The present invention relates to a process for the preparation of eszopiclone.
Eszopiclone is a nonbenzodiazepine hypnotic agent and it is the dextrorotatory isomer of zopiclone. Eszopiclone is chemically (+)-(5S)-6-(chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b] pyrazin-5-yl 4-methyl- piperazine-1-carboxylate of Formula II



(Formula Removed)
Eszopiclone is presently in the market for the treatment of insomnia. Eszopiclone decreases sleep latency and improves sleep maintenance when administered at bed time.
US 6,444,673 provides a process for the preparation of eszopiclone by resolving zopiclone using D(+)-O,O'-dibenzoyltartaric acid. Zopiclone is a racemic compound, which is chemically 6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-£>]pyrazin-5-yl 4-methylpiperazine-1-carboxylate of Formula II.



(Formula Removed)
According to the process provided in US '673 patent, a first reaction mixture is formed by mixing a solution of D(+)-O,0'-dibenzoyltartaric acid in dichloromethane to a solution of zopiclone in dichloromethane. The reaction mixture is concentrated to dryness to form a dry salt. The salt is recrystallized from acetonitrile to form a first crystallized salt. The first crystallized salt is dissolved in dichloromethane with reflux, followed by the addition of acetonitrile to form a second reaction mixture. The second reaction mixture is left standing for 1 h form a second crystallized salt. The second crystallized salt is again recrystallized using dichloromethane and acetonitrile to obtain third crystallized salt. The third crystallized salt is dissolved in water in the presence of dichloromethane to form a third reaction mixture. The third reaction mixture is alkalinized to pH 11 and the organic phase is separated after two extractions. The organic phase is dried over magnesium sulfate, filtered and the solvent is removed by evaporation. The eszopiclone so obtained is recrystallized from acetonitrile. The process also involves the use of about 103 times of acetonitrile to the quantity of starting substrate of zopiclone.
WO 07/083188 and US 2007/0054914 provide a process for the preparation of eszopiclone by resolving zopiclone using D(+)-0,O'-di-p-toluyl-D-tartaric acid. WO 07/088073 provides a process for the preparation of eszopiclone by resolving zopiclone using L-tartaric acid. The processes provided in these prior art references also involve huge amount of solvents and multiple crystallization of the optically active salts to obtain desired purity levels.
The present inventors have developed an advantageous process for the preparation of eszopiclone, which substantially reduces the amount of solvents involved in the resolution of zopiclone and avoids the crystallization steps involved in purifying the optically active salts. The present process also provides eszopiclone with high chiral purity. Thus, the present invention is simple and efficient to prepare eszopiclone in an economic and industrially preferable manner.

A first aspect of the present invention provides a process for the preparation of
eszopiclone of Formula I,
(Formula Removed)
wherein the process comprises, a) treating zopiclone of Formula II,



(Formula Removed)
with an optically active acid in a solvent system comprising one or more water miscible organic solvents, to obtain eszopiclone of Formula I in the form of a salt with the optically active acid,
b) treating the salt obtained in step a) with a base to obtain eszopiclone of
Formula I, and
c) isolating eszopiclone of Formula I from the reaction mixture thereof.
Zopiclone of Formula II, which is used as a starting material, can be obtained by following the method provided in US 3,862,149. Zopiclone is treated with an optically active acid in a solvent system comprising one or more water miscible organic solvents. The optically active acid is preferably D(+)-O,0'-dibenzoyltartaric acid, D(+)-O,0'-di-p-toluyl-D-tartaric acid or L-tartaric acid, or hydrates thereof. The optically active acid is more preferably D(+)-0,0'-dibenzoyltartaric acid or its hydrate. The water miscible organic solvent is

selected from a group consisting of acetonitrile, methanol, ethanol, n-propanol, isopropanol, acetone, tetrahydrofuran, dioxane, and dimethylsulfoxide, dimethylformamide, and mixtures thereof. The water miscible organic solvent is more preferably selected from the group consisting of acetonitrile, methanol, and ethanol. The solvent system preferably comprises two water miscible organic solvents. The solvent system can optionally contain water. The treatment of zopiclone with the optically active acid is preferably carried out by contacting a mixture comprising zopiclone in a solvent system comprising one or more water miscible organic solvents, with the optically active acid. The mixture so obtained is heated to a temperature of about 60°C to about 85°C and optionally filtered at this temperature. The mixture is cooled to about 50°C or below. The mixture is preferably cooled to about 50°C and subsequently to about 20° to about 45°C to obtain eszopiclone of Formula I in the form of a salt with the optically active acid. The salt so obtained has a chiral purity of about 99% or above, and preferably about 99.3% or above. The salt is optionally isolated as a solid from the reaction mixture thereof by filtration, concentration, distillation, or a combination thereof, and washed.
The salt so obtained is further converted into eszopiclone of Formula I by treating with a base. The treatment with base is carried out in the presence of a mixture of a water immiscible or partially miscible organic solvent and water. The water immiscible or partially miscible organic solvent is selected from a group consisting of dichloromethane, toluene, pentane, methyl ethyl ketone, methyl t-butyl ether, iso-octane, hexane, heptane, diethyl ether, ethyl acetate, 1,2-dichloroethane, cyclohexane, chloroform, carbon tetrachloride and petroleum ether. The water immiscible or partially miscible organic solvent is preferably dichloromethane. The base is selected from the group consisting of hydroxides, bicarbonates or carbonates of alkali metals or alkaline earth metals, alkoxides and amines. The base is preferably sodium hydroxide. The base is used in a quantity to attain a pH of about 9 to about 12. The treatment with base is optionally accompanied by stirring. The organic layer is subsequently separated and eszopiclone of Formula I is isolated from the organic layer. The isolation is

carried out by concentration, distillation, precipitation, filtration or combinations thereof.
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.
EXAMPLE 1
PREPARATION OF D(+)-O,O'-DIBENZOYLTARTARIC ACID SALT OF ESZOPICLONE:
Zopiclone (30 g) was suspended in a mixture of water (240 ml), acetonitrile (360 ml) and ethanol (60 ml). The suspension was stirred for 10 minutes at 20° to 25°C and D(+)-0,0'-dibenzoyltartaric acid monohydrate (29.4 g) was added to the suspension. The reaction mixture was heated to 60° to 70°C, maintained at the same temperature for 30 minutes and filtered at 60° to 70°C. The filtrate was heated to 60° to 70°C to obtain a solution, cooled to 35°C in about 2 h and stirred for further 2 h at 35° to 30°C. The solid was filtered at 35° to 30°C, washed with acetonitrile (15 ml) and dried at 45° to 55°C to obtain the title compound.
Yield: 24 g
HPLC Purity: 99.9%
Chiral Purity: 99.8%
EXAMPLE 2
PREPARATION OF D(+)-O,O'-DIBENZOYLTARTARIC ACID SALT OF ESZOPICLONE:
A stirred mixture of zopiclone (30 g) and D(+)-O,O'-dibenzoyltartaric acid monohydrate (29.4 g) in acetonitrile (360 ml) and ethanol (60 ml) was heated to 70° to 80C°. The mixture was maintained at 70° to 80C° for 1 h, slowly cooled to 50°C and maintained for 30 minutes. The temperature was further reduced to 30° to 35°C and maintained for 30 minutes. The solid material was filtered,

washed with acetonitrile (60 ml) and dried at 45° to 50°C for 6 to 7 h to obtain the
title compound.
Yield: 24 g
Chiral Purity: 99.33%
EXAMPLE 3 PREPARATION OF ESZOPICLONE:
Dichloromethane (900 ml) was added to D(+)-0,0'-dibenzoyltartaric acid salt of eszopiclone (100 g) and stirred at 25° to 30°C, followed by the addition of water (900 ml). The mixture was cooled to 5° to 10°C and the pH was adjusted to 10 to 11 by slow addition of 2 N aqueous sodium hydroxide solution, while maintaining the temperature at 5° to 10°C. The layers were separated. Dichloromethane (900 ml) was added to the aqueous layer, stirred for 10 to 15 minutes, and the layers were separated. Dichloromethane (500 ml) was added to the aqueous layer so obtained, stirred for 10 to 15 minutes, and the layers were separated. The organic layers were combined together and washed with water (900 ml). The solvent was distilled out from the organic layer and the solid obtained was suspended in acetonitrile (500 ml). The mixture was stirred for 60 minutes at 25° to 30°C and the solid was filtered and dried under vacuum at 40° to 45°C for 8 to 10 h to obtain the title compound.
Yield: 40 g
HPLC Purity: 99.9%
Chiral Purity: 99.9%

WE CLAIM:

1. A process for the preparation of eszopiclone of Formula I,
(Formula Removed)
wherein the process comprises, a) treating zopiclone of Formula II ,
(Formula Removed)
with an optically active acid in a solvent system comprising one or more water miscible organic solvents, to obtain eszopiclone of Formula I in the form of a salt with the optically active acid,
b) treating the salt obtained in step a) with a base to obtain eszopiclone of
Formula I, and
c) isolating eszopiclone of Formula I from the reaction mixture thereof.

2. A process according to claim 1, wherein the optically active acid is D(+)-
O,O'-dibenzoyltartaric acid, D(+)-O,O'-di-p-toluyl-D-tartaric acid or L-
tartaric acid, or hydrates thereof.

2. A process according to claim 2, wherein the optically active acid is D(+)-
0,O'-dibenzoyltartaric acid or its hydrate.

3. A process according to claim 1 , wherein the water miscible organic solvent
is selected from a group consisting of acetonitrile, methanol, ethanol, n-
propanol, isopropanol, acetone, tetrahydrofuran, dioxane, and
dimethylsulfoxide, dimethylformamide, and mixtures thereof.
4. A process according to claim 3, wherein the water miscible organic solvent
is selected from the group consisting of acetonitrile, methanol and ethanol.
5. A process according to claim 1 , wherein the solvent system comprises two
water miscible organic solvents.
6. A process according to claim 1, wherein step a) is carried out by
contacting a mixture comprising zopiclone in a solvent system comprising
one or more water miscible organic solvents, with the optically active acid.
7. A process according to claim 1, wherein step a) is carried out at a
temperature of about 60°C to about 85°C.
8. A process according to claim 1, wherein the salt obtained in step a) has a
chiral purity of about 99% or above.
9. A process according to claim 8, wherein the salt obtained in step a) has a
chiral purity of about 99.3% or above.