Processes for the preparation of lorcaserin

Zydus Cadila Healthcare Ltd

WO 2015102017, 09 July2015 

On 10 May 2012, after a new round of studies submitted by Arena, an FDA panel voted to recommend lorcaserin with certain restrictions and patient monitoring. The restrictions include patients with a BMI of over 30, or with a BMI over 27 and a comorbidity such as high blood pressure or type 2 diabetes.

On 27 June 2012, the FDA officially approved lorcaserin for use in the treatment of obesity for adults with a BMI equal to or greater than 30 or adults with a BMI of 27 or greater who “have at least one weight-related health condition, such as high blood pressure, type 2 diabetes, or high cholesterol

Useful for treating obesity.

The present invention relates to stable crystalline Form I of Iorcaserin hydrochloride of Formula (IA) and processes for its preparation. The invention also relates to processes for the preparation of lorcaserin and pharmaceutically acceptable salts, solvates and hydrates thereof.

Stable crystalline form I of lorcaserin hydrochloride and its process of preparation are claimed.  Represents the first patenting from Cadila on lorcaserin, which was developed and launched by Arena Pharma and Eisai.

In July 2015, Newport Premium™ reported that Cadila is potentially interested in lorcaserin.

Lorcaserin hydrochloride is an agonist of the 5-HT_2c receptor and shows effectiveness at reducing obesity in animal models and humans developed by Arena Pharmaceuticals. It is chemically represented as (R)-8-chloro-l -methyl -2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride having Formula (I) as depicted herein below.

(IA)

U.S. Patent No. 6,953,787 B2 discloses compound of Formula (I) and pharmaceutically acceptable salt, solvates or hydrates thereof and process for preparation thereof.

U.S. Patent No. 8,168,624 B2 discloses (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride hemihydrate and process for its preparation. The patent also discloses crystalline Form I, Form II and Form III of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride. The crystalline Form

I and Form II are reported as anhydrous, non-solvated crystal forms. The crystalline Form III displays a dehydration feature calculated as a 3.7% weight loss which is consistent with the theoretical weight loss of 3.7% for a hemihydrate.

The patent discloses that anhydrous Form I and Form II readily converts to a hemihydrate, upon exposure to moisture. The dynamic vapor sorption (DVS) data for each of the three crystal forms reveals the hygroscopic nature of both Forms I and II, which readily adsorb moisture at relative humidity (RH) greater than about 40-60%. In addition, both Forms I and II were calculated to adsorb about 3.8% moisture between about 40 and about 80% RH which is consistent with conversion to the hemihydrate (Form III). X-ray powder diffraction (XRPD) carried out on both Forms I and II after the DVS cycle confirmed this conversion. In contrast, the DVS data in connection with Form III shows that it is substantially non-hygroscopic, adsorbing less than 0.5% water at 90% RH and the XRPD pattern showed no change in crystalline form after the DVS cycle.

International (PCT) Publication Nos. WO 2003/086306 Al, WO 2005/019179 Al, WO 2006/069363 Al, WO 2007/120517 Al, WO 2008/07011 1 Al and WO 2009/1 1 1004 Al disclose various synthetic approaches for the preparation of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, its related salts, enantiomers, crystalline forms and intermediates.

International (PCT) Publication No. WO 2006/071740 Al discloses combination of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine with other agents. International (PCT) Publication No. WO 2012/030938 Al discloses various salts of lorcaserin with optically active acids.

U.S. PG-Pub No. US 2014/0187538 Al discloses amorphous lorcaserin hydrochloride and amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers and processes for their preparation.

International (PCT) Publication No. WO 2014/135545 Al discloses solid dispersion comprising amorphous lorcaserin hydrochloride and one or more pharmaceutically acceptable water soluble polymers.

see…..https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015102017&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example-7: Preparation of crystalline Form I of lorcaserin hydrochloride. In a round bottom flask, 560g of methyl ethyl ketone and 40 ml water were taken and 100 g of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine was added and stirred for 10 minutes. The reaction mass heated to 55 to 60°C and 19.3 g of. L-(+)-tartaric acid was added slowly and stirred for one to two hours. The reaction mass was further stirred at 10-15°C for an hour and the product was filtered and washed with a mixture of methyl ethyl ketone and water. The wet cake and 150 ml methyl ethyl ketone were taken in another flask and heated to 75-80°C. 20-25 ml water was, added and stirred for an hour. Further, the reaction mass was stirred for an hour at 0-5°C. The product was filtered and washed with methyl ethyl ketone.

100 g tartrate salt of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine and 300 mL water were taken in another round bottom flask. 200 mL methylene dichloride was added and the reaction mass was cooled to 10-20°C. 17.2 g sodium hydroxide dissolved in 89 ml water was added into the reaction mass at 10-20°C. The reaction mass was stirred for an hour at 25-30°C and the layers were separated. The solvent was removed from the organic layer under vacuum and then 100 mL ethyl acetate was added into that and distilled out. Further, 100 mL ethyl acetate was added and stirred for 15 minutes. The reaction mass was filtered through a hyflow bed and the filtrate was treated with dry HC1 gas till a pH of 1.5 to 2.5 was obtained at 0-10°C and it was stirred for about 30 minutes to an hour. The product was then filtered and washed with ethyl acetate and then dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride. Yield: 87.5-98.6 %.

Example-8: Preparation of crystalline Form I of lorcaserin hydrochloride

In a round bottom flask, 2.20 g lorcaserin, 30 mL methylene chloride, 17.4 mL of 1M HCI in ether were added and the mixture was stirred for 5-15 minutes at room temperature. The solvent was removed under reduced pressure to give a white solid. This solid was again dissolved in 30 ml methylene chloride, 17.4 mL of 1M HCI solution and stirred for 5-15 minutes at room temperature. The solvent was removed under reduced pressure to give lorcaserin hydrochloride. The product was dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride.

Example-9: Preparation of crystalline Form I lorcaserin hydrochloride

50 g of lorcaserin hydrochloride hemihydrate and 50 g of hydroxypropylmethyl cellulose (HPMC) 3CPC were mixed in a blender at 25°C to 35°C. The mixture was mixed for 30 minutes and unloaded. The solid thus obtained was dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride.

Pankaj R. Patel (right), Chairman and Managing Director,

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