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 purity and good yield.

BACKGROUND OF THE INVENTION:
Milnacipran  is chemically known as cyclopropanecarboxamide  2-(Aminomethyl)-N N-diethyl-1-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 following:

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

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 Milnacipran 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 1-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 A1 discloses a process for preparing Milnacipran  which involves the hydrolysis of (Z)-1-phenyl-1-diethylaminocarbonyl-2-phthalimidomethylcyclopropane in the presence of aqueous methylamine solution having concentration of from 1 to 25% by weight to obtain (Z)-1-phenyl-1-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 A1 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-HCl 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 B1 discloses a process for preparing Milnacipran hydrochloride  which comprises the reaction of potassium phthalimide with 1-Phenyl-3-oxabicyclo [3 1 0] hexan-2-one in presence of high boiling solvent such as dimethyl sulfoxide at 150-2000C 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:

The PCT Patent Application No. WO2010/086394 A1 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-HCl. The reaction is schematically represented by scheme 6.
Scheme-6:

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 levo-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-(Aminomethyl)-N N-diethyl-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:

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 2005/118 564).
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 levo-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 R1 and R2 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 R1 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 levo-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 R1 and R2 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)

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 1-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 (Ia):

comprising the following successive steps:
a) reacting l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one  a compound of formula (IIa)

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 (IIIa) of 1-phenyl-1-diethylaminocarbonyl-2–hydroxymethylcyclopropane 

b) optionally isolating the compound of formula (IIIa) 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 (Ia).
wherein the reactions steps (a) to (f) will advantageously be carried out without isolating the intermediate products (IIIa)  (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 n-butyllithium  hexllithium  lithium di-isopropyl amide (LDA)  lithium bis(trimethylsilyl)amide (LiHMDS) etc.
The reaction step-a  is carried out in a suitable organic solvent preferably selected  but is not limited to aliphatic hydrocarbons such as C1-C10 straight chain or branched hydrocarbons such as n-hexane  n-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 C1-C10 straight chain or branched hydrocarbons such as n-hexane  n-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 C1-C10 straight chain or branched hydrocarbons such as n-hexane  n-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; dimethylformamide  n-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 C1-C10 straight chain or branched hydrocarbons such as n-hexane  n-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)  n-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 C1-C10 straight chain or branched hydrocarbons such as n-hexane  n-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 R1 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 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).
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 R1 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 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).
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 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.
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 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. 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. 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-1-diethylaminocarbonyl-2–hydroxymethylcyclopropane (100 g) was dissolved in (1000 ml) MDC at room temperature and cooled to 0-100C followed by added thionyl chloride (80 g) at to 0-100C 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.HCl (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 Milnacipran hydrochloride.
Example 7: Preparation of cis-(±)-l-phenyl-1-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-1-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 sodium 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 (110 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.HCl 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. 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 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 (1S  2R)-1-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 (135 g).
Example 12: Preparation of (1S  2R)-l-phenyl-l-diethylaminocarbonyl-2-chloromethyl cyclopropane.
(1S  2R)-1-Phenyl-1-diethylaminocarbonyl-2–hydroxymethylcyclopropane (135 g) was dissolved in (1000 ml) MDC at room temperature and cooled to 0-100C followed by addition of thionyl chloride (80 g) at to 0-100C 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 (1S  2R)-l-phenyl-l-diethylaminocarbonyl-2-azidoromethyl cyclopropane.
(1S  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 50-60oC. 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 (1S  2R)-l-phenyl-l-diethylaminocarbonyl-2-chloromethyl cyclopropane (Levomilnacipran) crude.

(1S  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. 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 15: Preparation of Levomilnacipran hydrochloride.
Levomilnacipran crude (80 g) was dissolved in IPA (150 ml)  IPA.HCl (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 (1S  2R)-l-phenyl-l-diethylaminocarbonyl-2-azidoromethyl cyclopropane
Sodium azide (37 g) and tetrabutyl ammonium bromide (10 g) was added to 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 (1S  2R)-l-phenyl-1-diethylaminocarbonyl-2-azidomethyl cyclopropane
(1S  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 60oC. 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 HCl 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 (1S  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 00C. 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 60-700C. 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.HCl : 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

Dated this 8th day of June  2012

XXXXXXXXXX
AGENT FOR THE APPLICANT(S)

WHAT CLAIM IS:
1. A process for the preparation of compound of formula (I)  its stereo specific isomers or pharmaceutically acceptable salts thereof 

wherein R1 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-3-oxabicyclo[3.1.0]hexan-2-one  a compound of formula (II)

with amine compound of formula (VI)

wherein R1 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 (IIa)

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

b) optionally isolating the compound of formula (IIIa) 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 (IIb)

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

b) optionally isolating the compound of formula (IIIb) 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 R1 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 R1 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 R1 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; 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 R1 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; 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 C1-C10 straight chain or branched hydrocarbons such as n-hexane  n-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.

“AN IMPROVED PROCESS FOR THE PREPARATION OF 1-ARYL 2-AMINOMETHYL CYCLOPROPANE CARBOXYAMIDE (Z) DERIVATIVES  THEIR ISOMERS AND SALTS THEREOF”
Abstract of the Invention

The present invention relates to an improved and one-pot process for the preparation of 1-Aryl 2-aminomethyl cyclopropane carboxyamide (z) derivatives  their isomers of formula (I) or its pharmaceutically acceptable salt thereof.

wherein R1 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.