Field of invention:

The present invention relates to an improved process for the preparation of Z-2- aminomethyl-1-phenyl-N,N-diethyl cyclopropane carboxamide (commonly known as Milnacipran) and its pharmaceutically acceptable salts. Milnacipran is chemically known as Z-2-aminomethyl-l-phenyl-N,N-diethyl cyclopropane carboxamide and is represented by following structural formula-1

Milnacipran (Ixel, Savella, Dalcipran, Toledomin) is a serotonin-nonepinephrine reuptake inhibitor (SNRI) used in the clinical treatment of major depressive disorder and fibromyalgia.

Background of the invention:

Milnacipran, its hydrochloride salt and process for its preparation was first disclosed in US 4478836.

2-oxo-l-phenyl-3-oxabicyclo [3.1.0] hexane is an important intermediate in the preparation of milnacipran. Process for its preparation and its conversion to milacipran has been disclosed in Journal of Medicinal Chemistry 1995, 38, (15), 2964-2966, Journal of Organic Chemistry 1996, 61(3), 915-923 and Synthesis 1978, 304-305. The disclosed processes for the said intermediate involves the reaction of 2-phenylacetonitrile with 2-(chloromethyl)oxirane in the presence of sodium amide in benzene and hydrolyzed the resulting compound provides 2-oxo-l-phenyl-3-oxabicyclo[3.1.0]hexane. The said process involves the usage of sodium amide as a base which is aerial oxidized and generates explosive substances, difficult to handle and not suitable on large scale synthesis.

US 2008/0064885 A1 also disclosed a process for the preparation of 2-oxo-l-phenyl-3- oxabicyclo[3.1.0]hexane. The said process comprises of reacting 2-phenylacetonitrile with 2-(chloromethyl)oxirane in the presence of sodium hydride in a mixture of toluene and N,N- dimethylimidazolidinone, followed by hydrolysis provides 2-oxo-l-phenyl-3- oxabicyclo[3.1.0]hexane. The said process involves the usage of sodium hydride which is pyrophoric in nature, difficult to handle and not suitable for commercial purposes.

In general, the reported processes for the preparation of 2-oxo-l-phenyl-3- oxabicyclo[3.1.0]hexane involves the usage of bases like sodium amide or sodium hydride for the condensation of 2-phenylacetonitrile with 2-(chloromethyl)oxirane. The usage of sodium amide or sodium hydride bases are difficult to handle and not recommendable in a commercial scale.

Hence there is a need in the art for the preparation of 2-oxo-l-phenyl-3- oxabicyclo[3.1.0]hexane, a key intermediate in the synthesis milnacipran by utilizing the simple bases that avoids the problems of prior art.

Advantages of the Present Invention:

• Provides an improved process for the preparation of 2-oxo-l-phenyl-3-oxabicyclo[3.1.0] hexane using simple bases like alkali metal hydroxides.

• Avoid the usage of sodium amide or sodium hydride, which are pyrophoric in nature, not suitable for commercial scale up.

• Provides an improved process for the preparation of milnacipran hydrochloride.

• Eco-friendly and economic process

Brief description of the invention:

The first aspect of the present invention is to provide an improved process for the preparation of 2-oxo-l-phenyl-3-oxabicyclo[3.1.0]hexane, compound of formula-4 which comprises of reacting 2-phenylacetonitrile, compound of formula-2 with 2-(chloromethyl) oxirane, compound of formula-3 in the presence of a suitable base in a suitable solvent, followed by hydrolyzing the obtained compound then treating it with suitable acid to provide compound of formula-4.

The second aspect of the present invention provides an improved process for the preparation of milnacipran hydrochloride salt, compound of formula-la, which comprises of following steps;

a) Reacting 2-phenylacetonitrile, compound of formula-2 with 2-(chloromethyl)oxirane, compound of formula-3 in the presence of a suitable base in a suitable solvent followed by hydrolyzing the obtained compound then treating it with an acid to provide l-phenyl-3- oxabicyclo[3.1.0]hexan-2-one, compound of formula-4,

b) condensing the compound of formula-4 with alkali metal salt of phthalimide in a suitable solvent to provide 2-((l,3-dioxoisoindolin-2-yl)methyl)-l-phenylcyclopropanecarboxylic acid, compound of formula-5,

c) reacting the compound of formula-5 with thionyl chloride, followed by treating the obtained acid chloride compound with diethylamine in a suitable solvent to provide 2-((l,3- dioxoisoindolin-2-yl)methyl)-N,N-diethyl-l -phenylcyclopropanecarboxamide, compound of formula-6,

d) reacting the compound of formula-6 with 40% aqueous primary alkyl amine in a suitable solvent to provide milnacipran compound of formula-1,

e) reacting the milnacipran,compound of formula-1 with hydrogen chloride in a suitable solvent to provide milnacipran hydrochloride compound of formula-la.

Brief Description of the drawings:
Figure-1: Illustrates the PXRD of crystalline milnacipran hydrochloride obtained as per the process disclosed in EP 200638

Figure-2: Illustrates the Infra-red spectrum of crystalline milnacipran hydrochloride obtained as per the process disclosed in EP 200638

Figure-3: Illustrates the DSC of crystalline milnacipran hydrochloride obtained as per the process disclosed in EP 200638

Detailed description of the Invention:

The suitable solvents, wherever necessary, used in the present invention are selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like
tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, pet.ether; "hydrocarbon solvents" like toluene, xylene, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethylacetamide, dimethylformamide, dimethyl sulfoxide, acetonitrile; "ketone solvents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; and "alcoholic solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol, and isobutaol; "chloro solvents" like dichloromethane, chloroform and ethylene chloride; polar solvents like water; and also mixtures there of.
As used herein the present invention the term "alkali metal hydroxides" refers to sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates" refers to sodium carbonate, potassium carbonate, cesium carbonate and the like; "alkali metal carbonates/bicarbonates" refers to sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like; "alkali metal alkoxides" refers to sodium methoxide, sodium tertiary butoxide, potassium tertiary butoxide and the like.
The first aspect of the present invention provides an improved process for the preparation of 2-oxo-l-phenyl-3-oxabicyclo[3.1.0]hexane, compound of formula-4

which comprises of reacting 2-phenylacetonitrile, compound of formula-2 with 2-(chloromethyl)oxirane, compound of formula-3

in the presence of a suitable base in a suitable solvent followed by hydrolyzing the obtained compound with a suitable base in presence or absence of a phase transfer catalyst, then treating it with a suitable acid to provide compound of formula-4, characterized in that the suitable base used for condensation of formula-2 and formula-3 is selected from alkali metal hydroxides, alkali metal carbonates/bicarbonates, alkalimetal alkoxides, LiHMDS or NaHMDS.
The suitable solvent used is selected from polar aprotic solvent like dimethylacetamide, dimethylformamide, dimethyl sulfoxide, acetonitrile; hydrocarbon solvents like toluene, xylene, hexane, heptane and cyclohexane or mixtures thereof. The suitable phase transfer catalyst selected from quaternary ammonium salt and phosphonium salt like benzyltrimethylammonium chloride, hexadecyltributylphosphonium bromide, tetra-n-butylammonium bromide, methyl trioctylammonium chloride and tetra-n-butylammonium iodide, preferably tetra-n- butylammonium bromide. The suitable acid used is selected from hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, preferably hydrochloric acid. The usage of milder bases here will reduce the cost and avoid explosions and easy to carry out in large scale.
In a preferred embodiment, the process for the preparation of 2-oxo-l-phenyl-3- oxabicyclo[3.1.0]hexane compound of formula-4 comprises of reacting the 2-phenylacetonitrile, compound of formula-2 with 2-(chloromethyl)oxirane, compound of formula-3 in the presence of sodium hydroxide in dimethylsulfoxide and extracting the obtained compound into toluene and treating with potassium hydroxide and tetrabutylammonium bromide at reflux temperature and then treating the obtained product with hydrochloric acid to provide compound of formula-4.
The second aspect of the present invention provides an improved process for the preparation of milnacipran hydrochloride compound of formula-la, which comprises of following steps;
a) Reacting 2-phenylacetonitrile, compound of formula-2



with 2-(chloromethyl)oxirane, compound of formula-3
in the presence of a suitable base in a suitable solvent followed by hydrolyzing the obtained compound with a suitable base in presence or absence of a phase transfer catalyst, then treating it with a suitable acid to provide compound of formula-4, characterized in that the suitable base used for condensation of formula-2 and formula-3 is selected from alkali metal hydroxides, alkali metal carbonates, alkalimetal alkoxides, LiHMDS or NaHMDS.
b) condensing the compound of formula-4 with alkali metal salt of phthalimide, specifically potassium salt in a suitable solvent selected from polar aprotic solvents or N-methyl pyrrolidine to provide 2-((l,3-dioxoisoindolin-2-yl)methyl)-l-phenylcyclopropane carboxylic acid, compound of formula-5,
c) reacting the compound of formula-5 with thionyl chloride, followed by treating the obtained
acid chloride compound with diethylamine in a suitable solvent selected from hydrocarbon solvents or chloro solvents, to provide 2-((l,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl-l- phenylcyclopropane carboxamide, compound of formula-6,

d) reacting the compound of formula-6 with 40% aqueous primary alkyl amine such as ethylamine, methyl amine, propyl amine in a suitable hydrocarbon solvent to provide milnacipran compound of formula-1,

e) reacting the milnacipran compound of formula-1 with ethylacetate-hydrogen chloride in a suitable solvent to provide milnacipran hydrochloride compound of formula-1 a.

In a preferred embodiment, the process for the preparation of milnacipran hydrochloride
compound of formula-la comprises of following steps;

a) Reacting the 2-phenylacetonitrile, compound of formula-2 with 2-(chloromethyl)oxirane, compound of formula-3 in the presence of sodium hydroxide in dimethylsulfoxide and extracting the obtained compound into toluene and treating with potassium hydroxide and tetrabutylammonium bromide at reflux temperature and then treating the obtained product with hydrochloric acid to provide compound of formula-4,

b) condensing the compound of formula-4 with potassium phthalimide in dimethylformamide to provide 2-((l,3-dioxoisoindolin-2-yl)methyl)-l-phenylcyclopropane carboxylic acid, compound of formula-5,

c) reacting the compound of formula-5 with thionyl chloride, followed by treating the obtained acid chloride compound with diethylamine in methylene chloride and isolating the obtained compound from suitable hydrocarbon solvent like cyclohexane to provide 2-((l,3- dioxoisoindolin-2-yl)methyl)-N,N-diethyl-1 -phenylcyclopropanecarboxamide, compound of formula-6,

d) reacting the compound of formula-6 with 40% aqueous methyl amine in toluene provides milnacipran compound of formula-1, e) reacting the milnacipran compound of formula-1 with ethylacetate-hydrogen chloride in mixutre of isoproyl alcohol and ethyl acetate provides milnacipran hydrochloride compound of formula-la.

Crystalline milnacipran hydrochloride with a melting point of 178-180°C was disclosed in EP 200638, but the PXRD, IR and DSC were not reported. When milnacipran hydrochloride prepared as per the process disclosed in EP 200638, it provided the crystalline solid with PXRD, IR and DSC which have been represented in figure-1, figure-2 and figure-3 respectively. The PXRD, IR and DSC of milacipran hydrochloride prepared as per the present invention is similar to the above disclosed one (i.e., figure-1, figure-2 and figure-3 respectively).

Milnacipran hydrochloride prepared as per the present invention is having the mean particle size in the range of 35 to 130 microns and can be further micronized or milled to get the desired particle size. The particle size of milnacipran hydrochloride is analyzed using Malvern Mastersizer 2000.

XRD analysis of milnacipran hydrochloride was carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min. FI-IR spectrum of milnacipran hydrochloride was recorded on Thermo model Nicolet-380 as KBr pellet. The thermal analysis of milnacipran hydrochloride was carried out on Waters DSC Q-10 model differential scanning calorimeter. The present invention is schematically represented as follows:
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:

Example-1: Preparation of 2-oxo-l-phenyl-3-oxabicyclo[3.1.0|hexane (Formula-4):
Sodium hydroxide (13.6 g) was added to a mixture of 2-phenylacetonitrile (20 g) and 2-(chloromethyl)oxirane (17.3 g) in dimethyl sulfoxide (100 ml) at 20-30°C and stirred for 3 hours at 25-30°C. After the reaction was completed, toluene (100 ml) and water (200 ml) was added to the reaction mass at 0-5°C and stirred for 15 minutes. Both the organic and aqueous layers were separated, the aqueous layer was extracted with toluene. Combined both the organic layers and potassium hydroxide (38.2 g) followed by tetrabutylammonium bromide (1.1 g) were added and stirred for 24 hours at 90-100°C. After the reaction was completed, the reaction mass was cooled to 20-30°C and the both the organic and aqueous layers were separated. Toluene was added to the aqueous layer and acidified with hydrochloric acid and stirred for 12 hours at 70- 75°C. After completion of the reaction, the reaction mass was cooled to 20-30°C. Both the organic and aqueous layers were separated; the aqueous layer was extracted with toluene. Combined both the organic layers, washed with sodium bicarbonate solution and distilled off the solvent under reduced pressure to get the title compound. Yield: 17 grams
Example-2: Preparation of 2-((l,3-dioxoisoindolin-2-yl)methyl)-l-phenylcyclopropane carboxylic acid (Formula-5):

A mixture of 2-oxo-l-phenyl-3-oxabicyclo[3.1.0]hexane compound of formula-4 (12 g) obtained from example-1 and potassium phthalimide (19 g) in dimethyl formamide (60 ml) was heated to 130-135°C and stirred upto completion of the reaction. After the reaction was completed, water (170 ml) was added to the above reaction mass at 20-30°C and stirred for 30 minutes. The reaction mass was filtered and acidified the filtrate with acetic acid at 40-45°C. The reaction mass was cooled to 0-5°C and stirred for 45 minutes. Filtered the obtained solid, washed with water and dried at 50-55°C to get the title compound. Yield: 10.5 grams

Example-3: 2-((13-dioxoisoindolin-2-yl)methyl)-N,N-diethyl-l-phenylcyclopropane carbox amide (Formula-6):

A mixture of 2-((l,3-dioxoisoindolin-2-yl)methyl)-l-phenylcyclopropane carboxylic acid compound of formula-5 (10 g) obtained from example-2 and thionyl chloride (30 g) was heated to 75-80°C and stirred for 6 hours. After the reaction was completed, excess thionyl chloride was distilled off under reduced pressure to get the corresponding acid chloride. The obtained acid chloride in dichloromethane (20 ml) was added to a solution of diethylamine (4.5 g) in dichloromethane (20 ml) at 0-5°C and stirred for 45 minutes at 0-5°C followed by 4 hours at 20- 30°C. After the reaction was completed, water (100 ml) was added to the reaction mass and stirred for 20 minutes. Both the organic and aqueous layers were separated; the aqueous layer was extracted with dichloromethane. Both the organic layers were combined and distilled off the solvent under reduced pressure. Cyclohexane (50 ml) was added to the obtained residue and stirred for 1 hour 30 minutes at 20-25°C. Filtered the obtained solid, washed with cyclohexane and dried to get title compound. Yield: 9.5 grams

Example-4: Preparation of milnacipran free base (Formula-1)
40% methyl amine solution (prepared by mixing methyl amine (210 g) with water (190 ml)) was added to 2-((l,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl-l-phenylcyclopropane carbox amide compound of formula-6 (100 g) obtained from example-3 in toluene (450 ml) at 20-30°C and stirred for 24 hours. After completion of the reaction both the organic and aqueous layers were separated; the aqueous layer was extracted with toluene. Both the organic layers were combined and washed with water.
Carbon (8 g) was added to the organic layer, heated to 50-55°C and stirred for 45 minutes. Filtered the reaction mass and washed with toluene. Distilled off the solvent from filtrate under reduced pressure to get the title compound. Yield: 65 grams
Example-5: Preparation of milnacipran hydrochloride (Formula-la):
Ethyl acetate-hydrochloride (90 g) was added to a mixture of milnacipran (65 g) obtained from example-4 in ethyl acetate (330 ml) and isopropyl alcohol (50 ml) at 20-25°C and stirred for 1 hour at 20-25°C. The reaction mass was cooled to 0-5°C and stirred for 40 minutes. Filtered the solid, washed with cooled ethyl acetate and dried at 50-55°C to get the title compound. Yield: 55 grams Purity by HPLC: 99.78%
Particle Size Distribution: D(0,l):5.09 μm; D(0,5): 41.20 μm ; D[0,9]: 134.16 μm; D [4.3] : 59.06 μm

We Claim:

1. An improved process for the preparation of 2-oxo-1-phenyl-3-oxabicyclo[3.1.0]hexane, compound of formula-4

which comprises of reacting 2-phenylacetonitrile, compound of formula-2 with 2-(chloromethyl)oxirane, compound of formula-3

in the presence of a suitable base in a suitable solvent followed by hydrolyzing the obtained compound with a suitable base in presence or absence of a phase transfer catalyst, then treating it with a suitable acid to provide compound of formula-4, characterized in that the suitable base used for condensation of formula-2 and formula-3 is selected from alkali metal hydroxides, alkali metal carbonates/bicarbonates, alkalimetal alkoxides, LiHMDS or NaHMDS.

2. The process according to claim 1, where in the suitable base is selected from "alkali metal hydroxides" refers to sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates" refers to sodium carbonate, potassium carbonate, cesium carbonate and the like; "alkali metal carbonates/bicarbonates" refers to sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like; "alkali metal alkoxides" refers to sodium methoxide, sodium tertiary butoxide and potassium tertiary butoxide and the like.

3. The process according to claim 1, the hydrolysis reaction is carried out in the presence of phase transfer catalyst.

4. The process according to claim 1, where in the solvent used is selected from polar aprotic solvent like dimethylacetamide, dimethylformamide, dimethyl sulfoxide, acetonitrile; hydrocarbon solvents like toluene, xylene, hexane, heptane and cyclohexane or mixtures thereof and n-methyl pyrrolidine.

5. The process according to claim 2, wherein the base is alkali metal hydroxide.

6. An improved process for the preparation of 2-oxo-1-phenyl-3-oxabicyclo[3.1.0]hexane compound of formula-4 comprises of reacting the 2-phenylacetonitrile, compound of formula-2 with 2-(chloromethyl)oxirane, compound of formula-3 in the presence of sodium hydroxide in dimethylsulfoxide and extracting the obtained compound into toluene and treating with potassium hydroxide and tetrabutylammonium bromide at reflux temperature and then treating the obtained product with hydrochloric acid to provide compound of formula-4.

7. A process for the preparation of milnacipran compound of formula-1, which comprises of preparing the compound of formula-4 as per the process claimed in claim 1 or claim 6 and converting it into milnacipran compound of formula-1.

8. Use of alkali metal hydroxides, alkalimetal carbonates/bicarbonates, alkali metal alkoxides for the condensation of 2-phenylacetonitrile compound of formula-2 with 2- (chloromethyl)oxirane compound of formula-3.

9. An improved process for the preparation of milnacipran hydrochloride compound of formula-la, which comprises of following steps;

a) Reacting 2-phenylacetonitrile, compound of formula-2

with 2-(chloromethyl)oxirane, compound of formula-3

in the presence of a suitable base in a suitable solvent followed by hydrolyzing the obtained compound with a suitable base in presence or absence of a phase transfer catalyst, then treating it with a suitable acid to provide compound of formula-4, characterized in that the suitable base used for condensation of formula-2 and formula-3 is selected from alkali metal hydroxides, alkali metal carbonates/bicarbonates, alkalimetal alkoxides, LiHMDS or NaHMDS,

b) condensing the compound of formula-4 with alkali metal salt of phthalimide, specifically potassium salt in a suitable solvent selected from polar aprotic solvents or N- methyl pyrrolidine to provide 2-((1,3-dioxoisoindolin-2-yl)methyl)-1- phenylcyclopropane carboxylic acid, compound of formula-5,

c) reacting the compound of formula-5 with thionyl chloride, followed by treating the obtained acid chloride compound with diethylamine in a suitable solvent selected from hydrocarbon solvents or chloro solvents, to provide 2-((1,3-dioxoisoindolin-2- yl)methyl)-N,N-diethyl-1- phenylcyclopropane carboxamide, compound of formula-6,

d) reacting the compound of formula-6 with 40% aqueous primary alkyl amine such as ethylamine, methyl amine, propyl amine in a suitable hydrocarbon solvent to provide milnacipran compound of formula-1,

e) reacting the milnacipran compound of formula-1 with ethylacetate-hydrogen chloride in a suitable solvent to provide milnacipran hydrochloride compound of formula-la.

10. An improved process for the preparation of milnacipran hydrochloride compound of formula-la, comprises of following steps;

a) Reacting the 2-phenylacetonitrile, compound of formula-2 with 2-(chloromethyl)oxirane, compound of formula-3 in the presence of sodium hydroxide in dimethylsulfoxide and extracting the obtained compound into toluene and treating with potassium hydroxide and tetrabutylammonium bromide at reflux temperature and then treating the obtained product with hydrochloric acid to provide compound of formula-4,

b) condensing the compound of formula-4 with potassium phthalimide in dimethylformamide to provide 2-((1,3-dioxoisoindolin-2-yl)methyl)-1- phenylcyclopropane carboxylic acid, compound of formula-5,

c) reacting the compound of formula-5 with thionyl chloride, followed by treating the obtained acid chloride compound with diethylamine in methylene chloride and isolating the obtained compound from suitable hydrocarbon solvent like cyclohexane to provide 2-(( 1,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl-1 -phenylcyclopropanecarboxamide, compound of formula-6,

d) reacting the compound of formula-6 with 40% aqueous methyl amine in toluene provides milnacipran compound of formula-1,

e) reacting the milnacipran compound of formula-1 with ethylacetate-hydrogen chloride in mixutre of isoproyl alcohol and ethyl acetate provides milnacipran hydrochloride compound of formula-la.