Claims:CLAIMS:
1. A process for the preparation of flibanserin of Formula I,

Formula I
comprising the steps of:
a) reacting 1-(prop-1-en-2-yl)-1,3-dihydro-2H-benzimidazol-2-one of Formula III;

Formula III
with 1-bromo-2-chloroethane to obtain a compound of the formula IV;

Formula IV
b) condensing the compound of Formula IV with 1-(3-trifluoromethylphenyl)-piperazine of Formula V

Formula V
or its salt in the presence of a base in aqueous medium to obtain a compound of Formula II; and

Formula II
c) deprotecting the compound of Formula II in the presence of an acid in aqueous medium to obtain the flibanserin of Formula I.

2. A process for the preparation of 1-(2-{4-3-(trifluoromethyl)phenyl}piperazin-1-yl)ethyl)-[3-(prop-1-en-2-yl)-1,3-dihydro-2H-benzimidazol-2-one] of Formula II,

Formula II
comprising the steps of:
a) reacting 1-(prop-1-en-2-yl)-1,3-dihydro-2H-benzimidazol-2-one of Formula III;

Formula III
with 1-bromo-2-chloroethane to obtain a compound of the formula IV; and

Formula IV
b) condensing the compound of Formula IV with 1-(3-trifluoromethylphenyl)-piperazine of Formula V

Formula V
or its salt in the presence of a base in aqueous medium to obtain the compound of the formula II.

3. A process for the preparation of a compound of Formula II,

Formula II
comprising, condensing a compound of Formula IV

Formula IV
with 1-(3-trifluoromethylphenyl)piperazine of Formula V

Formula V
or its salt in the presence of a base in aqueous medium to obtain the compound of Formula II.

4. A process for the preparation of flibanserin of Formula I,

Formula I
comprising, deprotecting a compound of Formula II

Formula II
in the presence of an acid in aqueous medium to obtain the flibanserin of Formula I.
5. The process according to claim 1 or 2, wherein the reaction of the compound of Formula III with 1-bromo-2-chloroethane is carried out in the presence of a base.
6. The process according to claim 5, wherein the base is potassium carbonate.
7. The process according to claim 1 or 2, wherein the reaction of the compound of Formula III with 1-bromo-2-chloroethane is carried out in the presence of acetone.
8. The process according to claim 1 or 2 or 3, wherein the condensation of the compound of Formula IV with 1-(3-trifluoromethylphenyl) piperazine of Formula V or its salt is carried out in the presence of potassium carbonate.
9. The process according to claim 1 or 2 or 3, wherein the condensation of the compound of Formula IV with 1-(3-trifluoromethylphenyl) piperazine of Formula V or its salt is carried out in the presence of sodium iodide.
10. The process according to claim 1 or 4, wherein the deprotection of the compound of Formula II is carried out with acid selected from the group consisting of mineral acid or organic acid.

, Description:A PROCESS FOR THE PREPARATION OF FLIBANSERIN

FIELD OF THE INVENTION
The present invention provides an improved process for the preparation of flibanserin and its intermediates.

BACKGROUND OF THE INVENTION
Flibanserin is chemically designated as 1,3-dihydro-1-[2-[4-[3-(trifluoromethyl)-phenyl]-1-piperazinyl]ethyl]-2H-benzimidazol-2-one and is being marketed for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder. Its chemical structure is represented by the following Formula I.

Formula I
U.S. Patent No. 5,576,318 discloses a process for the preparation of flibanserin, which comprises reacting 1-(phenylvinyl)-2,3-dihydro-1H-benzimidazol-2-one with 1,2-dichloroethane to obtain 1-(2-chloroethyl)-2,3-dihydro-1H-benzimidazol-one, which is then reacted with m-trifluoromethylphenylpiperazine hydrochloride in the presence of sodium carbonate to obtain flibanserin hydrochloride. The obtained flibanserin hydrochloride is subsequently treated with sodium hydroxide in aqueous ethanol to obtain flibanserin. The yield and purity of flibanserin obtained by the above process is lower.

Organic Process Research & Development, Volume 20, Issue 9, Pages 1576 to 1580 (2016), discloses a process for the preparation of flibanserin, which comprises condensing benzene-1,2-diamine and ethyl acetoacetate to obtain 1-(prop-1-en-2-yl)-1,3-dihydro-2H-benzimidazol-2-one, which is then reacted with 1,2-dibromoethane in presence of potassium carbonate and N,N-dimethylformamide to obtain 1-(2-bromoethyl)-3-(prop-1-en-2-yl)-1,3-dihydro-2H-benzimidazol-2-one. The obtained product is further reacted with 1-(3-trifluoromethylphenyl)piperazine hydrochloride in the presence of potassium carbonate in acetonitrile to obtain 1-(2-{4-3-(trifluoromethyl)phenyl}piperazin-1-yl)ethyl)-[3-(prop-1-en-2-yl)-1,3-dihydro-2-H-benzimidazol-2-one], which is subsequently converted into flibanserin by treating with hydrochloric acid in isopropanol and then aqueous sodium hydroxide. The overall yield obtained by the above process is only 16%.
The present inventors have developed a simple, efficient, economical, and industrially feasible process that provides flibanserin and its intermediates in good yield.

SUMMARY OF THE INVENTION
A first aspect of the present invention provides a process for the preparation of flibanserin of Formula I,

Formula I
comprising the steps of:
a) reacting 1-(prop-1-en-2-yl)-1, 3-dihydro-2H-benzimidazol-2-one of Formula III;

Formula III
with 1-bromo-2-chloroethane to obtain a compound of the formula IV;

Formula IV
b) condensing the compound of Formula IV with 1-(3-trifluoromethylphenyl)-piperazine of Formula V

Formula V
or its salt in the presence of a base in aqueous medium to obtain a compound of Formula II; and

Formula II
c) deprotecting the compound of Formula II in the presence of an acid in aqueous medium to obtain the flibanserin of Formula I.

A second aspect of the present invention provides a process for the preparation of 1-(2-{4-3-(trifluoromethyl)phenyl}piperazin-1-yl)ethyl)-[3-(prop-1-en-2-yl)-1,3-dihydro-2H-benzimidazol-2-one] of Formula II,

Formula II
comprising the steps of:
a) reacting 1-(prop-1-en-2-yl)-1,3-dihydro-2H-benzimidazol-2-one of Formula III;

Formula III
with 1-bromo-2-chloroethane to obtain a compound of the formula IV; and

Formula IV
b) condensing the compound of Formula IV with 1-(3-trifluoromethylphenyl)-piperazine of Formula V

Formula V
or its salt in the presence of a base in aqueous medium to obtain the compound of the formula II.

A third aspect of the present invention provides a process for the preparation of a compound of Formula II,

Formula II
comprising, condensing a compound of Formula IV

Formula IV
with 1-(3-trifluoromethylphenyl)piperazine of Formula V

Formula V
or its salt in the presence of a base in aqueous medium to obtain the compound of Formula II.

A fourth aspect of the present invention provides a process for the preparation of flibanserin of Formula I,

Formula I
comprising, deprotecting a compound of Formula II

Formula II
in the presence of an acid in aqueous medium to obtain the flibanserin of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

Various embodiments and variants of the present invention are described hereinafter.

The term "about", as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.

The term “solvent”, as used herein, refers to a solvent which may include but not limited to alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or t-butyl alcohol; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.

The term “base”, as used herein, refers to an inorganic base or organic base which may include but not limited to the group comprising of inorganic base like hydroxides of alkali metal or alkaline earth metal such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide and the like; carbonates of alkali metal or alkaline earth metal such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like; and phosphates such as disodium monohydrogenphosphate, dipotassium monohydrogen phosphate, trisodium phosphate, tripotassium phosphate and the like; or organic base like tertiary amines such as triethylamine, diisopropylethylamine, tri(n-propyl)amine, tri(n-bulyl)amine, cyclohexyl-dimethylamine, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like; and aromatic amines such as pyridine, lutidine, N,N-dimethylaniline and the like.

The term “metal halide”, as used herein, refers to the lithium fluoride, lithium chloride, lithium bromide, lithium iodide, sodium fluoride, sodium chloride, sodium bromide, sodium iodide, potassium fluoride, potassium chloride, potassium bromide, potassium iodide, calcium fluoride, calcium chloride, calcium bromide, calcium iodide, magnesium fluoride, magnesium chloride, magnesium bromide, magnesium iodide, strontium fluoride, strontium chloride, strontium bromide, strontium iodide, barium fluoride, barium chloride, barium bromide, or barium iodide.

The reaction of a compound of Formula III with a 1-bromo-2-chloroethane is carried out in the presence of a base. Preferably, the base is potassium carbonate.

The reaction of a compound of Formula III with a 1-bromo-2-chloroethane is carried out in the presence of a solvent. Preferably, the solvent is acetone.

The reaction of a compound of Formula III with a 1-bromo-2-chloroethane is carried out at the temperature of about 0°C to about 56°C. Preferably, the reaction is carried out at a temperature of about 50°C to about 56°C.

The reaction of a compound of Formula III with a 1-bromo-2-chloroethane is carried out for about 5 hours to about 15 hours. Preferably, the reaction is carried out for about 10 hours to about 12 hours.

The compound of Formula IV is optionally isolated or carried forward to the next step without isolation.

The condensation of a compound of Formula IV with 1-(3-trifluoromethylphenyl) piperazine of Formula V or its salt is carried out in the presence of a base and a metal halide. Preferably, the base is potassium carbonate and the metal halide is sodium iodide.

The condensation of a compound of Formula IV with 1-(3-trifluoromethylphenyl) piperazine of Formula V or its salt is carried out in the presence of an aqueous medium, wherein the aqueous medium is water.

The condensation of a compound of Formula IV with 1-(3-trifluoromethylphenyl) piperazine of Formula V or its salt is carried out at the temperature of about 50°C to about 150°C. Preferably, the reaction is carried out at a temperature of about 90° to about 100°C.

The condensation of a compound of Formula IV with 1-(3-trifluoromethylphenyl) piperazine of Formula V or its salt is carried out for about 5 hours to about 15 hours. Preferably, the reaction is carried out for about 10 hours to about 12 hours.

Preferably, the salt of 1-(3-trifluoromethylphenyl) piperazine of Formula V is hydrochloric acid salt.

The compound of Formula II is optionally isolated or carried forward to the next step without isolation.

The deprotection of a compound of Formula II with acid is carried out in the presence of an aqueous medium.

The acid is selected from the group consisting of mineral acids or organic acids. The mineral acid is selected from the group comprising hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, boric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, or perchloric acid. The organic acid is selected from the group comprising formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, or an acidic ion exchange resin.

Preferably, the acid is hydrochloric acid and the aqueous medium is water.
The deprotection of a compound of Formula II with acid in aqueous medium is carried out at the temperature of about 40°C to about 100°C. Preferably, the deprotection is carried out at a temperature of about 65°C to about 75°C.
The deprotection of a compound of Formula II with acid in aqueous medium is carried out for about 2 hours to about 8 hours. Preferably, the reaction is carried out for about 3 hours to about 5 hours.

Subsequent to the deprotection of a compound of Formula II with acid, the reaction mixture is further treated with a base to obtain flibanserin. Preferably, the base is sodium hydroxide.

The base can be used in the form of a solid or a solution obtained by dissolving a base in water. Preferably, the concentration of a solution is about 10% (weight/volume) to about 30% (weight/volume).

Flibanserin can be isolated by common isolation techniques such as extraction, crystallization, precipitation, filtration, decantation, centrifugation, or a combination thereof.

The compound of Formula III used as a starting material may be prepared by processes known in the art, such as by the processes described in the U.S. Patent No. 5,652,246.

While the present invention has been described in terms of its specific aspects and embodiments, 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 invention.

EXAMPLES:
Example-1: Preparation of 1-[2-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]ethyl)-[3-(prop-1-en-2-yl)-1,3-dihydro-2H-benzimidazol-2-one]
To a stirred solution of 1-(prop-1-en-2-yl)-1,3-dihydro-2H-benzimidazol-2-one (50 g) in acetone (500 mL), 1-bromo-2-chloroethane (103 g) was added to obtain a mixture. To this mixture, potassium carbonate (238 g) was added, heated to 56±2°C and stirred for 12 hours. After completion of the reaction, the mixture was cooled to 25°C to 30°C. The mixture was filtered and washed with acetone (150 mL). The filtrate was distilled and then stripped out with toluene (100 mL x 2) to obtain oily mass. To the obtained oily mass, water (410 mL) was added followed by 1-(3-trifluoromethylphenyl)piperazine hydrochloride (76.57 g), potassium carbonate (43.93 g) and potassium iodide (43.38 g) were added to the mixture. The mixture was heated to 90°C to 100°C and stirred for 12 hours. After completion of the reaction, the mixture was cooled to 25°C to 30°C and stirred for 60 minutes. The mixture was filtered and washed with water (200 mL) to obtain crude desired product. To the obtained crude product, isopropyl alcohol (330 mL) was added, heated the mixture to 80±2°C and stirred for 30 minutes. The mixture was cooled to 25±3°C and stirred for 1 hour. The mixture was filtered, washed with isopropyl alcohol (110 mL) and dried under vacuum at 55±5°C for 8 hours.
Yield: 100 g (81.0%)
HPLC purity (by % area): 99.6%

Example-2: Preparation of flibanserin
To a stirred solution of 1-[2-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]ethyl)-[3-(prop-1-en-2-yl)-1,3-dihydro-2-H-benzimidazol-2-one] (90 g) in water (900 mL), concentrated hydrochloric acid (135 mL) was slowly added to obtain a mixture. The obtained mixture was heated to 60°C to 70°C and stirred for 4 hours. After completion of the reaction, the mixture was cooled to 20°C to 30°C and pH was adjusted to 8.0 to 9.0 with 30% aqueous sodium hydroxide solution (200 mL). Ethyl acetate (900 mL) was added to the mixture, stirred for 15 minutes at 25°C to 31°C and the layers were separated. To the aqueous layer, ethyl acetate (180 mL) was added and stirred for 15 minutes at 25°C to 31°C. The layers were separated and organic layers were combined and further extracted with water (180 mL). The layers were separated and the organic layer was then filtered through hyflo® bed and washed the bed with ethyl acetate (90 mL). The filtrate was evaporated completely under reduced pressure at 55°C and stripped out with acetone (270 mL x 2). To the obtained residue, acetone (360 mL) was added, heated to 50°C to 56°C and stirred for 30 minutes at 56°C. The mixture was cooled to 2°C to 8°C and stirred for 1 hour at 2°C to 8°C. The obtained solid was filtered and washed with chilled acetone (90 mL) and dried at 50°C to 55°C for 8 hours.
Yield: 60 g (79.3%)
HPLC purity (by % area): 99.88%

Example-3: Preparation of flibanserin
To a stirred solution of 1-(prop-1-en-2-yl)-1,3-dihydro-2H-benzimidazol-2-one (25 g) in acetone (250 mL), 1-bromo-2-chloroethane (51.5 g) was added to obtain a mixture. To this mixture, potassium carbonate (119 g) was added, heated to 55±2°C and stirred for 12 hours. After completion of the reaction, the mixture was cooled to 27°C to 31°C, filtered and washed with acetone (50 mL). The filtrate was distilled and stripped out with toluene (50 mL x 2) to obtain oily mass. To the obtained oily mass, water (150 mL) was added and stirred for 10 minutes. To this mixture, 1-(3-trifluoromethylphenyl)piperazine hydrochloride (38.26 g), potassium carbonate (21.83 g) and potassium iodide (21.49 g) were added, heated to 90°C to 100°C and stirred for 12 hours. After completion of the reaction, the mixture was cooled to 27°C to 31°C and stirred for 60 minutes. The mixture was filtered and washed with water (100 mL) to obtain wet solid.

To the obtained wet solid, water (560 mL) was added, stirred for 10 minutes and then concentrated hydrochloric acid (112 mL) was added to obtain a mixture. The mixture was heated to 60°C to 70°C and stirred for 4 hours. After completion of the reaction, the mixture was cooled to 20°C to 30°C and ethyl acetate (560 mL) was added. The mixture was stirred for 30 minutes at 25°C to 31°C and then pH was adjusted to 8.0 to 9.0 with 30% aqueous sodium hydroxide solution (100 mL). The layers were separated, ethyl acetate (50 mL) was added to the aqueous layer and stirred for 15 minutes at 25°C to 31°C. The layers were separated and the combined organic layer was washed with water (400 mL). The organic layer was filtered through hyflo® bed and washed the bed with ethyl acetate (50 mL). The filtrate was distilled under reduced pressure at 55°C and stripped out with acetone (100 mL x 2). To the obtained residue, acetone (250 mL) was added, heated to 50°C to 56°C and stirred for 15 minutes. The mixture was cooled to 2°C to 8°C and stirred for 1 hour. The obtained solid was filtered, washed with chilled acetone (50 mL) and dried under vacuum at 50°C to 55°C for 8 hours.
Yield: 27 g (48.2%)
HPLC purity (by % area): 99.57%