Field of the invention:

The present invention relates to an improved process for the preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide compound represented by the following structural formula-1.

The present invention also provides solid state forms of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-1 H-indole-7-carbonitrile compound of formula-5, its hydrochloride salt of formula-5a and also provides a process for the preparation of compound of formula-1 in P-crystalline form.

Background of the Invention:

1 -(3-Hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl] -2,3-dihydro-lH-indole-7-carboxamide is a selective alpha-1 adrenergic receptor antagonist and is currently marketed under the brand name RAPAFLO in United States, Silodyx in Europe and Rapilif in India (Ipca Urosciences). It is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).

1 -(3-Hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl] -2,3-dihydro-lH-indole-7-carboxamide and its pharmaceutically acceptable salts were first disclosed in US5387603A. This patent disclosed a multi-step process for the preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3- dihydro-1 H-indole-7-carboxamide from 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate and l-acetyl-5-(2-aminopropyl)indoline-7-carbonitrile.

Various processes for the preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-l H-indole-7-carboxamide and its intennediates have been disclosed in JP2001-199956, JP2002-265444, JP2006-188470, WO2011030356A2, WO2011101864A1 and WO2011124704A1.

One of the major disadvantages with the prior-art processes is the formation of the dimer impurity represented by the structural formula

Dimer impurity during the condensation of the 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yljpropyl benzoate or its tartrate salt with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate. This impurity is formed due to the reaction of one molecule of benzoate compound with two molecules of methanesulfonate compound. The content of the dimer impurity in the condensation product is found to be nearly 10-15%. Due to the formation of this dimer impurity the yield and purity of the product becomes very low. In order to meet the ICH purity levels the content of the dimer impurity must be reduced to non-detectable levels.

As the above said dimer impurity is not removed by the general purification techniques such as recrystallization, there is a significant need in the art to develop a process for the removal of dimer impurity foiTned in the condensation step.

Advantages of the present invention:

• Provides an effective process for the removal of dimer impurity formed during the condensation of 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate compound of formula-2 with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate compound of formula-3.

• Provides 1 -(3-hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino) propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5 and its hydrochloride salt compound of formula-5a in crystalline forms.

• Provides a time-saving and industrially applicable process for the preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide compound of fomiula-l with high yield and purity.

• Provides a process for the preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2- tritluoroethoxy)phenoxy]ethyi} amino)propyl]-2,3-dihydro-1 H-indole-7-carboxamide compound of formula-1 in |3-crystalline form.

Brief Description of the Invention:

The first aspect of the present invention is to provide an improved process for the preparation of 1 -(3-hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino) propyI]-2,3-dihydro-lH-indoIe-7-carbonitriIe compound of formula-5 as a solid, comprising of;

a) Condensing the 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate compound of formula-2 with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate compound of formula-3 in presence of dipotassium hydrogen phosphate and optionally in presence of a phase transfer catalyst in a suitable solvent to provide 3- {7-cyano-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-1 H-indol-1 -yl} propyl benzoate compound of formula-4,

b) in-situ hydrolyzing the compound of formula-4 in presence of a suitable base and optionally in presence of a phase transfer catalyst in a suitable solvent to provide l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5,

c) purifying the compound of formula-5 by in-situ treating with a suitable adid followed by treating with a suitable base and then isolating from a suitable solvent to provide pure l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5 as a solid.

The second aspect of the present invention is to provide an improved process for the preparation of 1 -(3-hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino) propyl]-2,3-dihydro-lH-indole-7-carboxamide compound of formula-1, comprising of;

a) Condensing the 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate compound of fonTiula-2 or its tartrate salt compound of formula-2a with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate compound of formula-3 in presence of a suitable base in a suitable solvent to provide 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-l H-indol-l-yl}propyl benzoate compound of formula-4,

b) in-situ hydrolyzing the compound of forTnula-4 in presence of a suitable base and optionally in presence of a phase transfer catalyst in a suitable solvent to provide l-(3-hydroxypropyl)-5-

[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-S,

c) purifying the compound of formula-5 by in-situ treating with a suitable acid followed by treating with a suitable base in a suitable solvent followed by isolating from a suitable solvent to provide pure 1 -(3-hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5 as a solid,

d) hydrolyzing the compound of formula-5 in presence of a suitable base in a suitable solvent to provide l-(3-hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino) propyl]-2,3-dihydro-lH-indole-7-carboxamide compound of formula-1,

e) optionally purifying the compound of formula-1 from a suitable solvent.

The third aspect of the present invention is to provide a purification process for l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5 comprising of treating the compound of formula-5 with a suitable acid followed by treating with a suitable base in a suitable solvent to provide pure l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5.

The fourth aspect of the present invention is to provide l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-1 H-indole-7-carbonitrile compound of formula-5 in crystalline form.

The fifth aspect of the present invention is to provide crystalline l-(3-hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-1 H-indole-7-carbonitrile hydrochloride salt compound of formula-5a.

The sixth aspect of the present invention is to provide a process for the preparation of 1 -(3-hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide compound of formula-1 in P-crystalline foim.

Brief description of the drawings:

Figure-l: Illustrates the X-Ray powder diffraction pattern of ciystalline fonn-M of l-(3- hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3- dihydro- lH-indole-7-caibonitrile compound of formula-5

Figure-2: Illustrates the X-Ray powder diffraction pattern of crystalline form-S of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitriIe hydrochloride salt compound of formula-5a

Detailed description of the invention:

The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethylether, diethylether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofiiran and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, dioxane, acetonitrile and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform and the like; "ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, t-butanol and the like; "polar solvents" such as water; and/or their mixtures thereof.

As used herein the present invention the term "suitable base" refers to "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 hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium tert.butoxide and the like; alkali metal phosphates such as disodium hydrogen phosphate, dipotassium hydrogen phosphate and organic bases like diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine and the like.

The first aspect of the present invention provides an improved process for the preparation of 1 -(3-hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-1 H-indole-7-carbonitrile compound of fonnula-5 as a solid, comprising of;

a) Condensing the 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate compound of formula-2

with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate compound of formula-3 FjCO

Formula-3

in presence of dipotassium hydrogen phosphate and optionally in presence of a phase transfer catalyst in a suitable solvent to provide 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate compound of formula-4,

Formula-4

b) in-situ hydrolyzing the compound of fonnula-4 in presence of a suitable base and optionally in presence of a phase transfer catalyst in a suitable solvent to provide l-(3-hydroxypropyl)-5- [(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7- carbonitrile compound of formula-5,

Formula-5

c) purifying the compound of formula-5 by in-situ treating with a suitable acid followed by treating with a suitable base and isolating from a suitable solvent to provide pure l-(3- hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3- dihydro-1 H-indole-7-carbonitrile compound of fonuula-S as a solid.

Wherein, in step-a) and step-b) the phase transfer catalyst is selected from tetra butyl ammonium bromide (TBAB), tetrabutyl ammonium iodide, tetramethyl ammonium chloride, preferably tetra butyl ammonium bromide; the suitable solvent is selected from hydrocarbon solvents, alcoholic solvents, polar-aprotic solvents and/or their mixtures thereof;

In step-b) and step-c) the suitable base is selected form hydroxides and carbonates of alkali metals;

In step-c) the suitable acid is acetic acid and the suitable solvent is selected from hydrocarbon solvents, alcoholic solvents, polar-aprotic solvents and/or their mixtures thereof;

A preferred embodiment of the present invention provides an improved process for the preparation of 1 -(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino) propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5 as a solid, comprising of;

a) Condensing the 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate compound of formula-2 with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate compound of formula-3 in presence of dipotassium hydrogen phosphate and tetra butyl ammonium bromide in toluene to provide 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl} amino)propyl]-2,3-dihydro-1 H-indol-1 -yl} propylbenzoate compound of formula-4,

b) in-situ hydrolyzing the compound of formula-4 in presence of sodium hydroxide in toluene to provide 1 -(3-hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino) propyI]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5,

c) purifying the compound of formula-5 by in-situ treating with acetic acid followed by treating with sodium hydroxide and then isolating from a mixture of cyclohexane and water to provide pure l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino) propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5.

The 1 -(3-hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino) propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5 obtained in step-c) can be further hydrolyzed in presence of a suitable base and a suitable oxidizing agent such as hydrogen peroxide to provide l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide compound of formula-1.
3-{7-Cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-1 H-indol-1 -yl}propyl benzoate compound of formula-2 utilized in the above condensation step-a) can be obtained by neutralizing its tartrate salt compound of formula-2a with a suitable base selected from hydroxides and carbonates of alkali metals in a suitable solvent.

US7834193B2 patent disclosed another process for the synthesis of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide comprising of refluxing a mixture of 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-lH-indol-l-yl]propy! benzoate (2R,3R)-monotartrate and 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate for 24 hrs in presence of sodium carbonate to provide 3-{7-cyano-5-[(2R)-2-({2- [2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-1 H-indol-1 -yl}propyl benzoate. Treating the obtained compound with oxalic acid to provide its oxalate salt, hydrolyzing the oxalate salt to provide l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile which on further hydrolysis provides 1 -(3-hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-1 H-indole-7-carboxamide.

In all the prior reported processes, the condensation reaction of benzoate compound of formula-2 with methanesulfonate compound of formula-3 takes longer time for completion of the reaction, i.e., around 24 hrs. The present inventors observed that when the base is changed the reaction time is very less when compared to the prior-art processes. It was surprisingly found that when dipotassium hydrogen phosphate is used as a base the reaction completes in 10-12 hrs only.

Also the usage of dipotassium hydrogen phosphate reduces the formation of dimer impurity in the condensation step when compared to the prior reported processes, thereby increasing the yield and purity of the condensation product and makes the process economic. The condensation product on further purification leads to highly pure compound with good yields. Thus the present invention is more advantageous over the prior-art.

The 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate compound of formula-3 utilized in the above condensation step can be synthesized by any of the methods known in the art.

The second aspect of the present invention provides an improved process for the preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1 H-indole-7-carboxamide compound of formula-1, comprising of;

a) Condensing the 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate compound of fonnula-2 or its tartrate salt compound of formula-2a with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate compound of fonnula-3 in presence of a suitable base in a suitable solvent to provide 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-l H-indol-l-yl}propyl benzoate compound of formula-4,

b) in-situ hydrolyzing the compound of formula-4 in presence of a suitable base and optionally in presence of a phase transfer catalyst in a suitable solvent to provide l-(3-hydroxypropyl)-5- [(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5,

c) purifying the compound of formula-5 by in-situ treating with a suitable acid followed by treating with a suitable base in a suitable solvent and then isolating from a suitable solvent to provide pure l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5 as a solid,

d) hydrolyzing the compound of formula-5 in presence of a suitable base in a suitable solvent to provide 1 -(3-hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino) propyl]-2,3-dihydro-1 H-indole-7-carboxamide compound of formula-1,

e) optionally purifying the compound of formula-1 from a suitable solvent.

Wherein, in step-a), step-b), step-c) and step-d) the suitable base is selected form hydroxides and carbonates of alkali metals; the suitable solvent is selected from hydrocarbon solvents, alcoholic solvents, polar-aprotic solvents, ketone solvents and/or their mixtures thereof;

In step-b) the phase transfer catalyst is same as defined for step-b) of the first aspect of the present invention; and the suitable acid used in step-c) is acetic acid;

In step-e) the suitable solvent is preferably selected from ester solvents.

Another preferred embodiment of the present invention provides an improved process for the preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide compound of formula-1, comprising of;

a) Condensing the 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate compound of formula-2 or its tartrate salt compound of formula-2a with 2-[2-(2,2,2-trif[uoroethoxy)phenoxy]ethyl methanesulfonate compound of fonnula-3 in presence of sodium carbonate in tert-butanol to provide 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate compound of fonnula-4,

b) in-situ hydrolyzing the compound of forraula-4 in presence of sodium hydroxide and tetra butyl ammonium bromide in tert-butanol to provide l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-1 H-indole-7-carbonitrile compound of formula-5,

c) purifying the compound of formula-5 by in-situ treating with acetic acid followed by treating with sodium hydroxide in toluene and then isolating from a mixture of cyclohexane and water to provide pure l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5 as a solid,

d) hydrolyzing the compound of formula-5 in presence of sodium hydroxide in dimethyl sulfoxide to provide l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino) propyl]-2,3-dihydro-l H-indole-7-carboxamide compound of formula-1,

e) optionally purifying the compound of formula-1 from a suitable ester solvent.

The hydrolysis of the compound of formula-5 in step-d) is generally carried out in presence of an oxidizing agent, preferably hydrogen peroxide.

The 1 -(3-hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino) propyl]-2,3-dihydro-lH-indole-7-carbonitrile compoimd of formula-5 obtained by the process of the present invention can be further converted to its acid addition slats by treating with a suitable acid in a suitable solvent.

Another embodiment of the present invention provides a process for the preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile hydrochloride salt compound of formula-5a

Formula-5a

comprising of;

a) Dissolving l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino) propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5 in a suitable solvent,

b) adding conc.hydrochloric acid to the reaction mixture,

c) stilling the reaction mixture,

d) filtering the compound and washing with a suitable solvent,

e) drying the compound to provide l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile hydrochloride salt compound of fonnula-5a.

Wherein in step a) & step d) the suitable solvent is selected From alcohol solvents, ester solvents, ether solvents, ketone solvents, hydrocarbon solvents, preferahly methyl tert.butyl ether.

The (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate 2,3-dihydroxysuccinate compound of fonTiula-2a utilized in the present invention can be synthesized as follows;

a) Condensing the 3-chloro propyl benzoate with indoline in presence of triethylamine in dimethyl formamide to provide 3-(indolin-l-yl)propyl benzoate hydrochloride,

b) formylation of the obtained hydrochloride salt with phosphorous oxychloride followed by reaction with nitroethane in presence of ammonium acetate to provide (E)-3-(5-(2-nitroprop-l-enyl)indolin-1 -yl)propyl benzoate,

c) reducing the nitro alkene compound with sodium borohydride, followed by formylation of the obtained compound with phosphorous oxychloride in dimethyl formamide to provide 3-(7-formyl-5-(2-nitropropyl)indolin-1 -yl)propyl benzoate,

d) treating the aldehyde compound obtained in step-c) with hydroxylamine hydrochloride in presence of pyridine followed by reducing the nitro group of the resulting compound with Raney-Ni to provide 3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate,

e) resolution of the amine compound with L(+)-tartaric acid in acetone provides (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate 2,3-dihydroxysuccinate compound of formula-2a.

One of the main objects of the present invention is to provide a process for the removal of dimer impurity fonned in the condensation of benzoate compound of fonTiula-2 or its tartrate salt compound of formu]a-2a with methanesulfonate compound of formula-3. The present inventors intensely studied and developed a simple but effective process for the removal of above said dimer impurity. The process involves the treatment of the hydroxy compound of formula-5 which is obtained by the removal of benzoyl group from the condensation product of formula-4 with a suitable acid followed by treating with a suitable base. By adopting such process for the purification of compound of formula-5 the content of dimer impurity in compound of formula-5 is reduced from 10-15% to minimum levels, preferably non-detected levels. Thus such purification process forms the basis of the present invention.

The third aspect of the present invention provides a purification process for l-(3-hydroxypropyl)-5-[{2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of fonnula-S, comprising of treating the compound of formula-5 with a suitable acid followed by treating with a suitable base in a suitable solvent to provide pure l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino) propyl]-2,3-dihydro-1 H-indole-7-carbonitrile compound of formula-5.

Wherein, the suitable acid is acetic acid; the suitable base is selected form hydroxides and carbonates of alkali metals; the suitable solvent is selected from hydrocarbon solvents, alcoholic solvents, polar-aprotic solvents, ketone solvents and/or their mixtures thereof;

A preferred embodiment of the present invention provides a purification process for 1 -(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of fonnula-5, comprising of treating the compound of formula-5 with acetic acid followed by treating with sodium hydroxide in toluene to provide l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5 substantially free of dimer impurity.

The fourth aspect of the present invention provides l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5 as a crystalline solid which is characterized by its X-Ray powder diffraction pattern having peaks at about 5.2, 5.8, 11.5, 12.6, 13.1, 17.2, 18.3, 18.5, 20.1, 20.4, 20.9, 26.5, 28.4 ± 0.2 degrees of 2-theta. The said crystalline form is herein designated as crystalline form-M and is further characterized by the PXRD pattern as depicted in figure-1.

The fifth aspect of the present invention provides l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile hydrochloride salt compound of formula-5a in crystalline fonn designated as form-S characterized by the X-Ray powder diffraction pattern having peaks at about 5.0, 5.8, 10.6, 14.2, 17.7, 21.0, 24.8± 0.2 degrees of 2-theta as depicted in figure-2.

The sixth aspect of the present invention provides a process for the preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide compound of fonnula-1 in P-ci-ystalline form, comprising of;

a) Adding isopropyl acetate to l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phcnoxy]ethyl}amino)propyl]-2,3-dihydro-1 H-indole-7-carboxamide of formula-1,

b) heating the reaction mixture to 60-80°C, preferably to 70-75°C,

c) stirring the reaction mixture for 5-10 min,

d) filtering the reaction mixture and cooling the filtrate to 20-40°C, preferably to 25-35°C.

e) adding isopropyl acetate to the filtrate,

f) stirring the reaction mixture for 2-3 hrs,

g) filtering the compound washing with isopropyl acetate,

h) drying the compound to provide l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide compound of formula-1 in P-crystalline form.

PXRD analysis of crystalline l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy] ethyl} amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5 and its hydrochloride salt compound of formula-5a were carried out using BRUKER/AXS X-Ray diffi"actometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.

The 1 -(3-hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino) propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5 obtained by the process of the present invention was analyzed by HPLC under the following conditions; Apparatus: A liquid chromatographic system equipped with variable wavelength UV detector and integrator; Colunm: Sunfire CI8, 250x4.6 mm, 5\i (or) equivalent; Flow rate: 1.0 mL/min; Wavelength: 225 nm; Column temperature: 30°C; Injection volume: 10 \iL; Run time: 55 min; Diluent: acetonitrile:buffer (1:1 v/v); Elution: gradient; Buffer: 1 mL of orthophosphoric acid (85%) and 1.0 gm of anhydrous 1-octane sulphonic acid sodium salt in 1000 ml of milli-Q-water; Mobile phase-A: Buffer; Mobile phase-B: acetonitrile:water (90:10 v/v); concentration: 1.0 mg/mL.

The 1 -(3-hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifIuoroethoxy)phenoxy]ethyl} amino) propyl]-2,3-dihydro-lH-indole-7-carboxamide compound of formula-1 produced by the process of the present invention was analyzed by HPLC under the following conditions; Apparatus: A liquid chromatographic system equipped with variable wavelength UV detector and integrator; Column: Unison C8, 150x4.6 mm, 5^ (or) equivalent; Flow rate: 1.0 mL/min; Wavelength: 225 nm; Column temperature: Ambient; Injection volume: 10 |iiL; Run time: 47 min; Diluent: water:acetonitrile (50:50)v/v; Elufion: gradient; Buffer: 2.72 gm of potassium dihydrogen orthophosphate and 1.0 gm of anhydrous 1-octane sulphonic acid sodimn salt in 1000 ml of water and adjust the pH to 3.0 with orthophosphoric acid.

The particle size distribution of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino) propyl]-2,3-dihydro-lH-indole-7-carboxamide compound of formula-] is measured under the following conditions:

Instrument: Malvern Mastersizer 2000; Measuring range: 0.02 to 2000 yim; Wet sampler: Hydro 2000S (A); Dispersant: cyclohexane; Refractive Index of cyclohexane: 1.427; Refractive index of particle: 1.650; Obscuration range: 14.65%; Sensitivity: normal.

The present invention is schematically represented as follows.

Scheme-I:

The best mode of canjnng out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

Examples:

ExampIe-1: Preparation of 3-(indolin-l-yl)propyl benzoate hydrochloride

A mixture of N,N-dimethyl formamide (504 ml), indoline (140 gm), triethyl amine (148 gm) and 3-chloropropyl benzoate (280 gm) was heated to 95-100°C and stirred for 14 hrs at the same temperature. After the completion of the reaction, cooled the reaction mixture to 25-30°C and water (700 ml) was added. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate solution followed by saturated sodiimi chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely from the organic layer. Ethyl acetate-HCl (280 ml) was added to the obtained residue at 25-30°C and stirred for 15 min. Distilled off the solvent completely from the reaction mixture and co-distilled with acetone. To the obtained crude compound, acetone (350 ml) was added at 25-30°C and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the compound, washed with acetone and then dried to get the title compound. Yield: 270 gm.

Example-2: Preparation of 3-(5-forraylindolin-l-yl)propyI benzoate

Phosphorous oxychloride (79.2 gm) was slowly added to a pre-cooled solution of N,N-dimethyl fomiamide (375 ml) at 0-5°C and stirred for 30 min at the same temperature. 3-(Indolin-l-yl)propyl benzoate hydrochloride (150 gm) was slowly added to the reaction mixture at 0-5°C. The temperature of the reaction mixture was raised to 25-30°C and stirred for 3 hrs at the same temperature. After the completion of the reaction, the reaction mixture was poured into pre-cooled water (1500 ml) at 5-10°C. The temperature of the reaction mixture was raised to 25-30°C and stirred for 30 min at the same temperature. Adjusted the pH of the reaction mixture to 8.0 with sodium carbonate and stiiTcd the reaction mixture for 30 min at 25-30°C. Both the organic and aqueous layers were separated and the organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely. Ethyl acetate-HCl (450 ml) was added to the obtained residue at 0-5°C and stirred for 60 min at the same temperature. Filtered the compound, washed with acetone and then spin-dried for 30 min. Water (150 ml) and ethyl acetate (300 ml) were added to the obtained wet compound and the pH of the reaction mixture was adjusted to 9.0 with IN sodium bicarbonate solution. Both the organic and aqueous layers were separated and washed the organic layer with saturated sodium chloride solution. Distilled off the solvent completely to get the title compound. Yield: 125 gm.

Example-3: Preparation of (E)-3-(5-(2-nitroprop-l-enyl)indolin-l-yl)propyl benzoate

A mixture of nitroethane (84 gm), 3-(5-formylindolin-l-yl)propyl benzoate (115 gm) and ammonium acetate (37 gm) was heated to 80-90°C and stirred for 3 hrs at the same temperature. After the completion of the reaction, cooled the reaction mixture to 25-3 0°C and sodium bicarbonate solution (575 ml) was slowly added. Both the organic and aqueous layers were separated and the organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely under reduced pressure. Isopropyl alcohol (575 ml) was added to the obtained residue, cooled the reaction mixture to 10-15°C and then stirred for 3 hrs at the same temperature. Filtered the compound, washed with isopropyl alcohol and then dried to get the title compound. Yield: 96.5 gm.

Example-4: Preparation of 3-(5-(2-nitropropyl)indolin-l-yl)propyl benzoate

Ethanol (50 ml) followed by a solution of (E)-3-(5-(2-nitroprop-l-enyl)indolin-l-yl)propyl benzoate (50 gm) in tetrahydrofuran (200 ml) were slowly added to a pre-cooled solution of tetrahydrofuran (150 ml) and sodium borohydride (15.5 gm) at 0-5°C and stiired the reaction mixture for 3 hrs at the same temperature. After the completion of the reaction, poured the reaction mixture into ice-water (350 ml). Adjusted the pH of the reaction mixture to 5.0 with acetic acid and sodium bicarbonate solution (100 ml) was added. Both the organic and aqueous layers were separated and washed the organic layer with sodium bicarbonate solution and saturated sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely to get the title compound. Yield: 50.0 gm.

Example-5: Preparation of 3-(7-formyl-5-(2-nitropropyI)indolin-l-yl)propyl benzoate

Phosphorous oxychloride (41.6 gm) was slowly added to pre-cooled N,N-dimethyI fonnamide (50 ml) at 0-5°C and stirred for 30 min at the same temperature. Slowly added a solution of 3-(5-(2-nitropropyl)indolin-l-yl)propyl benzoate (50 gm) in N,N-dimethyl formamide (50 ml) to the reaction mixture at 0-5°C. Heated the reaction mixture to 45-50°C and stirred for 3 hrs at the same temperature. After the completion of the reaction, poured the reaction mixture into ice-water (500 ml) and adjusted the pH of the reaction mixture to 8.0 using 10% sodium bicarbonate solution. Both the organic and aqueous layers were separated and the combined organic layer was washed with 10% sodium chloride solution and distilled off the solvent. Methanol (100 ml) was added to the obtained residue and the reaction mixture was heated to reflux. Cooled the reaction mixture to 10-15°C and stirred for 30 min at the same temperature. Filtered the compound, washed with methanol and then dried to get the title compound. Yield: 24.0 gm.

ExampIe-6: Preparation of 3-(7-cyano-5-(2-nitropropyl)indolin-l-yl)propyl benzoate

A mixture of tetrahydrofuran (150 ml), 3-(7-formyl-5-(2-nitropropyl)indolin-l-yl)propyl benzoate (50 gm), hydroxy! amine hydrochloride (10.5 gm) and pyridine (37.5 gm) was heated to 50°C and stined for 2 hrs at the same temperature. After the completion of the reaction, acetic anhydride (51.5 gm) was slowly added to the reaction mixture at 50°C and stirred for 4 hrs at the same temperature. After the completion of the reaction, cooled the reaction mixture to 25-30°C and 500 ml of water was slowly added. Both the organic and aqueous layers were separated and washed the organic layer with HCl solution, 10% sodium bicarbonate solution and 10% sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent under reduced pressure. Added acetone (50 ml) to the obtained residue and stirred the reaction mixture to get clear solution. Isopropyl alcohol (150 ml) was added to the reaction mixture at 25-3 0°C and stirred for 3 hrs at the same temperature. Filtered the compound, washed with a mixture of acetone and isopropyl alcohol and then dried to get the title compound. Yield: 40.0 gm.

Example-7: Preparation of 3-(5-(2-aminopropyI)-7-cyanoindolin-l-yl)propyl benzoate

A mixture of methanol (500 ml), 3-(7-Cyano-5-(2-nitropropyl)indolin-l-yl)propyl benzoate (50 gm), Raney-Ni (20 ml) and calcium carbonate (5 gm) was heated to 50-55°C in a clean and dry autoclave vessel and stirred for 10 hrs under 4-5 kg of hydrogen gas pressure. After the completion of the reaction, filtered the reaction mixture through hyflow bed, washed with methanol and distilled off methanol completely under reduced pressure to get the title compound. Yield: 40.0 gm.

Example-8: Preparation of (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate 2,3-dihydroxysuccinate (Formula-2a)

A mixture of acetone (45 ml) and 3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate (15 gm) was heated to reflux and stirred for 10 min at the same temperature. A solution of L(+)-tartaric acid in water (prepared by dissolving 3.4 gm of L(+)-tartaric acid in 10 ml of water) was slowly added to the reaction mixture at reflux temperature and stiired for 15 min at the same temperature. Cooled the reaction mixture to 25-35°C and stirred for 3 hrs at the same temperature.

Filtered the precipitated compound, washed with a mixture of acetone and water and then dried to get the title compound. Yield: 6.5 gm,

Example-9: Purification of (R)-3-(5-(2-aminopropyI)-7-cyanoindolin-l-yl)propyl benzoate 2,3-dihydroxysuccinate (Formula-2a)

(R)-3-(5-(2-Aminopropyl)-7-cyanoindolin-1 -yl)propyl benzoate 2,3-dihydroxysuccinate (Formula-2a) (6.5 gm) in a 1:1 mixture of acetone and water (15 ml) was heated to reflux to get clear solution. The temperature of the reaction mixture was reduced to 25-3 5°C and stirred for 3 hrs at the same temperature. Filtered the precipitated compound and washed with a mixture of acetone and water to get the title compound.

Example-10: Preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile (Formula-5)

Toluene (400 ml) and 100 gm of 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate tartrate salt (formula-2a) were charged into a clean and dry RBF at 25-35°C. Adjusted the pH of the reaction mixture to 11 using IN sodium carbonate solution and stirred the reaction mixture for 45 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. The combined toluene layer was heated to reflux temperature and water was removed by azeotropic distillation. The temperature of the reaction mixture was reduced to 25-35°C and 76.5 gm of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate (formula-3), dipotassium hydrogen phosphate (101.6 gm) and tetra butyl ammonium bromide (12.5 gm) were added. Heated the reaction mixture to reflux temperature and stirred for 12 hrs at the same temperature. 200 ml of water was added to the reaction mixture at 25-35°C and both the organic and aqueous layers were separated. Methanol (50 ml), tetra butyl ammonium bromide (12.5 gm) and sodium hydroxide solution (prepared by dissolving 9.8 gin of sodium hydroxide in 40 ml of water) were added to the organic layer at 25-35°C. Heated the reaction mixture to 50°C and stined for 3 hrs at the same temperature. After the completion of the reaction, cooled the reaction mixture to 25-35°C. 150 ml of water was added to the reaction mixture at 25-35°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was utilized in the next purification step. Dimer impurity: 10-11%.

Example-11: Preparation of l-(3-hydroxypropyl)-5-((2R)-2-({2-[2-(2,2,2-trifliioroethoxy) pheno\yJethyl}amino)propylj-2,3-dihydro-lH-indo!e-7-carbonitrile (Formula-5)

Toluene (300 ml) and 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl} propyl benzoate tartrate salt (formula-2a) (100 gm) were charged into a clean and dry RBF at 25-35°C. The pH of the reaction mixture was adjusted to 11 with IN sodium carbonate solution and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with tert-butanol. The obtained residue was dissolved in tert-butanol (500 ml) and 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate (formula-3) (91.5 gm) followed by sodium carbonate (31 gm) were added. Heated the reaction mixture to 85-90°C and stirred for 30 hrs at the same temperature. After the completion of the reaction, reduced the temperature of the reaction mixture to 25-35°C and filtered the reaction mixture. Sodium hydroxide solution (prepared by dissolving 9.8 gm of sodium hydroxide in 120 ml of water) followed by tetra butyl ammonium bromide (12.5 gm) were added to the filtrate. Heated the reaction mixture to 50-52°C and stirred for 3 hrs at the same temperature. After the completion of the reaction, distilled off the solvent completely from the reaction mixture under reduced pressure. To the obtained crude compound, toluene (400 ml) was added at 25-35°C and stirred for 15 min at the same temperature. To the resulting reaction mixture, 150 ml of water was added at 25-35°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was utilized in the next purification step. Dimer impurity: 10-11%.

ExampIe-12: Purification of l-(3-hydroxypropyl)-5-[(2R)-2-({2-I2-(2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyI]-2,3-dihydro-lH-indole-7-carbonitrile(Formula-5)

20% Acetic acid solution (500 ml) was added to the organic layer obtained in example-10 or example-11 at 25-35°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and toluene (250 ml) was added to the aqueous layer. Adjusted the pH of the reaction mixture to 11 using IN sodium hydroxide solution. Both the organic and aqueous layers were separated and extracted the aqueous layer with toluene. The combined organic layer was washed with water and distilled off the solvent completely under reduced pressure.

To the obtained crude compound, water (60 ml) followed by cyclohexane (240 ml) were added at 25-35°C and stirred the reaction mixture for 90 min at the same temperature. Filtered the precipitated solid, washed with water and then dried to get the title compound. The PXRD of the obtained compound is similar to figure-1. Yield: 60.0 gm; M.R:58-62°C; Dimer impurity: 0.6%.

Example-13: Preparation of l-(3-hydroxypropyl)-5-I(2R)-2-({2-I2-(2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyI]-2,3-dihydro-lH-indole-7-carbonitrile hydrochloride salt (formula-5a)

A mixture of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile (formula-5) (10.0 gm), methyl tert.butyl ether (20 ml) and conc.hydrochloric acid (10 ml) was stirred for 1-2 hrs at 25-35°C. Filtered the precipitated solid, washed with water and then dried under reduced pressure to get the title compound. Yield: S.Ogm. MR: 95-100°C

Example-14: Preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyl}-2,3-dihydro-lH-indole-7-carboxamide (Formula-1)

50% Hydrogen peroxide solution (21.4 ml) was added to a pre-cooled solution of dimethyl sulfoxide (150 ml), l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyl} amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile (Formula-5) (50 gm) and sodium hydroxide (6.3 gm) at 20-30°C and stirred for 12 hrs at the same temperature. After the completion of the reaction, slowly added sodium sulfite solution (prepared by dissolving 17.5 gm of sodium sulfite in 300 ml of water) followed by ethyl acetate (250 ml) to the reaction mixture at 25-35°C and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with sodium chloride solution and distilled off the solvent completely under reduced pressure. Ethyl acetate (200 ml) was added to the obtained compound, heated the reaction mixture to reflux and stirred for 10 min at the same temperature. Reduced the temperature of the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Filtered the compound, washed with ethyl acetate and then dried to get the title compound. Yield: 35.0 gm Purity by HPLC: 97.04%.

Example-15: Purification of l~(3-hydroxypropyl)-5-[(2R)-2-({2-I2-(2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyll-2,3-dihydro-lH-lndole-7-carboxamide (Formula-1)

A mixture of ethyl acetate (250 ml) and l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-1 H-indole-7-carboxamide (Formula-1) (50 gra) was heated to 70-75°C and stined for 10 min at the same temperature. Carbon (5.0 gm) was added to the reaction mixture at 70-75°C and stined for 15 min at tlie same temperature. Filtered the reaction mixture through hyllow bed and washed with ethyl acetate. Reduced the temperature of the filtrate to 25-30°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and spin dry the material for 45 min. Ethyl acetate
(200 ml) was added to the wet compound and heated the reaction mixture to 70-75°C and stirred for 10 min at the same temperature. Reduced the temperature of the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Filtered the compound and then dried to get the title compound.

Yield: 45.0 gm;

Purity by HPLC: 99.72%.

Particle Size Distribution: D(O.l): 1.898 ^m; D(0.5):8.164 fxm; D(0.9):38.92 ^m; D( 1.0): 150.75 xm.

Example-16: Preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)
phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide (Formula-1) in p-
crystalline form

A mixture of isopropyl acetate (400 ml) and l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-1 H-indole-7-carboxamide (formula-1) (50 gm) was heated to 70-75°C and stirred for 10 min at the same temperature. Filtered the reaction mixture and reduced the temperature of the filtrate to 25-35°C. Isopropyl acetate (200 ml) was added to the reaction mixture at 25-35°C and stirred for 3 hrs at the same temperature. Filtered the compound, washed with isopropyl acetate and then spin dried the material for 45 min. Dried the compound at 30-35°C under reduced pressure to get the title compound in P-crystalline form. The PXRD of the obtained compound is similar to P-crystalline form disclosed/designated in US20060142374 Al. Yield: 40.0 gm.

We Claim:

1. An improved process for the preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-1 H-indole-7-carbonitrile compound of formula-5 as a solid, comprising of;

a) Condensing the 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate compound of formula-2

FomuIa-2 with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate compound of fonnula-3

Fonnula-3 in presence of dipotassium hydrogen phosphate and optionally in presence of a phase transfer catalyst in a suitable solvent to provide 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl) amino)propyl]-2,3-dihydro-1 H-indol-1 -yl} propyl benzoate compound of formula-4,
Formula-4

b) in-situ hydrolyzing the compound of foiTnula-4 in presence of a suitable base and optionally

in presence of a phase transfer catalyst in a suitable solvent to provide l-(3-hydroxypropyI)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile compound of formula-5,

c) purifying the compound of fomiula-5 by in-situ treating with a suitable acid and then treating with a suitable base followed by isolating from a suitable solvent to provide pure l-(3-hydiox>'propyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroeihoxy)phenoxy]ethyl}amino)propyl]- 2,3-dihydro-lH-indole-7-carbonitrne compound of formula-5 as a solid.

2. A process according to claim 1, wherein

in step-a) and step-b) the phase transfer catalyst is tetra butyl ammonium bromide; the suitable solvent is selected from hydrocarbon solvents, alcoholic solvents, polar-aprotic solvents, water; in step-b) and step-c) the suitable base is selected from hydroxides and carbonates of alkali metals, preferably sodium hydroxide;

in step-c) the suitable acid is acetic acid; and the suitable solvent is selected from hydrocarbon solvents, alcoholic solvents, polar-aprotic solvents and water.

3. An improved process for the preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-
trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitriIe compound of formula-5 as a solid, comprising of;

a) Condensing the 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate compound of formula-2 with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate compound of formula-3 in presence of dipotassium hydrogen phosphate and tetra butyl ammonium bromide in toluene to provide 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-1 H-indol-1 -yl} propyl benzoate compound of formuIa-4,

b) in-situ hydrolyzing the compound of formula-4 in presence of sodium hydroxide and tetra butyl ammonium bromide in toluene to provide l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-1 H-indole-7-carbonitrile compound of fonnula-5,

c) purifying the compound of formula-5 by in-situ treating with acetic acid and treating with sodium hydroxide followed by isolating from a mixture of cyclohexane and water to provide pure 1 -(3-hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino) propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-S as a solid.

4. An improved process for the preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2- trifluoroethoxy)phenoxy]e{hyl}amino)propyl]-23-dihydro-lH-indole-7-carboxamide compound of fonnula-1, comprising of;

a) Condensing the 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate compound of formula-2 or its tartrate salt compound of formula-2a with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate compound of formula-3 in presence of a suitable base selected from hydroxides and carbonates of alkali metals in a suitable solvent selected from hydrocarbon solvents, alcoholic solvents, ether solvents, ketone solvents to provide 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl}amino)propyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate compound of formula-4,

b) in-situ hydrolyzing the compound of formula-4 in presence of a suitable base selected from hydroxides and carbonates of alkali metals and optionally in presence of a phase transfer catalyst such as tetra butyl ammonium bromide and in a suitable solvent such as water, hydrocarbon solvents, alcoholic solvents, ester solvents to provide l-(3-hydroxypropyl)-5-[(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl }amino)propyl]-2,3-dihydro-1 H-indole-7-carbonitrile of formula-5,

c) purifying the compound of formula-5 by in-situ treating with a suitable acid followed by treating with a suitable base in a suitable solvent followed by isolating from a suitable solvent to provide pure l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile of formula-5 as a solid,

d) hydrolyzing the compound of formula-5 in presence of a suitable base and a suitable oxidizing agent such as hydrogen peroxide in a suitable solvent such as water, polar-aprotic solvents, ester solvents to provide l-(3-hydroxypropyI)-5-[(2R)-2-({2-[2-(2,2,2-trifIuoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide compound of formula-1,

e) optionally purifying the compound of formula-1 from a suitable solvent.

5. An improved process for the preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide compound of formula-1, comprising of;

a) Condensing the 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate compound of formula-2 or its tartrate salt compound of formula-2a with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate compound of fon'nula-3 in presence of sodium caibonate in tert-butanol to provide 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2- trifluoroethoxy)phenoxy] ethyl) amino)propyl]-2,3-dihydro-1 H-indoI-1 -yljpropyl benzoate compound of formula-4,

b) in-situ hydrolyzing the compound of formula-4 in presence of sodium hydroxide and tetra butyl ammonium bromide in tert-butanol to provide l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-1 H-indole-7-carbonitrile of formula-5,

c) purifying the compound of formula-5 by in-situ treating with acetic acid followed by treating with sodium hydroxide in toluene and then isolating from a mixture of cyclohexane and water to provide pure l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indoIe-7-carbonitriIe of formula-5 as a solid,

d) hydrolyzing the compound of formula-5 in presence of sodium hydroxide and hydrogen peroxide in dimethylsulfoxide to provide l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl} amino)propyl]-2,3-dihydro-1 H-indole-7-carboxamide compound of formula-1,

e) optionally purifying the compound of formula-1 from a suitable ester solvent.

6. A process for the purification of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of formula-5, comprising of treating the compoimd of formula-5 with acetic acid followed by treating with sodium hydroxide in toluene to provide highly pure l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-1 H-indole-7-carbonitrile compound of formula-5.

7. Crystalline form-M of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl }amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound of fonTiula-5 characterized by its X-Ray powder diffraction pattern having peaks at 5.2, 5.8, 11.5, 12.6, 13.1, 17.2, 18.3, 18.5, 20.1, 20.4, 20.9, 26.5, 28.4 ± 0.2 degrees of 2-theta as depicted in figure-1.

8. Crystalline form-S of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl} amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile hydrochloride salt compound of formula-5a characterized by its X-Ray powder diffraction pattern having peaks at about 5.0, 5.8, 10.6, 14.2, 17.7, 21.0, 24.8± 0.2 degrees of 2-theta as depicted in figure-2.

9. A process for the preeparation ofI-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-{2,2,2-trinioroethoxy)phenoxy] ethyl}amino)propyl]-2.3-dihydro-lH-indole-7-carbonitrile hydrochloride compound of formula-5a comprising of,

a) Dissolving 1 -(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile compound in a suitable solvent,

b) adding cone, hydrochloric acid to the reaction mixture,

c) stirring the reaction mixture,

d) filtering the compound and washing with a suitable solvent,

e) drying the compound to provide l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)

phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile hydrochloride salt compound of formula-5a.

10. A process for the preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide compound of formula-1 in P-crystalline form, comprising of;

a) Adding isopropyl acetate to l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxyjethyl} amino)propyl]-2,3-dihydro-1 H-indole-7-carboxamide of formula-1,

b) heating the reaction mixture,

c) stirring the reaction mixture,

d) filtering the reaction mixture and cooling the filtrate,

e) adding isopropyl acetate to the filtrate,

f) stirring the reaction mixture,

g) filtering the compound and washing with isopropyl acetate,

h) drying the compound to provide l-(3-hydroxypropyl)-5-[(2R)-2-{{2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide compound of foi-mula-1 in p-crystalline form.