WO2014118606A2

WO2014118606A2 - A novel process for the preparation of silodosin

Info

Publication number: WO2014118606A2
Application number: PCT/IB2013/060614
Authority: WO
Inventors: Venkat Raman JAYARAMAN; Chetan PATIL; Viral Parekh; Hirali PATEL; Hiral Shah; Mahesh LADANI; Indrajit Thakor; Samir Patel
Original assignee: Alembic Pharmaceuticals Ltd
Current assignee: Alembic Pharmaceuticals Ltd
Priority date: 2013-01-29
Filing date: 2013-12-04
Publication date: 2014-08-07
Anticipated expiration: 2015-07-29
Also published as: WO2014118606A3

Abstract

The present invention relates to a novel process for the preparation of Silodosin.

Description

TITLE: A NOVEL PROCESS FOR THE PREPARATION OF SILODOSIN

RELATED APPLICATION

This application claims the benefit of priority of our Indian patent application numbers 251/MUM/2013 filed on 12th January 2013 and 1305/MUM/2013 filed on 04th April 2013 which are incorporated herein by reference.

FIELD OF THE INVENTION The present invention relates a novel route to asymmetric synthesis of Silodosin by the application of alkane or arene sulfinamide and regioselective N-alkylation of the indole intermediate is described.

BACKGROUND OF THE INVENTION

Silodosin is an indoline compound, chemically known as l-(3-Hydroxypropyl)-5-[(2R)-2- ( { 2- [2-(2,2,2-trifluoro-ethoxy)phenoxy] ethyl } amino)propyl] -2 ,3 -dihydro- 1 H- indole-7- carboxamide and r

(I)

Silodosin was disclosed in U.S. Patent No. 5387603 as therapeutic agents for the treatment of dysuria, urinary disturbance associated with benign prostatic hyperplasia.

Silodosin was first disclosed in US5387603, where a process for producing the compound is also disclosed. However, since Silodosin is an optically active compound (a single enantiomer) and has a complex chemical structure, its synthesis is rather complex requiring a number of different synthesis steps which includes too much protection- deprotection chemistry and purification steps including an optical resolution. Several patent applications have been filed for improved processes for preparing Silodosin.

U.S. Publication No. 2007/0197627 provides a process for the preparation of Silodosin which involves preparation of oxalate salt of 3-{7-cyano-5-[(2R)-2- ({2-[2-(2,2,2- trifluoroethoxy) phenoxy] ethyl} amino) propyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate which is subsequently hydro lyzed to yield l-(3- hydroxypropyl)-5-[(2R)-2-({2- [2-(2,2,2-trifluoroethoxy) phenoxy] -ethyl} amino) propyl]- 2,3-dihydro-lH-indole-7- carbonitrile and further hydrolyzing it in dimethylsulfoxide with aqueous sodium hydroxide solution and 30% hydrogen peroxide solution to obtain Silodosin.

One synthesis route proceeds over an intermediate of formula II, which is then coupled with a compound of formula III, The reaction product is then further reacted to Silodosin.

This route of synthesis is disclosed in EP 1 806 340, JP 2002-265444 and JP 2001- 199956, and it solves many problems of the prior art, in particular, since the optical resolution to a single enantiomer occurs relatively early in the production process. This is advantageous from an economic point of view. However, the preparation of the intermediate compound of formula II which is a single enantiomer is not easy.

According to JP 2001-199956, keto compound is converted into the amino derivative by a series of reactions which involve treating with an optically active compound such as L- 2-phenylglycinol with molecular hydrogen in the presence of platinum oxide to obtain a mixture which is not further defined but said to have a diastereomer ratio of 3.8: 1. This mixture is then hydrogenated on palladium/carbon and treated with L-tartaric acid in order to obtain the L-tartaric acid salt of the compound of formula (II) which can be further crystallized to get a higher enantiomeric excess of L-tartaric acid salt of compound This process is complicated and costly, as L-2-phenylglycinol is expensive and not recovered from the reaction.

Further, conversion of nitro compound to oxo compound in general is described in so many references, such as - J.Am.Chem.Soc. 99pp.3861 (1977); J. Org.Chem., 39, pp.259 (1974); J.Am.Chem.Soc, 93. pp.5309 (1971); J. Org.Chem., 27, pp.3699 (1962); Med.Chem., 9, pp.52 (1966); J. Chem.Soc.Perkin Transl., 1997 (3), pp.207; J.Chem.Soc.Chem.Commun., 1982 (11), pp.635; Tetrahedron Lett., 22 (52), pp. 5235 (1987) and Synthesis 1986 (9). pp.766.

However, these methods have some difficulties. For example, an acid-hydrogen peroxide method, and a base-hydrogen peroxide method the reaction condition is intense, therefore when functional groups, such as ester, amide, and a cyano group are present side reactions, such as hydrolysis, occur and it has an adverse effect on yield and quality. In an ozonate method or an electrode reaction method, expensive equipment is required and processing of the heavy metal residue is a big problem.

JP4491 104 discloses conversion of nitro compound to oxo compound for Silodosin intermediate in presence of hydrogen peroxide and silyl compound. However, Silyl compounds are expensive which impact the overall cost.

Thus, a need still remains for an improved and commercially viable process of preparing pure Silodosin that will solve the aforesaid problems associated with process described in the prior art and will be suitable for large-scale preparation.

To address this need, a process has been developed which gives assurance about the ease of scale up in commercial quantity.

SUMMARY OF THE INVENTION:

In one general aspect there is provided a novel process for the preparation of Silodosin. In one aspect present invention provides a process for preparation of Silodosin which comprises use of sulphinamide of formula (X) for diastereoselective reductive amination of ketone.

O I I

NH₂

(X)

Wherein sulphinamide enantiomer is R or S, wherein, X is any substituted or unsubstituted alkyl or aryl group.

In another aspect present invention provides a novel compound of formula IV and its diastereomers.

In another aspect present invention provides a process to get required isomer i.e.

wherein Rl is selected from H, any protective group or any protected propoxy group. R2 is H, CN, CONH2, any halogen, any aldehyde or any alkyl group.

In another aspect present invention provides a process for preparation of Silodosin which comprises, treatment of compound of formula (VI) with base and subsequently with acid to get compound of formula (V).

In yet another aspect present invention provides a Acid addition salt of l-(3- benzyloxypropyl)-5-[(2R)-2-({2-[2-(2,2,2- trifluoroethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carbonitrile and its use in process for preparation of Silodosin.

DETAILED DESCRIPTION OF THE INVENTION:

An embodiment of the present invention provides a novel process for the preparation of Silodosin.

The main embodiment of the present invention is to provide a process for preparing Silodosin from comprising steps, which can be shown by scheme- 1.

Scheme-1 Wherein Rl is selected from H, any protective group or any protected propoxy group. Protecting group is selected from the group comprising of Acetyl, Benzoyl, substituted Benzoyl, Benzyl, substituted benzyl, Dimethoxy trityl, Methoxy trityl, Pivaloyi, Tetrahydro pyranyl, Trityl, β-Methoxyethoxymethyl ether, Methoxymethyl ether , p- Methoxybenzyl ether, Methylthiomethyl ether, Silyl ether (such as trimethylsilyl, tert- butyldimethylsilyl, tri-iso-propylsilyloxymethyl , trimethylsilyl, triethylsilyl, t- butyldiphenylsilyl, triphenylsilyl and triisopropylsilyl), Methyl Ethers, Ethoxyethyl ethers, t-butyl, t-butoxymethyl, 1 -ethoxyethyl, l-(2-chloroethoxy)ethyl, p-chlorophenyl, 2,4- dinitrophenyl, diphenylmethyl, , benzoylformate, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyi, 9-fluorenyl-methyl carbonate, mesylate, tosylate, triflate, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl, substitutedpixyl, Carbobenzyloxy, p-Methoxybenzyl carbonyl , tert-Butyloxycarbonyl, 9-Fluorenylmethyloxy carbonyl, Acetyl , Benzoyl, Benzyl , Carbamate , p-Methoxybenzyl, 3,4-Dimethoxybenzyl , p- methoxyphenyl, Tosyl and the like.

Pv2 is H, CN, CONH2, any halogen, any aldehyde or any alkyl group.

X is any substituted or unsubstituted alkyl or aryl group. X is selected from any substituted or unsubstituted alkyl or aryl group, such as p-tolyl, p-t-butylphenyl, 2,4,6- trimethylphenyl, 2,4,6-triisopropylphenyl, 2-methylbutyl, 3-ethylpentyl, or tert-butyl group. Variety of alkane or arene sulphinamide is as shown below.

In an another embodiment present invention provides a novel compound of formula (IV) and its diastereomers

wherein X is any substituted or unsubstituted alkyl or aryl group; Rl is selected from H, any protective group or any protected propoxy group and R2 is H, CN, CONH2, any halogen, any aldehyde or any alkyl group. This compound is further converted in to the Silodosin.

In one more embodiment present invention provides a process for preparation of Silodosin of formula (I) comprising, reaction of compound of formula (VI) with any suitable base and s f formula (V).

Suitable base used is selected from the group comprising the category of inorganic bases like alkali metal or alkaline earth metal hydroxides, alkoxides, carbonate, bicarbonate or organic bases like cyclic or non cyclic compound containing nitrogen; more preferably alkali metal alkoxides.

Suitable alkali carbonates used may be selected from potassium carbonate, sodium carbonate, cesium carbonate and lithium carbonate; alkali earth metal carbonate mey be selected from magnesium carbonate, zinc carbonate; alkali hydroxides used may be selected from sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali hydroxides used may be selected from sodium methoxide, sodium ethoxide, potassium methoxide or like; organic bases like cyclic or non cyclic compound containing nitrogen such as pyridine, methyl amine, imidazole, benzimidazole, histidine or like. Suitable acid used is selected from the group comprising the category of strong inorganic acids like hydrochloric acid, sulfuric acid, hydro bromic acid, hydro iodic acid, chloric acid, perchloric acid or any organic acid like Acetic acid, Citric acid, Fumaric acid, Formic acid, Gluconic acid, Lactic acid, Oxalic acid, Tartaric acid, etc; more preferably sulphuric acid.

As described in WO2012062229 benzyl protected l-(3-hydroxypropyl)-2,3- dihydroindole, is subjected to a Vilsmeier reaction with dimethylformamide and phosphoryl chloride, which affords the 5-formyl derivative with high selectivity. Bromination of resultant compound attached bromine at 7 position of the indoline moiety. Bromo aldehyde compound is cyanized with cyanides in polar organic solvents selected from dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone or dimethyl sulfoxide, in the temperature range from 60oC to the boiling point of the solvent gives 1 -[3-(Benzyloxy)propyl]-5-formylindoline-7-carbonitrile (cyano-aldehyde), compound of formula (H).

Cyano-aldehyde, compound of formula (H) is condensed with nitro ethane in the presence of a slightly basic catalyst in the presence or absence of an organic solvent in the temperature range of 0 to 40°C; the produced nitro styrene of general formula (G) which is subsequently reduced with reducing agent to afford the nitro compound of formula (F).

In an embodiment, the present application provide process for preparation of Silodosin, embodiments comprising,

(a) reacting nitro compound of formula (F) with suitable base and subsequently with suitable acid;

The reaction can be carried out in the presence of suitable base and suiatable solvent. Suitable bases that can be employed include, but are not limited to: inorganic bases like alkali metal or alkaline earth metal hydroxides, alkoxides, carbonate, bicarbonate and the like; and organic bases like cyclic or non cyclic compound containing nitrogen such as triethyl amine, diisopropyl amine, morpholine, N-methyl morpholine, DABCO, pyridine, methyl amine, imidazole, benzimidazole, histidine,and the like. In a preferred embodiment, sodium tert butoxide has been employed.

Suitable polar solvents that can be employed include, but are not limited to: polar protic solvents that include alcohols, such as methanol, ethanol, 2-propanol, n- butanol, isoamylalcohol, ethylene glycol, water, polar aprotic solvents such as N, N- dimethylformamide, Ν,Ν-dimethyl acetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitriles and any mixtures of two or more thereof. In a preferred embodiment, methanol is employed as a solvent. Mixtures of polar protic and polar aprotic solvent can also be employed.

Acids are selected from the category of strong acids like hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, chloric acid or perchloric acid. Acid can also be organic acid. Organic acid are selected from group of carboxylic acid such as Acetic acid, Citric acid, , Fumaric acid, Formic acid, Gluconic acid, Lactic acid, Oxalic acid, Tartaric acid, etc.

(b) reacting ketone of formula (E) with sulfinamide of formula (X) in presence of lewis acid and suitable solvent and subsequently reducing the resulting sulphinyl kitimines in presence of reducing agent;

More specifically reaction is carried out as below.

Lewis acid employed in step (b) can be TI(OEt)4 or TI (Oipr)zt, Al(0-i-Pr)₃, trialkylaluminiums, BF₃-Et₂0, and Et₂Zn, T1CI₄ or SnCL_t, A1C1₃, Znl; We have found Ti(OEf)4 to be the ideal water scavenger and Lewis acid for the preparation of tert- butanesulfinyl ketimines.

Suitable solvent selected from aliphatic hydrocarbons like hexane, cyclohexane, petroleum ether; or aromatic hydrocarbons like xylene, toluene; or halogenated hydrocarbons like dichloromethane, chloroform, 1 ,2-dichloroethane; or ethers like diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxy ethane; or ketones like acetone, methyl ethyl ketone, diethyl ketone; or acetates like ethyl acetate, propyl acetate, butyl acetate; alcohols like methanol, ethanol, propanol, butanol, isopropanol; or nitriles like acetonitrile and propionitrile; dimethyl formamide, dimethyl acetamide and dimethyl sulphoxide, N-methyl pyrrolidine or mixtures thereof; preferably tetrahydrofuran.

Treating a compound of formula E with sulfanamide of formula (X) can be performed at a temperature of from 30°C to the reflux temperature for a time period sufficient to complete the reaction, preferably 5 to 10 hours.

After completion of reaction, product is used without isolation in the next step for reduction. Reducing agent are selected from the group of NaBH4, LiAlH4, DIBAL, 9-BBN, Nascent (atomic) hydrogen, Sodium amalgam, Compounds containing the

Sn2+ ion, such as tin(II) chloride, Sulfite compounds, Lindlar catalyst, Phosphites, hypophosphites, and phosphorous acid, Dithiothreitol (DTT), compounds containing the Fe2+ ion, such as iron(II) sulfate. The temperature range to carry out the reduction can be selected from -10°C to 10°C.

(c) hydrolysis of sulphinyl group of compound of formula (D) in presence of suitable acid.

The sulfinyl group is removed from the product by brief treatment with stoichiometric quantities of HC1 in a protic solvent to provide the desired amine hydrochloride in near quantitative yields. Cleavage of the sulphinyl group is in presence of suitable acid and suitable solvent, more specifically HC1 and methanol.

Enantiomerically pure material may be obtained by resolving the remaining undesired isomer using suitable enantiopure acid such as S (+)Mandelic acid to obtain mandelate salt of 5-[(2R)-2-Aminopropyl]-l-(3-benzyloxypropyl)indoline-7- carbonitrile, compound of formula (C).

The 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate utilized condensation step can be synthesized by any of the methods known in the art. Treating a compound of formula (C ) with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate may be performed in one or more solvents in the presence of a base and optionally in presence of phase transfer catalyst at a temperature of from about 40°C to reflux temperature for a time period sufficient to complete the reaction.

The term solvent includes any solvent or solvent mixture, including for example, waters, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof; more preferably water.

The base may include one or more of organic or inorganic bases selected from the group consisting of alkali metal and alkaline earth metal carbonates or bicarbonates or hydroxides, for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydroxide and the like; primary, secondary, and tertiary amines such as pyridine, piperidine, triethyl amine, diisopropylamine, N- methyl morpholine, and the likes; ammonia and ammonium salts (quaternary ammonium salts); more preferably potassium carbonate.

After completion of the reaction, the compound of formula (B) can be isolated by a common isolation technique, such as extraction, removal of solvents, crystallization.

The isolated compound of formula (B) may be further purified by salt formation or crystalisation.

The intermediate may contain an impurity derived from the reaction of compound of formula (C) with two molecules of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate, i.e. the corresponding tertiary amine. In order to remove said impurity, the intermediate compound of formula (B) may be crystallized in form of its oxalic acid addition salt. The dimer impurity substantially come down to very minimum level after oxalic acid treatment which is unexpected/substantial result makes the present process more economical & commercially viable. The compound of formula (B) is further hydrolyzed to amide, compound of formula

(A) which is subsequently convert in to Silodosin by debenzylation.

Main embodiment of the present invention is to provide scheme as below.

Silodosin form Gamma

The present invention further illustrated in detail by the below examples which are however not limit to the scope of the invention. Examples:

Example: 1 Preparation of [(3-chloropropoxy) methyl] benzene Charged Dichloromethane (5.0 lit), 3-Chloro-l-propanol (1.0 kg), Benzyl bromide (1.646 kg), Tetra butyl ammonium bromide (0.17 kg) at 25-35°C in the reactor and Stirred for 5- 10 min at 25-35°C. Slowly charged solution of sodium Hydroxide (2.65 Kg in 3.0 Lit of water) at 25-35°C. Heated reaction mass at 42-48°C for 4 hours. After completion of the reaction, cooled reaction mass to 10-20°C. Charged water (1 Lit) to the reaction mass below 35°C and stirred for 15-20 min at 25-35°C. The organic layer was separated out and slowly charged aq HC1 solution (0.25 lit in 2.0 Lit water) at 25-35°C (pH < 4.0) and stirred for 5-10 min. The organic layer was separated out and washed with sodium bicarbonate solution (0.1 Kg in 1.0 Lit) at 25-35°C (pH > 8.0). Distilled out organic layer below 50°C under vacuum to yield oily mass (1.85 Kg, 95% yield).

Example: 2 Preparation of l-[3-(Benzyloxy)propyl]indoline:

Under Nitrogen atmosphere charged Dimethyl formamide (1.5 lit), Indoline (1.0 kg), N- diisopropyl ethyl amine (1.3 kg) and Sodium Bromide (0.863 kg) at 25-35°C in the reactor. Heated reaction mixture at 84-90°C and slowly charged [(3-Chloropropoxy) methyl] benzene] (1.86 Kg). Maintained reaction mass for 12 hrs at 84-90°C. After completion of the reaction, cooled at 65-70°C and charged water (4.0 L). Charged Cone. Hydrochloric acid (0.25 Lit) to the mass at 25-35°C followed by Cyclohexane (1.0 L) and stirred the mass for 10-15 min at 25-35°C. The organic layer was separated out and aqueous layer was re-extracted with Cyclohexane (0.5 L). In combined organic layers, slowly charged Aqueous Hydrochloric acid solution (1.25 Lit in 2.0 Lit Water) at 25- 35°C and stirred reaction mass for 15-20 min (pH < 2.0). Separated out layers and charged water (2.0 L) to the aqueous layer at 25-35°C. Charged portion wise sodium bicarbonate (1.1 Kg) to the aqueous layer at 25-35°C (pH > 8.0) followed by cyclohexane (1.5 Lit) and stirred mass for 5-10 min. The organic layer was separated out and aqueous layer was re-extracted with cyclohexane (0.5 Lit). Combined organic layers were washed with water (2.0 Lit) and removed under vacuum below 50°C to yield oily mass (2.0 Kg, 89 % yield).

Example: 3 Preparation of l-[3-(Benzyloxy)propyl]indoline-5-carbaldehyde

Charged Dimethyl formamide (1.5 Lit) in the reactor under nitrogen and then cooled it at -10 -0°C. Slowly charged Phosphorous oxychloride (1.19 kg) at -10-0°C and stirred reaction mass for 10-15 min at -10-0°C. Slowly charged l-[3-(Benzyloxy)propyl]indoline (1.0 Kg) to the reaction mass at -5-5°C and stirred reaction mass for 10-15 min. Raised temperature of reaction mass at 19-25°C and stirred reaction mass for 60-90 min. After completion of the reaction, slowly charged reaction mass to previously prepared solution of ice (4.5 kg) and water (0.5 L) at 1-9°C and stirred reaction mass for 10-15 min below 25°C. Charged Aqueous Ammonia solution (3.0 Lit) to the reaction mass below 30° (pH>8) followed by Ethyl acetate (3.0 lit) at 25-35°C and stirred reaction mass for 5-10 min. The organic layer was separated out and aqueous layer was re-extracted with Ethyl Acetate (2.0 L). Combined organic layers were washed with solution of Sodium chloride (0.4 Kg in 4.0 L of water ). Distilled out organic layer under vacuum below 50°C to yield oily mass (0.9 Kg, 91 % yield). Example: 4 Preparation of l-[3-(Benzyloxy)propyl]-7-bromoindoline-5- carbaldehyde

Charged Glacial Acetic acid (2.5 lit), l-[3-(Benzyloxy) propyl] indoline-5-carbaldehyde (1.0 kg) at 25-35°C in the reactor and stirred reaction mass for 5-10 min. Cooled the reaction mass to 14-20°C and slowly charged solution of Liquid Bromine (0.59 Kg) and Glacial Acetic acid (0.5 L). Stirred reaction mass for 10-15 min at 14-20°C. After completion of the reaction, slowly charged solution of Sodium meta bisulphite (0.13 kg in 4.0 L of water) at 15-25°C and stirred reaction mass for 5-10 min. Charged Toluene (4.0 L) into the reaction mass and stirred reaction mass for 5-10 min at 25-35°C. The organic layer was separated out and aqueous layer was re-extracted with Toluene (2.0 L). Combined organic layers were washed with Sodium carbonate (0.6 Kg in 3.0 L of water) solution, water (4.0 L) followed by Sodium chloride (0.40 Kg in 4.0 L of water) solution at 25-35°C. Distilled out organic layer under vacuum below 60°C to yield oily mass (1.2 Kg, 94% yield).

Example: 5 Preparation of l-[3-(Benzyloxy)propyl]-5-formylindoline-7-carbonitrile

Under nitrogen atmosphere, charged Dimethyl formamide (3.0 Lit), l-[3-(Benzyloxy) propyl]-7-bromoindoline-5-carbaldehyde (1.0 Kg), Copper (I) Cyanide (0.263 Kg) into the in the reactor at 25-35°C and stirred reaction mass for 10-15 min. The reaction mass was heated to 140-150°C and stirred for 2-3 hrs. After completion of the reaction, cooled reaction mass to 10-20°C and slowly charged Ammonia solution (1.5 L) followed by water (2.5 L) at 25-35°C. Charged Dichloromethane (3.0 L) into reaction mass at 25- 35°C and stirred for 5-10 min. The organic layer was separated out and aqueous layer was re-extracted with Dichloromethane (3.0 L). Combined organic layers were passed through Hyflow bed and washed bed with Dichloromethane (1.0 L) at 25-35°C. Organic layer was washed with water (4.0 L ^x 2) at 25-35°C. Distilled out organic layer completely. Charged Ethyl acetate (6.0 Lit) to residue and stirred the mass for 5 min at 25-35°C. Ethyl acetate layer was washed with water (4.0 L) followed by solution of Sodium chloride (0.40 Kg in 4.0 L of water). Activated carbon (0.020 Kg) treatment was given to Ethyl acetate layer. Distilled out Ethyl acetate under vacuum below 60°C. Charged Isopropanol (2.0 L) to residue at 50-60°C and heated the mass to get clear solution at 50-55°C. Cooled the reaction mass gradually to 20-30°C and stirred for 2-2.5 hrs at 20-30°C. Filtered the solid, washed with Isopropanol (0.5 L) and suck it to dry. Product was collected and dried under vacuum at 37-43°C (0.6 Kg, 70 % yield). Example: 6 Preparation of l-[3-(benzyloxy)propyl] 5-(2-nitroprop-l-yl) indoline-7- carbonitrile

Under N₂ atmosphere, charged Nitroethane (2.0 Lit), l-[3-(Benzyloxy)propyl]-5- formylindoline-7-carbonitrile (1.0 Kg) and Ammonium acetate (0.082 Kg) to the reaction mass at 25-35 ° C in the reactor. Heated the reaction mass to 98-102°C and stirred for 1-2 hrs. After completion of the reaction, cooled the reaction mass to 78-82°C and charged water (2.0 L). Further cooled reaction mass to 25-35°C, charged Dichloromethane (3.0 L) and stirred the reaction mass for 25-30 min. The organic layer was separated out and aqueous layer was re-extracted with Dichloromethane (1.0 L). Combined organic layers were washed with solution of Sodium bicarbonate (0.24 Kg in 3.0 Lit of water) followed by water (3.0 L) at 25-35°C. Distilled out organic layer under vacuum below 60°C. Cooled the mass at 35-45°C, charged Tetrahydrofuran (3.5 Lit) and stirred for 15-20 min. Charged Isopropyl alcohol (2.5 Lit) to reaction mass at 35-45°C and cooled at -1 to 5°C. Charged portion wise Sodium Borohydride (0.176 Kg) into the reaction mass at -1 to 5°C. Raised temperature of the reaction mass to 24-30°C and stirred the mass for 90-120 min. Cooled the reaction mass to -1 to 5°C, slowly charged water (0.3 Lit) to the reaction mass and stirred for 25-30 min. Slowly charged glacial acetic acid (1.3 lit) to the reaction mass below 0-10°C and stirred for 45-60 min. Raised temperature of the reaction mass to 24-30°C and stirred for 1.5-2 hrs. Charged water (5.0 Lit) followed by Dichloromethane (4.0 Lit) to the reaction mass at 25-35°C and stirred for 15-20 min. The organic layer was separated out and aqueous layer was re-extracted with Dichloromethane (1.0 L). Combined organic layers were distilled out under vacuum below 60°C. Charged Ethyl acetate (1.25 L) to oily mass and heated to 57-63°C till it is clear solution. Cooled reaction mass to 25-35°C and stirred for 600-720 min, filtered the solid and washed with mixture of Ethyl acetate: Methyltertbutylether (20: 80, 1.0 Lit) at 25-35°C. Dried the material at 35-45°C (0.7 Kg, 59% yield).

Example: 7 Preparation of l-[3-(Benzyloxy)propyl]-5-(2-oxopropyl)indoline-7- carbonitrile Under N₂ atmosphere, charged Methanol (10.0 Lit) in the reactor and cooled it to 20- 30°C. Charged lot wise Sodium tert butoxide (0.38 Kg) to the cold Methanol and stirred the reaction mass for 15-20 min. Charged l-(3-Benzyloxypropyl)-5-(2-nitropropyl) indoline-7-carbonitrile (1.0 Kg) and stirred for 60 min. Cooled reaction mass to -35 to- 25°C, slowly charged previously prepared solution of Sulphuric acid in methanol (0.92 Kg of 98% Sulphuric acid in 1.0 L of Methanol) and stirred for 15-20 min. Raised temperature of reaction mass 24-30°C and stirred for 45-60 min. Charged water (10.0 L) followed by Toluene (5.0 L) into the reaction mass and stirred for 25-30 min at 25-35°C. The organic layer was separated out and aqueous layer was re-extracted with Toluene (2.0 L). Combined organic layers were washed with solution of Sodium bicarbonate (0.24 Kg in 3.0 Lit of water) followed by water (3.0 L). Distilled out Organic layer under vacuum below 60°C to yield oily mass (0.85 Kg, 92% yield).

Example: 8 Preparation of 5-[(2R)-2-Aminopropyl]-l-(3-benzyloxypropyl)indoline- 7-carbonitrile mandelate salt Under N₂ atmosphere, charged Tetrahydrofuran (5.0 Lit), l-[3-(Benzyloxy) propyl]-5-(2- oxopropyl) indoline-7-carbonitrile (1.0 Kg), R (+) Tert Butylsulfinamide (0.365 Kg), Titanium tetraethoxide (1.31 Kg) in to the reactor at 25-35°C. Heated reaction mass to 64-68°C and stirred for 7-9 hours. Cooled reaction mass to -10 to 0°C, charged Sodium Borohydride (0.163 Kg) portion wise and stirred for 30-60 min. Slowly charged Methanol (0.5 Lit) to the reaction mass at -10 to 0°C and stirred 30 min. Slowly charged Cone. Hydrochloric acid (1.0 Lit) to the reaction mass at -5 to 20°C, warmed the reaction mass to 20-30°C and stirred for 30-60 min. Charged water (6.0 Lit) followed by Ethyl acetate (5.0 Lit) to the reaction mass at 20-30°C and stirred for 25-30 min. The organic layer was separated out and aqueous layer was re-extracted with Ethyl acetate (1.0 Lit) at 25-35°C. In combined organic layers, charged Ammonia solution (1.5 Lit) at 25-35°C (pH > 8.0) and stirred for 10-15 min. Filtered the upper organic layer through the Hyflow at 25-35°C and washed solid with Ethyl acetate (1.0 Lit^x2). Combined organic layers were washed with water (5.0 Lit) at 25-35°C. Distilled out organic layer under vacuum below 50°C. Cooled oily mass to 25-35°C and charged Ethyl acetate (5.0 L). Organic layer was washed with diluted Hydrochloric acid (1.1 Lit of Cone. Hydrochloric acid in 5.0 L of water), diluted Ammonia solution (1.5 L of 20% Ammonia solution in 3.0 L of water) and Water (7.0 L) at 25-35°C. Distilled out Ethyl acetate under vacuum below 50°C. Cooled the oily mass at 25-35°C, charged Ethyl acetate (5.0 Lit) followed by Mandelic acid (415 gm). Heated reaction mass to 32-42°C and stirred for 2-3 hrs. Gradually cooled reaction mass to 25-35°C and stirred for 30-60 min. Filtered reaction mass, washed with Ethyl acetate (0.5 Lit) at 25-35°C. Charged wet cake to Ethyl acetate (3.0 Lit) at 25-35°C and stirred mass for 10-15 min. Filtered reaction mass and washed with Ethyl acetate (0.5 Lit). Product collected and dried at 40-50°C (0.7 Kg, 49% yield).

Example: 9 Preparation of (l-[3-(Benzyloxy)propyl]-5-{(2R)-2-({2-[2-(2,2,2- trifluoroethoxy)-phenoxy] ethyl} amino) propyl] indoline-7-carbonitrile oxalate

Charged Dichloromethane (4.0 Lit), 5-[(2i?)-2-Aminopropyl]-l-(3-benzyloxypropyl) indoline-7-carbonitrile mandelate (1.0 Kg), water (4.0 Lit) in to the reactor at 25-35°C and stirred for 10-15 min. Slowly charged Sodium Carbonate solution (0.40 Kg in 2.0 L of water) at 25-35°C and stirred for 20-25 min(pH > 9.0). The organic layer was separated out and aqueous layer was re-extracted with Dichloromethane (2.0 Lit). Combined organic layers were washed with water (4.0 L) followed by Sodium chloride solution (0.6 Kg in 3.0 L of water) at 25-35°C. Distilled out organic layer under vacuum below 50°C. Cooled oil to 25-35°C and charged water (7.0 Lit). Charged 2-[2-(2,2,2- trifluoroethoxy)phenoxy] ethyl methanesulfonate (0.721Kg), Potassium carbonate (0.331 Kg) and Tertabutylammoniumbromide (0.344 Kg) to the mass at 25-35°C. Heated reaction mass to 88-92°C for 12-14 hrs. After completion of the reaction, cooled reaction mass to 25-35°C, charged Ethyl acetate (3.0 Lit) and stirred for 20-25 min. The organic layer was separated out and aqueous layer was re-extracted with Ethyl acetate (1.0 Lit) at 25-35°C. Combined organic layers were washed with Sodium chloride solution (0.2 Kg in 2.0 L of water). Distilled out organic layer under vacuum below 50°C. Charged Isopropyl alcohol (1.0 Lit) at 40-50°C and distilled out mixture of Isopropyl alcohol and Ethyl acetate under vacuum completely. Cooled the oily mass to 25-35°C, charged Isopropyl alcohol (10.0 Lit), Denature ethanol (with Acetone) (2.0 Lit) and stirred for 5- 10 min. Charged Oxalic acid (0.180 Kg) to the reaction mass and heated to 67-73°C to get clear solution. Gradually cooled reaction mass to 55-59°C, and stirred for 15-20 min. Cooled reaction mass to 33-37°C and stirred for 1.0-1.5 hrs. Filtered the solid and washed with Isopropanol (2.0 Lit) at 25-35°C. Product was collected and dried at 40-50°C (0.8 Kg, 61% yield). Example: 10 Preparation of l-[3-(benzyloxy) propyl]-5-{(2R)-2-({2-[2-(2, 2, 2- trifluoroethoxy)-phenoxy] ethyl} amino) propyl] indoline-7-carboxamide

Charged Dichloromethane (3.0 Lit), (l-[3-(Benzyloxy)propyl]-5-{(2R)-2-({2-[2-(2,2,2- trifluoroethoxy)-phenoxy]ethyl} amino) propyl] indoline-7-carbonitrile oxalate (1.0 Kg), water (5.0 Lit) in to the reactor at 25-35°C. Slowly charged Sodium Carbonate solution (0.23 Kg in 2.25 L of water) at 25-35°C and stirred for 25-30 min (pH > 9.0). The organic layer was separated out Organic layers was washed with water (5.0 Lit) followed by sodium chloride solution (0.3 Kg in 3.0 L of water) at 25-35°C. Distilled out organic layer under vacuum below 50°C. Cooled oily mass to 25-35°C, charged Dimethyl sulphoxide (10.0 Lit) and Sodium Hydroxide solution (0.116 Kg in 0.5 L of Water). Cooled reaction mass at 14-20°C and slowly charged Hydrogen Peroxide (0.55 Lit). Warmed reaction mass at 15-25°C and stirred for 12-14 Hrs. After completion of the reaction, cooled reaction mass at 14-20°C and slowly charged water (4.0 lit) and Sodium bisulphite (0.334 Kg in 2.0 L of water) at 14-20°C. Charged water (8.0 Lit) followed by Ethyl acetate (10.0 Lit) to the reaction mass at 25-35°C and stirred for 15-20 min. The organic layer was separated out aqueous layer was re-extracted with Ethyl acetate (2.0 Lit) at 25-35°C. Combine both Organic layers were washed with water (8.0 Lit). Cooled reaction mass at 15-25°C, slowly charged Hydrochloric acid solution (0.3 lit of Cone. HC1 in 1.7 L of water) and stirred for 20-25 min (pH > 2.0). The layers were separated out, charged Ethyl acetate (2.0 Lit) to the aqueous layer at 15-25°C and stirred the mass for 15-20 min. The layers were separated out, charged sodium carbonate solution (1.0 kg in 5.0 L of water) to the aqueous layer at 25-35°C (pH > 8.0). Charged Dichloromethane (4.0 Lit) to the aqueous layer and stirred for 15-20 min at 25-35°C. The organic layer was separated out and aqueous layer re-extracted with Dichloromethane (2.0 Lit) at 25-35°C. Combined Organic layers were washed with water (4.0 Lit) at 25-35°C. Removed solvent under vacuum below 50°C. Cooled the oily mass at 25-35°C, charged Ethyl acetate (4.0 Lit). Charged water (6.0 Lit) at 25-35°C followed by solution of Hydrochloric acid (0.6 lit Conc.HCl in 3.4 L of water) and stirred for 20-25 min (pH > 2.0). The layers were separated out, charged Ethyl acetate (3.0 Lit) to the aqueous layer at 25-35°C and stirred the mass for 15-20 min. The layers were separated out, charged solution of Sodium carbonate (1.6 kg in 8.0 L of water) to the aqueous layer at 25-35°C (pH > 8.0). Charged Dichloromethane (4.0 Lit) to the aqueous layer at 25-35°C and stirred the mass for 15-20 min. The organic layer was separated out and aqueous layer was re-extracted with Dichloromethane (2.0 Lit) at 25-35°C. Combined Organic layers were washed with water (4.0 Lit). Distilled out organic layer under vacuum below 50°C. Charged Cyclohexane (1.0 Lit) to the oily mass and cooled mass to 30-40°C. Charged Dichloromethane (1.0 Lit) to the mass followed by Cyclohexane (1.0 Lit). Distilled out Dichloromethane and Cyclohexane completely. Charged Cyclohexane (5.0 Lit) to the solid and heated mass to 45-55°C and stirred for 30-60 min. Cooled reaction mass to 25-35°C and stirred for 25-30 min. Filtered the solid at and washed the solid with Cyclohexane (1.0 Lit). Product was collected and dried it at 38-42°C (0.8 Kg, 90% yield)

Example: 11 Preparation of Silodosin l-[3-(Benzyloxy propyl]- 5-{(2R)-2-( {2-[2-(2,2,2-trifluoroethoxy)-phenoxy] ethyl}amino) propyl] indoline-7-carboxamide)(1.0 Kg), Methanol (2.5 Lit) and 10 % Pd/C (50% wet) (0.05 Kg) were taken to Hydrogenator at 25-35°C. Charged Methanolic HCl (2.0 Lit) and cooled reaction mass to 20-30°C. Maintained 4-5 Kg/Cm pressure of Hydrogen for 90-150 min at 20-30°C. Filtered mass through hyflo bed and washed bed with methanol (3.0 Lit) at 20-30°C. Solvent was removed by vacuum below 50°C. Charged Ethyl acetate (2.0 Lit) to reaction mass at 15-25°C followed by diluted Hydrochloric acid (2.5 Lit in 2.5 L of water) and stirred for 25-30 min. The organic layers were separated out and aqueous layer was re-extracted with Ethyl acetate (2.0 Lit). Slowly charged solution of Sodium carbonate (1.2 kg in 6.0 L of water) (pH>9.0) at 25- 35°C followed by Dichloromethane (5.0 Lit) and stirred the reaction mass for 25-30 min. Activated carbon treatment given to organic layers. Organic layer was washed with DM water (5.0 Lit). Distilled out organic layer under vacuum below 50°C. Cooled residue, charged Toluene (10.0 Lit) followed by Ethyl alcohol (0.40 Lit). Heated reaction mass to 53-57°C to get clear solution and stirred for 10-15 min. Cooled reaction mass to 33-37°C and stirred for 2-3 hrs. Filtered the solid and washed with Toluene (1.0 Lit) at 25-35°C. The product was collected and dried it at 50-60°C (0.50 Kg. 59 % yield). Example: 11 Purification of Silodosin

Dissolved Silodosin (40.0gm) in ethyl acetate (500ml) under reflux and then allowed to cool to room temperature and filtered it. Wet cake again dissolved in MDC (500ml) under reflux, allowed to cool to room temperature and filtered it. Charged wet cake with Toluene (1200ml). Heated reaction mass to 53-57°C to get clear solution and stirred for 10-15 min. Cooled reaction mass to 33-37°C and stirred for 2-3 hrs. Filtered the solid and washed with Toluene. The product was collected and dried it.

Claims

Claims:

1. A process for preparation of Silodosin (compound of formula I);

comprising use of sulphinamide of formula (IV) for diastereoselective reductive amination of ketone of formula (V);

wherein sulphinamide enantiomer is R or S; X is any substituted or unsubstituted alkyl or aryl group; Rl is selected from H, any protective group or any protected propoxy group; R2 is H, CN, CONH2, any halogen, any aldehyde or any alkyl group.

2. A novel compound of formula (IV) and its diastereomers

(IV) wherein X is any substituted or unsubstituted alkyl or aryl group; Rl is selected from H, any protective group or any protected propoxy group and R2 is H, CN, CONH2, any halogen, any aldehyde or any alkyl group.

3. Use of compound of formula (IV) as claimed in claim 2 in process for preparation of Silodosin (compound of formula I).

4. A process for preparation of Silodosin of formula (I) comprising, reaction of compound of formula (VI) with any suitable base and subsequently with any suitable acid to give compound of formula (V).

(VI) (V)

5. The process as claimed in claim 4, wherein any suitable base used is selected from the group comprising the category of inorganic bases like alkali metal or alkaline earth metal hydroxides, alkoxides, carbonate, bicarbonate or organic bases like cyclic or non cyclic compound containing nitrogen; more preferably alkali metal alkoxides.

6. The process as claimed in claim 4, wherein any suitable acid used is selected from the group comprising the category of strong inorganic acids like hydrochloric acid, sulfuric acid, hydro bromic acid, hydro iodic acid, chloric acid, perchloric acid or any organic acid like Acetic acid, Citric acid, Fumaric acid, Formic acid, Gluconic acid, Lactic acid, Oxalic acid, Tartaric acid, etc; more preferably sulphuric acid.

7. A novel process for preparation of Silodosin comprising the process of preparation of intermediate of formula (C) which further comprising steps of a) reacting nitro compound of formula (F) with suitable base and subsequently with suitable acid; reacting ketone of formula (E) with sulfanamide of formula (X) in presence of lewis acid and subsequently reducing the resulting sulphinyl kitimines of formula (G) in presence of reducing agent; hydrolysis of sulphinyl group of compound of formula (D) in presence of suitable acid.

8. The process of claim 7 wherein any suitable base used in step (a) is selected from the group comprising the category of inorganic bases like alkali metal or alkaline earth metal hydroxides, alkoxides, carbonate, bicarbonate or organic bases like cyclic or non cyclic compound containing nitrogen; more preferably alkali metal alkoxides.

9. The process of claim 7 wherein any suitable acid used in step (a) is selected from the group comprising the category of strong inorganic acids like hydrochloric acid, sulfuric acid, hydro bromic acid, hydro iodic acid, chloric acid, perchloric acid or any organic acid like Acetic acid, Citric acid, Fumaric acid, Formic acid, Gluconic acid, Lactic acid, Oxalic acid, Tartaric acid, etc; more preferably sulphuric acid.

10. The process of claim 7 wherein lewis acid used in step (b) is selected from the group comprising TI(OEt)4 or TI (Oipr)4, Al(0- -Pr)3, trialkylaluminiums, BF3- Et20, Et₂Zn, TiCl₄, SnCl₄, A1C1₃ and Znl; more preferably TI(OEt)₄.

11. The process of claim 7 wherein reducing agent used in step (b) is selected from the group comprising NaBH₄, LiAlH₄, DIBAL, 9-BBN, Nascent (atomic) hydrogen and Sodium amalgam; more preferably aBH₄

12. The process of claim 7 wherein suitable acid used in step (c) is selected from the group comprising inorganic acid such as hydrochloric acid, sulphuric acid or nitric acid.

13. Oxalic acid salt of l-(3-benzyloxypropyl)-5-[(2R)-2-({2-[2-(2,2,2- trifluoroethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7- carbonitrile, compound of formula (B).

14. Use of Oxalic acid salt of compound of formula (B) as claimed in claim 13 in process for preparation of Silodosin.

15. Mandelate salt of 5-[(2R)-2-Aminopropyl]-l-(3-benzyloxypropyl)indoline-7- carbonitrile, compound of formula (C).

16. Use of Mandelate salt of compound of formula (C) as claimed in claim 15 in process for preparation of Silodosin.

17. An improved process for preparation of Silodosin of formula (I), comprising of; condensing the 5-[(2i?)-2-Aminopropyl]-l-(3-benzyloxypropyl) indoline-7- carbonitrile compound of formula (C) with 2-[2-(2,2,2- trifluoroethoxy)phenoxy] ethyl methanesulfonate in presence of suitable base, water and phase transfer catalyst.