FIELD OF INVENTION
The invention relates an improved process for preparing the (7?)-(-)5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide of Formula I

and its pharmaceutical^ acceptable salts
BACKGROUND OF THE INVENTION
(7?)-(-)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide is know as Tamsulosin. Presently Tamsulosin is being marketed as its hydrochloride salt under the trade name FLOMAX. It is an a-adrenergic antagonist used preferably for treating benign prostatic hyperplasia.
US 4,703,063 describes two processes for the preparation of Tamsulosin, one of which involves the conversion of a hydroxyl substituted analogues of Tamsulosin, i.e., a compound having the Tamsulosin structure but contains the hydroxyl substituent at a position a to the benzenesulfonamide ring, by halogenation followed by reduction and the other process involves condensation of an appropriately substituted benzyl methyl ketone with the substituted phenoxy amine, followed by reduction of the resulting imino compound.
The above described processes are non-stereospecific and the final product requires an additional step of resolution of enantiomers to specifically obtain (/?)-enantiomer Tamsulosin.
CA 1,282,077 discloses a process to prepare Tamsulosin wherein (tf)-enantiomer of sulfonamide amine has been condensed with ethoxyphenoxy bromide in

dimethylformamide to obtain Tamsulosin (Scheme 1) that was subsequently purified by crystallization before converting into hydrochloride salt

Tamsulosin Hydrochloride
Scheme I
As per the above described process, Tamsulosin hydrochloride is obtained in low yield, and therefore this process is not suitable for commercial production.
WO 2002/068383 Al discloses a process to prepare sulfamoyl substituted phenethylamine derivatives including Tamsulosin. The described process involves a coupling reaction between (i?)-(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide with an acid or a corresponding acid chloride or mixed anhydride to produce Tamsulosin amide and thereafter reduction of the obtained compound to give Tamsulosin. The coupling reaction presents the disadvantage that the acid or acid chloride or anhydride should be provided in a high purity in order to obtain a good yield in the coupling reaction and it is known in the art that purification of such products is not always easy.

WO 2004/022532 Al discloses a process to prepare Tamsulosin (Scheme II) wherein protected amine is used during condensation with ethoxy phenoxy derivative to obtain protected Tamsulosin. In this process, an additional step of removing the protecting group to obtain Tamsulosin in involved.
H
H2N02S. ^. /\ N CH2^( )
\^ ^^T ^r \s. y/ Xylene
£ 2-(2-ethoxyphenoxy)ethyl
JL ^J Q(_) methanesulfonate
■ J QQ^^ ^^^^ Magnesium oxide
^ JL H3C. O. ^' JL 1
H2N02S. ^^. ^X\ ^N \Z^\0^^X^
^\^^ CH3
H3CO ^^
BENZYL TAMSULOSIN
Pd/C/Hydrogen
H JL
H2N02S. >x ys. . N s^/X /%/
/\^ SH3
H3CO ^^
TAMSULOSIN SCHEME-II
H
H2N02S. ^. /\ N CH2^( )
\^ ^^T ^r \s. // Xylene
£ 2-(2-ethoxyphenoxy)ethyl
JL ^J Q(_) methanesulfonate
■ J Q,0 Ni^ Magnesium oxide
' JL i
H2N02S. ^^. ^X\ ^N \Z^\0^^X^
^\^^ CH3
H3CO ^^
BENZYL TAMSULOSIN
Pd/C/Hydrogen
H JL
H2N02S. >x ys. . N -v^x^^^o^^^^
/\^ SH3
H3CO ^^
TAMSULOSIN SCHEME-II
The process involves the use of a protected amine derivative, which needs to be deprotected after the formation of Tamsulosin

EP 0 380 144 Bl describes a process for preparing Tamsulosin in stereospecific form, by reaction of a benzenesulfonamide amine with predetermined stereospecificity, with 2-(2-ethoxyphenoxy)ethyl halide, specifically the bromide. In this process Tamsulosin base has been purified with column chromatography.
WO 2004/016582 discloses a process to prepare Tamsulosin hydrochloride (Scheme III). This process involves two additional steps, first the protection of amine group before condensing with ethoxyphenoxy halide and thereafter the deprotection to obtain Tamsulosin.

This process involves the use of a protected amine derivative, which needs to be deprotected after the formation of Tamsulosin

b) reacting the (i?)-(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide of Formula III
with a substituted phenoxy compound of Formula IV,
Formula IV
wherein Z represents a leaving group such as 0-S02CH3, -OSO2C6H4CH3, -F, -Br, -Cl, or
-I,
c) extracting the reaction mass with aliphatic hydrocarbon solvents and chlorinated
and
d) recrystallizing the obtained reaction mass to obtain compound of Formula I
DETAILED DESCRIPTION OF THE INVENTION
The present process provides an improved method for preparing Tamsulosin and in particular, optically pure (^)-Tamsulosin.
In the first embodiment of the invention the (7?)-(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide hydrochloride of Formula II is neutralized by using liquid ammonia to yield compound of Formula III. Normally in all the prior-art process, inorganic salts like sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide are used which generate lot of solid waste. In order to reduce the solid effluent, the inventors have utilized liquid ammonia as neutralizing agent. The compound of Formula III is finally recrystallized from hot water.
The compound of Formula III is condensed with the compound of Formula IV in an alcoholic solvent. The reaction mass was heated to reflux temperature and maintained for 48 hrs. After completion of the reaction, methanol was distilled off and aliphatic hydrocarbons were added and heated to 50 °C for 30 minutes. The aliphatic hydrocarbons employed for extraction are selected from hexanes, heptanes, cyclohexanes more preferably n-hexane. During this n-hexane reflux, the unreacted compound of Formula IV

gets carried into the hexane layer which can be recovered and reused again. Initially the compound at this stage is having a purity of 30 %. After the hexane washing, the compound of Formula I at this stage has a purity of 50-55%. The slurry is filtered off and the obtained cake is extracted in chlorinated solvents selected from chloroform, dichloromethane, carbon tetrachloride etc. The preferred choice of solvent is dichloromethane. During this dichloromethane extraction, the unreacted (7?)-5-(2-amino-l-propyl)-2-methoxy benzenesulfonamide is recovered. Further, traces of the amine compound was removed by washing the dichloromethane layer with 20% aqueous potassium carbonate solution, followed by water washings to get crude base.
The obtained crude base of compound of Formula I additionally contains large amounts of overalkylated compound which were further eliminated by recrystallisation the crude reaction mass from aromatic hydrocarbon solvents selected from toluene, xylene etc, more preferably toluene. After recrystallization from toluene, the Tamsulosin base obtained contains less than 1 % of overalkylated product i.e 5-(7?)-2{Bis-[2-(2-ethoxy-phenoxy)-ethyl] -amino }-propyl)-2-methoxy-benzenesulfonamide and the compounds of Formula II and III are less than 0.5 %.
The major advantage realized in the present process of invention is the use of various solvents for purification of the crude compound of Formula I. Normally in the prior-art process this condensation leads to generation of many impurities and by-products which are difficult to remove. Hence, column chromatography is employed to remove these impurities/byproducts so as to make a purer product. Instead, a combination of solvents have been employed in the present invention so as to remove these impurities in various stages thereby avoiding column chromatography altogether.
The Tamsulosin base is further converted to hydrochloride in ethanol with ethanolic HC1 to give pure Tamsulosin hydrochloride having less than 0.1 % of all individual impurities and less than 0.2 of total impurities.
The compound of Formula II is prepared by known methods in literature.

Example-1
Preparation of i?-(-)-5-(2-AminopropyI-2-methoxybenzene sulphonamide
27?,li?-2-Methoxy-5-[2-(l-Methyl benzyl amino)propyl]benzene sulphonamide HC1 (150 g 0.39 moles) of and 1500 ml methanol was charged with 15 g of activated carbon and maintained for 30 min at room temperature. After completion of the reaction, the reaction mass was filtered. The obtained filtrate was diluted with 1500 ml methanol and charged with 30 g of 10% Pd/C 50% wet. Debenzylation was carried out under 4-5 Kg/cm2 H2 pressure at 60-65°C. The reaction was monitored by HPLC. After completion of the reaction, methanol was distilled off under vacuum at 45-50°C. The residue was neutralized with aqueous ammonia (240 ml of 20% solution) and crystallized from hot water to give pure product. Weight :76 g (80% yield) HPLC purity 99.8%, and chiral purity 99.8%.
Example-2
Preparation of Tamsulosin base
i?-(-)-5-(2-Amino propyl-2-methoxybenzene sulphonamide (25 g 0.10 moles) of in 425 ml of methanol and l-(2-Bromoethoxy)-2-ethoxy benzene (37.5 g, 0.15 moles) was charged at 25-35°C. The reaction mass was heated to reflux and maintained for 48 hours. The methanol was distilled off under vacuum at below 55°C. The residue was extracted with 375 ml of n-hexane twice to recover l-(2-Bromoethoxy)-2-ethoxy benzene. The residue after n-Hexane extracts is further extracted twice with methylene chloride 300 ml the undissloved is R-(-)-5-(2-Amino propyl-2-methoxybenzene sulphonamide and can be recycled. The methylene chloride layer is washed twice with 210 ml of 20% potassium carbonate solution. Wash twice with 210 ml of water, distill off methylene chloride. The crude product was recrystallized twice with 290 ml Toluene. Material was dried at 50°C. Weight: 15 g : HPLC purity : 99% Dimer content NMT 1.0%

Example -3
Preparation of Tamsulosin Hydrochloride
Tamsulosin base (15 g, 0.036 moles) was dissolved in 225 ml of ethanol at 75-78°C. The reaction mass was cooled to 65°C and charcolized. The reaction mass was filtered. The reaction mass cooled to 20°C and pH of the reaction mass was adjusted to 2.0 with 10% ethanolic HC1. The reaction mass was maintained at 25-30°C for 3.0 hours and subsequently heated to reflux for 30 minutes. Cool the reaction mass to 40-45°C and filtered and washed the cake with 20 ml ethanol. Dry the material under vacuum at 40-50 °C. Dry Weight: 16.0 g HPLC Purity : 99.9%

WE CLAIM :
1) An improved process for the preparation (7?)-5-(2-(2-ethoxyphenoxy)ethylamino)-l-propyl)-2-methoxybenzenesulfonamide of Formula I
Formula I
and its pharmaceutical^ acceptable salts which comprises :
a) neutralizing the (7?)-(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide
hydrochloride of Formula II,
l_l MA O
Formula II
with a base to give (7?)-(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide of Formula HI,
Formula III
b) reacting the (7?)-(-)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide of Formula III
with a substituted phenoxy compound of Formula IV,
Formula IV wherein Z represents a leaving group such as O-SO2CH3, -OSO2C6H4CH3, -F, -Br, -CI, or
-I,
c) extracting the reaction mass of claim lb with aliphatic hydrocarbon solvents,
chlorinated solvents,

d) recrystallizing the crude reaction mass of claim lc to give compound of Formula I
2) The process according to claim 1, wherein the base employed in step(a) is ammonia.
3) The process according to claim 1, step (c) wherein extraction is performed by employing aliphatic hydrocarbons, chlorinated hydrocarbons.
4) The process according to claim 3, wherein the extraction is performed employing
aliphatic hydrocarbons that are selected from n-hexanes, heptanes, cyclohexane
5) The process according to claim 4, wherein the solvent employed is n-hexane
6) The process according to claiml,step(c) wherein the extraction is performed
employing chlorinated hydrocarbons that are selected from chloroform, carbon
tetrachloride or dichloromethane
7) The process according to claim 6, wherein the chlorinated hydrocarbon employed is
dichloromethane.
8) The process according to claim 1, step(d) wherein the compound of Formula I is
recrystallized from aromatic hydrocarbon solvents selected from toluene, xylene more
preferably toluene.
9) The process according to claim 8, wherein the hydrocarbon solvent employed is
toluene.
10) The process according to claim 1, wherein the compound of Formula I is having a
purity of > 99%.