FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of

Agomelatine consisting reduction of 2-(7-methoxynaphthalen-1 -yl) acetamide (formula VI) using reducing agent in organic solvent to give 2-(7-methoxynaphthalen-1 -yl) ethanamine (formula VII). The invention further relates to preparation of Agomelatine by reducing the impurity level of N-acetyl-N-[2-(7-methoxy-1 -naphthalenyl) ethyl]acetamide. BACKGROUND OF THE INVENTION

Agomelatine, represented by structural formula I and chemically named as N-[2-(7- methoxy-1 -naphthalenyl) ethyl]acetamide is a melatonine receptor agonist. It is used for the treatment of severe depression, seasonal affective disorders, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue resulting from jetlag, appetite disorders and obesity.

Formula 1 : Agomelatine

EP0447285 (EP '285) discloses Agomelatine, a process for the preparation of Agomelatine and use of Agomelatine as a melatonine receptor agonist.

The process as described in EP '285 involves Reformatsky reaction between 7- methoxy-1 -tetralone and organozinc reagent generated from ethyl bromoacetate, followed by dehydration of the carbinol intermediate in the presence of P ₂ 0 ₅ to give 2-(7-methoxy- 1 ,2,3,4-tetrahydro-1 -naphthylidene)acetic acid ethyl ester. Further, aromatization and saponification gives 2-(7-methoxy-1 -naphthyl)acetic acid, which is then converted to amide and subsequently dehydrated to yield 2-(7-methoxy-1 -naphthyl)acetonitrile, this being followed by reduction, and then condensation with acetyl chloride to obtain Agomelatine. The aforementioned process involves nine steps giving an average yield of less than 30%.

J. Med. Chem., 1992, 35, 1486-1489 discloses the synthesis of Agomelatine wherein condensation of (7-methoxy-1 -naphthyl) acetic acid with thionyl chloride followed by treatment with aqueous ammonia to produce amide and subsequently reduced to amine using UAIH ₄ and further acylated to give Agomelatine. LiAIH ₄ is pyrophoric reagent, has short shelf life and limited solubility which reduces its industrial applicability. Agomelatine is recrystallized from cyclohexane-toluene but the process impurity is difficult to eliminate using mixture of cyclohexane-toluene for purification of Agomelatine.

Synthetic communication, 2001 , 31 (4), 621 -629 discloses the synthesis of

Agomelatine from 7-methoxy-1 -tetralone by using LiCH ₂ CN at -78°C followed by dehydrogenation with DDQ. Use of cryogenic condition renders the process commercially unviable.

CN101 7090362 discloses the use of a reducing agent in the presence of a Lewis acid to prepare (7-methoxy-1 -naphthyl)ethylamine from (7-methoxy-1 -naphthyl)acetamide.

CN101 735091 discloses a process wherein dehydrogenation of 3,4-dihydro-7- methoxy-1 -naphthaleneacetonitrile in the presence of DDQ followed by reduction with NaBH ₄ in the presence of nickel chloride and amidation with acetyl chloride to obtain Agomelatine.

In view of above, there is need for an alternative way to prepare Agomelatine which is safe, cost effective, and industrially feasible.

SUMMARY OF THE INVENTION

The principal object of present invention is to provide an improved process for the preparation of Agomelatine by reducing the number of synthetic steps.

Another object of present invention is to provide the process for preparation of Agomelatine consisting reduction of 2-(7-methoxynaphthalen-1 -yl) acetamide (formula VI) using reducing agent in organic solvent to give 2-(7-methoxynaphthalen-1 -yl) ethanamine (formula VII).

Yet another object of present invention is to provide pure 2-(7-methoxynaphthalen-1 - yl) ethanamine (formula VI I).

Yet another object of present invention is to provide the process for purification of agomelatine by eliminating the impurities.

Yet another object of present invention is to provide the process for the preparation of Agomelatine which improves overall yield.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 X-ray diffraction spectrum of purified Agomelatine obtained by present invention Figure 2 2theta values of purified Agomelatine obtained by present invention

Figure 3 HPLC chromatogram of Agomelatine obtained by present invention. DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention to provide the process for the preparation of Agomelatine by reducing the number of synthetic steps comprises Reformatsky reaction of 7-methoxy-1 -tetralone (formula I I) with organozinc compound derived from zinc and ethyl bromoacetate (formula VI II) to give 2-(1 -hydroxy-7-methoxy-1 ,2,3,4-tetrahydro-1 - naphthalene)acetic acid ethyl ester (formula II I). The ester of formula I II on dehydration results mixture of 3,4-dihydro-7-methoxy-1 -naphthaleneacetic acid ethyl ester (formula IVa) and 2-(3,4-dihydro-7-methoxy-1 (2H)-naphthalenylidene)-acetic acid ethyl ester (formula IVb). Further, aromatization of compound of formulae IVa and IVb at elevated temperature results 2-(7-methoxynaphthalen-1 -yl) acetic acid ethyl ester of formula V which on amidation affords 2-(7-methoxynaphthalen-1 -yl) acetamide (formula VI), followed by reduction to yield 2-(7-methoxynaphthalen-1 -yl) ethanamine (formula VI I). The ethanamine (formula VI I) is optionally isolated as its acid addition salt (formula Vi la). The ethanamine (formula VII) or its acid addition salt (formula Vi la) on acetylation yields Agomelatine (formula I) which is optionally purified to give pure Agomelatine. The present invention is further elaborated below:

The improved process according to present invention for the preparation of agomelatine (formula I), comprising the steps of:

(a) reacting 7-methoxy-1 -tetralone (formula I I) with organozinc compound derived from zinc and ethyl bromoacetate (formula VII I)

Formula I I Formula VII I

in presence of an organic solvent to give 2-(1 -hydroxy-7-methoxy-1 ,2,3,4-tetrahydro-1 naphthalene)acetic acid ethyl ester (formula II I);

Formula II I

(b) dehydrating 2-(1 -hydroxy-7-methoxy-1 ,2,3,4-tetrahydro-1 -naphthylidene) acetic acid ethyl ester (formula I II) using proton source, to give mixture of 3,4-dihydro-7-methoxy-1 - naphthaleneacetic acid ethyl ester (formula IVa) and 2-(3,4-dihydro-7-methoxy-1 (2H)- naphthalenylidene)-acetic acid ethyl ester (formula IVb);

Formula IVa Formula IVb

(c) aromatizing mixture of 3,4-dihydro-7-methoxy-1 -naphthaleneacetic acid ethyl ester (formula IVa) and 2-(3,4-dihydro-7-methoxy-1 (2H)-naphthalenylidene)-acetic acid ethyl ester (formula IVb) using aromatization catalyst at elevated temperature, to give 2-(7- methoxynaphthalen-1 -yl) acetic acid ethyl ester (formula V);

Formula V

(d) amidating 2-(7-methoxynaphthalen-1 -yl)acetic acid ethyl ester (formula V) using ammonia or ammonia providing compound in an alcohol to give 2-(7-methoxynaphthalen-1 - yl) acetamide (formula VI);

Formula VI

(e) reducing 2-(7-methoxynaphthalen-1 -yl) acetamide (formula VI) using reducing agent in organic solvent to give 2-(7-methoxynaphthalen-1 -yl) ethanamine (formula VI I);

Formula VII

(f) optionally, preparing 2-(7-methoxynaphthalen-1 -yl) ethanamine acid addition salt (formula Vi la) from 2-(7-methoxynaphthalen-1 -yl) ethanamine free base (formula VI I) using acid; and

Formula Vila

(g) acetylating 2-(7-methoxynaphthalen-1 -yl) ethanamine (formula VI I) obtained in step (e) or the acid addition salt of 2-(7-methoxynaphthalen-1 -yl) ethanamine (formula Vi la) obtained in step (f) using acetyl chloride in presence of base and organic solvent to give agomelatine of formula I.

The process for the preparation of Agomelatine of formula I according to present invention is further depicted by following scheme:

Agomelatine (Formula I) The reaction conditions are elaborated below which further state the present invention.

The organic solvent used in step (a) is selected from hydrocarbon such as benzene, toluene, xylene; cycloalkanes such cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane; aliphatic hydrocarbon such as hexane, heptane; ethers such as tetrahydrofuran (THF), 2-methyl THF, diethylether, dioxane, monoglyme, 1 ,3-dimethoxy propane, methyl t-butyl ether (MTBE) or mixtures thereof. The organic solvent used in step (a) is preferably selected from ethers wherein methyl t-butyl ether (MTBE) the most preferred solvent.

The proton source used in step (b) is selected from acid such as sulphuric acid, hydrochloric acid, phosphoric acid, p-toluene sulphonic acid. The proton source used in step (b) is preferably sulphuric acid.

The aromatization catalyst used in step (c) is selected from sulfur or selenium, preferably sulfur.

The reagent used in step (d) for amidation is selected from ammonia or ammonia releasing compounds selected from urea, ammonium carbonate, ammonium hydroxide or ammonium chloride.

The alcohol used in step (d) is selected from d to C ₄ alcohols such as methanol, ethanol, propanol, 2-propanol (IPA), n-butanol, 2-butanol, tert-butanol or mixtures thereof.

The alcohol used in step (d) is preferably methanol.

In another embodiment, optionally pressure is applied during amidation in step (d) to increase efficiency of the reaction.

The reducing agent used in step (e) is selected from the group of borane- tetrahydrofuran (BTHF); borane-dimethylsulfide (borane- DMS); sodium dihydro(trithio)borate; sodium acetoxyborohydride or sodium trifluoro-acetoxyborohydride.

The reducing agent used in step (e) is preferably used from borane complex. According to present invention, borane-dimethylsulfide is the most preferable reducing agent.

In another embodiment in step (f) optionally, 2-(7-methoxynaphthalen-1 -yl) ethanamine is converted to addition salt of 2-(7-methoxynaphthalen-1 -yl) ethanamine acid of formula Vi la using suitable acid. The acid addition salt of formula Vi la is further used for acetylation. The acid addition salt is prepared by using acid selected from inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, p - toluene sulphonic acid, methane sulphonic acid or benzene sulphonic acid; organic acid such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid or citric acid. The acid addition salt is optionally purified to achieve desired purity. The base used in step (g) is selected from dimethylaminopyridine (DMAP), N, N- diisopropylethylamine (DI PEA), N-methyl morpholine, lutidine or collidine. The base used in step (g) is preferably N, N-diisopropylethylamine.

The organic solvent used in step (e) and (g) is selected from aromatic hydrocarbon such as benzene, toluene, xylene; cycloalkanes such cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane; aliphatic hydrocarbons such as hexane, heptane; ethers such as tetrahydrofuran (THF), 2-methyl THF, diethylether, dioxane, monoglyme, 1 ,3- dimethoxy propane, diisopropyl ether (DIPE); halogenated solvents such as dichloromethane (MDC), chloroform, 1 ,2-dichloroethane, tetrachloroethane or mixtures thereof.

Further, the process for the preparation of Agomelatine according to the present invention consisting of the following steps:

(a) reacting 7-methoxy-1 -tetralone with organozinc compound derived from zinc and ethyl bromoacetate in methyl t-butyl ether (MTBE) to give 2-(1 -hydroxy-7-methoxy-1 ,2,3,4- tetrahydro-1 -naphthalene) acetic acid ethyl ester;

(b) dehydrating 2-(1 -hydroxy-7-methoxy-1 ,2,3,4-tetrahydro-1 -naphthylidene) acetic acid ethyl ester using sulphuric acid to give mixture of 3,4-dihydro-7-methoxy-1 - naphthaleneacetic acid ethyl ester (formula IVa) and 2-(3,4-dihydro-7-methoxy-1 (2H)- naphthalenylidene)-acetic acid ethyl ester (formula IVb);

(c) aromatizing the mixture of 3, 4-dihydro-7-methoxy-1 -naphthaleneacetic acid ethyl ester (formula IVa) and 2-(3,4-dihydro-7-methoxy-1 (2H)-naphthalenylidene)-acetic acid ethyl ester (formula IVb) using sulphur at 215-225 ^° C temperature to give 2-(7- methoxynaphthalen-1 -yl) acetic acid ethyl ester;

(d) amidating 2-(7-methoxynaphthalen-1 -yl)acetic acid ethyl ester using ammonia in methanol to give 2-(7-methoxynaphthalen-1 -yl) acetamide;

(e) reducing 2-(7-methoxynaphthalen-1 -yl) acetamide using Borane-DMS in toluene to obtain 2-(7-methoxynaphthalen-1 -yl) ethanamine;

(f) preparing 2-(7-methoxynaphthalen-1 -yl) ethanamine acid addition salt from 2-(7- methoxynaphthalen-1 -yl) ethanamine free base; and

(g) acetylating acid addition salt of 2-(7-methoxynaphthalen-1 -yl) ethanamine with acetyl chloride in using DIPEA as a base in dichloromethane to give crude agomelatine. (h) the crude agomelatine is optionally purified to give pure agomelatine

In another embodiment the present invention also provides a process for purifying

Agomelatine as described in step (h) of above descried process which comprises:

(i) suspending or dissolving Agomelatine in toluene; and

(ii) isolating crystals of pure Agomelatine. During the purification Agomelatine is dissolved in toluene about at 40 ^° C to reflux temperature, preferably at 75-80 ^° C. The isolation in step (ii) is performed by cooling, drying, adding an anti-solvent or seeding. The isolation in step (ii) is preferably performed by cooling. The agomelatine purification using toluene is eliminating process impurities which are difficult to remove using prior art processes. The major process impurities which are eliminated according to present invention are depicted below:

Formula IX Formula X

Formula XI Formula XII

By purification using toluene, the present invention also provides Agomelatine having less than about 0.15% of N-acetyl-N-[2-(7-methoxy-1 -naphthalenyl) ethyl]acetamide impurity (Formula IX). The corresponding impurity as per formula IX is preferably below 0.1 %, and more preferably less than 0.05% achieved as per present invention. The chromatographic parameters of HPLC analysis performed to measure the purity of Agomelatine obtained according to present invention is mentioned below:

Column Hypersil 100 C18 (4.6x250mm), 5 μιη

Column Temperature 45°C

Detection Wavelength 230nm

Flow Rate 1 .00 imL/min

Injection Volume 10 μΙ_

Runtime 60.0 min

Buffer preparation Dissolve 1 .36 g of potassium dihydrogen phosphate in l OOOmL water, adjust pH 3.0 ± 0.05 using dilute orthophosphoric acid and filter the buffer through 0.45 μ membrane filter.

Mobile phase Buffer & Acetonitrile

Diluent Prepare and degas a mixture of water : acetonitrile in the volume ratio of 500 : 500.

The X-ray diffraction spectrum and corresponding 2theta values of purified Agomelatine obtained by present invention is depicted in Figure 1 and 2. The HPLC chromatogram of Agomelatine obtained by present invention is depicted in Figure 3.

The above described improved process for the preparation of Agomelatine is resulting in cost-effective and reproducible process on industrial scale. The process of present invention provides Agomelatine with higher overall yield and purity.

The present invention is further illustrated by following non-limiting examples and reference examples.

Example 1 : Preparation of 2-(1 -hydroxy-7-methoxy-1 ,2,3,4-tetrahydro-1-naphthylidene) acetic acid ethyl ester (formula III)

A stirred solution of 7-methoxy tetralone (40gm) and ethyl bromoacetate (68.31 gm) in MTBE (160 ml) was added to Zn (52.1 gm) in MTBE (280 ml) at 55-60 ^< €. On completion the reaction mixture is cooled at 1 0-15 Ό followed by addition of dilute HCI. The reaction mass was filtered and water was added and extracted with MTBE. The organic layer was washed with water and dried over sodium sulphate. The organic layer was dried under pressure to obtain oily mass. Weight of oily mass = 57 gm (95% yield).

Example 2: Dehydration of 2-(1-hydroxy-7-methoxy-1 ,2,3,4-tetrahydro-1-naphthylidene) acetic acid ethyl ester to obtain mixture of 3,4-dihydro-7-methoxy-1 -naphthaleneacetic acid ethyl ester (formula IVa) and 2-(3,4-dihydro-7-methoxy-1 (2H)-naphthalenylidene)- acetic acid ethyl ester (formula IVb)

A mixture of 2-(1 -hydroxy-7-methoxy-1 ,2,3,4-tetrahydro-1 -naphthylidene) acetic acid ethyl ester (55 gm) in toluene (165 ml) with sulphuric acid (2.04 gm) was stirred at reflux temperature. The reaction mass was cooled at room temperature. The water was added and stirred. The organic layer was separated and washed with water followed by washing with sodium bicarbonate and water. The organic layer is dried over anhydrous sodium sulphate. The organic layer was dried under pressure to obtain oily mass of titled compound. Weight of oily mass = 49 gm (95.6% yield).

Example 3: Preparation of 2-(7-methoxynaphthalen-1 -yl) acetic acid ethyl ester (formula V)

A mixture of oily mass as obtained in example 2 (40 gm) and sulphur (5.2 gm) was heated at 215-225 ^° C until reaction completes. The reaction mass was cooled at room temperature, ethyl acetate (200 ml) and charcoal (2 gm) were added to reaction mass, and stirred for 30 min at reflux temperature. The reaction mass was cooled and filtered. The organic layer was evaporated to dryness under reduced pressure to obtain product.

Weight of oily mass = 38gm (95.79% yield).

Example 4: Preparation of 2-(7-methoxynaphthalen-1-yl) acetamide (formula VI)

200 gm of mixture of 2-(7-methoxynaphthalen-1 -yl) acetic acid ethyl ester in methanol was kept into an autoclave. The autoclave was then pressurized to 5-6 kg/cm ² with ammonia gas. The reaction mass was stirred at above 80°C. On completion, the reaction mass was cooled at room temperature and pressure was released. The reaction mass was filtered and washed with MTBE. The solid was dried to give title product. Weight of solid= 129 gm (73.1 9% yield)

Example 5: Preparation of 2-(7-methoxynaphthalen-1 -yl) ethanamine hydrochloride (formula Vila)

Borane-DMS (106 gm) was added to a stirred solution of 2-(7-methoxynaphthalen-1 - yl) acetamide (1 00 gm) and toluene (500 ml) at room temperature. The reaction mixture was heated and maintained at 80-85 °C until reaction completes. The reaction mixture was cooled to room temperature. The reaction mass was slowly quenched into 10% HCI. Solvent was evaporated and Ethyl acetate (50 ml) was added. pH was adjusted to 12 using NaOH solution. The organic layer was separated and washed with water and dried over sodium sulphate. The organic layer was evaporated to dryness under reduced pressure at 45 ^° C to obtain 2-(7-methoxynaphthalen-1 -yl) ethanamine (oily mass). 10% Ethyl acetate hydrogenchloride (18.7 ml) was added to a stirred solution of 2-(7-methoxynaphthalen-1 -yl) ethanamine in ethyl acetate (30 ml) at low temperature. The reaction mixture was stirred at room temperature for 2 hr, filtered and evaporated to dryness to obtain 2-(7- methoxynaphthalen-1 -yl) ethanamine hydrochloride (71 gm, 64.28% yield).

Example 6: Preparation of 2-(7-methoxynaphthalen-1-yl) ethanamine (formula VII)

Borane-THF (1 .93 gm) was added dropwise to a stirred solution of 2-(7- methoxynaphthalen-1 -yl) acetamide (1 gm) and THF (10 ml) at room temperature. The reaction mixture was heated and maintained at 70-75 °C for 6-8 hr. The reaction mixture was cooled to room temperature. The reaction mass was slowly quenched into 10% HCI with stirring. The reaction does not proceed to completion.

Example 7: Preparation of 2-(7-methoxynaphthalen-1-yl) ethanamine (formula VII)

Vitride (3 ml) was added dropwise to a stirred solution of 2-(7-methoxynaphthalen-1 - yl) acetamide (1 gm) and toluene (1 0 ml) at room temperature. The reaction mixture was heated and maintained at 80-85 °C for 6-8 hr. The reaction mixture was cooled to room temperature. The reaction mass was slowly quenched into 1 0% HCI with stirring. The reaction does not proceed to give desired 2-(7-methoxynaphthalen-1 -yl) ethanamine.

Example 8: Purification of 2-(7-methoxynaphthalen-1-yl) ethanamine hydrochloride

Crude 2-(7-methoxynaphthalen-1 -yl) ethanamine hydrochloride (2 gm) was stirred with acetone (10 ml) for 5 hr. The solid was filtered and dried to give 2-(7- methoxynaphthalen-1 -yl) ethanamine hydrochloride (1 .85 gm, 92.5% yield).

Example 9: Preparation of Agomelatine

Solution of acetyl chloride (40 gm) in methylene dichloride (MDC) was added dropwise to a stirred solution of 2-(7-methoxynaphthalen-1 -yl) ethanamine (80 gm), DIPEA (1 08.7 gm) and MDC (400 ml). The reaction mass was stirred for 2 hr at below 0 ^° C and quenched with water. The organic layer was separated and washed with water and dried over anhydrous sodium sulphate. The organic layer was dried under reduced pressure. DIPE (240 ml) was added to the reaction mass and stirred for 4 hr at room temperature. The reaction mass was filtered and dried to obtain Agomelatine (68 gm, 82.92% yield).

Example 10: Purification of Agomelatine

Agomelatine (25 gm) was dissolved in toluene (75 ml) at 75-80 ^° C to get clear solution. Charcoal (3.75 gm) was added to the solution and stirred for 1 hr. The reaction mass was filtered through hyflo and washed with toluene. The solution was cooled and maintained at below 0°C for about an hour to obtain Agomelatine (21 gm, 84% yield, 0.05% of N-acetyl-N-[2-(7-methoxy-1 -naphthalenyl) ethyl]acetamide impurity, HPLC Purity 99.88%).

Agomelatine obtained according to present invention is having purity more than 99.5% or more. Agomelatine according to present invention is also having less than 0.1 5% of N-acetyl-N-[2-(7-methoxy-1 -naphthalenyl) ethyl]acetamide impurity.