DESC:FIELD OF THE INVENTION

The present invention relates to a process of preparing silodosin. In particular, the invention provides an improved process for the preparation of silodosin.

BACKGROUND OF THE INVENTION

Silodosin, 1-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide of Formula (I) is an indoline antidysuric which has a selectively inhibitory effect against urethra smooth muscle constriction, and decreases urethra internal pressure without great influence on blood pressure.

(I)

U.S. Patent No. 5,387,603 discloses the process for the preparation of silodosin and salts thereof with a pharmaceutically acceptable acid and their therapeutic use.

U.S. Patent No. 7,834,193 (the US ‘193) discloses the process for preparing silodosin via formation of oxalate salt of intermediate compound of formula (IIIa),

(IIIa)
U.S. PG-Pub. No. 2006/0142374 A1 discloses three polymorphic forms of silodosin namely crystal form a, crystal form ß and crystal form ?, which are characterized by XRPD and process for the preparation of crystal forms thereof.

International (PCT) Publications WO 2011/030356, WO 2011/101864, WO 2012/077138, WO 2012/131710, WO 2012/147019, WO 2013/072935, and WO 2015/015512 disclose processes for the preparation of silodosin and intermediates thereof.

Our own international (PCT) publication No. WO 2013/072935 discloses the process for the preparation of silodosin substantially free from impurity X at RRT 0.87 to 0.90, which is a dehydro impurity having molecule mass 494.7.

The process reported in the prior art suffers from the drawbacks of preparing acid addition salts of intermediates in order to restrict the formation of dimeric impurity. The US ‘193 in reference example-1 discloses the preparation of 3-{7-cyano-5-[(2R)({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}-propyl benzoate containing 13.6% of dimeric impurity (by-product (C-a)). The US ‘193 provides the formation of acid addition salt of 3-{7-cyano-5-[(2R)({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}-propyl benzoate with oxalic acid, to form monooxalate salt having 0.9% by-product (C-a). The US ‘193 B2 however discloses that the method adopted for removing the dimeric impurity can reduce it to 1% or less, but no further information is provided in the silodosin. This formation of acid addition salts (e.g. oxalate) of intermediates leads the additional steps for preparing pure silodosin. The inventors of the present invention have developed a process for the preparation of highly pure silodosin without formation of acid addition salts of intermediates.

Therefore, there is still a need for an alternative process for preparing silodosin which restricts the formation of one or more impurities and prepare highly pure silodosin without preparing acid addition salts of intermediates.

SUMMARY OF THE INVENTION

In one general aspect, there is provided a process of preparing silodosin, the process comprising:
(a) reacting compound of Formula (V) with compound of Formula (IV) in mixture of solvents in the presence of a base,

(V) (IV)
to obtain compound of Formula (III);

(III)
(b) hydrolyzing the compound of Formula (III) in the presence of a base in one or more solvents to obtain compound of Formula (II); and

(II)
(c) hydrolyzing the compound of Formula (II) with a base in the presence of an oxidizing agent in one or more solvents to obtain silodosin, wherein the compound of Formula (III) and Formula (II) are not converted to acid addition salts.

In another general aspect, there is provided a process of preparing silodosin, the process comprising:
(a) reacting compound of Formula (V) with compound of Formula (IV) in mixture of solvents in the presence of a base,

(V) (IV)
to obtain compound of Formula (III);

(III)
(b) hydrolyzing the compound of Formula (III) in the presence of a base in one or more solvents to obtain compound of Formula (II); and

(II)
(c) hydrolyzing the compound of Formula (II) with a base in the presence of oxidizing agent in one or more solvents to obtain silodosin, wherein the compound of Formula (III) and Formula (II) are not converted to acid addition salts, the solvent in step (b) and (c) is same.

In another general aspect, there is provided a silodosin substantially free from dimer impurity, prepared by a process comprising:
(a) providing a solution of silodosin prepared by the process of the invention in one or more solvents;
(b) extracting silodosin in one or more solvents;
(c) removing the solvent to obtain a residue;
(d) treating the residue with an aqueous acid solution to obtain an aqueous layer;
(e) basifying the aqueous layer with a base in the presence of one or more solvents;
(f) obtaining silodosin by the removal of the solvent; and
(g) recrystallizing the silodosin with one or more ester solvents to obtain the silodosin substantially free from dimer impurity.

In another general aspect, there is provided a silodosin substantially free from dehydro impurity, prepared by a process comprising:
(a) providing a solution of silodosin prepared by the process of the invention in one or more solvents;
(b) treating the solution with a reducing agent to obtain a reaction mixture;
(c) quenching the reaction mixture in water and basifying with one or more base;
(d) extracting the reaction mixture with one or more solvents;
(e) removing the solvent to obtain a residue;
(f) treating the residue with one or more solvents; and
(g) obtaining silodosin substantially free from dehydro impurity by recrystallizing silodosin in one or more ester solvents.

In another general aspect, there is provided silodosin substantially free from dimer impurity and dehydro impurity, prepared by the process comprising reacting compound of Formula (V) and compound of Formula (IV) to obtain compound of Formula (III); and converting the compound of Formula (III) to obtain silodosin without formation of acid addition salts.

In another general aspect, there is provided substantially pure silodosin prepared by the process of present invention substantially free from dimeric impurity.

In another general aspect, there is provided substantially pure silodosin prepared by the process of present invention substantially free from dehydro impurity.

In another general aspect, there is provided a pharmaceutical composition comprising silodosin substantially free from dimeric impurity having one or more pharmaceutically acceptable excipients, diluents and carriers.

BRIEF DESCRIPTION OF THE DRAWINGS
FIG.1 illustrates crystalline form a prepared by the process of the present invention

DETAILED DESCRIPTION OF THE INVENTION
In general, the inventions of the present invention have surprisingly found that the compound of Formula (V) and the compound of Formula (IV) may be reacted to obtain the compound of Formula (III), which may be converted to silodosin without simultaneous formation of acid addition salts thereof. In particular, the inventors have developed a process for the preparation of silodosin wherein the conversion of compound of Formula (III) to compound of Formula (II) and further to silodosin may be facilitated by using a common solvent, avoiding exchange of solvents unlike the prior art processes.

The aforementioned general and further specific aspects of the invention are fulfilled by the description of the invention provided herein after.

The terms ‘reacting’ and ‘treating’ are generally interchangeable and are used in their ordinary meaning as they are used in the field of the invention, unless defined specifically otherwise.

The term ‘converting’ means reacting the compound to which it refers to with another compound and/or reagent; and/or subjecting it to condition(s) wherein it transforms to another compound as a result of such treatment.

The terms ‘isolating’, ‘obtaining’ and ‘recrystallizing’ are generally interchangeable and include but not specifically limited to extraction, evaporation, crystallization, filtration, purification or chromatographic operations.

The product(s) obtained may further be dried additionally to achieve desired level of moisture and/or residual solvents. The product(s) obtained may further be converted to any other physical forms thereof which includes but not specifically limited to polymorph(s), salt(s), solvate(s), hydrate(s), co-crystal(s) or solid dispersion(s); and crystalline or amorphous forms thereof.
In general, the “substantially pure” means silodosin having purity of about 99.5% or more, in particular 99.7% or more, more particular, having purity of about 99.9% or more, when measured by area percentage of HPLC.

In general, the term “substantially free” means silodosin having purity of about 99.7% or more having dimeric impurity less than 0.1% or less and dehydro impurity less than 0.1% or less by area percentage of HPLC. In particular, the silodosin prepared the present invention is having purity of about 99.75% or more having dimeric impurity not in detectable amount and dehydro impurity 0.05% or less, when measured by area percentage of HPLC.

In one general aspect, there is provided a process of preparing silodosin, the process comprising:
(a) reacting compound of Formula (V) with compound of Formula (IV) in mixture of solvents in the presence of a base,

(V) (IV)
to obtain compound of Formula (III);

(III)
(b) hydrolyzing the compound of Formula (III) in the presence of a base in one or more solvents to obtain compound of Formula (II); and

(II)
(c) hydrolyzing the compound of Formula (II) with a base in the presence of an oxidizing agent in one or more solvents to obtain silodosin, wherein the compound of Formula (III) and Formula (II) are not converted to acid addition salts.

In another general aspect, there is provided a process of preparing silodosin, the process comprising:
(a) reacting compound of Formula (V) with compound of Formula (IV) in mixture of solvents in the presence of a base,

(V) (IV)
to obtain compound of Formula (III);

(III)
(b) hydrolyzing the compound of Formula (III) in the presence of a base in one or more solvents to obtain compound of Formula (II); and

(II)
(c) hydrolyzing the compound of Formula (II) with a base in the presence of an oxidizing agent in one or more solvents to obtain silodosin, wherein the compound of formula (III) and formula (II) are not converted to acid addition salts, the solvent in step (b) and (c) is same.

In general, the compound of Formula (IV) as free base or a salt thereof, is reacted with compound of Formula (V) in the presence of a base. The compound of Formula (IV) may be reacted with a base to obtain a free base compound in one or more solvents. Further, the compound of Formula (V) may be added to the free base solution of compound of Formula (IV).

In general, the solvent in step (a) comprises one or more of methanol, ethanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, butyl acetate, methylene dichloride, toluene, xylene, ethyl benzene, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, water, or mixture thereof. In particular, the reaction is performed in a mixture of toluene and dimethylsulfoxide, dimethylformamide or dimethyl acetamide.

The reaction of compound of Formula (V) and free base compound of Formula (IV) may be performed under heating conditions from about 30 °C to about reflux temperature of solution. In particular, the reaction may be performed from about 30 °C to about 180 °C. More particularly, the reaction may be performed at about 50 °C to about 120 °C. For example, the reaction may be performed at about 90 °C to about 110 °C, when the one or more solvents is a mixture of toluene and dimethylsulfoxide, dimethylformamide or dimethyl acetamide

In general, the base in step (a) comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, ammonia or mixture thereof. In particular, the compound of Formula (IV) may be treated with sodium carbonate to obtain free base compound of Formula (IV), which is further reacted with compound (V) in the presence of sodium bicarbonate as a base, to obtain compound of Formula (III).

In general, the reaction involves concentrating the reaction mixture to remove toluene and further dilution with dimethylsulfoxide. The compound of Formula (III), thus obtained may be further used without being isolated in any form of acid addition salts.

In general, the hydrolysis of compound of Formula (III) in step (b) may be performed by addition of the base in reaction mixture obtained in step (a). The hydrolysis may be performed at an ambient temperature from about 15 °C to about 40° C. In particular, the hydrolysis may be performed at about 25 °C to about 30 °C.

The base in step (b) comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, ammonia or mixture thereof. In particular, sodium hydroxide may be used.

The hydrolysis of compound of Formula (III) with sodium hydroxide at about 25°C to about 30°C in dimethylsulfoxide or methanol as solvent from reaction step (a) provided compound of Formula (II). The compound of Formula (II), thus obtained may be further used without being isolated in any form of acid addition salts.

In general, the hydrolysis of compound of Formula (II) thus obtained in step (b) may be performed with a base in the presence of oxidizing agent in one or more solvents. However, the solvent and the base may be similar to step (b) and the oxidizing agent comprises one or more of peroxy acid, hydrogen peroxide, m-chloroperbenzoic acid, iodobenzene, N-halosuccinimide, tertiary butyl hydrogen peroxide, tert-butyl hypochlorite. In particular, 30% hydrogen peroxide may be used.

In particular, the hydrolysis of the compound (II) is performed in dimethylsulfoxide from the reaction mixture of step (b) with sodium hydroxide at an ambient temperature from about 15 °C to about 40° C. In particular, the hydrolysis may be performed at about 25 °C to about 30 °C.

In general, the silodosin obtained in step (c) may be isolated by solvent extraction and work-up followed by crystallization or may be subjected further for converting silodosin thus obtained in step (c) to silodosin substantially free from dimer impurity and dehydro impurity.

In general, the dimer impurity and the dehydro impurity of the present invention has the following structures.

(dimer impurity)

(dehydro impurity)

In another general aspect, there is provided a process for preparing silodosin substantially free from dimer impurity, the process comprising:
(a) providing a solution of silodosin prepared by the process of the invention in one or more solvents;
(b) extracting silodosin in one or more solvent;
(c) removing the solvent to obtain a residue;
(d) treating the residue with an aqueous acid solution to obtain an aqueous layer;
(e) basifying the aqueous layer with a base in the presence of one or more solvents;
(f) obtaining silodosin by the removal of the solvent; and
(g) recrystallizing the silodosin with one or more ester solvents to obtain the silodosin substantially free from dimer impurity.

In general, the silodosin prepared by the process of the present invention may be used to prepare the solution in one or more solvents. The solvent comprises one or more of methanol, ethanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, tetrahydrofuran, 2-methyl tetrahydrofuran, water, or mixture thereof. In particular, the solvent may be dimethylsulfoxide.

In general, the solvent in step (b) comprises one or more of methylene dichloride, ethylene dichloride, chlorobenzene, ethyl acetate, isopropyl acetate, butyl acetate, toluene, xylene, and ethyl benzene. In particular, the solvent is methylene dichloride or ethyl acetate.

In general, the acid in step (d) comprises one or more of hydrochloric acid, hydrobromic acid, formic acid, phosphoric acid, acetic acid, citric acid, and trifluroacetic acid. In particular, citric acid may be used. The aqueous solution of acid may be prepared by dissolving appropriate quantity of acid in water.

The base in step (e) comprises one or more of comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, ammonia or mixture thereof. In particular, sodium carbonate may be used.

In general, the separated aqueous layer is treated with base to adjust the pH 7.5 to 8.5 in presence of one or more solvents. The solvent comprises one or more of ester solvents selected from ethyl acetate, isopropyl acetate, and butyl acetate. In particular, ethyl acetate may be used.

The silodosin solution in ethyl acetate thus obtained by concentrated to obtain silodosin residue which may be recrystallized in ester solvent selected from ethyl acetate, isopropyl acetate, and butyl acetate. In one of the aspect of the invention, the recrystallization of silodosin obtained in step (f) may be performed by heating the solution at reflux temperature of solvent, cooling and removing the solvent. The obtained crystalline silodosin may be triturated in water or ethyl acetate or ether to obtain crystalline silodosin substantially free from dimer impurity.

In another general aspect, there is provided a process for preparing silodosin substantially free from dehydro impurity, the process comprising:
(a) providing a solution of silodosin prepared by the process of the invention in one or more solvents;
(b) treating the solution with a reducing agent to obtain a reaction mixture;
(c) quenching the reaction mixture in water and basifying with one or more base;
(d) extracting the reaction mixture with one or more solvents;
(e) removing the solvent to obtain a residue;
(f) treating the residue with one or more solvents; and
(g) obtaining silodosin substantially free from dehydro impurity by recrystallizing silodosin in one or more ester solvents.

In general, the silodosin prepared by the process of the present invention may be used to prepare the solution in one or more solvents. The solvent comprises one or more of methanol, ethanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, tetrahydrofuran, 2-methyl tetrahydrofuran, water, acetic acid, trifluoroacetic acid, formic acid or mixture thereof. In particular, the solvent may be trifluoroacetic acid.

In general, the reducing agent in step (a) comprises one or more of sodium borohydride, lithium borohydride, Pd/C, Pt/C, Fe/HCl, Sn/HCl, SnCl2, and Raney nickel. In particular, sodium borohydride may be used.

In general, the solvent in step (b) comprises one or more of acetic acid, formic acid, and triflouroacetic acid.

The base in step (c) comprises one or more of comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, ammonia or mixture thereof. In particular, sodium hydroxide may be used. In general, the aqueous layer is treated with base to adjust the pH 9.0 to 10.0.

In general, the solvent in step (d) comprises one or more of methylene dichloride, ethylene dichloride, chlorobenzene, ethyl acetate, isopropyl acetate, butyl acetate, toluene, xylene, and ethyl benzene. In particular, the solvent is methylene dichloride or ethyl acetate.

The silodosin solution in ethyl acetate thus obtained by concentrated to obtain silodosin residue which may be recrystallized in ester solvent selected from ethyl acetate, isopropyl acetate, and butyl acetate. In one of the aspect of the invention, the recrystallization of silodosin obtained in step (f) may be performed by heating the solution at reflux temperature of solvent, cooling and removing the solvent. The obtained crystalline silodosin may be triturated in water, methyl tertiary butyl ether or ethyl acetate to obtain crystalline silodosin substantially free from dehydro impurity.

In another general aspect, there is provided silodosin substantially free from dimer impurity and dehydro impurity, prepared by the process comprising reacting compound of Formula (V) and compound of Formula (IV) to obtain compound (III) and converting the compound of Formula (III) to silodosin without formation of acid addition salts.

In another general aspect, there is provided substantially pure silodosin prepared by the process of present invention substantially free from dimeric impurity.

In another general aspect, there is provided substantially pure silodosin prepared by the process of present invention substantially free from dehydro impurity.

In another general aspect, there is provided a pharmaceutical composition comprising silodosin substantially free from dimeric impurity having one or more pharmaceutically acceptable excipients, diluents and carriers.

In general, the crystalline form prepared by the process of the present invention is form a characterized by characteristic x-ray powder diffraction pattern having characteristic peaks expressed in terms of 2? at about 5.5°, 6.1°, 9.8°, 11.1°, 12.2°, 16.4°, 19.7° and 20.0°±0.2 2?. In general, the x-ray powder diffraction pattern of crystalline form a of silodosin is substantially as same as depicted in Fig.1.

The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

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 (III):
To a mixture of toluene (50 mL) and 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-1H-indol-1-yl]propyl benzoate tartrate (10.0 g), an aqueous solution (50 mL) of sodium carbonate (5.2 g) was added and the mixture was stirred at room temperature for 1 hour. The toluene layer was separated, and the aqueous layer was extracted with toluene (10 mL). The reaction mixture was refluxed at 105 °C to 110 °C by heating for 12 hours with atmospherically removing toluene partially The toluene layer was diluted with dimethylsulfoxide (5 mL) followed by addition of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate (6.84 g) and sodium bicarbonate (7.76 g). After completion of reaction mass was filtered and upper solid washed with toluene (10 ml). The toluene was distilled completed and the reaction mixture containing 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoro- ethoxy)phenoxy]ethyl}amino)propyl)-2,3-dihydro-1H-indol-1-yl)-propyl benzoate (III) in dimethylsulfoxide was used in the next step. The dimeric compound was present to the level of 8.75%. The product was used in the next reaction.

Example-2:
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 (II):
The solution 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 in dimethyl- sulfoxide from example-1 was diluted with methanol (30 ml) and added aqueous sodium hydroxide solution, prepared from sodium hydroxide (1.55 g) and water (4 mL). The reaction mixture was stirred at 25 °C for 3 hours. After completion of reaction, the reaction mixture was diluted with water (100 mL) and 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino) propyl]-2,3-dihydro-1H-indole-7-carbonitrile compound was extracted in ethyl acetate (80 mL). The separated aqueous layer was extracted with ethyl acetate (40 mL). The combined ethyl acetate layer was washed with water (80 mL) and distilled under vacuum to obtain residue. The residue containing 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)-propyl]-2,3-dihydro-1H-indole-7-carbonitrile used in the next step. The dimeric compound was present to the level of 6.6%. The product was used in the next reaction.

Example-3:
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)
The residue of 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoro-ethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile from example-2 were dissolved in dimethylsulfoxide (82 mL) and solution of aqueous sodium hydroxide (4.0 mL) prepared by dissolving 1.55 g sodium hydroxide were taken in round bottom flask. To the reaction mixture, 30% hydrogen peroxide (15.16 ml) was added at 25° C and stirred for 8 hours. To the reaction mixture, an aqueous sodium sulfite solution of sodium sulfite (9.5 g) dissolved in water (225 mL) was added. The reaction mixture was extracted with methylene dichloride (50 mL). The separated aqueous layer was again extracted with methylene dichloride (20 mL) and the combined methylene dichloride layer was washed with water. The separated methylene dichloride layer was concentrated to residue. Aqueous citric acid monohydrate solution (80 mL) prepared by dissolving 4.07 g citric acid monohydrate was added to the residue and methylene dichloride (20 mL) was added. The separated aqueous layer was washed with methylene dichloride (20 mL) and extracted twice with ethyl acetate (100 mL). The extract was neutralized with sodium bicarbonate to adjust the pH of 7.5 to 8.5 using sodium carbonate (5.1 g) solution in 51 mL water. The separated ethyl acetate layer was concentrated to residue. Water (50 mL) was added and the reaction mixture was stirred for 1 hour and filtered. The wet-cake was washed with water and dried under vacuum at 50 °C to 55 °C to obtain crystalline silodosin having dimer impurity 0.06%.

Example-4:
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):
The solution of 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide (5 g) obtained in example-3 was prepared in trifluoroacetic acid (21 mL) at 25 °C. The reaction mixture was cooled to 15 °C and sodium borohydride (133 mg) was added. The reaction mixture was stirred for 3 hours. After completion of the reaction as monitored by HPLC, the reaction mass was concentrated to residue. The residue diluted with water 50 ml and ethyl acetate (20 mL) and the pH to 9.0 to 10 was adjusted using sodium hydroxide (4.5 g) solution in 45 mL water and added ethyl acetate (30 mL). Aqueous layer was extracted with ethyl acetate (15 mL). The combined ethyl acetate layer washed with water (50 ml). The separated ethyl acetate layer was concentrated to residue under vacuum. Water (25 mL) was added and stirred for 30 min and filtered. The wet-cake was washed with water and dried under vacuum at 50 °C to 55 °C to obtain 4.2 g crystalline silodosin. The silodosin thus obtained was recrystallized in ethyl acetate (42 mL) at 65 °C to 70 °C, cooled to 20°C to 25°C, filtered and washed with ethyl acetate. The product thus obtained was dried in vacuum tray drier for 10 hours at 40 °C to 45 °C till constant weight having purity of 99.75% containing dehydro impurity 0.05%, dimer impurity ND by HPLC. The X-ray powder diffraction of silodosin confirms to a form (Fig.1).

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 (III):
To a mixture of toluene (50 mL) and 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-1H-indol-1-yl] propyl benzoate tartrate (10.0 g), an aqueous solution (50 mL) of sodium carbonate (5.2 g) was added and the mixture was stirred at room temperature for 1 hour. The toluene layer was separated, and the aqueous layer was extracted with toluene (10 mL). The toluene layer was diluted with dimethylsulfoxide (5 mL) followed by addition of 2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyl methanesulfonate (6.84 g) and sodium bicarbonate (7.76 g). The reaction mixture was refluxed at 95 °C to 100 °C by heating for 12 hours with atmospherically removing toluene partially. After completion of reaction the reaction mass was filtered. Charge filtrate, potable water and separate the layers. Collect toluene layer. The toluene was distilled to obtain a residue. To the above residue was added citric acid solution in acetone and cyclohexane and stir for 30 minutes. Decant the upper layer and charge cyclohexane and stir for 30 minutes. Decant the upper layer and add ethyl acetate and sodium carbonate solution to adjust the pH to about 8.0. Stir for some time and collect ethyl acetate layer. Distill out the solvent under vacuum to obtain residue containing 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 (III) to be used in the next step. The dimeric compound was present to the level of 1.27%. The product was used in the next reaction.

Example 6:
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 (II):
The residue 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 obtained from example 5 was dissolved in methanol (30 ml) and added aqueous sodium hydroxide solution, prepared from sodium hydroxide (1.75 g) and water (5 mL). The reaction mixture was stirred at 25 °C for 3 hours. After completion of reaction, the reaction mixture was diluted with water (100 mL) and 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)-propyl]-2,3-dihydro-1H-indole-7-carbonitrile compound was extracted in ethyl acetate (80 mL). The separated aqueous layer was extracted with ethyl acetate (40 mL). The combined ethyl acetate layer was washed with water (80 mL) and distilled under vacuum to obtain residue. The residue containing 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)-propyl]-2,3-dihydro-1H-indole-7-carbonitrile used in the next step. The dimeric compound was present to the level of 1.47%. The product was used in the next reaction as per example 3 & 4.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

,CLAIMS:We claim:
1. A process of preparing silodosin, the process comprising:
(a) reacting compound of Formula (V) with compound of Formula (IV) in mixture of solvents in the presence of a base,

(V) (IV)
to obtain compound of Formula (III);

(III)
(b) hydrolyzing the compound of Formula (III) in the presence of a base in one or more solvents to obtain compound of Formula (II); and

(II)
(c) hydrolyzing the compound of formula (II) with a base in the presence of oxidizing agent in one or more solvents to obtain silodosin, wherein the compound of formula (III) and formula (II) are not converted to acid addition salts thereof.
2. The process as claimed in claim 1, wherein the solvent used in step (a) is selected from a group comprising methanol, ethanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, butyl acetate, methylene dichloride, toluene, xylene, ethyl benzene, dimethylformamide, dimethylacetamide, dimethylsulfoxide N-methylpyrro-lidone, tetrahydrofuran, 2-methyltetrahydrofuran, water, or mixture thereof.
3. The process as claimed in claim 1, wherein the solvent in step (a) is mixture of toluene with dimethylformamide or dimethyl sulfoxide or dimethylacetamide.
4. The process as claimed in claim 1, wherein the base is selected from a group comprising sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, ammonia or mixture thereof.
5. A process for preparing silodosin of Formula (1) free from dehydro impurity, the process comprising:
(a) treating silodosin with a reducing agent in one or more solvents to obtain a reaction mixture; and
(b) recrystallizing the silodosin obtained with one or more ester solvent to obtain the silodosin substantially free from dehydro impurity.
6. The process as claimed in claim 5, wherein the reducing agent used in step (a) is selected from a group comprising of sodium borohydride, lithium borohydride, Pd/C, Pt/C, Fe/HCl, Sn/HCl, SnCl2, and Raney nickel.
7. The process as claimed in claim 5, wherein the solvent used in step (a) is selected from a group comprising of one or more of acetic acid, formic acid and trifluoroacetic acid.
8. The process as claimed in claim 5, wherein the solvent used in step (b) is selected from a group comprising ethyl acetate, isopropyl acetate and n-butyl acetate.
9. The process as claimed in claim 5, wherein the silodosin obtained is having purity of about 99.7% or more and having dehydro impurity 0.1% of less, when measured by area percentage of HPLC.
10. The process as claimed in claim 1, wherein the silodosin obtained is having purity of about 99.7% or more and having dimeric impurity 0.1% or less, when measured by area percentage of HPLC.

Dated this 16th day of November 2018.

(ASHISH KUMAR SHARMA)
[IN/PA-858]
of SUBRAMANIAM & ASSOCIATES
Attorneys for the applicants