CLIAMS:1. A process for the preparation of 2-(4-chlorophenyl)ethylamine or salt thereof of Formula II,

Formula-II
the process comprises the steps of,
a) contacting aqueous ammonia to solution of 2-(4-chlorophenyl)acetonitrile or salt thereof in methanol,
b) adding suspension of raney nickel with water to the reaction mixture of step (a) and hydrogenate under suitable hydrogen pressure,
c) isolating compound of formula-II or salt thereof.

2. The process of claim 1, wherein hydrogen pressure range in between at about 5.0 to 7.0 kg/cm2.

3. The process of claim 1, wherein step (a) to (b) are carried out at temperature of about 25°C to 35°C.

4. The process of claim 1, wherein stirring the reaction mixture the period of about 5 to 8 hours.

5. The process of claim 1, wherein the purity of 2-(4-chlorophenyl)ethylamine, has purity more than 94 % by as measured HPLC.

6. The process according to claim 1, wherein compound of formula-II subsequently converted to Lorcaserin or a pharmaceutically acceptable salt thereof.

7. The process according to claim 1, wherein the salt thereof is hydrochloride salt.
,TagSPECI:Field of Invention

The present invention relates to an improved process for the preparation of intermediate of Lorcaserin, 2-(4-chlorophenyl) ethylamine or salt thereof, in high yield under mild reaction conditions, has purity more than 94%. A further aspect of the present invention relates to conversion of said intermediate to Lorcaserin or salt thereof.

Background of the invention

Lorcaserin hydrochloride is a serotonin 2C receptor agonist for oral administration used for chronic weight management. It has the chemical name (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride hemihydrate, and has the structural formula I,

Formula I

Lorcaserin hydrochloride is marketed under the trade name BelviqTM in USA. Lorcaserin or a pharmaceutically acceptable salt first described in U.S. Patent No. 6,953,787 with its process for the preparation. The process for the preparation also described in several patents, e.g. US patent Nos. US 8,546,379, US 7,977,329, US 8,367,657, US 8,168,624 US 8,697,686 and US application no 20130310369.

The object of present invention is to provide an improved process of preparation of 2-(4-chlorophenyl) ethylamine or salt thereof, which involves mild reaction condition and employed at commercial scale. The intermediate prepared by the process of present invention provides both enhanced yield as well as high purity.

Summary of the Invention

The present invention provides an improved process for the preparation of 2-(4-chlorophenyl) ethylamine or salt thereof, has purity more than 94 % when measured by HPLC. A further aspect of the present invention relates to conversion of said intermediate of Lorcaserin to Lorcaserin or salt thereof.

The present invention provides a process for the preparation of 2-(4-chlorophenyl)ethylamine or salt thereof, the process includes steps of ;
a) contacting aqueous ammonia to solution of 2-(4-chlorophenyl)acetonitrile or salt thereof in methanol,
b) adding suspension of raney nickel with water to the reaction mixture of step (a) and hydrogenate under suitable hydrogen pressure,
c) isolating 2-(4-chlorophenyl)ethylamine or salt thereof.

In another aspect, the present invention provides 2-(4-chlorophenyl)ethylamine or salt thereof, has purity more than or equal to 94% when measured by HPLC.

Description of the Invention

For purposes of the present invention, the following terms are defined below.

The intermediates and starting materials of the present invention may be used as free bases or its salts.

The salt used is pharmaceutically acceptable salt and it refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide, and the like; organic salt may include acetate, mesylate, tosylate, trifluoroacetate, fumarate, mandalate, lactate, glutamate, ascorbate, citrate and the like.

The present invention provides a process for the preparation of 2-(4-chlorophenyl)ethylamine or salt thereof of Formula II,

Formula-II
the process includes steps of ;
a) contacting aqueous ammonia to solution of 2-(4-chlorophenyl)acetonitrile or salt thereof in methanol,
b) adding suspension of raney nickel with water to the reaction mixture of step (a) and hydrogenate under suitable hydrogen pressure,
c) isolating compound of formula-II or salt thereof.

The step a) of the present invention involves addition of 2-(4-chlorophenyl)acetonitrile in methanol with aqueous ammonia solution and the step b) of the present invention involves addition of raney nickel suspension with water to the reaction mixture of step (a) followed by hydrogenation of reaction mixture under string for period of 7 hours at temperature between the range of 25oC to 35oC at suitable hydrogen pressure, wherein the hydrogen pressure can range in between 5.0 Kg/cm2 to 7.0 Kg/cm2.

The step c) of the present invention involves isolation of the 2-(4-chlorophenyl)ethylamine or salt thereof from the reaction mixture obtained in step b). The isolation involves the filtration and washing of the reaction mixture obtained in step b) in methanol. The filterate was distilled to obtain yellow mass. The yellow mass was dissolved in dichloromethane and washed with water. The dichloromethane layer treated with concentrated hydrochloric acid (0.3 L) and the resulting precipitate was filtered and washed with dichloromethane to obtain 2-(4-chlorophenyl)ethylamine hydrochloride.

In another aspect, the present invention provides 2-(4-chlorophenyl)ethylamine or salt thereof has purity more than or equal to 94 % when measured by HPLC.
The 2-(4-chlorophenyl)ethylamine hydrochloride can be converted into Lorcaserin hydrochloride according to known methods in the art, e.g. US patent number 8,367,657 and PCT application number WO2014187768.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.
Examples

Example-1: Preparation of 2-(4-chlorophenyl)ethylamine hydrochloride

Charged aqueous ammonia solution (2.0L) to the solution of 2-(4-chloro phenyl)acetonitrile (1.00Kg) in methanol ( 4.0 L) followed by addition of Raney nickel ( 0.250 Kg) in water (0.5 L) to the reaction mass. The reaction mixture was stirred for a period of 7 hours at temperature 25oC to 35oC with hydrogen pressure 7.0Kg/cm2. The resulting suspension was filtered and washed with methanol and the filterate is distilled to get yellow precipitate of 2-(4-chlorophenyl)ethylamine free base. The yellow precipitate is dissolved in dichloromethane and washed with water followed by addition of concentrated Hydrochloric acid (0.3 L). The resulting precipitate was filtered and washed with dichloromethane to get the titled compound.

Yield: 0.65 Kg
HPLC Purity: 94 %