organic solvent,
c) optionally removing the solvent,
d) treating reaction mass with acid and
e) recovering salt of (1R,2S)-rel-2-(amino methyl)-N,N-diethyl-l-phenyl-cyclopropane carboxamide.
(1R,2S)-rel-2-[(l, 3-dihydro-l,3 dioxo-2H-isoindol-2-yl) methyl]-N,N-diethyl-l-phenyl-cyclopropane carboxamide used in this process is known compound and can be prepared

by person skilled in the art. For example, such process is described in US Patent No. 5034541.
The monomethylamine used in the reaction is having concentration of 20- 60 % preferable 30- 50 % and more preferably 40 %.
The Organic solvent used in reaction step b) is selected from C6-C12 aromatic hydrocarbons, mono-,di-, or tri-C1-C4 alkyl substituted or unsubstituted benzenes and the like.
Examples of mono-, di-, or tri-C1-C4 alkyl substituted or unsubstituted benzenes include benzene, toluene, xylene and the like.
Combined organic extract can optionally washed with water or sodium chloride solution. Further organic extract can be treated with activated charcoal.
The solvent is optionally removed by distillation. The solvent removed by distillation to 20- 80 % preferably 40- 60 % and more preferably 50 % of its original volume by avoiding solid formation or complete distillation to get solid formation. The milnacipran free base solution may be prepared by dissolution of reaction mass (Formula-II) in organic solvent.
Acids employed to form salts in step d) include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids. Pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate,

benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycollate, maleate, tartrate, methanesulfonate, propanesulfonates, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like salts. Preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such oxalic acid and maleic acid. Acid used for salt formation is preferably inorganic acid, more preferably hydrochloric acid.
Acid used in the step d) is optionally present in the form of gas, aqueous solution or aqueous solution of acid in organic solvent or solution of gas in organic solvent.
Acid is added slowly in amine (Formula-II) solution by maintaining reaction temperature at about 5- 40 °C preferably 5- 35 °C and more preferably at 25- 35 °C. Reaction mixture is stirred for 20 minutes- 3 hours preferably 30 minutes - 2 hours and more preferably 1-1.5 hours. The stirring is carried out at temperature from 0- 30 °C preferably 5- 20 °C and more preferably at 5- 10 °C.
The recovery of product can be carried out by filtration, solvent distillation and the like. Product is dried by conventional method such as heating, drying at room temperature under vacuum, heating under vacuum and the like.
Salt of (1R,2S)-rel-2-(amino methyl)-N,N-diethyl-l-phenyl-cyclopropane carboxamide (Formula-II) may be inorganic acid salts such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acid salts such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids. Pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,

isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycollate, maleate, tartrate, methanesulfonate, propanesulfonates, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like salts. Preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such oxalic acid and maleic acid. Preferred inorganic acid salt of (1R,2S)-rel-2-(arnino methyl)-N,N-diethyl-l-phenyl-cyclopropane carboxamide (Formula-II) is formed with hydrochloric acid i.e. (1R,2S)-rel-2-(amino methyl)-N,N-diethyl-l -phenyl-cyclopropane carboxamide hydrochloride (Formula-I).
Salt of compound of Formula-II obtained by above process is having higher yield and purity.
Milnacipran Hydrochloride (Formula-I) obtained by above process is having higher yield and purity.
Purity of Milnacipran Hydrochloride (Formula-I) obtained by above process is at least about 98 % preferably 99% and more preferably 99.9% when measured by HPLC.
In yet another aspect of the present invention Milnacipran Hydrochloride (Formula-I) obtained by this process is having 0.035% impurity at 1.060 RRT, 0.009 at 1.328 RRT and 0.013 at 1.699 RRT when measured by HPLC.
Milnacipran Hydrochloride (Formula-I) of present invention is having particle size D 90 less than 150 μm, D 50 less than 100 μm and D 10 less than 50 μm. More preferably Milnacipran Hydrochloride (Formula-I) obtained by above process is having particle size D 90 less than 15 urn, D 50 less than 30 μm and D 10 less than 10 μm.

Milnacipran Hydrochloride (Formula-I) of present invention is having toluene content less than 600 ppm preferably less than 550 ppm.
More preferably Milnacipran Hydrochloride (Formula-I) obtained by above process is having is having toluene content less than 540 ppm.
Melting point of product obtained by above process is 180 ± 2 °C.
The present invention provides a Milnacipran hydrochloride, obtained by the process herein, is characterized by specific surface area of about 0.1 m2/gm to about 2 m2/gm. The present invention further provides Milnacipran hydrochloride, obtained by the process herein, is characterized by specific surface area of about 0.72 m2/gm.
The present invention provides a Milnacipran hydrochloride, obtained by the process herein, is characterized by having bulk density of particles of about 0.17 gm/ml. The present invention further provides Milnacipran hydrochloride, obtained by the process herein, is characterized by having bulk density of particles of about 0.20 gm/ml.
The present invention provides a Milnacipran hydrochloride, obtained by the process herein, is characterized by Hausner's Ratio of particles of about 1.4. The present invention further provides Milnacipran hydrochloride, obtained by the process herein, is characterized by Hausner's Ratio of particles of about 1.7.
Hausner's Ratio of Milnacipran hydrochloride particles can be measured by using formula Hausner's Ratio is equal to tapped density divided by untapped density.
The present invention provides a Milnacipran hydrochloride, obtained by the process herein, is characterized by compressibility Index (CI) of about 30. The present invention further provides Milnacipran hydrochloride, obtained by the process herein, is characterized by compressibility Index (CI) of about 42.

The compressibility Index (CI) of Milnacipran hydrochloride particles can be measured using the formula

VB= freely settled volume of given mass of powder Vy = Tapped volume of the same mass of powder.
Certain specific aspects and embodiments of this invention are described in further detail by the examples below, which are provided only for the purpose of illustration and are not intended to limit the scope of the invention in any manner.
Example 1:
The mixture of (1R,2S)-rel-2-[(l, 3-dihydro-1,3 dioxo-2H-isoindol-2-yl) methyl]-N,N-diethyl-1-phenyl-cyclopropane carboxamide (50gm) and 40% monomethylamine (250 ml) was stirred till completion of reaction (about two hour). Reaction mixture was extracted by toluene (3 X 250ml). Toluene extracts combined and washed with 15 % Sodium chloride solution (125ml). Activated charcoal (5gm) was added to reaction mixture and stirred the reaction mixture for 30 minutes. Reaction mixture was filtered through celite and washed the celite bed with toluene (50ml). Solvent was distilled out below 50 °C under vacuum to half of its original volume. The pH of reaction mass is adjusted to 2- 2.5 by slowly addition of isopropanol-hydrochloric acid solution in it at 25-30 °C. Reaction mass was stirred for 15- 20 minutes at room temperature and at 5-10 °C for one hour. Product was filtered and washed with toluene (50ml). Solid was dried under vacuum at 45- 50 °C to for 10-12 hrs to obtain 30gm milnacipran hydrochloride. The particle size of product D 90 is 73.91 urn and toluene content is 538 ppm.
Example 2:
The mixture of (1R,2S)-rel-2-[(l, 3-dihydro-l,3 dioxo-2H-isoindol-2-yl) methyl]-N,N-diethyl-1 -phenyl-cyclopropane carboxamide (50gm) and 40% monomethylamine (250

ml) was stirred till completion of reaction (about two hour). Reaction mixture was extracted by toluene (3 X 250ml). Toluene extracts combined and washed with 15 % Sodium chloride solution (125ml). Activated charcoal (5gm) was added to reaction mixture and stirred the reaction mixture for 30 minutes. Reaction mixture was filtered through celite and washed the celite bed with toluene (50ml). Solvent was distilled out below 50 °C under vacuum to half of its original volume. The pH of reaction mass is adjusted to 2- 2.5 by slowly addition of toluene-hydrochloric acid solution in it at 25- 30 °C. Reaction mass was stirred for 15- 20 minutes at room temperature and at 5-10 °C for one hour. Product was filtered and washed with toluene (50ml). Solid was dried under vacuum at 45- 50 °C to for 10-12 hrs to obtain milnacipran hydrochloride
Example 3:
The mixture of (1R,2S)-rel-2-[(l, 3-dihydro-l,3 dioxo-2H-isoindol-2-yl) methyl]-N,N-diethyl-1-phenyl-cyclopropane carboxamide (50gm) and 40% monomethylamine (250 ml) was stirred till completion of reaction (about two hour). Reaction mixture was extracted by toluene (3 X 250ml). Toluene extracts combined and washed with 15 % Sodium chloride solution (125ml). Activated charcoal (5gm) was added to reaction mixture and stirred the reaction mixture for 30 minutes. Reaction mixture was filtered through celite and washed the celite bed with toluene (50ml). Solvent was distilled out below 50 °C under vacuum to half of its original volume. The pH of reaction mass is adjusted to 2- 2.5 by slowly passing hydrochloric acid gas in it at 25- 30 °C. Reaction mass was stirred for 15- 20 minutes at room temperature and at 5-10 °C for one hour. Product was filtered and washed with toluene (50ml). Solid was dried under vacuum at 45- 50 °C to for 10-12 hrs to obtain milnacipran hydrochloride

We claim
1. A process of preparation of (1R,2S)-rel-2-(amino methyl)-N,N-diethyl-l-phenyl-
cyclopropane carboxamide and salts thereof which comprises the steps of;
a) treating (1R,2S)-rel-2-[(l, 3-dihydro-l,3 dioxo-2H-isoindol-2-yl) methyl]-N,N-diethyl-1-phenyl-cyclopropane carboxamide with monomethylamine,
b) extracting reaction mass by organic solvent,
c) optionally removing a solvent,
d) treating reaction mass with acid and
e) recovering salt of (1R,2S)-rel-2-(amino methyl)-N, N-diethyl-1-phenyl-cyclopropane carboxamide, wherein the single or same solvent is used in step b) to e).

2. The process as claimed in claim 1 step a), wherein the monomethylamine used in the reaction is having concentration of 20- 60 % preferably 40%.
3. The process as claimed in claim 1 step b), wherein the organic solvent used for extracting reaction mass is selected from the group consisting of C6-C12 aromatic hydrocarbons, mono-,di-, or tri-C1-C4 alkyl substituted or unsubstituted benzenes.
4. The process as claimed in claim 4, wherein organic solvent is selected from the group consisting of benzene, toluene and xylene.
5. The process as claimed in claim 1 step d), wherein acid is present in the form of gas, aqueous solution or aqueous solution of acid in organic solvent or solution of gas in organic solvent.
6. The process as claimed in claim 1, wherein Salt of (1R,2S)-rel-2-(amino methyl)-N,N-diethyl-l-phenyl-cyclopropane carboxamide are selected from group consisting of

hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, pharmaceutically acceptable salts such as sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, (3-hydroxybutyrate, glycollate, maleate, tartrate, methanesulfonate, propanesulfonates, naphthalene-1 -sulfonate, naphthalene-2-sulfonate, mandelate.
7. The process as claimed in claim 1, wherein Salt of (1R,2S)-rel-2-(amino methyl)-N, N-diethyl-l-phenyl-cyclopropane carboxamide is hydrochloric acid salt (milnacipran hydrochloride).
8. The process as claimed in claim 1, wherein the purity of (1R,2S)-rel-2-(amino methyl)-N,N-diethyl-l-phenyl-cyclopropane carboxamide and salts thereof is more than 99.9 % when measured by HPLC.
9. The process as claimed in claim 1 and 7, wherein the purity of Milnacipran hydrochloride is more than 99.9 % when measured by HPLC, specific surface area is 0.1-2 m2/gm, bulk density of particles is 0.17- 0.20 gm/ml, Hausner's Ratio of particles is 1.4-1.7 and compressibility Index is 30-42.

10. The process as claimed in claim 1 and 7, wherein the particle size of milnacipran hydrochloride is D 90 less than 75 μm, D 50 less than 30 μm and D 10 less than 10μm, specific surface area is 0.72 m2/gm.