DESC:FORM 2
THE PATENTS ACT, 1970
[39 of 1970]
&
PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

PROCESS FOR THE PREPARATION OF SILODOSIN
THROUGH NOVEL SALT OF CYANO HYDROXY INTERMEDIATE

IND-SWIFT LABORATORIES LIMITED,
S.C.O. NO. 850, SHIVALIK ENCLAVE,
NAC, MANIMAJRA,
CHANDIGARH-160 101
(AN INDIAN ORGANIZATION)

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention provides an improved and efficient process for the preparation of silodosin of formula I and pharmaceutically acceptable salts thereof

Formula I

through novel tartrate salt of cyano hydroxy intermediate of formula II.

Formula II

BACKGROUND OF THE INVENTION
Silodosin is represented by formula I and is commercially available in the US under the trade name of Rapaflo.

Formula I

It acts as an selective a1-adrenoceptor antagonist and is useful in the symptomatic treatment of benign prostatic hyperplasia (BPH). Chemically it is known as 1-(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.

Scheme 1
As represented in scheme 1, silodosin is prepared by the reaction of 1-acetyl-5-(2-aminopropyl)indoline-7-carbonitrile with 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl methanesulfonate in the presence of sodium bicarbonate in ethanol to give 1-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 deprotection. 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.

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-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-1H-indol-1-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 cannot be achieved by simple purification techniques like recrystallization or precipitation using solvent-antisolvent system. Column chromatographic purification is acceptable for small scale purpose but for commercial preparation, column chromatographic purification is not suitable.
US patent 7,834,193 discloses a process for preparation of silodosin with similar condensation of 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-1H-indol-1-yl]propyl benzoate or its salts like monotartrate with 2-[2-(2,2,2-trifluoro ethoxy)phenoxy]ethyl methanesulfonate, but 3-{7-cyano-5-[(2R)-2-({2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl)-2,3-dihydro-1H-indol-1-yl)-propyl benzoate is purified by preparing monooxalate salt as shown below in scheme 3.

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-1H-indol-1-yl)-propylbenzoate to remove N,N-dialkyl impurity, but impurity has not been removed completely, it has been removed to certain extend.

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-1H-indol-1-yl]propyl benzoate have been invented and 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-1H-indol-1-yl]propyl benzoate is condensed with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate and the resulting benzoate compound is hydrolyzed to give 1-(3-hydroxy propyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-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 application WO2012/147019 preparation of silodosin is described via 3-{7-cyano-5-[(2R)-2-({2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl)-2,3-dihydro-1H-indol-1-yl)-propyl benzoate tartrate salt, as per the process presented below in Scheme- 4.

Scheme 4
PCT publication WO2012/147107 describes preparation of silodosin by preparing hydrochloride and acetic acid salts of 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-7-carbonitrile to remove N,N dialkyl impurity.
It has been observed that in exemplified process, wherein hydroxy compound namely 1-(3-hydroxy propyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy] ethyl}amino)propyl]-2,3-dihydro-1H-indol-7-carbonitrile is purified by preparing its acetate salt to remove the impurities, N, N-dialkyl impurity remains in an amount of 0.6% even after purification, which is difficult to remove in next stage or require extra purifications.
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. The difference in physical properties of different salt or polymorph results from orientation and intermolecular interactions of adjacent molecule or complexes in bulk solid.
Even though a number of salts are known in the art, the discovery of a new salt of 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino) propyl]-2,3-dihydro-1H-indol-7-carbonitrile can provide new ways to improve synthesis of silodosin in removal of N,N-dialkyl and other impurities. 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 an industrially advantageous and efficient process for preparation of highly pure silodosin.
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 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino) propyl]-2,3-dihydro-1H-indol-7-carbonitrile.
Another object of the present invention is to provide a process for synthesis of silodosin through novel salt of 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-7-carbonitrile
Yet another object of the present invention is to provide a process for the synthesis of novel salt of 1-(3-hydroxypropyl)-5-[(2R-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl-2,3-dihydro-1H-indol-7-carbonitrile.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved and efficient process for preparation of silodosin of formula I and pharmaceutically acceptable salts thereof,

Formula I

through novel tartrate salt of cyano hydroxy intermediate of formula II.

Formula II

According to one other embodiment, the present invention provides 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino) propyl]-2,3-dihydro-1H-indol-7-carbonitrile tartrate of formula II.
According to one other embodiment, the present invention provides a process for preparation of 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-7-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) reacting 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-1H-indol-1-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-1H-indol-1-yl)-propyl benzoate intermediate of formula IV,

Formula IV

b) hydrolyzing cyano benzyloxy intermediate of formula IV by using a suitable base in the presence of a suitable solvent to form 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethylamino)propyl]-2,3-dihydro-1H-indol-7-carbo-nitrile intermediate of formula V;

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; and

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.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an exemplary XRPD pattern of 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-7-carbonitrile D(-) tartrate.
Figure 2 is an exemplary DSC of 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-7-carbonitrile D(-) tartrate.
Figure 3 is an exemplary XRPD pattern of 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-7-carbonitrile L(+) tartrate.
Figure 4 is an exemplary DSC of 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-7-carbonitrile L(+) tartrate.

DETAILED DESCRIPTION OF THE INVENTION
As used herein 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-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.
The present invention provides a novel process for preparation of silodosin of formula I and pharmaceutically acceptable salts thereof.
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 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-1H-indol-1-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 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-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 can 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, ethanol, 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-methyl 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 -20oC to a boiling point of solvent used, for a period of 30 minutes to 48 hours, preferably 20oC to 80oC 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-1H-indol-1-yl]propyl benzoate(2R,3R)-monotartrate 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)phenoxy]ethyl 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 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino) propyl] -2,3-dihydro-1H-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 such 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 methanol, 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 0oC to boiling point of a used solvent, for 30 minutes to 48 hours, preferably at 10-50oC 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 0oC 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.
The resulting tartrate salt of cyano hydroxy compound can be characterized by suitable techniques known in the art. Preferably, tartrate salt of cyano hydroxy compound of the present invention can be characterized by various spectroscopic techniques like X-ray diffraction chromatogram (XRD) and differential scanning calorimetry (DSC).
According to one embodiment, present invention provides tartrate salt of cyano hydroxy compound having purity of greater than 99% by HPLC and N,N-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 scan calorimetry (DSC) thermogram, which shows one endothermic peak at 168.64oC as shown in figure 2.
Melting point: 164.5-165.7oC
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 scan calorimetry (DSC) thermogram, which shows major endothermic peak at 137.42oC as depicted in figure 4.
Melting point: 128.6-139.8 oC
X-ray diffraction of tartrate salt of cyano hydroxy intermediate can be measured on a PANalytical X’Pert Pro diffractometer with Cu radiation and expressed in terms of two-theta [2?], d-spacing and relative intensities. One of the ordinary skills in the art understands the experimental differences may arise due to differences in instrumentation, sample preparation or the other factors. DSC analysis was performed using a Mettler Toledo 822e. The crucible was crimped and punched prior to analysis. The weight of the samples was about 4-6mg; the samples were scanned at a rate of 5oC/min from 30oC to 250oC. The oven was constantly purged with nitrogen gas at a flow rate of 80ml/min. Standard 40 µl aluminium crucibles covered by lids with one hole were used.
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 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-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 forms 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 0oC to reflux temperature of the solvent employed for 1 to 24 hours, preferably 10oC to 60oC 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 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, derivatization, 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, dimethylsulfoxide, 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 N,N-dialkyl impurity and other impurities not more than 0.10% by HPLC.
In another aspect of the invention, silodosin of formula I, obtained by following the process 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. The process of the present invention is efficient, reproducible as well as industrially advantageous.
EXAMPLES:
Example 1: Preparation of 3-{7-cyano-5-[(2R)-2-({2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl} amino)propyl)-2,3-dihydro-1H-indol-1-yl)-propyl benzoate
To a mixture of ethyl acetate (500 ml) and an aqueous solution (500ml) of potassium carbonate (135g), 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-1H-indol-1-yl]propyl benzoate(2R,3R)-monotartrate (50g) was added in small portions. The reaction mixture was stirred at 20-30oC for 2 hours. After complete hydrolysis layers were separated. The aqueous layer was extracted again with ethyl acetate solution (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 methanesulfonate (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 (500ml), 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 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoro ethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-7-carbonitrile
3-{7-Cyano-5-[(2R)-2-({2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl)-2,3-dihydro-1H-indol-1-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 20-25oC. 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 (600ml) and brine (600ml) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give title compound having purity 80.12%; N,N-dialkyl impurity 13.67% and other impurities around 6% by HPLC.
Example 3a: Preparation of 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-7-carbonitrile D(-) tartrate
Isopropyl alcohol (50ml) and D(-)tartaric acid (1.57g) were added to 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino) propyl]-2,3-dihydro-1H-indol-7-carbonitrile (5g) and the mixture was heated to 75-85oC and stirred for 1 hour at same temperature. The suspension was slowly cooled to 20-25oC, stirred for 4 hours at 20-25oC. 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 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-7-carbonitrile L(+) tartrate
Isopropyl alcohol (10ml) and L(+)tartaric acid (0.3g) were added to a suspension of1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl] -2,3-dihydro-1H-indol-7-carbonitrile (1g) and the mixture was heated to 70-75oC and stirred for 1 hour at same temperature. The suspension was slowly cooled to 20-25oC, stirred for 4 hours at 20-25oC. 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 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoro ethoxy)phenoxy] ethyl}amino)propyl]-2,3-dihydro-1H-indol-7-carboxamide
Method A: 1-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy] ethyl}amino) propyl]-2,3-dihydro-1H-indol-7-carbonitrile tartrate (10g) dissolved in dimethylsulfoxide (125ml) and to this solution, was added 5 mol/L aqueous sodium hydroxide solution (15ml). To the reaction mixture, 30% hydrogen peroxide (4.25ml) was added and keeping the temperature below 25 oC. The reaction mixture was stirred at 20-25oC, 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 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 layer 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 solution was cooled to 20-25°C, stirred 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: 1-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy] ethyl}amino)propyl]-2,3-dihydro-1H-indol-7-carbonitrile tartrate (13.5g) dissolved in ethyl acetate (150ml), adjusted pH 8 by aqueous potassium carbonate solution (75ml) and stirred for 30 minutes. Ethyl acetate layer was separated and aqueous layer was extracted with an ethyl acetate solution (75ml) and combined ethyl acetate layer was washed with an 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, keeping temperature below 25oC. The reaction mixture was stirred at 20-25oC, 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 (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 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 sodium sulfate and ethyl acetate solution was concentrated. 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: 1-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy] ethyl}amino) propyl]-2,3-dihydro-1H-indol-7-carbonitrile tartrate (10g) dissolved in dimethylsulfoxide (120 ml) and to this solution, was added 5mol/L aqueous sodium hydroxide solution (15ml). To the reaction mixture, 30% hydrogen peroxide (5ml) was added and keeping the temperature below 25oC. The reaction mixture was stirred at 20-25oC, 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 toluene (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.
,CLAIMS:We Claim

1. A process for the preparation of silodosin of formula I and pharmaceutically acceptable salts thereof

Formula I
comprises the steps of;
a) reacting3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-1H-indol-1-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-1H-indol-1-yl)-propyl benzoate intermediate of formula IV;

Formula IV

b) hydrolyzing cyano benzyloxy intermediate of formula IV using a suitable base in the presence of a suitable solvent to form 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy)phenoxy]ethylamino)propyl]-2,3-dihydro-1H-indol-7-carbonitrile intermediate of formula V;

Formula V

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

Formula II
d) hydrolysing tartrate salt of cyano hydroxy intermediate 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 C1-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,C1-C3 alcohol, and mixtures thereof.

4. The process as claimed in claim 1,wherein in step c) solvent is selected from C1-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; C1-C3 alcohol; water soluble organic solvent such as acetone, tetrahydrofuran, 1,4 dioxane, dimethylsulfoxide, dimethylformamide, dimethylacetamide and mixtures thereof.
6. A compound, namely,,1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2,2,2-trifluoroethoxy) phenoxy]ethyl}amino) propyl]-2,3-dihydro-1H-indol-7-carbonitrile tartrate of formula II.

Formula II
7. The compound of formula II, as claimed in claim 6 is crystalline.
8. A process for preparation of silodosin of formula I,

Formula I
comprises the steps of;
hydrolysing tartrate salt of cyano hydroxy intermediate of formula II

Formula II
in the presence of a suitable base, a oxidizing agent, in a suitable organic solvent to prepare silodosin of formula 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 preparation of silodosin of formula I, using tartrate salt of cyano hydroxy intermediate of formula II.

Dated this 25th day of July, 2014
Dr. Asha Aggarwal,
Head-IPM Department,
Ind-Swift Laboratories Limited,
E-5,Phase-II, Industrial Area,
Mohali-160055,
Punjab, India