Field of the Invention

The present invention provides a process for the preparation of agomelatine and its intermediate compounds. The invention also provides intermediate compounds of agomelatine, represented b Formula TV, Formula V and Formula VUl.

Formate IV

Formula V Formula VIII

Background of the Invention

Agomelatine is chemically known as N-[2-(7-methoxynaphthalen- 1 - yl)ethyl]acetamide. It is indicated for the treatment of major depressive episodes in adults and is represented by Formula I.

Formula I

Agomelatine and its preparation are disclosed in U.S. Patent No.5,225,442. The preparation comprises converting {7-methoxy- 1 -naphthy l)acetic acid to (7-methoxy-i- naphthy!)ethanamine via preparation of (7-methoxy- 1 -naphthy l)ac tamide or (7-methoxy- 1 -naphthyl)acetonitrile intermediate compounds. U.S. Patent Nos. 7,476,751 ; 7,479,569; and 7,470,806 and U.S. Publication Nos. 2010/0137628 and 2010/0036161 describe a process for the preparation of agomelatine comprising reduction of (7-methoxy- 1 -naphthyl)acetonitrile into (7-methoxy- 1 - naphthyl)ethylamine followed by an acetylation step.

U.S. Publication No. 201 1/0130571 describes a process for the preparation of agomelatine comprising reacting 7-methoxy- 1 -naphthyl ethanol with benzenesulfonyl chloride to obtain 7-methoxy- l-naphthylethyl benzene sulfonate and condensing it with potassium phthalimide, followed by sequential hydrolysis and acetylation steps.

The present invention provides an alternate process for the preparation of agomelatine and its intermediate compounds.

Summary of the Invention

The present invention provides a process for the preparation of agomelatine using 2-(7-methoxynaphthalen- 1 -yl)ethyl 4-nitrobenzene sulfonate (Formula IV), l-[2-(7- methoxynaphthalen-l-yl)ethyl]-2λ ⁵ -triaz- l-en-2-yne (Formula V) and the carbon dioxide adduct of 2-(7-methoxynaphthalen- 1 -yl)ethanamine (Formula VIII) as intermediate compounds.

Formula V Formula VIII

The present invention is also directed towards compounds of Formula IV, Formula V and Formula VIII. Brief Description of the Drawing

Figure 1 depicts the X-ray powder diffraction pattern of the crystalline adduct of Formula VIII recorded on a PANalytical X'pert Pro instrument. The measurements were done using CuK _a radiation at 45kV.

Detailed Description of the Invention

The term "organic solvent", as employed herein, is meant to comprise polar solvent (for example, dichloromethane, methanol, tetrahydrofuran, dimethylformamide, ethyl acetate, etc.) and/or non-polar solvents (for example, cyclohexane, diethyl ether, toluene, etc.). Some non- limiting examples of "organic solvents" are dichloromethane, ethyl acetate, butyl acetate, dichloroethane, tetrahydrofuran, acetonitrile, acetone, cyclohexane, toluene, chloroform, 1 ,4-dioxane, dimethylsulfoxide, dimethylformamide, methanol, ethanol, propanol and/or butanol.

The term "base", as employed herein, is meant to comprise organic bases (for example, pyridine, triethylamine, etc.) and/or inorganic bases (for example, sodium hydride, ammonium hydroxide, sodium carbonate, etc.). Some non- limiting examples of "base" are sodium hydroxide, potassium hydroxide, magnesium hydroxide, dipotassium hydrogen orthophosphate, magnesium carbonate, sodium carbonate, potassium carbonate, pyridine, trimethylamine, triethylamine, diisopropylethylamine and/or N-methyl morpholine.

The term "about", as employed herein, when used with values assigned to certain measurements and parameters means a variation of 10% from such values, or in the case of a range of values, means a 10% variation from both the lower and upper limits of such ranges.

The present invention can be explained by way of the following aspects.

A first aspect of the present invention provides a process for the preparation of agomelatine wherein the process comprises converting a carbon dioxide adduct of 2-(7- methoxynaphthalen- 1 -yl)ethanamine (Formula VIII) into agomelatine.

Formula VIII

In an embodiment of this aspect, the carbon dioxide adduct (Formula VIII) is acetylated to obtain agomelatine.

In another embodiment, the adduct compound of Formula VIII can be acetylated using acetyl chloride or acetic anhydride.

Accordingly, the compound of Formula VIII is acetylated using acetic anhydride in the presence of methanol to obtain agomelatine.

A second aspect of the present invention provides a process for the preparation of agomelatine comprising a step of converting l-[2-(7-methoxynaphthalen- l-yl)ethyl]^ ⁵ - triaz-l-en-2-yne (Formula V)

Formula V

into a carbon dioxide adduct of 2-(7-methoxynaphthalen-l-yl)ethanamine (Formula VIII).

Formula VIII

In an embodiment of this aspect, the conversion of the compound of Formula V into the compound of Formula VIII can be performed with or without isolating the 2-(7- methoxynaphthalen- 1 -yl)ethanamine intermediate compound of Formula VII.

Formula VII

In an another embodiment, the conversion of the compound of Formula V into the compound of Formula VIII can be performed without isolating the 2-(7- methoxynaphthalen- 1 -yl)ethanamine intermediate compound of Formula VII.

In an another embodiment, the compound of Formula V is converted to the compound of Formula VIII by reducing the compound of Formula V, followed then treating the reduced product with carbon dioxide.

In an another embodiment of this aspect, the reduced product is 2-(7- methoxynaphthalen- 1 -yl)ethanamine of Formula VII.

Accordingly, the compound of Formula V is reduced and then treated with carbon dioxide to obtain an adduct compound of Formula VIII which is acetylated to get agomelatine.

The reduction of the compound of Formula V can be performed using hydrogen gas in the presence of a reduction catalyst. The reduction catalyst can be platinum, palladium, rhodium and/or Raney nickel. The reduction can be carried out at a temperature range of about 10°C to about 70°C. The hydrogen pressure can be in the range of about 1.0 kg/cm ² to about 3.0 kg/cm ² .

The compound of Formula VII (reduction product), if isolated or in concentrated form (wet), can be dissolved in non-polar solvent and then treated with carbon dioxide to obtain the adduct compound of Formula VIII.

The obtained adduct can be converted into agomelatine by following the process described hereinabove in the first aspect of the present invention.

A third aspect of the present invention provides a process for the preparation of agomelatine comprising a step of converting 2-(7-methoxynaphthalen- 1 -yl)ethyl 4- nitrobenzene sulfonate of Formula IV

Formula IV

into l-[2-(7-methoxyna hthalen-l-yl)ethyl]-2λ ⁵ -triaz-l-en-2-yne of Formula V.

Formula V

In an embodiment of this aspect, the compound of Formula IV is converted to the compound of Formula V by treatment of the compound of Formula IV with an azide salt.

In another embodiment of this aspect, the azide salt can be selected from the group comprised of sodium azide, silver azide and phenyl azide.

Accordingly, the compound of Formula IV is treated with sodium azide to obtain the compound of Formula V, which is reduced, then treated with carbon dioxide to provide an adduct compound of Formula VIII. This adduct is then acetylated to obtain agomelatine.

The compound of Formula V can be converted into the carbon dioxide adduct of Formula VIII by following the process described hereinabove in the second aspect of the present invention.

The obtained adduct (Formula VIII) can be converted into agomelatine by following the process described hereinabove in the first aspect of the present invention.

A fourth aspect of the present invention provides a process for the preparation of agomelatine comprising the steps of: (a) reacting (7-methoxy- 1 -naphthyl)ethanol of Formula III

Formula III

with 4-nitrobenzene sulfonyl chloride to obtain 2-(7-methoxynaphthalen- 1 - yl)ethyl 4-nitrobenzene sulfonate of Formula IV; and

Formula IV

(b) converting the compound of Formula IV obtained in step (a) into

agomelatine.

In one embodiment, the compound of Formula III is reacted with 4-nitrobenzene sulfonyl chloride in the presence of a base and an organic solvent.

In another embodiment, the base used is triethylamine.

In another embodiment, the organic solvent is dichloromethane.

In another embodiment, the conversion of the compound of Formula IV into agomelatine can be performed via preparation of l-[2-(7-methoxynaphthalen-l-yl)ethyl]- 2λ ⁵ -ίΠ3ζ- 1 -en-2-yne (Formula V), 2-(7-methoxynaphthalen- 1 -yl)ethanamine (Formula VII), and/or a carbon dioxide adduct of 2-(7-methoxynaphthalen- 1 -yl)ethanamine (Formula VIII) intermediate compounds.

Accordingly, (7-methoxy- l-naphthyl)ethanol (Formula III) is reacted with 4- nitrobenzene sulfonyl chloride in the presence of triethylamine and dichloromethane to obtain 2-(7-methoxynaphthalen- 1 -yl)ethyl 4-nitrobenzene sulfonate (Formula IV). This compound is then reacted with sodium azide to get l-[2-(7-methoxynaphthalen-l- yl)ethyl]-2λ ⁵ -triaz-l-en-2-yne (Formula V) which, upon sequential reduction and carbon dioxide treatment, gives a carbon dioxide adduct of 2-(7-methoxynaphthalen- l- yl)ethanamine (Formula VIII). This adduct is then acetylated to obtain agomelatine.

The compound of Formula IV can be converted into the compound of Formula V by following the process described hereinabove in the third aspect of the present invention.

The compound of Formula V can be converted into the carbon dioxide adduct of Formula VIII by following the process described hereinabove in the second aspect of the present invention.

The obtained adduct (Formula VIII) can be converted into agomelatine by following the process described hereinabove in the first aspect of the present invention.

A fifth aspect of the present invention provides 2-(7-methoxynaphthalen- 1 -yl)ethyl 4-nitrobenzene sulfonate compound of Formula IV.

Formula IV

embodiment, the compound of Formula IV can be used as an intermediate for the preparation of agomelatine.

Accordingly, the compound of Formula IV can be used to prepare agomelatine described hereinabove in the third aspect of the present invention.

A sixth aspect of the present invention provides l-[2-(7-methoxynaphthalen-l- yl)ethyl]-2λ ⁵ -triaz-l-en-2-yne compound of Formula V.

Formula V In an embodiment, the compound of Formula V can be used as an intermediate for the preparation of agomelatine.

Accordingly, the compound of Formula V can be used to prepare agomelatine as described hereinabove in the second aspect of the present invention.

A seventh aspect of the present invention provides a carbon dioxide adduct of 2-(7- methoxynaphthalen-l-yl)ethanamine represented by Formula VIII.

Formula VIII

In one embodiment, the compound of Formula VIII can be used as an intermediate for the preparation of agomelatine.

Accordingly, the compound of Formula V can be used to prepare agomelatine as described hereinabove in the first aspect of the present invention.

In another embodiment, compound of Formula VIII can be crystalline.

In another embodiment, the crystalline adduct of Formula VIII can be

characterized by X-ray powder diffraction peaks (expressed in degrees 2Θ) at about 10.07, 15.14, 16.03, 16.80, 17.36, 19.01, 20.29, 22.06, 22.72, 24.43, 25.89, 26.70, and 26.97 (± 0.2°) 2Θ.

In another embodiment, the crystalline adduct of Formula VIII can be

characterized by the X-ray powder diffraction pattern depicted in Figure 1.

The starting material (7-methoxy- l-naphthyl)ethanol, as used herein, in this invention can be prepared by treating 7-methoxy- 1 -naphthyl acetic acid represented by Formula II with lithium aluminum hydride in the presence of tetrahydrofuran.

Formula II

The 7-methoxy- l-naphthyl acetic acid of Formula II can be prepared by any method known in the art, for example, by following the process described in U.S. Patent No. 5,225,442.

While the present invention has been described in terms of its specific aspects, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be within the scope of the present invention.

In the following section, aspects are described by way of examples to illustrate the processes of the invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.

EXAMPLES

Example 1 : Preparation of (7-Methoxy- l-Naphthyl)Ethanol

Formula III

To a solution of 7-methoxy- 1 -naphthyl acetic acid (Formula II, 60 g) in tetrahydrofuran (240 mL), a suspension of lithium aluminum hydride (16.8 g) in tetrahydrofuran (1500 mL) was slowly added over a period of 15 minutes to 20 minutes at 0°C. The reaction mixture was stirred for 4 hours at 25°C to 30°C. After completion of the reaction, ethyl acetate (120 mL) was added, followed by the slow addition of 5N hydrochloric acid (100 mL) over a period of 30 minutes at 0°C. The reaction mixture was stirred and the layers were allowed to settle. The organic layer was separated and removed under vacuum (40°C to 45°C, -100 mbar). The residue so obtained was used for the next step.

Example 2: Preparation of 2-(7-Methoxynaphthalen- 1 -Yl)Ethyl 4-Nitrobenzene Sulfonate

Formula IV

To a mixture of (7-methoxy- 1 -naphthyl)ethanol (Formula III, obtained in Example 1), triethyl amine (55 g), dichloromethane (550 mL), and 4-nitrobenzene sulfonyl chloride (72.3 g) were added in small lots at 0°C. The reaction mixture was stirred and heated to 25°C to 30°C. After completion of the reaction, 2.5% sodium hydroxide solution (200 mL) was added at 25°C to 30°C. The reaction mixture was stirred and the product was extracted with the addition of dichloromethane (550 mL). The organic layer was concentrated under vacuum. The residue so obtained was stirred in toluene (165 mL) and then in methanol (165 mL) for 30 minutes. This was filtered and the product obtained was dried under vacuum (5-10 mbar) at 45°C to 50°C.

Yield (w/w): 83%

Example 3: Preparation of l-Γ2- 7-Methoxynaphthalen-l-Yl Ethyl1-2λ ⁵ -Triaz-l-En-2-Yne

Formula V

A mixture of 2-(7-methoxynaphthalen-l-yl)ethyl 4-nitrobenzene sulfonate (Formula IV, obtained as per Example 2, 2 g) and sodium azide (0.4 g) were stirred in dimethylformamide (10 mL) at 30°C to 35°C. The reaction was monitored and after its completion, the product was extracted with diethyl ether (20 mL). The solvent was recovered to obtain the title product.

Yield (w/w): 79%

Example 4: Preparation of 2-(7-Methoxynaphthalen- 1 -Yl)Ethanamine Carbon Dioxide Adduct

Formula VIII

A solution of l-[2-(7-methoxynaphthalen-l-yl)ethyl]-2λ ⁵ -triaz-l-en-2-yne (Formula V, obtained as per Example 3, 1 g) in methanol (10 mL) was treated with hydrogen gas (2 Kg/cm ² ) in the presence of Raney nickel (1.0 g) at 40°C. After completion of the reaction, the reaction mixture was filtered through Hyflo®. The filtrate was concentrated under vacuum (50°C to 55°C, 200-210 mbar) and the residue was obtained. A solution of the residue in toluene (15 mL) was purged with carbon dioxide gas (for at least 2 hours) at 10°C to 15°C. The solid so obtained was filtered and dried under vacuum (5-10 mbar) at 30°C over 10 hours to 15 hours.

Yield (w/w): 87%

Example 4(A): Preparation of 2-(7-Methoxynaphthalen- 1 -YDEthanamine Carbon Dioxide Adduct

Formula VIII

A solution of (7-methoxynaphthalen- 1 -yl)acetonitrile (5 g) in methanol (20 mL) and aqueous ammonia (10 mL) was treated with hydrogen gas (2 Kg) in the presence of Raney nickel (2.5 g) at 40°C. After completion of the reaction, the reaction mixture was filtered through Hyflo®. The filtrate was concentrated under vacuum to obtain a residue. The residue was dissolved in toluene (30 mL), and was purged with carbon dioxide gas (for at least 4 hours to 5 hours) at 10°C to 15°C to obtain a solid. The solid was dried under vacuum at 30°C to 35°C for 10 hours to 15 hours.

Yield (w/w): 81%

Mass = 202.4 (M+l)

^! H NMR (CDC1 ₃ ): 2.31 (bs, NH ₂ ), 3.10-3.13 (m, 2H), 3.17-3.20 (m, 2H), 3.92 (s, 3H), 7.15 (dd, 1H), 7.20-7.32 (m, 3H), 7.65 (d, 1H), 7.75 (d, 1H)

XRD (degrees 2Θ) = 5.00, 10.07, 14.30, 15.14, 16.03, 16.80, 17.36, 18.08, 19.01, 20.29, 22.06, 22.72, 22.99, 24.43, 25.89, 26.70, 26.97, 28.92, 35.83 and 38.37 (± 0.2°) 2Θ

The X-ray powder diffractograms (XRPD) were recorded on a PANalytical X'pert Pro instrument. The measurements were done using CuK _a radiation at 45kV.

Example 5: Preparation of Agomelatine

Formula I

To a mixture of 2-(7-methoxynaphthalen-l-yl)ethanamine carbon dioxide adduct (Formula VIII, obtained as per Example 4, 0.6 g) and sodium acetate (0.24 g) in methanol (9 mL), acetic anhydride (0.3 g) was added drop-wise. The reaction mixture was heated to reflux temperature and stirred for 1 to 2 hours. After completion of the reaction, the reaction mixture was cooled to 30°C to 35°C. Ice (18 g) was added to the reaction mixture and stirred for another 2 hours at 10°C to 15°C. The solid product was filtered and dried under vacuum (5-10 mbar) at 45°C to 50°C over a time period of 10 to 15 hours to get the title product.

Yield (w/w): 91%