BACKGROUND OF THE INVENTION (R)-5-[2-[[2-(2-ethoxyphenoxy) ethyl] amino] propyl]-2- methoxybenzenesulfonamide or tamsulosin has the following chemical formula : Tamsulosin is a known, commercially available drug, used in the treatment of benign prostate hypertrophy. Tamsulosin is commonly prepared as its hydrochloride salt.

Chemical synthesis of an organic compound of the complexity of tamsulosin is commonly a multi-stage, complicated process, where losses of yield of intermediate products at various stages and requirements for purification of intermediates at various stages can add up to an overall process of unsatisfactory yield and consequent economic disadvantage. Various processes for its preparation are disclosed in the art.

United States Patent Nos. 4,703,063 and 4,558,156 as well as counterpart European Patent No. 0,034,432, all of Imai et al., describe two processes for

preparing tamsulosin, one of which involves the conversion of a hydroxy substituted analogue of tamsulosin, i. e., a compound having the tamsulosin structure but having a hydroxyl substituent at a position a to the benznesulphonamide ring, by halogenation followed by either reduction or reaction with an alkali followed by hydrogen iodide; the other of which involves condensation of a benzenesulfonamide aldehyde with the appropriate substituted phenoxy amine, followed by reduction of the resulting imino product. These processes present some disadvantages. In particular, a sulfonamide substituent is easily displaced from a benzene ring, so that subsequent chemical steps involving a benzenesulfonamide have to be conducted with great care if yield is not to be lost. Moreover, the benzenesulfonamide aldehyde compound prepared and used in these processes is an unstable oil.

Another significant disadvantage of these processes is that they are not stereospecific, i. e., they are not suitable for the preparation of individual optical isomers of tamsulosin. The final products require a step of optical resolution to obtain specific optical isomers.

European Patent No. 0380144 of Okada et al., describes a process for preparing tamsulosin and the like, in stereospecific form, by reaction of a benzenesulfonamide amine with predetermined stereospecificity, with a halogenated methyl phenyl ketone, specifically the bromide compound. This bromide compound, however, is problematic in terms of purification and storage.

Canadian Patent No. 1,340,332 of Koishi et al. describes an analogous coupling reaction, but using an aldehyde for coupling with the amine instead of the ketone. This process suffers from similar disadvantages.

Published PCT Application WO 02/068382 A1 of Ham et al. discloses a process for the preparation of some sulfanoyl-substituted phenethylamine derivatives including tamsulosin, which involves a coupling reaction between (R)-5- (2-amino) propyl-2-methoxy-benzenesulfonamide with an acid or a corresponding acid chloride or mixed anhydride to obtain tamsulosin amide. This coupling reaction presents the disadvantage that the acid or acid chloride or anhydride should be provided in a high purity in order to obtain a good yield for the-coupling reaction; and it is known in the art that purification of such products is not always easy.

It is generally known in the art that formation of amide from direct reaction between an ester and an amine is in general very difficult to achieve. Successes in such reaction have been reported in the following references: Basha, A. ; Lipton, M.;<BR> Weinreb, S. M. Tetrahedron Lett. 1977,4171-4174. Levin, J. l. ; Turos, E. ; Weinreb,<BR> S. M. Synth. Comm. 1982, 12, 989-993. Huang, P-Q.; Zheng, X. ; Deng, X-M.

Tetrahedron Lett. 2001, 42, 9039-9041. In these references, an aluminum reagent is used to activate the amine.

As can be seen, the various synthetic processes of tamsulosin described in the above patents each present some disadvantages. Thus, there remains a need for a practical, economic and efficient synthesis of tamsulosin, in optically pure form.

SUMMARY OF THE INVENTION It is thus an object of the present invention to provide an improved process for the preparation of tamsulosin, which is reasonably simple, economic and efficient.

It was the surprising discovery of the inventors that although known reactions between an amine and ester to produce an amide are difficult to achieve, it is possible to form tamsulosin amide with relative ease by coupling an ester of general formula 2A below with (R)-5- (2-amino) propyl-2-methoxy-benzenesulfonamide (3), in the presence of an aluminium reagent which activates amine (3), thus facilitating the coupling reaction. The reaction functions relatively well despite the presence of the sulfonamide group on the amine.

The invention provides, in one aspect, a process for the preparation of (R)-5- [2-[[2-(2-ethoxyphenoxy) ethyl] amino] propyl]-2-methoxybenzenesulfonamide (tamsulosin) of formula: 5 and pharmaceutical acceptable salts thereof, which comprises coupling an ester of formula : 2A 5 with (R)-5- (2-amino) propyl-2-methoxy-benzenesulfonamide of formula : 3 in the presence of an aluminum reagent to yield tamsulosin amide of formula :

4 The aluminum reagent used in the coupling reaction between the ester (2A) and the amine (3), as outlined above, is preferably a trivalent aluminum reagent. It can be selected from diisobutyl aluminum hydride, trimethyl aluminum, triethyl aluminum, dimethyl aluminum chloride, aluminum isopropoxide and aluminum trichloride. This coupling reaction is preferably carried out in the present of an aprotic solvent. Solvents reaction such as tetrahydrofuran, methylene chloride, toluene and benzene can be used.

The above amide (4) is reduced with a reducing agent to form tamsulosin (5) above.

According to another aspect, the ester used in the coupling reaction is obtained by reacting 2-ethoxy phenol with an alkyl halogeno acetate, in the presence of a base. For example, methyl 2-ethoxyphenoxy acetate is obtained by reacting 2-ethoxy phenol with methyl bromo acetate in the presence of potassium hydroxide. Preferred esters are alkyl esters, more preferably alkyl esters wherein the alkyl substituent is straight or branched and has 1 to 6 carbon atoms.

According to yet another aspect, the reduction reaction to yield tamsulosin is carried out in the presence of a metal reagent, which can be an aluminum reagent or a borane reagent. More preferably, sodium bis (2-methoxyethoxy) aluminum dihydride or borane dimethylsulfide can be used.

According to another aspect, the process comprises the further step of treating tamsulosin with an acid to yield a pharmaceutically acceptable salt thereof.

For example, tamsulosin is treated with hydrochloric acid to yield tamsulosin hydrochloride salt.

According to another aspect, the invention provides a process for the preparation of tamsulosin, which comprises: reacting 2-ethoxy phenol with methyl bromo acetate in the presence of a base to obtain methyl 2-ethoxyphenoxy acetate; coupling 2-ethoxyphenoxy acetate with (R)-5- (2-amino) propyl-2-methoxy- benzenesulfonamide in the presence of diisobutyl aluminum hydride to obtain tamsulosin amide; and subjecting tamsulosin amide to a reduction reaction in the presence of sodium bis (2-methoxyethoxy) aluminum dihydride or borane dimethylsulfide to yield tamsulosin.

The ester of formula 2A may be contaminated with up to about 10% of 2- ethoxy phenol.

BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1 is a reaction scheme illustrating the general process according to the invention; and FIGURE 2 is a reaction scheme illustrating a preferred embodiment of the process according to the invention.

While the invention will be described in conjunction with the embodiments illustrated in the reaction schemes, it will be understood that it is not intended to limit the invention to such embodiments. On the contrary, it is intended to cover all alternatives, modifications and equivalents as may be included within the scope of the invention as defined by the appended claims, including any reagents, steps or intermediate compounds that would be recognized as equivalent to those described herein by one skilled in the art.

DETAILED DESCRIPTION OF THE INVENTION In the following description, molecules have been given similar reference numerals as in the reaction schemes illustrated in the drawings.

Fig. 1 illustrates the general process according to the invention. 2- Ethoxyphenol (1) is treated with an alkyl halogeno acetate in the presence of a base to yield an ester (2A). The ester is further subjected to a coupling reaction with (R)-

5-(2-amino) propyl-2-methoxy-benzenesulfonamide (3) to yield tamsulosin amide (4).

The coupling reaction is carried out in an aprotic solvent, in the presence of an aluminum reagent. This reaction is easy to perform and its success is tolerant to the quality of the ester (2). Good results were obtained in a coupling reaction carried out using an ester sample contaminated with 10% of 2-ethoxyphenol.

Tamsulosin amide (4) may be further subjected to a reduction reaction to yield tamsulosin (5), which can be further treated with an acid to yield a salt of tamsulosin (6A). Tamsulosin obtained through the process according to the invention is in optically pure form. Indeed, the amine (R)-5- (2-amino) propyl-2- methoxy-benzenesulfonamide (3) used has the appropriate stereochemistry, which is transferred to the final product; no racemization occurred, either during the coupling reaction or during the reduction of tamsulosin amide.

The ester (2A) obtained after reaction of ethoxyphenol (1) with alkyl halogeno acetate can be used"as-is", without any purification for the coupling reaction.

Turning to Fig. 2, there is illustrated an example embodiment of the process according to the invention. The ester, 2-ethoxyphenoxy acetate (2) is obtained by treating 2-ethoxyphenol (1) with methyl bromo acetate in the presence of potassium hydroxide. The ester is further subjected to a coupling reaction with (R)-5- (2- amino) propyl-2-methoxy-benzenesulfonamide (3) to yield tamsulosin amide (4).

The coupling reaction is carried out in tetrahydrofuran, in the presence of diisobutyl aluminum hydride.

Tamsulosin amide (4) is further subjected to a reduction reaction, using either sodium bis (2-methoxyethoxy) aluminum dihydride or borane dimethylsulfide, to yield tamsulosin (5), which can be further treated with hydrochloric acid to yield tamsulosin hydrochloride salt (6).

EXAMPLE 1: Formation of methyl 2-ethoxyphenoxy acetate (2) A 500 mi three-neck, round bottom flask was charged with 6.25 ml of water and 6.55g of potassium hydroxide. The resulting mixture was gently stirred at ambient temperature to give a clear solution. The resulting mixture was further charged with 250 mi of toluene and 11.5 ml of 2-ethoxyphenol (75 g), then heated to

reflux. Water distilled out of the reaction mixture was collected in the Dean-Stark trap. After 3 hours of heating, distillation of water from the reaction mixture had stopped. The reaction mixture was allowed to cool to room temperature. A solution of 11.2 ml of methyl bromoacetate and 12.5 ml of toluene was added to the reaction vessel over a period of 10 minutes, resulting in a white suspension which was allowed to stir vigorously at room temperature for 2 hours. Then, 65 ml of water and 4.86 ml of ethylenediamine were added. The resulting biphasic mixture was stirred vigorously for 60 minutes. The mixture was transferred to a 500 ml separatory funnel and the biphasic layer was separated. The organic layer was collected and washed with diluted HCI solution, followed by water. The organic extract was filtered and the resulting solution was concentrated via atmospheric distillation. This solution of ester 2 in toluene was used"as-is"for the next reaction.

EXAMPLE 2: Formation of tamsulosin amide (4) A 500 ml three-necked, round bottom flask was charged with 15.12g of amine 3 and 76 mi of THF. With moderate stirring under nitrogen, a heavy white suspension was formed. The suspension was then cooled in an ice-water bath to 0- 5°C. With moderate stirring, 65 ml of a 1 M solution of diisobutylaluminum hydride in THF was added to the suspension at a rate such that the batch temperature was maintained at 5-10°C. After the addition was completed, the mixture was stirred at 5-10C for 5 minutes to give a light white suspension. The cooling bath was removed and the mixture was allowed to warm to 20-25°C and agitated for 1 hour at this temperature. With moderate agitation, 13.02 g of 2 in toluene was charged into the mixture via a syringe. The resulting reaction mixture was stirred at 20-25°C for 16 hours and then cooled in an ice-water bath to 0-5°C. With vigorous agitation, HCI was charged in slowly such that the reaction temperature was maintained at 20- 25°C. A heavy white suspension was formed. The above suspension was transferred to a 1 L Erlenmeyer flask equipped with a magnetic stirring bar with the aid of CH2CI2. This mixture was stirred vigorously for 30 minutes at 20-25°C to give a biphasic solution. The layers were separated and the lower organic layer was collected and washed with water. The cloudy solution was filtered and concentrated

via distillation under atmospheric pressure. The solution was cooled to 40-50°C and ethanol was added. The resultant solution was again concentrated via distillation under atmospheric pressure to generate a heavy white suspension. The heavy white suspension obtained above was cooled to 20-25°C. With moderate stirring, MTBE was charged. The resultant mixture was stirred for 5 minutes and then cooled in an ice-water bath to 0-5°C. Agitation continued for another 30 minutes.

The white solid in the suspension was collected by suction filtration while cold. The cake was collected and dried under vacuum at 45°C for 16 hours to give 20.2 g of the amide 4 with a yield of 77%.

EXAMPLE 3: Formation of tamsulosin hydrochloride (6) using borane- dimethylsulfide A 1L, 3 necked round bottom flask equipped with a condenser, a mechanical stirrer, a thermometer and a nitrogen inlet, was charged 47.4 g of 4 with 500 mL of THF. The resulting suspension was brought to reflux. While maintained at reflux, the reaction solution was charged slowly and carefully with borane-dimethylsulfide (63.8 mL). The reaction mixture was continued with the. reflux for 5 hours at which point the reaction was usually seen complete by HPLC.

Next, the mixture was cooled to room temperature and concentrated to dryness to give a thick pale yellow oil. To this oil, methanol (300 mL) and 7 M ethanol/HCI solution (100 mL) were added and the resulting white suspension was refluxed for 0.5 hour. Then, the mixture was evaporated to dryness to give white solid. The solid was dissolved in refluxing methanol (300 mL) and then, cooled to room temperature. Diethyl ether (500 mL) was added and the suspension was stirred at room temperature for a period of 2 hours. The solid was filtered and washed with cold MeOH/diethyl ether solution (1: 3,80 mL). The white solid was vacuum dried at 40°C overnight to give 44 g of the product (6) (92% yield).

EXAMPLE 4: Formation of tamsulosin hydrochloride (6) using sodium bis (2- methoxyethoxy) aluminum hydride

Toluene (60 mL) was added into a round bottom flask containing 6.33 g of 4.

The resulting suspension was stirred moderately under nitrogen at 5-10°C. Excess sodium bis (2-methoxyethoxy) aluminum hydride (Red-AI, 6.5 equivalents) was slowly charged into this suspension. The reaction mixture was agitated at ambient temperature overnight (21 hours). The reaction was quenched with aqueous hydrochloric acid and the crude tamsulosin hydrochloride was isolated. Purification of the crude product was accomplished by the liberation of the free base from the crude HCI salt with sodium hydroxide and then the extraction of the amine into dichloromethane followed by the regeneration of the salt with HCI in ether. This material was further purification by recrystallisation from methanol. The final product was isolated as a crystalline white powder in 71 % yield (4.75 g).

The present invention has been described in part by reference to detailed descriptions of preferred embodiments. However, this invention is not limited to these examples but rather it extends departures and variations of the described embodiments including to the full scope of the appended claims including the chemical equivalents of aspects defined therein.