WO 2014/009767 Al 16 January 2014 (16.01.2014) P O PCT

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/009767 Al 16 January 2014 (16.01.2014) P O PCT

(51) International Patent Classification: Pramod Kumar [IN/IN]; Micro Labs Limited, API Divi C07D 307/33 (2006.01) C07C 235/40 (2006.01) sion, Plot No. 43-45, K.I .A.D.B., Jigani-Bommasandra C07C 231/10 (2006.01) C07C 237/24 (2006.01) Link Road, Anekal Taluk, Bangalore-560 105, Karnataka C07C 233/58 (2006.01) (IN). (21) International Application Number: (74) Agents: NAIR, Manoj Vasudevan et al; M/s Lex Orbis PCT/IB20 12/00 1765 (Intellectual Property Practice), 709/710, Tolstoy House, 15-17 Tolstoy Marg, New Delhi - 110 001 (IN). (22) International Filing Date 12 September 2012 (12.09.2012) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, English (25) Filing Language: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (26) Publication Language: English BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (30) Priority Data: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 2752/CHE/2012 7 July 2012 (07.07.2012) IN KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (71) Applicant (for all designated States except US): MICRO ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, LABS LIMITED [IN/IN]; No.27, Race Course Road, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, Bangalore 560 001 (IN). RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (72) Inventors; and ZM, ZW. (75) Inventors/Applicants (for US only): GADDAM, Venugo- pal Reddy [IN/IN]; Micro Labs Limited, API Division, (84) Designated States (unless otherwise indicated, for every Plot No. 43-45, K.I .A.D.B., Jigani-Bommasandra Link kind of regional protection available): ARIPO (BW, GH, Road, Anekal Taluk, Bangalore-560 105, Karnataka (IN). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, VARADA, Jayakrishna [IN/IN]; Micro Labs Limited, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, API Division, Plot No. 43-45, K.I .A.D.B., Jigani-Bom TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, masandra Link Road, Anekal Taluk, Bangalore-560 105, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Karnataka (IN). CHELUVARAJU [IN/IN]; Micro Labs MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Limited, API Division, Plot No. 43-45, K.I .A.D.B., Jigani- TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Bommasandra Link Road, Anekal Taluk, Bangalore-560 ML, MR, NE, SN, TD, TG). 105, Karnataka (IN). GAJULA, Madhusudana Rao Published: [IN/IN]; Micro Labs Limited, API Division, Plot No. 43- 45, K.I .A.D.B., Jigani-Bommasandra Link Road, Anekal — with international search report (Art. 21(3)) Taluk, Bangalore-560 105, Karnataka (IN). RASTOGI,

(54) Title: AN IMPROVED PROCESS FOR THE PREPARATION OF 1-ARYL 2-AMINOMETHYL CYCLOPROPANE CARBOXYAMIDE (Z) DERIVATIVES, THEIR ISOMERS AND SALTS

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(57) Abstract: The present invention relates to an improved and one-pot process for the preparation of 1-Aryl 2-aminomethyl cyclo - propane carboxyamide (z) derivatives, their isomers of formula (I) or its pharmaceutically acceptable salt thereof wherein R and R 2 are represents independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, and lower-alkylaryl, which aryl or alkylaryl group is optionally substituted by a halogen atom. AN IMPROVED PROCESS FOR THE PREPARATION OF 1-ARYL 2- AMINOMETHYL CYCLOPROPANE CARBOXY AMIDE (Z) DERIVATIVES, THEIR ISOMERS AND SALTS

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 Milnacipran, its stereo specific isomers and its derivatives or a pharmaceutically acceptable salts, hydrate, or solvate thereof. More particularly, the present invention relates to the process for preparation of Milnacipran by in-situ and also using with single solvent to give the high urity and good yield.

BACKGROUND OF THE INVENTION: Milnacipran, is chemically known as cyclopropanecarboxamide, 2- (Aminomethyl)-N,N-diethyl-l -phenyl-, cis-(±)-; (±)-[lR(S) ', 2S(R)]-2-(Aminomethyl)- N,N-diethyl-l-phenylcyclopropanecarboxamide in the form of a base or of a pharmaceutically acceptable salt, and in particular the hydrochloride thereof.

Milnacipran is an antidepressant inhibiting recapture of serotonin- noradrenaline recommended in the treatment of depression. It was first approved in France in December 1996. Milnacipran hydrochloride is currently marketed in the form of tablets in Europe, it is available under the brand name Ixel®. It is also available in Japan under the brand name Toledomin® and Mexico under the brand name Dalcipran® for depression. While In January 2009 the U.S. Food and Drug Administration (FDA) approved Milnacipran under the brand name Savella® only for the treatment of fibromyalgia, making it the third medication approved for this purpose in the United States.

Milnacipran hydrochloride is a racemic mixture of two of the four possible stereoisomers; specifically, a 1:1 mixture of the two Z (cis) isomers and chemical structurally represented as followin :

( 1 S . 2R) ( 1 R, 2S)

The structural formula for Milnacipran hydrochloride will signify for subsequently convenient as followin :

Various methods for Milnacipran hydrochloride was specifically disclosed in the art, first United States Patent No. 4,478,836 (referred to as '836 patent hereinafter). The '836 patent discloses for the preparation of Milnaciprah and its hydrochloride salt form, which involves a hydrolysis of 1-phenyl- 1-ethoxy carbonyl-2-aminomethyl cyclopropane in ethanol as a solvent in the presence of sodium hydroxide as base to obtained an acid compound. The intermediate of acid compound was chlorinated by using thionyl chloride in organic solvent to obtained the acid chloride intermediate. The resulting acid chloride compound is condensed with diethyl amine at room temperature to get crude milnacipran hydrochloride. The desired Milnacipran hydrochloride is recrystallized from petroleum ether. The reaction is schematically represented by scheme 1.

Scheme- 1: The process involves multi step and ether as solvent, which is not commercially feasible.

The United States Patent No. 5,034,541 discloses a process for the preparation of phthalimide derivative, which involves the l-Phenyl-3-oxabicyclo [3,1,0] hexan-2- one reacted with diethyl amine in presence of lewis acid such as aluminum chloride in dichloroethane as a solvent to get the hydroxyl compound. The obtained intermediate of hydroxyl compound is chlorinated by using with thionyl chloride in dichloroethane as solvent and the resulting chloro compound was reacted with potassium phthalimide in dimethyl formamide to get a phthalimide derivative. The reaction is schematically represented.by scheme 2. Scheme-2:

The United States Patent Application No.US2008/0051604 Al discloses process for preparing Milnacipran, which involves the hydrolysis of (Z)-l -phenyl- 1 diethylaniinocarbonyl-2-phthalimidomethylcyclopropane in the presence of aqueous methylamine solution having concentration of from 1 to 25% by weight to obtain (Z)- 1-phenyl- l-diethylaminocarbonyl-2-aminoethylcyclopropane. The reaction is schematically represented by scheme 3. Scheme-3:

The process involves costly key starting material and uses methyl amine, which is irritating to eyes, nose and throat.

The United States Patent Application No.US 2010/0145099 Al discloses a process for preparing Milnacipran, which involves the hydrolysis of (Z)- 1-Phenyl- 1- diethylaminocarbonyl-2-phthalimidomethylcyclopropane in presence of aqueous hydrazine hydrate in ethanol. The resulting Milnacipran hydrochloride was obtained in a mixture of IPA-HC1 and ethyl acetate. The reaction is schematically represented by scheme 4. Scheme-4:

The process involves costly key starting material and uses hydrazine hydrate, which is highly explosive.

The European Patent No. EP 0200638 Bl discloses a process for preparing Milnacipran hydrochloride, which comprises the reaction of potassium phthalimide with l-Phenyl-3-oxabicyclo [3,1,0] hexan-2-one in presence of high boiling solvent such as dimethyl sulfoxide at 150-200°C to get the intermediate of acid compound. The intermediate of acid compound was treated with thionyl chloride and followed by diethyl amine to resulting phthalimide compound, further it's hydrolyzed in presence of organic base in organic solvent to get the desired compound. The reaction is schematically represented by scheme 5. Scheme-5:

SOCI2

The PCT Patent Application No. WO2010/086394 A l discloses a process for the preparation of Milnacipran hydrochloride, which comprises the reaction of phenylacetonitrile and (R)-epichlorohydrin in presence of alkaline metal base, followed by basic hydrolysis and acid treatment to obtain the lactone compound. The lactone compound is opened by using diethyl amine in presence of lewis acid such as aluminum chloride in toluene as a solvent and further chlorination with thionyl chloride in dichloroethane as solvent. The resulting chloro compound is reacted with potassium phthalimide in toluene to forms phthalimide intermediate. The resulting compound of phthalimide intermediate is hydrolyzed in ethanolamine as base in presence of toluene. The desired Milnacipran hydrochloride was isolated in mixture of isopropyl acetate and IPA-HC1. The reaction is schematically represented by scheme 6. Scheme-6: Ethanolamine 1PA -HC1

Moreover, various syntheses for the racemic Milnacipran have been described in the literature as EP 1 845 084; EP 1 757 597; EP 1 767 522; and Shuto S. et al., J. Med. Chem. 1995, 38, 2964-2968.

Also very recently few of references were directed towards chiral synthesis of /evo-Milnacipran terminated as (IS, 2R)-Milnacipran is more active than the recemic mixture. It is chemically known as Cyclopropanecarboxamide, 2-(aminomethyl)-N,N- diethyl- 1-phenyl-, cis-(+)-; (1S,2R)-2-( Aminomethy l)-JV,JV-diethy1- 1- phenylcyclopropane carboxamide in the form of a base or of a pharmaceutically acceptable salt, and in particular the hydrochloride thereof. Structurally absolute stereochemistry levorotation "(+ " represented as following:

( 1S, 2R) Firstly demonstrated the method for obtaining this enantiomer in enriched form has been the separation or resolution of enantiomers from the racemic mixture (Bonnaud B. et al., J Chromatogr. 1985, 318, 398-403). The synthetic process for enantiomer of (IS, 2R)-Milnacipran is not cost effective industrially an account of very low out put.

Moreover, various syntheses for the (IS, 2R)-Milnacipran have been described in the literature as (Doyle M. P. and Hu W. Adv. Synth. Catal . 2001, 343, 299-302 ; Roggen H. et al., Bloorg. Med. Chem. 2007, 17, 2834-2837 ; Shuto S. et al . , Tetrahedron Lett. 1996, 37, 641-644 ; (Viazzo P. et al., Tetrahedron Lett. 1996, 37, 26, 4519-4522) Wang X. -Q. et al., Chinese journal of Pharmaceuticals 2004, 35, 259-260 ; WO 2005/1 18 564).

Still, most of these syntheses use multistep process and costly reagents and reactant with poor yield and less purity. Theses process may hardly be contemplated industrially because of said problems. Therefore there is still a significant need for new methods for synthesizing Milnacipran which are more secure, economical and efficient.

However, there is a unmet need to developed an improved process for the preparation of the Milnacipran, its stereo specific isomers or acid addition salts of the formula (I), which is commercially viable and which has advantage over the. processes, described in the prior art documents.

OBJECTS OF THE INVENTION: The main objective of the present invention is to provide a single pot process for the preparation of Milnacipran, derivatives and its stereospecific isomers or acid addition salts.

Another object of the present invention is to provide is simple and rapid work up process in a single solvent for the isolation of Milnacipran, derivatives and/or its stereospecific isomers or its pharmaceutically acceptable salts thereof, which employs less time consuming with unproblematic, convenient to carry out. Yet another object of the present invention is to provide Milnacipran hydrochloride and /evo-Milnacipran hydrochloride having purity >99.8%.

Yet another object of the present invention is to provide a pharmaceutical composition containing Milnacipran, its stereospecific isomers and its pharmaceutically acceptable salts, prepared according to instant invention.

SUMMARY OF THE INVENTION:

On the subject of the foregoing technical problems, the present inventors have proceeded with extensive research. As a result, it has been found surprisingly that a reaction using novel skills affords to provide the process for the preparation of Milnacipran, derivatives and its stereospecific isomers or its pharmaceutically acceptable salts thereof. In one embodiment, the present invention relates to provide an improved process for preparing a compound of formula (I)

wherein R and R are independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, and lower-alkylaryl, wherin aryl or alkylaryl group is optionally substituted by a halogen atom.

This is schematically represented by scheme 7, which is as follows: Scheme 7 : wherein and R2 are the same as defined above.

In another embodiment, the present invention relates to a process, which is carried out without isolating any intermediate products (a method described as a one- pot method).

In another embodiment, the present invention relates to the preparation of stereo specific isomer of Milnacipran by carrying the similar stereo specific isomers of intermediates.

In another embodiment, the present invention can be carried out in a reaction medium comprising same and single suitable solvent system such as toluene or multiple organic solvents.

In another embodiment, the present invention relates to a process which affords good quality and yield. The process is simple and cost-effective.

In another embodiment, the present invention relates to prepare substantially pure crystalline forms of Milnacipran hydrochloride.

In yet another embodiment, the present invention relates to prepare substantially pure crystalline forms of /evo-Milnacipran hydrochloride. Further, it is the aim of the invention to provide a process for the preparation of Milnacipran and its pharmaceutically acceptable salts, prepared according to present invention.

DETAILED DESCRIPTION OF THE INVENTION:

Accordingly, the present invention provides a process for the preparation of highly pure Milnacipran, derivatives and its stereo specific isomers or a pharmaceutically acceptable salt thereof, with good yield and purity.

According to the present invention, an improved process for preparing a compound of formula (I), its stereospecific isomers or a pharmaceutically acceptable salt thereof is provided ,

wherein and R represents independently selected group consisting of hydrogen, lower alkyl, lower aryl, and lower-alkylaryl, wherein aryl or alkylaryl group is optionally substituted by a halogen atom, and, with the adjacent nitrogen atom, a heterocycle of 5 or 6 ring members; comprising the following successive steps: a) reacting l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one, a compound of formula (II)

with amine compound of formula (VI) H— \ (VI) R2 in the presence of lewis acids or metal alkoxide or metal hydride or organolithium reagents in organic solvent to form a compound of formula (III) of l-phenyl-2- hydroxymethylcyclopropane,

b) optionally isolating the compound of formula (III) and reacting with a chlorinating agent in organic solvent to form l-phenyl-2-chloromethylcyclopropane, a compound of formula (IV) and

c) optionally isolating the compound of formula (IV) and reacting with an azide and optionally in the presence of phase transfer catalyst in organic solvent, to form an azide compound of formula (V)

d) optionally isolating the compound of formula (V) and reduction with reducing agent in organic solvent, to form a compound of formula (I) e) optionally salification of the compound of step (d) in suitable organic solvents, in the presence of a pharmaceutically acceptable acid salts. f) optionally purification of the compound of step (d) or (e) in a suitable organic solvents to get the pure compound of formula (I). wherein the reactions steps (a) to (f will advantageously be carried out without isolating the intermediate products (III), (IV), (V).

According to the present invention, the present invention relates to a method for synthesizing a pharmaceutically acceptable acid addition salt of milnacipran, its stereo specific isomers of the following formula (la):

comprising the following successive steps: a) reacting l-phenyl-3-oxabicyclo[3 .1.0]hexan-2-one, a compound of formula (Ila)

with diethylamine in the presence of lewis acids or metal alkoxide or metal hydride or organolithium reagents in organic solvent to form a compound of formula (Ilia) of 1- phenyl- 1-diethylaminocarbonyl-2-hydroxymethylcyclopropane, b) optionally isolating the compound of formula (Ilia) and reacting with a chlorinating agent in the presence of organic solvent to form l-phenyl-l-diethylaminocarbonyl-2- chloromethylcyclopropane, a compound of formula (IVa) and

c) optionally isolating the compound of formula (IVa) and reacting with an azide and optionally in the presence of phase transfer catalyst in organic solvent, to form a azide compound of formula (Va)

d) optionally isolating the compound of formula (Va) and reduction with reducing agent in organic solvent, to form a Milnacipran compound, and e) optionally salification of the compound of step (d) in suitable organic solvents, in the presence of a pharmaceutically acceptable acid. f) optionally purification of the compound of step (d) or (e) in a suitable organic solvents to get the pure compound of formula (la). wherein the reactions steps (a) to (f) will advantageously be carried out without isolating the intermediate products (Ilia), (IVa), (Va) and Milnacipran or its isomers (a method described as a one-pot method).

In particular, steps (a) to (e) will advantageously be carried out in a reaction medium comprising a same and single solvent such as toluene. The reaction step-a is condensation reaction between l-phenyl-3- oxabicyclo[3.1.0]hexan-2-one compound of formula (II) and amine compound of formula (VI) in the presence of lewis acids or metal alkoxide or metal hydride or organolithium reagents in suitable organic solvents.

The reaction step-a, is carried out with molar equivalent of amine compound of formula (VI) inhabits 1 to 5 equivalents with respect to the compound of formula II. Preferably about 2 to 3 equivalents are used.

The reaction step-a is carried out with the suitable lewis acids which includes, but are not limited to aluminium chloride, aluminium bromide, aluminium triethoxide, aluminium triisopropoxide, boron trifluoride, boron trichloride, iron(III) chloride (ferric chloride), iron(III) bromide (ferric bromide), tin(IV) chloride (stannic chloride), titanium tetrachloride, titanium isopropoxide. Preferably, the lewis acid is selected from aluminum chloride, aluminum bromide.

The reaction step-a, is carried out with molar equivalent of lewis acid employed is from about an equimolar amount to about 4 times the equimolar amount with respect to the compound of formula II. Preferably about 1 to 1.5 equivalents are used.

Optionally the reaction also can carried out using the metal alkoxide such as sodium methoxide, potassium ethoxide, potassium tertiary butoxide etc or metal halides such as sodium hydride, lithium hydride, potassium hydride etc or organolithium reagents such as «-butyllithium, hexllithium, lithium di-isopropyl amide (LDA), lithium bis(trimethylsilyl)amide (LilTMDS) etc.

The reaction step-a, is carried out in a suitable organic solvent preferably selected, but is not limited to aliphatic hydrocarbons such as CI-CIO straight chain or branched hydrocarbons such as n-hexane, «-heptane, cyclohexane, pentane, etc; and aromatic hydrocarbons such as toluene, xylene, etc; ethers such as diethyl ether, , diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane, etc; and mixtures thereof. Preferably, the organic solvent is selected from toluene, diethyl ether; more preferably the solvent is toluene. The reaction step-a, is carried out at a temperature of about -10°C to about 80°C. Preferably, the reaction is carried out at a temperature of about 20°C to about 30 °C.

The reaction step-a, is carried out for a period of about 30 minutes to about 3 hours. Preferably from about 1 hour to about 2 hours.

The completion of reaction may be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).

After completion of reaction, the reaction mixture is quenched either into water or into dilute hydrochloric acid. The organic layer may be optionally washed with aqueous sodium chloride solution and the organic layer, containing 1-phenyl-l- diethylaminocarbonyl-2-hydroxymethylcyclopropane, the compound of formula (III), is used for step (b) in the process, just described in above detailed description.

Optionally above said washed out organic layer distilled the solvent completely under vacuum. The resulting residue was dissolved in suitable organic solvents and stirred for 1 hour to 2 hours at 0°C to 30°C. The precipitated compound of formula (III) is used for step (b) in the process, just described in above detailed description.

The reaction step-b is chlorination reaction between hydroxy compound and chlorinating agent in suitable organic solvents.

The reaction step-b is carried out with the suitable chlorinating agents which includes, but is not limited to organic or inorganic chlorinating agents such as thionyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorous oxychloride, etc; preferably the chlorinating agent is thionyl chloride.

The reaction step-b is carried out the suitable organic solvent preferably selected, but is not limited to aliphatic hydrocarbons such as CI-CIO straight chain or branched hydrocarbons such as -hexane, «-heptane, cyclohexane, pentane, etc; and aromatic hydrocarbons such as toluene, xylene, etc; haloalkanes such as dichloromethane, chloroform, etc; ethers such as diethyl ether, , diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane, etc; and mixtures thereof. Preferably, the organic solvent is selected from dichloromethane, toluene; More preferably the solvent is dichloromethane.

The reaction step-b is magnificently carried out at a temperature of about - 10°C to about 160°C. Preferably, the reaction is carried out at a temperature of about 50°C to about 110°C.

The reaction step-b is well carried out for a period of about 15 minutes to about 2 hours. Preferably about 30 minutes to about 45 minutes.

The completion of reaction may be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).

After completion of reaction, optionally the reaction mixture is quenched either into water or into partially alkaline solution. The organic layer may be optionally washed with weak base such as alkali metal carbonate, alkali metal bicarbonate agents such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate. Preferably the base is sodium bicarbonate. The organic layer, containing 1-phenyl-l- diethylaminocarbonyl-2-chloromethylcyclopropane, the compound of formula (IV), is used for (c) in the process, just described in above detailed description.

Optionally above said washed out organic layer distilled the solvent completely under vacuum. The resulting residue compound of formula (IV) is used for step (c) in the process, just described in above detailed description.

The reaction step-c is an azide formation, the reaction between chloro compound and an azide compound in the presence or absence of a phase-transfer catalyst in suitable organic solvents.

The reaction step-c is carried out with a suitable azide compound which includes, but is not limited to metal azide such as sodium azide, potassium azide, zinc azide, tributyltin azide, aluminum azide, trialkyl silyl azide etc; preferably the azide compound is sodium azide. The reaction step-c is carried out the suitable organic solvent preferably selected, but is not limited to aliphatic hydrocarbons such as CI-CIO straight chain or branched hydrocarbons such as tt-hexane, rc-heptane, cyclohexane, pentane, etc; alcoholic solvents such as branched or chain C1-C4 selected alcohols as methanol, ethanol, isopropyl alcohol, etc; and aromatic hydrocarbons such as toluene, xylene, etc; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane, etc; dimethylformaniide, w-methylpyrrolidone, etc; and mixtures thereof. Preferably, the organic solvent is selected from toluene, diethyl ether; more preferably the solvent is toluene.

The reaction step-c is well carried out at a temperature of about 30°C to about 150°C. Preferably, the reaction is carried out at a temperature of about 90°C to about 110°C.

The reaction step-c is incredibly carried out with the suitable phase transfer catalyst which includes, but is not limited to tetrabutylammonium bromide. triethylbenzylammonium chloride, tricaprylmethylammonium chloride and tetrabutylammonium hydroxide etc; preferably the phase transfer catalyst is tetrabutylammonium bromide.

The reaction step-c is carried out in the presence of phase transfer catalyst for a period of about 30 minutes to about 5 hours. Preferably about 1 hour to about 2 hours. In absence of phase transfer catalyst the reaction carried out for a period of about 15 hours to 30 hours. Preferably about 20 hour to about 24 hours.

The completion of reaction may be monitored by ,thin layer chromatography (TLC) or high performance liquid chromatography (HPLC). After completion of reaction, the reaction mixture is cooled to 0 to 30°C and proceeds for step-d in the process. Optionally the reaction mixture is quenched in water and separates the layers; optionally the organic layer washed with water and the resulting organic layer is used for step-d in the process, just described in above detailed description. Optionally above said washed out organic layer distilled the solvent completely under vacuum. The resulting residue compound of formula (V) is used for step-d in the process, just described in above detailed description.

The reaction step-d is reduction reaction between an azide compound and reducing agent in suitable organic solvents. The reaction may takes place in an aqueous or non-aqueous medium.

The reaction step-d is carried out with a suitable reducing agent which includes, but is not limited to metal or non-metal reducing agents such as iron, zinc, magnesium, palladium, platinum, triphenylphosphine, etc; preferably the reducing agent is tiphenyl phosphine or iron.

The reaction step-d is carried out in suitable organic solvent preferably selected, but is not limited to aliphatic hydrocarbons such as CI-CIO straight chain or branched hydrocarbons such as w-hexane, rc-heptane, cyclohexane, pentane, etc; alcoholic solvents such as branched or chain C1-C4 selected alcohols as methanol, ethanol, isopropyl alcohol, etc; haloalkanes such as dichloromethane, chloroform, etc; and aromatic hydrocarbons such as toluene, xylene, etc; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane, etc; dimethylformamide (DMF), «-methylpyrrolidone, etc; and mixtures thereof. More preferably, the organic solvent selected is toluene.

The reaction step-d is well carried out at a temperature of about 10°C to about 150°C. Preferably, the reaction is carried out at a temperature of about 60°C to about 110°C.

The reaction step-d is carried out for a period of about 10 minutes to about 5 hours. Preferably about 30 minutes to about 1 hour using triphenyl phosphine as reducing agent. In particularly the reaction will proceeds for a period of about 3 to 4 hrs using iron/ammonium chloride as reducing agent in suitable solvents such as alcohols or chlorinating solvents.

The completion of reaction may be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC). After completion of reaction, the reaction mixture is distilled out completely under vacuum. The resulting residue is quenched either into water or into dilute hydrochloric acid and filtered the reaction mixture. The resulting filtrate was dissolved in suitable organic solvent; adjust the pH 9-12 using with base such as alkali metal hydroxide, alkali metal carbonate, and alkali metal bicarbonate agents such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate. Preferably the base is sodium hydroxide. The layers were separated; the organic layer optionally washed with aqueous sodium chloride solution and optionally the organic layer distilled the solvent completely under vacuum. The resulting residue compound of formula is used in step-e in the process, just described in above detailed description.

The reaction step-e is salification reaction between the resulting compound of step-d and pharmaceutical acceptable acid salts in suitable organic solvents for the conventional methods.

The reaction is carried out with the pharmaceutical acceptable acid salts includes, but is not limited to mineral acids or inorganic acids or organic acids such as 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2- oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor- 10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene- 1,5- disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), undecylenic acid; etc. more preferably, the salt is hydrochloric acid.

The reaction step-e is carried out the suitable organic solvent preferably selected, but is not limited to aliphatic hydrocarbons such as CI-CIO straight chain or branched hydrocarbons such as n-hexane, «-heptane, cyclohexane, pentane, etc; alcoholic solvents such as branched or chain C1-C4 selected alcohols as methanol, ethanol, isopropyl alcohol, etc; and aromatic hydrocarbons such as toluene, xylene, etc; haloalkanes such as dichloromethane, chloroform, etc; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane, etc; and mixtures thereof. Preferably, the organic solvent is selected from dichloromethane, toluene, and diethyl ether; More preferably the solvent is toluene.

The reaction step-e is well carried out at a temperature of about 0°C to about 110°C. Preferably, the reaction is carried out at a temperature of about 20°C to about 30°C.

The reaction step-e is carried out for a period of about 10 minutes to about 1 hour. Preferably about 20 minutes to about 30 minutes.

The reaction step-f is purification reaction for the resulting compound of step- d or step-e in suitable organic solvents for the conventional methods.

The present invention provides an additional new aspect i.e. one-pot process in a single solvent, with high yield and purity.

In another embodiment, the reaction can either be carried out in a reaction medium comprising a same and single suitable solvent such as toluene or multiple solvent systems with different suitable organic solvents.

According to the present invention, relates to provides an improved process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein and R2 are represents independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, and lower-alkylaryl, which aryl or alkylaryl group is optionally substituted by a halogen atom, and, with the adjacent nitrogen atom, a heterocycle of 5 or 6 ring members; comprising the following successive steps: a) reacting l-phenyl-2-hydroxymethylcyclopropane, a compound of formula (III)

treated with an azide in the presence of DEAD (diethylazodicarboxylate) and reducing agent in organic solvent to form a compound of formula (I).

The reaction is well carried out at a temperature of about 0°C to about 110°C. Preferably, the reaction is carried out at a temperature of about 10°C to about 30°C.

The reaction is incredibly carried out for a period of about 30 minutes to about 5 hours. Preferably about 1 hour to about 3 hours.

The reaction is carried out the suitable organic solvents for preferably selected, the organic solvent is selected from dimethylformamide, dichloromethane, chloroform, toluene, diethyl ether; more preferably the solvent is dimethylformamide, toluene.

According to the present invention, relates to provides an improved process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein i and R2 are represented by independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, and lower-alkylaryl, which aryl or alkylaryl group is optionally substituted by a halogen atom, and, with the adjacent nitrogen atom, a heterocycle of 5 or 6 ring members; comprising the following successive steps: a) reacting l-phenyl-2-hydroxymethylcyclopropane, a compound of formula (III)

treated with an azide in the presence of carbon tetrabromide in organic solvent, followed by reducing agent to form a compound of formula (I).

The reaction is well carried out at a temperature of about 0°C to about 110°C. Preferably, the reaction is carried out at a temperature of about 10°C to about 30°C.

The reaction is carried out for a period of about 30 minutes to about 5 hours. Preferably about 1 hour to about 3 hours.

The term milnacipran, its stereospecific isomers compound of formula (I) as used herein refers to inclusive all polymorphs forms of milnacipran or its pharmaceutically acceptable salt thereof, for example polymorphs of crystalline form, or hydrates, and solvates thereof.

The invention is illustrated by the following examples which are only meant to illustrate the invention and not act as limitations.

Examples

Example 1: Preparation of Cyclopropanecarboxamide, 2-(aminomethyl)-N,N-diethyl- 1-phenyl-, cis-(±)-; [Milnacipran hydrochloride]

Step i: Aluminium chloride (100 g) was suspended in (600 ml) toluene and then added diethylamine (109 g) under stirring at below room temperature. cis-(±)-l- Phenyl-3-oxabicyclo[3.1.0]hexan-2-one was added to the reaction mass for 1 hour. The temperature of the reaction mass was raised at room temperature and stirred for 1 hour. After completion of the reaction, quenched the reaction mass in ice-cooled water (700 ml). The organic layers was collected and washed with water and hydrochloric acid. This was directly taken as such for the next stage.

Step ii: Thionyl chloride (80 g) was added to the above toluene layer at room temperature. The reaction mass was stirred for 1 hour at reflux temperature. After completion of the reaction, water (600 ml) was added. The organic layer was washed with aqueous sodium bicarbonate and water. This was dried and taken for the next stage without any further purification.

Step iii: Sodium azide (37 g) and tetrabutyl ammonium bromide (10 g) was added to the above toluene layer at room temperature. The reaction mass was refiuxed for 5 to 8 hour. After completion of the reaction, triphenylphosphine (155 g) was added to the reaction mass for 30 minutes and refluxed for 1 hour. After completion of the reduction, distilled out completely under vacuum. Water (600 ml) was added to the reaction mass and adjust the pH of the reaction mass to 1-2 with con. HC1 and stirred for 1 hour at room temperature. Filtered the precipitate (triphenylphosphine oxide) and extracted the compound from filtrate with dichloromethane by adjusting pH to 9- 10 using with sodium hydroxide solution. The resulting reaction mass was distilled out completely under vacuum. To the residual mass was added IPA and IPA.HCl and stirred for 30 minutes at room temperature. Distilled out completely under vacuum. The resulting crude compound was suspended in ethyl acetate. The reaction mass was refluxed for 1 hour and cooled to 20 to 30°C and maintained for 30 minutes. The solid was filtered and dried at 50 to 60°C for 4 hours to obtain 135 gm of Milnacipran hydrochloride. According to this process there may also be produced in analogous derivatives and their isomers such as Levomilnacipram Hydrochloride.

Example 2: Preparation of 1-phenyl-1-diethylaminocarbonyl-2- hydroxymethylcyclopropane.

Aluminium chloride (100 g) was suspended in (600 ml) EDC and then added diethylamine (109 g) under stirring at below room temperature. cis-(±)-l-phenyl-3- oxabicyclo[3.1.0]hexan-2-one was added to the reaction mass for 1 hour. The temperature of the reaction mass was raised at room temperature and stirred for 1 hour. After completion of the reaction, quenched the reaction mass in ice-cooled water (700 ml). The layers were separated and the aqueous layer was discarded. The resulting organic layer was distilled out completely under vacuum. The residue was dissolved in (400 ml) diisopropyl ether and stirred for 1 hour at 0°C to 30°C, filtered the precipitated desired compound (135 g).

Example 3: Preparation of l-phenyl-l-diethylaminocarbonyl-2- chloromethylcyclopropane.

1-Phenyl-l-diethylaminocarbonyl-2-hydroxymethylcyclopropane (100 g) was dissolved in (1000 ml) MDC at room temperature and cooled to 0-1 0°C followed by added thionyl chloride (80 g) at to 0-1 0°C for about 1 hour. The reaction mass was stirred for 2 hour at reflux temperature. After completion of the reaction, quenched the reaction mass in water (600 ml). The layers were separated and the aqueous layer was discarded, collected the MDC layer and wash with water and sodium bicarbonate solution. The resulting organic layer was distilled out completely under vacuum. The desired compound residue was obtained (100 g).

Example 4: Preparation of l-phenyl-l-diethylaminocarbonyl-2- azidoromethylcyclopropane.

l-Phenyl-l-diethylaminocarbonyl-2-chloromethylcyclopropane (100 g) was dissolved in DMF (200 ml) at room temperature and followed by addition of .sodium azide (24 g). The reaction mass was stirred for 1 to 2 hours at 50-60°C. After completion of the reaction, quenched the reaction mass in water (400 ml) followed by ethyl acetate (500 ml). The layers were separated and the aqueous layer was discarded, collected the ethyl acetate layer and wash with water. The resulting organic layer was distilled out completely under vacuum. The desired compound residue was obtained (100 g).

Example 5: Preparation of l-phenyl-l-diethylaminocarbonyl-2- chloromethylcyclopropane.

l-Phenyl-l-diethylaminocarbonyl-2-azidoromethylcyclopropane (100 g) was dissolved in toluene (300 ml) at room temperature and triphenylphosphine (100 g) and toluene (200 ml) was added to the reaction mass for 30 minutes and stirred for 1 hour. After completion of the reduction, distilled out completely under vacuum. Water (400 ml) was added to the reaction mass and adjust the pH of the reaction mass to 1-2 with con. HCl and stirred for 1 hour at room temperature. Filtered the precipitate (triphenylphosphine oxide) and extracted the compound from filtrate with dichloromethane by adjusting pH to 9-10 using with sodium hydroxide solution. The resulting reaction mass was distilled out completely under vacuum. The desired compound residue was obtained (80 g).

Example 6: Preparation of Milnacipran hydrochloride.

Milnacipran (80 g) was dissolved in IPA (150 ml), IPA.HC1 (100 ml) and stirred for 30 minutes at room temperature. Distilled out completely under vacuum. The resulting crude compound was suspended in ethyl acetate. The reaction mass was stir for refluxed for 1 hour and cooled to 20 to 30°C and maintained for 30 minutes. The separated solid was filtered, washed with ethyl acetate (200 ml) and dried at 50 to 60°C for 4 hours to obtain 82 g of Milnacipran hydrochloride.

Example 7: Preparation of cis-(±)-l-phenyl-l-diethylaminocarbonyl-2-azidomethyl cyclopropane

Sodium azide (37 g) and tetrabutyl ammonium bromide (10 g) was added to a toluene layer obtained from step-ii in Example 1 at below room temperature. The reaction mass was stirred for 4 to 5 hour at reflux. After completion of the reaction, quenched the reaction mass in water (300 ml). The layers were separated and the aqueous layer was discarded. The residue of title compound (120 g) was isolated by concentrating the toluene layer.

Example 8: Preparation of cis-(±)-l-phenyl-l-diethylaminocarbonyl-2-azidomethyl cyclopropane

l-Phenyl-l-diethylaminocarbonyl-2-chloromethylcyclopropane (140 g) was dissolved in DMF (500 ml) at room temperature and followed by addition of odium azide (37 g) and tetrabutyl ammonium bromide (10 g) at room temperature. The reaction mass was stirred for 1 to 2 hour at 50 to 60oC. After completion of the reaction, quenched the reaction mass in water (300 ml). Extract the compound with ethyl acetate and followed by distillation of the solvent completely under vacuum. Obtain the title compound of residue (120 g).

Example 9: Preparation of Cyclopropanecarboxamide, 2-(aminomethyl)-N,N-diethyl- 1-phenyl-, cis-(±)-; [Milnacipran hydrochloride]

A residue obtained from Example- 1 (600 ml) was dissolved in water (200 ml).

Iron (38 g) and ammonium chloride ( 10 g) was added to the reaction mass. The reaction mass was refluxed for 4 to 5 hours at room temperature. After completion of the reduction, cooled the reaction mass and filtered through hyflo bed. Concentrating the filtrate and extract the compound from filtrate with dichloromethane. The solvent of resulting reaction mass was distilled out completely under vacuum. To the residual mass was added ethyl acetate, IPA.HC1 and stirred for 30 minutes at room temperature. The reaction mass was cooled to 10 to 15°C and maintained for 1 hour 30 minutes. The separated solid was filtered and dried at 50 to 60°C for 4 hours to obtain milnacipran hydrochloride (125 gm).

Example 10: Preparation of cyclopropanecarboxamide, 2-(aminomethyl)-N,N- diethyl-1-phenyl-, cis-(+)-; [Levomilnacipran hydrochloride]

Step i: Aluminium chloride (100 g) was suspended in (600 ml) toluene and then added diethylamine (109 g) under stirring at below room temperature. cis-(+)-l- Phenyl-3-oxabicyclo[3.1.0]hexan-2-one was added to the reaction mass for 1 hour at below room temperature. The temperature of the reaction mass was raised at room temperature and stirred for 1 hour. After completion of the reaction, quenched the reaction mass in ice-cooled water (700 ml). The organic layers was collected and washed with water and hydrochloric acid. This was directly taken as such for the next stage.

Step ii: Thionyl chloride (80 g) was added to the above toluene layer at below room temperature. The reaction mass was stirred for 1 hour at reflux temperature. After completion of the reaction, water (600 ml) was added. The organic layer was washed with aqueous sodium bicarbonate and water. This was dried and taken for the next stage without any further purification.

Step iii: Sodium azide (37 g) and tetrabutyl ammonium bromide (10 g) was added to the above toluene layer at below room temperature. The reaction mass was refluxed for 5 to 8 hour. After completion of the reaction, triphenylphosphine (155 g) was added to the reaction mass for 30 minutes and refluxed for 1 hour. After completion of the reduction, distilled out completely under vacuum. Water (600 ml) was added to the reaction mass and adjust the pH of the reaction mass to 1-2 with con. HC1 and stirred for 1 hour at room temperature. Filtered the precipitate (triphenylphosphine oxide) and extracted the compound from filtrate with dichloromethane by adjusting pH to 9-10 using sodium hydroxide solution. The resulting reaction mass was distilled out completely under vacuum. To the residual mass was added IPA and IPA.HCl and stirred for 30 minutes at room temperature. Distilled out completely under vacuum. The resulting crude compound was suspended in ethyl acetate. The reaction mass was refluxed for 1 hour and cooled to 20 to 30°C and maintained for 30 minutes. The solid was filtered and dried at 50 to 60°C for 4 hours to obtain 135 gm of Levomilnacipran hydrochloride.

Example 11: Preparation of (IS, 2R)-l -phenyl-1-diethylaminocarbonyl-2- hydroxymethyl cyclopropane.

Aluminium chloride (100 g) was suspended in (600 ml) EDC and then added diethylamine (109 g) under stirring at below room temperature. cis-(+)-l-phenyl-3- oxabicyclo[3.1.0]hexan-2-one was added to the reaction mass for 1 hour. The temperature of the reaction mass was raised at room temperature and stirred for at least 1 hour. After completion of the reaction, quenched the reaction mass in ice- cooled water (700 ml). The layers were separated and the aqueous layer was discarded. The resulting organic layer was distilled out completely under vacuum. The residue was dissolved in (400 ml) diisopropyl ether and stirred for 1 hour at 0°C to 30°C, filtered the precipitated desired compound ( 5 g).

Example 12: Preparation of (IS, 2R)-l-phenyl-l-diethylaminocarbonyl-2-chloromethyl cyclopropane.

(IS, 2R)-1-Phenyl-1-diethylaminocarbonyl-2-hydroxymethylcyclopropane (135 g) was dissolved in (1000 ml) MDC at room temperature and cooled to 0-1 0°C followed by addition of thionyl chloride (80 g) at to 0-1 0°C for about 1 hour. The reaction mass was stirred for 2 hours at reflux temperature. After completion of the reaction, quenched the reaction mass in water (600 ml). The layers were separated and the aqueous layer was discarded, collected the MDC layer and washed with water and sodium bicarbonate solution. The resulting organic layer was distilled out completely under vacuum. The desired compound residue was obtained (100 g).

Example 13: Preparation of (IS, 2R)-l-phenyl-l-diethylaminocarbonyl-2- azidoromethyl cyclopropane. (IS, 2R)-l-Phenyl-l-diethylaminocarbonyl-2-chloromethylcyclopropane (100 g) was dissolved in DMF (200 ml) at room temperature and followed by added Sodium azide. The reaction mass was stirred for 1 to 2 hours at 50-60°C. After completion of the reaction, quenched the reaction mass in water (400 ml) followed by ethyl acetate (500 ml). The layers were separated and the aqueous layer was discarded, collected the ethyl acetate layer and washed with water. The resulting organic layer was distilled out completely under vacuum. The desired compound residue was obtained (100 g).

Example 14: Preparation of (IS, 2R)-l-phenyl-l-diethylaminocarbonyl-2-chloromethyl cyclopropane (Levomilnacipran) crude.

(IS, 2R)-l-Phenyl-l-diethylaminocarbonyl-2-azidoromethylcyclopropane ( 100 g) was dissolved in toluene (300 ml) at room temperature and triphenylphosphine (100 g) + toluene (200 ml) was added to the reaction mass for 30 minutes and stirred for 1 hour. After completion of the reduction, distilled out completely under vacuum. Water (400 ml) was added to the reaction mass and adjusted the pH of the reaction mass to 1-2 with con. HC1 and stirred for 1 hour at room temperature. Filtered the precipitate (triphenylphosphine oxide) and extracted the compound from filtrate with dichloromethane by adjusting pH to 9-10 using with sodium hydroxide solution. The resulting reaction mass was distilled out completely under vacuum. The desired compound residue was obtained (80 g).

Example 15: Preparation of Levomilnacipran hydrochloride.

Levomilnacipran crude (80 g) was dissolved in IPA (150 ml), IPA.HC1 (100 ml) and stirred for 30 minutes at room temperature. Distilled out completely under vacuum. The resulting crude compound was suspended in ethyl acetate. The reaction mass was stir for refluxed for 1 hour and cooled to 20 to 30°C and maintained for 30 minutes. The separated solid was filtered, washed with ethyl acetate (200 ml) and dried at 50 to 60°C for 4 hours to obtain 82 gm of Levomilnacipran hydrochloride.

Example 16: Preparation of (IS, 2R)-l-phenyl-l-diethylaminocarbonyl-2- azidoromethyl cyclopropane Sodium azide (37 g) and tetrabutyl ammonium bromide (10 g) was added t a toluene layer obtained from step-ii in Example 10 at below room temperature. The reaction mass was stirred for 4 to 5 hour at reflux. After completion of the reaction, quenched the reaction mass in water (300 ml). The layers were separated and the aqueous layer was discarded. The residue of title compound (120 g) was isolated by concentrating the toluene layer.

Example 17: Preparation of (IS, 2R)-l-phenyl-l-diethylaminocarbonyl-2-azidomethyl cyclopropane

(IS, 2R)-l-Phenyl-l-diethylaminocarbonyl-2-chloromethylcyclopropane (140 g) was dissolved in DMF (500 ml) at room temperature and followed by added .sodium azide (37 g) and tetrabutyl ammonium bromide (10 g). The reaction mass was stirred for 1 to 2 hour at 50 to 60°C. After completion of the reaction, quenched the reaction mass in water (300 ml). Extract the compound with ethyl acetate and followed by distilled out completely under vacuum. Obtain the title compound of residue (120 g).

Example 18: Preparation of Cyclopropanecarboxamide, 2-(aminomethyl)-N,N- diethyl-1-phenyl-, cis-(+)-; [levomilnacipran hydrochloride]

A residue obtained from Example- 10 (600 ml) was dissolved in water (200 ml). Iron (38 g) and ammonium chloride ( 110 g) was added to the reaction mass. The reaction mass was reflex for 4 to 5 hour at room temperature. After completion of the reduction, cooled the reaction mass and filtered through hyflo bed. Concentrating the filtrate and extract the compound from filtrate with dichloromethane. The resulting reaction mass was distilled out completely under vacuum. To the residual mass was added ethyl acetate, isopropyl alcohol in HC1 and stirred for 30 minutes at room temperature. The reaction mass was cooled to 10 to 15°C and maintained for 1 hour 30 minutes. The separated solid was filtered and dried at 50 to 60°C for 4 hours to obtain levomilnacipran hydrochloride (125 gm).

Example 19: Preparation of cis-(+)-l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one or (IS,

5R) -1- Phenyl-3-oxabicyclo (3, 1, 0) hexane -2-one [(S)-Lactone] : Sodium amide (20 g) was suspended in toluene (100 ml) and added phenyl acetonitrile (20 g) at below room temperature. The reaction mass was stirred for 1 hour at 0°C. Added the (R)-epichlorohydrin (15 g) to the reaction mass and stirred for 2 hours at room temperature. After completion of the reaction, quenched the reaction mass in ice-cooled water (400 ml). The layers were separated and the aqueous layer was discarded, collected the residue compound (20 g) by concentrating the toluene layer. The above residue was hydrolyzing with sodium hydroxide solution at reflex temperature. Followed by cooled the reaction mass at room temperature, added toluene (200 ml), and adjust the pH to 1-2 with con HCl. The reaction mass was stirred for 3 to 4 hours at 60-70°C. Cooled the reaction mixture at room temperature, separate the toluene layer and wash with sodium bicarbonate. The title compound (10 g) was isolating from isopropyl alcohol.

Abbreviations:

EDC : Ethylene dichloride MDC : Dichloromethane DMF : Dimethylformamide IPA.HC1 : Isopropyl alcohol, hydrochloride LDA : Lithium di-isopropyl amide LiHMDS : Lithium bis(trimethylsilyl)amide TLC : Thin layer chromatography HPLC : High performance liquid chromatography PTC : Phase Transfer Catalyst WHAT CLAIM IS: 1. A process for the preparation of compound of formula (I), its stereo specific isomers or pharmaceutically acceptable salts thereof,

wherein R and R are independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, and lower-alkylaryl, wherein aryl or alkylaryl group is optionally substituted by a halogen atom; comprising: a) reacting l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one, a compound of formula (II)

with amine compound of formula (VI)

/ N \ (VI)

wherein R and R2 are represented as above, in the presence of lewis acids or metal alkoxide or metal hydride or organolithium reagents to form a compound of formula (III) of 1-phenyl-2-hydroxymethylcyclopropane, b) optionally isolating the compound of formula (III) and reacting with a chlorinating agent to form l-phenyl-2-chloromethylcyclopropane, a compound of formula (IV)

c) optionally isolating the compound of formula (IV) and reacting with an azide and optionally in the presence of phase transfer catalyst to form a azide compound of formula (V)

d) optionally isolating the azide compound of formula (V) and reduction with reducing agent and optionally salification with pharmaceutically acceptable acids in suitable organic solvents, to form a compound of formula (I).

2. A process according to claim 1, wherein the lewis acid is selected from the group comprising of aluminium chloride, aluminium bromide, aluminium triethoxide, aluminium triisopropoxide, boron trifluoride, boron trichloride, iron(III) chloride (ferric chloride), iron(III) bromide (ferric bromide), tin(IV) chloride (stannic chloride), titanium tetrachloride, titanium isopropoxide or a mixture thereof.

3. A process according to claim 1, wherein the metal alkoxide is selected from the group comprising of sodium methoxide, potassium ethoxide, potassium tertiary butoxide or a mixture thereof.

4. A process according to claim 1, wherein the metal halides is selected from the group comprising of sodium hydride, lithiumhydride, potassium hydride or a mixture thereof. 5. A process according to claim 1, wherein the organolithium reagents is selected from the group comprising of n-butyl lithium, hexyl lithium, lithium di-isopropyl amide (LDA), lithium bis(trimethylsilyl)amide (LiHMDS) or a mixture thereof.

6. A process according to claim 1, wherein the chlorinating agent is selected from the group comprising of thionyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorous oxychloride, or a mixture thereof.

7. A process according to claim 1, wherein the an azide is selected from the group comprising of sodium azide, potassium azide, zinc azide, tributyltin azide, aluminum azide, trialkyl silyl azide or a mixture thereof.

8. A process according to claim 1, wherein the phase transfer catalyst is selected from the group comprising of tetrabutylammonium bromide, triethylbenzylammonium chloride, tricaprylmethylammonium chloride and tetrabutylammonium hydroxide or a mixture thereof.

9. A process according to claim 1, wherein the reducing agent is selected from the group comprising of iron, zinc, magnesium, palladium, platinum, triphenylphosphine or a mixture thereof.

10. A process according to claim 1, wherein the base is selected from the group comprising of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, ammonium , ammonium chloride or a mixture thereof.

11. A process according to claim 1, wherein the reactions steps (a), (b), (c), (d), and (e), are described as a one-pot method, without isolating the intermediate products (III), (IV), and (V).

12. A process according to claim 1, wherein the reactions steps (a), (b), (c), (d), and (e), will advantageously be carried out in a reaction medium comprising a same and single solvent such as toluene.

13. A process according to claim 1, the compound of Milnacipran or its pharmaceutically acceptable salts thereof, comprising: a) reacting l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one, a compound of formula (Ila)

with diethylamine in the presence of lewis acids or metal alkoxide or metal hydride or organolithium reagents to form a compound of formula (Ilia) of 1-phenyl- 1- diethylaminocarbonyl-2-hydroxymethylcyclopropane,

b) optionally isolating the compound of formula (Ilia) and reacting with a chlorinating agent to form l-phenyl-l-diethylaminocarbonyl-2- chloromethylcyclopropane, a compound of formula (IVa) and

c) optionally isolating the compound of formula (IVa) and reacting with an azide optionally in the presence of phase transfer catalyst to form a azide compound of formula (Va) d) optionally isolating the azide compound of formula (Va) and reduction with reducing agent to form a Milnacipran compound, and e) optionally salification of the Milnacipran in a suitable organic solvents, to prepare a pharmaceutically acceptable acid.

14. A process according to claim 1, the compound of Levomilnacipran or its pharmaceutically acceptable salts thereof,

comprising: a) reacting l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one, a compound of formula (lib)

with diethylamine in the presence of lewis acids or metal alkoxide or metal hydride or organolithium reagents to form a compound of formula (Illb) of 1-phenyl- 1- diethylaminocarbonyl-2-hydroxymethylcyclopropane, b) optionally isolating the compound of formula (Illb) and reacting with a chlorinating agent to form l-phenyl-l-diethylaminocarbonyl-2- chloromethylcyclopropane, a compound of formula (IVb) and

c) optionally isolating the compound of formula (IVb) and reacting with an azide and optionally in the presence of phase transfer catalyst to form a azide compound of formula (Vb)

d) optionally isolating the azide compound of formula (Vb) and reduction with reducing agent to form a Levomilnacipran compound, and e) optionally salification of the Levomilnacipran in a suitable organic solvents to prepare pharmaceutically acceptable acid.

15. A process for the preparation of compound of formula (I), its stereo specific isomers or pharmaceutically acceptable salts thereof, wherein and R2 are independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, and lower-alkylaryl, wherein aryl or alkylaryl group is optionally substituted by a halogen atom; comprising: a) reacting l-phenyl-2-chloromethylcyclopropane, a compound of formula (IV)

with an azide and optionally in the presence of phase transfer catalyst to form a azide compound of formula (V)

b) optionally isolating the azide compound of formula (V) and reduction with reducing agent and optionally salification with pharmaceutically acceptable acids in suitable organic solvents, to form a compound of formula (I).

16. A process for the preparation of compound of formula (I), its stereo specific isomers or pharmaceutically acceptable salts thereof, wherein R and R2 are independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, and lower-alkylaryl, wherein aryl or alkylaryl group is optionally substituted by a halogen atom; comprising: a) reacting a azide compound of formula (V)

with reducing agent and optionally salification with pharmaceutically acceptable acids in suitable organic solvents, to form a compound of formula (I).

17. A process for the preparation of compound of formula (I), or a pharmaceutically acceptable salt thereof,

wherein R \ and R are represents independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, and lower-alkylaryl, which aryl or alkylaryl group is optionally substituted by a halogen atom; comprising: a) reacting 1-phenyl-2-hydroxymethylcyclopropane, a compound of formula (III)

treated with an azide in the presence of DEAD (diethylazodicarboxylate) and reducing agent in organic solvent to form a compound of formula (I). 18. A process for the preparation of compound of formula (I), or a pharmaceutically acceptable salt thereof,

wherein and R are represents independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, and lower-alkylaryl, which aryl or alkylaryl group is optionally substituted by a halogen atom; comprising:

a) reacting 1-phenyl-2-hydroxymethylcyclopropane, a compound of formula (III)

treated with an azide in the presence of carbon tetrabromide in organic solvent, followed by reducing agent to form a compound of formula (I).

19. A process according to any of the preceding claims, wherein the organic solvent is selected from the group comprising of preferably selected, but is not limited to aliphatic hydrocarbons such as CI-CIO straight chain or branched hydrocarbons such as -hexane, rc-heptane, cyclohexane, pentane; alcoholic solvents such as branched or chain C1-C4 selected alcohols as methanol, ethanol, isopropyl alcohol; and aromatic hydrocarbons such as toluene, xylene; haloalkanes such as dichloromethane, chloroform; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane or a mixture thereof.

20. A process according to claim 1 or, wherein the compound of formula (I) has purity greater than 99.8%. 21. A process for preparing highly pure Milnacipran or Levomilnacipran, substantially as herein described with reference to forgoing examples. A . CLASSIFICATION O F SUBJECT MATTER INV. C07D307/33 C07C231/10 C07C233/58 C07C235/40 C07C237/24 ADD.

According to International Patent Classification (IPC) o r t o both national classification and IPC

B . FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) C07D C07C

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) EPO-Internal , BEI LSTEIN Data

C . DOCUMENTS CONSIDERED T O B E RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

SATOSHI SHUTO ET AL: " (+-) - 16, 18-21 (Z) -2-Ami nomethyl ) -1-phenyl cycl opropanecar boxami de Deri vati ves as a new prototype of NMDA receptor antagoni sts . " , JOURNAL OF MEDICINAL CHEMISTRY. , vol . 38, 1995 , pages 2964-2968, XP002692749 , USAMERICAN CHEMICAL SOCI ETY. WASHINGTON . ISSN : 0022-2623 ci ted i n the appl i cati on Scheme 3 ; 1-15 , 17 exampl es 1,4,5 , 7,8,

EP 1 770 084 Al (SUMITOMO CHEMICAL CO 1-15 , 17 [ P] ) 4 Apri l 2007 (2007-04-04) cl aim 1

□ Further documents are listed in the continuation of Box C . See patent family annex.

* Special categories of cited documents : "T" later document published after the international filing date o r priority date and not in conflict with the application but cited to understand "A" document defining the general state of the art which is not considered the principle o r theory underlying the invention to be of particular relevance "E" earlier application o r patent but published o n o r after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel o r cannot b e considered to involve a n inventive "L" documentwhich may throw doubts o n priority claim(s) orwhich is step when the document is taken alone cited to establish the publication date of another citation o r other "Y" document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve a n inventive step when the document is "O" document referring to a n oral disclosure, use, exhibition o r other combined with one o r more other such documents, such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

26 February 2013 12/03/2013

Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 N L - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 Voyi azogl ou, D Information on patent family members PCT/IB2012/001765

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