FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of an optically active indoline derivative of a compound of formula (II), wherein R is hydroxyl protecting group.

The compound of formula (II) is the key intermediate in the synthesis of Silodosin of formula (I).

BACKGROUND OF THE INVENTION

Silodosin is chemically known as l-(3-hydroxypropyl)-5-[(2#)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide. Silodosin is a selective antagonist of post-synaptic alpha-1 adrenoreceptors, which are located in the human prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra. Blockade of these alpha-1 adrenoreceptors can cause smooth muscle in these tissues to relax, resulting in an improvement in urine flow and a reduction in benign prostatic hyperplasia (BPH) symptoms. Silodosin is approved for the treatment of the signs and symptoms of BPH and is marketed under the brand name Rapaflo .
Silodosin is disclosed in US 5,387,603. This patent also discloses a process for the preparation of Silodosin using a multiple-step synthesis as shown in Scheme-I. The process involves condensing l-acetyl-5-(2-aminopropyl)indoline-7-carbonitrile (III) with 2-[2-(2,2,2-trifiuoroethoxy) phenoxy]ethyl methanesulfonate (IVa) or 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl bromide (IVb) in the presence of a base to produce
racemic l-acetyl-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carbonitrile (V). Resolution of the obtained racemic Compound (V) is carried out using (+)-mandelic acid to produce R-isomer of the Compound (V), which is further treated with di-tert-butyl dicarbonate (Boc) to produce (R)-l-acetyl-5-[2-[N-Boc-2-(2,2,2-trifluoroethoxyphenoxy)ethylamino] propyl]indoline-7-carbonitriIe (VI). The obtained Compound (VI) is deacetylated to produce (R)-5-[2-[N-Boc-2-(2,2,2-trifluoroethoxyphenoxy)ethylamino]propyl]indoline-7-carbonitrile (VII), which undergoes hydrolysis in the presence of peroxide in an alkaline environment to produce (R)-5-[2-[N-Boc-2-(2,2,2-trifluoroethoxyphenoxy]ethylamino] propyl]indoline-7-carboxamide (VIII). The obtained Compound (VIII) is reacted with 3-tert-butyldimethylsilyloxypropylalcohol nosylate to produce (R)-5-[2-[N-Boc-2-(2,2,2-trifluoroethoxyphenoxy]ethylamino]propyl-l-(3-tert-butyldimethylsilyloxy)propyl] indoline-7-carboxamide (IX), which is further reacted with tetrabutylammonium fluoride (TBAF) to produce (R)-5-[2-[N-Boc-2-(2,2,2-trifluoroethoxyphenoxy]ethylamino]propyl]-l-(3-hydroxypropyl)indoline-7-carboxamide (X), followed by treating the obtained Compound (X) with trifluoroacetic acid to produce Silodosin (I). The process given in this patent is not particularly suitable for large-scale production, because it involves more number of steps. This results in more production time and renders the process more costly and less eco friendly. Further the above process is low yielding and with less purity.
JP 4634560 discloses a variant process for the preparation of Silodosin (I). The process comprises, reacting l-(3-(benzoyloxy)propyl)-2,3-dihydro-5-(2-nitropropyl)-lH-indole-7-carbonitrile (XI) with hydrogen peroxide (H2O2) in the presence of potassium carbonate (K2CO3) to produce l-[3-(benzoxyloxy)propyl]-2,3-dihydro-5-(2-oxopropyl)-l//-indole-7-carbonitrile (XII). The obtained Oxo Compound XII is further converted to amine compound, by treating with L-2-phenylglycinol and then subjected to catalytic reduction in the presence of platinum oxide (PtCh) to produce diastereomeric mixture of Compound (XIII), which is further undergoes catalytic reduction in the presence of palladium on carbon (Pd/C) and then the resultant mixture is further treated with L-tartaric acid to produce enantiomerically pure L-tartrate salt of 5-[(2R)-2-aminopropyl]-l-[3-(benzoyloxy)propyl]-2,3-dihydro-lH-indole-7-carbonitrile (Ha). The obtained tartrate salt
of Compound (Ila) is condensed with Compound (IV) to produce l-(3-benzyoloxypropyl)-5-[(2i?)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile (XIV). Oxidation of the Compound (XIV) to produce l-(3-benzyloxypropy])-5-[(2i?)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide (XV), which on hydrogenation using Pd/C to produce Silodosin (I). The process is shown in Scheme-II give below:
The disadvantage with the above process is that it involves the use of expensive L-2-phenylglycinol and Pt02. Further, the use of Pt02 in the reduction required an autoclave. Hence, the above process is not suitable for commercial scale synthesis of Silodosin.
WO 2012/147019 discloses a process for the preparation of an optically active indoline derivative, wherein l-[3-(benzoxyloxy)propyl]-2,3-dihydro-5-(2-oxopropyl)-lH-
indole-7-carbonitrile (XII) is reacted with L-2-phenylglycinol and then subjected to reduction using sodium triacetoxyborohydride (Na(OAc)3BH) to produce diastereomeric mixture of compound of formula (XIII). The process is shown in Scheme-Ill give below:
CN 101585798 discloses a process for the preparation of an optically active indoline derivative, wherein l-[3-(benzoxyloxy)propyl]-2,3-dihydro-5-(2-oxopropyl)-lH-indole-7-carbonitrile (XII) is reacted with R-l-phenylethylamine and then subjected to reduction in the presence of Raney Ni in organic or inorganic acid to produce l-[3-(benzoyloxy)propyl]-2,3-dihydro-5-[(2R)-2-[[(lR)-l-phenylethyl]amino]propyl]-lH-indole-7-carbonitrile (XHIa). The process is shown in Scheme-IV give below:
Applicant found that the use of sodium triacetoxyborohydride (Na(OAc)3BH) or Raney Ni resulted in incomplete conversion and further degradation was observed and hence the given process is not suitable for commercial scale preparation.
However, there is always a need for an alternative preparative routes, which for example, involve fewer steps, use reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity.
The present invention is related to a process for the preparation of Silodosin (I) with high yield and high purity, wherein optically active indoline derivative of formula (II) is prepared using a reducing agent which is cheaper and easier to handle on commercial scale.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a simple and cost effective process for the preparation of an optically active indoline derivative of a compound of formula (II) or a pharmaceutically acceptable salt thereof; with high purity and good yield on commercial scale.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides an improved process for the preparation of an optically active indoline derivative of a compound of formula (II) or a pharmaceutically acceptable salt thereof,
wherein, R is hydroxyl protecting group, which comprises: (i) oxidizing nitro compound of formula (XIa) to produce oxo compound of formula (Xlla) in presence of an oxidizing agent;
wherein, R is hydroxyl protecting group,
(ii) reacting oxo compound of formula (Xlla) with an amino compound of formula (XVI), followed by reducing the ensuing compound in presence of a reducing agent to produce a compound of formula (Xlllb) or a pharmaceutically acceptable salt thereof:
wherein, R is hydroxyl protecting group and R1 is hydrogen or hydroxyl group; (iii) hydrogenating the compound of formula (Xlllb) or a pharmaceutically acceptable salt thereof in presence of a catalyst to produce an indoline derivative of compound of formula (XVII); and
wherein, R is hydroxyl protecting group, (iv) treating the indoline derivative of compound of formula (XVII) with an optically active acid to produce an optically active indoline derivative of a compound of formula (II) or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides an improved process for the preparation of a compound of formula (Xlllb) or a pharmaceutically acceptable salt
thereof, which comprises reacting oxo compound of formula (Xlla) with an amino compound of formula (XVI) to produce a reaction mixture followed by reducing the ensuing compound in presence of a reducing agent selected from a group consisting of sodium cyanoborohydride (NaBHsCN), Fe, Sn, Zn in acidic media, sodium borohydride (NaBHU), Lithium borohydride (LiBFL;), diborane, Sodium aluminium hydride (NaAlHU), hydrazine hydrate, sodium dithionate (Na2S2C>4), sodium sulfide, ammonium sulfide, hydrogenation catalysts comprises rhodium, Pd-C, raney cobalt, raney iron, lithium aluminum hydride (LiAlFL}), sodium amalgam, borane-tetrahydrofuran complex, and in combination with hydrogen.

In yet another aspect, the present invention provides a process for the preparation of Silodosin (I) by using a compound of formula (XHIb) and/or compound of formula (II) prepared according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides an improved process for the preparation of an optically active indoline derivative of a compound of formula (II) or a pharmaceutically acceptable salt thereof.

■ wherein, R is hydroxyl protecting group.
In an embodiment of the present invention, the hydroxyl protecting group represented as R is selected from substituted or unsubstituted aralkyl compound selected from a group comprising benzyl, naphthyl, p-methoxybenzyl; substituted or unsubstituted aroyl compound selected from a group comprising benzoyl or naphthoyl.
In another embodiment of the present invention, the oxidizing agent used in step (i) is selected from the reagent comprising hydrogen peroxide (H2O2), sodium nitrite (NaN02), potassium permanganate (Kmn04), nitrous oxide (N2O), osmium tetroxide
(OSO4), potassium nitrate (KNO3), oxone, bis(trimethylsilyl)peroxide, sodium percarbonate, tetrapropylammonium perruthenate, and/or mixtures thereof.
In still another embodiment of the present invention, the oxidation is carried out in presence of a base and in the presence or absence of solvent. The base is organic or inorganic base. The inorganic base comprises potassium carbonate, lithium carbonate, sodium carbonate, sodium ethoxide, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, and mixtures thereof; the organic base comprises diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and/or mixtures thereof. The solvent comprises dimefhylformamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane (CH2CI2), dichloroethane, 1,4-dioxane, tetrahydrofuran (THF), ethyl acetate, acetonitrile, acetone, and/or mixtures thereof. The said oxidation reaction may also carried out optionally in presence of a copper salt in oxygen atmosphere. The copper salt comprises copper chloride, copper sulfate, copper nitrate or copper thiocyanate.
The oxidation reaction of step (i) is carried out at a temperature of 0° C to 35° C for a time period of 12-24 hrs. After completion of the reaction, compound of formula (Xlla) is isolated by conventional methods such as by removing the solvent under reduced pressure or can be taken to next stage without isolation. The compound of formula (Xlla) is optionally subjected to purification either by column chromatography or by known crystallization methods.
In another embodiment, reacting oxo compound of formula (Xlla) with an amino compound of formula (XVI), followed by reducing the ensuing compound in presence of a reducing agent to produce a compound of formula (Xlllb) or a pharmaceutically acceptable salt thereof.
In still another embodiment of the present invention, the reducing agent used in step (ii) is selected from a group consisting of sodium cyanoborohydride (NaBFbCN), Fe, Sn, Zn in acidic media, sodium borohydride (NaBH4), Lithium borohydride (LiBH4), diborane, Sodium aluminium hydride (NaAlHU), hydrazine hydrate, sodium dithionate (Na2S204), sodium sulfide, ammonium sulfide, hydrogenation catalysts comprises
rhodium, Pd-C, Raney cobalt, Raney iron, lithium aluminum hydride (L1AIH4), sodium amalgam, borane-tetrahydrofuran complex, and in combination with hydrogen.
In one more embodiment of the present invention, the reducing reaction is carried out the presence or absence of solvent and in the presence of acid. The solvent comprises ethanol, methanol, isopropanol, DMF, DMSO, dichloromethane, dichloroethane, 1,4-dioxane, diisopropylethyl ether, tetrahydrofuran (THF), ethyl acetate, acetonitrile, and/or mixtures thereof. The acid comprises an organic acid selected from acetic acid, formic acid, p-toluene sulfonic acid, and mixtures thereof; an inorganic acid selected from HC1, H2SO4, and/or mixtures thereof.
The reduction is carried out at a temperature of 0° C to 55° C for a time period of 3-12 hrs. After completion of the reaction, compound of formula (Xlllb) is isolated by conventional methods like removing the solvent under reduced pressure or taken to next stage without isolation. The compound of formula (Xlllb) or a pharmaceutically acceptable salt thereof is subjected to purification either by column chromatography or by crystallization.
After completion of the reaction, the Compound of formula (Xlllb) is treated with an acid comprises HC1, H2SO4 in a solvent selected from a group comprising ethanol, methanol, isopropanol, DMF, DMSO, dichloromethane, dichloroethane, 1,4-dioxane, diisopropylethyl ether, THF, ethyl acetate, acetonitrile and mixtures thereof to produce a pharmaceutically acceptable salt thereof.
In another embodiment, the process comprises, hydrogenating the compound of formula (Xlllb) or a pharmaceutically acceptable salt thereof in the presence of a catalyst in a solvent to produce an indoline derivative of compound of formula (XVII).
In still another embodiment of the present invention, the hydrogenation in step (iii) is carried out using a catalyst comprises palladium on carbon (Pd/C), platinum on carbon (Pt-C), Raney-Ni, sodium borohydride (NaBH4), Zn, Mg or PtC>2, and mixtures thereof. The said hydrogenation is preferably carried out in a solvent selected from group comprises ethanol, methanol, isopropanol, DMF, DMSO, dichloromethane,
dichloroethane, 1,4-dioxane, diisopropylethyl ether, THF, ethyl acetate, acetonitrile, water, and mixtures thereof.
The hydrogenation in step (iii) is carried out at a temperature of 0° C to 55° C for a time period of 12-24 hrs. After completion of the reaction compound of formula (XVII) is isolated by conventional methods or taken to next stage without isolation. If needed compound of formula (XVII) is subjected to purification by conventional methods.
The reaction mixture is neutralized with a base selected from NaOH, KOH, sodium carbonate, potassium carbonate in a solvent selected from a group comprises ethanol, methanol, isopropanol, DMF, DMSO, dichloromethane, dichloroethane, 1,4-dioxane, diisopropylethyl ether, THF, ethyl acetate, acetonitrile, water and mixtures thereof.
In another embodiment, the compound of formula (XVII) is treated with an optically active acid to produce an optically active acid addition salt of an indoline derivative of the compound of formula (II).
In still another embodiment of the present invention, the optically active acid used in step (iv) is selected from comprises L-tartaric acid, dibenzoyltartaric acid, mandelic acid, camphoric acid, camphorsulfonic acid, p-hydroxymandelic acid, /?-Cl-mandelic acid, phenoxypropionic acid, /?-hydroxyphenoxypropionic acid or lactic acid.
The reaction is carried out at a temperature in the range of 0° C to 55° C for a time period of 12-24 hrs. After completion of the reaction, the compound of formula (II) is isolated by conventional methods. If needed the compound of formula (II) is subjected to purification either by column chromatography or by crystallization technique like by dissolving in a solvent selected from a group comprising acetone, acetonitrile, hexane, heptane, methanol, ethanol, dimethyl formamide (DMF), dimethyl acetamide (DMAc) and dimethyl sulfoxide (DMSO), water, and mixtures thereof; precipitating pure crystalline compound of formula (II) by cooling the solution or by adding an anti solvent selected from a group comprising ketone, ether and esters, acetone, THF or ethyl acetate.
In another embodiment, the process comprises the use of optically active indoline derivative of a compound of formula (II) or a pharmaceutically acceptable salt thereof and/or a compound of fonnula (Xlllb) or a pharmaceutically acceptable salt thereof, prepared by the present invention in the preparation of Silodosin (I).
In yet another embodiment of the present invention, the compound of formula (II) prepared by the present invention is converted to Silodosin (I) by known methods. Accordingly the method comprises condensing L-tartrate salt of 5-[(2R)-2-aminopropyl]-l-[3-(benzoyloxy)propyl]-2,3-dihydro-lH-indole-7-carbonitrile (Ila) with compound of formula (IV) to produce l-(3-benzyoloxypropyl)-5-[(2i?)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile (XIV). Oxidation of the compound of formula (XIV) to produce 1-(3-benzyloxypropyl)-5-[(2i?)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide (XV), which on hydrogenation using Pd/C to produce Silodosin (I).
In another embodiment of the present invention, the starting material of compound of formula (XIa) used in the present invention is prepared by the process disclosed in conventional methods for example the one as disclosed in JP 4634560.
The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE:

STEP - I; PREPARATION OF l-[(3-(BENZOYLOXY)PROPYL)-2,3-DIHYDRO-5-(2-OXOPROPYL)-lH-INDOLE-7-CARBONITRILE(XII)
To the solution of l-[(3-(Benzoyloxy)propyl]-2,3-dihydro-5-(2-nitropropyl)-lH-indole-7-carbonitrile (XI) (100 g, 0.25 moles) in dimethylformamide (500 ml), potassium carbonate (70.2 g, 0.5 moles) was added at 25° C. The reaction mixture was cooled to 0-5° C and 34% hydrogen peroxide (50.37 g, 0.5 moles) was added slowly at 5-10° C. The reaction was continued at 50° C till completion of the reaction. After completion of reaction water was added. The reaction mixture was extracted twice with and the combined organic layer was washed with aqueous sodium bicarbonate solution followed by washing with
saturated brine. The toluene layer was treated with carbon, filtered and distilled under reduced pressure. The crude product l-[(3-(benzoxyloxy)propyl]-2,3-dihydro-5-(2-oxopropyl)-lH-indole-7-carbonitrile (XII) was isolated as a liquid yield: 70 g.
The crude product was purified by column chromatography with 30% v/v ethyl acetate :hexanes.
STEP - II; PREPARATION OF l-[(3-(BENZOYLOXY)PROPYL)-2,3-DIHYDRO-5-[(2R)-2-[[(lR)-l-PHENYLETHYL]AMINO]PROPYL]-lH-INDOLE-7-CARBONITRILE HYDROCHLORIE (XIHa)
l-[(3-(Benzoyloxy)propyl]-2,3-dihydro-5-(2-oxopropyl)-lH-indole-7-carbonitrile (XII) (65 g, 0.18 moles) was dissolved in absolute ethanol (650 ml) and acetic acid (12.92 g, 0.2 moles) was added followed by (R)-a-methylbenzylamine (26.24 g, 0.2 moles). After stirring the reaction mixture for ~1 h, sodium cyanoborohydride (24.8 g, 0.39 moles) was added. Upon completion of reaction the ethanol was distilled off and ethyl acetate and DM water were added. The biphasic mixture was stirred and the organic layer was separated. The organic layer was washed with saturated sodium bicarbonate solution followed by saturated sodium chloride solution. Activated carbon was added to the ethyl acetate layer, stirred, filtered and the filtrate was concentrated under reduced pressure. The oily residue was treated with 30% w/w ethanolic solution of hydrogen chloride (98.72 g) at 0-15°C and stirred for 2 h. The mixture was concentrated under reduced pressure at 45-50°C followed by the addition of diisopropylethyl ether. The precipitated solid was filtered, off washed with diisopropyl ethyl ether and dried under reduced pressure at 25-30°C to furnish l-[3-(benzoyloxy)propyl]-2,3-dihydro-5-[(2RS)-2-[[(lR)-l-phenylethyl]amino]propyl]-lH-indole-7-carbonitrile hydrochloride (XHIa) (45 g).
STEP-III: PREPARATION OF 5-[(2R)-2-AMINOPROPYL]-l-[3-
(BENZOYLOXY)PROPYL]-2,3-DIHYDRO-lH-INDOLE-7-CARBONITRILE
(2R,3R)-2,3-DIHYDROXYBUTANEDIOATE(IIa)
l-[(3-(Benzoyloxy)propyl]-2,3-dihydro-5-[(2RS)-2-[[(lR)-l-phenylethyl]amino]propyl-lH-indole-7-carbonitrile hydrochloride (XHIa) (15.65 g, 0.03 mole) was dissolved in methanol (400 ml) and hydrogenated at 50° C under a pressure of 4 Kg / Cm2 in presence of 10% palladium on charcoal for 15 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The oily residue was basified with sodium
hydroxide solution to pH 9.1 in ethyl acetate / water (1:1, 160 ml). The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (20 ml). The combined ethyl acetate layer was washed with saturated sodium bicarbonate solution (200 ml). The organic layer was concentrated to produce 5-[(2RS)-2-aminopropyl]-l-[3-(benzoyloxy)propyl]-2,3-dihydro-lH-indole-7-carbonitrile (XVIIa) 11.5 g having chiral purity 82.19%. The obtained 5-[(2RS)-2-aminopropyl]-l-[3-(benzoyloxy)propyl]-2,3-dihydro-lH-indole-7-carbonitrile (XVIIa) (11.48 g) was dissolved in acetone (34 ml) and heated to 56° C. An aqueous solution of (2R,3R)-tartaric acid (2.6 g, 0.017 moles) in water (11 ml) was added under reflux for 15 min. The reaction mixture was cooled to 25-30° C and stirred for 15 min. The precipitated solid was filtered off, washed with acetone / water solution (1:1, 15 ml) and dried under reduced pressure to yield 8.1 g of 5-[(2R)-2-aminopropyl]-l-[3-(benzoyloxy)propyl]-2,3-dihydro-lH-indole-7-carbonitrile (2R,3R)-2,3-dihydroxybutane dioate (Ha) with chiral purity of 92.14% by HPLC.

WE CLAIM:

1. An improved process for the preparation of an optically active indoline derivative of a compound of formula (II) or a pharmaceutically acceptable salt thereof,
wherein, R is hydroxyl protecting group, which comprises: (i) oxidizing nitro compound of formula (XIa) to produce oxo compound of formula (Xlla) in presence of an oxidizing agent;
wherein, R is hydroxyl protecting group,
(ii) reacting oxo compound of formula (Xlla) with an amino compound of formula (XVI), followed by reducing the ensuing compound in presence of a reducing agent to produce a compound of formula (XHIb) or a pharmaceutically acceptable salt thereof:
wherein, R is hydroxyl protecting group and R1 is hydrogen or hydroxyl group; (iii) hydrogenating the compound of formula (Xlllb) or a pharmaceutically acceptable salt thereof in presence of a catalyst to produce an indoline derivative of compound of formula (XVII); and
wherein, R is hydroxyl protecting group, (iv) treating the compound of formula (XVII) with an optically active acid to produce an optically active indoline derivative of a compound of formula (II) or a pharmaceutically acceptable salt thereof.
The process according to claim 1, wherein the oxidizing agent used in step (i) is selected from the reagent comprising hydrogen peroxide (H2O2), sodium nitrite (NaNCh), potassium permanganate (KMnC^), nitrous oxide (N2O), osmium tetroxide (Os04), potassium nitrate (KNO3), oxone, bis(trimethylsilyl)peroxide, sodium percarbonate, tetrapropylammonium perruthenate and/or mixtures thereof.
The process according to claim 1, wherein step (i) is carried out in presence of a base and a solvent.
The process according to claim 3, wherein the base is selected from the reagent comprising potassium carbonate, lithium carbonate, sodium carbonate, sodium ethoxide, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and/or mixtures thereof.
The process according to claim 3, wherein the solvent is selected from the reagent comprising dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (CH2CI2), dichloroethane, 1,4-dioxane, tetrahydrofuran (THF), ethyl acetate, acetonitrile, acetone, and/or mixtures thereof.
The process according to claim 1, reducing agent used in step (ii) is selected from the reagent comprising; sodium cyanoborohydride (NaBHbCN), Fe, Sn, Zn in acidic media, sodium borohydride (NaBFLi), lithium borohydride (LiBH4), diborane, sodium aluminium hydride (NaAlHU), hydrazine hydrate, sodium dithionate (Na2S204), sodium sulfide, ammonium sulfide, hydrogenation catalysts comprises rhodium, Pd-C, Raney cobalt, Raney iron, lithium aluminum hydride (LiAlH4), sodium amalgam, borane-tetrahydrofuran complex, and in combination with hydrogen.
The process according to claim 1, wherein the catalyst used in step (iii) is selected from the reagent comprising; palladium on carbon (Pd/C) or platinum on carbon (Pt-C), raney-Ni, sodium borohydride (NaBHU), Zn, Mg or PtC>2 and/or mixtures thereof.
The process according to claim 1, the optically active acid used in step (iv) is selected from the reagent comprising; L-tartaric acid, dibenzoyltartaric acid, mandelic acid, camphoric acid, camphorsulfonic acid, /7-hydroxymandelic acid, p-Cl-mandelic acid, phenoxypropionic acid, ^-hydroxyphenoxypropionic acid or lactic acid and/or mixtures thereof.
An improved process for the preparation of a compound of formula (Xlllb) or a pharmaceutically acceptable salt thereof:
wherein, R is hydroxyl protecting group and R1 is hydrogen or hydroxyl group;
which comprises reacting oxo compound of formula (Xlla) with an amino compound of formula (XVI) to produce a reaction mixture followed by reducing the ensuing compound in presence of a reducing agent selected from a group consisting of sodium cyanoborohydride (NaBHsCN), Fe, Sn, Zn in acidic media, sodium borohydride (NaBlHU), Lithium borohydride (LiBH4), diborane, Sodium aluminium hydride (NaAlPLj), hydrazine hydrate, sodium dithionate (Na2S2C>4), sodium sulfide, ammonium sulfide, hydrogenation catalysts comprises rhodium, Pd-C, raney cobalt, raney iron, lithium aluminum hydride (LiAlHU), sodium amalgam, borane-tetrahydrofuran complex, and in combination with hydrogen.

The process according to claim 1, further comprising converting the compound of formula (II) into Silodosin of formula (I).