WO2004016582A1

WO2004016582A1 - An improved process for the preparation of tamsulosin hydrochloride

Info

Publication number: WO2004016582A1
Application number: PCT/IN2002/000200
Authority: WO
Inventors: Durga Prasad Konakanchi; Ramachandran Sambasiva; Nannapaneni Venkaiah Chowdary
Original assignee: Natco Pharma Limited
Priority date: 2002-08-14
Filing date: 2002-10-07
Publication date: 2004-02-26

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-I given below. (I) The process employs the novel intermediates quarternised benzylidene ammonium salts, N-(phenyl substituted)-[2-(2-ethoxyphenoxy)ethyl]-[2-(4-methoxy-3-sulphamoylphenyl)-1(R)-methyl-ethyl]ammonium halides of the formula-II, (II) where R represents H, 4-OCH3, 4-OH or 4-fluoro and X represents C1, 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-III. (III) where R represents H, 4-OCH3, 4-OH or 4-fluoro.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF TAMSULOSΪIN HYDROCHLORIDE

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.

Formula-I

The process employs the novel intermediates quarternised benzylidene ammonium sadts, N-(phenyl substituted)-[2-(2-ethoxyph.enoxy)ethyl]-[2-(4-mettιoxy-3-sulphamoylphen5^1)- l(R)-methyl-ethyl] ammonium halides of the formula-ϋ,

where R represents H, 4-OCH₃, 4-OH or 4-fluoro and X represents CI, Br or I. and SchifPs bases, novel phenyl substituted 2-methoxy-5-[(2R)-[(l-E/Z-phe_.nyl methylene)amino]propyl]benzenesulfonamide of the formula-IEI.

Fo rm uia-III

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 thesir preparation have bee__n made the subject matters of our co pending applications nos. 598 AS/2002 & 597/MAS/2002 respectively. Prior Art:

Tamsulosin hydrochloride is first disclosed in JP 55-14382 dt. 8-2-1980 and its equivalentt US 4731,478 dt. 1 5/3/1988, wherein the intermediate R(-)-5-[(2-ajnino-2-methyl)ethyl]-2 - methoxybenzenesulfonamide of formι la-IV is refluxed for 16hrs with anothe=r intermediate 2-(2-ethoxyphenoxy) ethylbromide of Formula-V in ethanol medium t«D obtain crude Tamsulosin base, which is purified by column chromatography to get pur-e base. The pure Tamsulosin base is treated with HC1 in ethanol to obtain Tamsulosia hydrochloride of formula-I in 36.8% of yield based on the ex_pensive intermediate of formula-IV. The synthetic route is given ^"below in scheme-A.

Foimula-IV Fbimula-V Forrrula-I

Scheme-A

The drawbacks in this process are low yields of compound of foxmula-I due to formation of side products mainly the dialkylated compound of formula- VI,

Formula-VI

further the reaction time required is very long (i.e) more than lόhrs resulting in poor yields. The expensive intermediate R(-)-5-[(2-amino-2-methy_)et_hyl~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-IN is reacted to form salt vith the liberated HBr formed during the coxipling 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-IN 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-Nil to get an imine compound of formula-NIII. Then the imine compound of formula-NIII is reduced with either platinum oxide or sodiu.ni borohydride / sodium cyano borohydride and on further treatment with HC1 to obtain Tamsulosin hydrochloride of formula-I. The process for making compound of formula- VII is also disclosed. G aiethol 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 sclαeme-B.

Guaie hol Formula-IX Formula-VII

Formula-VII Formula-X Formula-IV

Formula-VIII

Formula-!

Scheme-B

The main drawbacks in this process are:

1. For the preparation of intermediates 2-(2-ethoj yphenoxy) 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-NIII 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-NIII expensive reagent sodium borohydride / sodium cyano borohydride is necessary.

IP 02306958 (1988-Ho uriku) 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-(bromoacetoxy)-2(R)-4-meth.oxyphenylisopropylamine of formula-XIII. The compound of formula-XIII is reacted with chlorosulphonic acid and then with ammonia solution to obtain its sulfonamide derivative of formula-XTV, which is reacted with guaiethol using potassium carbonate as base to obtain an amide derivative of formula-XV. The amide derivative of formula-XN is reduced with lithium aluminium hydride to secondary amine compound, which on treatment with HCI gives Tamsulosin hydrochloride of formula-I. The synthetic route is outlined in the following scheme-C.

Formula-XII

Fornnula-XIV Formula-XV

Formula-I

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 talcing into account the difficulties 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-metkιoxybenzenesulfonamide of formula-IN.

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 irrvention is to provide aji improved process forr 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 forr 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 fo r the preparation of Tamsulosin hydrochloride, wherein the usage of specialized equipment like hydrogenator 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 reagen^~t like sodium borohydride are not used thereby making the process safer and economical.

The scheme of the process of the present invention is shown in scheme-D.

HJ Δ

Formula-XVII Formula-IV Formula-XVI Formula-I

Alkali

Formula-XVIII Formula-I Tamsulosin Hydrochloride

Scheme-D where R = H, 4-OH, 4-OCH₃ or 4-fluoro and X = CI, Br and I.

The monoalkylation of the primary amine of formula-IN is carried out by the method of Decker & Becker [Decker & Becker, Ann, 3^5, 328 (1913)]. So far this method has not been used earlier 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-XNI, 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)- [(l-E/Z-pheylrnethylene)amino] propyl] benzenesulfonamide of formula-HI, where R represents H_, 4-OH, 4-OCH₃ or 4-fluoro (ii) reacting the resulting compound of the formula-Ill w th 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 quarternary ammonium salts, namely -(phenyl substituted)-[2-(2-ethoxyphenoxy>ethyl]-[2-(4-methoxy-3 - sulphamoyl-phenyl)-l(TR)-methyletfc_yl] ammonium halides of the formula-II, where R represents H, 4-OH, 4-OCH₃ or -4-fluoro groups and X represents CI, Br or I

(iii) hydrolysing the quarternary 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 ttie formula-XVTfl, and

(v) converting the Tamsulosin ba.se of the formula _XVffl into Tamsulosin hydrochloride of formula-I by conventional methods.

In a preferred embodiment of the present invention the step (i) may be effected b»y azeotropically removing the water using a solvent such as toluene, xylene etc. or h»y 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-D 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 alkylhalide. In step (iii) the hydrolysis may be carried out using hot water. The liberated aldehyde, may be removed by stea m 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-XVπi. 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)-[(l-E/Zpheylmethylene)amino]propyl]benzenesulfonamide of formula-Ill, 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-Ill with 2-(2-ethoxyphenoxy) ethylhalide of the formula-XNII, where t_he halo group is CI, Br or I at a temp in the range of 80° to 130° -to obtain the novel quarternary ammonium salts, namely Ν-(phenyl substituted)-[2-(2-ethoxyphenoxy)ethyl]-[2-(4- methoxy-3 -sulphamoylphenyl)-l(R.)-methyl-ethyl]ammoniι_ιm halides of the forrnula-II, where R represents H, 4-OH, 4-OCH₃ or 4-fluoro gromps.

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-phenylmethylene)amino]propyl} benzenesulfonamide of formula-HIa.

Formula-IV 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 lO.όgms (O.lmole) of beixzaldehyde are charged- Azeotropic distillation was carried out and 1.8ml (O.lmole) of ^water separated. Then t_he 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 { [( 1 -E/Z- phenylmethylene)amino]propyl}benzenesulfonamide of formula-IIIa (33.0gm) formed, crystallized soon. Purified sample (recrystallized from EPA) has the following characteristics.

MR : 121 - 126°C

1H INMR : (200MHz, CDCl₃+DMSO-d6) δ 1.26 - 1.29 (d, 3H), 2.86 - 2.90 (t, 2H),

3.49 - 3.59 (m, 1H), 3.92 (s, 3H), 6.0 (broad, 2H), 6.9 - 7.7 (aromatic, 8H), 8.07 (s, imine, 1H)

IR : (KBr), 3385, 3294, 2847, 1640, 1492, 1344, 1158 cm ¹

(ii) Preparation of N-benzylidene-[2-(2-ethoxyphenoxy)ethyl]-[2-(-4-methoxy-3- sulphamoyl phenyl)- l(R)-rnethyl-ethyl]ammonium iodide of formula-IIa.

Formula-IIIa Formula-lla

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 1OO°C under nitrogen atmosphere. A solution of 29.1gms (O.lmole) of 2-(2-ethoxyphenoxy) ethyl iodide in 30rnl of n-butanol is slowly added at 100 — 105°C over a period of 3 — 4 hrs and maintained -at 100 - 110°C for _urthe_r 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 resulting uniform slurry is allowed to solidify at 0 - 5°C. The reaction mixture is filtered, washed with 50ml of n-hexane and tlhe product is dried at 40 — 50°C under vacuum to obtain a solid of novel quarternary ammonium salt of formula-IIa. 35.0gms. Recrystallized (from acetonitrile) sample has the following characteristics.

MR : 208 - 210°C

1HNMR : (200MHz, DMSO-d6) δ 1.14 - 1.17 (d, 3H), 1.24 - 1.36 (t, 3H),

2.79 - 2.83 (m, 2H), 3.4-0 (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 (s, imine, 1H)

ΪR : (KBr), 3306, 3270, 3000, 2926, 2840, 1638, 1609, 1494, 1331, 1282,

1251, 1167, 1011 cm^-1

(iii) Hydrolysis of quarternary ammonium iodide salts of formuLa-Ha.

To the solid mass novel quarternary 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 enzaldehyde is steam distilled and is separated (lO.Ogms) from distillate. Proceeded with the residue for neutralization step.

(iv) Neutralization of Tamsulosin hydrochloride salt to octain Tamsulosin crude 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 crude product is extracted into ethyl acetate (500. Oml) and the solvent is removed by distillation. The crude mass is purified by column chrornatography (Ethyl acetate : methanol : ammonia 9 : 1 : 0.2) to obtain Tamsulosin base (18.0gm). Dried the material under vacuum at 40°C. HPLC purity 99.8% with single largest impurity <0.1%. Chiral purity > 99.9%.

(v) Preparation of Tamsulosin hydrochloride of formula-I.

The pure base of Tamsulosin (18.0gms) obtained from example-iv (a) is dissolved in 360ml of methanol at 55°C. IPA HCI (12% w/w - 13.4ml) is added at 25 - 35°C over a period of Ihr. stirred at same te p for further lhr. Cooled to 0 - 5°C. Maintained at 0 - 5°C for further 3hrs. Filtered. Dried the material at 50°C xinder vacuum. Yield 18.0>gms.

MR : 229 - 230°C

HPLC : Purity > 99.8% (with single impurity < 0.1°/S) Chiral Purity > 99.9°Xo.

Example 2. i) Preparation of 2-Methoxy-5-(2R)-2-{[(l-E ^rZ-4-methoxyphenylmethylene) amino] propyl} benzene sulfonamide of formula-IHb.

Formula-IV ,_ . ....

Formula-I I lb

Into a 4-necked 500ml round bottom flask, equipped with Dean-Stark apparatus, 150.0ml of toluene, 24.4gm (O.lmole) of R-5-(2-aminoproply)-2-methoxy benzene sulfonamide of formula-IV and 13.6gm (O.lmole) of 4-methoxybenzaldehyde are charged . Carried out azotropy 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-phenylmethylene)amino]propyl} benzene sulfonamide of formula-IHb is obtained (37.0gms). Recrystallized sample (from IPA) has the following characteristics.

MR : 122 - 128°C

1HNMR : (200MHz₃ CDCl₃+DMSO-d6) δ 1.24 - 1.27 (d, 3H), 2.82 - 2.86 (t, 2H), 3.41 - 3.5 1 (m, 1H), 3.80 (s, 3H), 3.91 (s, 3H), 4.5 (broad, 2H), 6.9 - 7.7 Caromatic, 8H), 8.07 (s, imine, 1H)

IR : (KBr), 3352, 2841, 1636, 1606, 1495, 1335, 1253, 1183, 1157, 1024 cm^"1

(ii) Preparation of N-(4-methoxybenzylϊdene)-[2-(2-ethoxyphenoxy)ethyl]-[2-(4- methoxy-3-sulphamoylphenyl)-l(R)-methyl et__yl]ammonium iodide of formula-IIb.

Formula-IIIb Formula-lib

The oily mass of formula-IIIb obtained in step (i) (b) is taken and dissolved in 125.0ml of n-butanol. The solution is heated to 10O°C under nitrogen atmosphere. A solution of 29.1gms (O.lmole) of 2-(2-ethoxyphenoxy) ethyl iodide in 30IΪL1 of n-butanol is slowly- added at 100 - 105°C 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 O - 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 quarternary ammonium salt of formula-lib (40.0gms). Recrystallized sample (from acetonitrile) has the following characteristics. MR : 115 - 120°C

1H NMR : C200MHz, DMSO-d6) δ 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, 2_H), 6.92 -7.67 (aromatic., 1 1H), 8.13 (s, imine, 1H)

IR : (KBr), 3352, 2841, 1636, 1605, 1495, 1354, 1269, 1157, 1074, 1023cm^"1

(iii) Hydrolysis of quarternary ammonium iodide salt of formula-IIb. 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 dist lled and 4-methoxybenzaldehyde (1 l.Ogms) 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-IHb is added 300ml off water. Adjusted pHto Θ.O - 10.0 with K₂C0₃ powder. A white precipitate is obtained. Tlie 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 : a.mmonia 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 <0.1%. Chiral purity - 99.9%.

(v) Preparation of Tamsulosin hydrochloride of formuh-I.

The pure base of Tamsulosin (19.0gms) obtained from srtep-iv (a) is dissolved in 380ml of methanol at 55°C. IPA HCI (12% w/w - 14.8ml) is added at 25 - 35°C over a period of lhr. stir at same temp for further lhr. 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 < 0.1 °Xo) Chiral Purity > 99.9%.

Example 3.

(i) Preparation of 2-methoxy-5-(2R)-2-{ [( 1 -E/Z-4-hydroxyphenylmethylene)amino] propyl} benzenesulfonamide of formula-IHc.

Formula-IV Formula-lllc

Into a 4-necked 500ml 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-IIIc ( 35.0gms). Recrystallized sample (from IPA) has the following characteristics.

MR : 96 - lO0°C

1H MR : (200MHz, CDCl₃+DMSO-d6> δ 1.23 - 1.26 (d, 3H), 2.84 - 2.87 (t, 2H),

3.43 - 3.52 (m, 1H), 3.92 (s, 3H), 6.0, (broad, 2H), 6.S - 7.7 (aromatic, 7H), 7.95 (s, imine, 1H)

IR : (KBr)₃ 3352, 3257, 2969, 164-0, 1606, 1585, 1484, 1394-, 1158, 1070,

1018 cm^-1

(ii) Preparation of N-(4-hydroxybenzylidene-[2-(2-ethoxyphenoxy)ethyl]-t2-(4-methoxy- 3-sulphamoyl phenyl)- l(R)-methyl ethyl] ammonium iodide of formula-EIb.

Formula-lllc Formula-llc

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 - 110°< for further 4hrs. Then n-butanol is distilled off under vacuum at temp not exceedirmg

80°C. The resulting 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 filtered. And washed with 50ml of n-hexane. The product is dried at 40 - 50°C under vacuum to obtain the solid quarterna_ry ammonium salt of formula-IIc (30.0gms). Recrystallized sample (from IPA) has ttie characteristics.

1H NMR : (_200MHz, DMSO-d6) δ 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), S.20 (s, imine, 1H)

IR : (KBr), 3352, 3243, 2973, 1639, 1606, 1586, 1495, 1322, 1281, 125 5,

1157,

1072, 1017 cm^-1

(iii) Hydrolysis of quarternary ammonrum iodide salts of formula-IIc. 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 fox 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 Λvith K₂CO₃ powder. A Λvhite 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 15.0gms of Tamsulosin base is obtained . The material is distilled under vacuum at 40°C. HPLC purity 99.8% with single largest impurity <0.1°/<>. Chiral purity > 99.9%.

(v) Preparation of Tamsulosin hydrochloride of formula-I.

The pure base of Tamsulosin (15.0gms) obtained from step-iv (c) is dissolved in 300ml of methanol at 55°C. IPA HCI (12% w/w - 10.0 ml) is added at 25 - 35°C over a period of lhr. stir at same temp for further lhr. Cooled to 0 - δ^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 < 0. 1%) Chiral Purity > 99.9%.

-Example 4.

(i) Preparation of 2-methoxy-5-(2R)-2--([(l-E/Z-4-fluorophen3rlmethylene)amino] propyl} benzene methane sulfonamide of formula-Hid.

Formula-IV Fo rmula-llld

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-fϊuorobenzaldehyde are charged. The reaction is effected azeotropically 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-Hid is obtained. Recrystallized sample (from IPA) has the following characteristics.

MR : 140 - 148°C

1H NMR : (200MHz, CDCl₃+DMSO-d6) δ 1.01 - 1.04 (d, 3H), 2.80 - 2.88 (t, 2HQ,

3.14 - 3.18 (m, 1H), 3.88 (s, 3H), 6.0, (broad, 2H), 7.12 - 7.57 (aromatic, 7H), 8.20 (s, imine, 1H)

IR : (KBr), 3385, 3315, Z948, 1643, 1606, 1576, 1495, 1404, 1334, 1249,

1154,

1074, 1114, 518, 471cm-¹

(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.

Formula-I Id

Formula-Hid

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 100°C under mtrogen atmosphere. A solution of 29.1gms (O.lmole) of _2-(2-ethoxyphenoxy) ethyl iodide in 30ml of n-butanol is slowly added at 10O - 105°C 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 resulting 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 quarternary ammonium salt of formula-IId. R ecrystallized (from acetonitrile) has the following characteristics.

MR : 200 - 208°C

1HNMR : (200MHz, DMSO-d6) δ 1.15 - 1.19 (d, 3H), 1.28 - 1.3 1 (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, 11H), 8.15 (s, imine, 1H)

TR : (KBr), 3305, 3210, 2930, 1632, 1609, 1494, 1439, 133 O, 1282, 1252,

1456, 1075, 1011, 533, 522, 454 cm^-1

(iii) Hydrolysis of quarternary 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 froma distillate. Proceeded with the residue for neutralization step.

To the residue obtained from step-IIId 3O Oml of water is added. The pH is adjusted to 9.C - 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 Ls 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 <0.1%. Chiral purity > 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 HCI (12% w/w - 8.0 ml) at 25 - 35°C over a period of lhr. stir at same temp for further lhr. Cooled to 0 - 5°C. Maintained at 0 - 5°C for further 3hrs. Th_e 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 < 0.1%) Chiral Purity > 99.9%.

Advantages of the invention z

1 ) The N-alkylation step of the process has several advantages over ttie previous methods mentioned in the prior art.

a) The dialkylation 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 borobrydride and sodium cyano borohydride are avoided there by making the process economical.

c) Usage of intermediate, such as 2-(2-e>thoxyphenoxy) acetalderxyde diethyl acetal, which is prepared by multi step synthesis is not necessary as the alkylation 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 pyrophioric palladium catalyst and also any specialized equipment like hydrogenator.

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%.

Claims

We claim

1. An improved process for the preparation of Tamsulosin liydrochloride of formula-I, which comprises

which comprises,

(i) reacting the compound of the formula-TV with a substituted aromatic benzaldehydes of the formula-XVT, where R represents group such as H, 4-OH, 4-OCH₃ or 4-fluoro to obtain novel compounds namely phenyl substituted 2-rnethoxy-5-(2R)-2-{[(l-E-/Z- pheylmethylene)amino]propyl}benzenesulfonamide of the formula-Ill,

Fo rmula-Ill where R represents H, 4-OH, 4-OCH₃ or 4-fluoro

(ii) reacting the resulting compound of the formula-Ill with 2-(2-ethoxypheno xy) ethylhalide of the formula-XVTI,

Formula-XVII where the halo group is CI, Br or I at a temp in ttie range of 80° to 130° to obtain the novel quarternary ammonium salts, namely N-(phenyl substituted)- [2-(2- ethoxyphenoxy)ethyl]-[2-(4-methoxy-3-sulphamoyl- phenyl)- 1 ^-methyl- ethyl] ammonium halides of the formula-II,

Formula-i

where R represents H, 4-OH., 4-OCH₃ or 4-fluoro groups

(iii) hydrolysing the quarternary ammonium salts of the resulting compound of the formula-II by heating in water to obtain the corresponding hydrogen hialide 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-ZXVTII, and

Forrrula-XVlll (vi) converting the Tamsulosin base of tlie 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 azeotropically 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 tire 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 5 wherein the reaction of step-ii is aJso carried out by using solvent such as toluene, xylene, n-buta.nol, dimethyl formamide, dimethyl acetamide etc.

7. An improved process as claimed in claims 1 to 6 wherein the compound of formula-13 is isolated by filtration.

8. An improved process as claimed in claims 1 to 6 wherein the compound of the formutla- 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 liberated 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 Civ) 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.

1 1. An improved process as claimed in claims 1 to 10 wherein the crude Tamsulosin base is purified by column 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.