DESC:FIELD OF THE INVENTION
The present application provides improved process for the preparation of (1R,2S)-2-(3,4-difluorophenyl) cyclopropan-1-amine hydrochloride which is a potential intermediate for the preparation of Ticagrelor in high yields and purity and suitable for manufacturing in commercial scale.

BACKGROUND OF THE INVENTION
Ticagrelor is a platelet aggregation inhibitor which is chemically known as (1S,2S,3R,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol and whose chemical structure is the following.

Ticagrelor shows pharmaceutical activity by functioning as a P2Y12 receptor antagonist and thus is indicated for the treatment or prevention of thrombotic events, for example stroke, heart attack, acute coronary syndrome or myocardial infection with ST elevation, other coronary artery diseases and arterial thrombosis as well as other disorders related to platelet aggregation.

Several processes have been discussed in the literature for the preparation of Ticagrelor and their pharmaceutically acceptable salts, which are disclosed in US6525060, US7067663, US7250419, W02000/034283, WO2008018823 and W02010030224.

Several synthetic methods have been reported in the literature to prepare (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride compound of formula (I)

Formula (I)
WO2001092200A1 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

According to WO2001092200A1 formula (I) is prepared as shown 3,4- Difluorobenzaldehyde is reacted with malonic acid in the presence of pyridine and piperidine to yield (E)-3-(3.4-difluorophenyl)-2-propenoic acid, which is converted to (E)-3-(3,4- d (fluorophenyl )-2-propenoyl chloride by using thionyl chloride in the presence of toluene and pyridine. A solution of L-menthol in toluene is added to the obtained compound in the presence of pyridine to yield (1 2S,5R)-2-isopropyl-5-methylcyclohexyl (E)-3-(3,4-difluorophenyl)-2- propenoate, which is with dimethylsulfoxonium methylide, sodium iodide and NaOH in DMSO converted to (1R, 2S,5R)-2-isopropyl-5-methyl cyclohexyltrans-2-(3,4-difluorophenyl)- cyclopropane carboxylate. The latter is then hydrolyzed to (1R,2R)-2-(3,4-difluorophenyl)- cyclopropanecarboxylic acid, which is subsequently converted to (1R,2R)-2-(3,4- difluorophenyl)cyclopropanecarbonyl chloride with thionyl chloride. In the last two steps, the obtained carbonyl chloride is first converted to the corresponding azide by addition of sodium azide and iert-butylammonium bromide, which is finally converted to formula (I), in downstream process involves tedious workup such as pH adjustment and extraction in to organic solvent and distillation.
U.S. Patent Application No. 2008/0132719A1 discloses a preparation process for ticagrelor based on the preparation of the compound (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride compound of formula (I).

According to the 2008/0132719 application, the (lR,2S)-2-(3,4-difluorophenyl)- cyclopropane amine is prepared by reacting 1,2-difluorobenzene with chloroacetyl chloride in the presence of aluminium trichloride to produce 2-chloro-l-(3,4-difluorophenyl)ethanone, followed by the reaction with trimethoxy borane and S-diphenylprolinol in toluene to produce 2-chloro-(lS)-(3,4-difluorophenyl)ethanol, which is then reacted with triethyl phosphono acetate in the presence of sodium hydride in toluene to produce ethyl (1R,2R)- trans-2-(3,4-difluorophenyl)cyclopropyl carboxylate. The ester compound is then reacted with methyl formate in the presence of ammonia to produce (lR,2R)-trans-2-(3,4- difluorophenyl)cyclopropyl carboxamide, which is then reacted with sodium hydroxide and sodium hypochlorite to produce (lR,2S)-2-(3,4-difluorophenyl)-cyclopropane amine. The process described in the 2008/0132719 application suffers from the disadvantages since it involves the use of explosive materials like sodium hydride.
Patent application WO2008018823A1 discloses a preparation process for ticagrelor based on the preparation of the compound (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride compound of formula (I).

According to the WO2008018823A1 publication, the (lR,2S)-2-(3,4-difluorophenyl)-l- cyclopropanamine is prepared by reacting (lS)-2-chloro-l-(3,4-difluorophenyl)-l-ethanol with sodium hydroxide in toluene to produce (2S)-2-(3,4-difluorophenyl)oxirane, followed by reaction with triethyl phosphonoacetate in the presence of sodium t-butoxide in toluene to produce ethyl (lR,2R)-2-(3,4-difluorophenyl)-l-cyclopropanecarboxylate, which is then hydro lyzed with sodium hydroxide in methanol to produce (lR,2R)-2-(3,4-difluorophenyl)-l- cyclopropanecarboxylic acid. The resulting carboxylic acid compound is reacted with thionyl chloride in toluene to produce a solution of (lR,2R)-2-(3,4-difluorophenyl)-l-cyclopropanecarbonyl chloride, followed by subsequent reaction with aqueous ammonia to produce (lR,2R)-2-(3,4-difluorophenyl)-l-cyclopropanecarboxamide, which is then reacted with sodium hydroxide in the presence of sodium hypochlorite to produce (lR,2S)-2-(3,4- difluorophenyl)- 1 -cyclopropanamine, in downstream process involves tedious workup such as pH adjustment and extraction in to organic solvent and distillation.
WO2011017108A2 particularly discloses the below is commercially not a viable to produce the required intermediate in industrial manufacturing scale. Use of the most hazardous reagents has been omitted, in situ formation of diazomethane and expensive diphenylphosphoryl azide, however, still do not satisfy the need for safe and cheap industrial process.

The patent application WO2012001531A2 discloses a preparation process for ticagrelor based on the preparation of the compound (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride compound of formula (I).

The disadvantage of the process described in WO2012001531A2 is the use of expensive chiral ligand, dichloro(p-cymene)ruthenium(ll) dimer, and use of toxic pyridine for the preparation of formula (I) is that the synthesis is long and/or expensive, or that environmentally unfriendly reagents are used, which makes the prior art processes unsuitable for large scale preparation of formula (I).
The patent application WO2013144295A1discloses a preparation process for ticagrelor based on the preparation of the compound (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride compound of formula (I).


The disadvantage of the process described in WO2013144295A1 is isolating (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride compound of formula (I) through Boc protection.
The patent application CN107827755A discloses a preparation process for ticagrelor based on the preparation of the compound (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride compound of formula (I).


The disadvantage of the process described in CN107827755A is the use of expensive chiral ligand, which makes the prior art processes unsuitable for large scale preparation of compound of formula (I).
Bioorganic & Medicinal Chemistry, vol. 17(6), pages 2388-2399 (2009) discloses a process for the preparation of racemic trans-2-(3,4- difluorophenyl)cyclopropylamine and its acid addition salt. J. Med. Chem., vol. 20, No. 7, pages 934-939 (1977) discloses a process for the preparation of l-aryl-3-nitro-l-propanones from l-aryl-3-chloro-l-propanones.
All the above prior art methods for the preparation of compound of formula (I) have inherent disadvantages such as the usage of unsafe reagents, high boiling solvents, extreme reaction conditions invariably resulting in the formation of low pure intermediates as well as in isolation of hydrochloride salt of compound of formula (I) using dry HCl gas purging in to organic solvents which is highly hazardous also highly irritating to the mucosal surfaces of the respiratory tract and the eyes, also having a considerably higher content of urea impurity. Accordingly, there remains a need for the industrial preparation of substantially pure (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride which is free of impurities with high yield. Therefore, still there is need for the development of commercially viable, cost-effective eco-friendly process for the preparation of Ticagrelor intermediate of compound of formula (I).

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a simple, effective and industrially feasible process for the preparation of high pure intermediate of Ticagrelor by using eco-friendly, cheaply available reagents and low boiling solvents which is cost effective, especially water is considered the greenest solvent, non-toxic also solvents expresses the goal to minimize the environmental impact resulting from the use of solvents, and with good yields on commercial scale by avoiding repeated cumbersome and lengthy purification steps.

SUMMARY OF THE INVENTION
The improved process for the preparation of substantially pure (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride disclosed herein has the following advantages over the processes described in the prior art:
i) Prior art applications process disclosed tedious workup such as pH adjustment, extraction into organic solvents and concentrating to get free amine residue with less purity.
ii) to isolate pure compound prior art applications adopted various techniques such as salt formation wherein tartrate, mandelate and HCl, different protecting groups wherein Boc, benzyl, benzoyl.
iii) The present invention avoid the use of tedious and cumbersome procedure like pH adjustment, workup, extractions and purifications and multiple isolations;
iv) the present invention provides significantly improved process that is direct isolation of high pure (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride slat from diluted hydrochloric acid media without any extraction or workup which helps to improve the greenness of industrial processes which in turn makes the process economic cost effective and eco-friendly;
v) water is non-toxic as compared to other organic solvents also water is considered the greenest solvent the idea of “green” solvents expresses the goal to minimize the environmental impact resulting from the use of solvents;
vi) using aqueous media for the isolation of Formula(I) leads to inconsistency in yields due to high solubility of Formula(I) in water, however the present invention provides that formula(I) is highly insoluble in diluted hydrochloric acid medium;
vii) the present invention provides not only eco-friendly commercial adoptable but also provides high yield with high pure compound with any impurities not more than 0.1 %;
viii) the solvents employed for purification and isolation of substantially pure (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride is selected from water, toluene, EtOAc, MeOH in EtOAc or mixtures thereof more preferably EtOAc;
ix) solvents recovered, can be reused after distillation, solvent recovery is a form of waste reduction and alternative to improving the greenness of industrial processes and which makes the process economic cost effective and eco-friendly;
x) the process avoids the use of expensive raw materials;
xi) the present invention provides a process for preparation of (1R,2S)-2-(3,4- difluorophenyl)cyclopropan-1-amine hydrochloride compounds which is advantageously reduces the impurity;
xii) the present invention provides a process for preparation of (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride compounds which is faster and cost-effective, eco-friendly and
xiii) the overall yield of the product is increased, and it is also substantially pure.

The present invention provides an improved process for the preparation of substantially pure (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride a Ticagrelor intermediate compound of formula (I).
In one aspect of the present application provides a process of isolating substantially pure compound of formula (I) or a salt thereof,

Formula (I)
which comprises:
a) isolating substantially pure compound of Formula (I) by treating with dilute hydrochloric acid aqueous solution;
b) washed with water, acidic water, methanol, ethanol, isopropyl alcohol, isopropyl acetate, tert-butanol, tert-Butyl acetate, acetone, THF, 2-methyl THF, MTBE, ethyl acetate and toluene or mixture thereof;
c) the % of any impurity is not more than 0.1%;
d) wherein compound of Formula (I) preparing from any one of the compounds having Formula (V) or Formula (VI) or Formula (VIa) or Formula (VII);

Formula (V); Formula (VIa); Formula (VII);

Formula (VI).

In an aspect of the present application provides an improved process for preparation of compound formula (I)

Formula (I)

a) reacting compound of formula (II) with thionyl chloride and solvent gives compound of formula (III); wherein the solvents are selected from toluene, benzene, acetonitrile, DMF, THF and 2-methy THF to form compound of formula (III);

Formula (III)
b) reacting compound of formula (III) with metal azides in presence of phase-transfer catalyst and solvent in aqueous base gives compound of formula (IV); wherein the azides are sodium azide, potassium azide and phase-transfer catalysts selected from TBAB, TBAF, TBAH, TEBA, TBAHS or TBAI and solvents are selected from toluene, benzene, acetonitrile, and the bases are selected from Na2CO3, K2CO3, NaHCO3 to form compound of formula (IV);

Formula (IV)
c) treating compound of formula (IV) with solvent gives compound of formula (V); wherein the solvents are selected from toluene, benzene, acetonitrile, THF and 2-methy THF most preferable hot toluene to form compound of formula (V);

Formula (V)
d) treating compound of formula (V) with acid in presence appropriate solvent at 60oC to 90oC to gives compound of formula (I); wherein the acid is selected from sulfuric acid (H2SO4), hydrochloric acid (HCl), and nitric acid (HNO3) mixture thereof more preferably hydrochloric acid (HCl) and the solvents selected from toluene, xylene, chloro benzene, acetonitrile, THF, 2-methy THF, diglyme more preferably toluene and xylene to form compound of formula (I); wherein the high pure compound of formula (I) isolated from diluted hydrochloric acid media of the reaction mixture after the conversion of 1,2-difluoro-4-((1S,2R)-2-isocyanato cyclopropyl) benzene is complete; wherein in the precipitated (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride isolated from diluted hydrochloric acid media is filter and wash; wherein the solvent for washing is selected form water, toluene, ethyl acetate, methanol, acetone, THF, 2-methyl THF, diglyme, acidic water or mixture thereof preferably acidic water, water, ethyl acetate and toluene or mixture thereof and dried to get the high pure compound of formula (I)
The present invention provides an improved process for the preparation of substantially pure (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride a Ticagrelor intermediate compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION
The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly indictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it is individually recited herein.
All processes described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus, if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description that follows, and the embodiments described herein, is provided by way of illustration of an example, or examples, of embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
It should also be appreciated that the present invention can be implemented in numerous ways, including as a system, a method, or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.
Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
The term, “halogen” as used herein refers to chlorine, fluorine, bromine or iodine.
In one embodiment of the present invention is to provide a process of isolating substantially pure compound of formula (I) or a salt thereof,

Formula (I)
which comprises:
a) isolating substantially pure compound of Formula (I) by treating with dilute hydrochloric acid aqueous solution;
b) washed with water, acidic water, methanol, ethanol, isopropyl alcohol, isopropyl acetate, tert-butanol, tert-Butyl acetate, acetone, THF, 2-methyl THF, MTBE, ethyl acetate and toluene or mixture thereof;
c) the % of any impurity is not more than 0.1%;
d) wherein compound of Formula (I) is preparing from any one of the compounds having Formula (V) or Formula (VI) or Formula (VIa) or Formula (VII);

Formula (V); Formula (VIa); Formula (VII);

Formula (VI).
In one embodiment the present invention particularly describes improved process for the preparation of substantially pure (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride a Ticagrelor intermediate compound of formula (I).
In one embodiment the following scheme- 1 describes the process for the preparation of (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride compound of formula (I)

Scheme 1

In another embodiment stage (a) of the present process involves compound of formula (II) with thionyl chloride and solvent gives compound of formula (III); wherein the solvents are selected from toluene, xylene, chrobenzene, benzene, acetonitrile, THF and 2-methy THF to form compound of formula (III);

In another embodiment stage (b) of the present process involves compound of formula (III) with metal azides in presence of phase-transfer catalyst and solvent in aqueous base gives compound of formula (IV); wherein the azides selected from sodium azide, potassium azide, phase-transfer catalysts selected from TBAB, TBAF, TBAH, TEBA, TBAHS or TBAI, solvents are selected from toluene, xylene, chlrobenzene, benzene, acetonitrile and the bases are selected from Na2CO3, K2CO3, NaHCO3 to form compound of formula (IV);

In another embodiment stage (c) of the present process involves compound of formula (IV) treated with solvents gives compound of formula (V); wherein the solvents are selected from toluene, benzene, xylene, chlrobenzene, acetonitrile, THF and 2-methy THF more preferably toluene to form compound of formula (V);

In another embodiment stage (d) of the present process involves compound of formula (V) treated with acid gives compound of formula (I); wherein the acid is hydrochloric acid (HCl) to form compound of formula (I);

In another embodiment compound of formula (V) with acid in presence appropriate solvent at 60oC to 90oC for 1 to 2 hours gives compound of formula (I), which is then isolated from diluted hydrochloric acid media of the reaction mixture and treated, washed with solvent to get high pure compound of formula (I); wherein the acid is selected from diluted hydrochloric acid (HCl) and the solvents selected from toluene, xylene, chlorobenzene, acetonitrile, THF, 2-methy THF, diglyme more preferably toluene to form compound of formula (I); wherein the high pure compound of formula (I) isolated from diluted hydrochloric acid media of the reaction mixture after the conversion of 1,2-difluoro-4-((1S,2R)-2-isocyanato cyclopropyl) benzene is complete; wherein in the precipitated (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride isolated from diluted hydrochloric acid media is separate and wash; wherein the solvents for washing is selected form acidic water, water, toluene, ethyl acetate, methanol, acetone, THF, 2 methyl THF, diglyme or mixture thereof more preferably acidic water , water, ethyl acetate, and toluene or mixture thereof and dried to get the high pure compound of formula (I);
In another embodiment the present invention specifically describes improved process for the preparation of substantially pure (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride a Ticagrelor intermediate compound of formula (I).

In one embodiment the following scheme- 2 describes the process for the preparation of (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine hydrochloride compound of formula (I)

Scheme 2

In another embodiment for stage(e) and stage (f) in above scheme specified process adopted from WO2008018823A1 to prepare compound of Formula (VIa).
In another embodiment compound of formula (VIa) with NaOH and Sodium hypochlorite in presence appropriate solvent at 20oC to 50oC to gives compound of formula (VI), which is then extracted into organic solvent is selected from isopropyl acetate, tert-Butyl acetate, ethyl acetate ; wherein the organic solution of compound of formula (VI) treated with diluted hydrochloric acid (HCl) to get compound of formula (I), which is then isolated from diluted hydrochloric acid media of the reaction mixture; wherein the solvent for washing is selected form water, toluene, isopropyl acetate, tert-Butyl acetate, ethyl acetate, methanol, acetone, THF, acidic water, 2 methyl THF, diglyme or mixture thereof more preferably water, ethyl acetate, acidic water and toluene or mixture thereof and dried to get the compound of formula (I);wherein the filtered compound of formula (I) further treated with solvents to get the substantially pure compound of formula (I); wherein in the solvents selected form ethyl acetate, toluene, methanol, isopropyl acetate, tert-Butyl acetate, MTBE, Ethanol, THF and mixture thereof, more preferably ethyl acetate, toluene, methanol and mixture thereof.
In another embodiment of the present invention is to provide an improved process for the preparation of substantially pure compound of formula (I) solid isolated from ethyl acetate, methanol, MTBE- or mixture thereof.
In certain embodiment of the present invention is to provide a process for the preparation of high pure compound of formula (I) or a salt thereof

Formula (VII) Formula (I)

which comprises
a) reacting 1,2-difluoro-4-((1S,2R)-2-nitrocyclopropyl)benzene compound of formula (VII) (which can be prepared by known processes) with Zn/acidic medium in appropriate solvent to give compound of formula (I).
The compounds obtained by the chemical transformations of the present application can be used for subsequent steps without further purification, or can be effectively separated and purified by employing a conventional method well known to those skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt followed by optionally washing with an organic solvent or with an aqueous solution, and eventually adjusting pH. Compounds at various stages of the process may be purified by precipitation or slurrying in suitable solvents, or by commonly known recrystallization techniques. The suitable recrystallization techniques include, but are not limited to, steps of concentrating, cooling, stirring, or shaking a solution containing the compound, combination of a solution containing a compound with an anti-solvent, seeding, partial removal of the solvent, or combinations thereof, evaporation, flash evaporation, or the like. An antisolvent as used herein refers to a liquid in which a compound is poorly soluble. Compounds can be subjected to any of the purification techniques more than one time, until the desired purity is attained.
Compounds may also be purified by slurrying in suitable solvents, for example, by providing a compound in a suitable solvent, if required heating the resulting mixture to higher temperatures, subsequent cooling, and recovery of a compound having a high purity. Optionally, precipitation or crystallization at any of the above steps can be initiated by seeding of the reaction mixture with a small quantity of the desired product. Suitable solvents that can be employed for recrystallization or slurrying include, but are not limited to: alcohols, such as, for example, methanol, ethanol, and 2-propanol; ethers, such as, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), and methyl THF; esters, such as, for example, ethyl acetate, xylene, chlorobenzene, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; hydrocarbons, such as toluene, xylene, and cyclohexane; nitriles, such as acetonitrile and the like; water; and any mixtures of two or more thereof.
In another embodiment the below are the abbreviations are used in the specification;
DMF-dimethylformamide; SOCl2- thionyl chloride; NaN3-Sodiumazide; HCl- Hydrochloric acid; NaOH-Sodium Hydroxide; MTBE- Methyl tert-butyl ether, TLC- Thin layer chromatography; TBAB- Tetrabutylammonium bromide, TBAHS- tetrabutylammonium hydrogen sulphate, TBAI- tetrabutyl ammonium iodide, Na2SO4- Sodium sulphate, NMT- not more than, HPLC- High performance liquid chromatography; DCM-Dichloromethane; Na2CO3-Sodium Carbonate; NaHCO3-Sodium bicarbonate, NaH-Sodium hydride; MeOH- Methanol; EtOAc-Ethyl acetate.

EXAMPLES
Example-1
Stage-a: Preparation of trans-(lR, 2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl chloride

To a stirred solution of (1R,2R)-2-(3,4-difluorophenyl) cyclopropanecarboxylic acid compound of formula (II) 100g in toluene 600 ml slowly added catalytic amount of DMF at room temperature. Reaction mass temperature raised to 60 to 70°C then slowly add thionyl chloride 75g at 60 to 70°C. Reaction was monitored by TLC, after completion of starting material solvent was completely distilled off. Reaction mass diluted with toluene at 25°C and use this toluene layer which contains around 110 g of acid chloride in 300 ml of toluene for the next reaction without any further isolation.
Example-2
Stage-b: Preparation of trans-(lR, 2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl azide

To a stirred suspension of sodium azide (35.6g) in 200mL of water slowly added tetrabutylammonium bromide (2.0 g) and sodium carbonate (29.6 g). The above obtained acid chloride solution was added to this suspension at 0°C to 10°C. Reaction was monitored by TLC, after completion of starting material reaction mass further diluted with water and compound was extracted in to toluene. And toluene layer was washed with water to obtain 112 g of acyl azide in 350 ml of toluene which was proceed for the next reaction without any further isolation.
Example-3
Stage-c and stage-d: Preparation of trans-(lR,2S)-2-(3,4-difluorophenyl)cyclopropylamine Hydrochloride:

The above acyl azide solution was added to a pre heated toluene under azotropic condition 100 to 110 and maintain for 1 to 2 hrs till starting material complies by TLC to obtain 1,2-difluoro-4-((1S,2R)-2-isocyanatocyclopropyl)benzene compound of formula(V). After completion of starting material reaction mass, slowly added to diluted HCl solution (500 mL) stirring at 70°C to 80°C. Reaction monitored by TLC after completion of starting material, aqueous layer was separated and washed with toluene. Obtained aqueous layer cooled to 0°C to 5°C. Solid was filtered and washed with toluene and dried at 60°C to 65°C. resulting solid taken into ethyl acetate and heated to 60°C to 70°C for 30 to 45 min. reaction mass cooled to room temperature and filtered washed with ethyl acetate to get pure compound of formula–(I). yield: 87.52g HPLC 99.789%.
Example-4
Stage-c and stage-d: Preparation of trans-(lR,2S)-2-(3,4-difluorophenyl)cyclopropylamine Hydrochloride:

The above acyl azide solution was added to a pre heated toluene under azotropic condition 100 to 110 and maintain for 1 to 2 hrs till starting material complies by TLC to obtain 1,2-difluoro-4-((1S,2R)-2-isocyanatocyclopropyl)benzene compound of formula(V). After completion of starting material reaction mass, slowly added to diluted HCl solution (500 mL) stirring at 70°C to 80°C. Reaction monitored by TLC after completion of starting material, aqueous layer was separated and washed with toluene. Obtained aqueous layer cooled to 0°C to 5°C. Solid was filtered and washed with ethyl acetate and dried at 60°C to 65°C, to get pure compound of formula–(I). yield: 86.8g HPLC 99.7%.
Example-5
Stage(g): Preparation of trans-(lR,2S)-2-(3,4-difluorophenyl)cyclopropylamine Hydrochloride:

(1R,2R)-2-(3,4-difluorophenyl)cyclopropane-1-carboxamide(VIa) (18.0g) and 30% sodium hydroxide aqueous solution (100g) were charged into a reaction vessel and the mixture was stirred, to this mixture aqueous 12% sodium hypochlorite solution (60g) was added the slurry maintaining the internal temperature at 30oC. The resultant mixture was stirred at 30oC for 13 hours, then at 40oC for 2 hours. After completion of the reaction, isopropyl acetate was poured to the resultant mixture, then the organic layer was separated, washed with water, to this slowly added 70mL of 6N HCl at 0 oC to 5oC and raise the reaction mass temperature to 70 oC to 80 oC, and two layers were separated and aqueous layer cooled to 0°C to 5°C. Solid was filtered and washed with ethyl acetate and dried at 60°C to 65°C, to get pure formula–I. yield: 86.8g HPLC 99.7%.

Example- 6
Preparation of (1R, 2S)-2-(3, 4-difluorophenyl)cyclopropanamine

1, 2-difluoro-4-((1S, 2R)-2-nitrocyclopropyl)benzene (5 g), and methanol charged into reaction vessel, then added zinkdust 5 g and acetic acid at room temperature and stirred at room temperature till TLC complies. Reaction mass filtered over celite and bed was washed with methanol. Reaction mass was basified with 1N sodium hydroxide and compound was extracted into ethyl acetate. then the organic layer was washed with water, to this slowly added 30 mL of 6N HCl at 0 oC to 5oC and raise the reaction mass temperature to 70 oC to 80 oC, and two layers were separated, and aqueous layer cooled to 0°C to 5°C. Solid was filtered and washed with ethyl acetate and dried at 60°C to 65°C, to get pure formula (I), yield: 2.1 g.
,CLAIMS:1. A process of isolating substantially pure compound of formula (I) or a salt thereof,

Formula (I)
which comprises
a) isolating substantially pure compound of Formula(I) by treating with dilute hydrochloric acid aqueous solution;
b) washed with water, acidic water, methanol, ethanol, isopropyl alcohol, isopropyl acetate, tert-butanol, tert-butyl acetate, acetone, THF, 2-methyl THF, MTBE, ethyl acetate and toluene or mixture thereof;
c) the % of any impurity is not more than 0.1%;
d) wherein compound of Formula (I) preparing from any one of the compounds having Formula (V) or Formula (VI) or Formula (VIa) or Formula (VII);

Formula (V); Formula (VIa); Formula (VII);

Formula (VI).
2. The process as claimed in claim 1, washing solvent selected from methanol, ethanol, water, acidic water, ethyl acetate and toluene or mixture thereof.

3. The process as claimed in claim 1, the preparation of compound of formula (I) or a salt thereof

Formula (I)
which comprises
a) reacting (1R,2R)-2-(3,4-difluorophenyl)cyclopropane-1-carboxylic acid compound of formula (II) (which can be prepared by known processes) with thionyl chloride in appropriate solvent at 60oC to 80oC gives compound of formula (III);


Formula (II) Formula (III)
b) reacting compound of formula (III) with metal azides in presence of phase-transfer catalyst and solvent in presence of aqueous base at 0oC to 20oC gives compound of formula (IV);

Formula (IV)
c) treating compound of formula (IV) with suitable solvent at 80 oC to 120oC gives compound of formula (V);

Formula (V)
d) reacting compound of formula (V) with acid in presence of appropriate solvent at 60oC to 90oC to give compound of formula (I); treating compound of Formula (I) with dilute hydrochloric acid aqueous solution; and isolating substantially pure compound of Formula (I) from dilute hydrochloric acid aqueous solution; washed with water, acidic water, methanol, ethanol, isopropyl alcohol, isopropyl acetate, tert-Butyl acetate, acetone, THF, 2-methyl THF, diglyme, ethyl acetate and toluene or mixture thereof.
4. The process as claimed in claim 1, the preparation of compound of formula (I) or a salt thereof

Formula (I)
which comprises
a) reacting (1R,2R)-2-(3,4-difluorophenyl)cyclopropane-1-carboxylic acid compound of formula (II) (which can be prepared by known processes from the corresponding ester) with thionyl chloride in appropriate solvent at 60oC to 80oC gives compound of formula (III);

Formula (II) Formula (III)
b) reacting compound of formula (III) with ammonium hydroxide in appropriate solvent at gives compound of formula (IVa);

Formula (VIa)
c) treating compound of formula (VIa) (which can be prepared by known processes) with NaOH and Sodium hypochlorite in presence appropriate solvent at 20oC to 50oC to give compound of formula (VI), which is then extracted into organic solvent; wherein organic solvent is selected from isopropyl acetate, tert-Butyl acetate, ethyl acetate and the organic solution of compound of formula (VI) treated with diluted hydrochloric acid to give compound of formula (I), and the compound of formula (I) filtered and isolated from diluted hydrochloric acid media, and washed to get high pure compound of formula (I).
5. The process as claimed in claim 1, the preparation of compound of formula (I) or a salt thereof

Formula (VII) Formula (I)

which comprises
reacting 1,2-difluoro-4-((1S,2R)-2-nitrocyclopropyl)benzene compound of formula (VII) (which can be prepared by known processes) with Zn/acidic medium in appropriate solvent to give compound of formula (I).