Field of the invention:

The present invention relates to novel intermediate compound useful 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 represented by the following structural formula-1 and process for its preparation.

The present invention also provides a novel 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.

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).

l-(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-lH-indole-7-carboxamide from 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate and l-acetyl-5-(2-aminopropyl)indoline-7-carbonitrile. It also discloses a multi-step process for the synthesis of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol and its mesylate salt from 2-methoxy phenol using expensive and hazardous reagents like l,l,l-trifluoro-2-iodo ethane, boron tribromide and lithium aluminium hydride.

Japanese patents/patent applications JP3331047, JP3331048 and JP09221473 discloses the synthesis of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol from 2-methoxy phenol and 1,1,1-trifluoro-2-iodo ethane using boron tribromide.

The l,l,l-trifluoro-2-iodo ethane utilized in the above said processes is a low-boiling reagent (Boiling point: 53-55°C) and hence is very difficult to handle at reflux conditions.

Also the usage of expensive reagents like l,l,l-trifluoro-2-iodo ethane and boron tribromide makes the process uneconomical and hence is not commercially feasible.

Almost all the prior-art processes involves the usage of either expensive or difficult to handle or both the types of reagents for the synthesis 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.

Hence there is a significant need in the art to develop a simple, safe, industrially and commercially feasible process by utilizing cheap, safer and easy to handle reagents.

The present invention overcomes all the above said problems and provides a novel 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 through novel intermediates by utilizing simple and cost-effective reagents.

Brief Description of the Invention:

The first aspect of the present invention is to provide (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetamido)propyl)indolin-l-yl)propyl benzoate compound of formula-4, which is an useful intermediate in the synthesis of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifiuoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-1 H-indole-7-carboxamide compound of formula-1.

The second aspect of the present invention is to provide a process for the preparation of (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetamido)propyl)indolin-l-yl)propyl benzoate compound of formula-4.

The third aspect of the present invention is to provide a novel process for the preparation of (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-rrifluoroemoxy)phenoxy)emylamino)propyl)indolin-l-yl)propyl benzoate compound of formula-5, comprising of reducing the (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetamido)propyl)indolin-l-yl)propyl benzoate compound of formula-4 with a suitable reducing agent in a suitable solvent to provide (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylamino)propyl)indolin-l-yl)propyl benzoate compound of formula-5.
The fourth aspect of the present invention is to provide a novel 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 (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate compound of formula-2 or its tartrate salt compound of formula-2a with 2-(2-(2,2,2-trifiuoroethoxy)phenoxy) acetic acid compound of formula-3 in presence of a suitable condensing agent optionally in presence of a suitable base in a suitable solvent to provide (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetamido)propyl)indolin-1 -yl)propyl benzoate of formula-4,

b) reducing the compound of formula-4 with a suitable reducing agent in a suitable solvent to provide (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylamino)propyl)indolin-l-yl)propyl benzoate compound of formula-5,

c) hydrolyzing the compound of formula-5 in presence of a suitable base in a suitable solvent to provide (R)-1 -(3-hydroxypropyl)-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylamino)propyl) indoline-7-carbonitrile compound of formula-6,

d) hydrolyzing the compound of formula-6 in presence of a suitable oxidizing agent and 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-1 H-indole-7-carboxamide compound of formula-1,

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

The fifth 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, comprising of;

a) Condensing the (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-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-7 in presence of a suitable base in a suitable solvent to provide (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylamino) propyl)indolin-l-yl)propyl benzoate compound of formula-5,

b) hydrolyzing the compound of formula-5 in presence of a suitable base in a suitable solvent to provide (R)-1 -(3 -hydroxypropyl)-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylamino)propyl) indoline-7-carbonitrile compound of formula-6,

c) hydrolyzing the compound of formula-6 in presence of a suitable oxidizing agent and 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-1 H-indole-7-carboxamide compound of formula-1.

The sixth aspect of the present invention is to provide a process for the preparation of l-(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, comprising of;

a) Condensing the (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate compound of formula-2 with 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate compound of formula-7 in presence of a suitable base in a suitable solvent to provide (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylamino)propyl)indolin-1 -yl)propyl benzoate compound of formula-5,

b) hydrolyzing the compound of formula-5 in presence of a suitable base in a suitable solvent to provide (R)-1 -(3 -hydroxypropyl)-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylamino)propyl) indoline-7-carbonitrile compound of formula-6,

c) converting the compound of formula-6 into its pharmaceutically acceptable acid addition salt by treating it with a suitable acid in a suitable solvent,

d) hydrolyzing the acid addition salt compound obtained in step-c) in presence of a suitable base and a suitable oxidizing agent in a suitable solvent to provide l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}airiino)propyl]-2,3-dihydro-lH-indole-7-carboxamide compound of formula-1.

The seventh aspect of the present invention is to provide a process for the preparation of (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate 2,3-dihydroxysuccinate compound of formula-2a, comprising of;

a) Reducing the 3-(7-cyano-5-(2-nitropropyl)indolin-l-yl)propyl benzoate compound of formula-8 with a suitable reducing agent in a suitable solvent to provide 3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate compound of formula-16,

b) resolving the compound of formula-16 using L(+)-tartaric acid in a suitable solvent to provide (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-1 -yl)propyl benzoate 2,3-dihydroxysuccinate compound of formula-
2a.

The eighth aspect of the present invention is to provide a process for the preparation of 3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate compound of formula-16, comprising of reducing the 3-(7-cyano-5-(2-nitropropyl)indolin-l-yl)propyl benzoate compound of formula-8 with a suitable reducing agent in a suitable solvent to provide 3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate compound of formula-16.

The ninth aspect of the present invention is to provide a process for the preparation of 2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetic acid compound of formula-3, comprising of reacting the 2-(2,2,2-trifluoroethoxy)phenol compound of formula-9 with sodium 2-chloroacetate in presence of a suitable base in a suitable solvent to provide sodium 2-(2-(2,2,2-trifiuoroethoxy)phenoxy)acetate, which on in-situ treatment with a suitable acid to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy) acetic acid compound of formula-3.

The tenth aspect of the present invention is to provide a process for the preparation of 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethanol compound of formula-11, comprising of reducing the ethyl 2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetate compound of formula-10 with a suitable reducing agent in a suitable solvent to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethanol of formula-11.

The eleventh aspect of the present invention is to provide an improved process for the preparation of 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate compound of formula-7, comprising of;

a) Reacting the 2-(2,2,2-trifluoroethoxy)phenol compound of formula-9 with ethyl 2-bromoacetate in presence of a suitable base in a suitable solvent to provide ethyl 2-(2-(2,2,2-trifiuoroethoxy)phenoxy)acetate compound of formula-10,

b) reducing the compound of formula-10 with a suitable reducing agent in a suitable solvent to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethanol compound of formula-11,

c) treating the compound of formula-11 with methanesulfonyl chloride in presence of a suitable base in a suitable solvent to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate compound of formula-7.

The twelfth aspect of the present invention is to provide a process for the preparation of 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate compound of formula-7, comprising of;

a) Reacting the 2,2,2-trifluoroethanol compound of formula-12 with p-toluenesulfonyl chloride in presence of a suitable base in a suitable solvent to provide 2,2,2-trifluoroethyl 4-methylbenzenesulfonate compound of formula-13,

b) reacting the compound of formula-13 with 2-methoxy phenol compound of formula-14 in presence of a suitable base in a suitable solvent to provide l-methoxy-2-(2,2,2-trifluoroethoxy) benzene compound of formula-15,

c) demethylating the compound of formula-15 by treating with a suitable demethylating agent in a suitable solvent to provide 2-(2,2,2-trifluoroethoxy)phenol compound of formula-9,

d) reacting the compound of formula-9 with sodium 2-chloroacetate in presence of a suitable base
in a suitable solvent, followed by in-situ treating with a suitable acid to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy) acetic acid compound of formula-3,

e) reducing the compound of formula-3 with a suitable reducing agent in a suitable solvent to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethanol compound of formula-11,

f) treating the compound of formula-11 with methanesulfonyl chloride in presence of a suitable base in a suitable solvent to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate compound of formula-7.

Detailed description of the invention:

The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert.butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrrolidone (NMP) and the like; "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride 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, isobutanol, tert-butanol and the like; "polar solvents" such as water; or mixtures thereof.

As used herein the present invention the term "suitable base" refers to "alkali metal carbonates" such as lithium carbonate, sodium carbonate, potassium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA) and the like; organic bases like methylamine, ethyl amine, diisopropyl amine, diisopropylethyl amine,

diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), imidazole or mixtures thereof.
The first aspect of the present invention provides (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetamido)propyl)indolin-l-yl)propyl benzoate of formula-4,
which is an useful intermediate in the synthesis 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.

The second aspect of the present invention provides a process for the preparation of (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetamido)propyl)indolin-1 -yl)propyl benzoate compound of formula-4, comprising of condensing the (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate compound of formula-2 or its tartrate salt compound of formula-2a with 2-(2-(2,2,2-trifiuoroethoxy)phenoxy)acetic acid compound of formula-3 in presence of a suitable condensing agent optionally in presence of a suitable base in a suitable solvent to provide (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifiuoroethoxy)phenoxy)acetamido)propyl)indolin-1 -yl)propyl benzoate compound of formula-4.
Wherein, the suitable condensing agent is selected from thionyl chloride, phosphorous oxychloride, phosphorous trichloride, phosphorous pentachloride, N,N'-dicyclohexyl carbodiimide(DCC), N,N'-diisopropylcarbodiimide(DIC), N,N'-carbonyldiimidazole(CDI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1 or EDAC.HC1) optionally in presence of l-hydroxy-7-azabenzotriazole(HOAt), N-hydroxybenzotriazole (HOBt), N-hydroxy succinimide(NHS) or sulfo-NHS, pentafluorophenol, benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate(BOP), 0-( lH-benzotriazol-1 -yl)-N,N,N',N'-tetramethyl-uronium hexafluorophosphate(HBTU),0-( 1 H-benzotriazol-1 -yl)-N,N,N',N'-tetramethyl-uronium tetrafluoro borate(TBTU) and the like; the suitable base is selected from alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates; the suitable solvent is selected from chloro solvents, ether
solvents, polar-aprotic solvents, ester solvents, alcoholic solvents or mixtures thereof.

The third aspect of the present invention provides a novel process for the preparation of (R)-3 -(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylamino)propyl)indolin-1 -yl)propyl benzoate compound of formula-5, comprising of reducing the (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetamido)propyl)indolin-l-yl)propyl benzoate compound of formula-4 with a suitable reducing agent in a suitable solvent.

Wherein, the suitable reducing agent is selected from sodium borohydride optionally in combination with BF3.ethertae, triethylsilane in combination with trifluoroacetic acid, Pd/C, Pt/C, Ru/C, Zn-Hg/HCl, FeCl3.6H20, diisobutylaluminium hydride (DIBAL), lithium aluminium hydride, L-selectride, Raney-Ni, boron trifluoride, titanium tetrachloride; the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents, chloro solvents or their mixtures.
The fourth aspect of the present invention provides a novel 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 (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate compound of formula-2 or its tartrate salt compound of formula-2a with 2-(2-(2,2,2-trifluoroethoxy)phenoxy) acetic acid compound of formula-3 in presence of a suitable condensing agent optionally in presence of a suitable base in a suitable solvent to provide (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetamido)propyl)indolin-1 -yl)propyl benzoate of formula-4,

b) reducing the compound of formula-4 with a suitable reducing agent in a suitable solvent to provide (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylamino)propyl)indolin-l-yl)propyl benzoate compound of formula-5,

c) hydrolyzing the compound of formula-5 in presence of a suitable base in a suitable solvent to provide (R)-1 -(3 -hydroxypropyl)-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylamino)propyl) indoline-7-carbonitrile compound of formula-6,

d) hydrolyzing the compound of formula-6 in presence of a suitable oxidizing agent and a suitable base in a suitable solvent to provide l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoro ethoxy)phenoxy]ethyl} amino)propyl]-2,3 -dihydro-1 H-indole-7-carboxamide of formula-1,

e) optionally purifying the compound of formula-1 from a suitable solvent.
Wherein, in step-a) the suitable condensing agent, the suitable base and the suitable solvent are same as described in second aspect of the present invention;

In step-b) the suitable reducing agent and the suitable solvent are same as described in third aspect of the present invention;

In step-c) the suitable base is selected from alkali metal hydroxides and alkali metal carbonates; the suitable solvent is selected from polar solvents, alcoholic solvents, polar-aprotic solvents, hydrocarbon solvents, ketone solvents or mixtures thereof;

In step-d) the suitable oxidizing agent is hydrogen peroxide; the suitable base is selected from alkali metal hydroxides and alkali metal carbonates; and the suitable solvent is selected from polar solvents, polar-aprotic solvents, ketone solvents, alcoholic solvents, ether solvents or mixtures thereof; and the suitable solvent in step-e) is selected from ester solvents.

The fifth 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 formula-1, comprising of;

a) Condensing the (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate 2,3-dihydroxysuccinate compound of formula-2a with 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate compound of formula-7 in presence of a suitable base in a suitable solvent to provide (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylamino)propyl)indolin-l-yl)propyl benzoate compound of formula-5,

b) hydrolyzing the compound of formula-5 in presence of a suitable base in a suitable solvent to
provide (R)-1 -(3-hydroxypropyl)-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylamino)propyl) indoline-7-carbonitrile compound of formula-6,

c) hydrolyzing the compound of formula-6 in presence of a suitable oxidizing agent and 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-1 H-indole-7-carboxamide compound of formula-1.

Wherein, in step-a) the suitable base is selected from inorganic bases such as alkali metal hydroxides, alkali metal carbonates and bicarbonates; and the suitable solvent is selected from alcoholic solvents, chloro solvents, ether solvents, ester solvents, polar-aprotic solvents or mixtures thereof; and the suitable reagents and solvents used in step-b) and step-c) are same as described for step-c) and step-d) of the fourth aspect of the present invention.

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 formula-1, comprising of;

a) Condensing the (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate compound of formula-2 with 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate compound of formula-7 in presence of a suitable base in a suitable solvent to provide (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylamino)propyl)indolin-1 -yl)propyl benzoate compound of formula-5,

b) hydrolyzing the compound of formula-5 in presence of a suitable base in a suitable solvent to provide (R)-1 -(3-hydroxypropyl)-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylamino)propyl) indoline-7-carbonitrile compound of formula-6,

c) converting the compound of formula-6 into its pharmaceutically acceptable acid addition salt by treating it with a suitable acid in a suitable solvent,

d) hydrolyzing the acid addition salt compound obtained in step-c) in presence of a suitable base and a suitable oxidizing agent 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.
Wherein, in step-a), step-b) and step-d) the reagents are same as used for step-a), step-b) and step-c) of the fifth aspect of the present invention;

In step-c) the suitable acid is selected from hydrochloric acid and oxalic acid; and the suitable solvent is selected from ketone solvents, alcoholic solvents, chloro solvents, ether solvents, ester solvents, hydrocarbon solvents, polar-aprotic solvents or mixtures thereof.

The seventh aspect of the present invention provides a process for the preparation of (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate 2,3-dihydroxysuccinate compound of formula-2a, comprising of;

a) Reducing the 3 -(7-cyano-5-(2-nitropropyl)indolin-1 -yl)propyl benzoate compound of formula-8 with a suitable reducing agent in a suitable solvent to provide 3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate compound of formula-16,

b) resolving the compound of formula-16 using L(+)-tartaric acid in a suitable solvent to provide (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-1 -yl)propyl benzoate 2,3-dihydroxysuccinate compound of formula-2a.

The obtained compound of formula-2a can be further converted into compound of formula-2 by treating it with a suitable base in a suitable solvent.

Wherein, in step-a) the suitable reducing agent is preferably Raney-Ni, sodium borohydride optionally in combination with BF3.etherate, lithium aluminium hydride, lithium borohydride, diborane, FeCl3.6H20, Pd/C, Pt/C, Pt02, Sn-HCl, Zn-HCl, Zinc dust, stannous chloride (SnCl2), Fe in combination with acidic media like HC1, acetic acid or NH4CI; and the suitable solvent is selected from alcoholic solvents, chloro solvents, ether solvents, ester solvents or mixtures thereof;

In step-b) the suitable solvent is selected from ketone solvents, alcoholic solvents, chloro solvents, ether solvents, ester solvents, polar solvents or mixtures thereof.

The 3-(7-cyano-5-(2-nitropropyl)indolin-l-yl)propyl benzoate compound of formula-8 utilized in step-a) of the seventh aspect can be synthesized by the process disclosed in JP2001199956A.
The eighth aspect of the present invention provides a process for the preparation of 3-(5-(2-aminopropyl)-
7-cyanoindolin-l-yl)propy] benzoate compound of formula-16, comprising of reducing the 3-(7-cyano-5-(2-nitropropyl)indolin-l-yl)propyl benzoate compound of formula-8 with a suitable reducing agent in a suitable solvent to provide 3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate compound of formula-16.
Wherein, the suitable reducing agent and the suitable solvent are same as defined for step-a) of the seventh aspect of the present invention.

The ninth aspect of the present invention provides a process for the preparation of 2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetic acid compound of formula-3, comprising of reacting the 2-(2,2,2-trifluoroethoxy)phenol compound of formula-9 with sodium 2-chloroacetate in presence of a suitable base in a suitable solvent to provide sodium 2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetate, which on further treatment with a suitable acid provides 2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetic acid compound of formula-3.

Wherein, the suitable base is selected from alkali metal hydroxides and alkali metal alkoxides; and the suitable solvent is selected from ether solvents, ester solvents, polar-aprotic solvents, hydrocarbon solvents, ketone solvents or mixtures thereof; and the suitable acid is preferably hydrochloric acid.

The tenth aspect of the present invention provides a process for the preparation of 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethanol compound of formula-11, comprising of reducing the ethyl 2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetate compound of formula-10 with a suitable reducing agent in a suitable solvent to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethanol compound of formula-11, wherein the suitable reducing agent is selected from sodium borohydride optionally in combination with BF3.etherate, lithium aluminium hydride, lithium triethylborohydride, lithium tri-sec-butyl(hydrido)borate(l-) (L-selectride), diisobutylaluminium hydride, diborane, borane-dimethylsulfide and the like; and the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, hydrocarbon solvents, chloro solvents, polar solvents or their mixtures.

The 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethanol compound of formula-11 can also be prepared by reducing the 2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetic acid compound of formula-3 with a suitable reducing agent defined in the tenth aspect of the present invention.

The eleventh aspect of the present invention provides improved process for preparation of 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate compound of formula-7, comprising of;

a) Reacting the 2-(2,2,2-trifluoroethoxy)phenol compound of formula-9 with ethyl 2-bromoacetate in presence of a suitable base in a suitable solvent to provide ethyl 2-(2-(2,2,2-trifluoroethoxy) phenoxy)acetate compound of formula-10,

b) reducing the compound of formula-10 with a suitable reducing agent in a suitable solvent to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethanol compound of formula-11,

c) treating the compound of formula-11 with methanesulfonyl chloride in presence of a suitable base in a suitable solvent to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate compound of formula-7.

Wherein, in step-a) the suitable base is selected from inorganic bases such as alkali metal carbonates and bicarbonates; and the suitable solvent is selected from polar-aprotic solvents, ether solvents, chloro solvents, hydrocarbon solvents or their mixtures;

In step-b) the suitable reagents are same as described in tenth aspect of present invention;
In step-c) the suitable base is selected from organic bases; and the suitable solvent is selected from chloro solvents, ether solvents, ester solvents, hydrocarbon solvents or their mixtures;
The twelfth aspect of the present invention provides a process for the preparation of 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate compound of formula-7, comprising of;

a) Reacting the 2,2,2-trifluoroethanol compound of formula-12 with p-toluenesulfonyl chloride in presence of a suitable base in a suitable solvent to provide 2,2,2-trifluoroethyl 4-methylbenzenesulfonate compound of formula-13,

b) reacting the compound of formula-13 with 2-methoxy phenol compound of formula-14 in presence of a suitable base in a suitable solvent to provide l-methoxy-2-(2,2,2-trifluoroethoxy) benzene compound of formula-15,

c) demethylating the compound of formula-15 by treating with a suitable demethylating agent in a suitable solvent to provide 2-(2,2,2-trifluoroethoxy)phenol compound of formula-9,

d) reacting the compound of formula-9 with sodium 2-chloroacetate in presence of a suitable base in a suitable solvent, followed by in-situ treating with a suitable acid to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetic acid compound of formula-3,

e) reducing the compound of formula-3 with a suitable reducing agent in a suitable solvent to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethanol compound of formula-11,

f) treating the compound of formula-11 with methanesulfonyl chloride in presence of a suitable base in a suitable solvent to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate compound of formula-7.

Wherein, in step-a) the suitable base is selected from organic bases; and the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents or their mixtures;
In step-b) the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and alkali metal bicarbonates; the suitable solvent is selected from polar-aprotic solvents, chloro solvents, hydrocarbon solvents, ether solvents or their mixtures;

In step-c) the suitable demethylating agent is aq.hydrobromic acid and the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents or their mixtures;

In step-d) the suitable base is selected from hydroxides, alkoxides, carbonates and bicarbonates of alkali metals; the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents or their mixtures; and the suitable acid is preferably hydrochloric acid;

In step-e) the suitable reducing agent and the suitable solvent are same as defined in the tenth aspect of the present invention;

In step-f) the suitable base is selected from organic bases; and the suitable solvent is selected from chloro solvents, ether solvents, hydrocarbon solvents or mixtures thereof.

The particle size distribution 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 is measured using Malvern Mastersizer 2000 instrument; The amide compound of formula-1 of the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product. The present invention is schematically represented as follows. Scheme-I:

The best mode of carrying 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: Example-1: Preparation of 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (Formula-13)

Triethylamine (126.5 gin) and p-toluenesulfonyl chloride (190.5 gm) were slowly added to a mixture of toluene (200 ml) and 2,2,2-trifluoroethanol compound of formula-12 (100 gm) at 30-35°C and stirred for 3 hrs at the same temperature. After completion of the reaction, water was added to the reaction mixture and both the organic and aqueous layers were separated. The organic layer was washed with water and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound; Yield: 254 gm. Example-2: Preparation of l-methoxy-2-(2,2,2-trifluoroethoxy)benzene (Formula-15)

N,N-Dimethyl formamide (250 ml), 2-methoxy phenol compound of formula-14 (118 gm) and potassium carbonate (276 gm) were added to 2,2,2-trifluoroethyl 4-methylbenzenesulfonate compound of formula-13 (254 gm) obtained in example-1 in a clean and dry RBF at 25-30°C. Heated the reaction mixture to 135-140°C and stirred for 8 hrs at the same temperature. After completion of the reaction, cyclohexane (300 ml) was added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Filtered the reaction mixture and water was added to the filtrate. Both the organic and aqueous layers were separated and the aqueous layer was extracted with cyclohexane. The combined organic layer was washed with water and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 160.0 gm. Example-3: Preparation of 2-(2,2,2-trifluoroethoxy)phenol (Formula-9)

A mixture of l-methoxy-2-(2,2,2-trifluoroethoxy)benzene compound of formula-15 (100 gm), acetic acid (100 ml) and aq.HBr (200 ml) was heated to 105-110°C and stirred for 12 hrs at the same temperature. After completion of the reaction, water was added to the reaction mixture at 30-35°C. Extracted the reaction mixture with cyclohexane and the organic layer was washed with water and sodium bicarbonate solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 93.2 gm. Example-4: Preparation of 2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetic acid (Formula-3)

Toluene (400 ml), sodium 2-chloroacetate (84.7 gm), sodium hydroxide (38.8 gm) and potassium iodide (3.0 gm) were added to 2-(2,2,2-trifluoroethoxy)phenol compound of formula-9 obtained in example-3. Heated the reaction mixture to reflux and stirred for 2 hrs at the same temperature. After completion of the reaction, filtered the reaction mixture at 30-35°C and water was added. Both the organic and aqueous layers were separated. The pH of the aqueous layer was adjusted to 2 using hydrochloric acid at 25-3 0°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 69.0 gm. Example-5: Preparation of 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethanol (Formula-11)

Boron trifluoride-etherate (102 gm) was slowly added to a pre-cooled mixture of tetrahydrofuran (500 ml) and sodium borohydride (22.7 gm) under nitrogen atmosphere at 0-5°C and stirred for 60 min at the same temperature. A solution of 2-(2-(2,2,2-trifluoroethoxy)phenoxy) acetic acid compound of formula-3 (100 gm) in tetrahydrofuran (300 ml) was slowly added to the reaction mixture at 0-5°C and stirred for 2 hrs at the same temperature. After completion of the reaction, aqueous hydrochloric acid was added to the reaction mixture at below 20°C. Heated the reaction mixture to 25-30°C, dichloromethane was added and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound; Yield: 94.5 gm. Example-6: Preparation of ethyl 2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetate (Formula-10)

Ethyl 2-bromoacetate (208.6 gm) was slowly added to a mixture of 2-(2,2,2-trifluoroethoxy)phenol compound of formula-9 (160 gm), dimethylformamide (1600 ml) and potassium carbonate (229 gm) at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 4 hrs at the same temperature. After completion of the reaction, a mixture of methyl tertbutyl ether and cyclohexane (800 ml, 1:1 mixture) was added to the reaction mixture at 25-30°C. Water (800 ml) was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with a mixture of methyl tert.butyl ether and cyclohexane. The combined organic layer was washed with water and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 230.0 gm. Example-7: Preparation of 2-(2-(2,2,2-trifIuoroethoxy)phenoxy)ethanol (Formula-11)

Sodium borohydride (100.6 gm) was slowly added to a pre-cooled mixture of ethyl 2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetate compound of formula-10 (370 gm), tetrahydrofuran (1850 ml) and methanol (370 ml) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. After completion of the reaction, water and ethyl acetate were added to the reaction mixture at 25-30°C. Both the organic and aqueous layers were separated and the organic layer was washed with water. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 265.5 gm.

Example-8: Preparation of 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate (Formula-7)
Triethylamine (101 gm) was added to a solution of 2-(2-(2,2,2-trifluoroethoxy)phenoxy) ethanol compound of formula-11 (95 gm) in dichloromethane (500 ml) at 25-30°C. Cooled the reaction mixture to 10-15°C and methanesulfonyl chloride (57.2 gm) was added. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. After completion of the reaction, water was added to the reaction mixture. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water, distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with isopropyl alcohol. 150 ml of Isopropyl alcohol was added to the reaction mixture at 25-30°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 20-25°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and dried to get the title compound; Yield: 85.0 gm. Example-9: Preparation of (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy) acetamido)propyl)indolin-l-yl)propyl benzoate (Formula-4)
Slowly added a solution of 2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetic acid compound of formula-3 (1.44 gm) in dichloromethane (15 ml) to a pre-cooled mixture of dichloromethane (15 ml), (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate compound of formula-2 (1.4

gm) and N-hydroxybenzotriazole (0.045 gm) at 0-5°C. A solution of N,N'-dicyclohexyl carbodiimide (1.19 gm) in dichloromethane (10 ml) was slowly added to the reaction mixture at 0-5°C and stirred for 60 min at the same temperature. After completion of the reaction, filtered the reaction mixture and washed the filtrate with 10% sodium bicarbonate solution and saturated sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely under reduced pressure to get the title compound; Yield: 2.0 gm. Example-10: Preparation of (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy) acetamido)propyl)indolin-l-yl)propyl benzoate (Formula-4)
Thionyl chloride (10 ml) was added to 2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetic acid compound of formula-3 (2 gm) and heated the reaction mixture to reflux temperature. Cooled the reaction mixture to 25-30°C and distilled off the excess thionyl chloride. To the obtained compound, dichloromethane (12 ml), triethylamine (4 ml) and (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate compound of formula-2 (2.7 gm) were added at 25-30°C and stirred for 60 min at the same temperature. After completion of the reaction, water was added to the reaction mixture. Both the organic and aqueous layers were separated and the organic layer was washed with sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely under reduced pressure to get the title compound; Yield: 3.0 gm. Example-11: Preparation of (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy) ethylamino)propyl)indolin-l-yl)propyl benzoate (Formula-5)
Boron trifluoride-etherate (0.92 gm) was slowly added to a pre-cooled solution of sodium borohydride (0.2 gm) in tetrahydrofuran (6 ml) at 0-5°C and stirred the reaction mixture for 2 hrs at the same temperature. A solution of (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy) phenoxy) acetamido)propyl)indolin-l-yl)propyl benzoate compound of formula-4 (1.2 gm) in tetrahydrofuran (6 ml) was slowly added to the reaction mixture at 0-5°C. Heated the reaction mixture to 40-45°C and stirred for 4 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 0-5 °C and slowly added to pre-cooled hydrochloric acid (6 ml) at 10-15°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Cooled the reaction mixture to 0-5°C and adjusted the pH of the reaction mixture to 10 with 30% sodium hydroxide solution. Distilled of the solvent completely from the reaction mixture under reduced pressure and extracted the reaction mixture with methyl tertiary butyl ether. The organic

layer was washed with 10% sodium chloride solution and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound; Yield: 1.0 gm. Example-12: Preparation of (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy) ethylamino)propyl)indolin-l-yl)propyl benzoate (Formula-5)

Boron trifluoride-etherate (4.6 gm) was slowly added to a pre-cooled mixture of sodium borohydride (1.02 gm) and tetrahydrofuran (60 ml) at 0-5°C under nitrogen atmosphere. A solution of (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetamido)propyl)indolin-1 -yl)propyl benzoate compound of formula-4 (6.0 gm) in tetrahydrofuran (60 ml) was slowly added to the reaction mixture at 0-5°C. Heated the reaction mixture to 40-45°C and stirred for 6 hrs at the same temperature. After completion of the reaction, slowly added chilled water to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and extracted the reaction mixture with toluene. The combined organic layer was washed with saturated sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure. The obtained residue was purified by silica gel column chromatography using 40% ethyl acetate in cyclohexane to get the title compound; Yield: 2.5 gm.

Example-13: Preparation of 3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate (Formula-16)
A mixture of methanol (500 ml), 3-(7-cyano-5-(2-nitropropyl)indolin-l-yl)propyl benzoate compound of formula-8 (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/Cm2 of hydrogen gas pressure at the same temperature. After 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-14: Preparation of (R)-3-(5-(2-aminopropyI)-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 compound of formula-16 (15 gm) was heated to reflux and stirred for 10 min at the same temperature. L(+)-tartaric acid solution (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 stirred for 15 min at the same temperature. Cooled the reaction mixture to 25-30°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-15: Purification of (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate 2,3-dihydroxysuccinate (Formula-2a)

A mixture of (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate 2,3-dihydroxysuccinate compound of formula-2a (6.5 gm) and acetone/water (15 ml, 1:1 mixture) was heated to reflux to get clear solution. Cooled the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid and washed with a mixture of acetone and water to get the title compound. Yield: 4.5 gm.

Example-16: Preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indoie-7-carbonitrile (Formula-6)
Toluene (400 ml) and 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl} propyl benzoate tartrate salt compound of formula-2a (100 gm) were charged into a clean and dry RBF at 25-30°C. Adjusted the pH of the reaction mixture to 11 using IN sodium carbonate solution and stirred for 45 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was heated to reflux temperature and water was removed by azeotropic distillation. 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate compound of formula-7 (76.5 gm), dipotassium hydrogen phosphate (101.6 gm) and terra butyl ammonium bromide (12.5 gm) were added to the reaction mixture at 25-3 0°C, heated the reaction mixture to reflux and stirred for 12 hrs at the same temperature. Water (200 ml) was added to the reaction mixture at 25-30°C and both the organic and aqueous layers were separated. Methanol (50 ml), tetra butyl ammonium bromide (12.5 gm) and sodium hydroxide solution (9.8 gm) were added to the organic layer at 25-30°C. Heated the reaction mixture to 45-50°C and stirred for 3 hrs at the same temperature. After completion of the reaction, water was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and 20% acetic acid solution was added to the organic layer at 25-30°C. Both the organic and aqueous layers were separated and toluene was added to the aqueous layer. Adjusted the pH of the reaction mixture to 11 with sodium hydroxide solution. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure. Water (60 ml) and cyclohexane (240 ml) were added to the obtained compound at 25-30°C and stirred for 90 min at the same temperature. Filtered the solid, washed with water and dried to get the title compound.

Yield: 60 gm; M.R:58-62°C; Dimer impurity: 0.6%.
Example-17: 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-6)
Aq.sodium hydroxide solution (1.93 gm of sodium hydroxide in 8 ml of water) was slowly added to a mixture of (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylamino) propyl)indolin-l-yl)propyl benzoate compound of formula-5 (8.0 gm) and methanol (32 ml) at 25-3 0°C and stirred for 4 hrs at the same temperature. After completion of the reaction, water and ethyl acetate were added to the reaction mixture at 25-30°C. Both the organic and aqueous layers were separated and the organic layer was washed with sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 6.0 gm.

Example-18: 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-l)
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 compound of formula-6 (50 gm) and sodium hydroxide (6.3 gm) at 15-25°C and stirred for 12 hrs at the same temperature. After the completion of the reaction, slowly added sodium sulfite solution 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. Cooled 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-19: 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)
Hydrogen peroxide solution (1.78 ml) was added to a pre-cooled mixture of dimethyl sulfoxide (50 ml), 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-6 (5 gm) and sodium hydroxide solution (0.21 gm of sodium hydroxide in 1.25ml of water) at 15-25°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 5 hrs at the same temperature. After completion of the reaction, sodium sulfite solution (1.75 gm of sodium sulfite in 75 ml of water) followed by ethyl acetate were slowly added to the reaction mixture at 25-30°C. Both the organic and aqueous layers were separated and the organic layer was washed with sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate (20 ml) was added to the obtained compound, heated the reaction mixture to 60-65 °C and stirred for 10 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound; Yield: 3.5 gm.

Example-20: Purification of l-(3-hydroxypropyI)-5-[(2R)-2-({2-[2-(2,2,2-trifiuoro ethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-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-lH-indole-7-carboxamide (50 gm) was heated to 70-75°C and stirred for 10 min at the same temperature. Carbon (5.0 gm) was added to the reaction mixture at 70-75°C and stirred for 15 min at the same temperature. Filtered the reaction mixture through hyflow bed, cooled the filtrate to 25-3 0°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 mm. 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. Cooled the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid and dried to get the pure title compound; Yield: 45.0 gm; Specific surface area: 1.34 m2/g; Purity by HPLC: 99.72%; Particle Size Distribution: D(0.1):1.898 urn; D(0.5):8.164 um; D(0.9):38.92 urn; D(1.0):150.75 urn. Example-21: Purification of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoro ethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide (Formula-1)
A mixture of ethyl acetate (15 ml) and l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide (3 gm) was heated to 70-75°C and stirred for 10 min at the same temperature. Carbon (0.3 gm) was added to the reaction mixture at 70-75 °C and stirred for 15 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Cooled the filtrate to 25-3 0°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get pure title compound; Yield: 2.5 gm.

We Claim:

1. (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetamido)propyl)indolin-l-yl) propyl benzoate compound represented by the structural formula-4

2. A process for the preparation of (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy) acetamido)propyl)indolin-l-yl)propyl benzoate compound of formula-4, comprising of condensing the (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate compound of formula-2 or its tartrate salt compound of formula-2a with 2-(2-(2,2,2-trifluoroethoxy) phenoxy)acetic acid compound of formula-3 in presence of in presence of N,N'-dicyclohexyl carbodiimide and N-hydroxybenzotriazole in dichloromethane to provide (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetamido)propyl)indolin-1 -yl)propyl benzoate compound of formula-4.

3. A novel process for the preparation of (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy) phenoxy)ethylamino)propyl)indolin-l-yl)propyl benzoate compound of formula-5, comprising of reducing the (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy) acetamido)propyl) indolin-l-yl)propyl benzoate compound of formula-4 with sodium borohydride-BF3.etherate in tetrahydrofuran to provide (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy) ethylamino)propyl)indolin-l-yl)propyl benzoate of formula-5.

4. A novel 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 (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate compound of formula-2 or its tartrate salt compound of formula-2a with 2-(2-(2,2,2-trifluoroethoxy) phenoxy)acetic acid compound of formula-3 in presence of a suitable condensing agent selected from thionyl chloride, phosphorous oxychloride, N,N'-dicyclohexyl carbodiimide

(DCC), N,N'-diisopropyl carbodiimide(DIC), N,N'-carbonyldiimidazole (CDI), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HC1 or EDAC.HC1) optionally in presence of l-hydroxy-7-azabenzotriazole(HOAt), N-hydroxybenzotriazole(HOBt), N-hydroxysuccinimide(NHS) or sulfo-NHS, pentafluorophenol and optionally in presence of a suitable base selected from hydroxides, carbonates and bicarbonates of alkali metals, organic bases in a suitable solvent selected from chloro solvents, ether solvents, polar-aprotic solvents, ester solvents, hydrocarbon solvents, alcoholic solvents or their mixtures to provide (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-

trifluoroethoxy)phenoxy)acetamido)propyl)indolin-l-yl)propyl benzoate compound of formula-4,

b) reducing the compound of formula-4 with a suitable reducing agent selected from sodium borohydride-BF3.etherate, Pd-C, triethylsilane-trifluoroacetic acid, Raney-Ni in a suitable solvent selected from chloro solvents, alcoholic solvents, ether solvents, hydrocarbon solvents or their mixtures to provide (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy) ethylamino)propyl)indolin-l-yl)propyl benzoate compound of formula-5,

c) hydrolyzing the compound of formula-5 in presence of a suitable base selected from hydroxides and carbonates of alkali metals in a suitable solvent selected from polar solvents, alcoholic solvents, polar-aprotic solvents, hydrocarbon solvents, ketone solvents or their mixtures to provide (R)-l-(3-hydroxypropyl)-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy) ethylamino)propyl)indoline-7-carbonitrile compound of formula-6,

d) hydrolyzing the compound of formula-6 in presence of a suitable oxidizing agent and a suitable base selected from hydroxides and carbonates of alkali metals in a suitable solvent selected from polar solvents, alcoholic solvents, polar-aprotic solvents, hydrocarbon solvents, ketone solvents or their mixtures 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.

5. A novel 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 (R)-3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate compound of formula-2 with 2-(2-(2,2,2-trifluoroethoxy) phenoxy)acetic acid compound of formula-3 in presence of N,N'-dicyclohexyl carbodiimide and N-hydroxybenzotriazole in dichloromethane to provide (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetamido)propyl) indolin-l-yl)propyl benzoate compound of formula-4,

b) reducing the compound of formula-4 with sodium borohydride-BF3.etherate in tetrahydrofuran to provide (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifiuoroethoxy)phenoxy) ethylamino)propyl)indolin-l-yl)propyl benzoate compound of formula-5,

c) hydrolyzing the compound of formula-5 in presence of sodium hydroxide in methanol to provide (R)-1 -(3-hydroxypropyl)-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylamino) propyl)indoline-7-carbonitrile compound of formula-6,

d) hydrolyzing the compound of formula-6 in presence of hydrogen peroxide and sodium hydroxide 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) purifying the compound of formula-1 from ethyl acetate to provide pure compound of formula-1.

5. A process for the preparation of 3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate compound of formula-16, comprising of reducing the 3-(7-cyano-5-(2-nitropropyl)indolin-l-yl)propyl benzoate compound of formula-8 with a suitable reducing agent selected from Raney-Ni, sodium borohydride optionally in combination with BF3.etherate in a suitable solvent selected from alcoholic solvents, chloro
solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents or their mixtures to provide 3-(5-(2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate compound of formula-16.

7. A process for the preparation of 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate compound of formula-7, comprising of;

a) Reacting the 2,2,2-trifluoroethanol compound of formula-12 with p-toluenesulfonyl chloride in presence of a suitable organic or inorganic base in a suitable solvent selected from chloro solvents, hydrocarbon solvents, ether solvents or their mixtures to provide 2,2,2-trifluoroethyl 4-methylbenzenesulfonate compound of formula-13,

b) reacting the compound of formula-13 with 2-methoxy phenol compound of formula-12 in presence of a suitable inorganic base in a suitable solvent selected from polar-aprotic solvents, chloro solvents, hydrocarbon solvents, ether solvents or their mixtures to provide 1-methoxy-2-(2,2,2-trifluoroethoxy) benzene compound of formula-15,

c) demethylating the compound of formula-15 by treating it with aq.hydrobromic acid in a suitable solvent selected from acetic acid, chloro solvents, hydrocarbon solvents, ether solvents or their mixtures to provide 2-(2,2,2-trifluoroethoxy)phenol compound of formula-9,

d) reacting the compound of formula-9 with sodium 2-chloroacetate in presence of a suitable inorganic base in a suitable solvent selected from hydrocarbon solvents, chloro solvents, ether solvents or their mixtures, followed by in-situ treating with hydrochloric acid to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetic acid compound of formula-3,

e) reducing the compound of formula-3 with a suitable reducing agent selected from sodium borohydride optionally in combination with BF3.etherate, lithium aluminium hydride, lithium triethylborohydride, lithium tri-sec-butyl(hydrido)borate(l-) (L-selectride), diisobutylaluminium hydride (DIBAL), diborane, borane-dimethylsulfide in a suitable solvent selected from ether solvents, hydrocarbon solvents, alcoholic solvents, ester solvents, polar solvents, chloro solvents or their mixtures to provide 2-(2-(2,2,2-trifluoroethoxy) phenoxy)ethanol compound of formula-11,

f) treating the compound of formula-11 with methanesulfonyl chloride in presence of a suitable organic base in a suitable solvent selected from chloro solvents, ether solvents, hydrocarbon solvents or their mixtures to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate compound of formula-7.

8. A process for the preparation of 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate
compound of formula-7, comprising of;

a) Reacting the 2,2,2-trifluoroethanol compound of formula-12 with p-toluenesulfonyl chloride in presence of triethylamine in toluene to provide 2,2,2-trifluoroethyl 4-methylbenzenesulfonate compound of formula-13,

b) reacting the compound of formula-13 with 2-methoxy phenol compound of formula-14 in presence of potassium carbonate in N,N-dimethyl formamide to provide l-methoxy-2-(2,2,2-trifluoroethoxy)benzene compound of formula-15,

c) demethylating the compound of formula-15 by treating with aq.hydrobromic acid in acetic acid to provide 2-(2,2,2-trifluoroethoxy)phenol compound of formula-9,

d) reacting the compound of formula-9 with sodium 2-chloroacetate in presence of sodium hydroxide in toluene, followed by in-situ treating with hydrochloric acid to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetic acid compound of formula-3,

e) reducing the compound of formula-3 with sodium borohydride-BF3.etherate in tetrahydrofuran to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethanol of formula-11,

f) treating the compound of formula-11 with methanesulfonyl chloride in presence of triethylamine in dichloromethane to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate compound of formula-7.

9. A process for the preparation of 2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetic acid compound of formula-3, comprising of reacting the 2-(2,2,2-trifluoroethoxy)phenol compound of formula-9 with sodium 2-chloroacetate in presence of a suitable inorganic base in a suitable solvent selected from hydrocarbon solvents, chloro solvents, ether solvents, ester solvents, polar-aprotic solvents, ketone solvents, polar solvents or their mixtures, followed by in-situ treating with a suitable acid such as hydrochloric acid to provide 2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetic acid compound of formula-3.

10. A process for the preparation of 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethanol compound of formula-11, comprising of reducing the 2-(2-(2,2,2-trifluoroethoxy)phenoxy)acetic acid compound of formula-3 or its ethyl ester compound of formula-10

with a suitable reducing agent selected from sodium borohydride optionally in combination with BF3.etherate, lithium triethylborohydride, lithium tri-sec-butyl(hydrido)borate(l-) (L-selectride), diisobutylaluminium hydride (DIBAL), diborane, borane-dimethylsulfide in a suitable solvent selected from alcoholic solvents, ether solvents, ester solvents, hydrocarbon solvents, chloro solvents, polar solvents or their mixtures to provide 2-(2-(2,2,2-trifluoroethoxy) phenoxy)ethanol compound of formula-11.