Claims:1. A process for the preparation of N-(4-Chlorophenethyl)-2-chloropropan-1-amine or salt thereof of Formula II,

Formula-II
the process includes steps of,
a) adding 2-(4-chlorophenyl) ethyl-N-2-chloropropionamide or salt thereof in tetrahydrofuran,
b) charging reducing agent to the reaction mixture of step (a) at low temperature and stirring at suitable temperature,
c) isolating N-(4-Chlorophenethyl)-2-chloropropan-1-amine or salt thereof.

2. The process of claim 1, wherein reducing agent is selected from the group comprising one or more of sodium borohydride, sodium borohydride/BF3-etherate, potassium borohydride, zinc borohydride, sodium cyanoborohydride, sodium sulfurated borohydride, sodium trioxyacetal borohydride, sodium trialkoxy borohydride, sodium hydroxyl borohydride, sodium borohydride anilide, tetrahydrofuran borohydride, di-methyl-butyl borohydride, lithium-aluminum hydride, lithium-aluminum tri-oxymethyl hydride, sodium-aluminum-2-methoxyethoxy hydride, and aluminum hydride.

3. The process of claim 1, wherein reducing agent is sodium borohydride/BF3-etherate.

4. The process of claim 1, wherein reducing agent is charged at temperature 0ºC to 10ºC.

5. The process of claim 1, wherein step b) is carried out at suitable temperature of about 60°C to 65°C.

6. The process of claim 1, wherein step c) isolation is carried out by means of acid base treatment.

7. The process of claim 1, wherein the purity of N-(4-chlorophenethyl)-2-chloropropan-1-amine, has purity more than 98 % by as measured HPLC.

8. The process according to claim 1, wherein N-(4-chlorophenethyl)-2-chloropropan-1-amine subsequently converted to Lorcaserin or a pharmaceutically acceptable salt thereof.
, Description:Field of Invention

The present invention relates to an improved process for the preparation of intermediate of Lorcaserin, e.g. N-(4-chlorophenethyl)-2-chloropropan-1-amine or salt thereof (hereinafter referred as propyl chloride intermediate), in high yield under mild reaction conditions, has purity more than 98%. A further aspect of the present invention relates to conversion of propyl chloride intermediate to Lorcaserin or a pharmaceutically acceptable 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 8,952,197; US 8,299,241; US 8,168,782; US 8,367,657; US 8,168,624; US 8,697,686; US application no 20130310369; US2009143363 and PCT application no. WO2015102017.

The object of present invention is to provide an improved process for the preparation of N-(4-chlorophenethyl)-2-chloropropan-1-amine, which is a key intermediate for the preparation to Lorcaserin or pharmaceutical acceptable salt thereof. The said process is very simple and cost effective, involves mild reaction conditions and may be employed at commercial scale. The intermediate according to the present invention process provides both enhanced yield as well as purity.

Summary of the Invention

The present invention provides an improved process for the preparation of N-(4-chlorophenethyl)-2-chloropropan-1-amine or salt thereof, has purity more than 98 %. A further aspect of the present invention relates to conversion of said intermediate of Lorcaserin to Lorcaserin or pharmaceutical acceptable salt thereof.

The present invention provides a process for the preparation of N-(4-chlorophenethyl)-2-chloropropan-1-amine or salt thereof, the process includes steps of
a) adding 2-(4-chlorophenyl) ethyl-N-2-chloropropionamide or salt thereof (hereinafter referred as propionamide) in tetrahydrofuran solvent and,
b) charging suitable reducing agent to the reaction mixture of step (a) at low temperature and stirring at suitable temperature,
c) isolating N-(4-Chlorophenethyl)-2-chloropropan-1-amine or salt thereof.

In another aspect, the present invention provides of N-(4-chlorophenethyl)-2-chloropropan-1-amine or salt thereof, has purity more than or equal to 98%.

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 salt. Inorganic salt may include hydrochloride, hydrobromide, and the like.

The present invention provides a process for the preparation of N-(4-chlorophenethyl)-2-chloropropan-1-amine or salt thereof of Formula II,

Formula-II
the process includes steps of
a) adding 2-(4-chlorophenyl) ethyl-N-2-chloropropionamide or salt thereof in tetrahydrofuran solvent,
b) charging reducing agent to the reaction mixture of step (a) at low temperature and stirring at suitable temperature,
c) isolating N-(4-Chlorophenethyl)-2-chloropropan-1-amine or salt thereof.

The step a) of the present invention involves addition of propionamide derivative in tetrahydrofuran solvent and cooling the reaction mixture to temperature between the ranges of 0ºC to 10ºC.

The step b) of the present invention involves charging suitable reducing agent to the reaction mixture of step (a) for a period of 1 to 2 hours at temperature 0ºC to 10ºC, followed by stirring the reaction mixture at suitable temperature for a period of 2 hours, where suitable temperature is between the range of 60ºC to 65ºC.

The reducing agent is selected from the group comprising one or more of sodium borohydride, potassium borohydride, zinc borohydride, sodium borohydride/BF3-etherate, sodium cyanoborohydride, sodium sulfurated borohydride, sodium trioxyacetal borohydride, sodium trialkoxy borohydride, sodium hydroxyl borohydride, sodium borohydride anilide, tetrahydrofuran borohydride, di-methyl-butyl borohydride, lithium-aluminum hydride, lithium-aluminum tri-oxymethyl hydride, sodium-aluminum-2-methoxyethoxy hydride, and aluminum hydride.

The step c) of the present invention involves isolation of the N-(4-chlorophenethyl)-2-chloropropan-1-amine or salt thereof from the reaction mixture obtained in step b).

The isolation involves cooling the reaction mixture at temperature between the range of 25ºC to 35ºC followed by further cooling at temperature between the range of 5ºC to 15ºC. The reaction mixture is then quenched with 2N hydrochloric acid. The solvent tetrahydrofuran is removed under vacuum at temperature 75ºC and the reaction mixture is stirred at temperature between the range of 95ºC to 100ºC for a period of 1 hour. The reaction mass is cooled at temperature between the range of 25ºC to 35ºC followed by addition of water and dichloromethane to the reaction mass and stirred for another 15 minutes, further the temperature is brought down to temperature between the range of 5ºC to 15ºC followed by adjustment of pH 8.5 to 9.5 by sodium hydroxide and stirring for another 15 minutes. The organic layer is collected and the aqueous layer is extracted by dichloromethane. The combined dichloromethane layer is washed with water and distilled out dichloromethane layer under vacuum, further isopropyl alcohol is added and the solvent is again evaporated under vacuum to obtain free base. The reaction mass is allowed to cool to temperature between the range of 25ºC to 35ºC and isopropyl alcohol is added to the reaction mass followed by adjusting the pH to 1-2 by concentrated hydrochloric acid. The reaction mixture is stirred for a period of 2 hours at temperature between the range of 5ºC to 15ºC. The resulting precipitate was filtered and washed with isopropyl alcohol to obtain white solid.

In another aspect, the present invention provides N-(4-chlorophenethyl)-2-chloropropan-1-amine or salt thereof has purity more than or equal to 98 %.

The compounds N-(4-chlorophenethyl)-2-chloropropan-1-amine or salt thereof can be converted into Lorcaserin hydrochloride according to known methods given in US patent number 8,952,197 and PCT application no WO2015102017.

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 N-(4-Chlorophenethyl)-2-chloropropan-1-amine hydrochloride

Charged tetrahydrofuran (6 L) to 2-(4-chlorophenyl) ethyl-N-2-chloropropionamide (1 Kg) and cool the reaction mixture to temperature between the range of 0ºC to 10ºC. Sodium borohydride (0.537 Kg) was added to the reaction mixture over the course of 1-2 hours followed by addition of boron trifluoride etherate (1.73 Kg) to the reaction mixture at temperature between the range of 0ºC to 10ºC and stirred at temperature between the range of 60ºC to 65ºC for a period of 2 hours. The reaction mixture was allowed to cool at temperature between the range of 25ºC to 35ºC followed by further cooling at temperature between the range of 5ºC to 15ºC. The reaction mixture was then quenched by 2N hydrochloric acid (8.0 L) and the solvent tetrahydrofuran was removed under vacuum at temperature 75 ºC. The reaction mixture was stirred at temperature between the range of 90ºC to 100ºC for a period of 1 hour and then cooled to temperature between the range of 25ºC to 35ºC; further, water (5.0 L) and dichloromethane (6.0 L) was added to the reaction mass. The reaction mixture was stirred for another 15 minutes and temperature was brought down to temperature between the range of 5ºC to 15ºC followed by adjustment of pH 8.5 to 9.5 by 30% sodium hydroxide (3.4 L) and stirring for another 15 minutes. After completion of reaction, the organic layer was collected and aqueous layer was extracted with dichloromethane (2.0 Lit). The combined organic layer was then washed with water (2 x 5.0L) and the dichloromethane layer was distilled out under vacuum. Further isopropyl alcohol (5.0 L) was added and the solvent was again evaporated under vacuum at temperature 50 ºC to obtain free base. The reaction mass was allowed to cool to temperature between the range of 25ºC to 35ºC and isopropyl alcohol (5.0L) was added to the reaction mass followed by adjusting the pH to 1-2 by concentrated hydrochloric acid (480 ml). The reaction mixture was stirred for a period of 2 hours at temperature between the range of 5ºC to 15ºC. The resulting precipitate was filtered and washed with isopropyl alcohol (0.5 L x2) to obtain white solid as titled compound.

Yield: 0.90Kg (w/w)
Practical yield: 82%
HPLC Purity: >98.0%