Title of Invention

PROCESSES FOR THE PREPARATION OF NOVEL TAMSULOSIN HYDROCHLORIDE INTERMEDIATES

Abstract The present invention relates to novel intermediates N-(phenyl substituted)-[2-(2- ethoxyphenoxy)ethyl]-[2-(4-methoxy-3-sulphamoylphenyl)-l(R)-methyl-ethyl]amm halides of formula-II, Tamsulosin Hydrochloride is a widely used drug for the treatment of benigh prostrate hyperplasia.
Full Text

The present invention relates to novel intermediates whicli. are useful for the preparation of Tamsulosin hydrochloride of formula-I.

The novel intermediates are quarternised benzylidene ammonium salts, namely N-(phenyl substituted)"[2-(2-ethoxyphenoxy)ethyl]-[2-(4-methoxy-3-sulphamoylphenyl)-l(R)-methyl-ethyl]ammonium halides having the formula-II,

where R is H, 4-OCH3, 4-OH or 4-fluoro and X represents CI, Br or I.
Tamsulosin hydrochloride is a widely used drug for the treatment of benign prostate hyperplasia.
The process employs the intermediates quarternised 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 defined above, and Schiffs bases, another novel compounds namely, phenyl substituted 2-methoxy-5-[(2R)-[(l-E/Z-phenylmethylene) amino]propyl]benzenesulfonamide of the formula-Ill.

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

The improved process for the preparation of Tamsulosin hydrochloride of formula-I using the novel intermediates of the formula II 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)-[(l-E/Z-pheylmethylene)amino]propyl]
benzenesulfonamide of formula-Ill,

where R represents H, 4-OH, 4-OCH3 or 4-fluoro.
(ii) reacting the resulting compound of the formula-Ill with 2-(2-ethoxyphenoxy)ethylhalide of theformula-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 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 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 the formula-XVIII , and

(v) converting the Tamsulosin base of the formula-XVIII into Tamsulosin hydrochloride of formula-I as defined above by conventional methods.

The scheme of reaction is shown in Scheme I below

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 earlier for making Tamsulosin hydrochloride of formula-I.
The above process has been made the subject matter of our co pending application no. 599/MAS/2002, which claimed a process for the preparation of Tamsulosin hydrochloride.
The present invention also relates to novel intermediates of the above mentioned formula-II which are as explained above, are useful for the preparation of Tamsulosin hydrochloride.

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 HC1 in ethanol to obtain 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

further the reaction time required is very long (i.e) more than 16hrs resulting 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-VIII. Then the imine compound of formula-VIII is reduced with either platinum oxide or sodium 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. Guaiethol is reacted with bromo acetaidehyde diethylacetal of formula-IX using sodium hydride as base and dimethyl formamide as solvent. The reaction sequence is shown in

The main drawbacks in this process are:
1. For the preparation of intermediates 2-(2-ethoxyphenoxy) acetaidehyde 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-(bromoacetoxy)-2(R)-4-methoxyphenylisopropylamine 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-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 HC1 gives Tamsulosin hydrochloride of formula-I. The synthetic route is outlined in the following scheme-C.


The main drawbacks in this process are:
1. More number of steps is involved there-by making the route very cumbersome.
2. Highly pyrophoric and expensive reagent lithium aluminium hydride is used 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 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-methoxybenzenesulfonamide of formula-IV. While developing the improved process we could identify two novel compounds namely the compounds, namely, N-(phenyl substituted)-[2-(2-ethoxyphenoxy)ethyl]-[2-(4-methoxy-3-sulphamoylphenyl)-l(R)-methyl-ethyl]ammonium halides having the formula-II as defined above and compounds having the formula-Ill.
where R represents H, 4-OCH3, 4-OH or 4-fluoro and X represents CI, Br or I.
The main objective of the present invention, therefore, is to provide novel intermediate namely, N-(phenyl substituted)-[2-(2-ethoxyphenoxy)ethyl]-[2-(4-methoxy-3-sulphamoylphenyl)-l(R)-methyl-ethyl]ammonium halides having the formula-II as defined above which are useful for the preparation of Tamsulosin hydrochloride of the formula-I,
Another objective of the present invention is to provide a process for the preparation of the novel intermedaites namely, N-(phenyl substituted)-[2-(2-ethoxyphenoxy)ethyl]-[2-(4-methoxy-3-sulphamoylphenyl)-l(R)-methyl-ethyl]ammonium halides having of the formula II as defined above.

Accordingly the present invention provides a process for the preparation of novel quarternary ammonium salts, namely, N-(substituted phenyl)methylene-N-2-(2-ethoxyphenoxy)ethyl-N-(5-(2-methoxy-l-sulphamoyl)phenyl-(2R)-propylamonium halides of formula-II, as defined above which are key intermediate for the preparation of Tamsulosin hydrochloride of formula-I, which comprises:
(i) reacting the compound of formula-IV with a substituted aromatic benzaldehyde of the formula-XVI,
where R represents the group such as H, 4-OCH3, 4-OH or 4-fluoro groups to obtain a novel compounds, namely, phenyl substituted 2-methoxy-5-{(2R)-[lE/Z-phenylmethylene) amino]propyl]benzene sulfonamide of formula-Ill,

where R represents group such as H, 4-OCH3,4-OH or 4-fluoro.
(ii) reacting te novel compound of the formula-Ill with 2-(2-ethoxyphenoxy)ethyl halide of formula-XVII,
where the halo group is CI, Br or I, at a temp in the range of 80° to 130°C to obtain the novel quarternary ammonium salts, namely, N-(phenyl substituted)-[2-(2-ethoxy- phenoxy)ethyl]-[2-

(4-methoxy-3-sulphamoylphenyl)-l(R)-methyl-ethyl]ammonium halides of the formula-II, as defined above.
In a preferred embodiment of the present invention the step (i) may be effected by azeotropically 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 alkylhalide.
In our co pending application no. 597/MAS/2002 we have described and claimed the novel intermediate of the formula III. Similarly in our co pending application no. 599/MAS/2002 we have described an claimed a process for the preparation of Tamsulosin hydrochloride using the novel intermediates of the formulae II & III.
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.

Into a 4-necked 500ml round bottom flask equipped with Dean-Stark apparatus, 150.0ml of toluene, 24.4gms (0.1 mole) 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-phenylmethylene)amino]propyl}benzenesulfonamide of formula-IIIa (33.0gm) formed, solidified soon. Purified sample (recrystallized from IP A) has the following characteristics.
MR : 121 - 126°C
1HNMR ; (200MHz, CDCl3+DMSO-d6) 5 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) a) 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 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°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 resulting 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 quarternary ammonium salt of formula-IIa 35.0gms. Recrystallized sample (from acetonitrile) has the following characteristics.

MR :208-210°C
1HNMR : (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 (s, imine, 1H)
IR : (KBr), 3306, 3270, 3000, 2926, 2840, 1638, 1609, 1494, 1331, 1282, 1251, 1167
1011cm"1
Example 2.
(i) Preparation of 2-Methoxy-5-(2R)-2-{[(l-E/Z-4-methoxyphenylmethylene)amino]propyl} benzene sulfonamide of formula-IIIb.

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-IIIb is obtained (37.0gms). Recrystallized sample (from IP A) has the following characteristics.
MR : 122 - 128°C
1H NMR : (200MHz, CDCl3+DMSO-d6) 8 1.24 - 1.27 (d, 3H), 2.82 - 2.86 (t, 2H),
3.41 - 3.51 (m, 1H), 3.80 (s, 3H), 3.91 (s, 3H), 4.5 (broad, 2H), 6.9 - 7.7 (aromatic, 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-methoxybenzylidene)-[2-(2-ethoxyphenoxy)ethyl]-[2-(4»methoxy-3-sulphamoylphenyl)-l(R)-methyl ethyl]ammonium iodide of formula-lib.

The oily mass of formula-IIIb obtained in step (i) 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 (0.1 mole) 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°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. 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 resultant product is dried at 40 - 50°C under vacuum to obtain a solid quarternary ammonium salt of formula-lib (40.0gms).
MR : 115-120°C
1HNMR : (200MHz, DMSO-d6) 8 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, 11H),
8.13(s,imine, 1H)
IR : (KBr), 3352, 2841, 1636, 1605, 1495, 1354, 1269, 1157, 1074, 1023cm'1

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 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 IP A) has the following characteristics.
MR :96-100°C
1H NMR : (200MHz, CDCl3+DMSO-d6) 5 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), 6.8 - 7.7 (aromatic, 7H), 7.95 (s, imine, 1H)
IR : (KBr), 3352, 3257, 2969, 1640, 1606, 1585, 1484, 1394, 1158, 1070, 1018 cm-1

(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) 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°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. 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 quarteraary ammonium salt of formula-IIc (30.0gms). Recrystallized sample (from IP A) has the characteristics.
1HNMR : (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, 1H)
IR : (KBr), 3352, 3243, 2973, 1639, 1606, 1586, 1495, 1322, 1281, 1255, 1157,
1072,1017 cm"1

Example 4.
(i) Preparation of 2-methoxy-5-(2R)-2- {[(1 -E/Z-4-fluorophenylmethylene)amino]propyl} benzene methane sulfonamide of formula-IIId.

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 (0.lmole) of 4-fluorobenzaldehyde are charged. The reaction is effected azeotropically and the water 1.8ml (0. 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 : 140-148°C
1H NMR : (200MHz, CDCl3+DMSO-d6) 5 1.01 - 1.04 (d, 3H), 2.80 - 2.88 (t, 2H),
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, 2948, 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.

The oily mass of formula-IIId obtained in step (i) 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°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. Recrystallized (from acetonitrile) has the following characteristics.
MR : 200 - 208°C
1HNMR : (200MHz, DMSO-d6) 8 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, 11H), 8.15(s,imine, 1H)
IR : (KBr), 3305, 3210, 2930, 1632, 1609, 1494, 1439, 1330, 1282, 1252, 1456,
1075,1011,533,522,454 cm*1

Advantages of the invention
The novel compounds are useful for the preparation of Tamsulosin hydrochloride, which is a widely used drug for the treatment of benign prostate hyperplasia. The process for the preparation of Tamsulosin hydrochloride using the novel compounds of the present invention makes the process not only simple but also economical and yielding Tamsulosin hydrochloride in high purity ( 99.5%).




We claim
1. A process for the preparation of quarternised benzylidene ammonium salts, N-(phenyl substituted)-[2-(2-ethoxyphenoxy)ethyl]-[2-(4-methoxy-3-sulphamoylphenyl)-l(R)-me ethyl] ammonium halides of the formula-II,

Where R is H, 4-OCH3, 4-OH or 4-fluoro and X represents CI, Br or I as defined in Claim 1, which comprises (i) reacting the compound R(-) 5-[(2-amino-2-methyl)ethyl]-2-methoxy benzene sulfonamide 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 groups azeotropically removing the water at reflux temperature using solvents such as toluene, xylene or by simultaneous distillation of water formed using an alcholic solvent such as methanol, ethanol, isopropyl alcohol, n-butanol etc .
(ii) reacting the resulting compound, 2-methoxy-5-(2R)-2 {[(1 -E/Z-pheylmethylene) amino] propyl} benzenesulfonamide of the formula-Ill


Where R is H, 4-OCH3, 4-OH or 4-fluoro groups with 2-(2-ethoxyphenoxy)ethylhalide of the formula-XVII,
where the X represents a halo group is CI, Br or I at a temperature in the range of 80°C to 130°C to obtain the novel quarternised 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-OH, 4-OCH3 or 4-fluoro groups and X represents a halogen such as CI, Br or I. The above compound of formula II, is a key intermediate for the preparation of Tamsulosin hydrochloride of formula I.

2 A process as claimed in claim 1 wherein the step (i) is effected by azeotropically removing the water using a solvent,
3 A process as claimed in claim 2 wherein the solvent, such as toluene, xylene etc. is used.
4 A 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,
5 A process as claimed in claim 1 wherein the reaction of step-(ii) is carried out neatly with out using solvent.
6 A process as claimed in claims 1 wherein the reaction of step-(ii) is carried out also by using solvent such as toluene, xylene, n-butanol, dimethyl formamide, dimethyl acetamide .
7 A process as claimed in claims 1 to 6 wherein the compound of formula-II is isolated by filtration.
8 A process as claimed in claims 1 to 7 wherein the compound of the formula-II is isolated by
removal of the solvent and by simple leaching with a suitable solvent such as methylene chloride .

9 A process for the preparation of quarternary 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, which are useful as key intermediates for the preparation of Tamsulosin hydrochloride of formula-I substantially as herein described with reference to the examples.


Documents:

598-mas-2002-abstract.pdf

598-mas-2002-claims duplicate.pdf

598-mas-2002-claims original.pdf

598-mas-2002-correspondence others.pdf

598-mas-2002-correspondence po.pdf

598-mas-2002-description complete duplicate.pdf

598-mas-2002-description complete original.pdf

598-mas-2002-form 1.pdf

598-mas-2002-form 5.pdf

598-mas-2002-other documents.pdf


Patent Number 208038
Indian Patent Application Number 598/MAS/2002
PG Journal Number 31/2007
Publication Date 03-Aug-2007
Grant Date 06-Jul-2007
Date of Filing 14-Aug-2002
Name of Patentee NATCO PHARMA LIMITED
Applicant Address NATCO HOUSE,ROAD NO.2, BANJARA HILLS, HYDERABAD-500 033.
Inventors:
# Inventor's Name Inventor's Address
1 KONAKANCHI DURGA PRASAD NATCO HOUSE,ROAD NO.2, BANJARA HILLS, HYDERABAD-500 033.
PCT International Classification Number A61K31/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA