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-b]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(+)-0,0'-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(+)-O,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 as well as the number of crystallization steps involved. The present process provides eszopiclone with high chiral purity and improved yield. Thus, the present invention is 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) forming a first reaction mixture comprising zopiclone of Formula II ,



(Formula Removed)
and an optically active acid in a first organic solvent,
b) treating the first reaction mixture obtained in step a) with a second organic
solvent,
c) isolating a salt as a solid from the reaction mixture thereof,
d) forming a second reaction mixture comprising the salt obtained in step c) and
the first organic solvent,
e) treating the second reaction mixture obtained in step d) with the second
organic solvent,
f) isolating a salt as a solid from the reaction mixture thereof,
g) treating the salt obtained in step f) with a base to obtain eszopiclone of
Formula I, and
h) 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. A first reaction mixture comprising zopiclone and an optically active acid in a first organic solvent is formed. The optically active acid is preferably D(+)-0,O'-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(+)-O,0'-dibenzoyltartaric acid or its hydrate. The first organic solvent is selected from a group consisting of halogenated hydrocarbons, cyclic ethers, and mixtures thereof. The first organic solvent is preferably dichloromethane or tetrahydrofuran. The first organic solvent is more preferably dichloromethane. The first organic solvent is used in a quantity of about 9 times or less to the weight of zopiclone. The first reaction mixture is preferably in the form of solution. The first reaction mixture is preferably formed by mixing a solution of the optically active acid in the first organic solvent with a solution of zopiclone in the first organic solvent at about 10°C to about 50°C and by stirring. The first reaction mixture is treated with a second organic solvent. The second organic solvent is selected from a group consisting of nitrites, C1-5 alkanols, and mixtures thereof. The second organic solvent is preferably selected from the group consisting of acetonitrile, methanol, ethanol and mixtures thereof. The second organic solvent is more preferably acetonitrile. The second organic solvent is used in a quantity of about 6 times or less to the weight of zopiclone. The reaction mixture so obtained is cooled to about 0°C to about 15°C and a salt is allowed to form as a precipitate. The salt is isolated as a solid from the reaction mixture thereof by filtration, concentration, distillation, or a combination thereof. The salt so obtained is optionally washed with a mixture of the first and second organic solvents. A second reaction mixture comprising the salt and the first organic solvent is formed. The first organic solvent is used in a quantity of about 9 times or less to the weight of the salt. The second reaction mixture is preferably formed by treating the salt with the first organic solvent and heating to reflux temperature. The second reaction mixture is treated with the second organic solvent at about 30°C to about 50°C. The second organic solvent is used in a quantity of about 6 times or less to the weight of the salt. The reaction mixture is cooled to about 0°C to about 15°C and stirred. The salt is isolated as a solid from

the reaction mixture thereof by filtration, concentration, distillation, or a combination thereof. The salt so obtained is optionally washed with a mixture of the first and second organic solvents. The salt so obtained is treated with a base to obtain eszopiclone of Formula I. 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, carbontetra chloride 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
PREPARATION OF ESZOPICLONE A) Preparation of zopiclone:
Sodium hydride (18.2 g) was added to dimethylformamide (500 ml) at 0° to 5°C and stirred for 15 minutes. 6-(5-Chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5/-/-pyrrolo[3,4-b]pyrazin-5-one (100 g) was added to the reaction mixture at 0° to 5°C. The reaction mixture was stirred for 30 minutes at 0° to 5°C to obtain a

heterogeneous mixture. A solution of 4-methylpiperazine-1-carbonyl chloride (71.2 g) in dimethylformamide (100 ml) was added to the reaction mixture slowly at 0° to 5°C. The reaction mixture was further stirred for 30 minutes at 0° to 5°C to obtain a clear solution. The solution so obtained was added to cool water (5° to 10°C, 2.5 L) and stirred for 30 minutes at 10° to 15°C. The solid was filtered and washed twice by suspending in water (2 X 500 ml). The solid was dried under vacuum at 50° to 55°C for 8 to 10 h to obtain the title compound.
Yield: 125g HPLC Purity: 99%
B) Preparation of eszopiclone:
D(+)-O,0'-dibenzoyltartaric acid monohydrate (96 g) was dissolved in dichloromethane (500 ml) by stirring at 25° to 30°C. Zopiclone obtained from step A) was dissolved in dichloromethane (300 ml) by stirring at 25° to 30°C. Both the solutions were mixed at 25° to 30°C and stirred for 30 minutes at 25° to 30°C. Acetonitrile (500 ml) was added to the solution so obtained at 25° to 30°C. The mixture was stirred at 25° to 30°C for 1 h. The solid was filtered, washed with a 1:1 mixture of dichloromethane and acetonitrile (200 ml) and dried under vacuum at 50° to 55°C for 5 h. Dichloromethane (1 L) was added to the solid so obtained, heated to reflux temperature and maintained at the reflux temperature for 30 minutes to obtain a solution. Acetonitirle (600 ml) was added to the solution at 35° to 40°C. The mixture was stirred at 35° to 40°C for 30 minutes. The solid was filtered, washed with a 1:1 mixture of dichloromethane and acetonitrile (200 ml), and dried under vacuum at 45° to 50°C for 8 to 10 h to obtain the title compound.
Yield: 75 g
HPLC Purity: 99.85%
Chiral Purity: 99.9%

WE CLAIM:
1. A process for the preparation of eszopiclone of Formula I,
(Formula Removed)
wherein the process comprises,
a) forming a first reaction mixture comprising zopiclone of Formula II ,

(Formula Removed)
and an optically active acid in a first organic solvent,
b) treating the first reaction mixture obtained in step a) with a second organic
solvent,
c) isolating a salt as a solid from the reaction mixture thereof,
d) forming a second reaction mixture comprising the salt obtained in step c) and
the first organic solvent,
e) treating the second reaction mixture obtained in step d) with the second
organic solvent,

f) isolating a salt as a solid from the reaction mixture thereof,
g) treating the salt obtained in step f) with a base to obtain eszopiclone of
Formula I, and
h) 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.
3. A process according to claim 2, wherein the optically active acid is D(+)-O,O'-
dibenzoyltartaric acid or its hydrate.
4. A process according to claim 1, wherein the first organic solvent is selected
from a group consisting of halogenated hydrocarbons, cyclic ethers, and mixtures
thereof.

5. A process according to claim 4, wherein the first organic solvent
dichloromethane or tetrahydrofuran.
6. A process according to claim 5, wherein the first organic solvent is
dichloromethane.

7. A process according to claim 1, wherein the first organic solvent is used in
step a) in a quantity of about 9 times or less to the weight of zopiclone.
8. A process according to claim 1, wherein the second organic solvent is selected
from a group consisting of nitriles, C1-5alkanols, and mixtures thereof.

9. A process according to claim 8, wherein the second organic solvent is selected
from the group consisting of acetonitrile, methanol, ethanol and mixtures thereof.
10. A process according to claim 9, wherein the second organic solvent is
acetonitrile.