DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

PROCESS FOR THE PREPARATION OF INDOLINE DERIVATIVES AND SALTS THEREOF

We, Tyche Industries Limited,
a company incorporated under the companies act, 1956 having address at
C-21/A, Road No.9, Film Nagar, Jubilee Hills, Hyderabad – 500096, India

The following specification particularly describes the nature of the invention and manner in which it is to be performed.
Field of the Invention
The present invention relates to a process for the preparation of indoline derivatives and salts thereof. In particular the present invention relates to process for the preparation of indoline derivative and salts thereof which may be used as intermediates in the preparation of alpha-1 adrenergic receptor antagonist preferably Silodosin.

Background of the Invention
RAPAFLO® is the brand name for Silodosin, a selective antagonist of alpha-1 adrenoreceptors. The chemical name of Silodosin is 1-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide and the molecular formula is C25H32F3N3O4with a molecular weight of 495.53. The structural formula of Silodosin is:

Silodosin is disclosed for the first time in U.S. Pat. No.5,387,603. This patent also discloses processes for the preparation of Silodosin and its intermediates which involve deprotecting
l-(3-hydroxypropyl)-5-[(2R)-2-[N-tert-butoxycarbonyl-2-(2,2,2-trifluoroethoxyphenoxy) ethylamino]propyl]indoline-7-carboxamide with trifluoroacetic acid in methylene chloride. The process is shown in the scheme given below:

Scheme I

US Patent No.7,834,193 relates to a process for the preparation of Silodosin comprising mixing 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate with oxalic acid to produce corresponding monooxalate salt compound. Hydrolyzing the obtained monooxalate compound to yield 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethy-l}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile, further, hydrolyzing the compound obtained to yield Silodosin. The process is shown in the scheme given below:

Scheme II

PCT Appl. No. WO 2012/147019 A1 discloses a process for the preparation of Silodosin which comprises treating 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate with 2-(2,2,2-trifluoroethoxy)phenoxyethyl methanesulfonate to produce 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate which is further converted to its tartrate salt followed by hydrolyzing the tartrate salt to 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethy-l}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile and finally converting the obtained compound to Silodosin. The process is shown in the scheme given below:

Scheme III

Considering the importance of Silodosin there is need for a simple, economical and industrially viable process for the synthesis of Silodosin. With a view to find a simple process the present applicant diligently worked and identified a robust and economical process for the preparation of Fumarate salt of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate of Formula II and its use in the preparation of Silodosin.

Objective of the Invention
The main objective of the present invention is to provide Fumarate salt of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate of Formula II.

Another objective of the present invention is to provide a robust and simple process for the preparation of Fumarate salt of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate of Formula II with high purity and yield.

Yet, another objective of the present invention is to provide an improved process for the preparation of Silodosin with high yield and purity.

Summary of the Invention
Accordingly, the present invention provides Fumarate salt of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate of Formula II.

In another aspect, the present invention provides a process for the preparation of Fumarate salt of compound Formula IIa which comprises the steps of
i) reacting the compound of Formula III or its salts

wherin Pg is a hydroxy protecting group; with the compound of Formula IV

wherein L is a leaving group; in a solvent in the presence of a base to obtain compound of Formula V,

ii) converting the compound of Formula V to its Fumarate salt of Formula IIa.

In yet another aspect, the present invention provides 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-1H-indole-7-carboxamide (Silodosin) of Formula I

which comprises the steps of
i) reacting the compound of Formula III or its salts

wherin Pg is a hydroxy protecting group; with the compound of Formula IV

wherein L is a leaving group; in a solvent in the presence of a base to obtain compound of Formula V,

ii) converting the compound of Formula V to its Fumarate salt of Formula IIa,

iii) hydrolyzing the Fumarate salt of compound of Formula IIa to obtain compound of Formula VI

in a solvent in the presence of a base; and
iv) converting the compound of Formula VI to compound of Formula I in a solvent and in the presence of a base and an oxidizing agent.

Detailed Description of the Invention
The present invention relates to 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-1H-indole-7-carboxamide (Silodosin) of Formula I.

Suitable hydroxy protecting group used in compound of Formula III is selected from formyl, acetyl, substituted acetyl, propionyl, butynyl, pivalamido, benzoyl, biphenylcarbonyl, substituted biphenylcarbonyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, benzyl, diphenylmethyl, triphenylmethyl, t-butyl, tetrahydropyranyl, allyl, N-phenylcarbamate, N-imidazoylcarbamate, trialkylsilyl, isopropyldialkylsilyl, alkyldiisopropylsilyl, triisopropylsilyl or t-butyldialkylsilyl.

Suitable leaving group used in compound of Formula IV is selected from halogen such as chlorine, bromine, fluorine, iodine or alkylsulfonyloxy group such as methanesulfonyloxy and like or trifluoroalkylsulfonyloxy such as a trifluoromethanesulfonyloxy and the like or arylsulfonyloxy group such as benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, o-nitrobenzenesulfonyloxy or fluorosulfonyl.

Suitable solvent used in step (i) for condensation of compound of Formula III and compound of Formula IV is selected from alcohols such as methanol, ethanol, propanol, butanol and the like or aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and the like or aliphatic hydrocarbons such as heptane, hexane and the like or halogenated hydrocarbons such as chloroform, dichloromethane and the like or esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate and the like or ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone and or mixtures thereof.

Suitable base used in step (i) is selected from an inorganic base like alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide and the like or alkali metal carbonates such as caesium carbonate, sodium carbonate potassium carbonateor lithium carbonate and the like oralkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate and the likeor an organic base selected from diisopropylamine, diisopropylethylamine, triethylamine, dimethylamine, trimethylamine, pyridine and the like or mixtures thereof;the base optionally being present in aqueous solution.

Suitable solvents used for conversion of compound of Formula V to its fumarate is selected from alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol, tert-butanol and the like or esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate and the like oraliphatic hydrocarbons such as heptane, hexane and the like or ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethyl methyl ketone, diethyl ketone and the like or water and or mixtures thereof.

Suitable solvents used for hydrolyzing the fumarate salt in step (iii) is selected from alcohols such as methanol, ethanol, propanol, butanol and the like or ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone and the likeor ethers such as diethyl ether, tetrahydrofuran, dioxane and the likeor water and or mixtures thereof.

Suitable base used for hydrolysis in step (iii) is selected from alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide and the like or alkali metal carbonates such as caesium carbonate, sodium carbonate potassium carbonateor lithium carbonate and the like oralkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate and or mixtures thereof.

Conversion of compound of Formula VI to Silodosin of Formula I in step (iv) is carried out using an oxidizing agent selected from hydrogen peroxide and the like.

Suitable solvents used for conversion in step (iv) is selected from alcohols such as methanol, ethanol, propanol, butanol and the like or ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone and the like or ethers such as diethyl ether, tetrahydrofuran, dioxane and the like or an aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile or water and or mixtures thereof.

Suitable base used for conversion in step (iv) is selected from alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide and the like or alkali metal carbonates such as caesium carbonate, sodium carbonate potassium carbonate or lithium carbonate and the like or alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate and or mixtures thereof.

In one embodiment, the present invention provides a process for the preparation of Fumarate salt of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate of Formula II which comprises the steps of
i) reacting the compound of Formula IIIa or its salts

with the compound of Formula IVa

in a solvent in the presence of a base to obtain compound of Formula Va,

ii) converting the compound of Formula Va to its Fumarate salt of Formula II.

In a preferred embodiment, the present invention provides a process for the preparation of Fumarate salt of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate of Formula II which comprises the steps of
i) reacting the compound of Formula IIIa or its salts

with the compound of Formula IVa

in isopropyl alcohol in the presence of sodium carbonate to obtain compound of Formula Va,

ii) converting the compound of Formula Va to its Fumarate salt of Formula II.

In a most preferred embodiment, the present invention provides a process for the preparation of Fumarate salt of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate of Formula IIwhich comprises the steps of
i) reacting the tartrate salt of compound of Formula IIIb

with the compound of Formula IVa

in isopropyl alcohol in the presence of sodium carbonate to obtain compound of Formula Va,

ii) converting the compound of Formula Va to its Fumarate salt of Formula II.

In another embodiment, the present invention provides an improved process for the preparation of Silodosin of Formula I which comprises the steps of
i) reacting the compound of Formula IIIa or its salts

with the compound of Formula IVa

in a solvent in the presence of a base to obtain compound of Formula Va

ii) converting the compound of Formula Va to its Fumarate salt of Formula II,

iii) hydrolyzing the Fumarate salt of compound of Formula II to obtain compound of Formula VI

in a solvent in the presence of a base; and
iv) converting the compound of Formula VI to compound of Formula I in a solvent and in the presence of a base and an oxidizing agent.

In another preferred embodiment, the present invention provides a process for the preparation of Silodosin of Formula I which comprises the steps of
i) reacting the compound of Formula IIIa or its salts

with the compound of Formula IVa

in isopropyl alcohol in the presence of sodium carbonate to give compound of Formula Va

ii) converting the compound of Formula Va to its Fumarate salt of Formula II,

iii) hydrolyzing the Fumarate salt of compound of Formula II to obtain compound of Formula VI

in methanol in the presence of sodium hydroxide; and
iv) converting the compound of Formula VI to compound of Formula I in DMSO in the presence of sodium hydroxide and hydrogen peroxide.

In another most preferred embodiment, the present invention provides a process for the preparation of Silodosin of Formula I which comprises the steps of
i) reacting the compound of Formula IIIb or its salts

with the compound of Formula IVa

in isopropyl alcohol in the presence of sodium carbonate to give compound of Formula Va

ii) converting the compound of Formula Va to its Fumarate salt of Formula II,

iii) hydrolyzing the Fumarate salt of compound of Formula II to obtain compound of Formula VI

in methanol in the presence of sodium hydroxide; and
iv) converting the compound of Formula VI to Silodosin in DMSO in the presence of sodium hydroxide and hydrogen peroxide.

In another embodiment, the present invention provides a process for the preparation of Fumarate salt of compound Formula IIa

which comprises the steps of
i) providing the compound of Formula V in a suitable solvent,

ii) adding fumaric acid to the solution obtained in step (i) and
iii) isolating the compound of Formula IIa.

In another preferred embodiment, the present invention provides a process for the preparation of Fumarate salt of compound of Formula II

which comprises the steps of
i) providing the compound of Formula Va in a suitable solvent,

ii) adding fumaric acid to the solution obtained in step (i) and
iii) isolating the compound of Formula II.

In a most preferred embodiment, the present invention provides a process for the preparation of Fumarate salt of compound of Formula II

which comprises the steps of:
i) providing the compound of Formula Va in a mixture of acetone and water or isopropyl alcohol or ethylacetate,

ii) adding fumaric acid to the solution obtained in step (i) and
iii) isolating the compound of Formula II.

The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative and relate to solutions which have been particularly effective on a bench scale.

EXAMPLES
Example 1
Preparation of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino) propyl)-2,3-dihydro-1H-indol-1-yl)-propyl benzoate Fumarate
A mixture of an aqueous solution of (40 mL) sodium carbonate (4.0 g) and 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-1H-indol-1-yl]propyl benzoate (2R,3R)-tartrate (10.0 g) were stirred at room temperature for 15 min. Methylene dichloride (150 ml ) was added and stirred at room temperature for 15 min. Methylene dichloride layer was separated and washed with water, dried over anhydrous sodium sulphate and concentrated. The obtained oil was dissolved in anhydrous isopropanol (90 mL) and 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate (7.2 g), sodium carbonate (4.0 g) were added to the solution thus obtained. Heated the reaction mixture to reflux temperature and maintained the reaction at the same temperature for about 30 hours. Cooled the reaction mixture to room temperature, filtered the mass and washed with isopropanol (20 ml). The filtrate was concentrated under reduced pressure to give crude compound. The crude compound was dissolved in ethyl acetate (40 ml) and washed with water. Ethyl acetate layer was separated and concentrated under reduced pressure to give 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate base (12.0 g). The above base (12.0 g) was dissolved in isopropanol and fumaric acid (2.3 g) was added. Heated the reaction mixture to 60-65ºC, cooled to room temperature, filtered and dried to give 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate fumarate salt (6.0 g).

Example 2
Preparation of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)
propyl)-2,3-dihydro-1H-indol-1-yl)-propyl benzoate Fumarate
A mixture of an aqueous solution of (40 mL) sodium carbonate (4.0 g) and 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-1H-indol-1-yl]propyl benzoate (2R,3R)-tartrate (10.0 g) were stirred at room temperature for 15 min. Methylene dichloride (150 ml ) was added and stirred at room temperature for 15 min. Methylene dichloride layer was separated, washed with water, dried over anhydrous sodium sulphate and concentrated. The obtained oil was dissolved in anhydrous isopropanol (90 mL) and 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate (7.2 g), sodium carbonate (4.0 g) were added to the solution thus obtained. Heated the reaction mass to reflux temperature for about 30 hours, cooled to room temperature, filtered the mass and washed with isopropanol (20 ml). The filtrate was concentrated under reduced pressure to give crude compound. The crude compound was dissolved in ethyl acetate (40 ml) and washed with water. Ethyl acetate layer was separated and concentrated under reduced pressure to give 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate base (12.0 g). The above base (12.0 g) was dissolved in 1:2 mixture of acetone and water (54 ml) andfumaric acid (2.3 g) was added. The mixture was heated to 60-65ºC. Cooled to room temperature, filtered and dried to give 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate fumarate salt (7.5. g).

Example 3
Preparation of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)
propyl)-2,3-dihydro-1H-indol-1-yl)-propyl benzoate Fumarate
A mixture of an aqueous solution of (40 mL), sodium carbonate (4.0 g) and 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-1H-indol-1-yl]propyl benzoate (2R,3R)-tartrate (10.0 g) were stirred at room temperature for 15 min. Methylene dichloride (150 ml ) was added and stirred at room temperature for 15 min. Methylene dichloride layer was separated, washed with water, dried over anhydrous sodium sulphate and concentrated. The obtained oil was dissolved in anhydrous isopropanol (90 mL) and 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate (7.2 g), sodium carbonate (4.0 g) were added to the solution thus obtained. Heated the reaction mixture to reflux temperature for about 30 hours and cooled to room temperature. Filtered the solid obtained and washed with isopropanol (20 ml). The filtrate was concentrated under reduced pressure to give crude compound. The crude compound was dissolved in ethylacetate (40 ml) and washed with water. Fumaric acid (2.3 g) was added to the ethyl acetate layer and heated to 60-65ºC. Ethyl acetate was concentrated to half the volume and hexane (30ml) was added. Cooled to room temperature and filtered and dried to give 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}a mino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate fumarate salt (8.0. g).

Example 4
Preparation of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)
propyl)-2,3-dihydro-1H-indol-1-yl)-propyl benzoate Fumarate
A mixture of 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-1H-indol-1-yl]propyl benzoate (2R,3R)-tartrate (10.0 g), 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate (8.0 g) and sodium carbonate (8.0 g) were refluxed to heating for about 30 hours. Cooled the reaction mixture to room temperature and filtered. The filtrate was concentrated under reduced pressure to give crude compound. The crude compound was dissolved in ethyl acetate (40 ml) and washed with water. Ethyl acetate layer was concentrated under reduced pressure to give 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate base (12.0 g). The above base (12.0 g) was dissolved in isopropanol and fumaric acid ( 2.3 g) was added. Heated the reaction mixture to 60-65ºC and cooled to room temperature. Filtered the solid and dried to give 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate fumarate salt (6.0 g).

Example 5
Preparation of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino) propyl)-2,3-dihydro-1H-indol-1-yl)-propyl benzoate Fumarate
A mixture of 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-1H-indol-1-yl]propyl benzoate (2R,3R)-tartrate (10.0 g), 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate (8.0 g) and sodium carbonate (8.0 g) were heated to refluxfor about 30 hours.Cooledthereaction mass to room temperature and filtered the reaction mass. The filtrate was concentrated under reduced pressure to give crude compound. The crude compound was dissolved in ethyl acetate (40 ml) and washed with water. Ethyl acetate layer was concentrated under reduced pressure to give 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate base (12.0 g). The above base (12.0 g) dissolved in 1:2 mixture of acetone and water (54 ml) and fumaric acid (2.3 g) was added. The reaction mixture was heated to 60-65ºC and cooled to room temperature. Filtered the reaction mass and dried to give 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate fumarate salt (7.5. g).
Example 6
Preparation of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino) propyl)-2,3-dihydro-1H-indol-1-yl)-propyl benzoate Fumarate
A mixture of 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-1H-indol-1-yl]propyl benzoate (2R,3R)-tartrate (10.0 g), 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate (8.0 g) and sodium carbonate (8.0 g) were heated to reflux for about 30 hours. Cooled the reaction mixture to room temperature and filtered. The filtrate was concentrated under reduced pressure to give crude compound. The crude compound was dissolved in ethyl acetate (40 ml) and washed with water. Fumaric acid ( 2.3 g) was added to the ethyl acetate layer and heated to 60-65ºC. Ethyl acetate was concentrated to half the volume and hexane (30ml) was added, cooled to room temperature, filtered and dried to give 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate fumarate salt (8.0. g).
Example 7
Preparation of 1-(3-hydroxypropyl)-5-[(2R)-2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]
amino]propyl]-2,3-dihydro-1H-indole-7-carbonitrile .
Toa mixture of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino) propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate fumarate salt (10.0 g) in methanol (75 ml) was addedsodium hydroxide solution (2.9 g in 20 ml water) at 10-15ºC, heated to RTand maintained at the same temperature for about 2 hours. Filtered the reaction mixture and washed with methanol(25 ml). Filtrate was concentrated under reduced pressure, the compound is taken in ethyl acetate (40 ml) and separatedthe aqueous layer. Ethyl acetate wasdistilled off and the product is crystallized from diisopropylether (35 ml) to get 1-(3-hydroxypropyl)-5-[(2R)-2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-2,3-dihydro-1H-indole-7-carbonitrile (5.8 g).
Example 8
Preparation of Silodosin
To a mixture of 1-(3-hydroxypropyl)-5-[(2R)-2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl] amino]propyl]-2,3-dihydro-1H-indole-7-carbonitrile (10.0 g) in DMSO (100 ml) were added sodium hydroxide solution (2.7 g in 10 ml water)and 30% hydrogen peroxide (18ml); maintained for about 8 hr.The reaction mixture was transferred into water and sodium sulphite solution and ethyl acetate (25 ml) were added. Layers were separated and organic layer was concentrated. Recrystallization from ethyl acetate afforded Silodosin (6.8 g). ,CLAIMS:We claim,
1. Fumarate salt of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate of Formula II.

2. A process for the preparation of Fumarate salt of compound Formula IIa which comprises the steps of
i) reacting the compound of Formula III or its salts

wherin Pg is a hydroxy protecting group; with the compound of Formula IV

wherein L is a leaving group; in a solvent in the presence of a base to obtain compound of Formula V,

ii) converting the compound of Formula V to its Fumarate salt of Formula IIa.

3. 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-1H-indole-7-carboxamide (Silodosin) of Formula I

which comprises the steps of
i) reacting the compound of Formula III or its salts

wherin Pg is a hydroxy protecting group; with the compound of Formula IV

wherein L is a leaving group; in a solvent in the presence of a base to obtain compound of Formula V,

ii) converting the compound of Formula V to its Fumarate salt of Formula IIa,

iii) hydrolyzing the Fumarate salt of compound of Formula IIa to obtain compound of Formula VI

in a solvent in the presence of a base; and
iv) converting the compound of Formula VI to compound of Formula I in a solvent and in the presence of a base and an oxidizing agent.

4. A process as claimed in claims 2 and 3 wherein the hydroxy protecting group used in compound of Formula III is selected from formyl, acetyl, substituted acetyl, propionyl, butynyl, pivalamido, benzoyl, biphenylcarbonyl, substituted biphenylcarbonyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, benzyl, diphenylmethyl, triphenylmethyl, t-butyl, tetrahydropyranyl, allyl, N-phenylcarbamate, N-imidazoylcarbamate, trialkylsilyl, isopropyldialkylsilyl, alkyldiisopropylsilyl, triisopropylsilyl or t-butyldialkylsilyl.

5. A process as claimed in claims 2 and 3 wherein the leaving group used in compound of Formula IV is selected from halogen such as chlorine, bromine, fluorine, iodine or alkylsulfonyloxy group such as methanesulfonyloxy and like or trifluoroalkylsulfonyloxy such as a trifluoromethanesulfonyloxy and the like or arylsulfonyloxy group such as benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, o-nitrobenzenesulfonyloxy or fluorosulfonyl.

6. A process as claimed in claims 2 and 3 wherein the solvent used in step (i) for condensation of compound of Formula III and compound of Formula IV is selected from alcohols such as methanol, ethanol, propanol, butanoland the like or aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and the like or aliphatic hydrocarbons such as heptane, hexane and the like or halogenated hydrocarbons such as chloroform, dichloromethane and the like or esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate and the like or ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone and or mixtures thereof.
7. A process as claimed in claims 2 and 3 wherein the base used in step (i) is selected from an inorganic base like alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide and the like or alkali metal carbonates such as caesium carbonate, sodium carbonate potassium carbonate or lithium carbonate and the like or alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate and the likeor an organic base selected from diisopropylamine, diisopropylethylamine, triethylamine, dimethylamine, trimethylamine, pyridine and the like or mixtures thereof;the base optionally being present in aqueous solution.

8. A process as claimed in claims 2 and 3 wherein the solvents used for conversion of compound of Formula V to its fumarate is selected from alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol and the like or esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate and the like oraliphatic hydrocarbons such as heptane, hexane and the like or ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone and the like or water and or mixtures thereof.

9. A process as claimed in claim 3 wherein the solvents used for hydrolyzing the fumarate salt in step (iii) is selected from alcohols such as methanol, ethanol, propanol, butanol and the like or ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone and the likeor ethers such as diethyl ether, tetrahydrofuran, dioxane and the like or water and or mixtures thereof.

10. A process as claimed in claim 3 wherein the base used for hydrolysis in step (iii) is selected from alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide and the like or alkali metal carbonates such as caesium carbonate, sodium carbonate potassium carbonate or lithium carbonate and the like or alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate and or mixtures thereof.

11. A process as claimed in claim 3 wherein the conversion of compound of Formula VI to Silodosin of Formula I in step (iv) is carried out using an oxidizing agent selected from hydrogen peroxide.

12. A process as claimed in claim 3 wherein the solvents used for conversion in step (iv) is selected from alcohols such as methanol, ethanol, propanol, butanol and the like or ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone and the like or ethers such as diethyl ether, tetrahydrofuran, dioxane and the like or an aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile or water and or mixtures thereof.

13. A process as claimed in claim 3 wherein the base used for conversion in step (iv) is selected from alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide and the like or alkali metal carbonates such as caesium carbonate, sodium carbonate potassium carbonate or lithium carbonate and the like or alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate and or mixtures thereof.

Dated this Fifteenth (15th) day of October 2015.

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Dr. S. Padmaja
Agent for the Applicant
IN/PA/883