The present invention relates to a process for the preparation of a sulfamoyl siistitiited
phenethylamine derivative, 2-hydroxy-5-[2-[[2-(2-hydroxyphenoxy)ethyl]amino]propyl]
ben/enesulfonamide, , the enantiomers thereof and their mixtures, and pharmaceutically acceptable acid addition salts thereof, which have α-adrenergic blocking activity.
Several sulfamoyl substituted phenethylamine derivatives having strong a-adrenergic blocking activity are disclosed in US Patent No. 4703063. A related patent US 4731478 discloses the (-) isomer of 5-[2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl]-2-methoxybenzenesulfonamide, i.e. tamsulosin of the formula A, as shown in the accompanied drawings. Tamsulosin is used in the treatment of benign prostatic hyperplasia (BPH), a condition characterized by modular enlargement of prostatic tissue which results in obstruction of proximal urethra. It is also marketed for the treatment of prostate cancer and for hypertension.
Canadian patent CA 1282077 describes a process for preparing compounds of the formula B. as shown in the accompanied drawings, wherein R1 represents a lower alkyl group, a lower alkoxy group, or a hydroxyl group; R~ represents a hydrogen atom, or a lower alkyl group; R' represents a hydrogen atom or a lower alkyl group; and R4 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a hydroxyl group.
The present invention concerns a compound of formula I , as shown in the accompanied drawings, which has the chemical name 2-hydroxy-5-[2-[[2-(2-hydroxyphenoxy)ethyl]amino]propyl | ben/enesulfonamide, the enantiomers thereof and their mixtures, and pharmaceutically acceptable acid addition salts thereof. The compounds of the present invention posess a-adrenergic blocking action. These compounds have not been specifically disclosed or prepared in the aforementioned Canadian patent.
The present invention provides a method for the preparation of the compound of formula I, as shown in the accompanied drawings, the enantiomers thereof and their mixtures, and pharmaceutically acceptable acid addition salts thereof, which comprises reacting the compound of formula II , as shown in the accompanied drawings, the enantiomers thereof or their mixtures, or a sail thereof with a Lewis acid to obtain the compound of formula I, the enantiomers thereof or their mixtures, which may then be converted to a salt if desired.

The process is advantageous in that the conversion of compound of formula II to compound of formula 1 is achieved in a single step by simultaneous demethylation and deethylation at the t\vo bezene rings of the compound of formula II.
Suitable Lewis acids which may be used for the O-dealkylation reaction include halidcs of aluminum, boron, zinc, iron, tin, bismuth, antimony and titanium. Examples of such Lewis acids include aluminum chloride, aluminum bromide, boron tribromide, born trifluoride, zinc chloride, zinc iodide, ferrous chloride, stannous chloride, bismuth chloride, antimony pentachloride, titanium tetrachloride, and the like. Aluminum chloride is preferred.
The reaction may be carried out in any organic solvent which is inert under the reaction conditions. Suitable solvents include halogenated solvents such as 1,2-dichloroethane, dichloromethane, and the like or hydrocarbons such as xylene, toluene, and the like. Toluene is preferred.
The reaction may be performed at room temperature or at higher temperature, preferably at 20"C to 100"C, most preferably at 60 to 85°C.
The compound of formula I can form pharmaceutically acceptable acid addition salts with inorganic or organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic , sulfuric, sulfamic, phosphoric and nitric acid, while examples of such organic acids are maleic, fumarie, benzoic, ascorbic, succinic, oxalic, methane sulfonic, ethane disulfonic, formic, acetic, propionic, tartaric, salicyclic, citric, gluconic, aspartic, stearic, palmitic, glycolic, p-aminoben/oic, glutamic, and benzenesulfonic acid. Most preferred is the hydrochloride salt.
The acid addition salts of the compound of formula I may be prepared by methods known in the art. The base is reacted with a calculated amount of acid in a water miscible solvent such as acetone, ethanol or methanol, with subsequent isolation of salt by concentration and cooling. Alternatively, the base is reacted with an excess of the acid in a water immiscible solvent such as ethyl acetate, with the salt separating out spontaneously.
The starting compound of Formula II, the enantiomers thereof, their mixtures, or a salt thereof can be prepared easily by methods known in the art, such as US 4703063, CA 1282077. EP 380144. US 473 1478, and J. Labelled Compd.Radiopharm. 27 (2), 171-180 (1989).

The starting compounds of Formula II may also be used in the form of acid addition salts, which may be the same or different from the salt of formula I. Any suitable inorganic or organic acid commonly used in synthetic chemistry may be used for salt formation. Example of such acids include the acids given above for the compound of formula I. Most preferred is the hydrochloridc
salt.
Methods known in the art may be used with the process of this invention to enhance any aspect of the process. The product obtained may be further purified by any techniques known to a person skilled in the art for example, by filtration, crystallization, column-chromatography, preparative high pressure liquid chromatography, preparative thin layer chromatography, extractive washing in solution or a combination of these procedures.
The compound of formula I of this invention and its salts may exist in unsolvated or solvated form with pharmaceutically acceptable solvents such as water, ethanol, isopropanol and the like. In general, the solvated forms are considered equivalent to the unsolvated form for the purpose of invention.
The compounds of Formula I, the enantiomers thereof or their mixtures, and the pharmaceuticaliy acceptable acid addition salts thereof may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. and in these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients. In addition to the common dosage forms set out about, the compound of the present invention may also be administered by controlled release means and/or delivery devices.
The compound of Formula I, the enantiomers thereof and their mixtures, and the acid addition salts thereof provided by the present invention exhibit an α-adrenergic blocking action and thus they can be utilized for various treatments such as for benign prostatic hyperplasia, lower urinary tract dysfunction, prostatic hypertrophy, hypertension, congestive heart failure, angina pectoris, pheochromocytoma and peripheral vascular disorders.
The example mentioned below demonstrates the specific preparation of the preferred compound. The example is given to illustrate details of the invention and is not intended in any way to limit the scope of the present invention.

Example 1
Process for the Preparation of R (-)-2-hydroxy -5-[2-[[2-(2-hydroxyphenoxy)ethyl]amino]propyl]benzenesulfonamide, hydrochloride
Anhydrous aluminium chloride (3.0g) was added to toluene (30ml) at room temperature under
nitrogen atmosphere. R(-)-5-(2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-
melhoxybenzenesulfonamide, hydrochloride (2.0g) was then added under stirring. Temperature of the reaction mixture was raised to 80°C and the mixture was strirred at this temperature for one hour. Reaction mixture was then cooled to room temperature, poured on crushed ice and stirred at 0 to 5°C. The hydrochloride salt which precipitated out was filtered and washed with cold water. Crude product so obtained was recrystallized from methanol to get the title compound (1.5g)
Mass (MH+): 367
1H-NMR (DMSO- d6; δ ppm); 1.18 (d, 3H), 2.69 (t, 1H), 3.29-3.45 (m, 4H), 4.28 (s, 2H), 6.70-
7.03 (m, 7H), 7.30-7.32 (m, 1H), 7.55 (s, 1H), 8.85 (s, 1H), 9.36 (brs, 2H), 10.74 (brs, 1H).
IR (KBr, cirf-1):3356, 2943, 2445, 1699, 1506, 1425, 1327.

WE CLAIM :
1. A method for the preparation of the compound of formula 1, as shown in the accompanied
drawings,, the enantiomers thereof and their mixtures, and pharmaceutically acceptable acid
addition salts thereof, which comprises reacting the compound of formula II, as shown in the
accompanied drawings, the enantiomers thereof or their mixtures, or a salt thereof with a Lewis
acid to obtain the compound of formula I, the enantiomers thereof, or their mixtures, which
may then be converted to a salt if desired.
2. The process of claim 1, wherein of the compound of formula I is isolated as the hyrochloridc
salt.
3. The process of claim 1, wherein R(-) isomer of the compound of formula 1 is prepared.
4. The process of claim 3, wherein of the R(-) isomer of the compound of formula I is isolated as
the hyrochloride salt.
5. The process of claim 1, wherein the Lewis acid is a halide of aluminum, boron, zinc, iron, tin,
bismuth, antimony and titanium.
6. The process of claim 5, wherein the Lewis acid is aluminum chloride.
7. The process of claim 1, wherein the reaction is carried out in an organic solvent selected from
halogenated solvents, hydrocarbons and mixtures thereof.
8. The process of claim 7, wherein the reaction is earned out in a halogenated solvent such as 1,2-
dichloroethane, dichloromethane, and the like.
9. The process of claim 7, wherein the reaction is carried out in a hydrocarbon such as xylcnc,
toluene, and the like.
10. The process of claim 1, wherein the reaction is carried out at 20°C to 100°C.

11. The process of claim 10, wherein the reaction is carried out at 60 to 85°C.
12. The process for the preparation of the compound of formula I, as shown in the accompanied
drawings, the enantiomers thereof and their mixtures, and pharmaceutically acceptable acid
addition salts thereof, as herein described and illustrated by the examples herein.