Process for the preparation of (±H1R(S), 2S(R)l-2-(aminomethyl)-N,N- diethyl-l-phenylcyclopropane carboxamide Hydrochloride

Related Application:

This application claims the benefit of priority of our Indian patent application numbers 2958/CHE/2010 filed on 06 ^th October 2010 & 2744/CHE/2011 filed on 10 ^th August 2011 which are incorporated herein by reference.

Field of the Invention:

The present invention relates to an improved process for the preparation of (±)- [1R(S), 2S(R)]-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide, which is represented by the structural formula- 1, and its pharmaceutically acceptable acid addition salts.

Formula- 1

(±)-[lR(S),2S(R)]-2-(aminomethyl)-N,N-diethyl-l-phenylcyclo propane carboxamide hydrochloride or (Z)-2-aminomethyl-l -phenyl -N,N-diethylcyclopropane carboxamide hydrochloride (Ixel, Savella, Dalcipran, Toledomin) is a serotonin- norepinephrine reuptake inhibitor (SNRI) used in the clinical treatment of major depressive disorder and fibromyalgia.

Background of the Invention:

(Z)-2-aminomethyl- 1 -phenyl -Ν,Ν-diethylcyclopropane carboxamide, its hydrochloride salt and process for its preparation was first disclosed in US 4478836.

(Z)-2-oxo-l-phenyl-3-oxabicyclo[3.1.0] hexane is an important intermediate in the preparation of (Z)-2-aminomethyl-l -phenyl -Ν,Ν-diethylcyclopropane carboxamide. Process for the preparation of said intermediate and its conversion to (Z)-2-aminomethyl- l-phenyl-N,N-diethylcyclopropane carboxamide 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(epichlorohydrin) in the presence of sodium amide in benzene and hydrolysis of the resulting compound provides (Z)-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, hence it is difficult to handle and not suitable on large scale synthesis.

US 2008/0064885 Al also disclosed a process for the preparation of (Z)-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 Ν,Ν'-dimethylimidazolidinone, followed by hydrolysis provides (Z)-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 prior reported processes for the preparation of (Z)-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. WO 2010/086394 Al patent disclosed a process for the preparation of (1S,2R) isomer of (Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide hydrochloride salt starting from the reaction of 2-phenyl acetonitrile with (R)- epichlorohydrin in presence of bases like sodium hydride and sodium amide. Hence there is a need in the art for the preparation of (Z)-2-oxo-l-phenyl-3- oxabicyclo[3.1.0] hexane, a key intermediate in the synthesis (Z)-2-aminomethyl-l- phenyl-N,N-diethylcyclopropane carboxamide 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 (Z)-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 a simple and safe process for the preparation of (Z)-2-aminomethyl-l- phenyl-N,N-diethylcyclopropane carboxamide hydrochloride by using mild bases like sodium hydroxide.

• 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 (Z)-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 is to provide an improved process for the preparation of (Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide 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 and then treating it with an acid to provide (Z)-2-oxo- 1 -phenyl-3-oxabicyclo[3.1.0] hexane 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-phenylcyclo propanecarboxylic 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 (Z)- 1 -phenyl- 1 -diethylaminocarbonyl-2-phthalimidomethylcyclo propane compound of formula-6,

d) reacting the compound of formula-6 with 40% aqueous primary alkyl amine in a suitable solvent to provide (Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide compound of formula- 1,

e) reacting the (Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide compound of formula- 1 with hydrogen chloride in a suitable solvent to provide (Z)-2- aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide hydrochloride compound of formula- la.

The third aspect of the present invention is to provide a one-pot process for the preparation of (Z)-2-aminomethyl-l-phenyl-N,N-diethyl cyclopropane carboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la comprising of the following steps,

a) Reacting the 2-phenyl acetonitrile compound of formula-2 with epichlorohydrin ^* compound of formula-3 in presence of a suitable alkali metal base in a suitable solvent followed by base hydrolysis of the resulting cyano compound, and then treating with a suitable acid in a suitable solvent to provide (Z)-2-oxo-l-phenyl-3- oxabicyclo[3.1.0] hexane compound of formula-4,

b) reacting the compound of formula-4 in-situ with diethylamine in presence of a suitable Lewis acid in a suitable solvent to provide (Z)- 1 -phenyl- 1- diethylaminocarbonyl-2-hydroxymethyl cyclopropane compound of formula-7, c) chlorinating the compound of formula-7 in-situ with a suitable chlorinating agent in a suitable solvent to provide (Z)-l -phenyl- l-diethylaminocarbonyl-2-chloromethyl cyclopropane compound of formula-8,

d) reacting the compound of formula-8 in-situ with potassium phthalimide in a suitable solvent to provide (Z)-l -phenyl- 1-diethylaminocarbonyl -2 -phthalimidomethyl cyclopropane compound of formula-6,

e) treating the compound of formula-6 in-situ with a suitable base in a suitable solvent to provide (Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide compound of formula- 1,

f) converting the compound of formula- 1 to its hydrochloride salt compound of formula- la by treating it in-situ with a suitable hydrochloride source in a suitable solvent,

g) optionally purifying the hydrochloride salt compound of formula- la from a suitable solvent or mixture of solvents to provide pure compound of formula- la.

The fourth aspect of the present invention is to provide a one-pot process for the preparation of (Z)-2-aminomethyl-l -phenyl -Ν,Ν-diethyl cyclopropane carboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la comprising of the following steps;

a) Reacting the 2-phenyl acetonitrile compound of formula-2 with epichlorohydrin compound of formula-3 in presence of sodium hydroxide in dimethyl sulphoxide followed by hydrolysis of the resulting cyano compound using sodium hydroxide, and then treating with hydrochloric acid in toluene to provide (Z)-2-oxo-l -phenyl-3 - oxabicyclo[3.1.0] hexane compound of formula-4,

b) reacting the compound of formula-4 in-situ with diethylamine in presence of aluminium chloride in toluene to provide (Z)-l -phenyl- 1- diethylaminocarbonyl-2- hydroxymethyl cyclopropane compound of formula-7,

c) chlorinating the compound of formula-7 in-situ with thionyl chloride in toluene to provide (Z)- 1 -phenyl- 1 -diethylaminocarbonyl-2-chloromethyl cyclopropane compound of formula-8,

d) reacting the compound of formula-8 in-situ with potassium phthalimide in toluene to provide (Z)-l -phenyl- l-diethylaminocarbonyl-2-phthalimido methyl cyclopropane compound of formula-6,

e) treating the compound of formula-6 in-situ with methylamine in toluene to provide (Z)-2-aminomethyl-l-phenyl-N,N-diethyl cyclopropane carboxamide compound of formula- 1,

f) converting the compound of formula- 1 to its hydrochloride salt compound of formula- la by treating it in-situ with ethylacetate-HCl in isopropyl alcohol. The fifth aspect of the present invention is to provide a one-pot process for the preparation of (Z)-l -phenyl- l-diethylaminocarbonyl-2-phthalimido methyl cyclopropane compound of formula-6 comprising of;

a) Reacting the 2-phenyl acetonitrile compound of formula-2 with epichlorohydrin compound of formula-3 in presence of a suitable alkali metal base in a suitable solvent followed by base hydrolysis of the resulting cyano compound, and then treating with a suitable acid in a suitable solvent to provide (Z)-2-oxo-l-phenyl-3- oxabicyclo[3.1.0] hexane compound of formula-4,

b) reacting the compound of formula-4 in-situ with diethylamine in presence of a suitable Lewis acid in a suitable solvent to provide (Z)-l -phenyl- 1-diethylamino carbonyl-2-hydroxymethyl cyclopropane compound of formula-7,

c) chlorinating the compound of formula-7 in-situ with a suitable chlorinating agent in a suitable solvent to provide (Z)-l -phenyl- l-diethylaminocarbonyl-2-chloromethyl cyclopropane compound of formula-8,

d) reacting the compound of formula-8 in-situ with potassium phthalimide in a suitable solvent to provide (Z)-l -phenyl- l-diethylaminocarbonyl-2-phthalimi do methyl cyclopropane compound of formula-6.

The sixth aspect of the present invention is to provide a process for the preparation of (Z)-2-aminomethyl-l-phenyl-N,N-diethyl cyclopropane carboxamide hydrochloride salt compound of formula- la comprising of;

a) Treating the (Z)-l -phenyl- l-diethylaminocarbonyl-2-phthalimidomethylcyclopropane compound of formula-6 with a suitable base in a suitable solvent to provide (Z)-2- aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide compound of formula- 1,

b) converting the compound of formula- 1 to its hydrochloride salt compound of formula- la by treating it in-situ with a suitable hydrochloride source in a suitable solvent. Brief description of the Figures:

Figure-1: Illustrates the PXRD of crystalline (Z)-2-aminomethyl-l-phenyl-N,N- diethylcyclopropane carboxamide hydrochloride obtained as per the process disclosed in EP 200638

Figure-2: Illustrates the Infra-red spectrum of crystalline , (Z)-2-aminomethyl- 1-phenyl- Ν,Ν-diethylcyclopropane carboxamide hydrochloride obtained as per the process disclosed in EP 200638

Figure-3: Illustrates the DSC of crystalline (Z)-2-aminomethyl-l -phenyl -N,N- diethylcyclopropane carboxamide hydrochloride obtained as per the process disclosed in EP 200638

Detailed Description of the Invention:

The prior reported processes for the preparation of (Z)-2-oxo-l-phenyl-3- oxabicyclo[3.1.0] hexane involves the usage of bases like sodium amide and sodium hydride for the reaction of 2-phenyl acetonitrile with epichlorohydrin. Such bases are pyrophoric in nature, difficult to handle and hence not recommendable on commercial scale. Whereas, the present inventors overcome the problems of prior-art by utilizing mild bases like sodium hydroxide. Hence the present invention provides a safe and eco- friendly process.

The present inventors carried out the entire process for (Z)-2-aminomethyl-l- phenyl-N,N-diethyl cyclopropane carboxamide hydrochloride, preferably from step-(b) to step-(e) using a single solvent, preferably toluene. Hence the process becomes simple and less-expensive, as there is no need to change the solvent at each stage.

The main advantage with the present invention is that, as the present invention proceeds through one-pot process using single solvent system, it is not necessary to isolate the intermediate products formed in different stages from the reaction mixture. By adopting such a process, the present inventors avoid the yield loss at each stage during intermediate purification steps and there by provides a highly economic process. As used herein the present invention, the term "suitable solvent" refers to the solvent selected from "polar solvents" such as water; "polar aprotic solvents" such as dimethylsulfoxide, dimethylacetamide, dimethyl formamide and the like; "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like; "ether solvents" such as di-tert-butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, pet. ether and dimethoxyethane; "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol and the like; "chloro solvents" such as methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform and the like; "hydrocarbon solvents" such as benzene, toluene, xylene, n-heptane,n-hexane and cyclohexane; "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like; "ester solvents" such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; and their mixtures thereof.

As used herein the present invention the term "suitable base" refers to the bases selected from "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates" such as sodium carbonate, potassium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal alkoxide" such as sodium methoxide, potassium methoxide, sodium tertiary butoxide and potassium tertiary butoxide and the like;

The first aspect of the present invention provides an improved process for the preparation of (Z)-2-oxo-l-phenyl-3-oxabicyclo[3.1.0] hexane compound of formula-4

Formula-4

which comprises of reacting 2-phenylacetonitrile compound of formula-2

Formula-2

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

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, alkali metal alkoxides, LiHMDS and NaHMDS.

The suitable solvent used is selected from polar aprotic solvent like dimethylacetamide, dimethylformamide, dimethyl sulfoxide, acetonitrile; hydrocarbon solvents like toluene, xylene, n-hexane, n-heptane and cyclohexane or mixtures thereof. The suitable phase transfer catalyst is selected from quaternary ammonium salt and phosphonium salt like benzyltrimethylammonium chloride, hexadecyltributyl phosphonium bromide, tetra-n-butyl ammonium bromide, methyl trioctylammonium chloride and tetra-n-butyl ammonium iodide, preferably tetra-n-butyl ammonium 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 (Z)-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 (Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide hydrochloride compound of formula- la, which comprises of following steps;

a) Reacting 2-phenylacetonitrile compound of formula-2

Formula-2

with 2-(chloromethyl)oxirane(e 7 c z compound of formula-3

Formula-3

in the presence of a suitable base in a suitable solvent followed by hydrolyzing the obtained compound with a suitable base in the 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 compounds of formula-2 and formula-3 is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxide NaHMDS.

Formula-4

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-phenylcyclo propane carboxylic acid compound of formula-5,

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 (Z)-l-phenyl- l-diethylaminocarbonyl-2-phthalimidomethylcyclo propane compound of formula-6,

Formula-6

d) reacting the compound of formula-6 with 40% aqueous primary alkyl amine such as , methyl amine, ethylamine, propyl amine in a suitable hydrocarbon solvent to provide (Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide compound of formula- 1,

e) reacting the (Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide compound of formula- 1 with ethyl acetate-hydrogen chloride in a suitable solvent to provide (Z)-2-aminomethyl- 1 -phenyl-N,N-diethylcyclopropane carboxamide hydrochloride compound of formula- la.

In a preferred embodiment, the process for the preparation of (Z)-2-aminomethyl- 1 -phenyl -Ν,Ν-diethylcyclopropane carboxamide 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 the 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-phenylcyclo propane 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 a suitable hydrocarbon solvent like cyclohexane to provide (Z)-l -phenyl- l-diethylaminocarbonyl-2-phthalimido methylcyclo propane compound of formula-6,

d) reacting the compound of formula-6 with 40% aqueous methyl amine in toluene provides (Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide compound of formula- 1 ,

e) reacting the (Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide compound of formula- 1 with ethyl acetate-hydrogen chloride in mixture of isopropyl alcohol and ethyl acetate provides (Z)-2-aminomethyl-l -phenyl -N,N-diethyl cyclopropane carboxamide hydrochloride compound of formula- 1 a.

The third aspect of the present invention provides a one-pot process for the preparation of (Z)-2-aminomethyl-l-phenyl-N,N-diethyl cyclopropane carboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la comprising of;

a) Reacting the 2-phenyl acetonitril 2

Formula-2

with epichlorohydrin compound of formula-3

Formula-3

in presence of a suitable alkali metal base in a suitable solvent followed by base hydrolysis of the resulting cyano compound and then treating with a suitable acid in a suitable solvent provides (Z)-2-oxo-l-phenyl-3-oxabicyclo[3.1.0]hexane compound of formula-4,

Formula-4

b) reacting the compound of formula-4 in-situ with diethylamine in a suitable solvent in presence of suitable Lewis acid provides (Z)-l -phenyl- l-diethylaminocarbonyl-2- hydroxymethyl cyclopropane compound of formula-7,

Formula-7

c) chlorinating the compound of formula-7 in-situ with a suitable chlorinating agent in a suitable solvent provides (Z)-l -phenyl- l-diethylaminocarbonyl-2-chloromethyl cyclopropane compound of formula-8,

Formula-8

d) reacting the compound of formula-8 in-situ with potassium phthalimide in a suitable solvent provides (Z)-l -phenyl- l-diethylaminocarbonyl-2-phthalimido methyl cyclopropane compound of formula-6,

Formula-6

e) treating the compound of formula-6 in-situ with a suitable base in a suitable solvent provides (Z)-2-aminomethyl-l-phenyl-N,N-diethyl cyclopropane carboxamide compound of formula- 1 ,

Formula- 1

f) converting the compound of formula- 1 to its hydrochloride salt compound of

formula- la by treating it in-situ with a suitable hydrochloride source in a suitable solvent,

g) optionally purifying the hydrochloride salt compound of formula- la from a suitable solvent or mixture of solvents to provide pure compound of formula- la.

Wherein, the suitable solvent used in any of the steps, i.e., from step-a) to step-e) is selected from polar-aprotic solvents like dimethyl acetamide, dimethylformamide, dimethyl sulphoxide, dioxane, acetonitrile; hydrocarbon solvents like toluene, xylene, n- hexane, n-heptane and cyclohexane or mixtures thereof; preferably toluene.

The suitable alkali metal base used in step-a) is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and alkali metal bicarbonates; preferably sodium hydroxide.

The suitable Lewis acid used in step-b) is selected from aluminium chloride, boron trifluoride and zinc chloride; preferably aluminium chloride. The suitable chlorinating agent used in step-c) is selected from thionyl chloride, PC1 ₅ and PCI3; preferably thionyl chloride.

The suitable base used in step-e) is selected from primary alkyl amines such as methylamine, ethylamine and n-propyl amine as 40% solution.

The suitable solvent used in step-f) is selected from "alcoholic solvents" such as methanol, ethanol, isopropanol, n-butanol and the like; "hydrocarbon solvents" such as n- hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like and/or their mixtures.

The fourth aspect of the present invention provides a one-pot process for the preparation of (Z)-2-aminomethyl-l-phenyl-N,N-diethyl cyclopropane carboxamide compound of formula- 1 and its hydrochloride salt compound of formula- la,

Formula- la

comprising of;

a) Reacting the 2-phenyl acetonitrile compound of formula-2 with epichlorohydrin compound of formula-3 in presence of sodium hydroxide in dimethyl sulphoxide followed by base hydrolysis of the resulting cyano compound using sodium hydroxide, and then treating with hydrochloric acid in toluene provides (Z)-2-oxo-l- phenyl-3 -oxabicyclo [3.1.0] hexane compound of formula-4,

b) reacting the compound of formula-4 in-situ with diethylamine in toluene in presence of aluminium chloride provides (Z)-l -phenyl- 1- diethylaminocarbonyl-2- hydroxymethyl cyclopropane compound of formula-7,

c) chlorinating the compound of formula-7 in-situ with thionyl chloride in toluene provides (Z)- 1 -phenyl- 1 -diethylaminocarbonyl-2-chloromethyl cyclopropane compound of formula-8, d) reacting the compound of formula-8 in-situ with potassium phthalimide in toluene provides (Z)-l -phenyl- l-diethylaminocarbonyl-2-phthalimido methyl cyclopropane compound of formula-6,

e) treating the compound of formula-6 in-situ with methylamine in toluene provides (Z)- 2-aminomethyl-l -phenyl -Ν,Ν-diethyl cyclopropane carboxamide compound of formula- 1,

f) converting the compound of formula- 1 to its hydrochloride salt compound of formula- la by treating it in-situ with ethylacetate-HCl in isopropyl alcohol. The fifth aspect of the present invention is to provide a one-pot process for the preparation of (Z)-l -phenyl- l-diethylaminocarbonyl-2-phthalimido methyl cyclopropane compound of formula-6 comprising of;

a) Reacting the 2-phenyl acetonitrile compound of formula-2 with epichlorohydrin compound of formula-3 in presence of a suitable alkali metal base in a suitable solvent followed by base hydrolysis of the resulting cyano compound, and then treating with a suitable acid in a suitable solvent to provide (Z)-2-oxo-l-phenyl-3- oxabicyclo[3.1.0] hexane compound of formula-4,

b) reacting the compound of formula-4 in-situ with diethylamine in presence of a suitable Lewis acid in a suitable solvent to provide (Z)-l -phenyl- 1 -diethylamino carbonyl-2-hydroxymethyl cyclopropane compound of formula-7,

c) chlorinating the compound of formula-7 in-situ with a suitable chlorinating agent in a suitable solvent to provide (Z)-l -phenyl- l-diethylaminocarbonyl-2-chloromethyl cyclopropane compound of formula-8,

d) reacting the compound of formula-8 in-situ with potassium phthalimide in a suitable solvent to provide (Z)-l -phenyl- l-diethylaminocarbonyl-2-phthalimido methyl cyclopropane compound of formula-6.

Wherein, the suitable solvent used in any of the steps, i.e., from step-a) to step-d) is selected from polar-aprotic solvents like dimethyl acetamide, dimethylformamide, dimethyl sulphoxide, dioxane, acetonitrile; hydrocarbon solvents like toluene, xylene, n- hexane, n-heptane and cyclohexane or mixtures thereof; preferably toluene. The suitable alkali metal base used in step-a) is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and alkali metal bicarbonates; preferably sodium hydroxide. ·

The suitable Lewis acid used in step-b) is selected from aluminium chloride, boron trifluoride and zinc chloride; preferably aluminium chloride.

The suitable chlorinating agent used in step-c) is selected from thionyl chloride, PC1 ₅ and PC1 ₃ ; preferably thionyl chloride.

The preferred embodiment of the present invention provides a one-pot process for the preparation of (Z)-l -phenyl- l-diethylaminocarbonyl-2-phthalimido methyl cyclopropane compound of formula-6 comprising of,

a) Reacting the 2-phenyl acetonitrile compound of formula-2 with epichlorohydrin compound of formula-3 in presence of sodium hydroxide in dimethyl sulphoxide followed by base hydrolysis of the resulting cyano compound using sodium hydroxide, and then treating with hydrochloric acid in toluene provides (Z)-2-oxo-l- phenyl-3-oxabicyclo[3.1.0] hexane compound of formula-4,

b) reacting the compound of formula-4 in-situ with diethylamine in toluene in presence of aluminium chloride provides (Z)-l -phenyl- 1- diethylaminocarbonyl-2-hydroxy methyl cyclopropane compound of formula-7,

c) chlorinating the compound of formula-7 in-situ with thionyl chloride in toluene provides (Z)- 1 -phenyl- 1 -diethylaminocarbonyl-2-chloromethyl cyclopropane compound of formula-8,

d) reacting the compound of formula-8 in-situ with potassium phthalimide in toluene provides (Z)-l -phenyl- l-diethylaminocarbonyl-2-phthalimido methyl cyclopropane compound of formula-6.

The sixth aspect of the present invention provides a process for the preparation of (Z)-2-aminomethyl-l-phenyl-N,N-diethyl cyclopropane carboxamide hydrochloride salt compound of formula- la comprising of,

a) Treating the (Z)-l -phenyl- l-diethylaminocarbonyl-2-phthalimido methyl cyclo propane compound of formula-6 with a suitable base selected from primary alkyl amines such as methylamihe, ethylamine, n-propylamine in toluene provides (Z)-2- aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide compound of formula- 1,

b) converting the compound of formula- 1 to its hydrochloride salt compound of formula- la by treating it inrsitu with ethylacetate-HCl in isopropyl alcohol.

The present invention provides (Z)-2-aminomethyl-l-phenyl-N,N- diethylcyclopropane carboxamide hydrochloride salt in highly pure form having purity of greater than 99.95%, preferably 99.99% by HPLC and is substantially free of the impurities represented by formulae-6, 9, 10 & 11 as mentioned below;

a) 1 -phenyl- 1 -diethylaminocarbonyl-2-phthalimidomethyl cyclopropane of formula-6, ·

Formula-6

b) 1 -phenyl- 1 -ethylamino carbonyl-2-phthalimidomethyl cyclopropane of formula-9,

Formula-9

c) 2-(aminomethyl)-N-ethyl- 1 -phenyl cyclopropane carboxamide of formula- 10,

Formula- 10

d) trans isomer of 2-(aminomethyl)-N,N-diethyl-l -phenyl cyclopropane carboxamide of formula- 11 as determined by

ormula- 11

Crystalline (Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide hydrochloride with melting point of 178-180°C was disclosed in EP 200638. The PXRD, IR and DSC of crystalline milnacripran hydrochloride obtained as per the process disclosed in EP 200638 were represented in figure- 1, figure-2 and figure-3 respectively. The PXRD, IR and DSC of (Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide hydrochloride prepared as per the present invention is similar to the above disclosed one (i.e., figure- 1, figure-2 and figure-3 respectively).

XRD analysis of (Z)-2-aminomethyl-l -phenyl -N,N-diethylcyclopropane carboxamide 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. FT-IR spectrum of (Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide hydrochloride was recorded on Thermo model Nicolet-380 as KBr pellet. The thermal analysis of (Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide hydrochloride was carried out on Waters DSC Q-10 model differential scanning calorimeter.

(Z)-2-aminomethyl- 1 -phenyl -Ν,Ν-diethylcyclopropane carboxamide hydrochloride obtained by the present invention was analyzed by HPLC under the following conditions;

Apparatus: A liquid chromatograph equipped with variable wavelength UV detector; Column: XTerra RP-18, 250^4.6 mm, 5μηι (or) equivalent; Flow rate: 1.0 mL/min; Wavelength: 225 nm; Column temperature: 25°C; Injection volume: 10 μί; Run time: 55 min; Elution: gradient; Mobile phase-A: Triethylamine:orthophosphoric acid: water (1:2:1000, v/v/v); Mobile phase-B: Acetonitrile: water (98:02, v/v); Diluent: water:methanol:acetonitrile (50:25:25, v/v/v); (Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide 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 (Z)-2-aminomethyl-l -phenyl -N,N-diethylcyclopropane carboxamide hydrochloride is analyzed using Malvern Mastersizer 2000.

(Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide hydrochloride as produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but are not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.

The present invention is schematically represented as follows.

Scheme-1:

Scheme-2:

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 (Z)-2-oxo-l-phenyl-3-oxabicycIo [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) were added to the reaction mixture 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 solution (38.2 g of potassium hydroxide in 160 ml of water) followed by tetrabutylammonium bromide (1.1 g) were added and the reaction mixture was heated to 90-100°C. Stirred the reaction mixture for 24 hours at 90-100°C. After the reaction was completed, the reaction mixture was cooled to 20-30°C and both the organic and aqueous layers were separated. Toluene was added to the aqueous layer and acidified with hydrochloric acid and the reaction mixture was heated to 70-75°C. Stirred it for 12 hours at 70-75°C. After completion of the reaction, the reaction mixture 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

ExampIe-2: Preparation of 2-((l,3-dioxoisoindolin-2-yI)methyI)-l-phenylcyclo propane carboxylic acid (FormuIa-5):

A mixture of (Z)-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, the reaction mixture was cooled to 20-30°C. Water (170 ml) was added to the above reaction mixture at 20-30°C and stirred for 30 minutes. The reaction mixture was filtered and acidified the filtrate with acetic acid at 40-45°C. The reaction mixture 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:(Z)-l-phenyl-l-diethylaminocarbonyl-2-phthaIimi do methylcyclo propane (ForrauIa-6):

A mixture of 2-((l, 3 -dioxoisoindolin-2-yl)methyl)-l -phenyl cyclopropane 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 mixture 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 (Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide free base (Formula-1)

40% methyl amine solution (prepared by mixing methyl amine (210 g) with water (190 ml)) was added to (Z)-l -phenyl- l-diethylaminocarbonyl-2- phthalimidomethylcyclo propane 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 mixture and washed with toluene. Distilled off the solvent from filtrate under reduced pressure to get the title compound.

Yield: 65 grams

Example-S: Preparation of (Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide hydrochloride (Formula-la):

Ethyl acetate-hydrochloride (90 g) was added to a mixture of (Z)-2-aminomethyl-

1 -phenyl -Ν,Ν-diethyl cyclopropane carboxamide (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 the same temperature. The reaction mixture 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(0.1):5.09 μπι; D(0.5): 41.20 μηι; D[0.9]: 134.16 μπι;

D[4,3]: 59.06 μηι.

Example-6: One-pot process for the preparation of (Z)-2-aminomethyI-l-phenyl- Ν,Ν-diethyl cyclopropane carboxamide hydrochloride

Step-(a): Preparation of (Z)-2-oxo-l-phenyl-3-oxabicyclo[3.1.0]hexane (FormuIa-4)

250 ml of dimethyl sulphoxide was charged into a clean and dry RBF at 20-30°C. To this 2-phenylacetonitrile (50 gm) and epichlorohydrin (43.5 gm) were added at the same temperature. 34 gm of sodium hydroxide was added to the reaction mixture at 25-35°C and stirred for 2-3 hrs at the same temperature. Another 34 gm of sodium hydroxide dissolved in 300 ml of water was added to the reaction mixture at 25-35°C. The reaction mixture was heated to 80-85°C and stirred for 4-5 hrs at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25- 35°C and washed with toluene. Both the organic and aqueous layers were separated and 100 ml of toluene was added to the aqueous layer. The reaction mixture was acidified by using conc.HCl and stirred for 3-4 hrs at 25-35°C. Separated the organic and aqueous layers and the aqueous layer was extracted with toluene. The total organic layer was washed with aq.sodium bicarbonate solution followed by sodium chloride solution. The resulting organic layer containing (Z)-2-oxo-l-phenyl-3-oxabicyclo[3.1.0]hexane was utilized in the next step without isolating the compound from the reaction mixture. Alternative process for Step-(a):

Sodium hydroxide (34 gm) was added to dimethyl sulphoxide (250 ml) at 25- 35°C in a clean and dry RBF. The reaction mixture was stirred for 20-30 min at the same temperature and then cooled to 15-25°C. To this reaction mixture 2-phenylacetonitrile (50 gm) and epichlorohydrine (44 gm) were added and stirred for 1-2 hrs at the same temperature. Sodium hydroxide (34 gm) solution was added to the reaction mixture at below 30°C. The reaction mixture was heated to 80-85°C and stirred for 5 hrs at the same temperature. The resulting reaction mixture was cooled to 20-35°C and washed with toluene. Both the organic and aqueous layers were separated and toluene (100 ml) was added to the aqueous layer. The pH of the reaction mixture was adjusted to 2.0 with cone. HC1 at 20-35°C and stirred 3-4 hrs at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. The total organic layer was washed with sodium bicarbonate solution followed by sodium chloride solution. The resulting organic layer containing (2)-2-oxo-l-phenyl-3- oxabicyclo[3.1.0]hexane was utilized in the next step without isolating the compound from the reaction mixture.

Step-(b): Preparation of (Z)-l-phenyl-l-diethylamino carbonyI-2-hydroxymethyl cyclopropane (Formula-7) ·

Toluene (200 ml) was charged into a clean and dry RBF and cooled to 15-25°C. To this, aluminium chloride (46 gm) was added at the same temperature and stirred for 10-15 min. Slowly added diethylamine (52.5 gm) to the reaction mixture at 15-25°C and stirred for 10-15 min. The resulting mixture was added to a solution of (Z)-2-oxo-l- phenyl-3-oxabicyclo [3.1.0]hexane obtained in step-(a) at 15-20°C and stirred for 2-3 hrs at the same temperature. 250 ml of water was added to the reaction mixture, raised the temperature to 25-35°C and stirred for 1-2 hrs. Separated the both organic and aqueous layers, the aqueous layer was extracted with toluene. The total organic layer was washed with sodium chloride solution and the resulting organic layer containing (Z)- 1 -phenyl- 1- diethylaminocarbonyl-2-hydroxy methyl cyclopropane was utilized in the next step without isolating the compound from the reaction mixture.

Step-(c): Preparation of (Z)-l-phenyl-l-die thy laminocar bony ί-2-chioromethy! cyclopropane (Formula-8)

23 ml of thionyl chloride was added to a solution of (Z)-l -phenyl- 1-diethylamino carbonyl-2-hydroxymethyl cyclopropane obtained in step-(b) at 25-35°C and stirred for 1-2 hrs at the same temperature. The reaction mixture was heated to 1 10-1 15°C, distilled off 80-100 ml of toluene and then cooled to 20-30°C. The resulting reaction mixture containing (Z)-l -phenyl- l-diethylaminocarbonyl-2-chloromethyl cyclopropane was utilized in the next step without isolating the compound from the reaction mixture.

Step-(d): Preparation of (Z)-l-phenyl-l-diethyIaminocarbonyl-2-phthalimidomethyl cyclopropane (FormuIa-6)

Potassium phthalimide (49 gm) was added to a solution of (Z)- 1 -phenyl- 1- diethylamino carbonyl-2-chloromethyl cyclopropane obtained in step-(c) at 20-30°C. The reaction mixture was heated to 80-85°C, stirred for 2-3 hrs at the same temperature and then cooled to 20-30°C. The resulting reaction mixture containing (Z)- 1 -phenyl- 1- diethylaminocarbonyl-2-phthalimidomethyl cyclopropane was utilized in the next step without isolating the compound from the reaction mixture.

Step-(e): Preparation of (Z)-2-aminomethyI-l-phenyl-N,N-diethyl cyclopropane carboxamide (Formula-1)

170 ml of 40% solution of methylamine was added to a solution of (Z)-l-phenyl- l-diethylaminocarbonyl-2-phthalimido methyl cyclopropane obtained in step-(d) at 20- 25°C. The reaction mixture was heated to 30-35°C and stirred for 1-2 hrs at the same temperature. 400 ml of water was added to the reaction mixture at the same temperature and stirred for 15-20 min. Separated both the organic and aqueous layers, the aqueous layer was extracted with toluene. 350 ml of water was added to the total organic layer and the reaction mixture was acidified using conc.HCl. Both the organic and aqueous layers were separated. Acidic carbon was added to the aqueous layer and the reaction mixture was stirred for 30-45 min at 20-30°C. Filtered the reaction mixture through hyflow bed. The filtrate was cooled to 0-5°C and toluene was added to it. The reaction mixture was basified using sodium hydroxide solution and stirred for 10-15 min. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. The total organic layer was dried over sodium sulphate. The resulting organic layer containing (Z)-2-aminomethyl-l-phenyl-N,N-diethyl cyclopropane carboxamide was utilized in the next step without isolating the compound from the reaction mixture.

Step-(f): Preparation of (Z)-2-aminomethyl-l-phenyl-N,N-diethyl cyclopropane carboxamide hydrochloride (Formula-la)

Isopropyl alcohol (30 ml) was added to a solution of (Z)-2-aminomethyl-l- phenyl-N,N-diethyl cyclopropane carboxamide obtained in step-(e). The reaction mixture was acidified by adding ethylacetate-HCl (70 ml) at 15-20°C and the resulting mixture was stirred for 30-45 min. The obtained solid was filtered, washed with toluene and then dried at 50-55°C to get (Z)-2-aminomethyl-l-phenyl-N,N-diethyl cyclopropane carboxamide hydrochloride.

Yield: 35-40 gm; Purity By HPLC: 99.99%;

Particle Size Distribution: D(0.1) is 9.98 μιη; D(0.5) is 30.96 μηι; D(0.9) is 95.40 μπι

Example-7: Preparation of (Z)-l-phenyl-l-diethylaminocarbonyl-2-phthalimido methyl cyclopropane (Formula-6)

Step-(a): Preparation of (Z)-2-oxo-l-phenyl-3-oxabicyclo[3.1.0]hexane (Formula-4)

250 ml of dimethyl sulphoxide was charged into a clean and dry RBF at 20-30°C. To this 2-phenylacetonitrile (50 gm) and epichlorohydrin (43.5 gm) were added at the same temperature. 34 gm of sodium hydroxide was added to the reaction mixture at 25-35°C and stirred for 2-3 hrs at the same temperature. Another 34 gm of sodium hydroxide dissolved in 300 ml of water was added to the reaction mixture at 25-35°C. The reaction mixture was heated to 80-85°C and stirred for 4-5 hrs at the same temperature. After completion of the reaction, the reaction mixture was cooled to 20- 30°C and washed with toluene. Both the organic and aqueous layers were separated and 100 ml of toluene was added to the aqueous layer. The reaction mixture was acidified by using conc.HCl and stirred for 3-4 hrs at 25-35°C. Separated the organic and aqueous layers and the aqueous layer was extracted with toluene. The total organic layer was washed with aq. sodium bicarbonate solution followed by sodium chloride solution. The resulting organic layer containing (Z)-2-oxo-l-phenyl-3-oxabicyclo[3.1.0]hexane was utilized in the next step without isolating the compound from the reaction mixture. Step-(b): Preparation of (Z)-l-phenyl-l-diethylamino carbonyI-2-hydroxymethyI cyclopropane (Formula-7)

200 ml of toluene was charged into a clean and dry RBF and cooled to 15-25°C. To this, aluminium chloride (46 gm) was added at the same temperature and stirred for 10-15 min. Slowly added diethylamine (52.5 gm) to the reaction mixture at 15-25°C and stirred for 10-15 min. The resulting mixture was added to a solution of (Z)-2-oxo-l- phenyl-3-oxabicyclo [3.1.0]hexane obtained in step-(a) at 15-20°C and stirred for 2-3 hrs at the same temperature. 250 ml of water was added to the reaction mixture, raised the temperature to 25-35°C and stirred for 1-2 hrs. Separated the both organic and aqueous layers, the aqueous layer was extracted with toluene. The total organic layer was washed with sodium chloride solution and the resulting organic layer containing (Z)- 1 -phenyl- 1- diethylamino carbonyl-2-hydroxymethyl cyclopropane was utilized in the next step without isolating the compound from the reaction mixture.

Step-(c): Preparation of (Z)-l-phenyl-l-diethyIaminocarbonyl-2-chloromethyI cyclopropane (Formula-8)

23 ml of thionyl chloride was added to a solution of (Z)-l -phenyl- l-diethylamino carbonyl-2-hydroxymethyl cyclopropane obtained in step-(b) at 25-35°C and stirred for 1-2 hrs at the same temperature. The reaction mixture was heated to 110-1 15°C, distilled off 80-100 ml of toluene and then cooled to 25-35°C. The resulting reaction mixture containing (Z)-l -phenyl- l-diethylaminocarbonyl-2-chloromethyl cyclopropane was utilized in the next step without isolating the compound from the reaction mixture.

Step-(d): Preparation of (Z)-l-phenyl-l-diethylaniinocarbonyl-2-phthalimidomethyl cyclopropane (Formula-6)

Potassium phthalimide (49 gm) was added to a solution of (Z)- 1 -phenyl- 1- diethylamino carbonyl-2-chloromethyl cyclopropane obtained in step-(c) at 25-35°C. The reaction mixture was heated to 80-85°C, stirred for 2-3 hrs at the same temperature and then cooled to 25-35°C. The obtained solid was filtered, washed with toluene and then dried to yield (Z)-l -phenyl- 1-diethylamino carbonyl-2-phthalimidomethyl cyclopropane (Formula-6).

Example-8: One-pot process for the preparation of (Z)-2-aminomethyl-l-phenyl- Ν,Ν-diethyl cyclopropane carboxamide hydrochloride

Step-(a): Preparation of (Z)-2-aminomethyI-l-phenyl-N,N-diethyl cyclopropane carboxamide (Formula-1)

170 ml of 40% methylamine solution was added to a solution of (Z)- 1 -phenyl- 1- diethylamino carbonyl-2-phthalimido methyl cyclopropane(60 gms) in toluene (350 ml) at 25-35°C. The reaction mixture was heated to 30-35°C and stirred for 1-2 hrs at the same temperature. 400 ml of water was added to the resulting reaction mixture at the same temperature and stirred for 15-20 min. Separated both the organic and aqueous layers, the aqueous layer was extracted with toluene. 350 ml of water was added to the total organic layer and the reaction mixture was acidified by adding conc.HCl. Both the organic and aqueous layers were separated. Acidic carbon was added to the aqueous layer and the reaction mixture was stirred for 30-45 min at 20-30°C. Filtered the reaction mixture through hyflow bed. The filtrate was cooled to 0-5°C and toluene (170 ml) was added to it. The reaction mixture was basified using sodium hydroxide solution and stirred for 10-15 min. Separated the organic and aqueous layers, the aqueous layer was extracted with toluene. The total organic layer was dried over sodium sulphate and the resulting mixture containing (Z)-2-aminomethyl-l-phenyl-N,N-diethyl cyclopropane carboxamide was utilized in the next step without isolating the compound from the reaction mixture.

Step-(b): Preparation of (Z)-2-aminomethyI-l-phenyl-N,N-diethyl cyclopropane carboxamide hydrochloride (Formula-la)

30 ml of isopropyl alcohol was added to a solution of (Z)-2-aminomethyl-l- phenyl-N,N-diethyl cyclopropane carboxamide obtained in step-(a). The reaction mixture was acidified by adding ethylacetate-HCl at 15-20°C and the resulting mixture was stirred for 30-45 min. The obtained solid was filtered, washed with toluene and then dried at 50-55°C for 4-5 hrs to get (Z)-2-aminomethyl-l-phenyl-N,N-diethyl cyclopropane carboxamide hydrochloride.

Yield: 35 grams

Example 9: Preparation of (Z)-l-phenyl-l-dicthylamino carbonyl-2-hydroxymethyl cyclopropane (Formula-7)

Toluene (200 ml) was charged into a clean and dry RBF and cooled to 15-25°C. To this, aluminium chloride (46 gm) was added at the same temperature and stirred for 10-15 min. Slowly added diethylamine (52.5 gm) to the reaction mixture at 15-25°C and stirred for 10-15 min. The resulting mixture was added to a solution of (Z)-2-oxo-l- phenyl-3-oxabicyclo [3.1.0]hexane (70 gm) at 15-20°C and stirred for 2-3 hrs at the same temperature. 250 ml of water was added to the reaction mixture, raised the temperature to 25-35°C and stirred for 1-2 hrs. Separated the both organic and aqueous layers, the aqueous layer was extracted with toluene. The total organic layer was washed with sodium chloride solution and distilled off the solvent completely from organic layer provides (Z)-l -phenyl- l-diethylaminocarbonyl-2-hydroxy methyl cyclopropane.

Yield: 90 gms.