'".

The (R) (-) Tamsulosin hydrochloride of formula (III) produced by the process has an alpha-adrenergic blocking action and possesses a hypotensive activity and is used mainly for the treatment of benign prostatic hyperplasia (BPH).

BACKGROUND OF THE INVENTION : WO 02/068382A1 describes the process for the preparation of (R) (-) -Tamsulosin hydrochloride III by the condensation of I with 2-ethoxy phenoxyacetyl chloride IV to give 2- (2-ethoxy-phenoxy)-N- [2- (4-methoxy-3-sulfamoyl-3-phenyl)-l- methylethyl] acetamide (V) which on, reduction with lithium aluminium hydride yielded R- (-) Tamsulosin hydrochloride (III), (Scheme-1). R'O HzNOaS 2 O lv Y= Cl, OR, OC (=O) R (R'= Et) base HaNO2S C r"'H N, HN,, o H3C0 (R'= Et) Lithium aluminium H2N02S hydride 0 H3CO HUI. III (R'= Et)

CHg YScheme I The main disadvantage of this process is the use of lithium aluminium hydride as reducing agent, which is extremely moisture sensitive and pyrophoric hence, difficult to use at industrial scale.

US patent 4731478 describes the synthesis of (R) (-) Tamsulosin

Scheme - II hydrochloride (III) by condensing R (-)-5- [ (2-amino-2-methyl) ethyl] -2-methoxy benzenesulfonamide (I) with 2- (2-ethoxy phenoxy) ethyl bromide (II) in ethanol (Scheme-11). The process described therein yields the Tamsulosin hydrochloride in a very poor yield (37%). Moreover, in the process described therein, (R) (-) Tamsulosin hydrochloride (III) purification is proposed using column chromatography which is expensive, time consuming and impractical at industrial scale.

Importantly, it is found that in the above process of US'478, the base compound of Formula I, which is used as a free base and reacted with the compound of Formula II resulted in a final product (Tamsulosin Base) with contaminants of

unreacted compound of Formula I. This lead to difficulties in isolating the final product and also loss in yield of Tamsulosin Hydrochloride alongwith problems of purity.

OBJECTS OF THE INVENTION It is thus the basic object of the present invention to provide a process for the preparation of (R) (-) Tamsulosin Hydrochloride, which would be high yielding, cost effective, easy to operate at industrial scale and would not involve the use of moisture sensitive, pyrophoric compounds.

Another object of the present invention is to provide a process of manufacture of [ (R) (-) -5- [2- [ [2- (o-ethoxy-phenoxy) ethyl] amino]-2-methylethyl]-2- methoxybenzenesulfonamide hydrochloride] which would avoid unreacted contaminants in the final product and provide for isolating and obtaining the final product with good yield and purity.

Yet another objective of the invention is to provide a process for the preparation of (R) (-) Tamsulosin Hydrochloride that would not require the handling of hazardous reagents, such as LAH A further objective of the invention is to provide a process of manufacture of [ (R) (-) -5- [2- [[2-(o-ethoxy-phenoxy) ethyl] amino]-2-methylethyl]-2- methoxybenzenesulfonamide hydrochloride] that, would involve selective mild reaction conditions.

A further object of the invention is to provide a process of manufacture of [ (R) (- ) -5- [2- [ [2- (o-ethoxy-phenoxy) ethyl] amino]-2-methylethyl]-2- methoxybenzenesulfonamide hydrochloride] that would be industrially favourable in that the same would use less amount of solvent, hence increase the plant capacity and will also require less manpower.

A further object of this invention is to provide the method of purification which would be industrially feasible for large scale preparation of [(R)-(-)-5-[2-[[2-(o- ethoxy-phenoxy) ethyl] amino]-2-methylethyl]-2-methoxy benzene sulfonamide hydrochloride].

SUMMARY OF THE INVENTION: The present invention provides a process for the preparation of (R) (-) Tamsulosin Hydrochloride [ (R) (-) -5- [2- [ [2- (o-ethoxyphenoxy) ethyl] amino]-2-methylethyl]- 2-methoxybenzenesulfonamide hydrochloride] (III) comprising reacting R- (-)-5- [ (2-amino-2-methyl) ethyl] -2-methoxy benzenesulfonamide hydrochloride (I) with the compound of formula (II) wherein X represents F, Cl, Br, I, OSO2CH3, OSO2CF3, OTs, OBs, ONs or any other suitable leaving group in the presence or absence of a suitable catalyst, a suitable base, in a organic solvent.

The reaction scheme followed is as shown in Scheme III hereunder : Scheme-111

DETAILED DESCRIPTION OF THE INVENTION: The present invention relates to a process for the preparation of (R) (-) Tamsulosin Hydrochloride [ (-)-5-[2-[[2-(o-ethoxyphenoxy) ethyl] amino]-2-methylethyl]-2- methoxybenzenesulfonamide hydrochloride] (III) comprising the reaction of R- (-)-5- [ (2- amino-2-methyl) ethyl]-2-methoxybenzenesulfonamide hydrochloride (I) with the compound of formula (11) l wherein X is halides such as Cl, Br, I, or sulphonates such as OS02CH3, OSO2CF3, OTs, OBs, ONs or any other suitable leaving group in the presence or absence of a suitable catalyst, a suitable base, in a organic solvent to give (R) (-) Tamsulosin base which is further crystallised with suitable solvent and converted into hydrochloride salt by suitable method and may be purified from water or polar solvents or mixtures thereof.

According to the present invention base is selected from the group comprising of metal carbonates; metal bicarbonates; alkali metal hydroxides, alkaline metal hydroxide or organic bases. The preferred base is selected from the group comprising of Potassium hydrogen carbonate. Sodium hydrogen carbonate, Sodium carbonate, Potassium carbonate, Lithium carbonate, Ammonium bicarbonate, sodium hydroxide or potassium hydroxide or tert-amines such as triethyl amine.

The organic solvent is selected from the group comprising of acetonitrile, propionitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, tetrahydrofuran, toluene, benzene, xylene,, dichloroethane, diisopropyl ether, polyethylene glycol or mixtures there of.

The catalyst is selected from potassium iodi'de, sodium iodide, tetrabutyl ammonium iodide, or a phase transfer catalysts like crown ethers, quaternary

ammonium salts, quaternary phosphonium salts or sequestering agents. The preferred catalyst is potassium iodide.

The amount of catalyst is used 0 to 2 equivalents of R (-)-5-[(2-amino-2-methyl) ethyl] -2-methoxy benzenesulfonamide hydrochloride.

The above condensation reaction is carried out at a temperature range of 20 to 120°C. The preferable temperature range is 60 to 90°C.

The above mentioned reaction is carried'out for 30 minutes to 48 hours.

Preferably the reaction is carried out for 18 to 30 hours and most preferably 24 hours.

The suitable solvent for the crystallisation of (R) (-) Tamsulosin base is selected from the group comprising of hydrocarbons, alcoholic solvent, ketonic solvent, aliphatic esters or mixtures thereof. The preferred solvent is selected from the group comprising of toluene, xylene, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, butyl acetate or mixtures there of.

The crystal structure of the Tamsulosin hydrochloride thus prepared has the endotherm in DSC at 235. 8°C (Figure 1) and the XRD (Figure II) reported as below d-spacing 16.10, 7.99, 6.06, 5.62, 5.29, 5. 06,. 4.62, 4.26, 3.98, 3.86, 3.75, 3.66, 3.52, 3.36, 3.29, 3.23, 3.01, 2.97, 2.85, 2.72, 2.55, 2.42 The process of the present invention is described by the following examples, which are illustrative only and not be construed so as to limit to the scope of the invention in any manner.

Examples: Example: 1 A mixture of R (-)-5-[(2-amino-2-methyl) ethyl]-2-methoxy benzenesulfonamide hydrochloride (5 g), 2- (2-ethoxy phenoxy) ethyl bromide (4.3 g), potassium hydrogen carbonate (3.5 g), potassium iodide as catalyst (0.6 g) and Acetonitrile (100 ml) was refluxed for 24 hrs. The solvent was distilled off under vacuum. Water (100 ml) was added in the reaction mixture. Stirred the reaction mixture for 1 hr. The separated solid was filtered and dried to give crude (R) (-) Tamsulosin Base (7.2 g).

The crude (R) (-) Tamsulosin base was crystallized from toluene to get pure (R) (-) Tamsulosin base. The base was dissolved in methanol (5 volume) and adjusted pH 2 by isopropanolic HCI to get (R) (-) Tamsulosin HC1. This may be crystallized from water (20 volumes) or methanol (50 volumes) to remove polar impurities.

[HPLC Purity 99.5%, [α] 24D-3. 8° (c=0. 35, Methanol), M. P. 230-232°C] 1H-NMR (DMSO-d6) ; # (ppm) = 9. 5 (bs, 2h),' 7. 62 (d, lH), 7.45 (dd, lH), 7.17 (d, lH) 7. 08 (s, 2H), 6.93 (m, 4H), 4.33 (t, 2H), 4.0 (q, 2H), 3. 88 (s, 3HO, 3.54 (b, 1H), 3. 40 (b, 2H), 3. 31 (d, lH), 2.66 (t, 1H), 1.25 (t, 3H), 1.16 (d, 3H).

13C-NMR (DMSO-d6) ; # (ppm) = 155.7, 149.52, 148. 14,135. 28,132. 03,129. 10, 123. 11,121. 55,116. 09,114. 39,113. 70,65. 90,64. 53,56. 95,55. 53,43. 81, 38. 05, 15. 58, 15.43.

IR: (cm-1) : 3354,3082, 2981, 2811, 2744,'1608, 1589, 1498, 1455,1414, 1392, 1338,1282, 1251,1215, 1159,1128, 1072,1045, 1018,915, 897,819, 749,718, 677,602, 577,514.

Example : 2 A mixture of R (-)-5-[(2-amino-2-methyl) ethyl]-2-methoxy benzenesulfonamide hydrochloride (5 g), 2- (2-ethoxy phenoxy) ethyl bromide (4.3 g), potassium hydrogen carbonate (3.5 g), potassium iodide as catalyst (0.6g) and DMF (100 ml) was refluxed for 24 hrs. The solvent was distilled off under vacuum. Water (100 ml) was added in the reaction mixture. Stirred the reaction mixture for 1 hr. The separated solid was filtered and dried to give crude (R) (-) Tamsulosin Base (5. 0 g).

It was purified and converted into hydrochloride salt by process as described in example 1.

Example: 3 A mixture of R (-)-5- [ (2-amino-2-methyl) ethyl] -2-methoxy benzenesulfonamide hydrochloride (5 g), 2- (2-ethoxy phenoxy) ethyl bromide (5 g), potassium hydrogen carbonate (3.5 gm), potassium iodide as catalyst (0.6 g) and Acetonitrile (100 ml) was refluxed for 24 hrs. The solvent was distilled off under vacuum. Water (100 ml) was added in the reaction mixture. Stirred the reaction mixture for 1 hr. The separated solid was filtered and dried to give crude (R) (-) Tamsulosin Base (6.0 g).

It was purified and converted into hydrochloride salt by process as described in example 1.

Example : 4 A mixture of R (-)-5-[(2-amino-2-methyl) ethyl]-2-methoxy benzenesulfonamide hydrochloride (5 g), 2- (2-ethoxy phenoxy) ethyl bromide (5.0 g), potassium hydrogen carbonate (3.5 g), potassium iodide as catalyst (0.6 g) and 2-Butanone (100 ml) was refluxed for 24 hrs. The solvent was distilled off under vacuum. Water (100 ml) was added in the reaction mixture. Stirred the reaction mixture for 1 hr. The separated solid was filtered and dried to give crude (R) (-) Tamsulosin Base (6.4 g).

It was purified and converted into hydrochloride salt by process as described in example 1.

Example: 5 A mixture of R (-)-5-[(2-amino-2-methyl) ethyl1-2-methoxy benzenesulfonamide hydrochloride (5 g), 2- (2-ethoxy phenoxy) ethyl mesylate (4.3 g), potassium hydrogen carbonate (3. 5 g) potassium iodide (0. 69) and Acetonitrile (100 ml) was refluxed for 24 hrs. The solvent was distilled off under vacuum. Water (100 ml) was added in the reaction mixture. Stirred the reaction mixture for 1 hr. The separated solid was filtered and dried to give crude (R) (-) Tamsulosin Base (6.4 g).

It was purified and converted into hydrochloride salt by process as described in example 1.

To demonstrate the comparative advantages of the process of the invention i. e. involving the use of hydrochloride salt of Formula I as the starting material instead of the use of the compound of Formula I as base as initial reactant (US'478) to react with the compound of Formula 11, the following example was carried out following the process as that of US '4731478 as detailed hereunder : Example 6 In 120ml of ethanol were dissolved 2. 4 g of (R) 5-[(2-amino-2-methyl) ethyl]-2- methoxybenzenesulfonamide and 1.2 g of 2-(o-ethoxyphenoxy) ethyl bromide and the mixture was refluxed under heating. The solvent was distilled away.

The reaction conditions followed under Examples 1 to 5 (in accordance with the invention) and that under Example 6 (of US 4731478) and the yield obtained are detailed in TABLE I hereunder: Table-1 Examples 2- (2-ethoxyphenoxy) Base Catalyst Solvent Yield ethyl bromide (Formula, (%) H as bromide derivative) 1. 4.3 g KHCO3 KI Acetonitirle 75.6% 3. 5 0. 6 g) (20 v) 2.4. 3 g KHCO3 KI DMF (20 v) 93.4% (3. 5 g) (0.6 3. 5 g KHC03-Acetonitirle 74.16% (3. 5 g) (20 v) 4. 5 g KHC03 KI (0. 6 g) 2-Butanone 51.42% (3. 5 g) 5. (F ormula II as Mesulate KHCO3 KI Acetonitirle 93. 22% derivative) (3. 5 g) (0.6 g) (20 v) 6.1. 2 g --- --- Ethanol (50 32% v)

It would be apparent from the above comparative study results of the process of the invention vis-à-vis the process of US'478 that the process of the invention which involves the use of salt of compound of Formula I instead of its base form as proposed in US'478 achieves higher yield of the final product (Tamsulosin Base) and serves as a selective industrially applicable process for the manufacture of Tamsulosin hydrochloride of Formula III.