Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF TAMSULOSIN HYDROCHLORIDE

Abstract

The present invention relates to an improved process for the preparation of Tamsulosin hydrochloride. Tamsulosin hydrochloride is a widely used drug for the treatment of benign prostate hyperplasia. Tamsulosin hydrochloride has the formula-1 given below. (I) The process employs the novel intermediates quartemised benzylidene ammonium salts, N-(phenyl ethyl]ammonium halides of the formula-II, (II) where R represents H, 4-0CH>3<, 4-0H or 4- fluoro 'and X represents C 1, Br or I. And Scruffs bases, novel phenyl substituted 2-methoxy-5- [(2R)-[(1-E/Z-phenyl methylene)amino]propyl]benzenesulfonamide of the formula-III. (III) where R represents H, 4-0CH>3<, 4-0H or 4-fluoro.

Full Text

The present invention relates to an improved process for the preparation of Tamsulosin hydrochloride. Tamsulosin hydrochloride is a widely used drug. for the treatment of benign prostate hyperplasia. Tamsulosin hydrochloride has the formula-I given below. The process employs the novel intermediates quartermaster benzylidene ammonium salts, N-(phenyl substituted)-[2-(2-ethoxyphenoxy)ethyl]-[2-(4-methoxy-3-sulphamoylphenyl)-l(R)-methyl-ethyl]ammonium halides of the formula-II, where R represents H, 4-OCH3, 4-OH or 4-fluoro and X represents CI, Br or I. and Schiff s bases, novel phenyl substituted 2-methoxy-5-[(2R)-[( 1 -E/Z-phenyl methylene)amino]propyl]benzenesulfonamide of the formula-Ill. where R represents H, 4-OCH3, 4-OH or 4-fluoro. The novel intermediates of the above mentioned formulae-II & III which are useful for the preparation of Tamsulosin hydrochloride and the processes for their preparation have been made the subject matters of our co pending applications nos. B/lVIAS/2002 & C/MAS/2002 respectively. Prior Art: Tamsulosin hydrochloride is first disclosed in JP 55-14382 dt. 8-2-1980 and its equivalent US 4731,478 dt. 15/3/1988, wherein the intermediate R(-)-5-[(2-amino-2-methyl)ethyl]-2-methoxybenzenesulfonamide of formula-IV is refluxed for 16hrs with another intermediate 2-(2-ethoxyphenoxy) ethylbromide of Formula-V in ethanol medium to obtain crude Tamsulosin base, which is purified by column chromatography to get pure base. The pure Tamsulosin base is treated with HCl in ethanol to obtund Tamsulosin hydrochloride of formula-I in 36.8% of yield based on the expensive intermediate of formula-IV. The synthetic route is given below in scheme-A. further the reaction time required is very long (i.e) more than 16hrs resuming in poor yields. The expensive intermediate R(-)-5-[(2-amino-2-methyl)ethyl-2-methoxybenzenesulfonamide of formula-IV is required in 2 mole equivalents to the other intermediate 2-(2-ethoxyphenoxy) ethylbromide of formula-V as the compound of formula-IV is reacted to form salt with the liberated HBr formed during the coupling reaction. It is also disclosed in JP 254326 and its Austrian equivalent patent AT 397960 B that R(-) 5-[(2-amino-2-methyl)ethyl]-2-methoxybenzenesulfonamide of formula-IV is reacted with 2-(2-ethoxyphenoxy)acetaldehyde of formula-X, which is generated insitu by acid treatment of 2-(2-ethoxyphenoxy)acetaldehyde dimethyl acetal of formula-VII to get an imine compound of formula-Vin. Then the imine compound of formula-VIII is reduced with either platinum oxide or sodium borohydride / sodium cyano borohydride and on further treatment with HCl to obtain Tamsulosin hydrochloride of formula-I. The process for making compound of formula-VII is also disclosed. Guaiethol is reacted with bromo acetaldehyde diethylacetal of formula-IX using sodium hydride as base and dimethyl formamide as solvent. The reaction sequence is shown in scheme-B. 1. For the preparation of intermediates 2-(2-ethoxyphenoxy) acetaldehyde of formula-X, more steps are involved and pyrophoric reagents like sodium hydride has to be used for synthesis of the compound of formula-X. 2. For the reduction of imine of formula-VIII expensive and pyrophoric hydrogenation catalyst platinum oxide has to be used and special hydrogenation equipment is necessary to carry out the catalytic hydrogenation. 3. For the reduction of imine of formula-VIII expensive reagent sodium borohydride / sodium cyano borohydride is necessary. JP 02306958 (1988-Hokuriku) discloses an alternate process for making Tamsulosin hydrochloride of formula-I. (2R)-4-Methoxyphenylisopropylamine of formula-XI is reacted with 2-bromoacetic acid of formula-XII using pivaloyl chloride and triethylamine to obtain N-2-(bromo acetoxy)-2(R)-4-methoxyphenylisopropylamine of formula-XIII. The compound of formula-Xi is reacted with chloro sulphonic acid and then with ammonia solution to obtain its sulfonamide derivative of formula-XIV, which is reacted with guaiethol using potassium carbonate as base to obtain an amide derivative of formula-XV. The amide derivative of formula-XV is reduced with lithium aluminium hydride to secondary amine compound, which on treatment with HCl gives Tamsulosin hydrochloride of formula-L The synthetic route is outlined in the following scheme-C. The main drawbacks in this process are: 1. More steps are involved there-by making the route very cumbersome. 2. Highly pyrophoric and expensive reagent lithium aluminium hydride is necessary to carry out the reduction of amide to secondary amine. Recognizing the importance of Tamsulosin hydrochloride of the formula-I as a widely used drug for the treatment of benign prostate hyperplasia, and taking into account the difficuhies of the hitherto known processes for its preparation, we under-took research to develop a simple, cheap and commercially viable process for producing Tamsulosin hydrochloride, starting with (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide of formula-IV. The main objective of the present invention, therefore, is to provide an improved process for the preparation of Tamsulosin hydrochloride, which is commercially viable. Another objective of the present invention is to provide an improved process for the preparation of Tamsulosin hydrochloride having single largest impurity less than 0.1% and total impurities less than 0.5%. Yet another objective of the present invention is to provide an improved process for the preparation of Tamsulosin hydrochloride having a chiral purity (enantiomeric excess) of more than 99.9%. Yet another objective of the present invention is to provide an improved process for the preparation of Tamsulosin hydrochloride, wherein the usage of specialized equipment like hydrogenate is not necessary thereby making the process simple. Yet another objective of the present invention is to provide an improved process for the preparation of Tamsulosin hydrochloride, wherein the usage of pyrophoric and expensive reagents like Lithium aluminium hydride, platinum oxide and also expensive reagent like sodium borohydride are not used thereby making the process safer and economical. The monoalkylation of the primary amine of formula-IV is carried out by the method of Decker & Becker [Decker & Becker, Ann, 395, 328 (1913)]. So far this method has not been used earner for making Tamsulosin hydrochloride of formula-I. Accordingly the present invention provides an improved process for the preparation of Tamsulosin hydrochloride of formula-I. Which comprises following steps: (i) reacting the compound of the formula-IV with a substituted aromatic benzaldehyde of the formula-XVI, where R represents group such as H, 4-OH, 4-OCH3 or 4-fIuoro to obtain novel compounds namely phenyl substituted 2-methoxy-5-[(2R)-[( 1 -E/Z- pheylmethylene)amino] propyl] benzenesulfonamide of formula-III, where R represents H, 4-OH, 4-OCH3 or 4-fluoro (ii) reacting the resulting compound of the formula-III vent 2-(2-ethoxyphenoxy) ethylhalide of the formula-XVII, where the halo group is CI, Br or I at a temp in the range of 80 to 130° to obtain the novel quart Mary ammonium sacs, namely N-(phenyl substituted)-[2-(2-ethoxyphenoxy)ethyl]-[2-(4-methoxy-3- sulphamoyI-phenyl)-l(R)-methylethyl]ammonium halides of the formula-H, where R represents H, 4-OH, 4-OCH3 or 4-fluoro groups and X represents CI, Br or I (iii) hydrolysing the quart Mary ammonium sacs of the resulting compound of the formula-H by heating in water to obtain the corresponding hydrogen halide salts of formula-I (iv) neutralising the hydrogen halide salts of the formula-I thus obtained by conventional methods to produce the Tamsulosin base of the formula-XVIII, and (v) converting the Tamsulosin base of the formula XVIII into Tamsulosin hydrochloride of formula-I by conventional methods. In a preferred embodiment of the present invention the step (i) may be effected by isotopically removing the water using a solvent such as toluene, xylene etc. or by simultaneous distillation of the water formed using an alcoholic solvent such as methanol, ethanol, isopropyl alcohol, n-butanol etc. The reaction of step (ii) may be performed either neatly or by using solvent such as toluene, xylene, n-butanol, dimethyl formamide, dimethyl acetamide etc. The compound of formula-II is isolated by filtration or by removal of the solvent and by simple leaching with a suitable solvent such as methylene chloride etc., to remove the unreacted alkyl halide. In step (iii) the hydrolysis may be carried out using hot water. The liberated aldehyde, may be removed by steam distillation or by extraction with a solvent such as methylene chloride. The neutralization in step (iv) may be done using solutions of alkali bicarbonates, carbonates such as sodium bicarbonate, potassium bicarbonate etc. and sodium carbonate, potassium carbonate, etc and alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide etc, to obtain the crude base compound of Tamsulosin of formula-XVHI. The crude Tamsulosin base may be purified by column chromatography or by recrystallization using suitable solvents such mixtures of dimethyl formamide and acetonitrile, dimethyl formamide and isopropyl ether etc. The Tamsulosin hydrochloride is prepared using solvents such as methanol, ethanol, isopropyl alcohol etc and hydrogen chloride solution in isopropyl alcohol. In an embodiment of the present invention the reaction of the compound of the formula-I with a substituted aromatic benzaldehyde of the formula-XVI, where R represents group such as H, 4-OH, 4-OCH3 or 4-fluoro to obtain novel compounds namely phenyl substituted 2-methoxy-5-[(2R)-[( 1 -E/Z-pheylmethylene)amino]propyl]benzenesulfonamide of formula-III, where R represents H, 4-OH, 4-OCH3 or 4-fluoro. In another embodiment of the invention the reaction of the resulting compound of the formula-Hi with 2-(2-ethoxyphenoxy) ethylhalide of the formula-XVII, where the halo group is CI, Br or I at a temp in the range of 80° to 130° to obtain the novel quart Mary ammonium salts, namely N-(phenyl substituted)-[2-(2-ethoxyphenoxy)ethyl]-[2-(4-methoxy-3-sulphamoylphenyl)-1 (R)-methyl-ethyl]ammonium halides of the formula-II, where R represents H, 4-OH, 4-OCH3 or 4-fluoro groups. The details of the invention are given in the examples given below which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention. Example-1. (i) Preparation of 2-methoxy-5-(2R)-2-{[(l-E/Z-phenyl ethylene)amino]propyl} benzenesulfonamide of formula-Ilia. Into a 4-necked 500ml round bottom flask equipped with Dean-Stark apparatus, 150.0ml of toluene, 24.4gms (O.lmole) of (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide of the formula-IV and 10.6gms (O.lmole) of benzaldehyde are charged. Azeotropic distillation was carried out and 1.8ml (O.lmole) of water separated. Then the toluene is distilled off completely under vacuum at temp max. 80°C. The reaction mixture is cooled to 25 - 35°C and the vacuum is released under nitrogen atmosphere. A thick oily compound 2-methoxy-5-(2R)-2{[(l-E/Z-phenyl ethylene)amino]propyl}benzenesulfonamide of formula-IIIa (33.0gm) formed, crystallized soon. Purified sample (recrystallized from IP A) has the following characteristics. MR : 121 - 126X IHNMR : (200MHz, CDCl3+DMSO-d6) 5 1.26-1.29(4 3H), 2.86-2.90 (t,2H), 3.49 - 3.59 (m, IH), 3.92 (s, 3H), 6.0 (broad, 2H), 6.9 - 7.7 (aromatic, 8H), 8.07 (s, imine, IH) IR : (KBr), 3385, 3294, 2847, 1640, 1492, 1344, 1158 cm"‘ (ii) Preparation of N-benzylidene-[2-(2-ethoxyphenoxy)ethyl]-[2-(4-methoxy-3-sulphamoyl phenyl)-l(R)-methyl-ethyl]ammonium iodide of formula-IIa. The oily mass of formula-IIIa obtained in step (i) (a) is taken and dissolved in 125.0ml of n-butanol. The solution is heated to lOO’C under nitrogen atmosphere. A solution of 29.1gms (O.lmole) of 2-(2-ethoxyphenoxy) ethyl iodide in 30ml of n-butanol is slowly added at 100 - 105°C over a period of 3 - 4 hrs and maintained at 100 - 1 lO’C for further 4hrs. Then n-butanol is distilled off under vacuum at temp not exceeding 80°C.The resulting mass is cooled to 20°C and vacuum released under nitrogen atmosphere. Added 50.0ml of n-hexane. The resuming uniform slurry is allowed to solidify at 0 - 5°C. The reaction mixture is filtered, washed with 50ml of n-hexane and the product is dried at 40 - 50’C under vacuum to obtain a solid of novel quart Mary ammonium salt of formula-IIa 35.0gms. Recrystallized (from acetonitrile) sample has the following characteristics. MR :208-210X IHNMR : (200MHz, DMSO-d6)5 1.14- 1.17 (d, 3H), 1.24- 1.36 (t, 3H), 2.79 - 2.83 (m, 2H), 3.40 (broad, 2H), 3.46 - 3.54 (m, 3H), 3.84 (s, 3H), 3.87 - 4.01(dd, 4H), 4.20- 4.22 (t, 2H), 6.92 -7.67 (aromatic, 12H), 8.10(simile, IH) IR : (KBr), 3306, 3270, 3000, 2926, 2840, 1638, 1609,1494, 1331, 1282, 1251, 1167 1011 cm"‘ (iii) Hydrolysis of quart Mary ammonium iodide salts of formula-IIa. To the solid mass novel quartemary ammonium salt of formula Ila obtained in step ii (b) 500.0ml of water is added and the resultant solution is heated at reflux temp for 2hrs. Then liberated benzaldehyde is steam distilled and is separated (lO.Ogms) from distillate. Proceeded with the residue for neutralization step. (iv) Neutralization of Tamsulosin hydrochloride salt to obtain Tamsulosin cmde base. To the residue obtained from step-IIIa is added 300ml of water. The pH was adjusted to 9.0 - 10.0 using K2CO3 powder. A white precipitate is obtained. The cmde product is extracted into ethyl acetate (500.0ml) and the solvent is removed by distillation. The cmde mass is purified by column chromatography (Ethyl acetate : methanol : ammonia 9:1: 0.2) to obtain Tamsulosin base (IS.Ogm). Dried the material under vacuum at 40°C. HPLC purity 99.8% with single largest impurity 99.9%. (v) Preparation of Tamsulosin hydrochloride of formula-I. The pure base of Tamsulosin (IS.Ogms) obtained from example-iv (a) is dissolved in 360ml of methanol at 55°C. IPA HCl (12% w/w - 13.4ml) is added at 25 - 35X over a period of Ihr. stirred at same temp for further Ihr. Cooled to 0 - 5°C. Maintained at 0 - 5’C for farther 3hrs. Filtered. Dried the material at 50°C under vacuum. Yield IS.Ogms. MR : 229-230X HPLC : Purity > 99.8% (with single impurity 99.9%. Example 2. Into a 4-necked 500ml round bottom flask, equipped with Dean-Stark apparatus, 150.0ml of toluene, 24.4gm (0.1 mole) of R-5-(2-aminoproply)-2-methoxy benzene sulfonamide of formula-IV and 13.6gm (0.1 mole) of 4-methoxybenzaldehyde are charged . Carried out isotropy and separated the water (1.8ml collected. The solvent is removed under vacuum at temp max. 80°C. The reaction mixture is cooled to 25 - 35®C and the vacuum is released under N2 atmosphere. A thick oily mass of compound of 2-methoxy-5-(2R)-2-{[(l-E/Z-phenyl ethylene)amino]propyl} benzene sulfonamide of formula-IIIb is obtained (37.0gms). Recrystallized sample (from IPA) has the following characteristics. MR : 122-128°C IH NMR : (200MHz, CDCl3+DMSO-d6) 8 1.24 - 1.27 (d, 3H), 2.82 - 2.86 (t, 2H), 3.41 - 3.51 (m, IH), 3.80 (s, 3H), 3.91 (s, 3H), 4.5 (broad, 2H), 6.9 - 7.7 (aromatic, 8H), 8.07 (s, imine, IH) IR : (KBr), 3352,2841,1636,1606, 1495,1335,1253,1183, 1157, 1024 cm'‘ (ii) Preparation of N-(4-methoxybenzylidene)-[2-(2-ethoxyphenoxy)ethyl]-[2-(4-methoxy-3-sulphamoylphenyI)-l(R)-methyl ethyl]ammonium iodide of formula-lib. The oily mass of formula-HIb obtained in step (i) (b) is taken and dissolved in 125.0ml of n-butanol. The solution is heated to lOO’C under nitrogen atmosphere. A solution of 29.1gms (O.lmole) of 2-(2-ethoxyphenoxy) ethyl iodide in 30ml of n-butanol is slowly added at 100 - 105*’0 over a period of 3 - 4 hrs and maintained at 100 - 110°C for further 4hrs. Then n-butanol is distilled off under vacuum at temp not exceeding 80°C. The resultant mass is cooled to 20°C and vacuum released under nitrogen atmosphere. Added 50.0ml of n-hexane and stirred to make uniform slurry and is cooled 0 - 5’C. The compound is filtered and washed with 50ml of n-hexane. The resultant product is dried at 40 - 50°C under vacuum to obtain a solid quartemary ammonium salt of formula-lib (40.0gms). Recrystallized sample (faro acetonitrile) has the following characteristics. MR : 115-120°C IHNMR : (200MHz, DMSO-d6)5 1.14- 1.17(d, 3H), 1.24- 1.36 (t, 3H), 2.79 - 2.83 (m, 2H), 3.40 (broad, 2H), 3.46 - 3.54 (m, 3H), 3.79 (s, 3H), 3.84 (s, 3H), 3.87 - 4.01(dd, 4H), 4.20- 4.22 (t, 2H), 6.92 -7.67 (aromatic, IIH), 8.13(simile, IH) IR : (KBr), 3352, 2841, 1636, 1605, 1495, 1354, 1269, 1157, 1074, 1023cm'‘ (iii) Hydrolysis of quartemary ammonium iodide say of formula-lib. To the solid mass obtained in step-lib 500.0ml of water is added and the resultant solution is heated at reflux temp for 2hrs. Then it is steam distilled and 4-methoxybenzaldehyde (1 logos) is separated from distillate. The residue is proceeded with neutralization step. (iv) b) Neutralization of Tamsulosin hydrochloride salt to obtain Tamsulosin crude base. To the residue obtained from step-IIIb is added 300ml of water. Adjusted pH to 9.0 - 10.0 with K2CO3 powder. A white precipitate is obtained. The crude product is extracted into ethyl acetate (500.0ml) and the solvent is removed by distillation. Purified the crude mass by column chromatography (Ethyl acetate : methanol : ammonia 9:1: 0.2) and obtained 19.0gms of Tamsulosin base. Dried the material under vacuum at 40’C. HPLC purity 99.8% with single largest impurity 99.9%. (v) Preparation of Tamsulosin hydrochloride of formula-I. The pure base of Tamsulosin (19.0gms) obtained from step-iv (a) is dissolved in 380ml of methanol at 55T. IPA HCl (12% w/w - 14.8ml) is added at 25 - 35*’0 over a period of Ihr. stir at same temp for further Ihr. Cooled to 0 - 5’C. Maintained at 0 - 5°C for further 3hrs. Filtered. Dried the material at 50°C under vacuum. Yield 19.0gms. MR : 229-230°C HPLC : Purity > 99.8% (with single impurity 99.9%. Example 3. (i) Preparation of 2-methoxy-5-(2R)-2-{[(l-E/Z-4-hydroxyphenylmethylene)amino]propyl} benzenesulfonamide of formula-IIIc. Into a 4-necked SOOml round bottom flask, equipped with Dean-stark apparatus, 150ml of toluene, 24,4gms (O.lmole) of (R)-5-(2-aminopropyl)-2-methoxy benzene sulfonamide of formula-IV and 12.2gms (O.lmole) of 4-hydroxybenzaldehyde are charged .The reaction was carried out azeotrophically and the water (1.8ml) collected and separated. Then the solvent is removed under vacuum at temp max 80°C. Cooled to 25 - 30°C .The vacuum is released under N2 atmosphere. A thick oily mass which solidified on storage which is the compound of 2-methoxy-5-(2R)-2-( [(l-E/Z-4-hydroxyphenylmethylene)amino]propyl} benzenesulfonamide of formula-nic ( 35.0gms). Recrystallized sample (from IP A) has the following characteristics. MR :96-100T IH NMR : (200MHz, CDCi3+DMSO-d6) 5 1.23 - 1.26 (d, 3H), 2.84 - 2.87 (t, 2H), 3.43 - 3.52 (m, IH), 3.92 (s, 3H), 6.0, (broad, 2H), 6.8 - 7.7 (aromatic, 7H), 7.95 (s, imine, IH) IR : (KBr), 3352, 3257,2969, 1640,1606, 1585, 1484, 1394, 1158, 1070, 1018 cm"‘ (ii) Preparation of N-(4-hydroxybenzylidene-[2-(2-ethoxyphenoxy)ethyl]-[2-(4-methoxy-3-sulphamoyl phenyl)-l(R)-methyl ethyl]ammonium iodide of formula-lib. The oily mass of formula-IIIc obtained in step (i) (c) is taken and dissolved in 125.0ml of n-butanol. The solution is heated to 100°C under nitrogen atmosphere. A solution of 29.1gms (O.lmole) of 2-(2-ethoxyphenoxy) ethyl iodide in 30ml of n-butanol is slowly added at 100 - 105°C over a period of 3 - 4 hrs and maintained at 100 - llO’C for further 4hrs. Then n-butanol is distilled off under vacuum at temp not exceeding 80°C. The resuming mass is cooled to 20’C and vacuum released under nitrogen atmosphere. Added 50.0ml of n-hexane. Uniform slurry is made and the product is allowed to solidify at 0 - 5°C. The reaction mixture is fibered. And washed with 50ml of n-hexane. The product is dried at 40 - 50°C under vacuum to obtain the solid quartemary ammonium salt of formula-IIc (30.0gms). Recrystallized sample (from IP A) has the characteristics. IHNMR : (200MHz, DMSO-d6)5 1.10- 1.12(d, 3H), 1.28-1.31 (t, 3H), 2.79 - 2.83 (m, 2H), 3.40 (broad, 2H), 3.46 - 3.54 (m, 3H), 3.84 (s, 3H), 3.87 - 4.01(dd, 4H), 4.20- 4.22 (t, 2H), 6.92 -7.67 (aromatic, 12H), 8.20 (s, imine, IH) IR : (KBr), 3352, 3243,2973, 1639, 1606,1586,1495,1322, 1281, 1255,1157, 1072,1017 cm"* (iii) Hydrolysis of quartemary ammonium iodide salts of formula-He. To the solid mass obtained in step-lib 500.0ml of water is added and the solution is heated at reflux temp for 2hrs. Then steam distilled and 4-hydroxybenzaldehyde (9.0gms) is separated from distillate. Proceeded with the residue for neutralization step. (iv) Neutralization of Tamsulosin hydrochloride salt to obtain Tamsulosin crude base. To the residue obtained from step-IIIc 300ml of water is added .The pH is adjusted to 9.0 - 10.0 with K2CO3 powder. A white precipitate is obtained. The crude product is extracted with ethyl acetate (500.0ml) and the solvent is removed by distillation. The crude mass is purified by column chromatography (Ethyl acetate : methanol : ammonia 9:1: 0.2) and IS.Ogms of Tamsulosin base is obtained . The material is distilled under vacuum at 40°C. HPLC purity 99.8% with single largest impurity 99.9%. (v) Preparation of Tamsulosin hydrochloride of formula-I. The pure base of Tamsulosin (IS.Ogms) obtained from step-iv (c) is dissolved in 300ml of methanol at 55°C. IPA HCl (12% w/w - 10.0 ml) is added at 25 - 35°C over a period of Ihr. stir at same temp for further Ihr. Cooled to 0 - 5°C. Maintained at 0 - 5°C for further 3hrs. Filtered. Dried the material at 50°C under vacuum. Yield 15.0gms. MR : 229-230°C HPLC : Purity > 99.8% (with single impurity 99.9%. Into a 4-necked 500ml round bottom flask, equipped with Dean-stark apparatus 150.0ml of toluene, 24.4gms of (R)-5-(2-aminopropyl)-2-methoxy benzene sulfonamide of the formula-IV and 12.4gms (O.lmole) of 4-fluoroben2aldehyde are charged. The reaction is effected isotopically and the water 1.8ml (O.lmole) is separated. Then the toluene is distilled off completely under vacuum at temp max 80°C. Cooled 25 - 35°C and released the vacuum under nitrogen atmosphere. 25.0gm of thick oily compound of 2-methoxy-5-(2R)-2-{[(l-E/Z-4-fluorophenylmethylene)amino] propyl} benzenesulfonamide of formula-IIId is obtained. Recrystallized sample (from IP A) has the following characteristics. MR :140-148T IH NMR : (200MHz, CDCl3+DMSO-d6) 5 1.01 - 1.04 (d, 3H), 2.80 - 2.88 (t, 2H), 3.14 - 3.18 (m, IH), 3.88 (s, 3H), 6.0, (broad, 2H), 7.12 - 7.57 (aromatic, 7H), 8.20(simile, IH) IR : (KBr), 3385, 3315, 2948, 1643, 1606, 1576, 1495, 1404, 1334, 1249, 1154, 1074, 1114, 518, 471cm"‘ (ii) Preparation of N-(4-fluorobenzylidene-[2-(2-ethoxyphenoxy)ethyl]-[2-(4-methoxy-3-sulphamoyl phenyl)-l(R)-methyl ethyl ammonium iodide of formula-IId. The oily mass of formula-IIId obtained in step (i) (c) is taken and dissolved in 125.0ml of n-butanol. The solution is heated to lOO’’C under nitrogen atmosphere. A solution of 29.1gms (O.lmole) of 2-(2-ethoxyphenoxy) ethyl iodide in 30ml of n-butanol is slowly added at 100 - 105°C over a period of 3 - 4 hrs and maintained at 100 - llOX for further 4hrs. Then n-butanol is distilled off under vacuum at temp not exceeding 80°C. The resuming mass is cooled to 20°C and vacuum released under nitrogen atmosphere. 50.0ml of n-hexane is added to the mixture. An uniform slurry is made and the product is allowed to solidify at 0 - 5’C. It is filtered and washed with 50ml of n-hexane. The product is dried at 40 - 50°C under vacuum to obtain 22.0gms solid of quartemary ammonium salt of formula-IId. Recrystallized (from acetonitrile) has the following characteristics. MR : 200 - 208°C IHNMR : (200MHz, DMS0-d6) 6 1.15 - 1.19 (d, 3H), 1.28 - 1.31 (t, 3H), 2.60 - 2.70 (m, 2H), 3.40 (broad, 2H), 3.46 - 3.54 (m, 3H), 3.9 (s, 3H), 3.87 - 4.01(dd, 4H), 4.20- 4.22 (t, 2H), 6.92 -7.67 (aromatic, 1IH), 8.15(simile, IH) IR : (KBr), 3305, 3210, 2930, 1632, 1609, 1494, 1439, 1330, 1282, 1252, 1456, 1075,1011, 533, 522,454 cm"‘ (iii) Hydrolysis of quartemary ammonium iodide salts of formula-IId. To the solid mass obtained in step lid 500.0ml of water is added and heated at reflux temp for 2hrs. Then steam distilled with 4-fluorobenzaldehyde (8.0gms) and is separated from distillate. Proceeded with the residue for neutralization step. (iv) Neutralization of Tamsulosin hydrochloride salt to obtain Tamsulosin crude base. To the residue obtained from step-IIId 300ml of water is added. The pH is adjusted to 9.0 - 10.0 with K2CO3 powder. A white precipitate is obtained. The crude product is extracted with ethyl acetate (500.0ml) and the solvent is removed by distillation. The crude mass is separated by column chromatography (Ethyl acetate: methanol: ammonia 9:1: 0.2) and lO.Ogms of Tamsulosin base is obtained . The material is dried under vacuum at 40°C. HPLC purity 99.8% with single largest impurity 99.9%. (v) Preparation of Tamsulosin hydrochloride of formula-I. The pure base of Tamsulosin (lO.Ogms) obtained from step-iv (d) is dissolved in 360ml of methanol at 55°C. IPA HCl (12% w/w - 8.0 ml) at 25 - 35T over a period of Ihr. stir at same temp for further Ihr. Cooled to 0 - 5°C. Maintained at 0 - 5’C for further 3hrs. The reaction mixture is filtered & dried and at 50°C under vacuum. Yield lO.Ogms. MR : 229-230°C HPLC : Purity > 99.8% (with single impurity 99.9%. Advantages of the invention: 1) The N-aikylation step of the process has several advantages over the previous methods mentioned in the prior art. a) The dealkylation of the primary amine is totally avoided as the reaction is carried out on the imine nitrogen. b) Expensive reagents like platinum oxide and sodium borohydride and sodium cyano borohydride are avoided there by making the process economical. c) Usage of intermediate, such as 2-(2-ethoxyphenoxy) acetaldehyde diethyl acetal, which is prepared by mushy step synthesis is not necessary as the aikylation is carried out with 2-(2-ethoxyphenoxy) ethyl halide of formula-V, which can be prepared easily. Thus the process is simplified. 2) The starting materials which are unused can be recovered and reused making the process economical. 3) The yield of the compound of the formula-I is about 58% calculated on compound of formula-IV. 4) The process is safe as it does not use pyrophoric palladium catalyst and also any specialized equipment like hydrogenate. 5) The purity of the compound of the formula prepared by this process is over 99.8% with single largest impurity less than 0.1%. We claim 1. An improved process for the preparation of Tamsulosin hydrochloride of formula-I, which comprises Which comprises, (i) reacting the compound of the formula-IV with a substituted aromatic benzaldehyde of the formula-XVI, where R represents group such as H, 4-OH, 4-OCH3 or 4-fluoro to obtain novel compounds namely phenyl substituted 2-methoxy-5-(2R)-2-{[(l-E/Z- phenylmethylene)amino]propyl}benzenesulfonamide of the formula-III, where R represents H, 4-OH, 4-OCH3 or 4-fluoro (ii) reacting the resulting compound of the formula-III with 2-(2-ethoxyphenoxy) ethylhalide of the formula-XVn, where the halo group is CI, Br or I at a temp in the range of 80° to 130° to obtain the novel quartemary ammonium sahs, namely N-(phenyl substituted -[2-(2-ethoxyphenoxy)ethyl]-[2-(4-methoxy-3-sulphamoyl- phenyl)-l(R)-methyl-ethyl]ammonium halides of the formula-II, where R represents H, 4-OH, 4-OCH3 or 4-fluoro groups (iii) hydrolysing the quartemary ammonium salts of the resulting compound of the formula-II by heating in water to obtain the corresponding hydrogen halide salts of formula-I (iv) neutralising the hydrogen halide salts of the formula-I thus obtained by conventional methods to produce the Tamsulosin base of the formula-XVIII, and (vi) converting the Tamsulosin base of the formula XVIII into Tamsulosin hydrochloride of formula-I by conventional methods. 2. An improved process as claimed in claim 1 wherein the step (i) is effected by isotopically removing the water using a solvent 3. An improved process as claimed in claim 2 wherein the solvent such as toluene, xylene etc. is used. 4. An improved process as claimed in claim 1 wherein the step (i) is effected by simultaneous distillation of the water formed using an alcoholic solvent such as methanol, ethanol, isopropyl alcohol, n-butanol etc. 5. An improved process as claimed in claims 1 to 4 wherein the reaction of step-ii is carried out neatly without using a solvent. 6. An improved process as claimed in claims 1 to S wherein the reaction of step-ii is also carried out by using solvent such as toluene, xylene, n-butanol, dimethyl formamide, dimethyl acetamide etc. 7. An improved process as claimed in claims 1 to 6 wherein the compound of formula-II is isolated by filtration. 8. An improved process as claimed in claims 1 to 6 wherein the compound of the formula-II is also isolated by removal of the solvent and by simple leaching with a suitable solvent such as methylene chloride etc. 9. An improved process as claimed in claims 1 to 8 wherein the hydrolysis in step (iii) is carried out using hot water and the Berated aldehyde, is removed by steam distillation or by extraction with a solvent such as methylene chloride. 10. An improved process as claimed in claims 1 to 9 wherein the neutralization in step (iv) is effected by using solutions of alkali bicarbonates, carbonates such as sodium bicarbonate, potassium bicarbonate etc. and sodium carbonate, potassium carbonate, etc and alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide etc. 11. An improved process as claimed in claims 1 to 10 wherein the crude Tamsulosin base is purified by colunm chromatography or by recrystallization using suitable solvents such as mixture of dimethyl formamide and acetonitrile, dimethyl formamide and isopropyl ether etc. 12. An improved process as claimed in claims 1 to 11 wherein the Tamsulosin base is converted into Tamsulosin hydrochloride by using solvents such as methanol, ethanol, isopropyl alcohol etc and hydrogen chloride solution in isopropyl alcohol. 13. An improved process for the preparation of Tamsulosin hydrochloride of formula-I, as defined in claim 1 substantially as herein described with reference to the Examples.

Documents:

599-mas-2002-abstract.pdf

599-mas-2002-claims filed.pdf

599-mas-2002-claims granted.pdf

599-mas-2002-correspondnece-others.pdf

599-mas-2002-correspondnece-po.pdf

599-mas-2002-description(complete)fild.pdf

599-mas-2002-description(complete)granted.pdf

599-mas-2002-form 1.pdf

599-mas-2002-form 19.pdf

599-mas-2002-form 3.pdf

599-mas-2002-form 5.pdf

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