WO2011158249A1

WO2011158249A1 - Process for preparation of milnacipran intermediate and its use in preparation of pure milnacipran

Info

Publication number: WO2011158249A1
Application number: PCT/IN2011/000387
Authority: WO
Inventors: Nagambar Genuji Jambukar; Milind Gharpure; Sudam Nanabhau Sinare; Pravin Chhaburao Thombre; Mubeen Ahmed Khan
Original assignee: Glenmark Generics Limited
Priority date: 2010-06-16
Filing date: 2011-06-09
Publication date: 2011-12-22

Abstract

Disclosed is a process for the preparation of milnacipran intermediate, a compound of formula ΙII, and its use in the preparation of pure milnacipran.

Description

PROCESS FOR PREPARATION OF MILNACIPRAN INTERMEDIATE AND ITS USE IN PREPARATION OF PURE MILNACIPRAN

PRIORITY

[0001] This application claims the benefit to Indian Provisional Application No.

1809/MUM/2010, filed on June 16, 2010, and entitled "PROCESS FOR PREPARATION OF MILNACIPRAN INTERMEDIATE AND ITS USE IN PREPARATION OF PURE MILNACIPRAN", which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Technical Field

[0002] The present invention relates to a process for the preparation of a compound cis-(±)-2-[(l ,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)methyl]-N,N-diethyl-l- phenylcyclopropane carboxamide and/or its pharmaceutically acceptable salts and its conversion to milnacipran.

Description of the Related Art

[0003] Milnacipran, also known as (±)-[lR(S), 2S(R)]-2-(aminomethyl)-N,N- diethyl-l-phenylcyclopropanecarboxamide is represented by the structure of formula II:

[0004] Milnacipran hydrochloride, formula I, a selective norepinephrine and serotonin reuptake inhibitor, is found useful in the treatment of depression and chronic pain conditions like fibromyalgia syndrome and lupus. Milnacipran hydrochloride inhibits norepinephrine uptake with greater potency than serotonin. Milnacipran hydrochloride is marketed in the United States under the brand name Savella^® in the form of 12.5, 25. 50 and 100 mg tablets for fibromyalgia syndrome; while in Europe, it is available under the brand name Ixel® in the form of 25, 50 and 100 mg tablets for depression.

l

10005] U.S. Patent No. 4,478,836 ("the '836 patent") discloses milnacipran and its hydrochloride salt form. The '836 patent discloses a process for the preparation of milnacipran hydrochloride by the reaction of an acid chloride of cis- 1 -phenyl- 1- ethoxycarbonyl-2-aminomethylcyclopropane with diethylamine and salifying with hydrochloric acid. The rocess is schematically represented b scheme I:

[0006] Patent Publication WO2008/104957 (the '957 publication) discloses a multistep process for the preparation of milnacipran hydrochloride by the reaction of (Z)- l-phenyl-l-diethylaminocarbonyl-2-phthalimidomethylcyclopropane of formula III with hydrazine hydrate and the resultant milnacipran product isolated as a wet compound with a significant amount of phthalimide by-products, which are removed by acid-base treatment and whereupon the milnacipran is directly converted to its hydrochloride salt form. The process disclosed in the '957 publication is schematically represented by scheme II:

(III) Milnacipran hydrochloride

Scheme II [0007] U.S. Patent No. 5,034,541 ("the '541 patent") discloses a process for preparation ofmilnacipran intermediate, cis-(±)-2-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)methyl]-N,N-diethyl-l-phenylcyclopropanecarboxamide of compound of formula III. The process comprises opening the cis-(±)-l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one of formula VI using diethylamine with the aid of a Lewis acid, converting the cis-(±)-l- phenyl-l-diethylaminocarbonyl-2-hydroxymethylcyclopropane of formula V resulting into its 2-chloro derivative of formula IV by the action of a chlorination reagent, then the 2-chloro derivative is converted into the compound of formula III by reaction with a phthalimide salt at 110°C.

[0008] The final step of the '541 patent process was carried out at high temperature; which may have led to formation of impurities in milnacipran. The process disclosed in the '541 patent is schematically represented by scheme III:

S chem e III

[0009] Impurities in milnacipran or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.

[0010] It is also known in the art that impurities in an API may arise from degradation of the API itself, which is related to the stability of the pure API during storage, and the manufacturing process, including the chemical synthesis. Process impurities include unreacted starting materials, chemical derivatives of impurities contained in starting material, synthetic by-products, and degradation products. [0011] The purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. For example, the International Conference on Harmonization of Technical Requirements for Registration for Human Use ("ICH") Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, like temperature, pressure, time, and stoichiometric ratios, and including purification steps such as washing with water or solvent, crystallization, distillation, and extraction, in the manufacturing process.

[0012] Thus there is a need in the art for improved processes for preparing pure milnacipran and its intermediates, which are more industrially applicable.

SUMMARY OF THE INVENTION

[0013] The present invention is drawn towards the preparation of compounds, that may be used as intermediates in the preparation of milnacipran or its pharmaceutically acceptable salts. The subsequent milnacipran or its pharmaceutical salts contain levels of impurity that render their favorable use as API.

[0014] In one aspect , the present invention provides a one-pot process for the preparation of cis-(±)-2-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)methyl]-N,N-diethyl- 1 -phenyl cyclo-propanecarbox mide, a compound of formula III:

comprising:

a) reacting cis-(±)-l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one, a compound of formula VI

with diethylamine in the presence of a Lewis acid and an organic solvent to form cis-i 1 -phenyl- 1 -diethylaminocarbonyl-2-hydroxymethylcyclopropane, a compound formula V,

b) reacting cis-(±)-l -phenyl- l-diethylaminocarbonyl-2-hydroxymethylcyclopropane, the compound of formula V with a chlorinating agent to form cis-(±)-l -phenyl- 1- diethylaminocarbonyl-2-chloromethylcyclopropane, a compound of formula IV and

IV

c) reacting cis-(±)-l -phenyl- l-diethylaminocarbonyl-2-chloromethylcyclopropane, the compound of formula IV with a phthalimide salt at a temperature range between about 20°C to about 60°C to form the compound of formula III.

[0015] In another embodiment, the present invention provides a process for the preparation of cis-(±)-2-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)methyl]-N,N-diethyl- 1 -phenylcyclo-propanecarbo mide, a compound of formula III,

the process comprising, reacting cis-(±)-l -phenyl- 1-di ethylaminocarbonyl-2- chloromethylcyclopropane, a compound of formula IV

IV with a phthalimide salt, in the presence of an organic solvent at a temperature range between about 20°C to about 60°C.

[0016] In another embodiment, the present invention provides a crystalline Form

A of cis-(±)-2-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)methyl]-N,N-diethyl-l - phenylcyclopropanecarboxamide, a compound of formula III

wherein the Form A has an XRD pattern substantially in accordance with Figure 1.

[0017] In another embodiment, the present invention provides crystalline Form A of cis (±)-2- [( 1 ,3 -dioxo- 1 ,3 -dihydro-2H-isoindol-2-yl)methyl] -Ν,Ν-diethyl- 1 - phenylcyclopropanecarboxamide a compound of formula III, as an intermediate

in the preparation of milnacipran or its pharmaceutically acceptable salts.

[0018] In another embodiment, the present invention provides cis-(±)-2-[(l ,3- dioxo-l ,3-dihydro-2H-isoindol-2-yl)methyl]-N,N-diethyl-l- phenylcyclopropanecarboxamide having purity of greater than 99.0%, as measured by high performance liquid chromatography.

[0019] In another embodiment, the present invention provides cis-(±)-2-[(l ,3- dioxo-l,3-dihydro-2H-isoindol-2-yl)methyl]-N,N-diethyl-l- phenylcyclopropanecarboxamide having purity of greater than 99.5%%, as measured by high performance liquid chromatography.

[0020] In another embodiment, the present invention provides a process for preparation of milnacipran or its pharmaceutically acceptable salts comprising, a) preparing cis-(±)-2-[(l ,3-dioxo-l ,3-dihydro-2H-isoindol-2-yl)methyl]-N,N- diethyl-1 -phenylcyclopropanecarboxamide by the process of the present invention, b) converting the cis-(±)-2-[(l ,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)methyl]-N,N- diethyl-l-phenylcyclopropanecarboxamide into milnacipran by reacting it with monomethylamine,

c) optionally, converting the milnacipran into its pharmaceutically acceptable salts.

[0021] In another embodiment, the present invention provides milnacipran hydrochloride having less than about 0.1% of impurity X, as measured by high performance liquid chromatography (HPLC).

[0022] In another embodiment, the present invention provides milnacipran hydrochloride having less than about 0.05% of impurity X, as measured by high performance liquid chromatography (HPLC).

[0023] In another embodiment, the present invention provides milnacipran hydrochloride having a total purity of at least about 98% containing impurity X less than about 0.1%), as measured by high performance liquid chromatography (HPLC).

[0024] In another embodiment, the present invention provides milnacipran hydrochloride having a total purity of at least about 99% containing impurity X less than about 0.1%, as measured by high performance liquid chromatography (HPLC).

[0025] In another embodiment, the present invention provides milnacipran hydrochloride having a total purity of at least about 99.8% containing impurity X less than about 0.1%, as measured by high performance liquid chromatography (HPLC).

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is a characteristic XRPD of cis (±)-2-[(l ,3-dioxo-l,3-dihydro-2H- isoindol-2-yl)methyl]-N,N-diethyl-l-phenylcyclopropanecarboxamide of formula III in crystalline Form-A prepared as in Example 1.

[0027] Figure 2 is a characteristic DSC thermogram of cis (±)-2-[(l,3-dioxo-l,3- dihydro-2H-isoindol-2-yl)methyl] -Ν,Ν-diethyl- 1 -phenylcyclopropanecarboxamide of formula III in crystalline Form-A prepared as in Example 1.

[0028] Figure 3 is a characteristic XRPD of milnacipran hydrochloride prepared as in Example 3.

[0029] Figure 4 is a characteristic DSC thermogram of milnacipran hydrochloride prepared as in Example 3. [0030] Figure 5 is a HPLC chromatogram from an analysis of a milnacipran hydrochloride prepared as in Example 3.

DETAILED DESCRIPTION OF THE INVENTION

[0031] For some of the terminologies as used herein, the term "impurity X" refers to a potential impurity of milnacipran having a relative retention time (RRT) of about 1.08 to about 1.30 as relative to the retention time of milnacipran hydrochloride, based on the high performance liquid chromatography (HPLC) method disclosed herein.

[0032] As used herein, the term "reduced pressure" refers to a pressure of under lOO mm Hg.

[0033] In the present application, the term "room temperature" means a temperature of about 25°C to about 30°C.

[0034] The present invention provides a one-pot process for the preparation of milnacipran intermediate cis-(±)-2-[(l ,3-dioxo-l ,3-dihydro-2H-isoindol-2-yl)methyl]- N,N-diethyl-l -phenyl cyclopro anecarboxamide, a compound of formula III:

the process comprising:

a) reacting cis-(±)-l-phenyl-3-oxabic clo[3.1.0]hexan-2-one, a compound of formula VI

with diethylamine in the presence of a Lewis acid and an organic solvent to form cis-(±)- 1 -phenyl- l-diethylaminocarbonyl-2-hydroxymethyl cyclopropane, a compound of formula V,

b) reacting cis-(±)-l -phenyl- l-diethylaminocarbonyl-2-hydroxymethylcyclopropane, the compound of formula V with a chlorinating agent to form cis-(±)-l -phenyl- 1- diethylaminocarbonyl-2-chlorom thylcyclopropane, a compound of formula IV and

[0035] In (a) of the above process, cis-(±)-l-phenyl-3-oxabicyclo[3.1.0]hexan-2- one (lactone of formula VI) is reacted with diethylamine in presence of a Lewis acid and an organic solvent to form cis-(±)-l -phenyl- 1 -diethylaminocarbonyl-2- hydroxymethylcyclopropane, a compound of formula V. The lactone of formula VI is a known compound and can be prepared by processes known in the art. The lactone of formula VI can be prepared by alkylation of phenyl acetonitrile with epichlorohydrin in presence of base which is not limited to sodium hydride, potassium hydride, sodium amide, potassium amide, alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like, alkali metal alkoxide such as sodium methoxide, sodium ethoxide, sodium propoxide, potassium methoxide, potassium ethoxide and the like, optionally in presence of phase transfer catalyst in an organic solvent selected from toluene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, dimethylacetamide, or mixtures thereof, followed by alkali hydrolysis, optionally in presence of phase transfer catalyst and acid treatment. Illustratively, herein incorporated by reference is the process disclosed by Shuto Satoshi in Journal of Organic Chemistry, 1996, 61 (3), 915-923.

[0036] Suitable Lewis acid include, 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. [0037] The reaction is normally and preferably effected in the presence of an inert organic solvent. The suitable organic solvent includes, but is not limited to dimethylformamide, dimethylsulfoxide, ethers such as diethyl ether, dimethyl ether, methylethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane and the like; aliphatic hydrocarbons such as Ci-Cio straight chain or branched hydrocarbons such as n-hexane, n-heptane, cyclohexane, pentane and the like; and aromatic hydrocarbons such as toluene, xylene and the like; haloalkanes such as dichloromethane, chloroform and the like; and mixtures thereof. Preferably, the organic solvent is selected from dichloromethane, chloroform, toluene, diethyl ether; more preferably the solvent is dichloromethane, toluene.

[0038] The 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 VI. Preferably about an equimolar amount to about 2 times the equimolar amount of the compound of formula VI is used.

[0039] The molar equivalent of diethylamine employed is from about an equimolar amount to about 5 times the equimolar amount with respect to the compound of formula VI. Preferably about 2 times equimolar amount to about 3 times the equimolar amount of the compound of formula VI is used.

[0040] The reaction can take place at a temperature of about 0°C to about 30°C. Preferably, the reaction is carried out at a temperature of about 10°C to about 25 °C.

[0041] The reaction 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 cis-(±)- 1 -phenyl- l -diethylaminocarbonyl-2-hydroxymethylcyclopropane, the compound of formula V, is used for (b) in the process, just described above.

[0042] In (b) of the process, the cis-(±)-l -phenyl- l-diethylaminocarbonyl-2- hydroxymethyl-cyclopropane, compound of formula V is converted into its chloro derivative (i.e. cis-(±)- 1 -phenyl- 1 -diethylaminocarbonyl-2-chloromethylcyclopropane, compound of formula IV by a reaction with a chlorinating agent.

[0043] The chlorinating agent includes, but is not limited to thionyl chloride, phosphorus trichloride, phosphorus pentachloride. Preferably the chlorinating agent is thionyl chloride.

[0044] The molar equivalents of the chlorinating agent employed is from about an equimolar amount to about 3 times the equimolar amount with respect to the compound of formula V. Preferably about an equimolar amount to about 1.5 times the equimolar amount of the compound of formula V is used.

[0045] The reaction can take place at a temperature of about - 10°C to about 30°C.

Preferably, the reaction is carried out at a temperature of about -10°C to about 20°C.

[0046] The reaction time can vary from about 10 minutes to about 1 hour.

Preferably about 20 minutes to about 30 minutes. 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 used for (c) in the process, just described above.

[0047] In (c) of the above process, the cis-(±)-l -phenyl- 1-diethylaminocarbonyl-

2-chloromethylcyclopropane, compound of formula IV is converted into cis-(±)-2-[(l,3- dioxo-l ,3-dihydro-2H-isoindol-2-yl)methyl]-N,N-diethyl-l -phenylcyclopropanecarboxa- mide, compound of formula III, by reaction with a phthalimide salt such a potassium phthalimide, sodium phthalimide, lithium phthalimide and the like. Preferably the phthalimide salt is potassium phthalimide.

[0048] The phthalimide salt employed in the reaction is from about 2 times the equimolar amount to about 6 times the equimolar amount with respect to the compound of formula IV. Preferably about 3 times equimolar amount to about 5 times the equimolar amount of the compound of formula IV.

[0049] The reaction is advantageously carried out at a temperature between about

20°C to about 60°C. Preferably, the reaction is carried out at a temperature between about 25°C to about 45°C.

[0050] The reaction time can vary from about 30 minutes to about 3 hours, preferably, 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 the reaction, the reaction mixture is quenched either with water or with base.

[0051] The base used can be any of those that are known in the art, for example sodium hydroxide, potassium hydroxide and the like, sodium carbonate, potassium carbonate and the like. Preferably the base is sodium hydroxide.

[0052] The organic layer is washed with water to remove the impurities and the compound may be isolated by removal of the solvent. The solvent may be removed using any suitable methods such as evaporation, atmospheric distillation, or distillation under vacuum.

[0053] Distillation of the solvent may be conducted under vacuum, such as below about 100 mm Hg to below about 600 mm Hg, at elevated temperatures such as about 20°C to about 60°C. Generally, any temperature and vacuum conditions may be used provided these do not influence the nature of the product. The vacuum and the temperatures used for the removal of the solvent depend on parameters like the boiling point range of the solvent, which may be readily determined by persons skilled in the art.

[0054] The crude compound of formula III may be purified by dissolving it in an organic solvent like C1-C5 alcohols, for example methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol and the like. Preferably the solvent is methanol, isopropanol.

[0055] The compound of formula III may be further purified by dissolving it in a solvent like water, ketones such as acetone, ethyl methyl ketone, butanone and the like and mixtures thereof.

[0056] The product is isolated by the methods known in the art such as filtration.

[0057] The present invention provides a process for the preparation of cis-(±)-2-

[(l ,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)methyl]-N,N-diethyl-l- phenylcyclopropanecarbox-amide a compound of formula III

the process comprising, reacting cis-(±)-l -phenyl- 1 -diethylaminocarbonyl-2- chloromethylcyclopropane, a com ound of formula IV

with a phthalimide salt in the presence of an organic solvent at a temperature range between about 20°C to about 60°C.

[0058] The starting compound of formula IV is a known compound and can be prepared by the processes known in the art. Illustratively, the '541 patent, which is referenced herein in its entirety discloses the method.

[0059] The reaction is conducted in a solvent inert to the reaction. The solvent includes, but is not limited to, ethers such as diethyl ether, dimethyl ether, methylethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane and the like; aliphatic hydrocarbons such as Ci-Cio straight chain or branched hydrocarbons such as n- hexane, n-heptane, cyclohexane, pentane and the like; and aromatic hydrocarbons such as toluene, xylene and the like; haloalkanes such as dichloromethane, chloroform and the like; dimethylformamide, dimethylsulfoxide and mixtures thereof. Preferably, the solvent is selected from dichloromethane, chloroform, toluene, diethyl ether, dimethylformamide; more preferably the solvent is dichloromethane, toluene.

[0060] The phthalimide salt is selected from potassium phthalimide, sodium phthalimide, lithium phthalimide and the like. Preferably the phthalimide salt is potassium phthalimide.

[0061] The phthalimide salt employed in the reaction is from about 2 times the equimolar amount to about 6 times the equimolar amount with respect to the compound of formula IV. Preferably about 3 times the equimolar amount to about 5 times the equimolar amount of the compound of formula IV is used.

[0062] The reaction is advantageously carried out at a temperature between about

20°C to about 60°C. Preferably, the reaction is carried out at a temperature between about 25°C to about 45°C. The reaction time can vary from about 30 minutes to about 3 hours, preferably, 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).

[0063] After completion of the reaction, the reaction mixture is quenched either with water or with base. The base used can be any of those that are known in the art, for example sodium hydroxide, potassium hydroxide and the like, sodium carbonate, potassium carbonate and the like. Preferably the base is sodium hydroxide.

[0064] The organic layer is washed with water to remove the impurities and the compound may be isolated by removal of the solvent. The solvent may be removed using any suitable methods such as evaporation, atmospheric distillation, or distillation under vacuum.

[0065] Distillation of the solvent may be conducted under vacuum, such as below about 100 mm Hg to below about 600 mm Hg, and at elevated temperatures such as about 20°C to about 60°C. Any temperature and vacuum conditions generally may be used provided these do not influence the nature of the product. The vacuum and the temperatures used for the removal of the solvent depend on parameters including the boiling of the solvent, which are readily apparent of one of ordinary skill in the art.

[0066] The crude compound of formula HI may be purified by dissolving it in an organic solvent like C1-C5 alcohols, as for example methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol and the like; ketone solvents, as for example acetone, methylethylketone, methyl isobutyl ketone, and the like. Preferably the solvent is methanol, isopropanol.

[0067] The compound of formula III may be further purified by dissolving it in a solvent like water, ketones such as acetone, ethyl methyl ketone, butanone and the like and mixtures thereof.

[0068] The product is isolated by the methods known in the art such as filtration.

[0069] The solid material obtained by the processes described above may be further dried. Drying may be suitably carried out by any method, known in the art, including but not limited to, using a tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash drier, and the like. The drying may be carried out under reduced pressures and at elevated temperatures. The temperature may range from about ambient temperature to about 100°C, for a time period that produces the desired result. [0070] Illustratively, the '541 patent discloses the conversion compound of formula IV into formula III by the reaction with potassium phthalimide at 1 10°C. Disadvantageous^, at this high temperature, degradation impurities may form in the compound of formula III. In contrast, the present invention provides a process for the preparation of formula III, the process comprising using a low temperature reaction, whereby impurities are reduced, subsequently enhancing the purity of compound of formula III.

[0071] The present invention provides a compound of formula III, prepared by the processes herein described, in crystalline form A.

[0072] The present invention provides a crystalline Form A of cis-(±)-2-[(l,3- dioxo- 1 ,3-dihydro-2H-isoindol-2-yl)methyl]-N,N-diethyl- 1 - phenylcyclopropanecarboxamide, a compound of formula III

[0073] The present invention provides a compound of formula III in crystalline form A characterized by an X-ray powder diffraction pattern, which is substantially in accordance with Figure 1.

[0074] The present invention provides a compound of formula III in crystalline form A characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2Θ±0.2°Θ at about 6.8, 13.5, 14.7, 23.3 and 27.2.

[0075] The X-Ray powder diffraction can be measured by an X-ray powder

Diffractometer equipped with a Cu-anode (λ=1.54 Angstrom), X-ray source operated at 45kV, 40 mA and a Ni filter is used to strip K-beta radiation. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=2-50° 2Θ; step width=0.017°; and measuring time per step=5 sec.

[0076] The present invention further provides the compound of formula III in crystalline form A, with a differential scanning calorimetric thermogram, which is as substantially in accordance with Figure 2. [0077] The scan is performed with a Differential Scanning Calorimeter (DSC

822, Mettler Toledo) at a scan rate of 10°C per minute with an Indium standard. The compound of formula III in crystalline Form A exhibits a predominant endotherm peak at about 132.3°C. Whereupon, the endotherm measured by a particular differential scanning calorimeter is dependent upon a number of factors, including the rate of heating (i.e., scan rate), the calibration standard utilized, instrument calibration, relative humidity, and upon the chemical purity of the sample being tested. Thus, an endotherm as measured by DSC on the instrument identified above may vary by as much as ±1°C or even ±2°C.

[0078] The present invention provides cis-(±)-2-[(l ,3-dioxo-l ,3-dihydro-2H- isoindol-2-yl)methyl]-N,N-diethyl-l-phenylcyclopropanecarboxamide, compound of formula III having a purity of greater than about 98.0%, as measured by high performance liquid chromatography.

[0079] The compound of formula III prepared by the processes of the present invention has a total purity of at least about 98.0%. Preferably the total purity is at least about 99.0%, most preferably the total purity is at least about 99.5%, as measured by high performance liquid chromatography.

[0080] The present invention provides a process for preparation of milnacipran or its pharmaceutically acceptable salts comprising providing a compound of formula III as obtained by the process described herein above, as a starting material or as an intermediate.

[0081] The present invention further provides a process for preparation of milnacipran or its pharmaceutically acceptable salts comprising,

a) preparing cis-(±)-2-[(l ,3-dioxo-l ,3-dihydro-2H-isoindol-2-yl)methyl]-N,N- diethyl-l-phenylcyclopropanecarboxamide, compound of formula III obtained by the process of the present invention,

b) converting the compound of formula III into milnacipran by reacting it with monomethylamine .

[0082] The process is shown in scheme-IV

Milnacipran acid addition salt

Scheme-IV

[0083] The monomethylamine may be in an aqueous, anhydrous or gaseous form.

For example, aqueous monomethylamine or solvent containing monomethylamine or gas containing monomethylamine may be used. Preferably, aqueous monomethylamine can be used.

[0084] Reaction of a compound of formula III with monomethylamine may be advantageously conducted in the presence of a suitable solvent. The solvent includes but is not limited to water, acetone, methanol, ethanol, isopropanol, toluene and the like. Preferably, the solvent is water.

[0085] The reaction time varies, depending on the amount and concentration of the monomethylamine used. In general, preferably, about 30 minutes to about 6 hours, or more preferably, about 30 minutes to about 3 hours. The reaction temperatures are preferably in the range of about 0°C to about 80°C, or more preferably, about 20°C to about 60°C.

[0086] 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 about room temperature and the compound of formula II (i.e. milnacipran base) is extracted into a water immiscible solvent. The water immiscible solvent that may be utilized for this step includes, but is not limited to halogenated hydrocarbons such as dichloromethane, chloroform and the like; esters such as ethyl acetate, n-propyl acetate, tertiary butyl acetate and the like; aromatic solvents such as toluene, chlorobenzene, and the like. Preferably the water immiscible solvent is toluene.

[0087] The solvent may be removed using any suitable method, known in the art, such as evaporation, atmospheric distillation, or distillation under vacuum. Distillation of the solvent may be conducted under vacuum, such as below about 100 mm Hg or below about 400 mm Hg at elevated temperatures such as about 20°C to about 70°C. Any temperature and vacuum conditions, generally, may be used provided these do not influence the nature of the product. The vacuum and the temperature used for the removal of the solvent depend on parameters like the boiling point range of the solvent, which are apparent to persons of ordinary skill in the art.

[0088] The compound may be isolated by adding suitable solvent/s to the residue like C 1-C5 alcohols, as for example methanol, ethanol, isopropanol and the like; ketones such as acetone, methylethylketone, methyl isobutyl ketone, and the like; esters such as ethyl acetate, n-propyl acetate, and the like; and mixtures thereof. Preferably, the solvent is ethyl acetate.

[0089] The reaction mass may be optionally treated with charcoal, whereupon, it can be optionally used for acid-addition salt formation.

[0090] The milnacipran acid addition salts may be prepared by reacting milnacipran with a pharmaceutically acceptable acid, where the acid may be an aqueous, anhydrous or gaseous form, for example, an aqueous acid or solvent containing an acid or a gas containing an acid. For example, such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like. Preferably the acid is hydrochloric acid. Preferably, a solvent containing an acid can be used.

[0091] The temperature for dissolution of milnacipran base ordinarily range from about 0°C to about 80°C and preferably about 20°C to about 50°C. The suitable acid is added to the solution containing milnacipran base at a temperature ranging from about 20°C to about 50°C and preferably at room temperature. The resulting mixture is stirred for about 10 minutes to about 5 hours. Preferably, from about 30 minutes to about 3 hours at about room temperature. The milnacipran salt precipitant can be isolated by filtration, where the collected crystals are preferably further solvent washed. The resultant product optionally may be further dried.

[0092] The present invention provides a process for purification of milnacipran hydrochloride comprising:

(a) providing a solution of milnacipran hydrochloride;

(b) adding an anti-solvent to the solution of (a); and

(c) recovering a solid formed in (b) to afford pure milnacipran hydrochloride

[0093] In (a) of the process directly described above, involves providing a solution of milnacipran hydrochloride in a solvent.

[0094] The solvent that may be utilized for this step includes, but is not limited to, alcohols such as methanol, ethanol, isopropanol and n-propanol; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform and carbon tetrachloride; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone; dimethyl sulfoxide; Ν,Ν-dimethyl formamide; N,N-dimethyl acetamide; and mixtures thereof. Preferably the solvent used for dissolution of milnacipran hydrochloride is dichloromethane, isopropanol.

[0095] Suitable temperatures for dissolution of milnacipran hydrochloride in a solvent may range from about 10°C to about the reflux temperature of the solvent.

[0096] Stirring may be continued for any desired time periods to achieve a complete dissolution of the compound. The stirring time may range from about 30 minutes to about 3 hours, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.

[0097] In (b) of the process directly described above, involves addition of an anti- solvent to the solution of (a). The anti-solvent that may be utilized for this step includes, but is not limited to, esters such as ethyl acetate, n-propyl acetate, and t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether, methyl t-butyl ether; hydrocarbon solvents such as n-heptane, cyclohexane, and n-hexane; and mixtures thereof. Preferably the anti-solvent used for this step is ethyl acetate. [0098] Suitable temperatures for addition of an anti-solvent to the solution of (a) may range from about 10°C to about the reflux temperature of the solvent.

[0099] After adding the anti-solvent, the reaction mass is stirred at about room temperature to about 0°C for a time period of about 1-2 hours.

[0100] In (c) of the process directly described above, involves recovering the solid of (b) by any method known in the art to afford pure milnacipran hydrochloride. The method, by which the solid material is recovered from the final mixture, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like. The isolated crystals will carry a small proportion of occluded mother liquor and may contain impurities. Optionally, the crystals may be washed with a solvent to wash out the mother liquor.

[0101] The wet cake obtained in (c) may be further dried. Drying may be suitably carried out in an equipment known in the art, such as a tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash drier and the like. The drying may be carried out at temperatures from about 35°C to about 100°C with or without vacuum. The drying may be carried out for any desired time until the required product quality is achieved. The drying time may vary from about 1 hour to about 20 hours, or longer.

[0102] The above steps (a), (b) and (c) can optionally be repeated to get the desired purity.

[0103] The mother liquor obtained in (c) may be optionally used to obtain second crop of milnacipran hydrochloride. The mother liquor is evaporated to dryness at about 50-55°C under vacuum. The residue is cooled to about room temperature and the solid is isolated by addition of solvent which is not limited to esters such as ethyl acetate, n- propyl acetate, and t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether, methyl t-butyl ether; hydrocarbon solvents such as n-heptane, cyclohexane, and n-hexane; and mixtures thereof. Preferably, the solvent is ethyl acetate.

[0104] The second crop of milnacipran hydrochloride may be purified by the process described herein above.

[0105] Milnacipran hydrochloride obtained by the above process, preferably contains impurity X in an amount of less than about 0.1%, preferably impurity X in an amount of less than about 0.05%, as measured by high performance liquid chromatography (HPLC).

[0106] The total purity of milnacipran hydrochloride obtained by the above process is of at least about 98%, more preferably, at least about 99% and most preferably at least about 99.8%, as measured by high performance liquid chromatography (HPLC).

[0107] The present invention provides milnacipran hydrochloride having less than about 0.1% of impurity X, as measured by high performance liquid chromatography (HPLC).

[0108] The present invention provides milnacipran hydrochloride having less than about 0.05% of impurity X, as measured by high performance liquid chromatography (HPLC).

[0109] The present invention provides milnacipran hydrochloride having a total purity of at least about 98% containing impurity X less than about 0.1%, as measured by high performance liquid chromatography (HPLC).

[0110] The present invention provides milnacipran hydrochloride having a total purity of at least about 99% containing impurity X less than about 0.1%, as measured by high performance liquid chromatography (HPLC).

[0111] The present invention provides milnacipran hydrochloride having a total purity of at least about 99.8% containing impurity X less than about 0.1%, as measured by high performance liquid chromatography (HPLC).

[0112] The purity, which is preferably measured by HPLC, is presented as % area as shown in the HPLC chromatogram, which is substantially in accordance with Figure 5.

[0113] The present invention provides characterization via X-ray powder diffraction pattern of milnacipran hydrochloride prepared by the process of present invention in a crystalline form, which is substantially in accordance with Figure 3.

[0114] The X-Ray powder diffraction can be measured by an X-ray powder

Diffractometer equipped with a Cu-anode (λ=1.54 Angstrom), X-ray source operated at 45kV, 40 mA and a Ni filter is used to strip -beta radiation. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range = 2-50° 20; step width = 0.017°; and measuring time per step = 5 sec. [0115] The present invention further provides milnacipran hydrochloride prepared by the process herein described in a crystalline form, with a differential scanning calorimetric thermogram, which is as substantially in accordance with Figure 4. The scan is performed with a Differential Scanning Calorimeter (DSC 822, Mettler Toledo) at a scan rate of 10°C per minute with an Indium standard. Milnacipran hydrochloride in crystalline form exhibits a predominant endotherm peak at about 180.2°C. Whereupon, the endotherm measured by a particular differential scanning calorimeter is dependent upon a number of factors, including the rate of heating (i.e., scan rate), the calibration standard utilized, instrument calibration, relative humidity, and upon the chemical purity of the sample being tested. Thus, an endotherm as measured by DSC on the instrument identified above may vary by as much as ±1 °C or even ±2°C.

[0116] The present invention further provides milnacipran hydrochloride prepared by the process herein described, having a relatively low content of one or more organic volatile impurities.

[0117] The present invention provides milnacipran hydrochloride prepared by the process herein described may have a residual solvent content that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines. The guideline solvent level depends on the type of solvent but is not more than about 5000 ppm, or about 4000 ppm_; or about 3000 ppm.

(0118] The present invention provides milnacipran hydrochloride prepared by the process herein described, having less than about 800 parts per million (ppm) C alcohols such as methanol, ethanol, isopropanol, preferably less than about 200 ppm; less than about 500 ppm ethyl acetate. Preferably less than about 100 ppm; less than about 500 ppm acetone, preferably less than about 100 ppm; less than about 500 ppm toluene, preferably less than about 100 ppm; less than about 500 ppm dichloromethane, preferably less than about 100 ppm.

[0119] The present invention provides milnacipran hydrochloride, as disclosed herein for use in a pharmaceutical composition, which may independently have a D₅₀ and D₉o particle size less than about 300 microns, preferably less than about 200 microns, more preferably less than about 150 microns, still more preferably less than about 50 microns and most preferably less than about 10 microns. Whereupon, the notation D_x means that X% of particles have a diameter less than a specified diameter D. Thus, a D₅₀ of about 300 microns means that 50% of the micronized particles in a composition have a diameter less than about 300 microns. Any milling, grinding, micronizing or other particle size reduction method known in the art can be used to bring the solid state milnacipran hydrochloride into any desired particle size range set forth above.

[0120] The present invention provides milnacipran or a pharmaceutically acceptable salt thereof or its intermediates, obtained by the above processes, as analyzed by chemical purity using high performance liquid chromatography ("HPLC") with the conditions described below:

Column : Inertsil ODS 3V, 250 x 4.6mm, 5μ; Column Temperature: 30°C

Mobile phase: Mobile Phase A: Buffer; Buffer: Adjust pH to 2.10 of water with trifluoroacetic acid; Mobile Phase B = Acetonitrile

Diluent: Water: Acetonitrile (1 : 1 , v/v); Flow Rate: l .OmL / minute; Detection: UV 215 nm; Injection Volume: 20 μΐ,

[0121] The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention in any manner.

EXAMPLES

EXAMPLE 1

[0122] Preparation of cis-(±)-2-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)methyl]-N,N-diethyl-l -phenyl cyclopropanecarboxamide, compound of Formula III Under nitrogen atmosphere, 115g of aluminum chloride was added into 750ml of methylene chloride and the slurry mass was cooled to about 0°C. lOOg of cis-(±)-l- phenyl-3-oxabicyclo[3.1.0]hexan-2-one, compound of formula VI was added at about 0°C and the reaction mixture was stirred for about 30min at about 10°C. Then diethyl amine solution (125.8g of diethyl amine in 200ml of methylene chloride) was added to the reaction mixture at about 10°C to about 15°C over a period of 45min and the reaction mixture was stirred for about 60min at about 10°C to about 15°C. Then 1800ml of water was added to the reaction mixture at about 10°C to about 20°C over a period of about 30min and stirred for about 2h at about room temperature. 25g of Hyflo was added and stirred for about lOmin. The reaction mixture was filtered through Hyflo bed and the Hyflo bed was washed with 100ml of methylene chloride. The organic layer was separated and taken into a clean container. The aqueous layer was again extracted with 300ml of methylene chloride; where a second organic layer was obtained. The combination of the organic layers was washed with 500ml of water followed by washing with 500ml of 10% aqueous sodium chloride solution, then the organic layer was treated with 50g of sodium sulphate. The organic layer was taken into a round bottomed flask and was cooled to 15°C and 95.75 gm of thionyl chloride was slowly added at about 15°C to about 20°C over a period of about 30min and the reaction mixture was stirred for about 30min at about 15°C to about 20°C. The reaction mass was cooled to about 0°C and 319g of potassium phthalimide was added, the temperature was raised to about 40°C to about 45°C and stirred at same temperature for about lh, then the reaction mass was cooled to about 10°C to about 15°C. Then 2.5 liters of 4% aqueous sodium hydroxide solution was added to the reaction mixture at about 10°C to about 20°C and stirred for about 30min. The aqueous and organic layers were separated and the organic layer was washed 4 times with 700ml each of water and solvent of the organic layer was distilled out completely under vacuum. 200ml of methanol was added to the residue mass at about 35°C to about 40°C and stirred for about lOmin. Then methanol was distilled out completely under vacuum. Then, 600ml of methanol was added to the residue mass and the temperature was raised to about 65 °C and stirred for about 30min. The reaction mixture was cooled to about 20°C to about 25°C and stirred for about 2h. The precipitated product was filtered and washed with 100ml of chilled methanol. The wet cake was added to 1500ml of water and the slurry was stirred at about 55°C to about 60°C for about 2h. The solid was filtered at about the same temperature and washed with 500ml of water. The wet cake was added to 350ml of acetone and heated about reflux temperature, then 5g of activated charcoal was added to the clear solution and maintained reflux for about 30min. The reaction mass was filtered through Hyflo bed and the bed was washed with 30ml of acetone. Slowly the clear solution was cooled to about room temperature over a period of lh. Solid was precipitated out and the slurry was maintained for about lh at about room temperature. The solid was filtered out and washed with 50ml of chilled acetone. The compound was dried at about 50°C to about 55°C for about 15h to yield 1 lOg of the title compound.

Purity by HPLC: 99.2%

PXRD peaks of Crystalline Form A of cis-(±)-2-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)methyl]-N,N-diethyl-l-phenylcyclopropanecarboxamide, compound of formula III:

EXAMPLE 2

[0123] Preparation of milnacipran hydrochloride

In a round bottom flask, 450ml of 40% aqueous methylamine solution was charged and 1 OOg of compound of formula III, prepared as in Example 1 , was added at about room temperature. Then the temperature was raised to about 40°C to about 45°C and stirred for about 2h. The reaction mixture was cooled to about room temperature and 700ml of toluene was added and stirred for about 30min. The layers were separated and the aqueous layer was extracted twice with each 200ml of toluene. The organic layers were combined and washed with 200ml of water followed by washing with 100ml of 20% aqueous sodium chloride solution. The organic layer was distilled out under reduced pressure at about 50°C to about 55°C, until substantially all of the solvent was distilled out. The crude was cooled to about room temperature and 350ml of ethyl acetate was added and stirred the contents for about 15min. Then 5g of activated charcoal (5g of charcoal in 50ml of isopropanol) was added to the solution and stirred for about 30min at about room temperature. The solution was filtered through Hyflo bed and the Hyflo bed was washed with 50ml of ethylacetate. The solution was cooled to about 20°C and 93g of 12% w/w hydrogen chloride solution in ethylacetate was added at about 20°C to about 25°C over a period of about 30min and the contents were stirred for about 2h at about 20°C to about 25°C. The precipitated product was filtered and washed with 100ml of ethylacetate. The product was dried at about 55°C to about 60°C under vacuum for about 6h to yield 50g of milnacipran hydrochloride.

Purity by HPLC: 99.1%

EXAMPLE 3

[0124] Purification of milnacipran hydrochloride

In a round bottom flask, charged 300ml of dichloromethane and 50g of milnacipran hydrochloride, prepared as in Example 2, was added at about room temperature. Then lOg of Celite® was added to the mass and stirred for about 30min. Filtered the reaction slurry through the Celite® bed and the bed was washed with 50ml of dichloromethane. The clear filtrate was charged into a clean flask and cooled to about 20°C; then 700ml of ethyl acetate was added slowly at about 20°C. The product was precipitated and the slurry mass was stirred for about 2h at about the same temperature. The precipitated solid was filtered out and washed with 50ml of ethyl acetate under nitrogen atmosphere. The solid was dried under vacuum at about 50°C to about 55°C for about l Oh.

Yield: 45g.

Purity by HPLC: 99.95%. Impurity X: 0.05%.

Peak Table

EXAMPLE 4

[0125] Preparation of cis-(±)-2-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)methyl]-N,N-diethyl- 1 -phenylcyclopropanecarboxamide, compound of Formula III

Under nitrogen atmosphere, 115g of aluminum chloride was added into 1900ml of toluene and the slurry mass was cooled to about 15°C to about 20°C. lOOg of cis-(±)-l- phenyl-3-oxabicyclo[3.1.0]hexan-2-one, compound of formula VI was added at about 15°C to about 20°C followed by 100ml of toluene and the reaction mixture was stirred for about 30min at about 15°C to about 25°C. Then diethyl amine solution (125.8g of diethyl amine in 200ml of toluene) was added to the reaction mixture at about 15°C to about 25°C over a period of about 45-60min and the reaction mixture was stirred for about 60min at about room temperature. Then 1000ml of dilute hydrochloric acid (127g concentrated hydrochloric acid in 1000ml of water) was added to the reaction mixture at about 10°C to about 25°C over a period of about 45-60min and stirred for about 30min at about room temperature. The organic layer was separated and the aqueous layer was extracted with 500ml of toluene. The combination of the organic layers was washed twice with each 500ml of water followed by washing with 500ml of 20% aqueous sodium chloride solution, then the organic layer was dried over 50g of sodium sulphate. The organic layer was taken into a round bottom flask and was cooled to about -10°C and 95.75g of thionyl chloride was slowly added at about -10°C to about 0°C over a period of about 50-60min and the reaction mixture was stirred for about 15min at about -10°C to about 0°C. 425g of potassium phthalimide was added at about -10°C to about 0°C over a period of 5-10min followed by 200ml of toluene. The temperature was raised to about room temperature and the reaction mass was stirred at same temperature for about 2h. Then 2.5 liters of water was added to the reaction mixture and stirred for about 15min at about room temperature. The reaction mass was filtered through Hyflo bed and the residue was washed thrice with each 300ml of toluene. The aqueous and organic layers were separated and the organic layer was washed 4 times with each 700ml each of water and the organic layer was distilled out completely under vacuum at about 50°C to about 55°C. 200ml of isopropanol was added to the residue mass at about 50°C to about 55°C and stirred for about 30min. Then isopropanol was distilled out completely under vacuum. The solid residue was degassed at about 50°C to about 55°C for about 60min. The residue was cooled to about 25°C to about 35°C and 400ml of acetone was added to it. The reaction mass was stirred for about 10-15min at about 25°C to about 35°C and then the temperature was raised to about 55°C to about 60°C to get a clear solution. 900ml of water was added to the reaction mass over a period of about 30-35min at about 55°C to about 60°C and further stirred for about 15-20min at the same temperature. The reaction mass was cooled to about room temperature and stirred for about 2h. The precipitated product was filtered and washed with 500ml of water. The compound was dried at about 55°C to about 60 for about 8h to yield 120g of the title compound.

EXAMPLE 5

[0126] Preparation of milnacipran hydrochloride

In a round bottom flask, 480ml of 40% aqueous methylamine solution was charged and lOOg of compound of formula III, prepared as in Example 4, was added at about room temperature. Then the temperature was raised to about 40°C to about 45°C and stirred for about 2h. The reaction mixture was cooled to about room temperature and 700ml of toluene was added and stirred for about 10-15min. The layers were separated and the aqueous layer was extracted twice with each 200ml of toluene. The organic layers were combined and washed with 200ml of water followed by washing with 100ml of 20% aqueous sodium chloride solution. The organic layer was distilled out under reduced pressure at about 50°C to about 55°C, until substantially all of the solvent was distilled out. The residue was degassed for 30min at about 50°C to about 55°C. The crude was cooled to about room temperature and 350ml of ethyl acetate was added and the contents were stirred for about 15min to obtain clear solution. lOg of activated carbon and 100ml of isopropanol was added to the clear solution and stirred at about room temperature for 30min. The solution was filtered through Hyflo bed and the Hyflo bed was washed with 100ml of ethyl acetate. The solution was cooled to about 20-25°C and 10-12% w/w hydrogen chloride solution in ethylacetate was added at about 20-25 °C over a period of about 30-45min and the contents were stirred for about 2h at about 20-25°C. The precipitated product was filtered under nitrogen atmosphere and washed with 300ml of ethyl acetate. The product was dried at about 50-55°C under vacuum for about 4h to yield 40g of milnacipran hydrochloride.

Purity by HPLC : 99.93%

EXAMPLE 6

[0127] Purification of milnacipran hydrochloride

In a round bottom flask, lOOg of milnacipran hydrochloride, prepared as in Example 5, was added into 250ml of isopropanol at about room temperature. The temperature was raised to about 80-85°C to get a clear solution for about 30min. The solution was filtered hot through celite and 50ml of hot isopropanol was further added. The filtrate was heated to about 80-85°C to get a clear solution. Then 1000ml of ethyl acetate was drop- wise added in about 25-30min at about 80-85°C and the reaction mass was stirred at the same temperature for about 10-20min. The reaction mass was then cooled to about room temperature and further to about 0-5 °C over a period of 60-90min under stirring. The solid obtained was filtered, washed with 100ml of ethyl acetate and dried at about 50- 55°C.

Yield: 85g.

Purity by HPLC: 100% Impurity X: below detection limit EXAMPLE 7

[0128] Preparation of cis-(±)-l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one (lactone of formula VI)

To a cooled solution of 6.8g of sodium hydride (60%) in 30ml of toluene was added drop wise a solution of lOg of phenyl acetonitrile in 30ml of toluene at about 10°C to about 20°C. The reaction mass was stirred at the same temperature for 2h and then a solution of 7.9g of epichlorohydrin in 30ml of toluene was drop wise added at about 10°C to about 20°C. After completion of reaction, as monitored by thin layer chromatography (TLC), 10ml of methanol and 30ml of water were added to the reaction mass. The two layers were separated and the organic layer was treated with 24% aqueous solution of 160g of potassium hydroxide and 0.3g of tetrabutyl ammonium bromide and heated to reflux. The two layers were separated and the organic layer was treated with 58.6g of 35% hydrochloric acid in 50ml of toluene and stirred for 2h at about 60°C to about 70°C. After the organic phase was separated by phase separation, the organic phase was further washed twice with 8% aqueous sodium hydrogen carbonate and twice with water and then the organic layer obtained was concentrated under reduced pressure to obtain 4.4g of title compound in the form of light yellow oily substance. The obtained oily substance was cooled to transform to crystals. The solid obtained was further stirred in hexane to get free solid.

Claims

CLAIMS:

1. A one-pot process for the preparation of cis-(±)-2-[(l ,3-dioxo- l ,3-dihydro-2H- isoindol-2-yl)methyl]-N,N-diethyl-l-phenylcyclopropanecarboxamide, a compound of formula III:

comprising:

a) reacting cis-(±)- l -phenyl-3-oxabicyclo[3.1.0]hexan-2-one, a compound of formula VI

with diethylamine in the presence of a Lewis acid and an organic solvent to form cis-(±)- 1 -phenyl- 1 -diethylaminocarbonyl-2 -hydroxymethylcyclopropane, a compound of formula V,

b) reacting cis-(±)- l -phenyl- 1 -diethylaminocarbonyl-2- hydroxymethylcyclopropane, the compound of formula V with a chlorinating agent to form cis-(±)-l -phenyl- l -diethylaminocarbonyl-2-chloromethylcyclopropane, a compound of formula IV and

c) reacting cis-(±)-l -phenyl- 1-diethy laminocarbonyl-2- chloromethylcyclopropane, the compound of formula IV with a phthalimide salt at a temperature range between about 20°C to about 60°C to form the compound of formula III.

2. The process as claimed in claim 1, wherein the Lewis acid is selected from the group consisting of aluminium chloride, aluminium bromide, boron trifluoride, boron trichloride, titanium tetrachloride, zinc chloride, ferric chloride, ferric bromide, stannic chloride.

3. The process as claimed in claim 1, wherein the organic solvent is selected from the group consisting of dichloromethane, chloroform, toluene, dimethylformamide, dimethylsulfoxide.

4. The process as claimed in claim 1, wherein the chlorinating agent is thionyl chloride.

5. The process as claimed in claim 1, wherein the phthalimide salt is selected from the group consisting of potassium phthalimide, sodium phthalimide, lithium phthalimide.

6. A process for the preparation of cis-(±)-2-[(l,3-dioxo-l ,3-dihydro-2H-isoindol-2- yl)methyl]-N,N-diethyl-l -phenyl cyclopropanecarboxamide, a compound of formula III

comprising, reacting cis-(±)-l -phenyl- 1 -diethylaminocarbonyl-2- chloromethylcyclopropane, a compound of formula IV

JY

7. The process as claimed in 6, wherein the organic solvent is selected from the group consisting of aprotic solvents such as dichloromethane, chloroform, toluene, dimethylformamide, dimethylsulfoxide.

8. Crystalline Form A of cis-(±)-2-[(l ,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)methyl]-N,N-diethyl- 1 -phenylcyclopropanecarboxamide, a compound of formula III

III

wherein the Form A has an X-ray diffraction pattern, which is substantially in accordance with Figure 1.

9. The use of crystalline Form A of cis-(±)-2-[(l,3-dioxo-l ,3-dihydro-2H-isoindol- 2-yl)methyl]-N,N-diethyl-l - henylcyclopropanecarboxamide, a compound of formula III

in the preparation of milnacipran or its pharmaceutically acceptable salts.

9. Cis-(±)-2-[(l ,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)methyl]-N,N-diethyl-l - phenylcyclopropanecarboxamide having purity of greater than 99.0%, as measured by high performance liquid chromatography.

1 1. Cis-(±)-2-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)methyl]-N,N-diethyl-l- phenylcyclopropanecarboxamide having purity of greater than 99.5%», as measured by high performance liquid chromatography.

12. A process for the preparation of milnacipran or its pharmaceutically acceptable salts comprising,

a) preparing cis-(±)-2-[(l ,3-dioxo-l ,3-dihydro-2H-isoindol-2-yl)methyl]-N,N- diethyl-1 -phenylcyclopropanecarboxamide by the process as claimed in any one of the claims 1 to 7, b) converting the cis-(±)-2-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)methyl]- N,N-diethyl-l-phenylcyclopropanecarboxamide into milnacipran by reacting it with monomethylamine,

13. Milnacipran hydrochloride having less than about 0.1% of impurity X, as measured by high performance liquid chromatography.

14. Milnacipran hydrochloride of claim 13 having less than about 0.05% of impurity X, as measured by high performance liquid chromatography.

15. Milnacipran hydrochloride having a total purity of at least about 98% containing impurity X less than about 0.1%, as measured by high performance liquid chromatography.

16. Milnacipran hydrochloride of claim 15 having a total purity of at least about 99% containing impurity X less than about 0.1%, as measured by high performance liquid chromatography.

17. Milnacipran hydrochloride having a total purity of at least about 99.8% containing impurity X less than about 0.1%, as measured by high performance liquid chromatography.