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 :
AN INDUSTRIAL PROCESS FOR THE PREPARATION OF ESZOPICLONE
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 an industrial process for the preparation of
eszopiclone.
The following specification particularly describes the invention and the manner
in which it is to be performed.

4. DESCRIPTION
The invention provides an industrial process for the preparation of eszopiclone. The invention further provides pure eszopiclone base having chiral purity of 99.0% or more and residual solvent below 0.5 %.
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 formula I.

O
N-
^N
"N

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.
Although some residual process solvent in an API or drug product may be an unavoidable consequence of the manufacturing process, the level of residual process solvent should be reduced to a minimum. Clearly, methods for reducing excess process solvents in eszopiclone to a level specified by ICH guidelines are needed.

The inventors have now developed an easy process for reducing residual solvent content in pure eszopiclone. The eszopiclone is produced when an eszopiclone salt is treated with a base in presence of a solvent. The product obtained is when again contacted with ketone solvent or optionally followed by contacting with antisolvent, yields eszopiclone having chiral purity of 99.0% or more with the residual solvent content below the ICH specifications.
In one of the aspect of the present invention there is provided a process for reducing residual solvent content in pure eszopiclone, which includes the steps of,
a) treating eszopiclone salt with a base in presence of solvent,
b) contacting product of step a) with ketone solvent and
c) isolating pure eszopiclone base from the reaction mixture thereof.
The process of invention involves treating eszopiclone salt with a base in a mixture of water and an organic solvent at a temperature of 20-40 °C and at a pH of about 7-11. The organic layer is separated and concentrated to obtain a residue. The residue obtained is then contacted with a ketone solvent or optionally followed by contacting with antisolvent. After contacting with ketone solvent, the reaction mixture was concentrated and maintained the mixture for two hours at 25-35 °C and filtered the material, washed with ketone solvent. Optionally when residue obtained after evaporating the ketone solvent is further contacted with antisolvent; the reaction mixture was concentrated and maintained the mixture for two hours at 25-35 °C. Filtered the material and washed with ketone solvent or antisolvent or mixture thereof. The material obtained was dried under vacuum to get pure Eszopiclone.
The base include from the group of sodium hydroxide, potassium hydroxide, magnesium hydroxide, ammonium hydroxide and the like; carbonate salts such as sodium carbonate, potassium carbonate and magnesium carbonate.

The organic solvent includes from the group of carbon tetrachloride, chloroform, cyclohexane, 1,2-dichloroethane, dichloromethane, diethyl ether, ethyl acetate, heptane, hexane, methyl-tert-butyl ether, pentane, toluene and 2,2,4-trimethylpentane or a mixture thereof.
The ketone solvent includes from group of methyl ethyl ketone, acetone, 3-pentanone.
'Antisolvent' herein refers to the organic solvent capable of precipitating out the product eszopiclone from the reaction mixture thereof. Antisolvent includes from the group of methanol, ethanol, isopropyl alcohol and isobutyl alcohol.
In general, the eszopiclone so formed has chiral purity and residual solvent limit as specified in table-1.

S. No Solvent system Residual solvent content Chiral purity

Obtained by the process of invention Limits as per ICH

1 Acetonitrile >0.1 % 0.04% 99.0%
2 Methyl ethyl ketone <0.2 % 0.5% 99.9%
3 Methyl ethyl ketone and Isopropyl alcohol. MEK:<0.05% IPA: 0.01 % 0.5% (both solvents 99.9%
In this disclosure, eszopiclone salt refers to salts zopidone with a chiral acid. The chiral acids include from the group 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'-bis-napthol, (+)-camphoric acid, D-glucuronic acid.

The present invention is further illustrated by the following example which are 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 present invention.
Example-1
Preparation of eszopiclone base (using Methyl ethyl ketone and isopropyl alcohol):
Eszopiclone tartrate (18.0 g) was suspended in a mixture of dichloromethane (180 ml) and water (45 ml) and adjusted the pH to 8.5 to 9.5 using 10% aqueous sodium carbonate solution at 10-15 °C. The layers were separated and the aqueous layer was back extracted with dichloromethane (45 ml). The combined organic layer was washed with water (45 ml) and concentrated organic layer. The residue was redissolved to methyl ethyl ketone (360 ml) and evaporated the solvents at atmospheric pressure. Then isopropyl alcohol (63 ml) was added to it. Maintained the reaction for 2 hours at 25-35 °C and filtered the material, washed with methyl ethyl ketone / isopropyl alcohol (180 ml). The material was dried under vacuum to get pure Eszopiclone Yield : 10.4 gm. Chiral purity: 99.9%.
Example-2
Preparation of eszopiclone base (using Methyl ethyl ketone):
Eszopiclone tartrate (3.1 g) was suspended in a mixture of dichloromethane (30 ml) and water (15 ml) and adjusted the pH to 8.5 to 9.5 using 10% aqueous sodium carbonate solution at 10-15 °C. The layers were separated and the aqueous layer was back extracted with dichloromethane (15 ml). The combined organic layer was washed with water (15 ml) and concentrated organic layer. The residue was redissolved to methyl ethyl ketone (50 ml) and evaporated the

solvents at atmospheric pressure. Maintained the reaction for 2 hours at 25-35 °C and filtered the material, washed with methyl ethyl ketone (6 ml). The material was dried under vacuum to get pure Eszopidone
Yield: 1.48 gm.
Chiral purity: 99.9%.

We Claim:
1. A process for reducing residual solvent content in pure eszopiclone, which
comprises the steps of,
a) treating eszopiclone salt with a base in presence of solvent,
b) contacting product of step a) with ketone solvent and
c) isolating pure eszopiclone base from the reaction mixture thereof

2. The process of claim 1, wherein a base is selected from the group of sodium hydroxide, potassium hydroxide, magnesium hydroxide, ammonium hydroxide and the like; carbonate salts such as sodium carbonate, potassium carbonate and magnesium carbonate.
3. The process of claim 1, wherein the solvent is mixture of water and an organic solvent.
4. The process of claim 3, wherein an organic solvent comprises of carbon tetrachloride, chloroform, cyclohexane, 1,2-dichloroethane, dichloromethane, diethyl ether, ethyl acetate, heptane, hexane, methyl-tert-butyl ether, pentane, toluene, 2,2,4-trimethylpentane or a mixture thereof.
5. The process of claim 1, wherein the ketone solvent is selected from group of methyl ethyl ketone, acetone and 3-pentanone.
6. The process of claim 1, wherein antisolvent is optionally added after contacting the product with ketone solvent.
7. The process of claim 6, wherein antisolvent selected from the group of
methanol, ethanol, isopropyl alcohol and isobutyl alcohol.
8. The process of claim 5, wherein the ketone solvent is methyl ethyl ketone.
9. The process of claim 7, wherein antisolvent is isopropyl alcohol.

10. The process of claim 1, wherein pure eszopiclone base a chiral purity of 99.0% or more and residual solvent below 0.5 %.

Abstract
The invention provides an industrial process for the preparation of eszopiclone. The invention further provides pure eszopiclone base having chiral purity of 99.0% or more and residual solvent below 0.5 %.