FORM-2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULE, 2003
PROVISIONAL SPECIFICATION
[See section 10, rule 13]


IMPROVED PROCESS FOR PREPARATION OF ESZOPICLONE
APPLICANT:
CALYX CHEMICALS AND PHARMACEUTICALS LTD. 2, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E), Mumbai-400 072, Maharashtra, India

Indian Company incorporated under the Companies Act 1956
The following specification particularly describes the invention:


TITLE
IMPROVED PROCESS FOR PREPARATION OF ESZOPICLONE
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of (+)-(5S)-(6-chloropyridin-2-yI)-7-oxo-6,7-dihydro-5H-pyrrol[3,4-b]pyrazin-5-yI-4-methylpiperazin-1-carboxylate), a dextrorotatory isomer of zopiclone which is commonly known as eszopiclone. More particularly, the present invention relates to a novel process for the resolution of zopiclone by means of an optically active acid in presence of water.
The present invention also relates to process for the purification of dextroisomer of optically active salt of zopiclone and eszopiclone. The present invention further relates to an improved process for the preparation of crystalline form A of eszopiclone.
BACKGROUND OF THE INVENTION
Zopiclone (Formula I), chemically known as 6-(chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrol[3,4-b]pyrazin-5-yl-4-methylpiperazin-l-carboxylate) is a racemic mixture consisting of equimoles of dextrorotatory and levorotatory isomers.
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Formula I
Eszopiclone is a dextrorotatory isomer of zopiclone. It is chemically described as (+)-(5S)-(6-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrol[3,4-b]pyrazin-5-yl-4-methyipiperazin-1-carboxylate) and represented by the structure of formula II.

It has been reported that eszopiclone is two times active and less toxic than zopiclone and is useful in the treatment of insomnia. On the other hand levorotatory isomer is almost inactive and more toxic. Eszopiclone is currently sold under the brand name of Lunesta for the treatment of insomnia.
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Eszopiclone was first disclosed in US patent nos. US 6,444,673 and US 6,864,257. It can be prepared by resolution of racemic zopiclone using optically active acids or enzymes.
US 6,444,673 discloses the process for preparation of eszopiclone by resolving zopiclone using D(+)-0,0'-dibenzoyltartaric acid in an organic solvent selected from halogenated aliphatic hydrocarbons such as dichloromethane followed by two crystallizations and neutralizing eszopiclone dibenzoyltartarate salt with a base such as aqueous sodium hydroxide in presence of dichloromethane. Base obtained is then further crystallized with acetonitrile.
US 6,339,086 describes the process of preparation N-desmethylzopiclone. The patent discloses the process of resolution of zopiclone by using the chiral acids such as D-malic acid, mandelic acid and dibenzoyltartaric acid in a mixture of acetone and methanol.
US 7,476,737 describes the process for preparing eszopiclone by reacting zopiclone with an enantiomerically pure di-p-toluoyl tartaric acid in a solvent such as acetonitrile, recovering the salt and reacting the salt with base.
WO 2007083188 discloses the process for preparation of substantially pure eszopiclone. The process comprises reaction of zopiclone with optically active acid in one or more first solvents followed by crystallization of desired isomer by removing first solvent and adding one or more second solvents. The salt obtained is further recrystallised followed by formation of eszopiclone free base.
WO 2008126105 discloses the process for preparation of eszopiclone by reaction of zopiclone with optically active acid in a mixture of water and water miscible organic solvent followed by work up.
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WO 2008094690 describes the process for preparation of eszopiclone free base by reacting eszopiclone salt such as eszopiclone malate salt with a mild base such as sodium bicarbonate in presence of water.
Thus, all the prior art processes report the use of organic solvent for the formation of eszopiclone salt. The processes involve tedious and repeated crystallization and require large volume of solvents, which make the processes complicated.
Hence, there is a need in the art for method for preparation of eszopiclone that uses environmental friendly solvents, improves yield, avoids huge volume of solvents and complications in the process. The present invention addresses these and other problems and provides a process that is simple, efficient, robust and readily scalable.
Also the present invention provides an eco friendly and less polluting process by using water as a reaction medium for the resolution of zopiclone.
OBJECT OF THE INVENTION
An object of the present invention is to provide an improved process for the preparation of eszopiclone of formula II
Another object of the present invention is to provide a novel process for the resolution of zopiclone by using optically active acid in presence of water.
Another object of the present invention is to provide a novel process for the preparation of dextroisomer of optically active salt of zopiclone (hereinafter called as eszopiclone salt) by avoiding the use of organic solvents.
Another object of the present invention is to provide a process for the purification of eszopiclone salt using the appropriate organic solvents.
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Yet another object of the present invention is to provide an improved process for the preparation of crystalline form A of eszopiclone of formula II
Yet another object of the present invention is to provide eszopiclone with chiral purity more than 99.9%.
Further object of the present invention is to provide an environmental friendly process for the resolution of zopiclone.
SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of eszopiclone of formula II comprising,

a) Reacting racemic zopiclone with an optically active acid in presence of water
b) Purifying eszopiclone salt obtained in step (a)
c) Reacting purified eszopiclone salt with an inorganic base
The present invention further provides an improved process for the preparation of eszopiclone of formula II by resolution of zopiclone using an optically active acid in presence of water, More particularly, the present invention provides a novel process
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for the preparation of eszopiclone salt by reacting racemic zopiclone with an optically active acid in presence of water and thereby avoiding the use of organic solvents.
The present invention also provides a process for the purification of eszopiclone salt using the appropriate organic solvents. The present invention still further provides an improved process for preparation of crystalline form A of eszopiclone of formula II.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of eszopiclone of formula II.

Formula II
The present invention also relates to a novel process for the resolution of zopiclone. The present invention still further provides an improved process for the preparation of crystalline form A of eszopiclone of formula II.
In an aspect, the present invention provides a novel process for the resolution of zopiclone. In particular, the present invention provides a novel process for the preparation of eszopiclone salt by reacting racemic zopiclone with an optically active acid in presence of water.
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All the prior art processes report the salt formation step in presence of organic solvent whereas the process of the present invention avoids the use of an organic solvent for the salt formation.
The process of present invention uses water as a solvent. Thus, the process is less polluting and more environmental friendly.
In another aspect of the present invention there is provided an improved process for the preparation of eszopiclone of formula II, comprising,

a) Reacting racemic zopiclone with an optically active acid in presence of water
b) Purifying eszopiclone salt obtained in step (a)
c) Reacting purified eszopiclone salt with a base
The process of the present invention is as depicted in Scheme-1 and Scheme-2 below.


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In step (a), eszopiclone salt is prepared by a novel process of the present invention, which process comprises the reaction of racemic zopiclone with an optically active acid in presence of water thereby avoiding the use of organic solvent.
In an embodiment of the present invention optically active acid used in formation of eszopiclone salt is selected form, D-tartaric acid, L-tartaric acid, D-dibenzoyl tartaric acid, D-malic acid, D-mandelic acid, D-di-p-toIuyl tartaric acid, Di-p-anisoyl-D-tartaric acid, (lS)-lO-camphor sulphonic acid, (S)-2-methoxy phenyl acetic acid, D-lactic acid, (S)-hydratropic acid , (S)-2-methoxy phenyl acetic acid, (R>2-methoxy-2-trifluoromethyl phenyl acetic acid, (S)-(+)-1,1 -binapthaIene-2,2,-dihydrogen
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phosphate or mixture thereof, preferably optically active acid used are D-dibenzoyl tartaric acid or D-di-p-toluyl tartaric acid
Optically active acid may be present in any amount sufficient to form the optically active acid salt of zopiclone.
In another embodiment of present invention amount of water used for preparing eszopiclone salt varies from 15 to 40 times (w/w) of racemic zopiclone.
The reaction of step (a) is carried out at temperature ranging from 50 to 100 °C for 1 to 5 hours.
In another aspect of the present invention there is provided a process for purification of eszopiclone salt. The salt is purified in step (b) using the two appropriate organic solvents. Eszopiclone salt is first treated with the first organic solvent. The mixture is heated at reflux temperature for 30 min. After 30 min. second organic solvent is added and the reaction mixture is further heated for an hour. Reaction mixture is then cool down to obtain pure eszopiclone salt.
The first organic solvent is selected from ketonic solvents such as methyl isobutyl ketone, acetone, ethyl methyl ketone, methyl vinyl ketone, isopropyl methyl ketone, methyl propyl ketone, diethyl ketone, diisopropyl ketone, ethyl propyl ketone, cyclopentanone or butyl methyl ketone, preferably acetone.
The second organic solvent is selected from aliphatic and aromatic hydrocarbons such as pentane, hexane, heptane, octane, cyclohexane, toluene, p-xylene, m-xylene, o-xylene and mixed xylene, preferably toluene.
The first and second organic solvents are used in the ratio of 20:50 and the reaction is carried out at temperature ranging from 30-70 °C.
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In step (c) eszopiclone free base is obtained from pure eszopiclone salt obtained in step (b) by well-known process. Pure eszopiclone salt is reacted with an inorganic base such as sodium hydroxide in presence of water and dichloromethane.
According to process of present invention eszopiclone free base is generated using 5-18 volumes of water in presence of 5-20 volumes of dichloromethane. Amount of water and dichloromethane is taken with respect of eszopiclone salt.
According to process of present invention eszopiclone free base is generated by maintaining pH between 8-12 and the reaction is carried out at temperature 15-40 °C.
In another aspect of the present invention there is provided a process for preparation of crystalline form A of eszopiclone of formula II by crystallizing crude eszopiclone base obtained in step (c) in xylene.
The crystallization is carried out at temperature 80-120 °C. The solution obtained is then cooled at 20-40 °C to get crystalline solid of eszopiclone Form A.
Chiral HPLC purity of eszopiclone obtained according to process of present invention is high.
Polymorphic form of eszopiclone, which is obtained according to present invention, is Form A and is confirmed by IR and XRD data.
Eszopiclone Form A is characterized by the main XRD peaks:
9.9, 11.1, 14.9,15.9,17.9,18.9,19.9,21.2,25.5,27.5, 29.6,42.5± 0.2 °2 0 .
Eszopiclone Form A produces a FTIR spectrum with characteristics absorption bands at about 3078, 2941, 1714, 1462, 1371,1290, 1140, 1088, 978, 849, 773 and 715 cm-1.
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The detail of the invention provided in the following examples is given by the way of illustration only and should not be construed to limit the scope of the present invention.
Example 1
Preparation of Dextroisomer of Dibenzoyl-D- tarate Salt of zopiclone
[Eszopiclone salt]
Racemic zopiclone (23.28g, 0.06 mol) and Dibenzoyl-D-tartaric acid monohydrate (22.56g, 0.06 mol) were taken in 600 ml of water. The reaction was stirred for 0.5 hour and subsequently temperature was raised to 95 to 99 °C. Reaction mixture was further stirred for 3 hours at the same temperature and slowly it was allowed to cool to 25-30 °C in one hour. Crystalline crude salt was filtered and dried at 50-60 °C. Yield: 44 g., [a] D20:38° (c=0.5% in acetone).
Example 2
Purification of eszopiclone Salt
42 g of crude salt was taken in 504 ml of acetone and allowed to reflux for 0.5 hour. Toluene (1176 ml) was added slowly maintaining the temperature 55-60 °C in 1 hour. Reaction temperature was brought down to 40 °C and it was maintained for further 2 -3 hours. Temperature of reaction was slowly brought to 25-30 °C and it was kept for additional 1 hour at the same temperature. Crystalline salt was filtered and dried at 50-60 °C for one hour. Yield: 20 g., [a]D20 : 102° ( c=0.5% in acetone)
Example 3 A
Preparation of eszopiclone free base
The pure salt obtained from example 2 was suspended in water (125 ml) and to it dichloromethane (125 ml) was added under stirring. Reaction temperature was kept in between 20-25 °C. 2 N solution of sodium hydroxide was added maintaining the temperature 20-25 °C. Reaction mixture pH was brought to 10-12. Organic layer was separated and further more aqueous layer was extracted with dichloromethane (2 x 25ml). Combined dichloromethane layer was washed with 2 x 25ml of water
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and the organic layer was concentrated to get the crude eszopiclone, which was further purified in isopropyl ether (150 ml) to get the pure dried eszopiclone. Yield: 6 g., [a]D20 : 122° (c= 1% in acetone).
Example 3B
Preparation of eszopiclone free base
The pure salt obtained from example 2 was suspended in water (125 ml) and to it dichloromethane (125 ml) was added under stirring. Reaction temperature was kept in between 20-25 °C. 2 N solution of sodium hydroxide was added maintaining the temperature 25-30 °C. Reaction mixture pH was brought to 10-12. Organic layer was separated and further more aqueous layer was extracted with dichloromethane (2 x 25 ml). Combined dichloromethane layer was washed with 2 x 25ml of water and the organic layer was concentrated to get the crude eszopiclone which was further crystallized in xylene.
Example 4
Preparation of crystalline Form A of eszopiclone
Crude eszopiclone obtained in the example 3B was taken in 160 ml of xylene and heated at 100-120 °C to get the clear solution. Slowly temperature was brought down. Crystallization starts at 65 °C and complete crystallization occur at 25-30 °C. Furthermore, stirring was done for additional 1 hour. Crystals were filtered and dried to get eszopiclone of Form A. Yield: 7 g., Chiral HPLC purity : > 99.9% ((S)-enantiomer).