FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of agomelatine starting from reaction of 7-methoxy-1-tetralone with organozinc compound.

BACKGROUND OF THE INVENTION
Agomelatine represented by structural formula I, is chemically named as N-[2-(7-methoxy-1-naphthalenyl) ethyl]acetamide which 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.

E.P. Patent No. 0447285 (EP ‘285) discloses agomelatine, a process for the preparation of agomelatine and use of agomelatine as a melatonine receptor agonist.
The process as disclosed in EP ‘285 involves Reformatsky reaction between 7-methoxy-1-tetralone and the organozinc reagent generated from ethyl bromoacetate, followed by dehydration of the carbinol intermediate in the presence of P2O5 to give 2-(7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid ethyl ester. Aromatization of obtained compound by heating with sulfur at 215oC results into the corresponding naphthalene derivative, which on basic hydrolysis of the ethyl ester group provides 2-(7-methoxy-1-naphthyl)acetic acid. Upon reaction with SOCl2, the crude acid chloride is obtained which is further reacted with ammonium hydroxide to produce corresponding amide, followed by dehydration of the amide with trifluoroacetic anhydride to afford the corresponding nitrile. The nitrile compound is then reduced to amine by catalytic hydrogenation. Finally, agomelatine is obtained by reaction of amine with acetyl chloride in pyridine using Schotten-Baumann reaction conditions. The aforementioned process involves nine steps giving an average yield of less than 30%. Moreover, the use of hygroscopic P2O5 for dehydration is cumbersome.
Synthetic communication, 2001, 31(4), 621-629 describes the preparation of agomelatine from 7-methoxy-1-tetralone by using LiCH2CN at -78oC followed by dehydrogenation with DDQ. Use of cryogenic condition renders the process commercially non-viable.
J. Med. Chem. 1992, 35, 1486-1489 describes the reaction of (7-methoxy-1-naphthyl) acetic acid with thionyl chloride followed by treatment with aqueous ammonia to produce amide. Further, reduction of amide to amine using LiAlH4 results in low yield. LiAlH4 is pyrophoric reagent, has short shelf life and limited solubility which limits its industrial applicability.
There is need for a process for the preparation of agomelatine which not only overcomes the problems of the prior art but is also safe, cost effective, and industrially feasible.

OBJECT OF THE INVENTION
The object of the present invention is to provide an improved process for the preparation of N-[2-(7-methoxy-1-naphthalenyl) ethyl]acetamide which reduces number of synthetic steps.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of N-[2-(7-methoxy-1-naphthalenyl) ethyl]acetamide of formula I, comprising the steps of:
(a) reacting 7-methoxy-1-tetralone of formula II, with organozinc compound derived from zinc and ethyl bromoacetate of formula VIII, in the presence of Zn dust in organic solvent to give 2-(1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid ethyl ester of formula III;
(b) dehydrating 2-(1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid ethyl ester of formula III using proton source, to give 2-(7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid ethyl ester of formula IV;
(c) aromatizing 2-(7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid ethyl ester of formula IV using aromatizing reagent at elevated temperature, to give 2-(7-methoxynaphthalen-1-yl) acetic acid ethyl ester of formula V;
(d) amidating 2-(7-methoxynaphthalen-1-yl)acetic acid ethyl ester of formula V using ammonia or ammonia providing compound in the presence of an alcohol to give 2-(7-methoxynaphthalen-1-yl) acetamide of formula VI;
(e) reducing 2-(7-methoxynaphthalen-1-yl) acetamide of formula VI using reducing agent in presence of organic solvent to give 2-(7-methoxynaphthalen-1-yl) ethanamine of formula VII; and
(f) acetylating 2-(7-methoxynaphthalen-1-yl) ethanamine of formula VII using acetyl chloride in presence of base and organic solvent to give N-[2-(7-methoxy-1-naphthalenyl) ethyl]acetamide of formula I.
The process for the preparation of N-[2-(7-methoxy-1-naphthalenyl) ethyl]acetamide of formula I is represented by following scheme:

The detailed reaction conditions are elaborated as mentioned below:
Organic solvent used in step (a) is selected from the group of hydrocarbon solvent 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 tert-butyl ether (MTBE) or mixtures thereof.
Proton source used in step (b) is selected from the group of acids such as sulphuric acid, hydrochloric acid, phosphoric acid, p –toluene sulphonic acid; acidic clay such as montmorillonite or molecular sieve.
Aromatizing reagent used in step (c) is selected from sulfur, selenium, DDQ, Chloranil, Raney Nickel or Palladium.
Amidating agent used in step (d) is selected ammonia or ammonia providing agent like urea, ammonium carbonate, ammonium chloride or ammonium hydroxide.
Alcohol used in step (d) is selected from the group of C1 to C4 alcohols such as methanol, ethanol, propanol, 2-propanol (IPA), n-butanol, 2-butanol, tert-butanol or mixtures thereof.
In an embodiment, optionally pressure is applied during amidation in step (d) to increase efficiency of the reaction.
Reducing agent used in step (e) is selected from the group of vitride; borane-tetrahydrofuran (BTHF); borane-dimethylsulfide (borane-DMS); sodium dihydro(trithio)borate; sodium borohydride with nickel chloride; sodium borohydride with cobalt chloride; sodium borohydride with iodine, sodium acetoxyborohydride or sodium trifluoro-acetoxyborohydride.
In an embodiment, optionally in step (e), 2-(7-methoxynaphthalen-1-yl) acetamide is converted to 2-(7-methoxynaphthalen-1-yl) acetimido chloride using chlorinating agent followed by reduction with reducing agent. Chlorinating agent is selected from the group of phosphorus pentachloride, phosphorus trichloride or phosphorus oxychloride. Reducing agent used in present embodiment is selected from the group of zinc, vitride, borane-tetrahydrofuran (BTHF), borane-dimethyl sulfide, sodium dihydro(trithio)borate, sodium borohydride with nickel chloride, sodium borohydride with cobalt chloride, sodium borohydride with iodine, sodium acetoxyborohydride or sodium trifluoro-acetoxyborohydride.
Base used in step (f) is selected from the group of triethylamine (TEA), dimethylaminopyridine (DMAP), N, N-diisopropylethylamine (DIPEA), N-methyl morpholine, lutidine or collidine.
Organic solvent used in step (f) is selected from the group of hydrocarbon solvent such as benzene, toluene, xylene; cycloalkanes such as 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, chloroform, 1,2-dichloroethane, tetrachloroethane or mixtures thereof.
In an embodiment, optionally in step (f), 2-(7-methoxynaphthalen-1-yl) ethanamine is converted to 2-(7-methoxynaphthalen-1-yl) ethanamine acid addition salt using acid followed by reprecipitation using base to give 2-(7-methoxynaphthalen-1-yl) ethanamine which is further used for acetylation. Acid is selected from the group of inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid: organic acid such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, p – toluene sulphonic acid, methane sulphonic acid, benzene sulphonic acid or citric acid. Base is selected from the group of hydroxides of alkali metals such as sodium hydroxide, lithium hydroxide, potassium hydroxide; carbonates of alkali metals such as sodium carbonate, potassium carbonate; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate. Acid addition salt formation helps in easy handling and prevents deterioration.
The process of the present invention is improved, cost-effective and reproducible on an industrial scale which reduces number of steps. The process of the present invention provides agomelatine with higher yield.

The present invention is further illustrated by following non-limiting examples:
Example 1: Preparation of 2-(1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene) acetic acid ethyl ester (formula III)
Solution of Zn (52.1 gm) in MTBE was added to a stirred solution of 7-methoxy tetralone (40gm) and ethyl bromoacetate (68.31 gm) in MTBE at 55-60oC. The reaction mixture was refluxed. The reaction mass was cooled at room temperature. Dilute HCl was added to reaction mass and stirred for 15 minutes. The reaction mass was filtered and water was added to it. The reaction mixture was extracted with MTBE. The organic layer was separated and washed with water and finally dried over sodium sulphate. The organic layer was evaporated to dryness under reduced pressure at 45oC to obtain titled compound. (Weight = 57 gm)
Example 2: Preparation of 2-(7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid ethyl ester (formula IV)
A mixture of 2-(1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene) acetic acid ethyl ester (55 gm) in toluene (275 ml) with sulphuric acid (2.04 gm) was stirred at ambient temperature. The reaction mixture was refluxed. The reaction mass was cooled at room temperature. Water was added to the reaction mass and stirred for 15 minutes. The organic layer was separated and washed with water followed by 10% sodium bicarbonate. Finally the crude was dried over sodium sulphate. The organic layer was evaporated to dryness under reduced pressure at 45oC to obtain titled compound.
(Weight = 46.2 gm)
Example 3: Preparation of 2-(7-methoxynaphthalen-1-yl) acetic acid ethyl ester (formula V)
A mixture of 2-(7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid ethyl ester (50 gm) and sulphur (6.5 gm) was heated at 215-225oC until reaction completes. The reaction mass was cooled at room temperature and ethyl acetate was added to it. Charcoal was added to the 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 titled product.
(Weight = 44.6 gm)
Example 4: Preparation of 2-(7-methoxynaphthalen-1-yl) acetamide (formula VI)
A mixture of 2-(7-methoxynaphthalen-1-yl) acetic acid ethyl ester (10 gm) in methanol (20 ml) with aq. ammonia (100 ml) was stirred at ambient temperature. The reaction mixture was refluxed and maintained at reflux temperature under pressure (4-5 kg) until reaction completes. The reaction mass was cooled at room temperature and pressure was released. The reaction mass was dried and washed with water followed by MTBE. The solid was dried to give titled product. (Weight = 7 gm)
Example 5: Preparation of 2-(7-methoxynaphthalen-1-yl) ethanamine (formula VII)
Borane-DMS (10.62 gm) was added dropwise to a stirred solution of 2-(7-methoxynaphthalen-1-yl) acetamide (10 gm) and THF (50 ml) at 0 to -5oC. The reaction mixture was refluxed and maintained at reflux temperature until reaction completes. The reaction mixture was cooled at 0 to -5oC. 10% HCl was added to reaction mass with stirring. Solvent was evaporated to obtain sticky mass. Water and ethyl acetate were added to the sticky mass. The mixture was basified up to pH 12 using 50% 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 45oC to obtain 2-(7-methoxynaphthalen-1-yl) ethanamine. (Weight = 10 gm)
Example 6: Preparation of 2-(7-methoxynaphthalen-1-yl) ethanamine hydrochloride
10% Ethyl acetate hydrogenchloride (18.7 ml) was added to a stirred solution of 2-(7-methoxynaphthalen-1-yl) ethanamine (10 gm) and ethyl acetate (30 ml) at 0 to -5oC. The reaction mixture was stirred at room temperature for 2 hr, filtered and evaporated to dryness to obtain 2-(7-methoxynaphthalen-1-yl) ethanamine hydrocloride. (Weight = 7.82 gm)

Date: 25/11/2010
For, Cadila Pharmaceuticals Limited,

______________________________
Dr. Bakulesh M. Khamar
Executive Director – Research