DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of silodosin and intermediates thereof. In particular, the present invention relates to an improved, ecofriendly, cost-effective commercially viable process for the preparation of silodosin and intermediates thereof.
BACKGROUND OF THE INVENTION

Silodosin is a selective alpha-1 adrenergic receptor antagonist, indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). Silodosin is approved under the brand name RAPAFLO® in the United States and Silodyx in Europe and is available in the form of capsule with dosage strengths of 4 and 8 mg.
Silodosin is chemically known as 1-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide and represented by structural formula I.

(I)
U.S. Patent No. 5,387,603 discloses the synthesis of silodosin and discloses a multistep synthesis of 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl mesylate from 2-methoxy phenol using 1 ,1 ,1-trifluoro ethyl iodide and boron tribromide and Lithium aluminium hydride.
The process is illustrated by scheme:
It also discloses the silodosin as illustrated by below scheme:

U.S. Patent No. 7,834,193 B2 discloses another process for preparing Silodosin via formation of oxalate salt of Silodosin as illustrated by below scheme:

U.S. Patent No. 8,471,039 B2 discloses process for preparing Silodosin using different intermediates as illustrated by the below schemes:


Silodosin

PCT application publication WO2012147107A2 discloses a process for preparing Silodosin and its intermediates as illustrated by the below schemes:

PCT application publication WO2014118606A2 discloses a process for preparing Silodosin and its intermediates as illustrated by the below schemes:


Japanese patents and applications JP3331047, JP3331048 discloses the synthesis of silodosin intermediate 2-[2-(2,2,2-Trifluoroethoxy)phenoxy]ethyl mesylate which is
illustrated by below scheme

The processes reported in the prior art uses expensive and hazardous chemicals like 1,1,1-trifluoro ethyl iodide and boron tribromide, hydrobromic acid and Lithium aluminium hydride which are not ecofriendly and difficult to handle on industrial scale and which also results in lower yields and purity of the desired compounds.
Thus there is unmet need for an improved, ecofriendly and commercially viable process for the preparation of silodosin and its intermediates, which avoids the use of hazardous and expensive chemicals, formation of isomeric, process related impurities and side products while ensuring the higher yields and purities of silodosin and its intermediates.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of silodosin and intermediates thereof. In particular, the present invention relates to an improved, ecofriendly, commercially viable, process for the preparation of silodosin and intermediates thereof.
In one aspect, the present invention relates to an improved process for the preparation of silodosin intermediate 2-[2-(2,2,2-Trifluoroethoxy)phenoxy]ethyl mesylate of formula (II), The process is schematically shown in scheme I below,

Scheme I
In another aspect, the present invention relates to an improved process for the preparation of Silodosin (I) illustrated by below scheme II
Scheme II
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides an improved process for preparation of silodosin intermediate compound of formula (II),
comprising the steps of :
1) Reacting pyrocatechol compound of formula (VI),with ethylene carbonate in the
presence of phase transfer catalyst to afford 2-(2- hydroxyethoxy)phenol compound of
formula (V)

2) Reacting the compound of formula (V) with 2,2,2-trifluoroethyltosylate compound of
formula (IV) in the presence of a base and an organic solvent to afford 2-(2-(2,2,2-
trifluoroethoxy)phenoxy) ethan-1-ol compound of formula III

3) Reacting the compound of formula (III) with methane sulfonic acid in the presence of a
base and an organic solvent to afford 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl
methanesulfonate compound of formula (II)

In the reaction step 1) the suitable phase transfer catalyst (PTC) that can be employed is selected from the group consisting of quarternary ammonium salts such as tertiary butyl ammonium bromide (TBAB), benzyltriethylammonium chloride, ethyltricaprylammonium chloride, methyltributylammonium chloride, methyltrioctylammonium chloride and the like; Organic phosphonium salts such as hexadecyltributylphosphonium bromide and the like; Preferably tertiary butyl ammonium bromide (TBAB).
The reaction step 1) is performed in the absence of organic solvent and optionally the step 1) is performed in the presence of organic solvent selected from hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like or mixture thereof.
The reaction step 1) can be performed at temperature range from about 35°C to about 185°C or the boing point of the solvent(s) used or the reaction mixture. Preferably from about 180°C to about 185°C.
The reaction time of step 1) may vary widely depending on various factors such as reaction temperature and the nature of the reagents and solvents employed. However, provided that the reaction is effected under the preferred conditions discussed above, a period of from about 2 hours to about 8 hours. Preferably a period of 4 to 6 hrs. is sufficient for the completion of the reaction to obtain desired compound with no or less impurities and side products.
The molar equivalents of reactants and reagents being used is to obtain the desired product with maximum yield and purity without formation of impurities and side products.
In one embodiment of present invention, the compound of formula V obtained is subjected to purification using toluene-water combination to afford high pure compound which is essential to achieve high purity of final compounds and which is not reported in the prior art.
In reaction step 2) the suitable base that can be employed is selected from the group consisting of inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate and the like; organic bases such as aqueous ammonia, methylamine, ethylamine, triethylamine and the like; or mixture thereof.
Inorganic base potassium carbonate is being preferred.

The reaction step 2) is performed in the presence of organic solvent selected from the group consisting of aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMA), acetonitrile and the like; hydrocarbons such toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; ethers such as tetrahydrofuran (THF), 1,4-dioxane, diethyl ether, methyl tertiary butyl ether (MTBE) and the like; esters such ethyl acetate, isopropyl acetate and the like; or mixture thereof. Preferably aprotic polar solvent N,N-dimethylformamide (DMF) is being used.
The reaction step 2) can be performed at temperature range from about 35°C to about 125°C or the boiling point of the solvent(s) used or the reaction mixture. Preferably from about 120°C to about 125°C.
The reaction time of step 2) may vary widely depending on various factors such as reaction temperature and the nature of the reagents and solvents employed. However, provided that the reaction is effected under the preferred conditions discussed above, a period of from about 12 hours to about 25 hours. Preferable a period of 20 to 24 hrs is sufficient for the completion of the reaction to obtain with no or less impurities and side products.
The molar equivalents of reactants and reagents being used is to obtain the desired product with maximum yield and purity without formation of impurities and side products.
In one embodiment of the present invention, the compound of formula III obtained is subjected to High vacuum distillation (HVD) at a temperature range of about 115°C to about 150°C under reduced pressure of 0.5 to 0.1mm Hg to obtain high pure form which is not known in the art thus resulting the desired intermediate and final compounds with high purity.
The reaction step 3) the reaction between the compound of formula III and methane sulfonyl chloride to afford compound of formula II is performed in the presence of a base selected from the group consisting of inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate and the like; organic bases such as aqueous ammonia, methylamine, ethylamine, triethylamine and the like; or mixture thereof. Organic base triethylamine is being preferred.
The reaction step 3) is performed in the presence of organic solvent selected from the group consisting of halocarbonate solvents such as dichloromethane (DCM), dichloroethane, chlorobenzene and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMA), acetonitrile and the like; hydrocarbons such toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; or mixture thereof. Halogenated solvent dichloromethane is being preferred.
The reaction step 3) can be performed at temperature range from about 15°C to about 35°C. Preferably from about 25°C to about 30°C.
The reaction time of step 3) may vary widely depending on various factors such as reaction temperature and the nature of the reagents and solvents employed. However, provided that the reaction is effected under the preferred conditions discussed above, a period of from about 2 hours to about 10 hours. Preferably a period of 4 to 5 hrs is sufficient for the completion of the reaction to obtain desired compound with no or less impurities and side products.
The molar equivalents of reactants and reagents being used is to obtain the desired product with maximum yield and purity without formation of impurities and side products.
In one embodiment of present invention, the compound of formula II obtained is subjected to attain pH at 5-6 using water washing which is essential to achieve high purity of final compounds and which is not reported in the prior art.

In one embodiment of present invention, the compound of formula II obtained is subjected to purification process by recrystallization employing aqueous methanol in any proportion without limitation. Preferably 10% aqueous methanol.
By this purification a significant improvement in the purity of compound of formula II was observed thus resulting in high pure compound of formula II which is a key intermediate in the synthesis of Silodosin (I).
In one embodiment of present invention, the reaction of compound of formula VII with tosyl chloride in the presence of a base triethylamine to afford the compound IV in high yield and pure form is only due to maintaining the pH of 8 to 9 which is vital. Hence the pH of the reaction is critical to obtain the desired compound with high yield and purity.
In yet another embodiment, the present invention provides an improved process for the preparation of Silodosin (I) comprising the steps of:
i) Reacting the compound of formula IX with a compound of formula II in the presence of a base and a phase transfer catalyst to afford the compound of formula XXI and

ii) Subjecting the compound of formula XXI to deprotection by hydrolysis using suitable agent and followed by oxidation using suitable agent to afford the compound Silodosin alpha form of formula (Ia)

iii) Recrystallization of compound Silodosin alpha form of formula (Ia) using ester solvent isopropyl acetate to afford the compound Silodosin beta form of formula I.


In step i) the reaction of compound of formula IX with compound of formula II in the presence of phase transfer catalyst not limited to quaternary ammonium salts such as triethylbenzylammonium chloride and the like and the base not limited to inorganic base such as potassium carbonate and the like;
In one embodiment, the reaction step i) is performed without using any organic solvent but using aqueous medium which is advantageous over the prior art by making the process simple, ecofriendly and most economical.
In one embodiment of present invention, the intermediate compound of formula IX is directly i.e., in tartarate salt form reacted with the intermediate compound of formula II to afford the compound of formula XXI which is tartrate salt thus makes the process simple, improve the yield and purity of the desired compound and viable on commercial scale.
The reaction step i) can be performed at a temperature range from about 35°C to about 75°C; preferably from about 70°C to 75°C and the reaction time from about 20 to about 25 hours at given fixed range of parameters preferably from about 22 to 23 hrs is suffice.
The reaction step ii) has two steps one is deprotection by base hydrolysis using any suitable base selected from inorganic base such as sodium hydroxide, potassium hydroxide and the like; or their aqueous or alcoholic mixture thereof in any proportion without limitation and the other is oxidation using suitable oxidizing agent such as hydrogen peroxide of any percentage wt. with preferably 30-35%w/v.
The organic solvent that is being used in step ii) is selected from the group consisting of aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethyl acetamide (DMA) and the like; preferably dimethyl sulfoxide (DMSO).
The oxidation reaction step is carried out preferably at 25 to 30°C for about 20 to 22 hrs.
In one embodiment, the compound silodosin resulted after oxidation is treated with oxalic acid to make a pH of about 2 to 2.5 to make oxalate salt by insitu during which the dialkyl and dimer impurities are washed off significantly thus the purity of the silodosin enhanced tremendously which is advantageous over the prior art.
The step iii) is not a synthesis step but recrystallization of silodosin Ia (silodosin alpha form) using ester solvents such as isopropyl acetate to convert into Silodosin I (Silodosin beta form).
The alpha and beta forms of silodosin obtained herein the process of present invention are well known and reported in the art by their characterization data like XRPD 2-theta and DSC.
In another embodiment of present invention some of the process steps are performed insitu i.e., without isolation of some of the intermediate compounds thus making the process simple, ecofriendly, most economical and commercially viable which is advantageous over the prior art processes.
In one embodiment of the present invention the intermediates or their salts obtained herein may be crystalline or amorphous or mixture thereof.
The processes reported in the art yields Silodosin (I) not more than 70%wt/wt whereas the yields of the final product by the process of present invention are usually more than 80%, more precisely, the yield is about 80% to about 90% by weight.
In yet another embodiment, the process of present invention provides substantially pure Silodosin (I) having purity greater than 99.5% and less than 0.5 % of total impurities as measured by chiral HPLC. Preferably purity greater than about 99.8% and less than about 0.2% of total impurities.
The term "substantially pure silodosin" refers to the total absence, or near total absence, of impurities, such as related-substance impurities. For example, when silodosin is said to be substantially pure, there are either no detectable related-substance impurities, or if a single related-substance impurity is detected, it is present in an amount not greater than 0.1 % by weight, or if multiple related-substance impurities are detected, they are present in aggregate in an amount not greater than 0.2% by weight.
Advantageously, the processes for the preparation of silodosin and intermediates of the present invention are simple, eco-friendly, economical, reproducible, robust and feasible on commercial scale.
The reagents used herein the process of present invention are cheaper, commercially available and may not form impurities or side products unlike in the prior art processes.
The silodosin (I) obtained is optionally purified by conventional methods known in the art and person skilled in the art. Preferably by recrystallizations using solvents or mixture thereof or their aqueous mixtures in any proportion without limitation.
The solvents used for the purification of silodosin include but not limited to polar protic solvent such as polar aprotic solvent such as tetrahydrofuran, acetonitrile, 1, 4-dioxane, N, N-dimethylacetamide, dimethylsulfoxide, acetone, ethyl acetate, diethyl ether, diisopropyl ether and the like; non-polar aprotic solvent such as diisopropyl ether, methylisobutylketone, diisobutylketone, substituted 2-pyrrolidones, alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol and the like; hydrocarbons such as n-hexane, heptane and the like; chlorinated hydrocarbons such as methylene chloride, ethylene chloride, dichlorobenzene and the like; and mixtures of said solvents. Preferably ester solvent isopropyl acetate.
The process of purification of silodosin of present invention does not limit the scope it also includes the acid base treatment of silodosin to get the desired purity to comply ICH limits.
The acids being used for purification of silodosin by converting it into its pharmaceutically salts can be customary list known to the person skilled in the art, preferably acid can be of carboxylic acid such as oxalic acid and the like.
The intermediate compound of Formula IX being used herein the process of present invention is well known in the art and can be prepared by any known methods described in the art for example US 5,387,603.
After completion of the reaction, the desired compounds can be obtained from the reaction mixture by conventional means known in the art. For example, the working-up of reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
In another embodiment of the present invention the silodosin (I) obtained by the process of present invention may have particle size distribution D90 is less than about 200 µm, D50 is less than about 100 µm and D10 is less than about 50 µm. The particle size of silodosin can be measured by suitable techniques such as Laser light scattering (e.g. Malvern Light Scattering), Coulter counter microscopy and any other technique known in the art.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.
EXAMPLES
PROCESS FOR THE PREPARATION OF COMPOUND OF FORMULA II
Example -1: Preparation of compound of formula V:

Charged 100g of catechol, 88g of ethylene carbonate and 3g of TBAB in a clean and dry RBF and raise the temperature to 180 -185°C Maintained the reaction mass at 180 -185°C for about 4 to 6 hrs. Monitored the reaction progress by TLC and after completion of the reaction , allow to reach the temperature 55-60°C, then added 200ml of Toluene, charged 10ml of DM water and then stirred for 1-2hrs at 55-60°C. Allowed to cool to 25-30°C stirred for 8 -10 hrs at 25- 30°C Filtered the solid and washed the solid with 50ml of toluene, suck dried for 3-5hrs and dried ATD for 20-24 hrs at 40-45 °C to yield 84 gms of title compound;

Example-2: Preparation of compound of formula IV:

Charged 100ml of toluene, 100g of trifluroethanol and 208 ml of triethylamine into a clean and dry RBF. 192 gms of paratoluene sulfonyl chloride (TsCl) solution was added slowly at 40-45°C (Exothermic go upto 50-55°C) (Preparation of TsCl solution: Dissolved p-toluene sulfonyl chloride in 500ml of toluene at 25- 30°C) Then stirred the resultant reaction mixture for 5-6 hrs at 40-45 °C. Reaction progress was monitored by TLC.After completion of reaction Charge DM water at 25-30 °C Stir for 5-10 min at 25-30 °C Collect the organic layer Then add 1NHCl at 5-10 °C Stir for 5-10 min at 5- 15 °C .Separate the organic layer Wash with DM Water separate the organic layer and Distil at 110- 130 °C Finally distil under vacuum at 40- 45 °C for 2-3h Dry for 1-2 h under vacuum Release the vacuum with nitrogen flow Unload the material in to fresh container Send the sample for complete analysis Store at 25-30 °C Send for complete analysis.

Example-3: Preparation of compound of formula III:

Charged 100ml of N,N-dimethylformamide (DMF), 100 gms of compound of formula V, 248 gms of compound of formula IV, 225 gms of potassium carbonate (K2CO3) and 300 ml of DMF into clean and dry RBF. Heated the reaction mixture to 120-125°C Then maintained the reaction mass for 20-24 hrs at 120 -125°C. Reaction progress was monitored by TLC, after completion of the reaction, allowed the reaction mass temperature to 75-80 °C and distilled the solvent DMF at 75-80°C under vacuum, cooled the reaction to 25-30 °C, 400ml of toluene, 700ml of RO water were charged at 25-30 °C Stirred for 20-25min The organic and aqueous layers were separated and organic layer was taken into RBF and cooled to 10-15 °C added 1M HCl solution and stirred for 10-15 mins Separated the organic layer and checked aqueous layer pH (limit 3-4).Taken Organic layer into RBF and charged 300ml of water and stirred for 10-15mins. Separated the organic layer and check aqueous layer pH Distilled off the organic layer at 55-60 °C under vacuum and then raise temperature to 115-120°C and distilled under high vacuum ( Collected the fraction -1) Temperature raise to 125 to 150 °C and distill under vacuum (collected the fraction –II)
Yield: 153 gms.
Example-4: Preparation of compound of formula II:

Charged 390ml of dichloromethane (DCM), 130 gms of compound of formula III in a clean and dry RBF, Cooled to 10 - 15°C Charged 115ml of triethylamine (TEA) at 10 - 15°C, Added 44.55 ml of methane sulfonyl chloride (MsCl) slowly at 10 - 15°C Raised the temperature to 25-30°C Stirred for 4-5 hrs at 25-30°C. Reaction progress was monitored by TLC, after completion of the reaction, added 390ml of DM water to the reaction mass Separated the organic layer checked pH of aq layer, collected the organic layer, charged 65 ml of DM water, cooled to 10- 15°C, Checked pH (Limit: 5-6) Then separated the organic layer charged 260 ml of DM water and stirred for 10- 15 min at 25 – 30°C. Separated the organic layer and distilled off the organic layer below 35°C co-distilled with 390 ml of petroleum ether.. Added aqueous methanol, heated the reaction mass to 40-45°C Maintained for 2-3 hrs at 40-45°C Then allowed to cooled at 25-30°C Stirred for 10-12 hrs at 25-30°C Then filtered the solid and washed with 65ml of DM water. Suck dried for 2-3 hrs at 25-30°C Dried for 10-12 hrs under vacuum at 40-45°C to afford the title compound.

PROCESS FOR THE PREPARATION OF SILODOSIN FROM THE ADVANCED INTERMEDIATES:
Example -1: Process for the preparation of compound of formula XXI

Step 1:

Charged 120ml of RO water and 35 g. of potassium carbonate (K2CO3) into a clean and dry RBF at 25-30 °C and 10 g. of compound of formula IX and stirred the reaction mixture for about 10-15 min (Observation: Heterogeneous mass) and 1 g. of Tri ethyl benzyl ammonium chloride (TEBAC), 7.9 g. of compound of formula II and the resultant reaction mixture was heated to 72.5±2.5 °C and maintained at 72.5±2.5 °C for 22-23 hrs. (Observation: Hazy solution will be formed). 40ml of ethyl acetate was charged to the reaction mass at 25-30 °C, stirred for 15-20 min at 25-30 °C. Separated the organic layer and aqueous layers followed by extraction of aqueous layer with 2X20 ml of ethyl acetate. The organic layers were combined and washed with sodium chloride (NaCl) solution separated the organic and aqueous layers and charged 1 g. of charcoal (SC-40) to organic layer and raised the reaction mass temperature to 40-45°C and maintained for 30-45 mins.
Filtered the solution through hyflow and collect the clear filtrate and washed the hyflow with 3X10ml of ethylaceate. Distilled off the solvent under vaccum at below 60 °C.
Charged ethyl acetate (2X20ml) distilled off at 60-65 °C under vacuum and Charged 300ml of ethyl acetate to the above crude and stirrd for 10-15 min at 25-30 °C , heated the Organic layer to 30-35 °C, charged 3 g. of Tartaric acid at 30-35 °C and stir for 8-9 hrs at 30-35 °C. Cooled the reaction mass to 10-15 °C and maintained for 30-45 mins. Filtered the solid and washed with 20ml of precooled ethyl acetate. Suck/Spin dried for 3-4 hrs. Charged wet solid and 25ml of ethyl acetate into a clean and dry RBF, stirred for 1-1½ hrs at 25-35 °C.
Cooled the reaction mass to 10-15 °C and stirred at 10-15 °C for 1-1½ hr. Filtered the solid and washed with 20ml of precooled ethyl acetate. Load the wet solid in to ATD and dried for 6-8 hrs at 45-50 °C. Yield Range: 7.6 -12.0 g. % Yield: 53.4 – 84.23.

Example -2: Process for the preparation of compound of formula Ia
(Silodosin alpha form)
Step-2:


Charged 1 lit., RO water and 252 g. of potassium carbonate (K2CO3) into a clean and dry RBF and stirred for 10-15 min at 25-30 °C. Charged 100 g. of compound of formula XXI to the reaction mass at 25-30 °C and stirred the resultant reaction mass for 10-15 min at 25-30 °C. Charged 1 lit. of ethyl acetate to the reaction mass at 25-30 °C and stirred the reaction mass for 15-20 min at 25-30°C. Separated the organic layer and extracted with 1 lit. of ethyl acetate. Separated the organic layer and washed with saturated sodium chloride (108 g. of sodium chloride + 300ml of water), stirred for 10-15 min at 25-30°C. Separated the organic layer and distilled off under vacuum at below 45°C to yield crude: 80 g.
Charged 200ml of dimethyl sulfoxide (DMSO) and distilled off the trace amount of ethyl acetate under vacuum, degas for 1-2 hours. Charged 680ml of dimethyl sulfoxide (DMSO) to the above crude at 25-30°C and stirred for 10-15 min. Slowly charged sodium hydroxide solution to the reaction mass at 25-30°C Preparation of Sodium hydroxide solution: 11.36 g sodium hydroxide dissolved in 104 ml of RO water).Cooled the reaction mass to 5-10°C
slowly added 30-35% hydrogen peroxide (H2O2) solution to the reaction mass at 5-10°C. Then raised the reaction mass temperature to 25-30°C and maintained for 20-22 hrs. Cooled the reaction mass to 5-10°C and slowly added ammonium acetate solution to the reaction mass at 5-10 °C (Preparation of Ammonium acetate Solution: 76.0 g Ammonium acetate is dissolve in 2.0 Lit of RO water) and maintained the reaction at 5-10°C for 1-1 ½ hr. Charged 800ml of ethyl acetate to the reaction mass at 25-30°C and stirred for 15-20 min at 25-30 °C, separated the organic and aqueous layers. Aqueous layer was extracted with 2x 800 ml of ethyl acetate. Separated the organic and aqueous layers (keep Aq. layer aside)
Combined the organic layers and taken in to the RBF prepared oxalic acid solution: Add 71 g of oxalic acid slowly into 2.1 Lit. of RO water. Oxalic acid solution divided into 3 lots, each lot having ~700 mL of oxalic acid solution. Added oxalic acid solution Lot-I to combined organic layer at 25-30 °C and stirred for 10-15 min. Separated the organic layer and aqueous layer (Note: Keep Aqueous layer a side, product will be in Aqueous layer).
Charged organic layer in to the RBF added oxalic acid solution-Lot-II to separated organic layer at 25-30 °C and stirred for 10-15 min. Separated the organic layer and Aqeous layer ( Note: Keep Aq layer a side, product will be in Aq.Layer ) Charged organic layer in to the RBF and added oxalic acid solution-Lot-III to separated organic layer at 25-30 °C and stirred for 10-15 min Sent sample for pH as 2.0 -2.5 ( Limit: 2.0- 2.5 ) If pH is not within the range, extract with Oxalic acid solution (23 g of oxalic acid Lot-II in 700 ml of RO Water (2 lit)) Separated the organic layer and Aqueous layers (Note: Keep Aq layer a side, product will be in Aq.Layer ) Combined all the aqueous layers and extracted with 3 x 400ml of ethyl acetate Separated the organic and aqueous layer and (Aq. layer initial pH will be around 2.5) adjusted the pH to 7.0 - 8.0 with sodium bicarbonate solution
(Preparation of sodium bicarbonates Solution: 80 g sodium bicarbonate dissolve in and 800ml of RO water) Stirred for 30-40 min at 25-30 °C If pH is not within the limits, readjust pH to 7.0 - 8.0, Extracted with 3x 1 lit of dichloromethane. Separated the organic layer and Aq layer Sent the Aq layer sample for pH as sample No. 10 (Limit: pH should be 7.0 - 8.0 ) If pH is not within the limits, readjust pH to 7.0 - 8.0 and extract with Ethyl acetate (lot- XII) Combined all organic layers and washed with 800 ml of RO water. Charged saturated sodium chloride solution Lot-II to the organic layer at 25-30 °C
Note: Preparation of Sodium chloride solution Lot-II: Dissolved 80 g Sodium chloride Lot-II in 800ml of RO water Stirred for 10-15 min and separated the layers at 25-30°C
Charge the organic layer in to the reactor at 25-30 °C distilled off the solvent under vacuum at below 50°C (Note: Release the vacuum under N2). Reaction mass cool to 25-35°C, charged Isopropyl alcohol to the reaction mass at 25-30 °C, charged 1 lit. of Ethyl acetate Raised the reaction mass temperature to 60-65°C Stirred for 20-30 min at 60-65 °C to get clear solution cooled the reaction mass to 25-30°C Stirred for 1-1½ hr at 25-35°C. Cooled the reaction mass to 0-5°C, Stirred at 0-5°C for 2-3 hrs. Filtered the solid and washed with 50 ml of precooled Ethyl acetate. Note: Since product is light sensitive, protect from light Load the wet material in to VTD and dry the material for 14-16 h at 40-45°C

Yield Range: 40.0 - 60.0 g; % of Yield: 59-88.6%; Purity by Chiral HPLC: 99.80%.
Example 3: Process for the preparation of Silodosin I (Beta Form)

Step-3:


Charged 240 ml of Isopropyl acetate and 30 g. of compound obtained in example 2 (Ia) into a clean and dry RBF at 25-30°C. Heated the reaction mass to temperature of 70-75 °C and maintained till to get clear solution (Observation: Clear/Not Clear). Slowly cooled the reaction mass to 25-30°C over about in 3-4 hrs. (Observation: Thick Solid formation takes place ) Slowly added 120 ml of Isopropyl acetate to the reaction mass at 25-30°C and maintained for 3-4 hours at 25-30°C. Filtered the solid and washed with 60 ml of pre filtered Isopropyl acetate. Spin dried the solid for 2-3 hours and dried the solid for 14-16 hours at 40-45°C under vacuum.

Yield : 26.0 g; % Yield: 60-86 % ; Purity by Chiral HPLC: 99.80%.

,CLAIMS:Claims:
1) An improved process for preparation of silodosin intermediate compound of formula (II),
comprising the steps of :
A) Reacting pyrocatechol compound of formula (VI),with ethylene carbonate in the
presence of phase transfer catalyst to afford 2-(2- hydroxyethoxy)phenol compound of
formula (V)

B) Reacting the compound of formula (V) with 2,2,2-trifluoroethyltosylate compound of
formula (IV) in the presence of a base and an organic solvent to afford 2-(2-(2,2,2-
trifluoroethoxy)phenoxy) ethan-1-ol compound of formula III

C) Reacting the compound of formula (III) with methane sulfonic acid in the presence of a
base and an organic solvent to afford 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl
methanesulfonate compound of formula (II)

2) The process according to claim 1, wherein the reaction step A) the suitable phase transfer catalyst (PTC) that can be employed is selected from the group consisting of quarternary ammonium salts such as tertiary butyl ammonium bromide (TBAB), benzyltriethylammonium chloride, ethyltricaprylammonium chloride, methyltributylammonium chloride, methyltrioctylammonium chloride and the like; Organic phosphonium salts such as hexadecyltributylphosphonium bromide and the like; Preferably tertiary butyl ammonium bromide (TBAB); wherein the reaction step A) is performed in the absence of organic solvent and optionally the step 1) is performed in the presence of organic solvent selected from hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like or mixture thereof.

3) The process according to claim 1, wherein the reaction step B) the suitable base that can be employed is selected from the group consisting of inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate and the like; organic bases such as aqueous ammonia, methylamine, ethylamine, triethylamine and the like; or mixture thereof. Inorganic base potassium carbonate is being preferred; wherein the solvent is selected from the group consisting of aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMA), acetonitrile and the like; hydrocarbons such toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; ethers such as tetrahydrofuran (THF), 1,4-dioxane, diethyl ether, methyl tertiary butyl ether (MTBE) and the like; esters such ethyl acetate, isopropyl acetate and the like; or mixture thereof. Preferably aprotic polar solvent N,N-dimethylformamide (DMF) is being used.

4) The process according to claim 1, wherein the reaction step C) the reaction between the compound of formula III and methane sulfonyl chloride to afford compound of formula II is performed in the presence of a base selected from the group consisting of inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate and the like; organic bases such as aqueous ammonia, methylamine, ethylamine, triethylamine and the like; or mixture thereof. Organic base triethylamine is being preferred; wherein the organic solvent selected from the group consisting of halocarbonate solvents such as dichloromethane (DCM), dichloroethane, chlorobenzene and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMA), acetonitrile and the like; hydrocarbons such toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; or mixture thereof. Halogenated solvent dichloromethane is being preferred.
5) An improved process for the preparation of Silodosin (I) comprising the steps of:
i) Reacting the compound of formula IX with a compound of formula II in the presence of a base and a phase transfer catalyst to afford the compound of formula XXI and

ii) Subjecting the compound of formula XXI to deprotection by hydrolysis using suitable agent and followed by oxidation using suitable agent to afford the compound Silodosin alpha form of formula (Ia)

iii) Recrystallization of compound Silodosin alpha form of formula (Ia) using ester solvent isopropyl acetate to afford the compound Silodosin beta form of formula I.


6) The process according to claim 5, wherein step i) the reaction of compound of formula IX with compound of formula II in the presence of phase transfer catalyst not limited to quaternary ammonium salts such as triethylbenzylammonium chloride and the like and the base not limited to inorganic base such as potassium carbonate and the like; wherein the reaction step is performed without using any organic solvent but using aqueous medium.

7) The process according to claim 5, wherein the reaction step ii) has two steps one is deprotection by base hydrolysis using any suitable base selected from inorganic base such as sodium hydroxide, potassium hydroxide and the like; or their aqueous or alcoholic mixture thereof in any proportion without limitation and the other is oxidation using suitable oxidizing agent such as hydrogen peroxide of any percentage wt. with preferably 30-35%w/v; wherein the organic solvent is selected from the group consisting of aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethyl acetamide (DMA) and the like; preferably dimethyl sulfoxide (DMSO); wherein the compound silodosin resulted after oxidation is treated with oxalic acid to make a pH of about 2 to 2.5 to make oxalate salt by insitu during which the dialkyl and dimer impurities are washed off significantly thus the purity of the silodosin enhanced tremendously.

8) The process according to claim 5, wherein the step iii) is recrystallization of silodosin Ia (silodosin alpha form) using ester solvents such as isopropyl acetate to convert into Silodosin I (Silodosin beta form); wherein the alpha and beta crystalline polymorphs of silodosin obtained herein are well known and reported in the art by their characterization data like XRPD 2-theta and DSC.

9) The process according to step 5, wherein the process provides substantially pure Silodosin (I) having purity greater than 99.8% and less than 0.2 % of total impurities as determined by chiral HPLC.