WO2008062468A2

WO2008062468A2 - Process for the preparation of optically pure indeno [5,4-b] furan derivatives

Info

Publication number: WO2008062468A2
Application number: PCT/IN2007/000491
Authority: WO
Inventors: Sanjog Ramdharane; Tejas Chandrakant Shah; Jayesh Mohanlal Pandya; Manoj Kumar Singh; Virendra Kumar Agrawal
Original assignee: Cadila Healthcare Ltd
Current assignee: Zydus Lifesciences Ltd
Priority date: 2006-10-26
Filing date: 2007-10-15
Publication date: 2008-05-29
Anticipated expiration: 2009-04-26
Also published as: WO2008062468A3

Abstract

The present invention relates to a novel and efficient method for the preparation of chirally active indeno[5,4-b]furan derivatives, which includes separation of chirally pure intermediates and / or racemic Ramelteon in its pure isomeric form and free from other impurities, by the separation of isomers using chiral and/or achiral stationary phases for batch process, super-critical or sub-critical chromatography and/or continuous process chromatography.

Description

PROCESS FOR THE PREPARATION OF OPTICALLY PURE INDENO[5,4-b] FURAN DERIVATIVES

FIELD OF INVENTION The present invention relates to process for the preparation of (-)-(S)-N-[2-

(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide (RAMELTEON) in its pure isomeric form and free from its enantiomeric isomer. BACK GROUND OF INVENTION

The present invention relates to process for the preparation of (-)-(S)-N-[2- (l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide (RAMELTEON) (I) in its pure isomeric form and free from its enantiomeric isomer.

1

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MTl and MT2 receptors and selectivity over the MT3 receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MTl or MT2 receptors, and high selectivity for human MTl and MT2 receptors compared to the

MT3 receptor.

Ramelteon is a selective melatonin receptor agonist that has demonstrated efficacy in the treatment of insomnia characterized by difficulty with sleep onset. Approximately one in three American adults complain of some type of insomnia and 20 million Americans suffer from chronic insomnia. It is characterized by difficulty falling asleep, difficulty staying asleep, or poor quality sleep, leading to impairment of next day functioning. Insomnia has been linked to a variety of health problems, including obesity, diabetes, hypertension, heart disease, and depression. Ramelteon is the first and only prescription sleep medication that has shown no evidence of abuse and dependence, and as a result, has not been designated as a controlled substance by the DEA. Its approval also allows physicians to prescribe ramelteon for long-term use in adults. Ramelteon provides a unique therapeutic mechanism of action for therapy of insomnia and represents a new treatment option. However, clinical comparisons with other hypnotic agents are not available and will be needed to better differentiate these products.

Our objective is to prepare either racemic Ramelteon (±)-l or it's intermediate 2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine (+)-(2) and separations of desired isomers of either (1) or (2) using chiral and/or achiral stationary phases for batch process, super-critical or sub-critical chromatography and/or continuous process chromatography.

United State patent 6,034,239 reports formation of chiral intermediate (-)-(S)-N- [2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)]ethylamine (S)-2 by the catalytic asymnjetric hydrogenation of 2-(l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8- ylidene)ethylamine (3) in the presence of catalytic amount of BINAP -ruthenium complex in approximately 89% ee followed by purification by preparing acid salt and its condensation with propionyl chloride to get Ramelteon (1) in pure form.

An alternate process for preparing Ramelteon is reported in JMC, 45,

4222-4239 (2002). Herein the exo double bond of the intermediate (A) was asymetrically reduced using (S)-2,2'-bis-(diphenylphosphino)-l,r-binaphthyl (binap)- Ru complex as the catalyst to obtain enantiomerically pure compound (B). Compound (B) is subsequently converted to (S)-(-) Ramelteon (1) through intermediate steps of Claisen condensation, ozonolysis and finally cyclization.

Thus both the above process uses expensive catalyst and involves very sophisticated reaction conditions which make them commercially less viable. Therefore, there exists a need to develop a process for obtaining Ramelteon in an enantiomerically pure form which is cost effective, uses easily available reagents, is scalable with ease and overall commercially more viable. We herein disclose such a process. The process is provided in the following Scheme 1 below:

Objects of the invention

It is an important object of the present invention to provide a process for the preparation of Ramelteon (1) with the use of easily and commercially available hydrogenation methods, avoiding the use of sophisticated and fancy catalysts and separations of desired isomer using techniques such as preparative chromatography using chiral and/or achiral stationary phases for batch process, super-critical or sub- critical chromatography and/or continuous process chromatography.

In another embodiment is provided a process for the preparation of the intermediate (2) in its enantiomeric forms with the use of easily and commercially available raw materials, avoiding the sophisticated and fancy catalysts and subsequent separations of desired isomer using easily available and commercially viable techniques such as optical resolution or preparative chromatography using chiral and/or achiral stationary phases for batch process, super-critical or sub-critical chromatography and/or continuous process chromatography. The pure enantionmer S-(2) may be suitably alkylated using suitable alkylating agent to provide enantiomerically pure compound of formula (1). In a further embodiment is provided a process of reduction of intermediate (3) for the preparation of compound of structural formula (2) in its racemic form, and separations of desired isomer of intermediate (2) by easily available and commercially viable and versatile techniques such as preparative chromatography using chiral and/or achiral stationary phases for batch process, super-critical or sub-critical chromatography and/or continuous process chromatography. The pure enantionmer S- (2) may be suitably alkylated using suitable alkylating agent to provide enantiomerically pure compound of formula (1).

In an embodiment of the present invention is provided a process comprising the reduction of intermediate (3) for the preparation of compound of structural formula (2) in its racemic form, followed by its condensation of propionyl chloride (4) to get racemic Ramelteon (1) and separation of desired isomer by easily available and commercially viable techniques such as preparative chromatography using chiral and/or achiral stationary phases for batch process, super-critical or sub-critical chromatography and/or continuous process chromatography. In another embodiment of the present invention is provided a process involving condensation of propionyl chloride (4) with compound of formula (3), followed by reduction to get racemic Ramelteon (1) and separation of desired isomer by easily available and commercially viable techniques such as preparative chromatography using chiral and/or achiral stationary phases for batch process, super-critical or sub- critical chromatography and/or continuous process chromatography. The above and other embodiments of the present invention are provided in details below. DESCRIPTION OF THE INVENTION

Chiral separation is always a big challenge for the scientists worldwide. Most of the biologically active molecules, which have chiral centers, are now accepted as the pure enantiomer or diastereoisomer only. In chiral active molecules, one enantiomer or diastereoisomer is frequently more active or has fewer side effects than the other. Obtaining the desired enantiomer or diastereoisomer as selectively as possible and as pure as possible is therefore of great importance in the case of chirally active molecules. One of the process for preparing enantiomerically pure Ramelteon involves - separation and subsequent removal of unwanted enantiomer from the intermediate N-[2-(l,6₅7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)]ethylamine (2) to get its pure and single isomer; - and its condensation with propionyl chloride to get chirally pure Ramelteon (1).

The separation of pure enantiomers of intermediate (2) is carried out either by optical resolution of racemic amine intermediate (2) by preparing acid salts with chirally pure acids followed by crystallization of salts and isolation of product (2) as a single isomer or by easily available and commercially viable techniques such as preparative chromatography using chiral and/or achiral stationary phases for batch process, super-critical or sub-critical chromatography and/or continuous process chromatography. An alternate process for preparing enantiomerically pure Ramelteon involves condensation of racemic amine intermediate N-[2-(l,6,7,8-tetrahydro-2H- indeno[5,4-b]furan-8-yl)]ethylamine (2) with propionyl chloride (4) to prepare

Ramelteon (1) in its racemic form; separation of pure enantiomer from racemic mixture by using easily available and commercially viable techniques such as preparative chromatography using chiral and/or achiral stationary phases for batch process, super-critical or sub-critical chromatography and/or continuous process chromatography.

Another novel process for preparing enantiomerically pure Ramelteon according to the present invention involves reduction of compound of structural formula (3) to prepare amine intermediate (2) as racemic mixture; - followed by separation of pure enantiomers of intermediate (2) either by optical resolution of racemic amine intermediate (2) by preparing acid salts with chirally pure acids followed by crystallization of salts and isolation of product (2) as a single isomer or by easily available and commercially viable techniques such as preparative chromatography using chiral and/or achiral stationary phases for batch process, super-critical or sub-critical chromatography and/or continuous process chromatography.

The compound of formula (2) may be prepared in racemic form by reduction of intermediate (3) by techniques known in the art, which may be subsequently be converted to racemic Ramelteon (1) by condensation with propionyl chloride (4). The desired pure isomer of (1) is subsequently obtained by either optical resolution or preparative chromatography using chiral and/or achiral stationary phases for batch process, super-critical or sub-critical chromatography and/or continuous process chromatography.

An alternate process for preparing compound of formula (3) involves reduction of the cyano group in compound of molecular formula (5) to the intermediate (3) which may be converted to enantiomerically pure Ramelteon by any one or more suitable process(es) from those disclosed above.

Thus, a key step in the present invention is the separation of compound of formula (2) or (1) to their two enantiomers.

(+)-(R)-N-[2-(1 ,6,7,8-tetrahydro-2H-indeno[5,4-b] (-)-(S)-N-[2-(1 ,6,7,8-tetrahydro-2H-indeno[5,4-b] furan-8-yl)]ethylamine furan-8-yl)]ethylamine

The separation of desired enantiomers are achieved by using chiral and/or achiral stationary phases either normal and/or reverse phase HPLC stationary chromatography. The composition of mobile phase is such that after getting pure enantiomer of desired intermediate (2) or final product (1) in said mobile phase composition; solvent removal and subsequent product recovery are achieved by simple operations. Accordingly, the separation of both the isomers of intermediate (2) are performed in a way suitable for use in batch process of preparative HPLC chromatography, super-critical or sub-critical chromatography and / or continuous preparative separations such as simulated moving bed, etc to get (S)-(2) substantially free from (R)-(2). The amount of (R)-(2) present in (S)-(2) is to be preferably less than 1.0% and more preferably below detection limit.

In an other option of the present invention, the separation of both the isomers of intermediate (2) are performed with a view to use it for batch process of preparative HPLC chromatography super-critical or sub-critical chromatography and/or continuous preparative separations such as simulated moving bed, etc to get (R)-(2) substantially free from (S)-(2). The amount of (S)-(2) present in (R)-(2) is to be preferably less than 1.0% and more preferably below detection limit.

•In a typical experiment, Amylose tris(3,5-dimethylphenylcarbamate) coated on 5 micron silica gel substrate is selected as chiral stationary phase for separation of (R)- (2) and (S)-(2). Mobile phase is selected from C₁-C₆ linear or branched alcohols, hydrocarbons such as n-hexane, n-heptane, toluene, benzene or their suitable mixtures, preferably a mixture of n-hexane and ethanol in varying proportions in presence of a suitable base. Flow rate is adjusted from 0.7 mL per minute onwards. Detection is done at 225nm. Retention times varies from 14.5 - 16.5 minutes for one enantiomer and 18.5 - 20.5 minutes for another enantiomer. Retention time of (S)-(2) and (R)-(2) is further adjusted as per the requirement by varying mobile phase composition and flow rate as described above.

When racemic Ramelteon (1) is resolved, the separation of both the isomers of product (1) are performed in a way suitable for use in batch process of preparative HPLC chromatography, super-critical or sub-critical chromatography and / or continuous preparative separations such as simulated moving bed, etc to get (S)-(I) substantially free from (R)-(I). The amount of (R)-(I) present in (S)-(I) is to be preferably less than 1.0% and more preferably below detection limit.

Alternatively, the separation of both the isomers of product (1) are performed with the view to use it for batch process of preparative HPLC chromatography, supercritical or sub-critical chromatography and/or continuous preparative separations such as simulated moving bed, etc to get (R)-(I) substantially free from (S)-(I). The amount of (S)-(I) present in (R)-(I) is to be preferably less than 1.0% and more preferably below detection limit. In a typical experiment, Amylose tris(3,5-dimethylphenylcarbamate) coated on

5 micron silica gel substrate is selected as chiral stationary phase for separation of (R)- (1) and (S)-(I). Mobile phase is selected from C₁-C₆ linear or branched alcohols, hydrocarbons such as n-hexane, n-heptane, toluene, benzene or their suitable mixtures, preferably a mixture of n-hexane and isopropanol in varying proportions. Flow rate is adjusted from 1.0 mL per minute onwards. Detection is done at 210nm. Retention times are varied from 10.7 - 12.7 minutes for one enantiomer and 15.4 - 17.4 minutes for another enantiomer. Retention time of (S)-(I) and (R)-(I) is further adjusted as per the requirement by varying mobile phase composition and flow rate as described above. Thus, the invention provides a process for the separation of both the isomers of product (1) by using achiral stationary phase for batch process of preparative HPLC chromatography, super-critical or sub-critical chromatography and / or continuous preparative separations such as simulated moving bed, etc to get (S)-(I) and (R)-(I) independently in their pure form and free from each other epimers.

With the expression " optically pure (S)-isomer " is meant the (S)-isomer of intermediates and/or product which is substantially free of the (R)-isomer of intermediates and/or product. Optically pure (S)-isomer of intermediates and/or product which is substantially free from the (R)-isomer of intermediates and/or product is meant to have content of (R)-isomer of intermediates and/or product in (S)-isomer of intermediates and/or product less than 10%, preferably less than 1%, more preferably less than 0.5% and most preferably less than below detection limits.

According to the present invention, there is provided a process for increasing the proportion of (S)-isomer of amine intermediate (2) in its R/S-isomer mixture, which comprises subjecting the R/S-isomer mixture of amine intermediate (2) to chromatography using a chiral and/or achiral stationary phases. The chirally pure single isomer of amine intermediate (2) further undergoes acylation with (4) to afford pure

Ramelteon as the single isomer and substantially free from its epimers at asymmetric carbon position. According to the present invention, there is provided a process for increasing the proportion of (S)-isomer of Ramelteon (1) in its R/S-isomer mixture, which comprises subjecting the R/S-isomer mixture of Ramelteon (1) to chromatography using a chiral and/or achiral stationary phases. The chirally pure single isomer of Ramelteon (1) obtained is substantially free from its epimers at asymmetric carbon position.

The chiral stationary phase according to the invention comprises an optically active high molecular compound, e.g. a polysaccharide derivative, such as esters or carbamates of cellulose or amylose, a polyacrylate derivative [e.g. a methacrylate derivative, such as poly(triphenylmethylmethacrylate)]or a polyamide derivative, a protein with an asymmetric or disymmetric chain (bovine serum albumin bonded to silica, cellulase covalently bonded to aldehyde silica), polymers with an asymmetric centre in its side chains etc. Another possibility is a chiral stationary phase comprising a low molecular weight compound having optical resolution capability, e.g. crown ethers ((S) or (R)-18-crown-6-ether on silica) and cyclodextrin derivatives (alpha cyclodextrin bonded to silica).

Other important chiral separation agents, which are included in the term 'chiral stationary phase', are suitable amino acids and derivatives thereof, esters or amide of amino acids, acetylated amino acids and oligopeptides.

Still another possibility is a particulate polysaccharide material, e.g. microcrystalline cellulose triacetate. Chiral stationary phases including polysaccharide derivatives and polyamides useful for separation of enantiomers as described in EP 0

, 147 804, EP 0 155 637, EP 0 157 365, EP 0 238 044, WO 95/18833, WO 97/04011, EP 0656 333 and EP 718 625 are considered to be within the scope of the present invention.

Particles of polysaccharides useful for the separation of optical enantiomers as described in EP 0706982 may be used along with suitable alternations/variations as may be necessary and are within the scope of a person skilled in the art. Preferably, the chiral stationary phase comprises a carbohydrate derivative, more preferred a polysaccharide derivative and most preferred an amylose or cellulose derivative.

Suitably, the polysaccharide adsorbed on the silica gel as is required for the present invention carries groups such as phenylcarbamoyl, 3,5-dimethyl- phenylcarbamoyl, 4-chlorophenylcarbamoyl, 3,5-dichlorophenylcarbamoyl, acetyl, benzoyl, cinnamoyl, 4-methylbenzoyl or S-α-phenylethyl carbamoyl.

Preferably, the carbohydrate derivative comprises phenyl carbamate substiruents, which optionally may be substituted with one or more C, 4- alkyl groups, preferably methyl groups.

The chiral compound, which is the chiral separating factor of the stationary phase, may suitably be adsorbed on a carrier, such as silica gel. Suitably, the chiral stationary phase is Chiralpak™ AD-H, a silica gel supported amylose derivative wherein the majority of the hydroxyl groups are substituted with 3,5-dimethylphenyl carbamate groups, or Chiralcel™ OD, a silica gel supported cellulose derivative wherein the majority of the hydroxyl groups are substituted with 3,5- dimethylphenyl carbamate groups. Chiralpak™ AD-H and Chiralcel™ OD. Exemplary of such chiral stationary phases is Chiralpak™ AD-H.

Any liquid chromatographic separation method may be used for the separation of the diastearomers. Preferably, the chromatographic separation method comprises a continuous chromatographic technology, suitably simulated moving bed technology, preparative HPLC.

The eluent is typically selected from the group comprising acetonitrile, THF, alcohols, such as methanol, ethanol or isopropanol, and C₅-C₈ alkanes which may be linear or branched aliphatic or cyclic alkanes and selected from cyclopentane, cyclohexane, hexane, heptane, octane, and mixtures thereof.

An acid such as formic acid, acetic acid and trifiuoroacetic acid and/or a base such as diethyl amine, triethyl amine, propyl amine, isopropyl amine, diisopropylethyl amine and dimethylisopropyl amine optionally may be added to the eluent. Alternatively, super or sub critical carbon dioxide containing a modifier may be used as eluent. The modifier is selected from lower alcohols such as methanol, ethanol, propanol and isopropanol. An amine, such as diethyl amine, triethyl amine, propyl amine, isopropyl amine, diisopropylethyl amine and dimethylisopropyl amine and optionally an acid, such as formic acid, acetic acid and trifiuoroacetic acid may be added.

Suitably, the chromatographic method used is a liquid chromatographic method.

A suitable eluent according to this embodiment of the invention is alcohol such as ethanol, isopropanol in mixture with alkanes such as cyclopentane, cyclohexane, and hexane. A suitable mixture contains alkanes 70% vol to 95% vol and alcohol 30% vol to 5% vol.

As used herein, with respect to a measured quantity, the term "about" indicates variations in the measured quantity as would be expected by the skilled artisan making the measurements or determination and exercising a level of care commensurate with the objective of the measurement and the precision of the measuring apparatus being used.

The examples mentioned below demonstrates further the preferred aspects of the present invention. The examples are given to illustrate the details of the invention and should not be construed to limit the scope of the present invention.

Example - 1 Separation of enantiomers of compound (2) using chiral stationary phase

500 ppm of 2 having approximately 50% (S)-2 and 50% (R)-2 in n-hexane, ethanol and diethyl amine in the ratio of 90%, 10% and 0.1% respectively was injected on CHIRALPAK AD-H and the mobile phase composition is same throughout analysis with flow rate 0.7 niL per minute with detection at 225 nm, retention times was 15.1 minutes for one enantiomer and 19.5 minutes for another enantiomer.

Example - 2

Separation of enantiomers of(l) using chiral stationary phase 500 ppm of 1 having approximately 50% (S)-I and 50% (R)-I in n-hexane and isopropanol in the ratio of 90% and 10% respectively was injected on CHIRALPAK AD-H and the mobile phase composition is same throughout analysis with flow rate 1.0 mL per minute with detection at 210 nm, retention times was 11.7 minutes for one enantiomer and 16.4 minutes for another enantiomer. Example - 3

Separation of enantiomers of compound (2) on Preparative HPLC using chiral stationary phase

2.0 gm of compound 2 having approximately 50% (S)-2 and 50% (R)-2 was dissolved in 50 mL of solution of cyclohexane (60%) and isopropanol (40%). 50 Injections of 1 mL solution each, containing approximately 40 mg racemic compound each were injected to the preparative HPLC column having chiral stationary phase [Kromasil, Cellucoat - 5μ, dimensions 21.2 x 250 mm] and eluted with the same solution [Mixture of Cyclohexane (60%) and Isopropanol (40%)] with flow rate of 10 mL per minutes with detection at 225nm. Both the enantiomers were collected separately and after evaporation of solvent under vacuum enentiomerically pure (S)-2 was obtained as 790 mg and (R)-2 was obtained as 770 mg.

Example - 4

Separation of enantiomers of compound (1) on Preparative HPLC using chiral stationary phase 2.0 gm of compound 1 having approximately 50% (S)-I and 50% (R)-I was dissolved in 50 mL of solution of Cyclohexane (60%) and Isopropanol (40%). 50 Injections of 1 mL solution each, containing approximately 40 mg racemic compound each were injected to the preparative HPLC column having chiral stationary phase [Kromasil, Cellucoat - 5μ, dimensions 21.2 x 250 mm] and eluted with the same solution [Mixture of Cyclohexane (60%) and Isopropanol (40%)] with flow rate of 12 mL per minutes with detection at 210 nm. Both the enantiomers were collected separately and after evaporation of solvent under vacuum enentiomerically pure (S)-I. was obtained as 650 mg and (R)-i_was obtained as 670 mg. Example — 5

Preparation of ChiraUy pure enantiomers of compound (1) using Chirally pure

Enantiomer of Compound (2)

ChiraUy pure compound - 2 (500 mg) was dissolved in dichloromethane (10 mL), to it was addes a solution of triethyl amine (273 gm) in dichloromethane (10 niL) and the reaction mass was stirred for 30 minutes. To the reaction mixture was added propionyl chloride (0.34 mg) at ambient temperature. The reaction mass was stirred for

1 hr at ambient temperature. Aqueous layer was again extracted with dichloromethane, all the organic layers were combined and washed with water, the organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to get solid residue which is recrystallized with a mixture of ethyl acetate and cyclohexane (1:1) to get 310 mg of desired product

Example - 6

Preparation ofRacemic Compound (2) Compound 5_(50 gm) was dissolved in a methanolic solution of ammonia (25 gm ammonia in 500 mL methanol), and to the solution was charged Raney Nickel (approximately 25 gm). The reaction mixture was hydrogenated under stirring for 12 hr at 2 bar pressure. Completion of reaction was monitored by TLC. The reaction mixture was filtered through hyflow bed and the solvent was removed in vacuo to get product 3 as an oily residue (50 gm).

The oily residue was dissolved in fresh methanol (500 mL) and hydrogenated in the presence of 5 % Pd/C (2.5 gm) under stirring for 2 hrs at 5 bar pressure. The reaction mixture was filtered through hyflow bed and evaporation of solvent under vacuum give product 2 (42 gm) as oily residue. The oily residue was purified by salt preparation with IPA-HCl (150 mL), crystallization of the salt, subsequently basifying the solution, extracting the product in dichloromethane and evaporation of solvent to give 18 gm of pure compound 2_as a racemic mixture.

It will be appreciated that several modifications and improvements of the disclosed invention are possible and within the scope of those of skilled in the art. Such modifications, improvements should be construed to be part of the present invention.

Claims

We claim:

1. A process for preparing enantiomerically pure Ramelteon (S)-I comprising the steps of i) reacting a compound of formula (2) either in racemic or enantiomerically pure form with propionyl chloride (4) to obtain Ramelteon (1) with retention of configuration;

ii) separating the pure (S)-I by use of chiral and/or achiral stationary phase and concurrent removal of another enantiomer, recovering desired isomer by removing solvent and isolating desired product.

2. The process as claimed in claim 1 wherein the separation is carried out using techniques selected from optical resolution or batch process, super-critical or sub- critical chromatography and / or continuous process chromatography.

3. A process as claimed in claim 1 wherein the undesired enantiomer content is preferably less than 1.0 % and more preferably below detection limits.

4. A process as claimed in claims 1- 3 wherein the mobile phase is selected from C₁-C₆ linear or branched alcohols, hydrocarbons selected from n-hexane, n-heptane, toluene, benzene or their suitable mixtures.

5. A process as claimed in claims 1- 3, wherein the batch process chromatography is performed using preparative HPLC.

6. A process as claimed in claims 1— 3, wherein the chiral and/or achiral stationary phase is carried out using liquid chromatography or super or sub critical chromatography.

7. A process as claimed in claims 1— 3, wherein the continuous process chromatography is accomplished using simulated moving bed chromatography.

8. A process of claim 1, wherein the compound of formula (2) is further separated to its enantiomers comprising the use of chiral and/or achiral stationary phase and concurrent removal of another enantiomer, recovering desired isomer by removing solvent and isolating desired product.

9. The process as claimed in claim 8 wherein the separation is carried out using either optical resolution or batch process, super-critical or sub-critical chromatography and / or continuous process chromatography.

10. The process of claim 8 wherein the undesired enantiomer content preferably is less than 1.0 % and more preferably below detection limits.

11. The process as claimed in claim 8, wherein the mobile phase is selected from C₁-C₆ linear or branched alcohols, hydrocarbons selected from n-hexane, n-heptane, toluene, benzene or their suitable mixtures.

12. The process as claimed in claim 8 wherein the batch process chromatography is performed using preparative HPLC.

13. A process as claimed in claims 8, wherein the chiral and/or achiral stationary phase is carried out using liquid chromatography or super or sub critical chromatography.

14. A process as claimed in claims 8, wherein the continuous process chromatography is accomplished using simulated moving bed chromatography.

15. A process of claim 8 wherein the pure enantiomer (S)-2 is further converted to Ramelteon (S)-I by reacting with compound of formula 4 as claimed in claim 1.