FIELD OF THE INVENTION
The present invention relates to process for the preparation of 5-[l-hydroxy-2-(l-methyl-3-phenylpropyl)aminoethyl] salicylamide hydrochloride having formula (I). The compound of formula (I) has adopted name "Labetalol Hydrochloride".

BACK GROUND OF THE INVENTION
Labetalol Hydrochloride is disclosed in US4012444, assigned to Allen & Hanburys Limited. It is used for the treatment of hypertension.
The process for preparation of Labetalol Hydrochloride of formula (I) is disclosed in US4012444, GB2149399 and GB2952931. Process disclosed in'these patent references results in lower yield and purity.
Therefore, it would be desirable to have a process for the preparation of Labetalol. Hydrochloride of formula (I) which gives higher yield and purity.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of Labetalol Hydrochloride of formula (I)
which comprises:
a) reacting l-methyl-3-phenyl propylamine of formula (A)
with 5-(bromoacetyl)-2-hydroxy benzamide of formula (B)

in the presence of solvent to give 2-hydroxy-5-{[(l-methy-3-phenylpropyl)amino]acetyI}benzamide of formula (C);
b) reducing 2-hydroxy-5-{[(l-methy-3-phenylpropyl)amino]acetyl}benzamide of formula (C) with sodium borohydrate in the presence of base and solvent to give 2-Hydroxy-5-{ l-hydroxy'2-[(l-methyl-3-phenylpropyl)amino]ethyl}benzamide of formula (D);
c)adding water and toluene to the above reaction mixture;
d)stirring for the period of 30 minutes and separate the resulting aqueous layer;
e)adding concentrated hydrochloride to the above obtained aqueous layer at room temperature for the period of 2 hours to give crude Labetalol Hydrochloride of formula (I);
f)dissolving the above obtained crude Labetalol Hydrochloride of formula (I) in methanol, followed by recrystallization using isopropyl alcohol to obtain pure Labetalol Hydrochloride of formula (I).
In another aspect, the present invention provides process for the preparation of Labetalol Hydrochloride of formula (I) which is highly pure.

In another aspect, the present invention provides process for the preparation of Labetalol Hydrochloride of formula (I) which results in higher yield.
In another aspect, the present invention provides process for the preparation of Labetalol HC1 of formula (I); which is simple, convenient, economical and environmental friendly.
DETAILED DESCRIPTION
Accordingly, the present invention relates to a novel process for the preparation of Labetalol Hydrochloride of formula (I).
Scheme -I illustrates the process for preparation of Labetalol Hydrochloride of formula (I).

In step-1 of the preparation, 4-phenyIbutan-2-amine of formula (A) is treated with 5-(bromoacetyl)-2-hydroxybenzamide of formula (B) in the presence of solvent to obtain 2-Hydroxy-5-{[(l-methyl-3-phenylpropyl)amino]acetyl}benzamide of formula (C). The solvent used in the reaction is selected from . the group consisting of methanol, ethanol, propanol, isopropanol or butanol, preferably using methanol. The reaction temperature may range from 25 °C to 35 °C and preferably at room temperature. The duration of the reaction may be in the range of 0.5 hour to 1.5 hours, preferably for a period of 1 hour.
In step-2 of preparation, the above obtained 2-Hydroxy-5-{[(l-methyl-3-phenyl propyl)amino] acetyl} benzamide of formula (C) is reduced with sodiumborohydrate in the presence of solvent and base to obtain 2-Hydroxy-5-{l.-hydroxy-2-[(l-methyl-3-phenyl propyl)amino]ethyl}benzamide of formula (D). The solvent used in the reaction is selected from the group consisting of methanol, ethanol, propanol, isopropanol or butanol, preferably using methanol. The base used in the reaction is selected from the group consisting of lithium hydroxide, sodium hydroxide or potassium hydroxide and preferably using sodium hydroxide. The reaction temperature may range from 25 °C - 35 °C and preferably at room temperature. The duration of the reaction may range from 1.5 hours to 2.5 hours and preferably for a period of 2 hours.
In step-3 of the preparation, add toluene and water mixture to the above obtained 2-Hydroxy-5-{l-hydroxy-2-[(l-methyl-3-phenyl propyl)amino]ethyl}benzamide of formula (D), stir for 30 minutes and separate the aqueous layer. Add concentrated HC1 to the aqueous layer to give crude Labetalol Hydrochloride of formula (I). The reaction temperature may range from 25 °C - 35 °C and preferably at room temperature. The duration of the reaction may range from 1.5 hours to 2.5 hours and preferably for a period of 2 hours.
In step-4 of the preparation, dissolve the above obtained crude Labetalol Hydrochloride of formula (I) in methanol and stir for 30 minutes, followed by recrystallization using isopropyl alcohol to obtain pure Labetalol Hydrochloride of formula (I). The reaction temperature may range from 25 °C - 35 °C and preferably at room temperature. The duration of the reaction may range from 1 hour to 1.5 hours and preferably for a period of 1 hour.
EXPERIMENTAL PORTION
The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.

Example: Process for the preparation of Labetalol Hydrochloride
Step -1: Process for the preparation of crude Labetalol Hydrochloride r
To the round bottom flask having methanol (500 mL) is charge 4-phenylbutan-2-amine (288.76 grams) at room temperature. Charged 5-Bromo acetylsalcylamide (100 grams) lot wise at room temperature and maintain for 1 hour. Reaction mass cooled to 15-20 °C. Charge 30% sodium hydroxide (100 mL) solution at 15-20 °C. Stir the contents for 30 minutes at 15-20 °C. Slowly added sodium borohydride (26 grams) lot wise at 15-25 °C. Raise the temperature to room temperature and maintain for 2 hours. Charge purified water (500 mL) and stir for 30 minutes at room temperature. Charge toluene (400 mL) and stir for 30 minutes. Separate the aqueous layer and kept toluene layer aside. Charge toluene (300 mL) to aqueous layer and stir for 30 minutes. Separate the aqueous layer and kept toluene layer aside. Charge toluene (300 mL) to aqueous layer and stir for 30 minutes. Separate the aqueous layer and kept toluene layer aside. All toluene layer combined and sent for the recovery of amine compound. Aqueous layer was taken in to another round bottom flask. Slowly adjusted the pH below 2 with hydrochloric acid at.room temperature. Stir for 2 hours at room temperature. Cool to 5-10 °C and stirred for 1 hour. Filtered the compound and washed with purified water (200 mL). The obtained wet compound was ' taken into another round bottom flask and charge ethyl acetate (500 mL). Heated to 45-50 °C and stirred for 1 hour. Cooled to room temperature and stirred for 2 hours. Filtered the compound and washed with ethyl acetate (100 ml). Dry the material at 85-90 °C in hot air oven to obtain crude Labetalol hydrochloride. Yield 68%.
>H - NMR (DMSO-d6): 1.35 - 1.31(3H,t), 1.84 - 1.75(1H, m), 2.19 - 2.10 (lH,m), 2.77 - 2.50(2H, m), 3.38 - 3.08(3H, br), 4.93 - 4.90(1H, t), 6.14 - 6.12(1H, t), 6.93 - 6.90 (1H, d), 7.33 - 7.17(1H, m), 7.47
- 7.44 (1H, d)s 7.94 (2H, s), 8.64 - 8.53(amine, br), 9.24 - 9.17 (1H, br);
Mass (m/z+1): 329.40.
Step - 2: Process for the preparation Labetalol Hydrochloride
To the round bottom flask having methanol (1000 mL) charge crude Labetalol Hydrochloride ((100 grams) at room temperature. Stirred for dissolution at room temperature. Charged activated carbon (5 grams) and stirred for 30 minutes at room temperature. Filtered the reaction mass through buchner funnel followed by micron filter and wash with methanol (100 mL). Filtrate was taken in to round bottom flask and distilled off methanol maximum extent under vacuum (600-700 mm of Hg at below 50 °C). Cooled the contents to 25-35 °C and charge isopropyl alcohol (500 mL) at room temperature and maintain the content for 1 hour at room temperature. Cool the contents to 0-5 °C and maintained the content for 1 hour at 0-5 °C. Filtered the compound and washed with isopropyl alcohol (200 mL). Dried the under vacuum at 85 - 95 °C to obtain Labetalol Hydrochloride. Yield: 90%. 'H-NMR(DMSO-d6): 1.35 - 1.31(3H,t), 1.84 to 1.75(1H, m), 2.19-2.10 (lH,m), 2.77 -2.50(2H, m), 3.38 - 3.08(3H, br), 4.93 - 4.90(1H, t), 6.14 - 6.12(1H, t), 6.93 - 6.90 (1H, d), 7.33 - 7.17(1H, m), 7.47
-7.44 (1H, d), 7.94 (2H, s), 8.64 - 8.53(amine, br), 9.24 - 9.17 (1H, br);
_ Mass (m/z +1): 329.40.

ADVANTAGES OF THE PRESENT INVENTION
1.It is a simple and cost effective process,
2.Toluene and water washing removes all the unreacted starting material (4-phenylbutan-2-amine) which yields highly pure Labetalol Hydrochloride.
3.The starting raw material (4-phenyIbutan-2-amine) which is recovered from the toluene layer can be used for the preparation of Labetalol Hydrochloride.

We claim:
1. A process for the preparation of Labetalol Hydrochloride of formula (I)
which comprises:
a) reacting l-methyl-3-phenyl propylamine of formula (A)
with 5-(bromoacetyl)-2-hydroxy benzamide of formula (B)
in the presence of solvent to give 2-hydroxy-5-{[(l-methy-3-phenylpropyl)amino]acetyl}benzamide of formula (C);
b) reducing 2-hydroxy-5-{[(l-methy-3-phenylpropyl)amino]acetyl}benzamide of formula (C) with sodium borohydrate in the presence of base and solvent to give 2-Hydroxy-5-{ l-hydroxy"2-[(l-methyl-3-phenylpropyl)amino]ethyl}benzamide of formula (D);

c)adding water and toluene to the above reaction mixture;
d)stirring for the period of 30 minutes and separate the resulting the aqueous layer;
e)adding concentrated hydrochloride to the above obtained aqueous layer at room temperature for the period of 2 hours to give crude Labetalol Hydrochloride of formula (I);
f) dissolving the above obtained crude Labetalol Hydrochloride of formula (I) in methanol, followed by
recrystallization using isopropyl alcohol to obtain pure Labetalol Hydrochloride of formula (I).
■*
2.The process according to claim 1, wherein said solvent used in step (a) and (b) is selected from the group consisting of methanol, ethanol, propanol or butanol.
3.The process according to claim 2, wherein said solvent used in step (a) and (b) is methanol.
4.The process according to claim 1, wherein said base used in step (b) is selected from the group consisting of lithium hydroxide, sodium hydroxide or potassium hydroxide.
5.The process according to claim 4, wherein said base used in step (b) is sodium hydroxide.