FORM I THEREOF

This application claims the benefit of priority of our Indian patent application numbers 1891 /MUM/2012 filed on 30 ^th June 2012 and 2421/MUM/2012 filed on 21 ^st August 2012 which are incorporated herein by reference.

Field of the invention

The present invention relates to an improved process for the preparation of Agomelatine of formula (I) and also concerns new process for the preparation of crystalline form I of Agomelatine.

Formula (I)

Background of the invention

Agomelatine is chemically known as N-[2-(7-methoxy-1 -naphthalenyl] acetamide. It was developed by the French company Servier. The current pharmaceutical product containing this drug is being sold using the trade name Valdoxan® / Thymanax®. The drug is approved by the EU for the treatment of adult depression treatment. Indeed Agomelatine has double feature of being, on the one hand, an agonist of melatoninergic system receptors, on the other hand, an antagonist of 5-HT _2c receptor. Those properties confer activity in the central nervous system and, more especially, in the treatment of severe depression, seasonal affective disorders, sleep disorders, cardiovascular pathologies, and pathologies of the digestive system, insomnia and fatigue resulting from jetlag, appetite disorders and obesity.

US 5225442 describes a process for the preparation of Agomelatine in eight steps starting from 7-methoxy tetralone giving and average yield of less than 30%. This process involves the action of ethyl bromoacetate, followed by aromatization and saponification to yield the corresponding acid, which is then converted to acetamide and subsequently dehydrated to yield (7-methoxy-1 -naphthyl) acetonitrile, which on reduction to amine and subsequent reaction with acetylene chloride to give Agomelatine of formula I.

In particular, the preparation of (7-methoxy-1 -naphthyl) acetonitrile involves six reaction steps and, transposed to an industrial scale, has quickly demonstrated the difficulties of carrying out the process, these being caused principally by problems of reproducibility of the first step, which constitutes the action of ethyl bromoacetate on 7- methoxy-1 -tetralone according to the Reformatsky reaction resulting in ethyl (7- methoxy-3,4-dihydro-1 (2H)-naphthalenylidene)ethanoate. Moreover, the subsequent step of aromatization of ethyl (7-methoxy-3, 4-dihydro-1 (2H)-naphthalenylidene) ethanoate has often been incomplete and resulted, after saponification, in a mixture of products that is difficult to purify.

Synthetic Communication, 2001 , 31 (4), 621 -629 describes process of obtaining (7-methoxy-1 -naphthyl) acetonitrile in three steps starting from 7-methoxy-1 -tetralone, by the action of LiCH2CN followed by dehydrogenation with DDQ (2,3-dichloro-5,6- dicyano-1 ,4-benzoquinone) and finally dehydration in acid medium. The total yield is mediocre (76%), however, and in particular the DDQ used in the dehydrogenation reaction and the benzene reflux necessary in the third step do not comply with industrial requirements in terms of cost and the environment.

US 7476751 disclose a process for the preparation of (7-methoxy-1 -naphthyl) acetonitrile in three steps starting from 7-methoxy-1 -tetralone, by the reaction of cyanoacetic acid in the presence of catalytic amount of a R'-NH ₃ ⁺ , O-C=0-R followed by dehydrogenation by hydrogenation catalyst in the presence of allyl compound.

S. Yous et al. in J. Med. Chem. 1992, 35, 1484-1486 describe a process for the preparation of Agomelatine, wherein Agomelatine is obtained from a biphasic medium of water and chloroform.

Bernard Tinant and Jean-Paul Declercq in Acta Cryst. (1994), C50, 907-910 disclose a full crystallographic investigation of the Agomelatine produced by Yous et al. The polymorph form of the product obtained by Yous et al. and analyzed by Tinant and Declercq is designated as the polymorph form I of Agomelatine. Tinant and Declercq provide the full crystal data of this polymorph form, and regarding the identification of the polymorph form I of Agomelatine, it is explicitly referred to Bernard Tinant and Jean- Paul Declercq in Acta Cryst, (1994), C50, 907-910. The most important crystal data is as follows:

C15H17N02

Mr=243.30

Orthorhombic

Pca2!

a=31 .501 (4)A

b=9.5280(10)A

c=17.906(2)A.

The density is D = 1203 kg m ^"3 , and the number of molecules in one cell is Z = 16. Tinant and Declercq also disclose the fractional atomic coordinates and equivalent isotropic displacement parameters and selected geometric parameters as well as the hydrogen bonding geometry of this polymorph form. This data is included herein by reference.

EP 0 447 285 in example 1 also discloses a process for the preparation of Agomelatine. In this process Agomelatine is obtained by recrystallization from isopropyl ether. No information on the polymorph form can be found in EP 0 447 285.

Later publications consider that the Agomelatine obtained according to EP 0 447 285 is the same polymorph form obtained by Yous et al. (e.g. US 2005/0182276) but no experimental data is provided. The known processes for obtaining the polymorph form I of Agomelatine are considered as providing the polymorph form I of Agomelatine not in a sufficiently reproducible and well- defined manner and with only poor filterability (US 2005/0182276).

Despite the existence of various processes for the preparation of Agomelatine, there remains a need for improved process for the preparation of Agomelatine producing high yields and purity and being well suited for use of industrial scale.

Further, there also remains a need for stable polymorphic forms of Agomelatine and process for making them.

Object of the invention

Object of the present application provide safe and simpler process for the preparation of Agomelatine. Each step of the process disclosed herein are contemplated both in the context of the multi step sequences described, and individually.

It is an object of the present invention is to provide an improved process for the preparation of Agomelatine comprising a step of converting compound of formula (la) to the compound of formula (lb).

(la) (lb)

Further object of the present invention is to provide a process for the preparation of Agomelatine comprising a step of converting compound of formula (lb) to the compound of formula (Ic).

Yet another object of the present invention is to provide a process for the preparation of Agomelatine comprising a step of converting a compound of formula (Ic) to compound of formula (Id) by aromatization in suitable solvent.

Further object of present invention is to provide a process for the preparation of Agomelatine comprising a step of converting compound of formula (Id) to compound of formula (If) by amidation of compound of formula (le)

Yet another object of present invention to provide a process for the preparation of Agomelatine comprising a step of converting compound of formula (If) to compound of formula (Ig) by dehydration of compound of formula (If).

(If) (ig)

Further object of present invention to provide a process for the preparation of Agomelatine comprising reduction of compound of formula (Ig) to obtain compound of formula (Ih).

(ig) (Ih)

Further object of present invention is to provide a process for the preparation of Agomelatine comprising acylation of compound of formula (Ih) to obtain compound of formula (I).

(Ih) (I)

Further object of the present invention is to provide process for the preparation of stable crystalline form I of Agomelatine, comprising the steps of

i) providing a solution of Agomelatine in organic amine or mixture there of ii) adding solution of organic acid and water to the solution obtain in step (i) iii) optionally seeding crystals of form I

iv) isolating the crystals of the polymorphic form I of Agomelatine.

Brief description of drawing

Fig: 1 depicts a powder X-ray diffractogram (PXRD) of crystalline Form I of Agomelatine

Detailed description of the invention

In accordance with the present invention to provide process for the preparation of Agomelatine by reducing number of synthetic steps comprises Wittig Horner reaction of 7-methoxy-tetralone formula (la) with ethyl 2~(diethoxyphosphory!)acetate to give compound of formula (lb). The hydrolysis of compound of formula (lb) results compound of formula (Ic). Further aromatization of compound of formula (Ic) results compound of formula (Id). Further compound of formula (Id) converted to acid chloride (le) which on amidation affords compound of formula (If), followed by dehydration and reduction to yield compound of formula (Ih). The ethanamine formula (Ih) is optionally isolated as its acid addition salt. The ethanamine or its acid addition salt formula (Ih) on acetylation in biphasic media such as toluene; water or acetone: water yields Agomelatine formula (I) which is optionally purified to give pure Agomelatine. The present invention for the preparation of Agomelatine is further elaborated below:

The present invention provides an improved process for the preparation of Agomelatine comprising a step of converting compound of formula (la) to the compound of formula (Ic) by in situ preparation of compound of formula (lb) in the presence of ethyl

2-(diethoxyphosphory!)acetate, base and suitable solvents.

(la) (lb) (Ic)

Suitable base that may be used in the conversion of formula (la) to (lb) may be selected from sodium hydride, potassium tertiary butoxide, butyl lithium and metal hydroxide such as KOH, NaOH and the like. The quantity of base used in this step may range from about 1 to about 3 molar equivalents, per mole of compound (la).

Suitable solvents that used for the reaction is selected form the group consisting of C1 to C5 alcohol such as ethanol, methanol, 1 -propanol, isoprpanol, 1 -butanol, 2- butanol, tert. Butanol, 1 -pantenol, 2-butanol, tert-pantenol and aromatic hydrocarban such as toluene, xylene and like or mixture there of. The amount of solvent that preferably used in this step may range from about 1 to 10 volumes to compound of formula (la).

Suitable temperatures for conversion of compound of formula (la) to compound of formula (lb) may be less than about 150°C, less than about 100°C, less than about 60°C, less than about 25°C, less than bout 0°C or any other suitable temperatures. The reaction may be carried out for time periods ranging from about 30 minutes to about 5 hours, or longer. After completion of the reaction, the compound of formula (lc) may be optionally be isolated and purified or the reaction mass comprising the compound of formula (lc) may be taken for next step of the process. In an embodiment the reaction mass comprising the compound of formula (lc) further be purified by a process involving acidifying and basifying steps, in any order, crystallization and combination thereof, to enhance the purity.

In another embodiment of the present invention provides a process for the preparation of Agomelatine comprising a step of converting a compound of formula (lc) to compound of formula (Id) by aromatization in suitable solvent.

For the reaction of aromatization the suitable reagent that may be used in the process of converting a compound of formula (lc) include but are not limited to sulphur, raney Ni/H ₂ , FeC , Pd/C-Acrylic acid, Raney Ni-methyl acrylate, and the like. The suitable aromatization reagent used in the above step is preferably Pd/C acrylic acid in the presence of sodium bicarbonate. The amount of acrylic acid that may be used ranges from about 1 to 3 mole eq. to compound (lc). The amount of Pd/C that may be used ranges from about 0.01 to about 0.1 mole eq to compound (lc). solvents used for aromatization includes but are not limited to water, alcoholic solvent such as methanol, ethanol, isoproanol and the like; The amount of solvent that preferably used in this step may range from about 3 to 10 volumes to compound of (lc).

Suitable temperatures for reaction may be less than about 125°C, less than about 100°C, less than about 60°C, less than about 25°C, less than about 0°C or any other suitable temperatures. The reaction may be carried out for time periods ranging from about 30 minutes to about 15 hours, or longer.

After completion of the reaction, the compound of formula (Id) may be optionally be isolated and purified or the reaction mass comprising the compound of formula (Id) may be taken for next step of the process. In an embodiment the reaction mass comprising the compound of formula (Id) further be purified by a process involving acidifying and basifying steps, in any order, crystallization and combination thereof, to enhance the purity.

Another embodiment of present invention provides a process for the preparation of Agomelatine comprising a step of converting compound of formula (Id) to compound of formula (If) by preparation of compound of formula (le)

Compound of formula (Id) is reacted with thionyl chloride (SOCI ₂ ), Phosphorus trichloride (PCI ₃ ), or Phosphorus pentachloride (PCI ₅ ) to obtained compound of formula (le). Residue of compound of formula (le), which is further reacted with source of ammonia to obtained compound of formula (If).

Source of ammonia is used for the conversion of formula (le) to l(f) selected from ammonia gas, liquid ammonia, aqueous ammonia, ammonium hydroxide, magnesium nitride and formamide with base and the like. The suitable source of ammonia that was used in this reaction is preferably ammonia gas. Ammonia gas is purged to the reaction mixture till pH is more then 8. The temperature on which ammonia gas purged to the reaction mixture is -10 to 20°C, preferably 0-5 °C. The product can be isolated from the reaction mass by quenching the reaction mixture in cold water and the separated organic layer was distilled off and recrystallized with methanol solvent to give pure compound of formula (If).

In another embodiment of the present invention provides a process for the preparation of Agomelatine comprising a step of converting compound of formula (If) to compound of formula (Ig) by dehydration of compound of formula (If) in the presence of POCI ₃ or combination of Ethyldichlorophsophate and DBU or P ₂ 0 ₅ or mixture there of, preferably in the presence of POCI ₃ .

(if) (ig)

The quantity of dehydrating agent preferably POCI ₃ used may range from about 0.8 to about 2 mol eq. to compound (Id), preferably 0.08 to 1.5 mole eq. The reaction relating to dehydration is carried out at 50°C to 120°C preferably at 80°C to 90°C. A suitable solvent includes but are not limited to aromatic hydrocarbons such as toluene, xylene, n-hexane, n-heptane and cyclohexane and the like preferably toluene or xylene. The amount of solvent that preferably used is 2 to 5 volume to compound of (If). The reaction may be carried out for time periods ranging from about 30 minutes to about 3 hours, or longer.

One of the embodiments of present invention provides reduction of Compound of formula (Ig) with suitable reducing agent in present of solvent, which is converted to its hydrochloride salt by IPA/ HCI to yield the compound of formula (Ih),

(ig) (Ih)

Reducing agents that may be used in this step of this process include but are not limited to Pd on carbon, raney nickel, or Pd(OH) ₂ under a hydrogen atmosphere. The reduction process of this step may be carried out in a presence of a solvent, including alcohols solvents such as methanol, ethanol, tert-butyl alcohol, or the like. The reduction may be carried out a temperature ranging from about 0°C to about 75°C or higher or about 20 to 40, based on the reagents.

Compound of formula (Ig) is treated with aq. NaOH solution and raney Ni/H ₂ . Hydrogen gas is applied up to 7 to 9 kg. The amount of raney Ni is preferably used 0.1 to 0.4 times to compound of formula (Ig). The amount of solvents that preferably used for the reaction is 8 to 10 times to compound of formula (Ig). The reaction is carried out at 50 to 100 °C preferably at 20 to 40 °C.

The obtained amine is treated with I PA. Hcl to obtain hydrochloride salt of amine

(Ih).

One of the embodiments of present invention provides a process for the preparation of Agomelatine comprising a step of converting compound of formula (Ih) to compound of formula (I) by acylation with acetic anhydride or acetyl chloride in the presence sol

Compound of formula (Ih) is dissolved in a mixture of toluene and water and then treated with aq. NaOH solution. The resultant organic layer is separated and distilled off the solvent the obtained residue is dissolved in acetic acid at 25 to 45°C. Acetic anhydride is added drop wise over a period of 30 to 60 minutes. Reaction temperature is about 30 to 50°C. For the extraction of compound of formula (I) water is used.

Further embodiment of the present invention is to provide process for the preparation of Agomelatine in pure crystalline form I, comprising the steps of;

i) providing a solution of Agomelatine in organic amine or mixture there of ii) adding solution of organic acid and water to the solution obtain in step (i) iii) optionally seeding crystals of form I

iv) isolating the crystals of the polymorphic form I of Agomelatine.

Furthermore, the crystals of polymorph form I of Agomelatine obtained by the process of the present invention have a specific surface and are therefore less hygroscopic than the crystals of polymorph form I of Agomelatine obtained by other processes.

Providing a solution in step i) include obtaining a solution of Agomelatine in organic amine or in a mixture of organic amine and water. Suitable organic amines that may be used for this step includes but are not limited to primary amine such as t-butyl amine, ammonia, propyl amine, methyl amine; secondary amine such as diethylamine, dimethyamine, methylethylamine, tertiary amine such as triethyl amine, tertiary butyl amine.

The temperature at which solution of Agomelatine prepared in organic amine is cooled, is not particularly restricted, but usually the temperature is in the range of 10°C to -80 °C, preferably 0 °C to -20 °C.

Step (ii) involves adding solution of organic acid and water to the solution obtains in step (i). Suitable organic acids that may be used for this step includes but are not limited to formic acid, acetic acid, propionic acid, butyric acid, lactic acid, preferred organic acid is propionic acid.

The process of step (ii) may be carried out in the presence of water, and the reaction may be carried out at temperature ranging from about 0°C to about -60°C, or about 0°C to about -20°C.

The solution obtained in step (iii) may be seeded with form I of Agomelatine crystals and may be cooled to a temperature below 10°C to precipitate the solid. In embodiments, the solution may be cooled to temperatures about 0°C to about 5°C.

Step (iv) involves isolating the crystals of the polymorphic form I of Agomelatine.

Drying may be suitable carried out using any equipment at atmospheric pressure or under reduced pressures, at temperatures less than about 70°C, less than about 50°C less than about 30°C and any other suitable temperatures. The drying may be carried out at any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours or longer.

The polymorphic form I of Agomelatine can be reliably obtained by an easy process in excellent reproducibility using process of present invention. The obtained polymorph form I of Agomelatine has a chemical purity of preferably 98% or more, more preferably 99% or more, in particular 99.5% or more, such as 99.8% or more. The obtained polymorphic form I of Agomelatine is pure crystalline form I, which is not contaminated with other crystalline form. The obtained polymorph from I of Agomelatine preferably has a low hygroscopic, and with the process of the invention Agomelatine of polymorph form I is obtained in the form of crystals having a very narrow particle size distribution

In the process of present invention seed crystal means crystals of form I of Agomelatine obtained by the prior art process or by the process of the present invention (Example I). It was also unexpectedly found that a very high reproducibility of the product characteristics can be obtained by seeding of the solution with seeds consisting of Agomelatine in crystalline form I.

The Agomelatine obtained by the process of the present invention is the polymorph form I of Agomelatine which is known from Acta Cryst. (1994), C50, 907-910. Regarding the details and the definition of the crystal form, it is referred to this document. The polymorph form I of Agomelatine can also be characterized by its powder diffraction diagram. An XRPD of form I that has been obtained by the process of the present invention is enclosed as figure I.

The process of present invention is depicted in below scheme.

The following example illustrates the invention further. It should be understood however, that the invention is not confined to the specific limitations set forth in the individual example but rather to the scope of the appended claims.

Examples Example-I- Preparation of N-[2-(7-methooxynaphthyk)ethyl]acetamide

A. Preparation of 2-(7-methoxy-1 ,2,3,4,-tetrahydro -1 -naphthylidine) acetic acid

A mixture of 7-methoxy-1 -tetralone (100g), tri ethyl phosphono acetate (184.48 g) and ter. Butanol (200 ml) was stirred at ambient temperature. Potassium tert. butoxide (95.51 g) was added portion wise to the stirred solution and the reaction mixture was heated at 85 to 90 °C for three hours. Potassium hydroxide (44. 57 g) was added to the reaction mixture and stirred for 2 hrs at 85 to 90°C. The solvent was distilled out completely under vacuum; 500 ml water was added to the residue. The mixture was cooled 10-15 ° C and acidified with cone. HCI, the precipitate was isolated and purified by toluene. There was thus obtained 2-(7-methoxy-1 ,2,3,4,-tetrahydro -1 -naphthylidine) acetic acid (yield 72%, HPLC purity 98%).

B. Preparation of 2-(7-methoxy-1 -naphthyl) acetic acid

A mixture of 2-(7-methoxy-1 ,2,3,4,-tetrahydro -1 -naphthylidine) acetic acid (100gm), water(600 ml), sodium bicarbonate (100 gm), acrylic acid (49.50 g) and Pd/C (3.0 g) was heated at 100-105 ° C for 12 hrs. Reaction mixture was cooled, filtered. The mixture was partitioned between toluene and water. The aqueous phase, cooled at 10 to 15 ° C and acidified with cone. HCI. the precipitate was isolated and dried to obtain 2- (7-methoxy-1 -naphthyl) acetic acid (Yield 95 %, HPLC purity 99%).

C. Preparation of 2-(7-methoxynaphthyl) acetonitrile

A mixture of 2-(7-methoxy-1 -naphthyl) acetic acid (100g), Dichloro methane(500 ml). Dimethyl formamide(l ml), thionyl chloride 65.98 g was stirred and heated to 35 to 40 °C 1 hr. The solvent was distilled out completely under vacuum. Toluene (800 ml) was added to the residue, ammonia gas was purged at 0-5 °C till pH 10-1 1. After the completion of reaction, reaction mixture was heated at 45-50°C. Cooled the reaction mass, filtered the solid, washed with toluene.

The materials so obtained, Phosphorous oxychloride (85.08 g) and toluene (500 ml) was stirred and heated at 85 °C for 2 hrs. The mixture was partitioned between water and toluene. Organic phase was washed with aq. NaHCO3 solution. The solvent was distilled out completely under vacuum. Toluene (50 ml), methanol (200 ml) was added to the residue and cooled 5- 10 °C. Filtered the solid and washed with methanol and dried to obtained 2-(7-methoxynaphthyl) acetonitrile (Yield 91 %, HPLC purity 99.5%).

D. Preparation of 2-(7-methoxynanphthyl)ethanamine hydrochloride

A mixture of 2-(7-methoxynaphthyl) acetonitrile (100g), methanol (800 ml), aq. sodium hydroxide (30.42 g sodium hydroxide in 100 ml water), 20 g of Raney Ni stirred in hydrogen atmosphere (apply H2 gas up to 10 kg) at 25 to 30 °C for 2-3 hrs. Filtered the reaction mixture, distilled out solvent completely under vacuum. IPA is added to the residue and heated at 50 to 55 °C, IPA HCI added at 50 to 55 °C and stirred for one hour. Cooled the reaction mixture at 10-15°C, filtered the solid, washed with IPA and dried. There was thus obtained 2-(7-methoxynanphthyl)ethanamine hydrochloride (Yield 90%, HPLC purity 99.5 to 99.9 %)

E. Preparation of Preparation of N-[2-(7-methoxynaphthalene-1-yl)ethyl]acetamide

A mixture of 2-(7-methoxynanphthyl)ethanamine hydrochloride (10 g), toluene (50 ml), water (50 ml), aq. sodium hydroxide (2 gm sodium hydroxide in 10 ml water) stirred 15 minutes at 20 -25 °C. The mixture was partitioned between water and toluene. Organic phase was washed with brine solution and solvent was distilled out completely under vacuum, acetic acid (30 ml) is added to the residue and heated at 35 to 40 °C. Acetic anhydride (5. 14g) is added drop wise at 35-40 °C and stirred for 1 hour. Water (30 ml) was added 35-40 °C and stirred for 1 hour, cooled the reaction mixture at 10-15 °C and stirred for 1 hour. The solid was filtered. There was thus obtained N-[2-(7- methoxynaphthalene-1 -yl)ethyl]acetamide (Yield 90%, HPLC purity 99.5 to 99.9 %) (XPRD: form 1 , equivalent to figure 1 )

Example-ll: Preparation of crystalline form I of Agomelatine

A mixture of Agomelatine (100 g), tertiary butyl amine (346.3 ml), and water was stirred and cooled to 0 °C to -10 °C. A pre dissolved solution of propionic acid (220 ml) in water (600 ml) was added to the above solution at °C to -10 °C. The crystallization started immediately and after the addition of solution of propionic acid, the reaction mixture was stirred at 0 °C to -10 °C for 30 minutes. Obtained crystals of form I were collected by filtration and dried for 10 hrs at 40-45 °C. Yield (80-87 g, 85 %). HPLC purity 99.7 to 99.9%. XPRD: form 1 depicted in figure 1.

Example-Ill: Preparation of crystalline form I of Agomelatine

A mixture of Agomelatine (100 g), tertiary butyl amine (346.3 ml), and water was stirred and cooled to 0 °C to -10 °C. A pre dissolved solution of propionic acid (220 ml) in water (600ml) was added to the above solution at °C to -10 °C. After the 30% addition of propionic acid solution, the solution was seeded with crystals of Agomelatine Form-I (0.05g) at 0 °C to -10 °C. The crystallization started immediately and after the addition of solution of propionic acid, the reaction mixture was stirred at 0 °C to -10 °C for 30 minutes. Obtained crystals of form I were collected by filtration and dried for 10 hrs at 40-45 °C. Yield (90 g, 89%). HPLC purity 99.7 to 99.9%. XPRD: form 1 depicted in figure 1.

Example IV: Preparation of crystalline form-ll

A mixture of form I (100 g) and Di isopropyl ether (300 ml) was stirred at 50-60 °C for one hour. Cooled the reaction mixture at 10-20 °C and stirred. Obtained crystals of form II were collected by filtration and dried. Yield (97 g, 95 -97%). HPLC purity 99.7 to 99.9%.

Example V: Preparation of crystalline form-ll

A mixture of form I (100 g) and cyclohexane (300 ml) was stirred at 50-60 °C for one hour. Cooled the reaction mixture at 10-20 °C and stirred. Obtained crystals of form II were collected by filtration and dried. Yield (97 g, 95 -97%). HPLC purity 99.7 to 99.9%.