Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF (R) (-) TAMSULOSIN HYDROCHLORIDE

Abstract

A process for the preparation of (R)(-)Tamsulosin hydrochloride (III) comprising of reacting R(-)-5-[(2-amino-2-methyl)ethyl]-2-methoxy benzenesulfonamide hydrochloride (I) with the compound of formula (II) wherein X represents F, CI, Br, I, OSO2CH3, OSO2CF3, OTs, OBs, ONsor any other suitable leaving group in presence of a suitable base and an organic solvent to give (R)(-) Tamsulosin base, which is isolated and crystallized from a suitable solvent and converted into the hydrochloride salt , optionally, purifying the said hydrochloride salt from any one or more of water, polar solvents and mixtures thereof. Ill

Full Text

FORM - 2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION (See Section RULE 13 I^FITLC Or INVENTION AN IMPROVED PROCESS FOR THE PREPARATION OF (R) (-) TAMSULOSIN HYDROCHLORIDE r > '. ' ' ALEMBIC LIMITED, Alembic Road, Vadodara-390 003, Gujarat, India, an Indian Company. The following specification particularly describes the nature of the invention and the manner in which it is to be performed. AN IMPROVED PROCESS FOR THE PREPARATION OF (R) (-) TAMSULOSIN HYDROCHLORIDE TECHNICAL FIELD: The present invention relates to a process for the preparation of (R)(-) Tamsulosin hydrochloride [(R)(-)-5-[2-[[2-(o-ethoxy-phenoxy)ethyl]aminop2-methylethyl]-2- methoxybenzenesulfonamide hydrochloride] of formula (III), III 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)-1- methylethyl] acetamide ( V .) which on reduction with lithium aluminium hydride yielded R-(-) Tamsulosin hydrochloride (III), (Scheme-I). 2 H2N02S H3CO R'O IV Y= CI, OR, OC(=0)R (R'= Et) base H3CO H2N02S CH, R'O, V (R'= Et) R'O, H2N02S H3CO Lithium aluminium hydride III (R'= Et) Scheme 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. 3 US patent 4731478 describes the synthesis of (R)(-) Tamsulosin H2N02,S H3CO s "I 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-ll). 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 1 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 4 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-phenpxy)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 o.f (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. 5 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] a'mino]-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, CI, Br, I, OSO2CH3, OSO2CF3, Tosylate o-Toluene Sulfonates (OTs), Brosylate p-Bromobenzene Sulfonate (OBs), Nosylate p-Nitrobenzene sulfonate (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: III Scheme - III 6 DETAILED DESCRIPTION OF THE INVENTION: The present invention relates to a process for the preparation of (R)(-) Tamsulosin Hydrochloride [(R)(-)-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 (II) wherein X is halides such as CI, Br, I, or sulphonates such as OS02CH3, OS02CF3, 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 iodide, sodium iodide, tetrabutyl ammonium iodide, or a phase transfer catalysts like crown ethers, quaternary 7 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)(-) Tarnsulosin 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 structureofjhe Tarnsulosin hydrochloride thus prepared has the endotherm in DSC at 235.8°C (Figure I) 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 HCI. This may be crystallized from water (20 volumes) or methanol (50 volumes) to remove polar impurities. [HPLC Purity 99.5%, [ a]24D -3.8° (c=0 35, Methanol),M.P. 230-232°C] 1H-NMR (DMSO-d6); 5 (ppm) = 9.5(bs,2h)," 7.62 (d,1H), 7.45 (dd,1H), 7.17(d,1H) 7.08 (S,2H), 6.93 (m,4H), 4.33 (t,2H), 4.0 (q, 2H), 3.88 (S.3H0. 3.54 (b,1H), 3.40(b,2H), 3.31(d,1H),2.66(t,1H), 1.25(t, 3H), 1.16 (d,3H). 13C-NMR (DMSO-d6); 5(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). 9 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 Teftuxed IOT 24 hrs. The so'rverrt was disti'rted off under vacuum. Vvater (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) ethyl]-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)(-) Tamsu'iosin Base (6.4 g). 10 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 II, 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) ethyl bromide (Formula II as bromide derivative) Base Catalyst Solvent Yield (%) 1. 4.3 g KHC03 (3.5 g) Kl (0.6 g) Acetonitirle (20 v) 75.6% 2. 4.3 g KHCO3 (3.5 g) Kl (0.6 g) DMF (20 v) 93.4% 3. 5g KHCO3 (3.5 g) Acetonitirle (20 v) 74.16 % 4. 5g KHCO3 (3.5 g) Kl (0.6 g) 2-Butanone 51.42 % 5. (Formula II as Mesulate derivative) KHCO3 (3.5 g) Kl (0.6 g) Acetonitirle (20 v) 93.22 % 6. ^ 1.2g — — Ethanol (50 v) 32% 11 12 It would be apparent from the above comparative study results of the process of the invention vis-a-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. we claim 1. A process for the preparation of (R)(-)Tamsulosin hydrochloride (III) comprising of reacting R(-)-5-[(2-amino-2-methyl)ethyl]-2-methoxy benzenesulfonamide hydrochloride (I) with the compound of formula (II) wherein X represents F, CI, Br, I, OSO2CH3, OSO2CF3, OTs, OBs, ONsor any other suitable leaving group in presence of a suitable base and an organic solvent to give (R)(-) Tamsulosin base, which is isolated and crystallized from a suitable solvent and converted into the hydrochloride salt , optionally, purifying the said hydrochloride salt from any one or more of water, polar solvents and mixtures thereof. Ill 2. A process for the preparation of (R)(-)Tamsulosin hydrochloride (III) as claimed in claim 1 wherein said condensation reaction of the compound of Formula I with the compound of Formula II is carried out in the presence of a catalyst. 3. Process according to anyone of claims 1 or 2 wherein the base is selected from the group comprising of alkali or alkaline earth metal carbonates, bicarbonates or hydroxides or organic bases. 4. Process according to anyone of claims 1 to 3 wherein base is preferably selected from the group comprising of Potassium hydrogen carbonate, Sodium hydrogen carbonate, Sodium carbonate, Potassium carbonate, Lithium carbonate, Ammonium bicarbonate, sodium hydroxide, potassium hydroxide and tert-amines preferably triethyl amine. 5. Process according to claim 4, wherein base is more preferably Potassium hydrogen carbonate. 6. Process according to any one of claims 1 to 5 wherein the amount of base used is 1 to 4 equivalents, preferably 1 to 3 equivalents of R(-)-5-[(2-amino-2-methyl)ethyl]-2-methoxybenzenesulfonamide hydrochloride 7. Process according to anyone of claims 1 to 6 wherein 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, aliphatic esters, tetrahydrofuran, dioxane, toluene, benzene, xylene, dichloroethane, diisopropyl ether, polyethylene glycol or mixtures thereof. 8. Process according to claim 7, wherein the organic solvent is preferably Acetonitrile. 9. Process according to any one of claims 1 to 8 wherein the amount of the organic solvent used is between 0.5 to 100 volumes, preferably 10 to 30 volumes of R(-)- 5-[(2-amino-2-methyl)ethyl]-2-methoxybenzenesulfonamide hydrochloride. 10. Process according to anyone of claims 2 to 9 wherein the reaction is carried out in the presence of a catalyst selected from Iodide salts preferably Potassium iodide, sodium iodide, a phase transfer catalysts preferably crown ethers, quaternary ammonium salts preferably tetrabutyl ammonium iodide, quaternary phosphonium salts, and sequestering agents, polyethylene glycols. 14 11. Process according to claim 10, wherein the catalyst used is preferably Potassium iodide or sodium iodide. 12. Process according to anyone of claims 2 to 11, wherein the amount of catalyst used is between 0 to 2 equivalents more preferably 0.05 to 1 equivalent, most preferably 0.2 equivalents of R(-)-5-[(2-amino-2-methyl)ethyl]-2-methoxybenzenesulfonamide hydrochloride" 13. Process according to anyone of claims 1 to 12 wherein the reaction is carried out at temperature of 20°C to 120°C, preferably 60°C to 90°C. 14. Process according to anyone of claims 1 to 13 wherein the reaction is carried out for 30 minutes to 48 hours, more preferably 18 to 30 hours, and most preferably 24 hours. 15. Process according to anyone of claims ltol4 wherein the ratio of (R)(-)-5-[(2-amino-2-methyl)ethyl]-2-methoxy benzenesulfonamide hydrochloride of formula (I) to compounds of formula (II) wherein X represents F, CI, Br, I, OS02CH3, OS02CF3, OTs, OBs, ONs or any other suitable leaving group) is 0.5 to 1.5 equivalents, more preferably 0.8 to 1.2 equivalents, most preferably 1 equivalent. 16. Process according to anyone of claims 1 to 15 wherein the (R)(-) Tamsulosin base is crystallised from suitable solvents selected from the group comprising of hydrocarbons, alcoholic solvent, ketonic solvent, aliphatic esters, other aliphatic solvents and mixtures thereof. 15 L 17.Process according to claim 16, wherein the (R)(-) Tamsulosin base is crystaliised from suitable solvents selected from the group comprising of toluene, benzene, xylene, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, butyl acetate or mixtures there of. 18. Process according to anyone of claims 16 to 17 wherein the (R)(-) Tamsulosin base is preferably crystallised from toluene. 19.Process according to anyone of claims 1 to 18 wherein the crude (R)(-) Tamsulosin base is converted to hydrochloride salt in solvent preferably selected from acetone, methanol, ethanol, propanol, water, using gaseous hydrogen chloride gas, its solution in methanol, ethanol, isopropanol and water. 20. Process according to anyone of _claims 1 to 19, wherein the crude (R)(-) Tamsulosin base is dissolved in methanol and acidified with isoprbpan'olic hydrogen chloride to obtain (R)(-) Tamsulo"siri"hydrochloride. 21. Process according to anyone of claims 1 to 20 wherein the (R)(-)-Tamsulosin hydrochloride is recrystallized from water or methanol to give a polymorph having the following d-spacing values in powder XRD, 16.10, 7.99, 6.06, 5.62, F* 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 (Figure II) and an endotherm in DSC at 235.8°C (Figure I). 22.A process for the preparation of (R)(-) Tamsulosin Hydrochloride (III) substantially as herein described and illustrated with reference to the accompanying examples and figures. Dated this 07th day of March 2003. SIDDHARTHA NAG Of S.MAJUMDAR & CO. Applicant's Agent 16

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