FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
IMPROVED PROCESS FOR THE PREPARATION OF
ESZOPICLONE
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANIES ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM
BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI
(WEST), MUMBAI -400 102, MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

TITLE OF THE INVENTION
Improved process for the preparation of Eszopiclone
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an improved and environmentally friendly process for the preparation of (+)-(5S)-6-(5-chloro-2-pyridyl)-5-[(4-methyl-l-piperazinyl) carbonyloxy)-7-oxo-6,7-dihydro-5-H-pyrrolo[3,4-b] pyrazine, commonly known as Eszopiclone.
BACKGROUND OF THE INVENTION
Eszopiclone is a pyrrolo[3,4-b] pyrazine derivative used for inducing hypnotic, sedative and tranquilizing effect in humans. Chemically eszopiclone is (+)-('5S)-6-(5-chloro-2-pyridyl)-5-[(4-methyl-l-piperazinyl) carbonyloxy]-7-oxo-6.7-dihydro-5-H-pyrrolo[3,4-b| pyrazine and is a dextrorotatory isomer of Zopiclone.
Eszopiclone is marketed in United States under the brand name Lunesta by Sepracor and is represented by formula I below


Unites States Patent No 6,444,673 Bl (Nov.. 2000, Claude et al) covers the dextro-rotatory isomer of Zopiclone or its pharmaceutically acceptable salts. The '673 patent teaches a method of resolution of Zopiclone to obtain Eszopiclone. The said method discloses the use of D (+)-0, O'-Dibenzoyltartaric acid monohydrate for resolution and the dextrorotatory isomer obtained was crystallized from acetonitrile. To crystallize the dibenzoyltartrate salt large amount of acetonitrile is required. To achieve the desired chiral purity, it was again recrystallized using a mixture of dichloromethane and acetonitrile To increase the throughput at the commercial scale it felt a need to improve the resolution process.
US Patent No 3,862, 149 (Dec, 1972, Claude et al) discloses the method for the preparation of Zopiclone by the reaction of 6-(5-chioropyrid-2-yI)-5-hydroxy-7-oxo-5.6-dihydropyrrolo [3,4-b] pyrazine and l-chlorocarbonyl-4-mefhylpiperazine in anhydrous dimethylformamide by using sodium hydride as base. The Zopiclone thus obtained was purified by column chromatography and further re-crystallized from a mixture of acetonitrile and diisopropyl ether. Since sodium hydride is pyrophorie. Use of sodium hydride at commercial scale is not preferred because of fire hazard. The use of column chromatography at commercial scale is lime consuming and mixing of solvent is not the preferred choice for plant production.
WO 2008/002629 Al (June 2007, Mainfeld et al) discloses a process for the preparation of Zopiclone by the reaction of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5.6-dihydropyrrolo [3,4-b] pyrazine and l-chlorocarbonyl-4-methylpiperazine in dichloromethane and 4-N,N-dimethylamino pyridine and the Zopiclone thus formed was resolved by using D(+) malic acid in a mixture of methanol and acetone to obtain eszopiclone. The use of expensive 4-N,N-dimethylamino pyridine is involved in the synthesis of zopiclone under '629 patent
WO 2008/126105 A2 (April 2008, Tyagi et al) also covers a method for synthesizing
Zopiclone by the reaction of 6-(5-chIoropyrid-2-yl)-5-hydroxy-7-oxo-5,6-
dihydropyrrolo [3,4-b] pyrazine and l-chlorocarbonyl-4-methylpiperazine in

dichloromethane and dimethyl formamide in presence of dimethylamino pyridine and alkaline earth metal carbonates, hydroxides or oxides.
US 7476737 Patent (Sep., 2006, Venkata Naga et al) covers a process for the preparation of Eszopiclone, wherein the said process comprises the steps of reacting 6-(5-
chlorocarbonyl-4-methylpiperazine hydrochloride in presence of inorganic base. quaternary amine salt catalyst and ketone solvent to form Zopiclone and then its resolution to obtain Eszopiclone.
All the above cited prior art methods suffer from the disadvantages such as use of costly reagents; no solvent recyclability. non-scalable, use of large amount of solvents for purification, low yields or less purity.
Thus in light of the above cited prior art. there exist a need for the development of an improved process for the synthesis of Zopiclone. which avoids use of hazardous agents. increases throughput and avoids mixing of solvents.
OBJECT OF THE INVENTION
An object of the present invention is to provide an improved process for the preparation of (+)-(5S)-6-(5-chloro-2-pyridyl)-5-[(4-methy 1-1 -piperazinyl) carbonyloxy]-7-oxo-6,7-dihydro-5-H-pyrrolg)[3;4-b] pyrazine, commonly known as eszopiclone.
Another object of the present invention is to provide an simple and environmentally friendly process for the preparation of eszopiclone. which avoids use of hazardous agents; and mixing of solvents.

Yet another object of the present invention is to provide an improved process for the resolution of Zopiclone, wherein the levorotatory isomer of Zopiclone obtained is less than 0.1%.
Another object of the present invention is to provide a Eszopiclone with a good yield and purity.
Yet another object of the present invention is to provide an industrially scalable process for the preparation of Eszopiclone .
SUMMARY OF THE INVENTION
The present invention provides an improved process for the synthesis of Eszopiclone, wherein the said process comprises the steps of:
a) Condensation of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5. 6-dihydropyrrolo [3, 4, b] pyrazine with l-chlorocarbonyl-4-methylpiperazine hydrochloride or its free base in a solvent in presence of pyridine, base and a catalyst to obtain zopiclone;
b) Resolution of Zopiclone of step (a) by using D(+) dibenzoyl tartaric acid monohydrate in a solvent or mixture thereof to obtain (+) dibenzoyl tartrate salt of Eszopiclone:
c) Neutralization of dibenzoyl tartrate salt of step (b) with an aqueous base solution and water immiscible solvent, separation of organic layer and concentration of organic layer to obtain Eszopiclone.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of ((+)-(5S)-6-(5-chloro-2-pyridyl)-5-[(4-methyl-l-piperazinyl)carbonyloxy]-7-0X0-6.7-dihydro-5-H-pyrrolo[3,4-b]pyrazine, known as eszopiclone.

The said process according to present invention comprises the steps of:
a) condensation of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5.6-dihydropyrrolo[3.4-
pyrazine with l-chlorocarbonyl-4-methylpiperazine hydrochloride or its free base in
presence of pyridine, base and a catalyst in a solvent to obtain Zopiclone:
b) resolution of Zopicione using D-(+)-dibenzoyl tartaric acid monohydrate in a solvent or mixture thereof to obtain a (+) dibenzoyl tartrate salt of Eszopiclone; and
c) neutralization of dibenzoyl tartarate salt with a base in water and water immiscible solvent, separation of organic layer and concentration of organic layer to obtain eszopiclone.
The process according to present invention, wherein the said catalyst used in the condensation step is alkali metal halide or a phase transfer catalyst. The alkali metal halide catalyst comprises sodium iodide, sodium bromide, potassium iodide or potassium bromide. The phase transfer comprises from tetrabutyl ammonium bromide, tetrabutyl ammonium iodide; preferably potassium iodide or tetrabutyl ammonium iodide. The base used in the condensation step is an organic base and it is selected from the group consisting of methylamine, diethylamine, triethylamine, diisopropyl amine, N,N-diisopropylethyl amine or the like; preferably it is triethyl amine.
Further, the solvent used for condensation reaction is of organic solvents. The said organic solvent comprises chlorinated hydrocarbon, hydrocarbon, ketones, esters, amides and nitriles or mixture thereof. The chlorinated hydrocarbons are selected from the group consisting of dichloromethane, dichloroethane, mono chlorobenzene or dichlorobenzene. The hydrocarbon which can be used are toluene or xylene The ketones are selected from the group consisting of acetone, methyl ethyl ketone or methyl isobutyl ketone. The esters are selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate or isopropyl acetate. The amides are selected from the group of dimethyl formamide, dimethyl acetamide. The nitriles are selected from the group consisting of acetonitrile, propionitrile, Preferably the solvent used for condensation is dichloromethane or dichloroethane and most preferably dichloromethane. The reaction temperature for the condensation reaction varies from room temperature to reflux temperature of the solvent; preferably it is the reflux temperature of the solvent used.

The said condensation reaction is conducted for 2 to 8 hrs. preferably for 4 to 6 hrs.
The key raw material used in the synthesis of Eszopiclone according to present invention i.e. 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5.6-dihydropyrrolo[3,4-bjpyrazine can be prepared by the method reported in US 3862149 patent.
The Zopiclone so obtained according to the process of the present invention, after workup has a purity of greater than 99.5%.
After the work up the crude product as such can be taken for resolution or purified by the suitable solvent such as ethyl acetate.
The racemic Zopiclone is resolved using chiral acid, preferably D-(+)-dibenzoyl tartaric acid monohydrate in a solvent or mixture thereof to obtain (+)-dibenzoyi tartaratc salt of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5.6-dihydropyrrolo|3,4-b]pyrazinc i.e. (+)-dibenzoyl tartarate salt of eszopiclone.
The solvent involved in resolution step comprises tetrahydrofuran alone or in combination with dichloromethane, acetonitrile and water, preferably tetrahydrofuran alone or in combination with water.
In preferred embodiment, the racemic Zopiclone is dissolved in tetrahydrofuran and water: followed by addition of D-(+)-dibenzoyl tartaric acid.
Suitable temperature for the resolution reaction can vary from 25°C to reflux temperature preferably at reflux temperature.
The dibenzoyl tartarate salt of eszopiclone so obtained was neutralized by treatment with a base in presence of water and water immiscible solvent to form eszopiclone.

The process according to present invention, wherein the base used in the neutralization step is selected from the group consisting of sodium bicarbonate, sodium carbonate. potassium bicarbonatre, potassium carbonate, sodium hydroxide, potassium hydroxide. lithium hydroxide, preferably it is sodium bicarbonate.
The water immiscible solvent used in the said neutralization step is selected from the group consisting of ethyl acetate, dichloromethane, toluene, xylene, preferably it is ethyl acetate.
The eszopiclone so obtained via process according to present invention has enantiomeric purity of greater than 99.5 % particularly the unwanted laevorotatory isomer of Zopiclone is less than 0.1%.
Further by performing the process according to present invention. Eszopiclone is obtained, wherein the purity of eszopiclone qualify in 1CH guideline wherein maximum single impurity is less than 0.1%. Scheme 1 can depict the process of the invetion.


Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the said invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the true spirit or scope of the present invention as defined herein above and as exemplified and claimed herein below.

EXAMPLES
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims
Preparation of Zopiclone: (Method 1)
Charge 85.0 gm (0.32 mole) of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5, 6-dihydropyrrolo [3, 4, b] pyrazine in 850 ml dichloromethane at room temperature in a three neck round bottom flask having overhead stirrer and cool the reaction mixture to 0-5°C. Add 84.41 gm (0.42 mole) of l-chlorocarbonyl-4-methylpiperazine hydrochloride at 0-5 °C in one lot under stirring. 103.15 gm (1.02 moles) of triethyl amine and 25.5 gm (0.32 mole) of pyridine were added at 5-10°C. 1.7 gm of potassium iodide was added and reaction mass was heated to reflux and maintain for 6.0 hrs. The progress of the reaction was monitored by hplc. After completion of reaction, the reaction mixture was cooled to room temperature and 850 ml of water was added at 25 °C. The organic layer was separated and aqueous phase was extracted with 255 ml of dichloromethane. The organic layer was combined and concentrated under vacuum. 425 ml of hexane was added and mass was stirred for 30 min. It was filtered and 117.0 gm of Zopiclone was obtained with purity 99.56%
Preparation of Zopiclone: (Method 2)
Charge 15.0 gm (0.057 mole) of 6-(5-chIoropyrid-2-y!)-5-hydroxy-7-oxo-5, 6-dihydropyrrolo [3, 4, b] pyrazine in 150 ml dichloromethane at room temperature in a 03 neck round bottom flask and cool the reaction mixture to 0-5 °C. Add 14.89 gm (0.0748 mole) of l-chlorocarbonyl-4-methylpiperazinc hydrochloride at 0-5 °C in one lot under stirring. 18.20 gm (0.179 moles) of triethyl amine and 4.51 gm (0.057 mole) of pyridine were added at 5-10 °C. 0.3 gm of tetrabutyl ammonium iodide was added and reaction

mass was heated to reflux and maintain for 5.0 hrs. The progress of the reaction was monitored by hplc. After completion of reaction, the reaction mixture was cooled to room temperature and 150 ml of water was added at 25 °C. The organic layer was separated and aqueous phase was extracted with 45 ml dichloromethane. The organic layers was combined and concentrated under vacuum. 75 ml of hexane was added and mass was stirred for 30 min. It was filtered and 22.0 gm of Zopiclone was obtained with purity 99.89%
Resolution of Zopiclone:
Charge 20.0 gm (0.051 mole) of Zopiclone in 160 ml tetrahydrofuran at room temperature in three neck round bottom flask having overhead stirrer. Charge 80.0 ml water at 25-30 °C under stirring. To this slurry charge 19.3 gm (.051 mole) of D (+) dibenzoyl tartaric acid at 25-30 °C. To the clear solution thus obtained was stirred for 2,0 hrs at 25-30 °C. In the reaction mixture slowly solid precipitated out. Raise temperature of the reaction mass to reflux and maintain for 1.0 hr. Cool the reaction mass to 30 °C. Filter the solid precipitated out and wash with 20 ml of tetrahydrofuran. Suck dried the material and unload. Dry the material at 55-60°C to obtain 15.0 gm of salt.
Preparation of Eszopiclone:
Charge 6.6 gm (0.0086 mole) of dibenzoyl tartrate salt of Zopiclone in 99.0 ml of ethyl acetate and 16.5 ml of water at 25-30 °C. Heat the reaction mass up to 40 °C and charge 1.86 gm (0.022 mole ) of sodium bicarbonate at 40 °C and heat to 60 °C to obtain clear solution and maintain for 1.0 hr. separate the organic layer and wash with 16.5 ml of water. Dry the organic layer over sodium sulphate and concentrate under vacuum. The solid obtained was cooled to 0-5 °C and stirred for 2.0 hrs. Filter the solid and washed with 6.6 ml of ethyl acetate. Unload and dried at 55-60 °C to obtain 2.85 gm of eszopiclone.

We Claim: -
1. An improved process for the preparation of Eszopiclone of formula (I) comprising the steps of

a) Condensation of 6-(5-chloropyrid-2-yl)-5~hydroxy-7-oxo-5. 6-dihydropyrrolo [3, 4, b] pyrazine with l-chlorocarbonyl-4-methylpiperazine hydrochloride or its free base in a solvent in presence of pyridine, base and a catalyst to obtain zopiclone;
b) Resolution of Zopiclone of step (a) by using D{+) dibenzoyl tartaric acid monohydrate in a solvent or mixture thereof to obtain (+) dibenzoyl tartrate salt of Eszopiclone;
c) Neutralization of dibenzoyl tartrate salt of step (b) with an aqueous base solution and water immiscible solvent, separation of organic layer and concentration of organic layer to obtain Eszopiclone.
2. The process according to claim 1, wherein the catalysts used for the condensation reaction step (a) comprises alkali metal halide or phase transfer catalyst.

3. The process according to claim 2. wherein the said alkali metal halidc comprises sodium iodide, sodium bromide, potassium iodide, potassium bromide preferably potassium iodide; and phase transfer catalyst comprises tetrabutyl ammonium bromide or tetrabutyl ammonium iodide preferably tetrabutyl ammonium iodide.
4. The process according to claim 1 (a), wherein the base comprises is an organic base selected from the group consisting of triethylamine, diethylamine or isopropyl amine preferably triethylamine
5. The process according to claim 1 (a), wherein the solvent comprises chlorinated hydrocarbon, hydrocarbon, ketones, esters, amides or nitriles.
6. The process according to claim 5, wherein the said solvent comprises dichloromethane, dichloroethane. xylene, toluene, acetone, methyl ethyl ketone. methyl iso butyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, dimethyl formamide, dimethyl acetamide. acetonitrile or propionitrile. preferably dichloromethane and dichloroethane most preferably dichloromethane.
7. The process according to claim 1 (b)., wherein the solvent involved in rcsofution step comprises tetrahydrofuran alone or in combination with acetonitrile and water, preferably tetrahydrofuran alone or in combination with water.
8. The process according to claim 1 (c), wherein the said water immiscible solvent comprises ethyl acetate, dichloromethane. toluene, preferably ethyl acetate.
9. The process according to claim I, wherein obtained Eszopiclone have enantiomeric purity greater than 99%, preferably greater than 99.5%
10. A process for the preparation of eszopiclone substantially as herein described with reference to the examples.