DESC:The following specification describes the nature of the application:
INTRODUCTION
The present application relates to improved processes for the preparation of intermediates useful in the preparation of Ticagrelor.
Ticagrelor and similar such compounds, are disclosed in WO 00/34283 and WO 99/05143 as pharmaceutically active P2T (which is now usually referred to as P2Y12) receptor antagonists. Such antagonists can be used as, inter alia, as inhibitors of platelet activation, aggregation, or degranulation. The compounds of Formula I is useful in the preparation of Ticagrelor or analogues thereof.
The present application provides a novel process for the preparation of a compound of Formula I or its salts:

Processes for the preparation of the compound of Formula I are described in Patent Application Publications. WO 01/92200 A1, WO 2008/018823 A1, and WO 2008/018822 A1, WO 2011/132083A2, WO 2012/001531A2, WO 2013/124280A1, WO 2013/144295A1, WO 2018/090929A1. These publications involve use of multi-step synthesis and/or use of chiral auxiliary for the preparation of the compound of Formula I. The reported methods results in low yields, involve use of expensive chiral compounds, and further do not directly result in desired purities of the intermediate compound of Formula I. Thus these processes may require an additional step of purification. Since the purity of intermediate compound play a major role in deciding the efficiency of the process for final compound, therefore there remains a need to prepare compounds of Formula I of high purity and in good yield. Despite the efforts of the research aimed at finding alternative routes, it would be desirable to study methods for preparing intermediate compound of Formula I, which allow overcoming the drawbacks presented by the processes described in the art.
The present application further provides an improved process for the preparation of a compound of Formula II or its salts:

Processes for the preparation of the compound of Formula II or its salts, its precursor compounds are described in Patent Application Publications WO 01/92263 A1, WO 2005/095377 A1 and WO 2009/064249 A1, WO 2010/030224A1, WO2012/158099A1, WO 2012/139455A1, WO 2015/067110A1, WO 2015/067111A1, WO 2012/063126A2, WO 2012/142983A1, WO 2012/172426A1, EP2666771A1.
The processes for the preparation of intermediates of Ticagrelor described in the prior art discussed above suffer from various disadvantages, such as multi-step synthesis and/or use of low temperature to minimize the side-reactions, use of chiral acid for resolution of key starting material, tedious and cumbersome work-up procedures, use of not so environment friendly solvents, reactions under pressure and high temperature, longer reaction times, column chromatographic purifications and thus resulting in low overall yields of the product.
Thus there remains a need to prepare intermediates of Ticagrelor of high purity and in good yield while overcoming the drawbacks presented by the processes described in the art.
Therefore, present application provides an improved and/or novel processes for the preparation of intermediates of Ticagrelor which is simple, cost effective, environment friendly and commercially viable by avoiding repeated cumbersome and lengthy purification steps.
SUMMARY
In first embodiment, the present application provides a novel process for preparation of compound of Formula I or its salts thereof, which comprises:
a) reacting 1,2-difluorobenzene with compound of Formula “R” to afford a compound of Formula Ia,

b) reducing the compound of Formula Ia with DIP-Cl to afford a compound of Formula Ib,

c) converting the compound of Formula Ib to a compound of Formula I.

In second embodiment, the present application provides an improved process for the preparation of compound of Formula I, which comprises reducing the compound of Formula Ia with DIP-Cl to afford a compound of Formula Ib,

In third embodiment, the present application provides a novel process for the preparation of compound of Formula I, which comprises reacting 1,2-difluorobenzene with a compound of Formula “R” to afford a compound of Formula Ia,

In fourth embodiment, the present application provides an improved process for preparation of compound of Formula II or its salts, which comprises, reacting a compound of Formula IIa with ethylene sulphite under suitable conditions to afford compound of Formula IIb followed by deprotection.

In a fifth embodiment, the present application provides an improved process for preparation of compound of Formula III, which comprises, reacting a compound of Formula IIIa with potassium permanganate under suitable reaction conditions.

DETAILED DESCRIPTION
In first embodiment, the present application provides a novel process for preparation of compound of Formula I or its salts thereof, which comprises:
a) reacting 1,2-difluorobenzene with compound of Formula “R” to afford a compound of Formula Ia,

Step a) involves a Friedel-Crafts reaction of 1, 2-difluorobenzene with reagent of Formula “R”.
There is no particular restriction on the nature of the acid catalysts used, and any Lewis acid commonly used in reactions of this type may equally be used here. Examples of Lewis acid include, but are not limited to: aluminium trichloride (AICI3), boron trichloride (BCI3), ferric chloride (FeCl3), boron trifluoride (BF3), boron trifluoride etherate (BF3OEt2), zinc chloride (ZnCl2), aluminum bromide. aluminum chloride THF complex, or the like.
In a preferred embodiment, aluminium trichloride (AICI3) as Lewis acid and 3-nitro-propanoyl chloride as a reagent are employed.
The step a) can optionally be carried out in presence of solvent. Suitable solvents inert to the reaction conditions can be chosen from the list provided in the application. In a preferred embodiment, dichloromethane is employed.
b) reducing the compound of Formula Ia with DIP-Cl to afford a compound of Formula Ib,

Suitable solvents inert to the reaction conditions can be chosen from the list provided in the application. In a preferred embodiment, toluene is employed.
Suitable temperatures in step b) may be less than about 40°C, or less than about 20°C, or less than about 5°C, or any other suitable temperatures.
c) converting the compound of Formula Ib to compound of Formula I.
The said conversion can be done by using an adaptation of literature methods, such as described in WO 2011132083, WO 2012085665, EP 2589587 or the method further described in the instant application.
In second embodiment, the present application provides an improved process for the preparation of compound of Formula I, which comprises reducing the compound of Formula Ia with DIP-Cl to afford a compound of Formula Ib,

Reaction conditions described above can be employed for instant embodiment.
In third embodiment, the present application provides a novel process for the preparation of compound of Formula I, which comprises reacting 1,2-difluorobenzene with a compound of Formula “R” to afford a compound of Formula Ia,

The “X” in compound of Formula “R” can be halogen or a suitable leaving group. In a preferred embodiment, X is Chlorine.
Suitable solvents inert to the reaction conditions can be chosen from the list provided in the application. In a preferred embodiment, dichloromethane is employed.
In fourth embodiment, the present application provides an improved process for preparation of compound of Formula II or its salts, which comprises, reacting a compound of Formula IIa with ethylene sulphite under suitable conditions to afford compound of Formula IIb followed by deprotection.

The Pg in compounds of Formulae IIa and IIb is a suitable protecting group, like the ones disclosed in T. W. Greene et al., Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, Inc., 1999, and other groups are described in the literature.
In a preferred embodiment, Pg is “phthalimide group”.
Suitable solvents inert to the reaction conditions can be chosen from the list provided in the application. In preferred embodiments, polar aprotic solvents are employed such as N,N’-dimethyl formamide (DMF), N,N’-dimethyl acetamide (DMAc), N-methyl pyrrolidone (NMP) and like. In a most preferred embodiment, N,N’-dimethyl formamide is employed.
The deprotection can be carried out under suitable reaction conditions as per the literature adopted methods.
In a preferred embodiment, hydrazine hydrate is employed for deprotection.
In a fifth embodiment, the present application provides an improved process for preparation of compound of Formula III, which comprises, reacting a compound of Formula IIIa with potassium permanganate under suitable reaction conditions.

The Pg in compounds of Formulae IIa and IIb is a suitable protecting group, like the ones disclosed in T. W. Greene et al., Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, Inc., 1999, and other groups are described in the literature.
In a preferred embodiment, Pg is “phthalimide group”.
Suitable solvents inert to the reaction conditions can be chosen from the list provided in the application. In preferred embodiments, acetone is employed.
The chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification, may be carried out at ambient temperatures, but particular reactions may require the use of higher or lower temperatures, depending on reaction kinetics, yields, and the like. Furthermore, any of the chemical transformations may employ one or more compatible solvents, which may influence the reaction rates and yields. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents, polar aprotic solvents, non-polar solvents, water or any of their combinations.
Suitable solvents inert to the reaction conditions include but are not limited to: alcohols, such as methanol, ethanol, 2-propanol, n-butanol, isoamyl alcohol and ethylene glycol; ethers, such as diisopropyl ether, dimethoxyethane, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), methyl THF, and diglyme; esters, such as ethyl acetate, isopropyl acetate, and t-butyl acetate and like; ketones, such as acetone and methyl isobutyl ketone and like; aliphatic hydrocarbons like n-hexane, cyclohexane, iso-octane and like; aromatic hydrocarbons like toluene, xylene and like; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and like; nitriles, such as acetonitrile; polar aprotic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, and the like; water; and any mixtures of two or more thereof.
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 anti-solvent 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, 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.
The compounds at various stages of the process may be recovered using conventional techniques known in the art. For example, useful techniques include, but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, and the like. The isolation may be optionally carried out at atmospheric pressure or under a reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher than desired percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor. Evaporation as used herein refers to distilling a solvent completely, or almost completely, at atmospheric pressure or under a reduced pressure. Flash evaporation as used herein refers to distilling of solvent using techniques including, but not limited to, tray drying, spray drying, fluidized bed drying, or thin-film drying, under atmospheric or a reduced pressure.
A recovered solid may optionally be dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 150°C, less than about 100°C, less than about 60°C, or any other suitable temperatures, in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, from about 1 hour to about 15 hours, or longer.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The term “about” when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1% of its value. For example “about 10” should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, isoamyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
A “hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called “aromatic.” Examples of “C5-C8 aliphatic or aromatic hydrocarbons” include, but are not limited to, isopentane, neopentane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6 esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include, but are not limited to, diethyl ether, diisopropyl ether, dimethoxy ethane, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A “polar aprotic solvent” has a dielectric constant greater than 15 and includes: amide-based organic solvents, such as hexamethyl phosphoramide (HMPA), hexamethyl phosphorus triamide (HMPT), and N-methylpyrrolidone, nitro-based organic solvents, such as nitromethane, nitroethane, nitropropane, and nitrobenzene; ester-based organic solvents, such as ?-butyrolactone, ethylene carbonate, propylene carbonate, butylene carbonate, dimethyl carbonate, and propiolactone; pyridine-based organic solvents, such as pyridine and picoline; and sulfone-based solvents, such as dimethylsulfone, diethylsulfone, diisopropylsulfone, 2-methylsulfolane, 3-methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethylsulfolane, 3-sulfolane, and sulfolane.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6 Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.
Any organic solvents may be used alone, or any two or more may be used in combination, or one or more may be used in combination with water in desired ratios.
Acid addition salts are typically pharmaceutically acceptable, non-toxic addition salts with “suitable acids,” including, but not limited to: inorganic acids such as hydrohalic acids (for example, hydrofluoric, hydrochloric, hydrobromic, and hydroiodic acids) or other inorganic acids (for example, nitric, perchloric, sulfuric, and phosphoric acids); organic acids, such as organic carboxylic acids (for example, xinafoic, oxalic, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, 2- or 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 2- or 4-chlorobenzoic, salicylic, succinic, malic, hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, oleic, and glutaric acids), organic sulfonic acids (for example, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, 2-hydroxyethanesulphonic, benzenesulfonic, toluene-p-sulfonic, naphthalene-2-sulphonic, and camphorsulfonic acids), and amino acids (for example, ornithinic, glutamic, and aspartic acids).
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at the very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material has 99% purity or higher, as determined using methods conventional in the art such as high performance liquid chromatography (HPLC), gas chromatography (GC), or spectroscopic methods. In general, this refers to purity with regard to unwanted residual solvents, reaction by-products, impurities, and unreacted starting materials. In the case of stereoisomers, "pure" also means 99% of one enantiomer or diastereomer, as appropriate. "Substantially pure” refers to the same as "pure,” except that the lower limit is about 98% purity or higher and, likewise, "essentially pure” means the same as "pure" except that the lower limit is about 97% purity.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

EXAMPLES
Example 1: Preparation of 2-((3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)isoindoline-1,3-dione (Formula IIb)
A flask was charged with isopropyl magnesium bromide (0.075 g), N, N’-dimethyl formamide (50 mL) and sodium hydride (2.37 g). The reaction mixture was cooled to 10oC followed by sequential and slow addition of 2-((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)isoindoline-1,3-dione (10 g) and ethylene sulphite (14.26 g) at the same temperature. The mixture was maintained at about 7oC for overnight and then quenched with sodium hydrogen phosphate (100 mL) followed by extraction with ethyl acetate (2x50 mL). The ethyl acetate layer was washed with water (100 mL) and then subjected to complete distillation under vacuum to afford the crude compound which was purified by column chromatography using ethyl acetate and hexane to afford the title compound.

Example 2: Preparation of 2-((3aS, 4R, 6S, 6aR)-6-(2-hydroxyethoxy)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)isoindoline-1,3-dione (Formula IIb)
A flask was charged with isopropyl magnesium chloride (0.075 g), N, N-dimethyl acetamide (20 mL) and sodium hydride (0.63 g). The reaction mixture was cooled to 10oC followed by sequential and slow addition of 2-((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)isoindoline-1,3-dione (2 g) and ethylene sulphite (4.28 g) at the same temperature. The mixture was maintained at about 0oC for 2 hours followed by further addition of sodium hydride (0.3 g) and ethylene sulphite (1g) at -10oC and maintenance of reaction mixture at 0oC for overnight and then quenched with potassium hydrogen phosphate (20 mL) followed by extraction with ethyl acetate (20 mL). The ethyl acetate layer was subjected to complete distillation under vacuum to afford the title compound.

Example 3: Preparation of 3-chloro-1-(3,4-difluorophenyl)propan-1-one
A flask was charged with dichloromethane (400 mL) and aluminium chloride (219 g) and stirred at 20-25oC for 15-20 minutes followed by addition of 1,2-difluorobenzene (200 g) and 3-chloropropionyl chloride (234 g) at about 20oC. The mixture was maintained at the same temperature for overnight and then cooled to 0-5oC. Then mixture was quenched with water (1000 mL), extracted with dichloromethane (2x400 mL). The combined organic layer was sequentially washed with 10% sodium bicarbonate solution (1000 mL) and water (1000 mL). The organic layer was subjected to complete distillation under vacuum to afford the title compound.

Example 4: Preparation of 1-(3,4-difluorophenyl)-3-nitropropan-1-one (Formula Ia)
A flask was charged with 3-chloro-1-(3,4-difluorophenyl)propan-1-one (50 g), N,N-dimethylformamide (200 mL) and mixture was cooled to 0-5oC. Then slowly sodium nitrite (33.7 g) was added to the above mixture at about 0oC and then maintained at about 10-15oC for about 5 hours. After completion of reaction, pre-cooled water was added (2000 mL) and obtained solid was filtered and washed with water (200 mL). The wet compound was slurried in n-hexane (200 mL), filtered and washed with n-hexane (200 mL) followed by drying to afford the title compound.

Example 5: Preparation of (S)-1-(3,4-difluorophenyl)-3-nitropropan-1-ol
A flask was charged with toluene (50 mL) and (-)-DIP-Cl (7.45 g) and cooled to 0-5oC. Then to this mixture, a solution of 1-(3,4-difluorophenyl)-3-nitropropan-1-one (50 g) in toluene (50 mL) was added over a period of 30 minutes. Then the mixture was stirred for overnight at about 10oC. After completion of reaction, brine solution (20 mL) was added and layers were separated. The organic layer was subjected to complete distillation and the obtained crude compound was purified by column chromatography using ethyl acetate and hexane as eluents to afford the title compound.

Example 6: Preparation of (R)-1-(3,4-difluorophenyl)-3-nitropropan-1-ol
A flask was charged with toluene (100 mL) and (+)-DIP-Cl (7.45 g) and cooled to 0-5oC. Then to this mixture, a solution of 1-(3,4-difluorophenyl)-3-nitropropan-1-one (5 g) in toluene (100 mL) was added over a period of 30 minutes. Then the mixture was stirred for overnight at about 10oC. After completion of reaction, brine solution (100 mL) was added and layers were separated. The organic layer was subjected to complete distillation and the obtained crude compound was purified by column chromatography using ethyl acetate and hexane as eluents to afford the title compound.

Example 7: Preparation of 1,2-difluoro-4-(2-nitrocyclopropyl)benzene
A flask was charged with (R)-1-(3,4-difluorophenyl)-3-nitropropan-1-ol (2g), tetrahydrofuran (20 mL), then mixture was maintained to 0-5oC followed by slow and sequential addition of methanesulfonyl chloride (1.26 g) and triethylamine (1.86 g). The mixture was filtered and DBU (4 g) was slowly added at 0oC. The reaction mixture was stirred overnight at room temperature. After completion of reaction, water was added and the desired compound was extracted in ethyl acetate (2x10 mL). The ethyl acetate layer was subjected to complete distillation and the crude was purified by column chromatography using ethyl acetate and n-hexane to afford the title compound.

Example 8: Preparation of (1R, 2S)-2-(3, 4-difluorophenyl)cyclopropanamine
A flask was charged with 1, 2-difluoro-4-((1S, 2R)-2-nitrocyclopropyl)benzene (0.5 g), methanol (3mL) and stirred at room temperature under inert atmosphere. Then slowly zinc dust was added to the mixture and mixture was cooled to 0-5oC followed by slow addition of acetic acid (12 mL) at the same temperature. Then the mixture was maintained at room temperature for overnight followed by filtration and washing of bed with methanol (3mL). Then 1N sodium hydroxide (9mL) was added to the filtrate and desired compound was extracted in dichloromethane (2x12mL). The DCM layer was subjected to complete distillation under vacuum to afford the desired compound.

Example 9: Preparation of 1-(3,4-difluorophenyl)-3-nitropropan-1-one (Formula Ia)
A flask is charged with 3-nitropranoic acid (1g), dichloromethane (10 mL) and cooled to 0-5oC followed by addition of DMF (catalytic) and thionyl chloride (0.73 mL).The reaction mixture was stirred at room temperature for 2 hours followed complete distillation of solvent under vacuum. A separate flask was charged with 1, 2-difluorobenzene (2.87 mL), aluminium chloride (3.35 g), dichloromethane (5 mL) under nitrogen atmosphere and cooled to 0-5oC followed by addition of mixture of above obtained residue in dichloromethane (5 mL) at 0-5oC. The mixture was stirred at room temperature for 2 hours and then quenched by addition of chilled water (100 mL). The organic layer was separated and aqueous layer was extracted with dichloromethane. The organic layers were combined and subjected to complete distillation under vacuum to afford the title compound.

Example 10: Preparation of 2-((1R,2S,3R,4S)-2,3,4-trihydroxycyclopentyl)isoindoline-1,3-dione (Formula III)
A flask was charged with 2-((1R,4S)-4-hydroxycyclopent-2-en-1-yl)isoindoline-1,3-dione (5 g), acetone (250 mL) and the mixture was cooled to -20oC. To this, aqueous acetone solution of potassium permanganate (5.1 g in 50 mL water and 50 mL) was slowly added. The reaction mixture was stirred at -20 to -30oC for 3-4 hours. After completion of reaction, it was quenched with precooled 30% aqueous sodium bisulfite (15 mL) and allowed to attain room temperature followed by filtration through celite bed and washing with acetone (2x20 mL). The aqueous layer was extracted with methanol and dichloromethane and then total organic layer was subjected to complete distillation to afford the crude compound which was slurried in ethyl acetate and hexane to afford the title compound as pale yellow solid.
,CLAIMS:I/We Claim;

Claim 1: A novel process for preparation of compound of Formula I or its salts thereof, which comprises:
a) reacting 1,2-difluorobenzene with compound of Formula “R” to afford a compound of Formula Ia,

b) reducing the compound of Formula Ia with DIP-Cl to afford a compound of Formula Ib,

c) converting the compound of Formula Ib to a compound of Formula I.

Claim 2: The process of claim 1, where “X” is a suitable leaving group or halogen.

Claim 3: A novel process for the preparation of compound of Formula I, which comprises reacting 1,2-difluorobenzene with a compound of Formula “R” to afford a compound of Formula Ia,

Claim 3: An improved process for preparation of compound of Formula II or its salts, comprises reacting a compound of Formula IIa with ethylene sulphite under suitable conditions to afford compound of Formula IIb followed by deprotection.

Claim 4: The “Pg” in compounds of Formulae IIa and IIb is a suitable protecting group.

Claim 5: An improved process for preparation of compound of Formula III, which comprises, reacting a compound of Formula IIIa with potassium permanganate under suitable reaction conditions.

Claim 6: The “Pg” in compounds of Formulae IIIa and III is a suitable protecting group.