Field of Invention

The present invention relates to a novel process for the preparation of an antihypertensive agent Labetalol hydrochloride.

Background of the Invention

Labetalol hydrochloride is a racemate having two asymmetric centres and therefore exists as a molecular complex of two diastereoisomeric pairs. Labetalol hydrochloride, also known by brand name "Trandate" is an adrenergic receptor blocking agents that has both selective alpha 1-adrenergic and non-selective beta-adrenergic receptor blocking actions.

Labetalol hydrochloride when used in combination with hydrochlorothiazide is known as "Normozyde" is a mixed alpha/beta adrenergic antagonist, which is used to treat high blood pressure. Labetalol hydrochloride chemically designated as 2-hydroxy-5-[l-hydroxy-2-[(lmethyl-3-phenylpropyl)amino]ethyl]benzamide monohydrochloride, which is represented by formula I.

I British patent 2152931 describes a process for the preparation of labetalol hydrochloride of formula I. The process comprises the reaction of 2-hydroxy-5-(l-hydroxy-2-aminoethyl)benzamide hydrochloride and l-phenyl-but-l-ene-3-one to give 2-hydroxy-5-(l -hydroxy-2-( 1 - phenyl-but-1 -ene-3-ylidene)imino]-ethyl)benzamide. The obtained compound is further treated with palladium on carbon using a solvent to form labetalol. It is further converted to hydrochloride salt using ethanolic hydrochloric acid.

British patent 2149399 describes a process for the preparation of labetalol hydrochloride of formula I in which 4-phenylbutan-2-amine and Bromo acetyl salicylamide is condensed in ethanol in presence of concentrated hydrogen chloride to obtain labetalone hydrochloride which is further reduced to Labetalol free base using a reducing agent sodium borohydride. Labetalol free base was then converted to labetalol hydrochloride of formula I using acetone and concentrated hydrogen chloride.

The process can be illustrated by the below scheme -1:

Scheme -1

The major drawbacks in above known process are the use of regulated solvent ethanol; distillation of ethanol is needed for the recovery of excess 4-phenylbutan-2-amine; the use of non-recoverable sodium borohydride; formation of large quantity of effluent; and it involves two steps for the conversion of labetalone hydrochloride to labetalol hydrochloride i.e. labetalone hydrochloride is reduced to labetalol and it is further converted to labetalol hydrochloride.
Thus there is a need to develop a process for the preparation of labetalol hydrochloride, which avoids regulated solvents and non-recoverable sodium borohydride and provides labetalol hydrochloride in single step by reducing labetalone hydrochloride.

Summary of the invention

Accordingly, the principal aspect of the present invention is to provide a process for the preparation of 2-hydroxy-5-[l-hydroxy-2-[(lmethyl-3- henylpropyl)amino]ethyl] benzamide monohydrochloride of formula I, which comprises:

a) condensing l-methyl-3-phenyl propylamine of formula IV with 5-bromo acetyl salicylamide of formula V in presence of solvent and hydrochloric acid to obtain 2-hydroxy-5 -(2-(4-phenylbutan-2-ylamino)acetyl)benzamide hydrochloride of formula III; and

b) reducing 2-hydroxy-5-(2-(4-phenylbutan-2-ylamino)acetyl) benzamide hydrochloride of formula III using a transition metal catalyst and hydrogen in presence of solvent to obtain 2-hydroxy-5-[l-hydroxy-2-[(lmethyl-3-phenylpropyl) amino]ethyl]benzamide monohydrochloride of formula I.

The present invention can be illustrated by the below scheme-2:

Scheme - 2

Another aspect of the present invention is to provide a process for the preparation of 2-hydroxy-5-[l-hydroxy-2-[(lmethyl-3-phenylpropyl)amino]ethyl] benzamide monohydrochloride of formula I, which comprises reduction of 2-hydroxy-5-(2-(4-phenylbutan-2-ylamino)acetyl)benzamide hydrochloride of formula HI using a transition metal catalyst and hydrogen in presence of solvent to obtain 2-hydroxy-5-[l-hydroxy-2-[(lmethyl-3-phenylpropyl)amino]ethyl]benzamide monohydrochloride of formula I.

The above process can be illustrated by below scheme - 3:

Scheme -3

Detail Description of the Invention

Accordingly in an embodiment of the invention, the condensation of 1-Methyl-3-phenyl propylamine of formula IV with 5-Bromo acetyl salicylamide of formula V is carried out in presence of solvent selected from the group comprising methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate etc. preferably ethyl acetate to obtain 2-Hydroxy-5-(2-(4-phenylbutan-2-ylamino)acetyl)benzamide hydrochloride. The reaction is carried out at temperature in the range of about -10 to 20°C, preferably at 0 to 10 °C.

In another embodiment of the invention, the reduction of 2-hydroxy-5-(2-(4-phenylbutan-2-ylamino)acetyl)benzamide hydrochloride of formula III is carried out using a transition metal catalyst selected from palladium on carbon, raney nickel, palladium acetate, platinum preferably palladium on carbon in an alcoholic solvent selected from methanol, ethanol, propanol, butanol, isopropanol and the like, preferably methanol to obtain 2-hydroxy-5-[l-hydroxy-2-[(lmethyl-3-phenylpropyl)amino] ethyljbenzamide monohydrochloride of formula I. The reaction is carried out at temperature in the range of about 30-70°C, preferably at 45-60 °C.

In another embodiment, the process of the present invention provides below key advantages which will be acknowledged and highly appreciated by a person skilled in the art:

1. The process of the present invention provides single step conversion of 2-hydroxy-5-(2-(4-phenylbutan-2-ylamino)acetyl)benzamide hydrochloride of formula III to 2-hydroxy-5-[l-hydroxy-2-[(lmethyl-3-phenylpropyl)amino] ethyljbenzamide monohydrochloride without forming and isolating the 2-hydroxy-5-[l-hydroxy-2-[(lmethyl-3-phenylpropyl)amino] ethyl]benzamide base.

2. The process of the present invention doesn't use the non-recoverable reagent sodium borohydride instead uses highly recoverable palladium on carbon.

3. The process of the present invention significantly reduces the quantity of effluent to provide eco-friendly process.

4. Impurity (if any) formed due to presence of 3-Bromo-5-(bromo acetyl)-2-hydroxy benzamide in Labetalone HC1 gets debrominated automatically during reduction using palladium on carbon to give impurity free Labetalol HC1.

The present invention can be illustrated by the following examples, which are not to limit the scope of invention.

Example 1: Preparation of 2-hydroxy-5-[l-hydroxy-2-[(lmethyl-3-phenylpropyl)amino] ethyljbenzamide monohydrochloride (Labetalol Hydrochloride):

(a) Preparation of 2-Hydroxy-5-(2-(4-phenylbutan-2- y!amino)acetyl)benzamide hydrochloride:

1-Methy 1-3-phenyl propylamine (28.9g) and 8.5 volume of ethyl acetate were charged into a RBF, cooled to 0-5°C. 5-Bromo acetyl salicylamide (9.7g) was added in lots at 0-5°C for 4 hours and stirred for 2-3 hours. Concentrated HC1 (14.9g) was added slowly and stirred for 10-12 hours. The white solid was filtered, isolated and pulped with water to remove the HC1 salt of excess 1-methy 1-3-phenyl propylamine. The material was dried at 65°C for 8 hours to get 2-hydroxy-5-(2-(4-phenyIbutan-2-ylamino)acetyl)benzamide hydrochloride (Labetalone Hydrochloride).

Yield: 95 % Purity: >96%

(b) Procedure for the preparation of 2-hydroxy-5-[l-hydroxy-2-[(lmethyI-3-phenylpropyl)amino] ethyl]benzamide monohydrochloride

2-Hydroxy-5-(2-(4-phenylbutan-2-ylamino)acetyl)benzamide hydrochloride and methanol were charged into an autoclave in the ratio 1:8. 7% of Pd/C was added to the above reaction mass, heated to 50-55°C for 8-10hrs. The catalyst was filtered and the filtrate is concentrated to residue under vacuum at 45°C. 5 volume of acetone was added to the residue, stirred for 30 minutes and cooled to 10-15°C. The obtained product was filtered at 10-15°C and dried.
Yield: 90% Purity: >99%

We claim:

1. A process for the preparation of 2-hydroxy-5-[l-hydroxy-2-[(lmethyl-3-phenylpropyl)amino]ethyl]benzamide monohydrochloride of formula I
which comprises:

a) condensing l-methyl-3-phenyl propylamine of formula IV with 5-bromo acetyl salicylamide in presence of solvent and hydrochloric acid to obtain 2-hydroxy-5-(2-(4-phenylbutan-2-ylamino)acetyl)benzamide hydrochloride of formula III; and

b) reducing 2-hydroxy-5-(2-(4-phenylbutan-2-ylamino)acetyl) benzamide hydrochloride of formula III using a transition metal catalyst and hydrogen in presence of solvent to obtain 2-hydroxy-5-[l-hydroxy-2-[(lmethyl-3-phenylpropyl)amino]ethyl]benzamide monohydrochloride of formula I.

2. A process according to claim 1, wherein the solvent in step (a) is selected from the group comprising methyl acetate, ethyl acetate, propyl acetate and isopropyl acetate.

3. A process according to claim 1, wherein the solvent in step (a) is ethyl acetate.

4. A process according to claim 1, wherein the transition metal catalyst in step (b) is selected from the group consisting of palladium on carbon, raney nickel, palladium acetate and platinum.

5. A process according to claim 1, wherein the transition metal catalyst in step (b) is palladium on carbon.

6. A process according to claim 1, wherein solvent in step (b) is an alcoholic solvent selected from methanol, ethanol, propanol, isopropanol or butanol.

7. A process according to claim 1, wherein solvent in step (b) is methanol.

8. A process for the preparation of 2-hydroxy-5-[l-hydroxy-2-[(lmethyl-3-phenylpropyl)amino]ethyl]benzamide monohydrochloride of formula I which comprises the reduction of 2-hydroxy-5-(2-(4-phenylbutan-2-ylamino)acetyl) benzamide hydrochloride of formula III

using a transition metal catalyst and hydrogen in presence of solvent to obtain 2-hydroxy-5-[ 1 -hydroxy-2-[( 1 methyl-3-phenylpropyl)amino]ethyl]benzamide monohydrochloride of formula I.

9. A process according to claim 8, wherein the transition metal catalyst is palladium on carbon.

10. A process according to claim 8, wherein solvent is an alcoholic solvent selected from methanol, ethanol, propanol, isopropanol or butanol.