Field of invention: Present invention relates to a process for the preparation of

enriched isomer (Eszopiclone) . The process is industrially advantageous and provides high yields in high purity with less number of synthetic steps.
Background of the invention: Zopiclone a cyclopyrrolone derivative, belonging to a novel chemical class which is structurally unrelated to existing hypnotics chemically

Eszopiclone represented by formula II and is the S-isomer of racemic product Zopiclone. Eszopiclone is found to be more specific for the GABA binding sites and possesses an approximately 50-fold higher binding affinity to GABA-A receptors than the R- Isomer. Also the hypnotic activity of S-Zopiclone is reported to be two folds more than racemic Zopiclone


US 6,319,926 discloses the process wherein (±)-Zopiclone is converted into diastereomeric salts using D(+)-0, O'-dibenzoyltartaric acid in dichloromethane which is subsequently double purified in the mixture of dichloromethane and acetonitrile. Finally essentially pure Eszopiclone is obtained in an over all yield of only 23%.
US 6,339,086 discloses the process wherein (±)-Zopiclone is converted into diastereomeric salts using D-malic acid and Eszopiclone is obtained in an over all yield of 36%.
US 6,444,673 discloses a process wherein Zopiclone is added to a solution of D(+)-0,0' dibenzoyltartaric acid in the form of a monohydrate in DCM and concentrated to dryness .The crude salt obtained is recrystallised in Acetonitrile and DCM which is further converted to Eszopliclone.
ES 2,101,653 discloses an enzymatic resolution of racemic mixture of compounds to yield optically pure Eszopiclone.

The present invention provides the process to prepare therapeutically active enantiomerically enriched isomer of Eszopiclone in higher yields, which is industrially applicable, non-hazardous and less expensive .
Summary of the invention:
The main objective of the present invention is to provide a novel process for the preparation of Zopiclone .
Another objective of the present invention is to provide a process for the preparation of enantiomerically enriched isomer of Eszopiclone with chiral purity of about 95 to 99.5%
Another aspect of the present invention is to provide a process for the resolution of racemic Zopiclone to yield the said Eszopiclone in high yields.
Another embodiment of the present invention discloses the process for the conversion of undesired enantiomer formed to one of the intermediates which can be converted to racemic Zopiclone.
Description of the drawings:

Detailed description of invention:
Thus in accordance with the present invention, process for the preparation of Eszopiclone comprises the following :

I. Reaction of 2-amino-5-chloro pyridine with pyrazine-2,3-dicarboxylic acid anhydride in presence of aromatic organic solvents to form a carbomoyl Pyrazine carboxylic acid compound
II. Cyclization of the compound obtained from step I to form the imide compound which is carried out in presence of stoichiometric quantities of thionyl chloride and a low boiling solvent with boiling points of about 40°C to about 70°C
III. Partial reduction of compound obtained from step II in presence of alkali
metalborohydrides and alkali metal hydroxides like sodium hydroxide in aqueous
medium.
IV. Condensation of l-chlorocarbonyl-4-methyl-piperazine with the compound
obtained from step III in presence of organic base , acid scavenger, acid fixation
agent, alkali metal oxides such as calcium oxide, potassium carbonate, sodium
bicarbonate, sodium carbonate, calcium carbonate, acid trapping polymer(such as
Dowex) to form racemic Zopiclone of formula I
V. Resolution of racemic zopiclone with chiral acids to form zopiclone chiral acid salt in presence of water miscible organic solvent and water
VI. Preparation of Eszopiclone with chiral purity of about 95 to 99.5% from chiral acid salt in presence of ester solvents , chlorinated solvents ,water or mixtures there of

dihydropyrrolo-[3,4-b]-pyrazine which can further be converted to racemic Zopiclone

The resolution of stereoisomers can be carried out by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, or lactic acid wherever applicable or chiral bases such as brucine, cinchona alkaloids, or their derivatives. In the present invention resolution is carried out in presence of chiral acids by forming the corresponding salts. Present invention also discloses that the purity of the chiral zopiclone salt can be controlled by varying the reaction temperature from about 25 to 60 °C and also by varying the time taken to maintain the reaction at that temperature.
In one embodiment of the invention it is disclosed that the seeding is made by either racemic zopiclone, zopiclone salt or R-zopiclone to get the said Eszopiclone of chiral purity of about 95 to 99.5%
The present invention also provide a process for the recycle of R-enantiomer by converting it to 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo-[3,4-b]-Pyrazine which can further be converted to racemic Zopiclone by the process as disclosed in step IV.
While the present invention has been described in terms of its specific embodiments, 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.
The invention is further illustrated with a few non-limiting examples

Examples

acid
2-amino-5-chloro pyridine (171.2 g) was suspended in 800 ml toluene and mixture was heated to 48-52°C. Pyrazine-2,3-dicarboxylic acid anhydride (100 g) was added to the suspension at same temperature. The resulting reaction mixture was stirred for 2hrs at 48-52°C . The reaction slurry was cooled to 20-25°C and stirred for 30 min. The solid was filtered and washed with 100 ml toluene. The filtered solid was added to a mixture of 1000 ml water and 100 ml cone. HC1 at 10-15°C. Stirred the solid for 60 min at 10-15°C and filtered. The solid was slurred in 400 ml water, filtered and washed with 100 ml water .The solid was dried at 60-70°C to yield 170 g of title compound of HPLC purity 99.5%

500 ml dichloromethane. The suspension was refluxed azeotropically for 60 min. The mixture was cooled to 25-30°C and dimethyl formamide (2.6 gm) was added followed by addition of thionyl chloride (72 g) in 45-60 min at 25-30°C. The resulting mixture was refluxed till completion of reaction. The reaction mixture was concentrated to dryness at atmospheric pressure. Cooled the solid to 20-25°C and 500 ml chilled water was added and the resulting slurry was degassed under reduced pressure at ~40°C. Cooled the slurry to 20-25°C and stirred for 30 min. Slurry was filtered and washed with 200 ml water. The solid was dried at 60-70°C to obtain 88 g of title compound of HPLC purity 99%


suspended in 900 ml water. The slurry was cooled to 0-5°C and 100 ml (7.2%) of aqueous sodium borohydride solution stabilized with O.lg sodium hydroxide was added in 3hrs under vigorous stirring. Stirred the reaction mixture at 0-5°C for 4 to 5hrs. After completion of reaction solid was filtered and washed with 2X300 ml water. The filtered solid was refluxed in 215 ml dichloromethane for 30 min and cooled to 25-30°C. The solid was filtered, washed with 100 ml dichloromethane and dried at 50-60°C to obtain 82g of title compound with HPLC purity of 99.5%.

piperazine carbomoyl chloride hydrochloride (106.1 g) was cooled to 10-15°C. Calcium oxide (42.66 g) and Dimethyl amino pyridine (2.5 g) were added to the mixture. Reaction mixture was warmed to 25-30°C and stirred till completion of reaction. After completion of reaction, mixture was filtered and washed with 400 ml dichloromethane. The dichloromethane layer was concentrated at atmospheric pressure till dryness. 400 ml of methanol was added to residual solid and stirred for 60 min at 25-30°C. Slurry was cooled to 0-5°C and stirred for 60 min at same temperature. Solid was filtered, washed with chilled methanol 2X25 ml and dried at 50-60°C to obtain 126 g of racemic Zopiclone


(Zopiclone) (lOOg) and D(+)-0? O'-dibenzoyltartaric acid (90.3 g) was stirred for 2hrs at 25-30°C The mixture was heated to 75-80°C till clear solution was obtained. The mixture was cooled slowly to 50°C and stirred for 60 min at the same temperature. The mixture was further cooled slowly to 30-32°C and solid obtained was filtered. The filtered solid was washed with 100 ml acetonitrile. The solid was dried at 60-65°C to obtain 92 g of Zopiclone salt with chiral purity > 99.0 %
Method II:

(Zopiclone)(100g) and D(+)-0,0'-dibenzoyltartaric acid (90.3 g) was stirred for 2hrs at 25-30°C. The mixture was heated to 75-80°C till clear solution obtained. The mixture was cooled slowly to 50°C and stirred for 60 min at the same temperature. The mixture was cooled slowly to 40°C and stirred for 60 min. The mixture was further cooled slowly to 28-30°C and stirred for 30 min at 28°C. Then the solid was filtered and washed with 100 ml acetonitrile. The solid was dried at 60-65°C to obtain 90 g of Zopiclone with chiral purity ~ 97.0 %.



carbonyloxy-7-oxo-5,6-dihydropyrrolo-[3,4-b]-pyrazine D(+)-0,0'-dibenzoyltartaric acid salt 100 g and water 250 ml was warmed to 40-42°C. Sodium bicarbonate (28.1 g) was added to the mixture and heated to 60-65°C . Reaction mixture was stirred for 30 min and organic layer was separated. The organic layer was washed with 200ml water. The organic layer was treated with activated carbon (5g) for 30min at 60°C. Carbon was filtered over high flow and washed with 100 ml ethyl acetate. The filtrate was concentrated to 250 ml under mild vacuum at 50-55°C The slurry was slowly cooled to 0-5°C and stirred for 2hrs at the same temperature. The solid was filtered and washed with 50 ml ethyl acetate. The solid was dried at 50-60°C to obtain 44 g Eszopiclone with chiral purity 99.5%
Different methods of preparation of enantiomerically enriched Eszopiclone,
Example 1:

050'-dibenzoyltartaric acid salt 100 g (Chiral purity 99%)and water 250 ml was wanned to 40-42°C. Sodium bicarbonate (28. lg) was added to the mixture and heated to 60-65°C. Reaction mixture was stirred for 30 min and organic layer was separated. The organic layer was washed with 200ml water. The organic layer was treated with activated carbon (5g) for 30 min at 60°C. Carbon was filtered over high flow and washed with 100 ml ethyl acetate. The filtrate was concentrated to 800 ml under mild vacuum at 50-55°C. Racemic Zopiclone (1.3 g) was seeded to the filterate. The filterate was concentrated to -250 ml volume. The slurry was slowly cooled to -5°C to -10°C and stirred for 2hrs at the same temperature .The solid was filtered and washed with chilled 50 ml ethyl acetate (-10°C).The solid was dried at 50-60°C to obtain 44 g Eszopiclone with chiral purity -99.1%


0,0'-dibenzoyltartaric acid salt lOOg (Chiral purity 99%)and water 250ml was wanned to 40-42°C. Sodium bicarbonate (28. lg) was added to the mixture and heated to 60-65°C. Reaction mixture was stirred for 30 min and organic layer was separated. The organic layer was washed with 200ml water. The organic layer was treated with activated carbon (5g) for 30 min at 60°C. Carbon was filtered over high flow and washed with 100 ml ethyl acetate. The filtrate was concentrated to 800 ml under mild vacuum at 50-55°C. Zopiclone salt (1.3 g) was seeded to the filterate. The filterate was concentrated to -250 ml volume. The slurry was slowly cooled to -5°C to -10°C and stirred for 2hrs at the same temperature .The solid was filtered and washed with chilled 50 ml ethyl acetate (-10°C).The solid was dried at 50-60°C to obtain 44 g Eszopiclone with chiral purity -99.1%

0,0'-dibenzoyltartaric acid salt 100 g (Chiral purity 99%)and water 250 ml was warmed to 40-42°C. Sodium bicarbonate (28.1 g) was added to the mixture and heated to 60-65°C. Reaction mixture was stirred for 30 min and organic layer was separated. The organic layer was washed with 200ml water. The organic layer was treated with activated carbon (5 g) for 30 min at 60°C. Carbon was filtered over high flow and washed with 100 ml ethyl acetate. The filtrate was concentrated to 800 ml under mild vacuum at 50-55°C. (R)- Zopiclone (0.65 g) was seeded to the filterate. The filterate was concentrated to -250 ml volume. The slurry was slowly cooled to -5°C to -10°C and stirred for 2hrs at the same temperature. The solid was filtered and washed with chilled 50 ml ethyl acetate (-10°C)and then dried at 50-60°C to obtain 44 g Eszopiclone with chiral purity -99.1 %

Example-2:

dibenzoyltartaric acid salt loog (Chiral purity 99%)and water 250 ml was warmed to 35-37°C. Sodium bicarbonate (28. lg) was added to the mixture and maintained at 35-37°C. Reaction mixture was stirred for 30-60 min and cooled to 25-30°C. Organic layer was separated. The organic layer was washed with 200 ml water and then treated with activated carbon (5 g) for 30 min at 20-25°C. Carbon was filtered over high flow and washed with 100 ml dichloromethane. The filtrate was concentrated to 150ml at atmospheric pressure. Zopiclone(1.3 g) was added to the mixture. Cyclohexane (600 ml) was added to residual solution at 25-30°C in 60 min. The slurry was slowly cooled to 0°C to 5°C and stirred for 60 min at same temperature .The solid was filtered and washed with chilled 50 ml Cyclohexane (10°C)and then dried at 50-60°C to obtain 44 g Eszopiclone with chiral purity -99.1% Optical rotation [a]D at 25.5°C is 133.92°
XRD of the compound is as depicted in Figure 1

0,0'-dibenzoyltartaric acid salt 100 g (Chiral purity 97%)and water 250 ml was warmed to 35-37°C. Sodium bicarbonate (28.1 g) was added to the mixture and maintained at 35-37°C. Reaction mixture was stirred for 30-60 min and cooled to 25-30°C. Organic layer was separated. The organic layer was washed with 200 water and then with activated carbon (5 g) for 30 min at 20-25°C. Carbon was filtered over high flow and washed with 100 ml dichloromethane. The filtrate was concentrated to 150 ml at atmospheric pressure. Cyclohexane (600 ml) was added to residual solution at 25-30°C in 60 min. The slurry was slowly cooled to 0 to 5°C and stirred for 60 min at same temperature .The solid was filtered and washed with chilled 50 ml Cyclohexane

(10°C)and then dried at 50-60°C to obtained 44 g Eszopiclone with chiral purity -97%. Optical rotation [a]D at 25.1°C is 130°
XRD of the compound is as depicted in Figure 2 .
ExampIe-3

D(+)-0,0'-dibenzoyltartaric acid salt 100 g (Chiral purity 99%) at 25-30°C.PrefiItered sodium bicarbonate solution (28.1 g sodium bicarbonate + 500 ml D.M.Water) was added in l-2hrs at 25-30°C . The resulting slurry was stirred for 2hrs at 25-30°C and filtered. The solid was washed with D.M.Water (2X200 ml) at 25-30°C. The solid was dried under vacuum at 50-60°C till moisture content NMT 0.2% to obtain 49 g Eszopiclone with chiral purity of-99.3%
Method II: Stirred the suspension of D.M.Water (1000ml) and 6-(5-chioropyrid-2-yl)-5-(4-methylpiperazin-l-yl)-carbonyloxy-7-oxo-5,6-dihydropyrrolo-[3,4-b]-Pyrazine D (+)-0, O'-dibenzoyltartaric acid salt 100 g (Chiral purity 97%) at 25-30°.Prefiltered sodium bicarbonate solution (28.1 g sodium bicarbonate + 500 ml D.M.Water) was added in l-2hrs at 25-30°C . The resulting slurry was stirred for 2hrs at 25-30°C and filtered. The solid was washed with D.M.Water (2X200 ml) at 25-30°C. The solid was dried under vacuum at 50-60°C till moisture content NMT 0.2%. To obtained 49 g Eszopiclone with chiral purity -97%

Concentrated the mother liquor (acetonitrile water mixture)of Step-V to 250 ml under reduced pressure at below 70°C Cooled the mixture to 25-30°C, added 300 ml water to the residue followed by 300 ml dichloromethane. Stirred the mixture for 15 min and

sodium bicarbonate (30 g) was added to the mixture. The mixture was stirred for 30 min at 25-3G°C, dichloromethane was separated. Solvent was concentrated at atmospheric pressure to dryness. Finally traces of dichloromethane were removed under reduced pressure. Formic acid 50 ml was added to the residue followed by 28 ml conc.HCl. The resulting reaction mixture was heated to 64-68°C and stirred for 3hrs at the same temperature. . Cooled the mixture to 25-30°C and 200 ml water was added to the reaction mixture. Cooled the slurry to 0-5 °C and stirred for 60 min at same temperature. The solid was filtered and washed with 100 ml water at 0-5°C . Dried the