FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003 COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention ""A NOVEL ONE POT PROCESS FOR THE PREPARATION OF TRANYLCYPROMINE SULFATE""
Centaur Pharmaceutical Private Limited, an Indian Company, having its Registered Office at Centaur House, Near Grand Hyatt, Shanti Nagar, Vakola, Santacruz (East), Mumbai- Maharashtra, 400055, India
1. The following specification describes the invention.

FIELD OF THE INVENTION:
The present invention relates to a novel process of preparing tranylcypromine sulfate compound of structural formula I
BACKGROUND OF THE INVENTION:
Tranylcypromine sulfate is a non-hydrazine monoamine oxidase inhibitor and it is chemicallydesignated as (±)-trans-2-phenylcyclopropylamine sulfate (2:1). It is known from U.S. Patent No. 2,997,422 and is represented by compound of structural formula I
Tranylcypromine sulfate is sold in USA market under the trade name "PARNATE" indicated for the treatment of Major Depressive Episode without Melancholia.
U.S. Patent No. 2,997,422 describes process for the preparation of tranylcypromine sulfate compound of the structural formula I as shown below in scheme no. 1.

The above process results in significant yield loss in that the cis-isomer is discarded and significant amounts of trans-isomer are lost in repeated recrystallizations during preparation of compound of the structural formula V. Furthermore, the trans-isomerof compound of the structural formula V is contaminated by some cis-isomer which results in an impure product.
U.S. Patent No. 3,079,403 describes process for the preparation of racemic-2-phenylcyclopropylamine compound of structural formula XII as shown below in scheme no. 2.

Wherein R is lower alkyl of from 1 to 6 carbon atoms; cyclohexyl; phenyl; substituted phenyl, the substituent being for example halogen of atomic weight less than 80, such as chlorine or bromine, lower alkyl such as methyl, lower alkoxy such as methoxy, trifluoromethyl, hydroxy or mcthylenedioxy; phenoxy; phenylthio; benzyl; naphthyl; thianaphenyl; indolyl; or benzofuryl; X is chlorine or bromine; and R2 is lower alkyl of from 1 to 4 carbon atoms.
The above process involves multi step and isolation in each step which increases cost and time for the process.
U.S. patent no. 7,449,447 describes a process of preparing cis-2-phenylcyclopropylamine hydrochloride compound of structural formula XVI as shown below in scheme no. 3

The above process involves multi step and isolation in each step which increases cost and time for the process.
Organic Letters, 5(13), 2331-2334; 2003 (By Armstrong, Alan and Scutt, James N) describes preparation of trans-ethyl-2-phenylcyclopropane carboxylate compound of structural formula XIX using R-styrene oxide compound of structural formula XVII and triethylphosphanoacetate compound of structural formula XVIII as shown below in scheme no. 4
The above process involves isolation of compound of structural formula XIX.
Accordingly there is need in the art to develop an improved and cost effective process for the preparation of tranylcypromine sulfate compound of structural formula I, which obviates prior art problems.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a novel one pot process of preparing tranylcypromine sulfate compound of structural formula I.
Another aspect of the present invention is to provide a novel one pot process of preparingtranylcypromine sulfate compound of structural formula I comprising:
a) reacting R-styrene oxide compound of structural formula XVII,

with triethylphosphanoacetate compound of structural formula XVIII
to obtain reaction mixture comprising compound of structural formula XIX
b) followed by reacting compound of structural formula XIX with hydrazine to obtain compound of structural formula XX,
c) followed by converting compound of structural formula XX into compound of structural formula XXI,
d) followed by reacting compound of structural formula XXI with base to obtain compound of structural formula VII, and

e) converting compound of structural formula VII into tranylcypromine sulfate compound of structural formula I
DETAILED DESCRIPTION OF INVENTION:
The R-styrene oxide compound of structural formula XVII used herein is commercially available at Sigma-Aldrich.
The triethylphosphanoacetate compound of structural formula XVIII used herein is commercially available at Sigma-Aldrich.
The reaction of compound of structural formula XVII with compound of structural formula XVIII may be carried out in presence of inorganic base in polar solvent to obtain reaction mixture containing compound of structural formula XIX.
The examples of polar solvent may include but not limited to mono-methyl formamide, dimethyl formamide, diethyl formamide, dimethyl acetamide,dimethyl sulphoxide, N-methyl pyrrolidone or mixture(s) thereof.
The examples of inorganic base may include but not limited to alkali metal hydride.
The reaction of compound of structural formula XVII with compound of structural formula XVIII may be carried out at a temperature in the range of 25°C to the reflux temperature of the solvent used, followed by quenching the reaction mixture with methanol and adjusting pH to 7.0 to 7.5 by adding acetic acid to obtain reaction mixture containing compound of structural formula XIX.

The reaction of compound of structural formula XIX with hydrazine may be carried out at a temperature in the range of 25°C to the reflux temperature of the solvent used, followed by quenching the reaction mixture with ice water and further toluene is added to the reaction mixture and stirred for 2 hours at the temperature in the range of 0 to 5°C to obtained reaction mixture containing compound of structural formula XX.
The conversion of compound of structural formula XX into compound of structural formula XXI may be carried out by reacting reaction mixture containing compound of structural formula XX with sodium nitrite and Hydrochloric acid at a temperature in the range of 0 to 25°C, followed by separating aqueous layer containing compound of structural formula XXI
The aqueous layer containing compound of structural formula XXI may be treated with base and extracted with toluene to obtained organic layer containing compound of the structural formula VII
Examples of suitable base may include but not limited to hydroxides of alkali metal or alkaline earth metal such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide and the like; carbonates of alkali metal or alkaline earth metal such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like; and phosphates such as disodium monohydrogenphosphate, dipotassium monohydrogen phosphate, tri sodium phosphate, tripotassium phosphate and the like.
The conversion of the compound of structural formula VII into the tranylcypromine sulfate compound of structural formula I may be carried out by reacting the organic layer containing compound of the structural formula VII with sulphuric acid in an alcohol solvent.
The compound of structural formula I may be isolated by the steps of filtration, centrimgation,' washing, drying or the combinations thereof.
The isolated compound of structural formula I may be further purified by recrystallization in an alcohol solvent to obtained pure tranylcypromine sulfate compound of the structural formula I

Examples of suitable alcohol may include but not limited to group comprising of methanol, ethanol, propanol, n-butanol, isopropanol, tertiary butanol, 1,2-dimethoxyethanol or mixture(s) thereof
The said process can be schematically illustrated as below in scheme no. 5

EXAMPLE:
In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of tranylcypromine sulfatecompoundof structural formula I
To a triethylphosphonoacetate compound of the structural formula XVIII (20Kg) added slowly sodium hydride followed by reaction with R-styrene oxide compound of the structural formula XVII (lOKg) at elevated temperature above 80°C in dimethylformamide. After the completion of reaction, the pH ofreaction mixture was adjusted to 7.0-7.5 by using acetic acid & added methanol in reaction mixture. The resulting reaction mixture is further reacted with hydrazine hydrate (32 litres) at reflux temperature. After completion of reaction ice water and toluene is added in reaction mixture and cool 0-5°C for 2 hours. The reaction mixture is further in-situ reacted with sodium nitrite (5.2 Kg) &commercial hydrochloric acid (23 litres) at 5°C. The reaction mixture is allowed to separate layers and the aqueous layer is neutralized with sodium hydroxide and is extracted with toluene. To the toluene layer, containing in situ formedtranylcypromine compound of the structural formula VII, is added methanol (30 L) and then reacted with concentrated sulphuric acid (0.93 litres)to obtain tranylcypromine sulfate compound of structural formula I. The product is isolated and purified from methanol to give of pure tranylcypromine sulfate compound of structural formula I
Yield: 6.1 Kg
Purity: 99.78% (by HPLC)

WE CLAIM:
1. One pot process for preparingtranylcypromine sulfate compound of structural formula I
comprising:
a) reacting R-styrene oxide compound of structural formula XVII
with triethylphosphanoacetate compound of the formula XVIII
to obtain reaction mixture comprising compound of structural formula XIX

b) followed by reacting compound of structural formula XIX with hydrazine to obtain compound of structural formula XX
c) followed by converting compound of structural formula XX into compound of structural formula XXI
d) followed by reacting compound of structural formula XXI with base to obtain compound of structural formula VII
e) followed by converting compound of structural formula VII into tranylcypromine sulfate compound of structural formula I

2. The process according to claim no. 1, wherein the reaction of compound of structural formula XVII with compound of structural formula XVIII is carried out in the presence of inorganic base in a polar solvent at a temperature in the range of 25 °C to the reflux temperature of the solvent to obtained reaction mixture containing compound of structural formula XIX.
3. The process according to claim no. 2, wherein inorganic base is selected from the group comprising of alkali metal hydride and polar solvent is selected from the group comprising of mono-methyl formamide, dimethyl formamide, diethyl formamide, dimethyl acetamide, dimethyl sulphoxide, N-methyl pyrrolidone or mixture(s) thereof.
4. The process according to claim no. 1, wherein reaction of compound of structural formula XIX with hydrazine is carried out at a temperature in the range of 25°C to the reflux temperature of the solvent usedto obtain compound of structural formula XX.
5. The process according to claim no. 1, wherein the conversion of compound of structural formula XX into compound of structural formula XXI is carried out by reacting reaction mixture containing compound of structural formula XX with sodium nitrite and hydrochloric acid at a temperature in the range of 0°C to 25°C.
6. The process according to claim no. 1 , wherein the conversion of compound of structural formula XXI into compound of structural VII is carried out by reacting compound of structural formula XXI with a base, wherein baseis selected from the group comprising of inorganic base like hydroxides of alkali metal or alkaline earth metal such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide and the like; carbonates of alkali metal or alkaline earth metal such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like; and phosphates such as disodium monohydrogenphosphate, dipotassium monohydrogen phosphate, trisodium phosphate, tripotassium phosphate and the like.

7. The process according to claim no. 1, wherein compound of structural formula VII is converted into the tranylcypromine sulfate compound of the structural formula I using sulphuric acid in an alcohol solvent.
8. The process according to claim no. 7, wherein in alcohol is selected from the group comprising of methanol, ethanol, propanol, n-butanol, isopropanol, tertiary butanol, 1, 2-dimethoxyethanol or mixture(s) thereof.