Field of the invention:

The present invention relates to an improved process for the preparation of (±)-[lR(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.

(±)-[lR(S),2S(R)]-2-(aminomethyl)-N,N-diethyl-l-phenylcyclopropane carboxamide or (Z)-2-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide (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-l-phenyl-N,N-diethyl cyclopropane carboxamide, 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 synthesis of (Z)-2-Aminomethyl-l -phenyl-N,N-diethylcyclopropane carboxamide. Process for the preparation of said intermediate and its conversion to milnacipran 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-phenyl acetonitrile with epichlorohydrin in the presence of sodium amide in benzene and hydrolysis of 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, hence it is difficult to handle and not suitable for use on commercial scale.

US 2008/0064885 Al also disclosed a process for the preparation of 2-oxo-l-phenyl-3-oxabicyclo[3.1.0]hexane, comprising of reacting 2-phenylacetonitrile with epichlorohydrin
in the presence of sodium hydride in a mixture of toluene and N,N'-dimethyl imidazolidinone followed by hydrolysis. The said process involves the usage of sodium hydride which is pyrophoric in nature, difficult to handle and not suitable for commercial purposes.

The prior reported processes for the preparation of 2-oxo-l-phenyl-3-oxabicyclo [3.1.0]hexane comprising of reacting 2-phenylacetonitrile with epichlorohydrin in presence of bases like sodium amide and sodium hydride, which are not recommendable for commercial scale-up.

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-aminomethyl-l-phenyl-N,N-diethylcyclopropane carboxamide by using simple bases that avoids the disadvantages mentioned in the prior-art processes.

Advantages of the present invention:

• Avoids the usage of bases like sodium amide or sodium hydride, which are pyrophoric in nature, difficult to handle and not suitable for commercial scale up.

• Provides a simple and safe process for the preparation of Milnacipran 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 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)-l -phenyl- l-diethylaminocarbonyl-2-hydroxymethyl cyclopropane compound of formula-5,

c) chlorinating the compound of formula-5 in-situ with a suitable chlorinating agent in a suitable solvent to provide (Z)-l-phenyl-l-diethylaminocarbonyl-2-chloromethyl cyclopropane compound of formula-
6,

d) reacting the compound of formula-6 in-situ with potassium phthalimide in a suitable solvent to provide (Z)-l-phenyl-l-diethylaminocarbonyl-2-phthalimidomethyl cyclopropane compound of formula-7,

e) treating the compound of formula-7 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 second 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 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-5,

c) chlorinating the compound of formula-5 in-situ with thionyl chloride in toluene to provide (Z)-l -phenyl- l-diethylaminocarbonyl-2-chloromethyl cyclopropane compound of formula-6,

d) reacting the compound of formula-6 in-situ with potassium phthalimide in toluene to provide (Z)-l-phenyl-l-diethylaminocarbonyl-2-phthalimido methyl cyclopropane compound of formula-7,

e) treating the compound of formula-7 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 third 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-7 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-diethylaminocarbonyl-2-hydroxymethyl cyclopropane compound of formula-5,

c) chlorinating the compound of formula-5 in-situ with a suitable chlorinating agent in a suitable solvent to provide (Z)-l-phenyl-l-diethylaminocarbonyl-2-chloromethyl cyclopropane compound of formula-6,

d) reacting the compound of formula-6 in-situ with potassium phthalimide in a suitable solvent to provide (Z)-l-phenyl-l-diethylaminocarbonyl-2-phthalimido methyl cyclopropane compound of formula-7.

The fourth 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-phthalimido methylcyclopropane compound of formula-7 with a suitable base in a suitable solvent to provide (Z)-2-aminomethyl-1-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.

Detailed description of the Invention:

The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as hexane, heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethylether, diethylether, methyl tert-butyl ether, THF and the like; "ester solvents" such as methyl acetate, ethylacetate, isopropyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulphoxide, dioxane, acetonitrile and the like; "chlorinated hydrocarbons" such as dichloromethane, dichloroethane, chloroform and the like; "ketonic solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, isopropanol, n-butanol and the like; "polar solvents" such as water; or their mixtures thereof.

As used herein the present invention the term "alkali metal base" refers to "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates" such as sodium carbonate, potassium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium tertbutoxide and the like.

The prior reported processes for the preparation of 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 avoids the yield loss at each stage during intermediate purification steps and there by provides a highly economic process.

The first 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 acetonitrile compound of formula-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,

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-5,

Formula-5

c) chlorinating the compound of formula-5 in-situ with a suitable chlorinating agent in a suitable solvent provides (Z)-l-phenyl-l-diethylaminocarbonyl-2-chloromethyl cyclopropane compound of formula-6,

Formula-6
d) reacting the compound of formula-6 in-situ with potassium phthalimide in a suitable
solvent provides (Z)-l -phenyl- l-diethylaminocarbonyl-2-phthalimido methyl
cyclopropane compound of formula-7,

Formula-7
e) treating the compound of formula-7 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, hexane, 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, PCI5 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 hexane, heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like and/or their mixtures.

The second 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-5,

c) chlorinating the compound of formula-5 in-situ with thionyl chloride in toluene provides (Z)-l-phenyl-l-diethylaminocarbonyl-2-chloromethyl cyclopropane compound of

formula-6,
d) reacting the compound of formula-6 in-situ with potassium phthalimide in toluene provides (Z)-l-phenyl-l-diethylaminocarbonyl-2-phthalimido methyl cyclopropane compound of formula-7,

e) treating the compound of formula-7 in-situ with methylamine in toluene provides (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 third aspect 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-7 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-5,

c) chlorinating the compound of formula-5 in-situ with thionyl chloride in toluene provides (Z)-l-phenyl-l-diethylaminocarbonyl-2-chloromethyl cyclopropane compound of formula-6,

d) reacting the compound of formula-6 in-situ with potassium phthalimide in toluene provides (Z)-l-phenyl-l-diethylaminocarbonyl-2-phthalimido methyl cyclopropane compound of formula-7.

The fourth 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 methylcyclopropane compound of formula-7 with a suitable base selected from primary alkyl amines such as methylamine, 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 in-situ with ethylacetate-HCl in isopropyl alcohol.

The present invention provides Milnacipran 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 formula-7, 8,9&10 as mentioned below;

a) 1 -phenyl-1 -diethylaminocarbonyl-2-phthalimidomethyl cyclopropane of formula-7,

Formula-7
b) 1 -phenyl-1 -ethylamino carbonyl-2-phthalimidomethyl cyclopropane of formula-8,

c) 2-(aminomethyl)-N-ethyl-1 -phenyl cyclopropane carboxamide of formula-9,


d) trans isomer of 2-(aminomethyl)-N,N-diethyl-1 -phenyl cyclopropane carboxamide of formula-10 as determined by HPLC.

Formula-10 Milnacipran 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, 250x4.6 mm, 5um (or) equivalent; Flow rate: 1.0 mL/min; Wavelength: 225 nm; Column temperature: 25°C; Injection volume: 10 uL; 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);
Milnacipran 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 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.

The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provides as illustration only and hence should not be construed as limitation of the scope of the invention.

Example-1:
One-pot process for the preparation of (Z)-2-aminomethyl-l-phenyl-N,N-diethyl
cyclopropane carboxamide hydrochloride

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 benzyl cyanide (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.

Step-(b): Preparation of (Z)-l-phenyl-l-diethylamino carbonyl-2-hydroxymethyl cyclopropane (Formula-5)
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)-l-phenyl-l-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-diethylaminocarbonyl-2-chloromethyl cyclopropane (Formula-6)
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 110-115°C, distilled off 80-100 ml of toluene and then cooled to 20-3 0°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-diethylaminocarbonyl-2-phthalimidomethyI cyclopropane (Formula-7)
Potassium phthalimide (49 gm) was added to a solution of (Z)-l-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)-l-phenyl-l-diethylaminocarbonyl-2-phthalimidomethyl cyclopropane was utilized in the next step without isolating the compound from the reaction mixture.

Step-(e): Preparation of (Z)-2-aminomethyl-l-phenyl-N,N-diethyl cyclopropane carboxamide (Formula-1)
170 ml of 40% solution of methylamine was added to a solution of (Z)-1-phenyl-1-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 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 yield (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 um; D(0.5) is 30.96 um; D(0.9) is 95.40 urn

Example-2:
Preparation of (Z)-l-phenyl-l-diethylaminocarbonyl-2-phthalimidomethyl cyclopropane (FormuIa-7)
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 benzyl cyanide (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 carbonyl-2-hydroxymethyl cyclopropane (Formula-5)
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 25-3 5°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)-l -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-diethylaminocarbonyl-2-chloromethyl cyclopropane (Formula-6)
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 110-115°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-diethylaminocarbonyl-2-phthalimidomethyl cyclopropane (Formula-7)
Potassium phthalimide (49 gm) was added to a solution of (Z)-l-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)-1-phenyl-1-diethylamino carbonyl-2-phthalimidornethyl cyclopropane (Formula-VII).

Example-3:
One-pot process for the preparation of (Z)-2-aminomethyl-l-phenyl-N,N-diethyl
cyclopropane carboxamide hydrochloride

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

170 ml of 40% methylamine solution was added to (Z)-l-phenyl-1-diethylamino carbonyl-2-phthalimido methyl cyclopropane 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-aminomethyl-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 yield (Z)-2-aminomethyl-l-phenyl-N,N-diethyl cyclopropane carboxamide hydrochloride.

We Claim:

1. An improved process for the preparation of (Z)-2-aminomethyl-1 -phenyl-N,N-diethyl cyclopropane carboxamide hydrochloride salt compound of formula-la, comprising:

a) Reacting the 2-phenyl acetonitrile compound of formula-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 to provide (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 presence of a suitable
Lewis acid in a suitable solvent to provide (Z)-l -phenyl-1-diethylaminocarbonyl-2-
hydroxymethyl cyclopropane compound of formula-5,

Formula-5 21

c) treating the compound of formula-5 in-situ with a suitable chlorinating agent in a suitable
solvent to provide (Z)-l -phenyl- l-diethylaminocarbonyl-2-chloromethyl cyclopropane compound of formula-6,

Formula-6
d) reacting the compound of formula-6 in-situ with potassium phthalimide in a suitable
solvent to provide (Z)-l-phenyl-l-diethylaminocarbonyl-2-phthalimido methyl cyclopropane compound of formula-7,
Formula-7

e) treating the compound of formula-7 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,
Formula- 1
f) converting (Z)-2-aminomethyl-l-phenyl-N,N-diethyl cyclopropane carboxamide 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 a mixture of solvents to provide pure (Z)-2-aminomethyl-l-phenyl-N,N-diethyl cyclopropane carboxamide hydrochloride salt compound of formula-la.

2. The process according to claim 1, wherein;
In step-a) the suitable alkali metal base is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and alkali metal bicarbonates;

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

in step-c) the suitable chlorinating agent is selected from thionyl chloride, PCI5 and PCI3;
preferably thionyl chloride;

in step-e) the suitable base is selected from primary alkyl amines such as methylamine,
ethylamine and n-propylamine;

in step-f) the suitable hydrochloride source is ethylacetate-HCl and the suitable solvent is a mixture of toluene and isopropyl alcohol.

3. The process according to claim 1, characterized in that step-(b) to step-(e) are carried out in a reaction medium comprising a single solvent.

4. The process according to claim 3, characterized in that the solvent is toluene.

5. The process according to any of the claims 1 & 2, characterized in that the suitable base used in step-(e) is 40% methylamine.

6. The process according to claim 1, characterized in that any of the intermediate compounds obtained from step-(a) to step-(e) is not isolated from the reaction mixture.

7. An improved process for the preparation of (Z)-2-aminomethyl-l -phenyl-N,N-diethyl cyclopropane carboxamide hydrochloride salt compound of formula-la, comprising:

a) Reacting the 2-phenyl acetonitrile compound of formula-2 with epichlorohydrin compound of formula-3 in dimethyl sulphoxide in presence of sodium hydroxide followed by base hydrolysis of the resulting cyano compound using sodium hydroxide, and then treating with HC1 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 toluene in presence of aluminium chloride to provide (Z)-l-phenyl-l-diethylaminocarbonyl-2-hydroxymethyl cyclopropane compound of formula-5,

c) chlorinating the compound of formula-5 by treating in-situ with thionyl chloride in toluene to provide (Z)-l-phenyl-l-diethylaminocarbonyl-2-chloromethyl cyclopropane compound of formula-6,

d) reacting the compound of formula-6 in-situ with potassium phthalimide in toluene to provide (Z)-l-phenyl-l-diethylaminocarbonyl-2-phthalimido methyl cyclopropane compound of formula-7,

e) treating the compound of formula-7 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 into its hydrochloride salt compound of formula-la by treating it in-situ with ethylacetate-HCl in isopropyl alcohol.

8. An improved process for the preparation of (Z)-1 -phenyl-1 -diethylaminocarbonyl-2-phthalimido methyl cyclopropane compound of formula-7, comprising: a) Reacting the 2-phenyl acetonitrile compound of formula-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 to provide (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 presence of a suitable
Lewis acid in a suitable solvent to provide (Z)-l -phenyl-1-diethylamino carbonyl-2-
hydroxymethyl cyclopropane compound of formula-5,

Formula-5
c) treating the compound of formula-5 in-situ with a suitable chlorinating agent in a suitable
solvent to provide (Z)-l-phenyl-l-diethylaminocarbonyl-2-chloromethyl cyclopropane compound of formula-6,

Formula-6
d) reacting the compound of formula-6 in-situ with potassium phthalimide in a suitable
solvent to provide (Z)-l-phenyl-l-diethylaminocarbonyl-2-phthalimido methyl cyclopropane compound of formula-7.


9. The process according to any of the claims 1 & 7, characterized in that (Z)-2-aminomethyl-l-
phenyl-N,N-diethyl cyclopropane carboxamide hydrochloride salt obtained is having purity of greater than 99.90%, preferably 99.95%, more preferably 99.99% by HPLC.

10. The process according to any of the claims 1 & 7, characterized in that (Z)-2-aminomethyl-l-
phenyl-N,N-diethyl cyclopropane carboxamide hydrochloride salt obtained is substantially free of the impurities represented by formulae-8, 9 & 10 as mentioned below;

a) 1 -phenyl-1 -ethylaminocarbonyl-2-phthalimidomethyl cyclopropane of formula-8,

Formula-8

b) 2-(aminomethyl)-N-ethyl-1 -phenyl cyclopropane carboxamide of formula-9,
Formula-9

c) trans isomer of 2-(amino methyl)-N,N-diethyl-l -phenyl cyclopropane carboxamide of
formula-10,

Formula-10 as determined by HPLC.