WO2015015512A2 - Process for the preparation of silodosin and its gamma form - Google Patents

Abstract

The present invention provides an improved and efficient process for the preparation silodosin of formula I and pharmaceutically acceptable salts thereof Formula I. through novel tartrate salt of cyano hydroxy intermediate of formula II. Formula II The present invention also provides an improved, industrially advantageous and novel process for preparation of pure polymorphic form gamma (γ) of silodosin, wherein residual solvents are present in specified limits as per ICH guidelines. ·

Description

TITLE OF THE INVENTION

"PROCESS FOR THE PREPARATION OF SILODOSIN AND ITS GAMMA FORM" FIELD OF THE INVENTION

The present invention provides an improved and efficient process for the preparation of

It acts as an selective ai -adrenoceptor antagonist and is useful in the symptomatic treatment of benign prostatic hyperplasia (BPH). Chemically it is known as l-(3-hydroxypropyl)-5-[(2R)- ( { 2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino) propyl] indoline-7-carboxamide.

Silodosin and its pharmaceutically acceptable salts are first disclosed in US patent 5,387,603. Synthetic approach for the production of silodosin, is described in patent '603 can be represented as shown below in scheme 1. l

Scheme 1

As represented in scheme 1, silodosin is prepared by the reaction of l-acetyl-5-(2r aminopropyl)indoline-7-carbonitrile with 2-[2-(2,2,2-trifiuoroethoxy)phenoxy] ethyl methanesulfonate in the presence of sodium bicarbonate in ethanol to give l-acetyl-5-[2-[2-[2- (2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carbonitrile, which upon reaction with di-tert-butyldicarbonate in methylene chloride produces protected acetyl indoline carbonitrile compound. Further deacetylation with sodium hydroxide in ethanol followed by treatment with acetic acid provides protected indoline carbonitrile compound, which upon hydrolysis using dimethyl sulfoxide, 30% hydrogen peroxide, sodium hydroxide and acetic acid gives protected indoline carboxamide, which upon further reaction with 2-tert- butyldimethylsiloxy)ethyl-4-nitrobenzene sulfonate in the presence of cis-dicyclohexano-18 crown-6 and potassium carbonate in dioxane gives protected (tert-butyl-dimethylsiloxy) ethyl indoline carbonitrile. Further treatment with tetrabutylammonium fluoride in tetrahydrofuran produces N-boc protected hydroxy deprotected propyl indoline carbonitrile, which under goes facile deprotection of boc group upon treatment with trifluoroacetic acid, in methylene chloride to yield silodosin. The complete process is very complex, make use of pyrophoric reagents which are very difficult to handle in large scale and have many extra steps involving protection and depfotection. Further in US patent '603, concrete detail of preparation and purification of silodosin have not been reported. Furthermore, isolated silodosin is characterized using IR, NMR and specific rotation but the patent is silent on product appearance and crystalline nature. There are several processes known for the preparation of silodosin and its intermediates viz; in JP 4634560; JP 4921646; JP-2006- 188470; WO2011/124704 and WO2011/101864. In most of the inventions, silodosin is prepared by following reaction as shown in scheme 2. Major disadvantages of these processes are the formation of N,N dialkyl impurity, and other impurities which forms during the condensation of 3-[5-((2/?)-2-aminopropyl)-7-cyano-2,3- dihydro-lH-indol-l-yl]propyl benzoate or its salts like monotartrate with 2-[2-(2,2,2- trifluoroethoxy)phenoxy] ethyl methanesulfonate. N,N dialkyl impurity forms in about 12-15% and may form due to reaction of one molecule of benzoate compound with two molecules of methanesulfonate compound. Removal of this impurity is not possible by simple purification

wherein R is benzoyl, benzyl, tetrahydropyranyl, 2-trimethylsilylethyl, dinitrophenyl, diphenyl methyl and the like

Scheme 2

US patent 7,834,193 discloses a process for preparation of silodosin with similar condensation of 3-[5-((2R)-2-arriinopropyl)-7-cyano-2,3-dihydro-lH-indol-l-yl]pfopyl benzoate or its salts like monotartrate with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate, but 3-{7- cyano-5-[(2R)-2-({2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl)-2,3-dihydro-lH- indol-l-yl)-propylbenzoate is purified by preparing monooxalate salt as shown below in scheme 3. This patent specifically prepares monooxalate salt of 3- {7-cyano-5-[(2R)-2-({ 2- (2,2,2-trifluoroethoxy)-phenoxy]ethyl }amino)propyl)-2,3-dihydro-lH-indol-l-yl)-propyl benzoate to remove N,N÷dialkyl impurity, but impurity has not been removed completely, only a certain % of it, has been removed.

Scheme 3

In PCT publication WO2012/131710, preparation of silodosin is described wherein improved processes for preparation of 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-lH-indol-l- yl]propyl benzoate have been disclosed which is then converted to silodosin by condensation with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate. In exemplified process, 3-[5- ((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-lH-indol-l-yl]propyl benzoate is condensed with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate and the resulting benzoate compound is hydrolyzed to give l-(3-hydroxy propyl)-5-[(2R)-2-({ 2-[2,2,2-trifluoroethoxy) phenoxy] ethyl }amino)propyr]-2,3-dihydro-lH-indol-7-carbonitrile.The carbonitrile compound is treated with oxalic acid to prepare its oxalate salt having purity greater than 99%, which is then hydrolyzed using a base to prepare free carbonitrile compound having purity greater than 99%, but this patent is silent about N, N- dialkyl impurity or its removal.

In PCT publication WO2012/147019, preparation of silodosin using 3-{ 7-cyano-5-[(2R)-2-({2- (2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl)-2,3-dihydro-lH-indol-l-yl)-propyl benzoate tartrate salt has been described as shown below in scheme 4.

Scheme 4

One other PCT publication WO2012/147107 describes preparation of silodosin by preparing hydrochloride and acetic acid salts of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2- trifluoroethoxy) phenoxy] ethyl }amino)propyl]-2,3-dihydro-lH-indol-7-carbonitrile to remove N,N dialkyl impurity. It has been observed that in exemplified process, wherein hydroxy compound namely l-(3-hydroxy propyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy) phenoxy] ethyl }amino)propyl]-2,3-dihydro-lH-indol-7-carbonitrile is purified by preparing its acetate salt to, remove the impurities but still N, N-dialkyl impurity remains in an amount of 0.6%, which is difficult to remove in next stage or require extra purifications.

Beside to use highly pure silodosin, use of a pure polymorphic form of API is an essential requirement of drug formulation, these both aspects when address jointly, and obtained silodosin can be converted to pure polymorph then only a complete solution of prior art problems can be achieved. Apart from above mentioned process patents/publications which aimed to prepare the pure silodosin, there are exist some polymorph patents/publications which also aims to prepare pure polymorphic form of silodosin. Polymorphism is considered as one of the- most important solid-state property of drug substance, since different polymorph have different physiochemical and biological properties and in pharmaceutical chemistry it is often desired to obtain one particular form that is biologically active and also offers ease of handling during formulation. The available literature references related to polymorph of silodosin are incorporated herein. Japanese patent 3331048 (publication No.H07-330726), discloses a process for purification of silodosin wherein silodosin is dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, solvent is distilled off and again dissolved in ethyl acetate at 70°C and crystallizes below room temperature. The resulting product is characterized by melting point, IR, NMR and specific rotation. Here also disclosure is silent about polymorphic form of product.

US patent publication US2006/0142374A1 (equivalent European patent EP1541554B 1) discloses polymorphic forms of silodosin including three crystalline polymorphic form of silodosin which are named as alpha (a), beta (β) and gamma (γ) and one amorphous form. These polymorphic forms have been characterized by X-ray powder diffraction pattern. In the patent publication, processes for the preparation of all these three crystalline forms have been disclosed. In. a given process, form alpha is prepared by dissolving crude silodosin in appropriate amount of ethyl acetate, ethyl formate, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran or mixture of acetone and acetonitrile (1: 1), preferably ethyl acetate under heating, allowing to stand at room temperature to precipitate the crystal gradually. Similarly, form beta is prepared by dissolving crude silodosin in appropriate amount of methanol under heating, adding petroleum ether as a anti-solvent, crystal precipitation is ensured using vigorous stirring. In a second process, to prepare the form beta, crude silodosin is dissolved in ethanol or 1-propanol and the reaction mass is cooled quickly. The crystalline form gamma is prepared by dissolving crude silodosin in appropriate amount of toluene or a mixture of acetonitrile and toluene (1:4) or ethyl acetate and toluene (1: 19), preferably in toluene, under heating, cooling to room temperature and allowing to precipitate gradually upon standing. In a second process to prepare form gamma, crude silodosin is dissolved in 2-propanol and the crystals are precipitated by adding an appropriate amount of toluene. In spite of disclosing three crystalline polymorphic forms, the patent publication prefers preparation and use of form alpha by highlighting the problems faced for preparation and use of other forms. It is disclosed that crystal form beta has manufacturing difficulties at industrial scale since precipitation occurs only when the nonpolar antisolvent is added to warm solution which leads to inconsistency in quality of crystals. With the second process for preparation of form beta, desired level of yield and purity has not been achieved. Further, according to this publication, preparation of gamma form involves use of toluene which can not be removed completely from final product, because of its high boiling point and raises the problem of residual solvent. In the case of toluene, a class 2 solvent, its limits should not be more than 890 ppm. In the exemplified process, toluene content has not been disclosed, which clearly reflects that product was not suitable for pharmaceutical composition having problem of high residual content of toluene. Furthermore patent publication also states that all the three crystal forms donot have any difference in hygroscopicity and stabilities.

Thereafter, several patents/publications disclose preparation of polymorphic forms alpha and beta. For example a PCT publication WO2012/147107 discloses a process for preparation of beta form using isopropyl acetate and methyl isobutylketone. In another PCT publication WO2012/077138, preparation of alpha and beta forms are disclosed using various solvent , system. Similarly, in a Chinese patent CN102010359, crystalline form beta is prepared by dissolving the crude silodosin in alcoholic solvent by heating and the product is crystallized by cooling or by adding an antisolvent such as ketone or ether.

European patent EP2474529 discloses new polymorphic forms delta (δ) and eta (ε) of silodosin by using a solvent (tetrahydrofuran) and antisolvent (n-heptane, n-hexane, cyclohexane, tert butylmethyl ether).Further it discloses conversion of delta form to beta form by just heating the delta form at a particular temperature. The form delta can also be transformed into form eta by. slurrying in aqueous methanol. One new crystalline form designated as delta has also been disclosed in a Chinese patent publication CN102229558. An Indian patent application 478/MUM/2010, also discloses a new polymorphic form Zy-S which is prepared by using solvent such as esters, aromatic hydrocarbons, ketones, and alcohols. All the above disclosures are silent about the preparation of gamma form of silodosin and only available disclosure reports that gamma form have problem of residual solvent, as impurity and is not suitable for pharmaceutical compositions.

Impurities may be formed or added during the manufacture of the API. Any component other than the API ii considered an impurity. The impurities present in the API could be process- ' related impurities such as starting materials, intermediates, by-products, reagents, ligands, catalysts, filter aids, carbon adsorbents, or salts as well as degradation products, enantiomeric impurities and residual solvents used in the manufacturing process.

The International Conference on Harmonization (ICH) guidelines on residual solvent Q3C(R5) for impurities in API indicates that the impurity profile method should be able to detect impurities (limit of quantification) at levels greater than the reporting threshold of 0.05% for drugs with maximum daily dose of <2 g/day and 0.03% for maximum daily dose >2 g/day. Residual solvents have had official limits in the United States as set in USP [30<467> and by the FDA in 1997, same in revised USP 37<467> applicable from May 2014] and have been monitored by most pharmaceutical manufacturers extensively for more than two decades in both bulk and finished products Residual solvents in pharmaceutical samples are monitored using gas chromatography (GC) with either flame ionization detection (FID) or mass spectrometry. Based on good manufacturing practices, measuring residual solvents is mandatory for the_, release testing of all active pharmaceutical ingredients and is routinely performed.

In ICH guidelines there is chapter on Classification of Residual Solvents by Risk Assessment. Solvents are evaluated for their possible risk to human health and placed into one of three classes as follows:

Class 1 solvents: Solvents to be avoided-

Known human carcinogens, strongly suspected human carcinogens, and environmental hazards.

Class 2 solvents'. Solvents to be limited- Nongenotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity. Solvents suspected of other significant but reversible toxicities.

Class 3 solvents: Solvents with low toxic potential -

Solvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 solvents have PDE's (permitted daily exposure) of 50 milligrams or more per day.

It has been noticed that polymorphic gamma form of silodosin when prepared as per the process reported in the prior art is not isolated in pure form it is found to have residual solvent (toluene) in unacceptable amounts and is difficult to remove even drying at higher temperature for longer durations.

It is evident from the available prior art processes that purification through different salts formation at different stage seems to be mandatory to remove impurities, mainly N,N dialkyl impurity and other impurities and to synthesize silodosin of required purity. Those skilled in pharmaceutical arts understand that purification via salt formation of an intermediate or final compound offers best method of attaining important qualities like chemical quality and polymorphic content. With advent of world wide pharmaceutical regulations, stricken cGMP norms and increased emphasis on drug product quality, it is very important for pharmaceutical . companies to produce drug substance having higher purity and lower impurity.

The prior art teaches number of ways of purification via different salt formation at different stages of process, in which purification through salt formation of intermediate compound or final stage compound proves to be beneficial in providing pure silodosin. Different salts of an API or an intermediate may possess different properties and even same salt may form different polymorphs. Even though a number of salts are known in the art, the discovery of a new salt of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-tri oroethoxy)phenoxy]ethyl }amino) propyl]-2,3- dihydro-lH-indol-7-carbonitrile can provide new ways to improve synthesis of silodosin in , removal of N,N-dialkyl and other impurities. Further no attempts have been made to prepare the polymorphic form gamma of silodosin using any other alternate process o if tried the process may not overcome the residual solvent problem hence were not documented. The availability of only one disclosure to prepare the gamma form of silodosin strongly necessitates the need in art to develop the other processes to prepare the gamma form which not only passes the criteria of residual solvent limits as per ICH guidelines, Q3C, but also, provides the consistency in crystal form. This provides a new opportunity to improve performance characteristics of a pharmaceutical product like silodosin. Therefore, the present invention provides a new salt of an intermediate of silodosin that proved to be beneficial and provide ari industrially advantageous and efficient process for preparation of highly pure silodosin and pure polymorphic form gamma of silodosin, wherein residual solvents are within limits as per ICH guidelines.

OBJECT OF THE INVENTION

The main object of the present invention is to provide a process for the preparation of silodosin and pharmaceutically acceptable salts thereof using novel salt intermediate.

Another object of the present invention is to provide a novel salt of l-(3-hydroxypropyl)-5- [(2R)-2-( { 2-[2,2,2-trifluoroethoxy)phenoxy]ethyl } amino)propyl]-2,3-dihydro- lH-indol-7- carbonitrile.

Another object of the present invention is to provide a process for synthesis of silodosin through novel salt of l-(3-hydroxypropyl)-5-[(2R)-2-({ 2-[2,2,2-trifluoroethoxy) phenoxyjethyl } amino) propyl]-2,3-dihydro-lH-indol-7-carbonitrile. Another object of the present invention is to provide a process for the synthesis of novel salt of l-(3-hydroxypropyl)-5-[(2R-2-({2-[2,2,2-trifluoroethoxy)phenoxy] ethyl }amino)propyl-2,3- dihydro-lH-indol-7-carbonitrile.

Yet another object of the present invention is to provide an improved, industrially advantageous, efficient and novel process for preparation of polymorphic form gamma of

According to one other embodiment, the present invention provides l-(3-hydroxypropyl)-5- [(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indol-7- earbonitrile tartrate of formula II.

According to one other embodiment, the present invention provides a process for preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3- dihydrorlH-indol-T-carbonitrile tartrate of formula II.

According to one other embodiment, the present invention provides a process for the preparation of silodosin and pharmaceutically acceptable salts thereof, which comprises the steps of: a) reacting3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-lH-indol-l-yl]propyl benzoate(2R,3R)-monotartrate compound of formula III,

Formula III

with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate in the presence of a base and a suitable solvent to form 3-{ 7-cyano-5-[(2R)-2-({2-(2,2,2-trifluoroethoxy)- phenoxy]ethyl } amino)propyl)-2,3-dihydro- lH-indol- l-yl)-propyl benzoate intermediate of formula IV;

Formula IV

b) of formula IV by using a suitable base in the presence of a suitable solvent to form l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2- trifluoroethoxy)phenoxy]ethylamino)propyl]-2,3-dihydro-lH-indol-7-carbo-nitrile

Formula V

c) formula V with tartaric acid in the presence of a esented by formula II; and

Formula II

1 L d) hydrolysing tartrate salt of cyano hydroxy intermediate represented by formula II in the presence of a suitable base and a suitable oxidizing agent in an organic solvent to prepare silodosin of formula I.

According to one other embodiment, the present invention provides a process for the preparation of silodosin and pharmaceutically acceptable salts thereof, which comprises the steps of:

a) reacting3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-lH-indol-l-yl]propyl

-monotartrate compound of formula III,

Formula III

with 2-[2.-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate in the presence of a base and a suitable solvent to form 3- {7-cyano-5-[(2R)-2-({2-(2,2,2-trifluoroethoxy)- phenoxy]ethyl }amino)propyl)-2,3-dihydro-lH-indol-l-yl)-propyl benzoate intermediate

Formula IV

b) hydrolyzing cyano benzyloxy intermediate of formula IV by using a suitable base in the presence of a suitable solvent to form l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2- )propyl]-2,3-dihydro-lH-indol-7-carbo-nitrile

Formula V

c) reacting cyano hydroxy intermediate of formula V with tartaric acid in the presence of a suitable solvent to form tartrate salt represented by formula II; Formula II

d) hydrolysing tartrate salt of cyano hydroxy intermediate represented by formula II in the presence of a suitable base and a suitable oxidizing agent in an organic solvent to prepare silodosin of formula I; and

e) converting silodosin of formula I into pure polymorphic form gamma of silodosin. According to one other embodiment, the present invention provides an efficient and novel process for preparation of polymorphic form gamma of silodosin of formula I, wherein residual solvents are present in specified limits as per ICH guidelines.

According to one other embodiment, the present invention provides a process for preparation of polymorphic form gamma of silodosin, which comprises the steps of:

a) dissolving any polymorphic form of silodosin in a suitable solvent by heating;

b) cooling the resulting solution;

c) seeding with form gamma of silodosin;

d) cooling the resulting solution to ambient temperature;

e) adding a suitable antisolvent;

f) stirring the reaction mixture;

g) isolating pure polymorphic form gamma of silodosin; and

h) optionally micronizing polymorphic form gamma of silodosin.

According to one other embodiment, the present invention provides a process for preparation of polymorphic form gamma of silodosin, which comprises the steps of: >

a) dissolving any polymorphic form of silodosin in a suitable solvent by heating;

b) cooling the resulting solution;

c) seeding with form gamma of silodosin;

d) cooling the resulting solution to ambient temperature; and

e) isolating pure polymorphic form gamma of silodosin.

According to one other embodiment, the present invention provides a process for preparation of polymorphic form gamma of silodosin, wherein residual solvents are present in specified limits as per ICH guidelines, which comprises the steps of: a) providing polymorphic form gamma of silodosin having toluene content greater than 890 ppm;

b) micronizing polymorphic form gamma of silodosin as described in above step;

c) optionally refluxing the micronized compound in a suitable sol vent;

d) drying the resulting compound; and

e) isolating polymorphic form gamma of silodosin having toluene content less than 890 ppm. ^

According to one other embodiment, the present invention provides pure polymorphic form gamma of silodosin, having residual solvents in specified limits as per ICH guidelines, specifically toluene content less than 890 ppm.

According to one other embodiment, the present invention provides a process for preparation of polymorphic form gamma of silodosin by incorporating step of seeding of gamma form of silodosin during crystallization of silodosin.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an exemplary XRPD pattern of l-.(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoro ethoxy)phenoxy] ethyl } amino)propyl]-2,3-dihydro- lH-indol-7-carbonitrileD(-) tartrate.

Figure 2 is an exemplary DSC of l-(3-hydroxypropyl)-5-[(2 ?)-2-({2-[2,2,2-triiluoroethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indol-7-carbonitrileD(-) tartrate.

Figure 3 is an exemplary XRPD pattern of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoro ethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indol-7-carbonitrile L(+) tartrate.

Figure 4 is an exemplary DSC of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoro ethoxy) phenoxy] ethyl } amino)propyl]-2,3-dihydro- lH-indol-7-carbonitrileL(+) tartrate.

Figure 5 is an exemplary XRPD pattern of polymorphic form gamma of silodosin.

Figure 6 is an exemplary DSC of polymorphic form gamma of silodosin.

DETAILED DESCRIPTION OF THE INVENTION

As used herein l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]-2,3-dihydro-lH-indol-7-carbonitrile tartrate of formula II includes its specific isomer like (R), (S) or racemates, dissolved forms, solvent free form or hydrate, anhydrate or a solvate, non-solvate form, both in crystalline and amorphous form thereof.

As used herein "form gamma (γ)" means a crystalline silodosin having X-ray diffraction pattern and DSC that substantially corresponds to as given in Figures 5 and 6. As used herein "crude silodosin" means the silodosin or silodosin base or any polymorphic form of silodosin prepared by prior art processes or can be procured from market. It can be used as such or can be purified.

As used herein "seed of gamma form of silodosin" means crystal of gamma form of silodosin which can be prepared by using process disclosed in literature or process as discloses herein. As used herein "pure polymorphic form gamma of silodosin" means the crystal of gamma form of silodosin which have residual solvents in specified limits as per ICH guidelines, specifically toluene content less than 890 ppm, preferably less than 500 ppm, more preferably less than 200 ppm, most preferably less than 100 ppm.

As used herein "micronization" means the process of reducing the average diameter of a solid materials particles. Micronization size reduction process involves acceleration of particles so that grinding occurs by particle-to-particle impact or impact against a solid surface.

As used herein "ambient temperature" means temperature of the surrounding. It means any suitable temperature found in the laboratory or the other working quarter, and is generally not below about 15°C. to and not above about 30°C.

The present invention provides a novel process for preparation of silodosin of formula I and pharmaceutically acceptable salts thereof.

According to one another aspect, present invention provides a novel process for preparation of pure polymorphic form gamma of silodosin by incorporating a step of seeding of gamma form of silodosin during crystallization of silodosin. Alternatively pure polymorphic form gamma of silodosin can be prepared by using micronization of polymorphic form gamma of silodosin having unacceptable limits of residual solvent. ,

The tartrate salt of cyano hydroxy compound and polymorphic form gamma of silodosin is characterized by X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC). The X-ray diffraction patterns were measured on PAN analytical, X'pert PRO powder diffractrometer equipped with goniometer of Θ/Θ configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2Θ range of 2.0^o-40.0°. One with ordinary skills in the art understands that experimental differences may arise due to differences in the instrument, sample preparation and other factors. The DSC analysis was performed using a Mettler Toledo 822^e instrument. The experiments were performed at heating rate of 5-10.0°C/min over a temperature range of 30°C to 250°C purging with nitrogen at a flow rate of 50-80ml/min. According to one aspect, the present invention provides a process for the preparation of silodosin and pharmaceutically acceptable salts thereof through novel salt of intermediate of formula II. Generally, the process involves reaction of compound of formula III with 2- [2- (2,2,2-trifluoroethoxy)phenoxy]ethyl mefhanesulfonate in the presence of a base and a suitable solvent to form 3-{7-cyano-5-[(2R)-2-({2-(2,2,2-trifluoroethoxy) phenoxy] ethyljamino) propyl)-2,3-dihydro-lH-indol-l-yl)-propyl benzoate intermediate of formula IV, hydrolyzing the intermediate of formula IV by using a suitable base in the presence of a suitable solvent to form l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]- 2,3-dihydro-lH-indol-7-carbonitrile intermediate of formula V, reacting the intermediate of formula V with tartaric acid in the presence of a suitable solvent to form a tartrate salt represented by formula II, that can be isolated from reaction mixture or can be insitu converted to silodosin and pharmaceutically acceptable salts thereof.

Generally, starting compound of formula III and 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate can be prepared by the methods known in art or can be procured from market. The compound of formula IV is prepared by reacting compound of formula III with 2- [2-(2,2,2-trifluoroethoxy)phenoxy] ethyl methanesulfonate in the presence of a base and suitable solvent. The base cart be selected from the class of compounds like inorganic base such as an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like; an alkali metal carbonate salt such as sodium carbonate, potassium carbonate, cesium carbonate and the like; and an organic base such as lower tertiary alkyl amine such as triethylamine, diisopropylethylamine and the like; of which an inorganic base is preferred. In a preferred embodiment an alkali metal carbonate is used.

The solvent used in reaction can be selected from the group comprising lower alcohols such as methanol, ethandl, propanol, isopropanol, tert-butanol and the like; an aprotic polar solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile, propionitrile and the like; ethers such as tetrahydrofuran, 2-mefhyl tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, 1,4 dioxane and the like; and a mixture of solvents, of which, the lower alcohol is preferred. In a more preferred embodiments tert-butanol is used. The reaction can be carried out at -20°C to a boiling point of solvent used, for a period of 30 minutes to 48 hours, preferably 20°C to 80°C for 10-30 hours, more preferably till the completion of the reaction. The completion of reaction can be monitored by any one of the chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-high pressure liquid chromatography (UPLC), and the like.

In a preferred embodiment, 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-lH-indol-l-yl] propyl benzoate(2R,3R)-monotartrate of compound of formula III converted insitu to its free base using suitable base and suitable solvent before its reaction with 2-[2-(2,2,2- trifluoroethoxy) phenoxyjethyl methanesulfonate. The hydrolysis reaction can be performed by using an alkali such as an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or the like; an alkali metal carbonate salt such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or the like; The solvent used for the hydrolysis, can be selected from esters, chlorinated solvents, ethers, hydrocarbons or the like. In one another embodiment, hydrolysis of the intermediate of formula IV is performed by using a suitable base in the presence of a suitable solvent to form l-(3-hydroxypropyl)-5-[(2R)-2-({2- [2,2,2-trifTuoroethoxy)phenoxy]ethyl } amino)propyl]-2,3-dihydro- lH-indol-7-carbonitrile intermediate of formula V. The hydrolysis reaction can be performed by using an alkali such as an alkali metal-hydroxide such as sodium hydroxide, potassium hydroxide or the like; an alkali metal carbonate salt siich as sodium carbonate, potassium carbonate or the like; or using an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or the like; of which an alkali is preferred. In a more preferred embodiments an alkali metal hydroxide is used. The solvent used for the hydrolysis, can be selected from water; a lower alcohol such as ethanol, ethanol, propanol, isopropyl alcohol and the like; and a mixture of solvents, of which a mixed solvent of water and lower alcohol preferred. In a more preferred embodiments a mixture of water and methanol is used. ^ The hydrolysis reaction can be carried out from 0°C to boiling point of a used solvent, for 30 minutes to 48 hours, preferably at 10-50°C for 1-10 hours, more preferably till the completion of the reaction. The completion of reaction can be monitored by any one of the chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-high pressure liquid chromatography (UPLC) and the like. In one another embodiment, intermediate of formula V is reacted with tartaric acid in the presence of a suitable solvent to form tartrate salt of cyano hydroxy intermediate. Tartaric acid used for salt preparation can be selected from D(+) tartaric acid, D(-) tartaric acid, L(+)tartaric acid, L(-)tartaric acid and DL tartaric acid or mixture thereof. The solvent used in reaction can be selected from the group comprising of lower alcohols such as methanol, ethanol, propanol, isopropyl alcohol and the like; aliphatic ketonic solvents such as acetone, methyl isobutyl ketone and the like; aliphatic nitrile solvents such as acetonitrile, propionitrile and the like; aliphatic ester solvents such as methyl acetate, ethylacetate, propyl acetate, butyl acetate and the like; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2- dimethoxyethane, 1,2-diethoxyethane, 1,4 dioxane and the like.

The reaction can be carried out at 0°C to reflux temperature of the solvent employed for 1 to 24 hours, preferably till the completion of the reaction. Optionally, seeding can be done with tartrate salt of formula II. The completion of reaction can be monitored by any one of the chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-high pressure liquid chromatography (UPLC), and the like. Preferably, after completion of the salt formation, tartrate salt of cyano hydroxy represented by formula II can be isolated from reaction mixture by lowering reaction temperature or by adding anti solvent to precipitate desired compound. The resulting salt can be isolated by suitable techniques such as filtration, centrifugation, chromatography and the like.

According to one embodiment, present invention provides tartrate salt of cyano hydroxy compound having purity of greater than 99% by HPLC and Ν,Ν-dialkyl impurity not more than 0.15% by HPLC. Specifically, the present invention relates to tartrate salt of cyano hydroxy compound in a solid or dissolved state. Solid tartrate salt of cyano hydroxy compound can be in an amorphous or crystalline state.

According to one other embodiment, the present invention provides D(-) tartrate salt of cyano hydroxy compound which is characterized by X-Ray powder diffraction (XRPD) as depicted in figure 1 and differential scanning calorimetry (DSC) thermogram, which shows one endothermic peak at 168.64°C as shown in figure 2.

Melting point: 164.5-165.7°C

According to one another embodiment, the present invention provides L(+) tartrate salt cyano hydroxy compound which is characterized by X-Ray powder diffraction (XRPD) as depicted in figure 3 and differential scaning calorimetry (DSC) thermogram, which shows major endothermic peak at 137.42°C as depicted in figure 4.

Melting point: 128.6-139.8°C It is advantageous to prepare tartaric acid salt because being tartaric acid as a chiral acid, it removes enantiomeric impurities also in comparison to simple acid addition salts like hydrochloric, acetate and oxalate known in literature. Further other acid addition salts of l-(3- hydroxypropyl)-5-[(2R)-2-( { 2-[2,2,2-trifluoroethoxy)phenoxy]ethyl } amino)propyl]-2,3- dihydro-lH-indol-7-carbonitrile using different acids like fumaric acid, mandelic acid, methanesulphonic acid, 2,3-dibenzyl D-tartaric acid, chloromandelic acid, camphorsulphonic acid, maleic acid, formic acid, aspartic acid, citric acid, cannot be isolated from reaction mass, because different salts of an compound may possess different physical properties. It is observed that during tartaric acid salt preparation, most of the impurities are removed in one attempt. Other advantage to preferably prepare tartaric acid salt of cyano hydroxy compound of formula V in place of cyano benzyloxy compound of formula IV is that it removes even those impurities which form during base assisted hydrolysis of cyano benzyloxy compound of formula IV.

In one another embodiment, tartaric acid salt of cyano hydroxy compound represented by formula II can be converted into silodosin of formula I by hydrolysis reaction of cyano to amide in a suitable solvent. The hydrolysis reaction can be performed using an alkali such as an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or the like; alkali metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate or the like, or using an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or the like, of which an alkali is preferred. In a more preferred embodiments an alkali metal hydroxide is used. In addition, it is preferable that the hydrolysis reaction is performed in the presence of an oxidizing agent such as hydrogen peroxide or the like. The solvent that can be used in the hydrolysis can be selected from water; a lower alcohol such as methanol, ethanol, propanol, isopropyl alcohol and the like; a water soluble organic solvent such as acetone, tetrahydrofuran, 1,4-dioxane, dimethylsulfoxide, dimethylformamide, dimethylacetamide and the like; and a mixture of solvents selected from the same and the like, of which dimethylsulfoxide is preferred. The hydrolysis reaction can be carried out at 0°C to reflux temperature of the solvent employed for 1 to 24 hours, preferably 10°C to 60°C for 1-10 hours, more preferably till the completion of the reaction.

In one other embodiment, intermediate of formula II produces silodosin of formula I, firstly by conversion into its freebase of formula V, which can be isolated from reaction mixture or can be insitu converted to silodosin in the presence of base and suitable solvent. The base is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or the like; alkali metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate or the like; of which, alkali metal hydroxide is preferred.

After completion of reaction at any stage namely at the intermediate stage of compound of formula III, IV, V and II of reaction, reaction mass can be quenched with water, if required, and the resulting compounds can be isolated from the reaction mixture using suitable techniques known in the art such as by generation of biphasic system in reaction mixture using suitable solvent. After layer separation, the organic layer can be washed with acid, base or water, dried and optionally solvent can be distilled off under reduced pressure.

In one other embodiment, silodosin obtained according to the present invention can be optionally purified by using suitable method to enhance purity of product and/or to remove presence of impurities_/ from the product. Any suitable purification procedure such as, for example, crystallization, derivatizatio^'n, slurry wash, salt preparation, various chromatographic techniques, solvent-antisolvent system or combination of these procedure, may be employed to get the purified material. However, other equivalent procedures such as acid-base treatment can also be used to purify the final product. It is advantageous to filter clear solutions through micro filter paper or hyflo to remove any suspended particle. The solvents used for the purification of final compound of the present invention may be selected depending upon the nature of compound to be purified. However the solvent can be chosen amongst water; alcoholic solvents such as methanol, ethanol, propanol, isopropanol, n-butanol, iso-butanol, tert-butanol and the like; ketonic solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; aliphatic hydrocarbons such as hexane, heptane, cyclohexane, cycloheptane and the like or aromatic hydrocarbons such as toluene, 1,2-xylene, 1,4-xylene, benzene and the like; aliphatic ester solvents such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; aliphatic ethers solvents such as, diethyl ether isopropyl ether, methyl t-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran and the like; aliphatic nitrile solvents such as acetonitrile, propionitrile and the like; halogenated solvents such as methylene chloride, chloroform, carbon tetrachloride and the like; aprotic solvents such as N,N-dimethyl formamide, dimethylsulfoxlde, dimethylacetamide, N-methyl pyrrolidinone, sulpholane and the like or mixtures thereof; of which alcoholic solvents and aromatic hydrocarbon are preferred. In a . more preferred embodiments, methanol, a mixture of isopropanol and toluene; isopropanol and cyclohexane are used. The compound of formula I can be converted to pharmaceutically _^ acceptable salts thereof. Silodosin of formula I, obtained by following the process of present invention is highly pure, having purity of greater than 99.5% and preferably greater than 99.8% and Ν,Ν-dialkyl impurity and other impurities not more than 0.10% by HPLC.

In one other embodiment, present invention provides a novel process for preparation of pure polymorphic form gamma of silodosin by incorporating a step of seeding of gamma form of silodosin during crystallization of silodosin. Alternatively pure polymorphic form gamma of silodosin can be prepared by using microriization of polymorphic form gamma of silodosin having acceptable limits of residual solvent.

Silodosin, crude silodosin, or any other form of silodosin, to be used as the starting material can be prepared by any one of the method known in prior art as described in US patent US5,387,603 and European patent EP1541554 and other prior arts available or as prepared in the present invention and is not a constrain for the present invention.

According to one other embodiment, the present invention provides a process for the preparation of gamma form of silodosin by dissolving any polymorphic form of silodosin by . heating in a suitable solvent at suitable temperature, cooling the resulting solution, seeding the reaction mixture with the polymorphic form gamma of silodosin, again lowering the temperature, adding a suitable antisolvent, stirring the reaction mass for sufficient time for complete crystallization and isolating pure polymorphic form gamma of silodosin.

The suitable solvent that can be used to dissolve the silodosin is selected from alcoholic solvent such as C₂-C₆ alcohols, and a mixture of alcoholic solvent with hydrocarbon solvents such as toluene, 1,2 and 1,4 xylene and the like. The solution of silodosin can be prepared by heating at a temperature that can vary from 30-100°C depending on the solubility of silodosin in the particular solvent and volume of solvent used. Particularly, the temperature required to dissolve the silodosin can be in range of 30-70°C, preferably temperature can be 40-60°C or the temperature at which silodosin dissolve completely to give clear solution is preferred. The resulting solution is then cooled to temperature ranging between 30-50°C, preferably between •35-45°C. The cooling conditions_, may be slow, rapid or gradual cooling over a specific time at a , specific temperature. In the warm reaction mass, a seed of crystalline gamma form may be added and subsequently reaction mass can be further cooled to ambient temperature to accelerate the crystallization process. Seeding a solution with a crystal of the product is a well- established technique to induce crystallization. It has also been used to encourage the formation of particular polymorph consistently. Seeding is preferably used to obtain crystals of high polymorphic purity, and especially with very high perfection and desired crystal orientation in consistent and reproducible manner. Using the seeding process during crystallization to prepare gamma form of silodosin forms a inventive part of the present invention, which overcome the drawbacks for preparation of gamma form of silodosin, mentioned in prior art.

The antisolvent that can used during crystallization includes but not limited to alkane such as n-hexane, cyclohexane cycloheptane; hydrocarbons such as toluene, 1,2 and 1,4 xylene; ethers such as methyl tertiary butyl ether or mixtures thereof. After addition of antisolvent, the reaction mass can be further stirred at ambient temperature for sufficient time for complete crystallization. Particularly, the reaction mass can be stirred at a temperature of 5°C to 30°C, for few minutes to few hours and preferably from 10 minutes to 4 hour. After complete crystallization, the solid compound can be recovered by known techniques such as filtration or centrifugation, preferably, filtration is carried out at a temperature of 5°C to 30°C and more preferably at a temperature of 15°C to 25°C. Thereafter, the resulting crystalline gamma form of silodosin can optionally be washed with a solvent such as alkane. Washing can be performed by routine wash or can be by slurring of resulting solid in a suitable solvent. Most preferably, the washing can be done using the same antisolvent as is used during crystal formation. Thereafter product can be dried, particularly, drying can be carried out under vacuum at a temperature of about 35 to about 60°C for the time ranging from few minutes to few hours and preferably from 1 hours to 20 hours. Alternatively, the resulting crystalline gamma form of silodosin can optionally be micronized to further reduced the desired level of residual solvent depending upon the solvent used during crystallization. Although process of present invention as described above, provides crystalline gamma form of silodosin which passes in the criteria of residual solvent limits, still a remarkable lowering of residual solvent can be achieved, if product is micronized. The residual solvents of gamma form of silodosin so obtained, are within limits i.e. toluene content less than 890 ppm by GC, preferably less than 500 ppm, more preferably less than 200 ppm, most preferably less than 100 ppm.

In one other aspect, the present invention provides a process for the preparation of gamma form of silodosin by dissolving any polymorphic form of silodosin in suitable solvent at suitable temperature, filtering the obtained solution through micron filter paper, removing the solvent, dissolving the residue in suitable solvent at suitable temperature, cooling the resulting solution, seeding the reaction mixture with the polymorphic form gamma of silodosin, again lowering the temperature, adding a suitable antisolvent, stirring the reaction mass for sufficient time for complete crystallization and isolating pure polymorphic form gamma of silodosin.

The suitable solvent which can be used to dissolve the silodosin is selected from alcoholic solvent especially lower alcohols such as methanol. The suitable temperature for dissolution of silodosin selected from range 15-30°C preferably room temperature. The obtained solution is filtered using a micron filter paper of suitable size preferably micron filter paper of size ranging from 10-0.22 micron can be used. The solvent from the obtained clear solution can be evaporated using suitable techniques such as distillation or like and the obtained residue is further dissolved in a suitable solvent. The suitable solvent that can be used .to dissolve the silodosin is selected from alcoholic solvent such as C₂-C₆ alcohols, and a mixture of alcoholic solvent with hydrocarbon solvents such as toluene, 1,2 and 1,4 xylene and the like. The solution of silodosin can be prepared by heating at a temperature that can vary from 30-100°C depending on the solubility of silodosin in the particular solvent and volume of solvent used. Particularly, the temperature required to dissolve the silodosin can be in range of 30-70°C, preferably temperature can be 40-60°C or the temperature at which silodosin dissolve completely to give clear solution is preferred. The resulting solution is then cooled to temperature ranging between 30-50°C, preferably between 35-45°C. The cooling conditions may be slow, rapid or gradual cooling over a specific time at a specific temperature. In the warm reaction mass, a seed of crystalline gamma form may be added and subsequently reaction mass can be further cooled to ambient temperature to accelerate the crystallization process.

The antisolvent that can used during crystallization includes but not limited to alkane such as n- hexane, cyclohexane, cycloheptane; hydrocarbons such as toluene, 1,2 and 1,4 xylene; ethers such as methyl tertiary butyl ether or mixtures thereof. After addition of antisolvent, the reaction mass can be further stirred at ambient temperature for sufficient time for complete crystallization. Particularly, the reaction mass can be stirred at a temperature of 5°C to 30°C, for few minutes to few hours and preferably from 10 minutes to 4 hour. After complete crystallization, the solid compound can be recovered by known techniques such as filtration or centrifugation, preferably, filtration is carried out at a temperature of 5°C to 30°C and more preferably at a temperature of 15°C to 25°C. Thereafter, the resulting crystalline gamma form of silodosin can optionally be washed with a solvent such as alkane. Washing can be performed by routine wash or can be by slurring of resulting solid in a suitable solvent. Most preferably, the washing can be done using the same antisolvent as is used during crystal formation. Thereafter product can be dried, particularly, drying can be canied out under vacuum at a temperature of about 35 to about 60°C for the time ranging from few minutes to few hours and preferably from 1 hours to 20 hours. Alternatively, the resulting crystalline gamma form of silodosin can optionally be micronized to further reduced the desired level of residual solvent depending upon the solvent used during crystallization. Although process of present invention as described above, provides crystalline gamma form of silodosin which passes in the criteria of residual solvent limits, still a remarkable lowering of residual solvent can be achieved, if product is micronized. The residual solvents of gamma form of silodosin so obtained, are within limits i.e. toluene content less than 890 ppm by GC, preferably less than 500 ppm, more preferably less than 200 ppm, most preferably less than 100 ppm.

In an another aspect, the present invention provides a process for reducing level of residual solvent from gamma form of silodosin wherein residual solvent is present in greater than specified limit. Generally gamma form of silodosin having toluene content greater than 890 ppm is prepared as per process reported in literature. Particularly gamma form of silodosin is prepared by recrystallization of silodosin in toluene and resulting gamma form have toluene content greater than 1800 ppm. Alternatively, gamma form is prepared by using isopropanol and toluene mixture and resulting gamma form have toluene content greater than 1600 ppm. Reduction in residual solvent content is achieved by using micronization process. In a specific aspect, gamma form " of silodosin having toluene content greater than 890 ppm can be micronized followed by drying of resulting compound. The drying can be done under vacuum at a temperature of about 35°C to about 60°C for few minutes to few hours. Optionally micronization process can be repeated to achieve residual solvent in specified limit and to maintain the quality of product. In an alternative embodiment, micronized gamma form of silodosin can be purified using a suitable solvent or a mixture of solvent.

The suitable solvent that can be used to purify the form gamma of silodosin can be selected from alcoholic solvents such as C₂-C alcohol, hydrocarbon solvents, alkane solvents, ethers solvents or mixtures thereof. The purification of gamma form using a suitable solvent can be performed before micronization or after micronization to achieve the desired level of product quality and hence these can be performed at various stage of process and can be repeated any number of times, if desired. The resulting compound can be dried under vacuum at a temperature of about 35 to about 60°C. Further micronization may be performed for semidry compound or wet material, or after the completion of drying of the product. Micronization process may be repeated to get desired specific results. Employing the micronization process along with seeding or independently, either of the process, to achieve the desired level of residual solvent, makes the process of present invention novel and inventive.

In a preferred aspect of the present invention, micronization process has been adopted which is a well known technique to reduce the particle size of substance. In the case of silodosin, reduction of particle size ease the removal of entrapped residual solvent, and this may be achieved due to collision, of material under air pressure with walls of micronizer. In a precise manner, small particles upon drying firstly loose the interparticle solvent and if these small particles further stirred in some suitable solvent then intraparticle solvent removes smoothly. As a consequence, problem of residual solvent has been solved which constitutes a novel part of the present invention. .

All the processes as described above and inherent variation of these, yield gamma form , of silodosin having residual solvent content much below the recommended ICH limit of residual solvents preferably below 890 ppm, more preferably below 500 ppm most preferably below 100 ppm and thus pass the criteria of ICH guidelines. Further decrease in the levels of residual solvents also improves the quality of product as entrapped solvent in silodosin makes it sticky and difficult to handle during preparation of tablets and capsules. Particularly, pure gamma form of silodosin, as obtained herein, is non-hygroscopic, solvent free, free flowing, having mean particle size less than 50μπι, and thus especially suitable for the preparation of pharmaceutical drug.

In another aspect of the invention, silodosin of formula I and polymorphic form gamma obtained by following the processes of present invention can suitably be formulated to provide a pharmaceutical composition and which is further provided by the present invention a pharmaceutical composition comprising silodosin or pharmaceutically acceptable salt thereof. The main advantage of the present invention is to provide an industrially advantageous and efficient process for preparation of silodosin and pharmaceutically acceptable salts thereof to remove mainly N,N dialkyl impurity and other impurities of greater extend that passes the regulatory limit and with good yield. Further, the present invention provides a novel salt of intermediate which is converted directly to silodosin and pharmaceutically acceptable salts thereof by using industrially friendly reagents and conditions. Furthermore the present invention provides a novel process for the preparation of polymorphic form gamma of silodosin, wherein residual solvents are within limits as per ICH guidelines specifically toluene content less than 890 ppm. The processes of the present invention is efficient, reproducible as well as industrially advantageous.

EXAMPLES:

Example IrPreparation of 3-{7-cyano-5-[(2R)-2-({2-(2,2,2-trifluoroethoxy)-phenoxy]ethyI} amino)propyl)-2,3-dihydro-lH-indol-l-yl)-propyl benzoate

To a mixture of ethyl acetate (500 ml) and an aqueous solution (500ml) of potassium carbonate (135g),3-[5-((2 ?)-2-aminopropyl)-7-cyano-2,3-dihydro-lH-indol-l-yl]propyl benzoate(2R,3R)- monotartrate (50g) was added in small portions. The reaction mixture was stirred at 20-30°C for 2 hours. After complete hydrolysis layers were separated. The aqueous layer was extracted again with ethyl acetate (500ml). The combined ethyl acetate layer was washed with an aqueous potassium carbonate solution (300ml) and dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting oil was dissolved in anhydrous tert-butanol (250ml) and 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate (38g) and sodium carbonate (10.6g) were added. The reaction mixture was refluxed for 24-26 hours. After completion of reaction, the reaction mixture was allowed to cool and an aqueous sodium bicarbonate solution (500ml) was added to it. The reaction mixture was extracted with ethyl acetate (2x500ml), the combined ethyl acetate layer was successively washed with an aqueous sodium bicarbonate solution (500ml), water (500tnl), sodium chloride solution (500ml) and dried over anhydrous sodium sulfate. The resulting ethyl acetate layer was concentrated under reduced pressure to give (56.58g) title compound.

Example 2:Preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoro ethoxy) phenoxy ] eth l }amino)propy 1] -2,3-dihydro- lH-indol-7-carbonitrile

3-{7-Cyano-5-[(2R)-2-({2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl)-2,3-dihydro- lH-indol-l-yl)-propyl benzoate (60g) was dissolved in methanol (240ml), then an aqueous potassium hydroxide solution (17.55g in 60ml water) was added dropwise and the mixture was stirred for 2 hours at 20-25°C. To the reaction mixture, water (600ml) was added and successively extracted with ethyl acetate (1x600 ml) and (1x300ml). The combined ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution (600 ml) and brine (600ml) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give title compound having purity 80.12 %; Ν,Ν-dialkyl impurity 13.67% and other impurities around 6% by HPLC. Example 3a:Preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoro ethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-l^ -mdoI-7-carbonitrile D(-) tartrate

Isopropyl alcohol (50ml) and D(-)tartaric acid (1.57g) were added to l-(3-hydroxypropyl)-5- [(2R)-2-( { 2-[2,2,2-trifluoroethoxy)phenoxy]ethyl } amino)propyl]-2,3-dihydro- lH-indol-7- carbonitrile (5g) and the mixture was heated to 75-85°C and stirred for 1 hour at same temperature. The suspension was slowly cooled to 20-25°C, stirred for 4 hours at 20-25°C. The resulting salt was filtered, washed with isopropyl alcohol and dried to give title compound having purity 99.4% and N, N-dialkyl impurity 0.109% by HPLC.

Example 3b: Preparation of l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoro ethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indol-7-carbonitrile L(+) tartrate

Isopropyl alcohol (10ml) and L(+)tartaric acid (0.3g) were added to a suspension of l-(3- hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3- dihydro-lH-indol-7-carbonitrile (lg) and the mixture was heated to 70-75°C and stirred for 1 hour at same temperature. The suspension was slowly cooled to 20-25°C, stirred for 4 hours at 20-25°C. The resulting salt was filtered and washed with isopropyl alcohol and dried to give title compound having purity 99.72% and N, N-dialkyl impurity not detected by HPLC.

Example 4:Preparation of l-(3-hydroxypropyI)-5-[(2R)-2-({2-[2,2,2-trifIuoro ethoxy) phenoxy] ethyl}amino)propyl]-2,3-dihydro-lH-indol-7-carboxamide

Method A: l-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy] ethyljamino) propyl]-2,3-dihydro-lH-indol-7-carbonitrile tartrate (lOg) dissolved in dimethylsulfoxide (125ml) and to this solution, was added 5 mol/L aqueous sodium hydroxide solution (15 ml). To the reaction mixture, 30% hydrogen peroxide (4.25ml) was added dropwise and keeping the temperature below 25°C. The reaction mixture was stirred at 20-25°C, for 6 hours. To the reaction mixture, sodium sulfite (8.0g) dissolved in water (250ml) was added slowly. The reaction mixture was extracted with ethyl acetate (2x100ml) and the combined ethyl acetate layer, was extracted with 2N hydrochloric acid (50ml). The aqueous hydrochloric acid layer was neutralized with sodium bicarbonate (950ml), and_x the aqueous layer was extracted with ethyl acetate (2x100ml). The combined ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution (100ml) and brine (100ml), dried over anhydrous sodium sulfate and ethyl acetate layer was concentrated under reduced pressure. The resulting product was dissolved in a mixture of toluene (100ml) and isopropyl alcohol (10 ml) at 50-55 °C and the solution was cooled to 20-25°C, stined for 4 hours, filtered and dried to give title compound having purity 99.9 % and N, N-dialkyl impurity not detected by HPLC.

Method B: l-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy] ethyl}amino) propyl]-2,3-dihydro-lH-indol-7-carbonitrile tartrate (13.5g) dissolved in ethyl acetate (150ml), adjust pH 8 by aqueous potassium carbonate solution (75 ml) and stirred for 30 minutes. Ethyl acetate layer was separated and the aqueous layer was extracted with an ethyl acetate solution (75ml) and combined ethyl acetate layer was washed with an^r aqueous potassium carbonate solution and dried over sodium sulfate. The filtrate was concentrated under reduced pressure. The obtained oil was dissolved in dimethylsulfoxide (120ml) and to this solution, was added 5 mol/L aqueous sodium hydroxide solution (7.5ml). To the reaction mixture, 30% hydrogen peroxide (4.5ml) was added dropwise keeping the temperature below 25°C. The reaction mixture was stirred at 20-25°C, for 6 hours. To the reaction mixture, an aqueous sodium sulfite (3.5g) dissolved in water (250ml) was added slowly. The reaction mixture was extracted with ethyl acetate (2x 100ml) and the combined ethyl acetate layer was extracted with 2N hydrochloric acid (50ml). The aqueous hydrochloric acid layer was neutralized with sodium bicarbonate (950ml), and the aqueous layer was extracted with ethyl acetate (2x100ml). The combined ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution (100ml) and brine (100ml), dried over anhydrous sodium sulfate and ethyl acetate solution was concentrated under reduced pressure. The resulting product was dissolved in a mixture of toluene (100ml) and isopropyl alcohol (10ml) at 50-55°C and the solution was cooled to 20- 25°C, stirred for 4 hours, filtered and dried to give title compound having purity 99.8% and N,>N-dialkyl impurity not detected by HPLC.

Method C: l-(3-HydroxypropyI)-5-[(2R)-2-({2-[2,2,2-trifIuoroethoxy)phenoxy] ethyl} amino) propyl]-2,3-dihydro-lH-indol-7-carbonitrile tartrate (lOg) dissolved in dimethylsulfoxide (120 ml) and to this solution, was added 5 mol/L aqueous sodium hydroxide solution (15ml). To the reaction mixture, 30% hydrogen peroxide (5ml) was added and keeping the temperature below 25°C. The reaction mixture was stirred at 20-25°C, for 5 hours. To the reaction mixture, sodium sulfite (5g) dissolved in water (100ml) was added slowly. The reaction mixture was extracted with ethyl acetate (1x200ml) and ethyl acetate layer was concentrated under reduced pressure. The resulting product was dissolved in methanol and clear solution was filtered through micron filter paper of size 0.22 micron two times and filtrate was concentrated.The resulting compound was dissolved in toliiene (70ml) and isopropyl alcohol (7ml) at 50-55°C and the solution was cooled to 20-25°C, cyclohexane was added and stirred for further 4 hours, filtered and dried to give title compound having purity 99.86% and N,N-dialkyl impurity not detected by HPLC. Example 5: Preparation of pure Polymorphic Form Gamma (γ) of Silodosin

Silodosin (15g) having toluene content 1872 ppm, was micronized under air pressure. The micronized product was dried under vacuum at 55°C-60°C for 23.0 hours to afford pure polymorphic form gamma of silodosin having toluene content 460 ppm.

Example 6: Preparation of pure Polymorphic Form Gamma (γ) of Silodosin

Silodosin [having toluene content 1327 ppm] was micronized under air pressure. The micronized product was dried under vacuum at 55°C-60°C for 16 hours to afford pure polymorphic form gamma of silodosin having toluene content 350 ppm.

Example 7: Preparation of pure Polymorphic Form Gamma (γ) of Silodosin

Silodosin crude (3.0g) was dissolved in isopropanol (12ml) at 50°C and reaction mass was cooled to 35°C and seed of silodosin gamma form (O.lg) was added. Thereafter reaction mass was again cooled to 15-20°C and cyclohexane (30ml) was added to the reaction mass and stirred for further 0.5 hour. The resulting solid, thus obtained, was filtered, washed with cyclohexane and dried to afford pure polymorphic form gamma of silodosin having toluene content 34 ppm.

Example 8: Preparation of pure Polymorphic Form Gamma (γ) of Silodosin

Silodosin crude(3.0g) was dissolved in a mixture of isopropanol (12ml) and toluene (0,45ml) at 50°C. Thereafter reaction mass was cooled to 40°C and seed of silodosin gamma form (O.lg) was added and further cooled to 30°C. To the resulting reaction mass, cyclohexane (30 ml) was added, cooled further and stirred for 2 hours at 10-15°C. The resulting solid, thus obtained, was filtered, washed with cyclohexane and dried to afford pure polymorphic form gamma of silodosin having toluene content 41 ppm.

Example 9: Preparation of pure polymorphic form gamma (γ) of silodosin

Silodosin crude (3.0g) was dissolved in isopropanol (12ml) at 50°C and reaction mass was cooled to 35°C and seed of silodosin gamma form (O.lg) was added. Thereafter reaction mass was again cooled to 15-20°C, cyclohexane (30 ml) was added and stirred for further 0.5 hour at 15-20°C. The resulting solid, thus obtained was filtered, washed with cyclohexane and dried to afford silodosin polymorphic form gamma. Toluene content was found 62 ppm.

Example 10: Preparation of pure Polymorphic Form Gamma (γ) of Silodosin Silodosin cmde (50.0g) was dissolved in methanol and stirred for 10 minutes at room temperature. The obtained clear solution is filtered through micron filter paper of size 0.22 micron and solvent was distilled out under vacuum at 40-45°C.

The residue was dissolved in isopropanol (200 . ml) at 50°C and stirred forlO minutes. Thereafter reaction mass was cooled to 40-43°C and seed of silodosin gamma form . (l.Og) was added and further cooled to 25-30°C. To the resulting reaction mass, cyclohexane (500 ml) was added, cooled further and stirred for 1.0 hours at 15-20°C. The resulting solid, thus obtained,, was filtered, washed with cyclohexane and dried to afford pure polymorphic form gamma of silodosin having toluene content 12 ppm.

Comparative Example 1: Preparation of Polymorphic Form Gamma (γ) of Silodosin using toluene

Silodosin (35.0g) was taken in toluene (350ml) and heated at 65°C to get a clear solution. Thereafter reaction mass was cooled to 20-25°C, stirred for 6 hours, filtered and washed with toluene, dried under vacuum at 55 °C for 15 hours. Toluene content was found 1872 ppm.

Comparative Example 2: Preparation of Polymorphic Form Gamma (γ) of Silodosin using toluene and isopropanol

Silodosin (48g) was taken in isopropanol (43.2ml) and toluene (432ml) and mixture was heated to 50-55°C to obtain clear solution. Thereafter reaction mass was cooled to 20-25°C and stirred for 6 hours at 20-25°C. The resulting solid was filtered and washed with toluene (43.2 ml) and dried at 50-55°C for 16 hours to obtain title compound having purity of 99.83 % by HPLC, and toluene content 1672 ppm by GC. , From the above resulting product, (28.9g), was purified in a mixture of toluene (115.6ml), and isopropanol (11.5ml) and dried at 55°C for 16 hours to obtain title compound having purity of 99.88%.and toluene content 1327 ppm.

Claims

We Claim

in of formula I and pharmaceutically

Formula I

a) reacting3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-lH-indol-l-yl]propyl

benzoate(2R,3R)-monotartrate compound of formula III,

Formula III

with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanes ulfonate in the presence of a base and a suitable solvent to form 3- {7-cyano-5-[(2R)-2-({2-(2,2,2-trifluoroethoxy)- phenoxylethyl } amino)propyl)-2,3-dihydro- IH-indol- l-yl)-propyl benzoate intermediate

Formula IV

b) hydrolyzing cyano benzyloxy intermediate of formula IV using a suitable base in the presence of a suitable solvent to form l-(3-hydroxypropyl)-5-[(2R)-2-({ 2-[2,2,2- trifluoroethoxy)phenoxy]ethylamino)propyl]-2,3-dihydro-lH-indol-7-carbonitrile intermediate of formula V;

Formula V

a V with tartaric acid in the presence of a

II; and

Formula II rmediate of formula II in the presence of

a suitable base and a suitable oxidizing agent in an organic solvent to prepare silodosin of formula I.

2. The process as claimed in claim 1, wherein in step a) base is selected from inorganic bases such as alkali metal hydroxides, carbonates and organic bases such as lower tertiary alkyl amine; solvent is selected from alcohols such as Cj-C₄ alcohols; aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile, propionitrile; and ethers such tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2- dimethoxyethane, 1,2-diethoxyethane, 1,4 dioxane and mixtures thereof.

3. The process as claimed in claim 1 , wherein in step b) a suitable base is selected from alkali metal hydroxides or alkali metal carbonates; solvent is selected from water,Ci-C₃ alcohol, and mixtures thereof.

4. The process as claimed in claim 1, wherein in step c) solvent is selected from Q-C3 alcohols; aliphatic ketones; aliphatic nitrile; aliphatic ester; ethers and mixtures thereof.

5. The process as claimed in claim 1, wherein in step d) a suitable base is selected from alkali metal hydroxides or alkali metal carbonates; oxidizing agent is hydrogen peroxide; solvent is selected from water; Q-C3 alcohol; water soluble organic solvent such as acetone, tetrahydrofuran, 1,4 dioxane, dimethylsulfoxide, dimethylformamide, dimethylacetamide and mixtures thereof.

6. A compound, namely,l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethOxy)

phenoxy]ethyl } amino) propyl]-2,3-dihydro-lH-indol-7-carbonitrile tartrate of formula

II. Formula II

7. The compound of formula II, as claimed in claim 6 is crystalline.

8.

Formula I

of formula II

Formula II

in a suitable organic solvent to

prepare silodosin of ormula I.

9. The process as claimed in claim 8, wherein hydrolysis is carried out using alkali metal hydroxides or alkali metal carbonates; oxidizing agent used is hydrogen peroxide; solvent is selected from water; C₁-C3 alcohol; water soluble organic solvent such as acetone, tetrahydrofuran, 1,4 dioxane, dimethylsulfoxide, dimethylformamide, dimethylacetamide and mixtures thereof.

10. A process for the preparation of polymorphic form gamma of silodosin comprises the steps of;

a) dissolving any polymorphic form of silodosin in a suitable solvent by heating at 30- . 100°C;

b) cooling the resulting solution at temperature 30-50°C;

c) seeding with form gamma of silodosin;

d) cooling the resulting solution to ambient temperature;

e) adding a suitable antisolvent;

IT, f) stirring the reaction mixture;

g) isolating pure polymorphic form gamma of silodosin; and

h) optionally micronizing polymorphic form gamma of silodosin.

11. The process according to claim 10, wherein in step a) solvent is selected from C₂-C₆ alcohols and mixtures of C₂-C₆ alcohols and hydrocarbons such as toluene, 1,2-xylene and 1,4-xylene.

12. The process according to claim 10, wherein in step e) antisolvent is selected from alkanes siich as n-hexane, cyclohexane, cycloheptane; hydrocarbons such as toluene, 1,2-xylene, 1,4-xylene; ethers such as methyl tertiary butyl ether or mixtures thereof.

13. A process for the preparation of polymorphic form gamma of silodosin comprises the steps of ;

a) dissolving any polymorphic form of silodosin in a suitable solvent by heating,

b) cooling the resulting solution at temperature 30-50°C;

c) seeding with form gamma of silodosin;

d) cooling the resulting solution to ambient temperature; and

e) isolating pure polymorphic form gamma of silodosin. .

14. The process according to claim 13, wherein in step a) a suitable solvent is selected from C₂-C₆ alcohols and mixtures of C₂-C₆ alcohols and hydrocarbons.

15. A process for the preparation of polymorphic form gamma of silodosin wherein residual solvents are present in specified limits as per ICH guidelines comprises the steps of; a) providing polymorphic form gamma of silodosin having toluene content greater than 890 ppm;

b) micronizing polymorphic form gamma of silodosin;

c) optionally refluxing the micronized compound in a suitable solvent;

d) drying the resulting compound;

e) isolating polymorphic form gamma of silodosin having toluene content less than 890 ppm.

16. The process according to claim 15, wherein in step c) suitable solvent is selected from C₂-C₆ alcohols; hydrocarbons; alkanes; ethers such as methyl tertiary butyl ether or mixtures thereof.

17. A pure polymorphic form gamma of silodosin wherein residual solvent i.e., toluene present in less than 890 ppm as specified in ICH guidelines.