FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION :
PROCESS FOR THE PREPARATION OF ESZOPICLONE SALTS
2. APPLICANT (S) :
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The invention provides a process for the preparation of eszopiclone salts. The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION

The invention provides a process for the preparation of eszopiclone salts.
Eszopiclone, is chemically known as (+)-(5S)-6-(chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b] pyrazin-5-yl 4-methyl- piperazine-1-carboxylate and is represented by following formula I.
N-CH3
,o
Formula I
Eszopiclone, marketed under the name LUNESTA, is a non-benzodiazepine hypnotic, indicated for the treatment of insomnia and is the more active dextrorotatory isomer of zopiclone.
There are several patents and patent applications, which discloses process for the preparation of eszopiclone or salts thereof such as U.S. Patent No. 6,444,673, U.S. Patent No. 7,125,874, U.S. Patent Application No. 2007/054914, U.S. Patent Application No. 2007/203145, International (PCT) Application No. 2006/136866, International (PCT) Application No. 2007/088073 and International (PCT) Application No. 2007/083188.
The inventors have now developed an easy process for the preparation of
eszopiclone salts. The eszopiclone salt is produced when zopiclone of formula II,
is stirred with a chiral acid in a suitable solvent.
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This process provides eszopiclone salt having specific optical rotation (SOR, [a]D25) of 77 ± 3° (c = 0.5% water) and chiral purity of less than 99.0%
In one aspect of the present invention there is provided a process for preparation of eszopiclone salt wherein the process includes the steps of:
(i) treating zopiclone of formula II, with a chiral acid in presence of a
suitable solvent; and
,0

Formula II
(ii) isolating eszopiclone salt from the reaction mixture thereof.
The process of invention involves stirring zopiclone of formula II, with a chiral acid in presence of a suitable organic solvent at a temperature of 20-40 °C to form eszopiclone salt. The eszopiclone salt is then isolated from the reaction mixture thereof.
In general, the eszopiclone salts so formed have specific optical rotation (SOR, [a]D25) of 77 ± 3° (c = 0.5% water) and chiral purity of less than 99.0%.
In this disclosure specific optical rotation ([a]D25) refers to the angle of rotation of plane polarized light at 25 °C with the sodium D line when plane-polarized light is passed through a sample with a path length of 1 decimeter and a sample concentration of 0.5 gram per 1 deciliter.
The non-limiting examples of chiral acids include L-tartaric acid, D-tartaric acid, di-p-anisoyl-D-tartaric acid, Di-p-toluyl-D-tartaric acid, dipivaloyl-D-tartaric acid, D-tartaric acid momoparachloro anilide, dibenzoyl-D-tartaric acid monodimethyl

amide, D-lactic acid, D-malic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenylacetic acid, D-mandelic acid, S-hydratropic acid, S(+)-1,1'-binaphthalene-2,2'-dihydrogen phosphate, 1S-10-camphor sulfonic acid, N-acetyl-l-aspartic acid (and other N-protected amino acids), (R)-(+)-1,1'-bi-s-napthol, (+)-camphoric acid, D-glucuronic acid or a mixture thereof.
The suitable solvent includes from the group of one or more of toluene, xylene,
dimethylformide, dimethylsulfoxide, tetrahydrofuran, N-methyl tetrahydrofuran,
dioxane, dimethylacetamide, hexamethylphosphorictriamide, N-
methylpyrrolidone, formamide or a mixture thereof or a mixture with 1-95% of an organic cosolvent comprising at least one solvent selected from a polar solvent, halogenated solvent and mixtures thereof.
The polar solvent includes from the group of one or more nitrile solvent, alcoholic solvent, ester solvent and ketone solvent. The nitrile solvent includes acetonitrile, propionitrile, benzonitrile, glutaronitrile, malononitrile, butyronitrile, adiponitrile and caprinitrile. The alcoholic solvent includes methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, 2-methoxyethanol and the like. The ester solvent includes methyl acetate, ethyl acetate, propyl acetate, butyl acetate, sec-butyl acetate, tert-butyl acetate, isoamyl acetate, isobutyl acetate, isopropyl acetate and the like. The ketone solvent includes acetone, methyl ethyl ketone, methyl iso-butyl ketone and the like. The halogenated solvent includes dichloromethane, trichloromethane, carbon tetrachloride and dichloroethane.
The invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Examples Example-1 Preparation of eszopiclone tartrate salt
Zopiclone (10.0 g, 0.025 mol) was suspended in a mixture of acetonitrile (250 ml), methanol (125 ml) and toluene (7.5 ml), then L-(+)-tartaric acid (2.0g, 0.013 mol) was added. The contents were refluxed for 15 minutes. After getting clear solution cooled the contents gradually to 25-30 °C and stirred for 4 hours. The solid material was filtered, washed with acetonitrile and eszopiclone tartrate salt was isolated from the reaction mixture thereof. Yield: 5.1 g
SOR [c = 0.5%, water]: 78.45°. Chiral purity: 97.10%.
Example-2
Preparation of eszopiclone tartrate salt
Zopiclone (10.0 g, 0.025 mol) was suspended in a mixture of acetonitrile (250 ml), isopropyl alcohol (125 ml) and toluene (7.5 ml), then L-(+)-tartaric acid (2.0g, 0.013 mol) was added. The contents were refluxed for 15 minutes. After getting clear solution, cooled the contents gradually to 25-30 °C and stirred for 6 hrs. The solid material was filtered, washed with acetonitrile and eszopiclone tartrate salt was isolated from the reaction mixture thereof. Yield: 5.7 g.
SOR [c = 0.5%, water]: 79.2°. Chiral purity: 97.99%.
Example-3
Preparation of eszopiclone tartrate salt
Zopiclone (10.0 g, 0.025 mol) was suspended in a mixture of acetonitrile (250 ml), and DMF (100 ml), then L-(+)-tartaric acid (2.0g, 0.013 mol) was added. The contents were refluxed for 15 minutes. After getting clear solution, cooled the contents gradually to 25-30 °C and stirred for 7 hrs. The solid material was

filtered, washed with acetonitrile and eszopiclone tartrate salt was isolated from
the reaction mixture thereof.
Yield: 5.5 g.
SOR [c = 0.5%, water]: 75.6°.
Chiral purity: 95.74%.
Example-4
Preparation of Eszopiclone DBDT salt
Zopiclone (50g, 0.128 mol) was suspended in a mixture of acetonitrile (1250 ml) and IPA (625 ml) then dibenzoyl-D-tartaric acid (DBDT) (24.2g, 0.064 mol) was added. The contents were refluxed for 15 minutes. After getting clear solution cooled the contents gradually to 25-30 °C and stirred for 6 hrs. The solid material was filtered, washed with acetonitrile and eszopiclone DBDT salt was isolated from the reaction mixture thereof. Yield: 43 g.
SOR [c = 0.5%, water]: 97.5°. Chiral purity: 96.5 %

We Claim:
1. A process for preparation of eszopiclone salt wherein the process comprises the steps of:
(i) treating zopiclone of formula II, with a chiral acid in presence of a
suitable solvent; and
,0

o
Formula II
(ii) isolating eszopiclone salt from the reaction mixture thereof.
2. The process of claim 1, wherein a chiral acid comprises of L-tartaric acid, D-tartaric acid, di-p-anisoyl-D-tartaric acid, Di-p-toluyl-D-tartaric acid, dipivaloyl-D-tartaric acid, D-tartaric acid momoparachloro anilide, dibenzoyl-D-tartaric acid monodimethyl amide, D-lactic acid, D-malic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenylacetic acid, D-mandelic acid, S-hydratropic acid, S(+)-1,1'-binaphthalene-2,2'-dihydrogen phosphate, 1S-10-camphor sulfonic acid, N-acetyl-l-aspartic acid (and other N-protected amino acids), (R)-(+)-1,1'-bi-s-napthol, (+)-camphoric acid, D-glucuronic acid or a mixture thereof.
3. The process of claim 1, wherein a suitable solvent comprises of mixture of organic solvent and organic co-solvent.
4. The process of claim 3, wherein organic solvent is selected from the group of toluene, xylene, dimethylformide, dimethylsulfoxide, tetrahydrofuran, N-methyl tetrahydrofuran, dioxane, dimethylacetamide, hexamethylphosphorictriamide, N-methyl pyrrolidone, formamide and mixture thereof.

4. The process of claim 3, wherein an organic co-solvent comprising at least one solvent selected from a polar solvent, halogenated solvent and mixtures thereof.
5. The process of claim 4, wherein a polar solvent is selected from the group of acetonitrile, propionitrile, benzonitrile, glutaronitrile, malononitrile, butyronitrile, adiponitrile, caprinitrile, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, sec-butyl acetate, tert-butyl acetate, isoamyl acetate, isobutyl acetate, isopropyl acetate, acetone, Methyl ethyl ketone, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and 2-methoxyethanol.
6. The process of claim 4, wherein halogenated solvent comprises of
dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane and the
like.
7. The process of claim 1, wherein the eszopiclone salt is eszopiclone tartrate.
8. The process of claim 7, wherein the eszopiclone salt has a [O]D25 = 77 ± 3° (c = 0.5% water).
9. The process of claim 7, wherein eszopiclone salt has a chiral purity of less than 99.0%.
Dated this _TH day of DECEMBER, 2007

Abstract
The invention provides a process for the preparation of eszopiclone salts.