DESC:The following specification particularly describes the application and the manner in which it is to be performed:
PROCESS FOR PREPARATION OF LORCASERIN
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of lorcaserin free base and its pharmaceutically acceptable salts.
BACKGROUND
Lorcaserin is chemically described as (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, compound of formula I. It has the chemical structure:

Lorcaserin hydrochloride is an agonist of the 5-HT2C receptor and shows effectiveness at reducing obesity in animal models and humans. Further, 5-HT2C receptor is recognized as a well-accepted receptor target for the treatment of obesity, psychiatric, and other disorders.
The US patent number 6,953,787 B2 discloses lorcaserin and pharmaceutically acceptable salts thereof. Various other crystalline forms, solvates and hydrates of lorcaserin are disclosed in the patent publication numbers WO 2006/069363A2, WO 2011/153206A1, WO 2012/030938A1, WO 2012/030951A1, WO 2012/030957A2 and WO 2012/030927A2 each of which is incorporated herein by reference in their entirety.
Various processes for the preparation of compound of Formula I, its salts, enantiomers and intermediates, have been reported in the patent publications WO 2003/086306A2, WO 2005/019179A2, WO 2006/069363A2, WO 2007/120517A2, WO 2008/070111A2, WO 2009/111004A1, WO 2010/148207A2, WO 2014/173928, WO 2014/187768A1 and WO 2015/007897A1 each of which is incorporated herein by reference in their entireties.
WO 2005/019179A2 disclosed a process for the preparation of lorcaserin hydrochloride hemihydrate by neutralizing lorcaserin tartrate salt with sodium hydroxide in the presence of water and dichloromethane. WO 2007/120517A2 disclosed a process for the preparation of lorcaserin hydrochloride hemihydrate by neutralizing lorcaserin hemitartrate salt with potassium carbonate in the presence of water and ethylacetate. These process are not suitable on industrial scale as lorcaserin L(+)-tartrate salt upon neutralization to obtain lorcaserin free base, racemization is observed resulting in decrease of chiral purity with the increase of S-isomer content.
The objective of the present invention is to provide a cost effective and an efficient process on a large scale for the preparation of lorcaserin which avoids the problem of racemization.
SUMMARY
In the first embodiment, the present invention provides a process for the preparation of lorcaserin of Formula I or a salt thereof, comprising:
a) neutralizing a pure salt of lorcaserin in the presence of a base and a solvent selected from water, toluene, methyl ter-butyl ether, cyclopentyl methyl ether or mixtures thereof,
b) recovering pure lorcaserin free base,
c) optionally converting the pure lorcaserin free base in to a salt to obtain pure lorcaserin salt,
d) optionally converting the pure lorcaserin salt in to pure lorcaserin free base.
In the second embodiment, the present invention provides a process for the preparation of lorcaserin of Formula I or a salt thereof, comprising:
a) neutralizing a pure tartrate salt of lorcaserin in the presence of a base and a solvent selected from water, toluene, methyl ter-butyl ether, cyclopentyl methyl ether or mixtures thereof,
b) recovering pure lorcaserin free base,
c) optionally converting the pure lorcaserin free base in to a salt to obtain pure lorcaserin salt,
d) optionally converting the pure lorcaserin salt in to pure lorcaserin free base.
In the third embodiment, the present invention provides a process for the preparation of lorcaserin of Formula I or a salt thereof, comprising:
a) neutralizing a pure tartrate salt of lorcaserin in the presence of a base and a solvent selected from water, toluene, methyl ter-butyl ether, cyclopentyl methyl ether or mixtures thereof,
b) recovering pure lorcaserin free base,
c) converting the pure lorcaserin free base in to HCl salt to obtain pure lorcaserin hydrochloride salt,
In the fourth embodiment, the present invention provides a process for the preparation of lorcaserin of Formula I or a salt thereof, comprising:
a) neutralizing a pure tartrate salt of lorcaserin in the presence of sodium hydroxide and a solvent selected from water, toluene, methyl ter-butyl ether, cyclopentyl methyl ether or mixtures thereof,
b) recovering pure lorcaserin free base,
c) converting the pure lorcaserin free base in to pure lorcaserin hydrochloride salt.
In the fifth embodiment, the present invention provides a process for the preparation of lorcaserin of Formula I or a salt thereof, comprising:
a) neutralizing a pure tartrate salt of lorcaserin in the presence of a base and water,
b) recovering pure lorcaserin free base,
c) optionally converting the pure lorcaserin free base in to a salt to obtain pure lorcaserin salt,
d) optionally, converting the pure lorcaserin salt in to pure lorcaserin free base.
DETAILED DESCRIPTION
The term "about" when used in the present invention preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1% of its value. For example "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
The term "pure" when used in the present invention with reference to lorcaserin or lorcaserin salt or lorcaserin tartrate or lorcaserin hydrochloride salt refers to a chiral purity of about 98% or about 98.5% or about 99% or about 99.5% or about 99.8% or about 99.9% or 100%.
Optionally, in carrying out the processes according to the present invention, the reaction product of a given step can be isolated and purified by the methods described herein or the methods known to a person skilled in the art before using in a subsequent step of the process.
In the present invention, the isolation of products after completion of the reactions can be effected by removing the solvent. Suitable techniques which can be used for the removal of the solvent include evaporation techniques such as evaporation using a Büchi® Rotavapor®, spray drying, thin film drying, nauta drying, tray drying, freeze drying (lyophilization) or any other suitable technique.
Isolated product can be optionally further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, Büchi® Rotavapor®, air oven, fluidized bed dryer, spin flash dryer, flash dryer, cone dryer, agitated nutsche filter cum dryer, nauta dryer or the like or any other suitable dryer. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 150°C, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, or any other suitable temperatures. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
The dried product can be optionally milled to get desired particle sizes. Milling or micronization can be performed before drying, or after the completion of drying of the product. Techniques that can be used for particle size reduction include, without limitation, ball, roller, hammer mills and jet mills.
The reaction time should be sufficient to complete the reaction which depends on scale and mixing procedures, as is commonly known to one skilled in the art. Typically, the reaction time can vary from about few minutes to several hours. For example the reaction time can be from about 10 minutes to about 24 hours, or any other suitable time period.
Room temperature as used herein refers to ‘the temperatures of the thing close to or same as that of the space, e.g., the room or fume hood, in which the thing is located’. Typically, room temperature can be from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.
The reactions of the processes described herein can be carried out in air or under an inert atmosphere. Typically, reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the person skilled in art.
Step (a) of first, second, third and fourth embodiments involve neutralization of pure salt of lorcaserin in the presence of a base and solvent. The said process involves addition of pure salt of lorcaserin to a solvent and then adding base.
The solvent used step (a) is selected from water, toluene, methyl ter-butyl ether, cyclopentyl methyl ether or mixtures thereof.
Step (a) of fifth embodiment involves neutralization of pure salt of lorcaserin in the presence of base and water. The said process involves addition of pure salt of lorcaserin to water and then adding base.
The pure salt of lorcaserin used as starting compound in step (a) is selected from but not limited to, tartaric acid salt, mandelic acid salt, dibenzoyl tartaric acid salt, N-acetylleucine salt, phenoxypropionic acid salt, pyroglutamic acid salt, Moshers acid salt, and phenylcarbamoyllactic acid salt.
The suitable base includes but not limited to, alkali metal hydroxide such as sodium hydroxide, lithium hydroxide or potassium hydroxide; carbonates of alkali metals such as sodium carbonate, lithium carbonate or potassium carbonate; or bicarbonates of alkali metals such as sodium bicarbonate or potassium bicarbonate or mixtures thereof.
The amount of base used in the reaction ranges from 0.5 to 5.0 molar equivalents with respect to the pure lorcaserin salt used as a starting compound. Preferably, it ranges from about 1.0 to about 4.0 equivalents. More preferably it ranges from about 2.0 to about 3.0 equivalents. In one variant it can be 2.5 equivalents.
The neutralization can be carried out at atmospheric pressure or under a reduced pressure, at temperatures of less than about 55°C, or less than about 45°C, or less than about 35°C, or any other suitable temperatures. In one variant step (a) can be preferably carried out at room temperature.
Step (b) involves recovery of lorcaserin free base. Lorcaserin free base can be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other techniques suitable for the recovery of solids. The recovered solid may optionally be dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at atmospheric pressure or under a reduced pressure, at temperatures less than about 55°C, or less than about 45°C, or less than about 35°C, or less than about 25°C, or any other suitable temperatures.
Step (c) involves optionally converting pure lorcaserin free base obtained in step (b) to pure lorcaserin pharmaceutically acceptable salts by known methods in the art or by the method described in the present application.
The pharmaceutically acceptable salts in step (c) can be inorganic or organic acid addition salts. Inorganic acids are selected from but not limited to hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid. Organic acid salts selected from but not limited to formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, fumaric acid and succinic acid. In one variant it can be lorcaserin hydrochloride salt.
Step (d) involves optionally converting the pure lorcaserin salt obtained in step (c) to pure lorcaserin free base by known methods in the art or by the methods described in the present application.
The present application also provides a process for preparing an amorphous solid dispersion from the pure lorcaserin or pure lorcaserin hydrochloride obtained by the process of the present invention and one or more pharmaceutically acceptable carriers by techniques such as lyophilization or spray-drying or extrusion/ melt extrusion.
Thus, the present invention addresses the short comings of the prior art by providing an improved process for preparing pure lorcaserin or pure lorcaserin salts in high chiral purity.
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present invention in any manner.
Example 1: Preparation of lorcaserin.
Lorcaserin L(+)-tartrate (250 gm, 924 mmol, S/R ratio: 0.03/99.97), toluene (1250 ml) and water (1250 ml) were charged in round bottom flask and stirred at room temperature. Sodium hydroxide flakes (37 gm, 924 mmol) were added to the reaction mixture and stirred for 5-10 minutes. The layers were separated and organic layer containing product was kept aside for further use. The aqueous layer was extracted with toluene (1250 ml). Toluene layer and organic layer containing product were combined and washed with water (1250 ml). The organic layer was washed with brine solution and the organic layer was separated and passed through hi-flow. The filtered organic layer was distilled under vacuum below 50°C to obtain the compound (162 gm, S/R ratio: 0.04/99.96).
Example 2: Preparation of lorcaserin Hydrochloride.
Lorcaserin L(+)-tartrate (160 gm, 296 mmol, S/R ratio: 0.02/99.98), water (200 ml) and toluene (800 ml) were charged in round bottom flask and stirred at room temperature. Sodium hydroxide flakes (23.65 gm, 591 mmol) were added to the reaction mixture and stirred for 5-10 minutes. The layers were separated and organic layer containing product was kept aside for further use. The aqueous layer was extracted with toluene (200 ml). Toluene layer and organic layer containing product were combined and washed with water (200 ml) and 5% NaCl solution (600 ml). The organic layer was distilled under vacuum below 50°C until 50% of the organic layer distilled and cooled to room temperature. Ethylacetate HCl (258 ml) solution was added to the above solution maintained at 10-15 oC for 15-20 minutes and the solid was filtered and dried under vacuum to give title compound. (105 gm, S/R ratio: 0.06/99.94).
Example 3: Preparation of lorcaserin Hydrochloride.
Lorcaserin L(+)-tartrate (25 gm, 46.2 mmol, S/R ratio: 0.02/99.98), water (150 ml) were charged in round bottom flask and stirred at room temperature. Sodium hydroxide solution (4.62 gm in 20 ml of water, 115 mmol) was added to the reaction mixture and stirred for 5-10 minutes. Then MTBE (125 ml) was charged into the reaction mixture and layers were separated and organic layer containing product was kept aside for further use. To the remaining aqueous layer MTBE (125 ml) was added and stirred for 15-20 minutes. Now the layers were separated and the MTBE organic layer and organic layer containing product were combined and washed with water (150 ml). The organic layer was separated and dried over sodium sulphate and cooled to 18oC. 10% Ethylacetate HCl (111 mmol) solution was added to the above solution maintained at 10-15oC for 4-5 hours and the solid was filtered and washed with MTBE (100 ml), distilled under vacuum and dried at 50oC to give title compound. (19.4 gm, S/R ratio: 0.02/99.98).
Example 4: Preparation of lorcaserin Hydrochloride.
Lorcaserin L(+)-tartrate (5 gm, 9.23 mmol, S/R ratio: 0.02/99.98), water (30 ml) were charged in round bottom flask and stirred at room temperature. Sodium hydroxide solution (0.923 gm in 4 ml of water, 23.09 mmol) was added to the reaction mixture and stirred for 5-10 minutes. Then CPME (25 ml) charged into the reaction mixture and layers were separated and organic layer containing product was kept aside for further use. To the remaining aqueous layer CPME (25 ml) was added and stirred for 5-10 minutes. Now the layers were separated and the CPME organic layer and organic layer containing product were combined and washed with water (30 ml). Organic layer was separated, washed with water (20 ml) and the solvent distilled to give crude lorcaserin free base (3.5 gm, S/R ratio: 0.02/99.98).

Lorcaserin free base (3 gm) was dissolved in CPME (25 ml) and cooled to 5oC, at this temperature Ethylacetate HCl (11.08 mmol) solution was added to the above solution maintained at the same temperature for 1-2 hours and the solid was filtered and dried at 50 oC to give title compound. (2 gm, S/R ratio: 0.05/99.95).
Example 5: Preparation of lorcaserin Hydrochloride
Lorcaserin L(+)-tartrate (50 gm, 92 mmol, S/R ratio: 0.02/99.98), water (500 ml) were charged in round bottom flask and stirred at room temperature. Sodium hydroxide solution (9.23 gm in 50 ml of water, 231 mmol) was added to the reaction mixture and stirred for 30-50 minutes. The layers were separated. To the product layer water (250ml), MTBE (50ml) were added and stirred for 30-40 minutes. The organic layer was separated and washed with 5% NaCl solution. Organic layer was separated and cooled to 0-3oC at this temperature Ethylacetate HCl (70 gm, 92 mmol) was added slowly. The above solution maintained at the same temperature for 1-2 hours and the solid was filtered and washed with MTBE (70 ml). The filtered layer distilled and dried at 50 oC to give title compound. (32.4 gm, S/R ratio: 0.07/99.90).
Example 6: Preparation of lorcaserin Hydrochloride.
Lorcaserin L(+)-tartrate (100 gm, 185 mmol, S/R ratio: 0.02/99.98), water (600 ml) were charged in round bottom flask and stirred at room temperature. Sodium hydroxide solution (18.47 gm in 100 ml of water, 462 mmol) was added to the reaction mixture and stirred for 10-15 minutes. Then DCM (500 ml) charged into the reaction mixture and layers were separated and organic layer containing product was kept aside for further use. To the remaining aqueous layer DCM (500 ml) was added and stirred for 5-10 minutes. Now the layers were separated and the DCM organic layer and organic layer containing product were combined and washed with water (500 ml). Organic layer was separated and dried with sodium sulphate under vacuum distillation to give crude lorcaserin free base (67 gm, S/R ratio: 1.17/98.83).

Crude Lorcaserin free base (50 gm) was dissolved in MEK (200 ml) and another portion of MEK (300 ml) was added and cooled to 5 oC. At this temperature Ethylacetate HCl (112 ml) solution was added to the above solution maintained at the same temperature for 45 minutes to 1 hour and the solid was filtered and washed with MEK (100 ml), dried at 45 oC under vacuum to give title compound. (50 gm, S/R ratio: 1.36/98.64).
Example 7: Preparation of lorcaserin
Lorcaserin L(+)-tartrate (5 gm, 9.24 mmol, S/R ratio: 0.02/99.98), water (50 ml) were charged in round bottom flask and stirred and Ethylacetate (50 ml) added at room temperature. pH of the reaction mixture was adjusted to approximately 10 by adding 30% potassium carbonate solution (20 ml). Layers were separated and organic layer containing product was kept aside for further use. Aqueous layer was extracted with ethylacetate (50 ml). Now the layers were separated and the ethylacetate organic layer and organic layer containing product were combined and washed with 10% brine solution twice (2x25 ml). Organic layer was separated and distilled under vacuum to give crude lorcaserin free base (3.2 gm, S/R ratio: 0.25/99.75).
,CLAIMS:We Claim:
1) A process for the preparation of lorcaserin of Formula I or a salt thereof, comprising:
a) neutralizing a pure salt of lorcaserin in the presence of a base and a solvent selected from water, toluene, methyl ter-butyl ether, cyclopentyl methyl ether or mixtures thereof,
b) recovering pure lorcaserin free base,
c) optionally converting the pure lorcaserin free base in to a salt to obtain pure lorcaserin salt,
d) optionally converting the pure lorcaserin salt in to pure lorcaserin free base.
2) A process for the preparation of lorcaserin of Formula I or a salt thereof, comprising:
a) neutralizing a pure tartrate salt of lorcaserin in the presence of a base and a solvent selected from water, toluene, methyl ter-butyl ether, cyclopentyl methyl ether or mixtures thereof,
b) recovering pure lorcaserin free base,
c) optionally converting the pure lorcaserin free base in to a salt to obtain pure lorcaserin salt,
d) optionally converting the pure lorcaserin salt in to pure lorcaserin free base.
3) A process for the preparation of lorcaserin of Formula I or a salt thereof, comprising:
a) neutralizing a pure tartrate salt of lorcaserin in the presence of a base and a solvent selected from water, toluene, methyl ter-butyl ether, cyclopentyl methyl ether or mixtures thereof,
b) recovering pure lorcaserin free base,
c) converting the pure lorcaserin free base in to HCl salt to obtain pure lorcaserin hydrochloride salt,
4) A process for the preparation of lorcaserin of Formula I or a salt thereof, comprising:
a) neutralizing a pure tartrate salt of lorcaserin in the presence of sodium hydroxide and a solvent selected from water, toluene, methyl ter-butyl ether, cyclopentyl methyl ether or mixtures thereof,
b) recovering pure lorcaserin free base,
c) converting the pure lorcaserin free base in to pure lorcaserin hydrochloride salt.
5) A process for the preparation of lorcaserin of Formula I or a salt thereof, comprising:
a) neutralizing a pure tartrate salt of lorcaserin in the presence of a base and water,
b) recovering pure lorcaserin free base,
c) optionally converting the pure lorcaserin free base in to a salt to obtain pure lorcaserin salt,
d) optionally, converting the pure lorcaserin salt in to pure lorcaserin free base.