The present invention relates to a process for the preparation of 6-(5-chloropyridin-2-
yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I.
(Formula Removed)
The present invention further relates to a process for the preparation of eszopiclone using 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I as an intermediate.
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, WO 07/083188, US 2007/0054914, and WO 07/088073 provide processes for the separation of eszopiclone from zopiclone of Formula III using optically active salts.

(Formula Removed)
US 3,862,149 provides a process for the preparation of zopiclone using 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I as an intermediate.

(Formula Removed)
The process provided in US '149 patent for preparing 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I involves reacting furo[3,4-b]pyrazine-5,7-dione of Formula IV,
(Formula Removed)
with 2-amino-5-chloropyridine in the presence of acetonitrile at reflux temperature to obtain 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic acid of
Formula V,
(Formula Removed)
and cyclizing the compound of Formula V at reflux temperature using thionyl chloride. The process involves isolation of the compound of Formula V as a solid by

pH adjustment and it is further purified by washing and drying before subjecting to cyclization.
The present inventors have developed an advantageous process for the preparation of 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I. The present process does not require the isolation of 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic acid of Formula V and it avoids the use of corrosive reagents such as thionyl chloride. Further, the present inventors have observed that the reaction of furo[3,4-b]pyrazine-5,7-dione of Formula IV with 2-amino-5-chloropyridine can be carried out at ambient temperature conditions. The present process also improves the yield and purity of 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I. Thus, by employing the present process, zopiclone and eszopiclone can be prepared in an economic and environmentally preferable way.
A first aspect of the present invention provides a process for the preparation of 6-(5-
chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I,
(Formula Removed)
wherein the process comprises, a) reacting furo[3,4-b]pyrazine-5,7-dione of Formula IV,
(Formula Removed)
with 2-amino-5-chloropyridine at about 35°C or below to obtain 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic acid of Formula V,

(Formula Removed)
b) cyclizing 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic acid of
Formula V to obtain 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione
of Formula I, and

c) isolating 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of
Formula I from the reaction mixture thereof.

A second aspect of the present invention provides a process for the preparation of 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I,
(Formula Removed)
wherein the process comprises, a) reacting furo[3,4-b]pyrazine-5,7-dione of Formula IV,
(Formula Removed)
with 2-amino-5-chloropyridine to obtain 3-{[(5-chloropyridin-2-yl)amino]carbonyl}
pyrazine-2-carboxylic acid of Formula V,
(Formula Removed)
b) cyclizing 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic acid of
Formula V in the presence of acetic anhydride to obtain 6-(5-chloropyridin-2-yl)-5H-
pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I, and
c) isolating 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of
Formula I from the reaction mixture thereof.
Furo[3,4-b]pyrazine-5,7-dione of Formula IV used as a starting material can be prepared according to the method provided in Chem. Ber, 40, 4850 (1907). 2-amino-5-chloropyridine can be prepared according to the method provided in Pharmazie, 19(10), 677 (1964). Furo[3,4-b]pyrazine-5,7-dione of Formula IV is reacted with amino-5-chloropyridine in the presence of an organic solvent. The organic solvent is selected from the group consisting of amides, nitriles, ethers, aliphatic or aromatic hydrocarbons, halogenated hydrocarbons, ketones, alcohols, and esters. The organic solvent is preferably dimethylformamide or acetonitrile. The organic solvent is more preferably dimethylformamide. The reaction is carried out at a temperature of about 35°C or below, preferably of about 0°C to about 30°C, more preferably of about 25°C to about 30°C. The formation of 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic acid of Formula V may be facilitated by stirring the reaction mixture. The compound of Formula V is optionally isolated from the reaction mixture and cyclized to obtain 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I. The cyclization is carried out in the presence of acetic anhydride. The reaction mixture for cyclization can also contain an organic solvent selected from the group consisting of amides, nitriles, ethers, aliphatic or aromatic hydrocarbons, halogenated hydrocarbons, ketones, alcohols, and esters. The organic solvent is preferably dimethylformamide. The cylization may be facilitated by heating the reaction mixture to a temperature of about 60°C to about 100°C. 6-(5-Chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I can be isolated from the reaction mixture by the methods including layer separation, concentration, precipitation, filtration, or a combination thereof.
A third aspect of the present invention provides a process for the preparation of 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I,

(Formula Removed)
wherein the process comprises, a) reacting furo[3,4-b)]pyrazine-5,7-dione of Formula IV,
(Formula Removed)
with 2-amino-5-chloropyridine to obtain 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic acid of Formula V,
(Formula Removed)
b) cyclizing 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic acid of
Formula V to obtain 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-517(6H)-dione
of Formula I, and
c) isolating 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of
Formula I from the reaction mixture thereof,
wherein the process is characterized by the fact that 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic acid of Formula V is not isolated from the reaction mixture before step c).
Furo[3,4-b]pyrazine-5,7-dione of Formula IV used as a starting material can be prepared according to the method provided in Chem. Ber., 40, 4850 (1907). 2-amino-5-chloropyridine can be prepared according to the method provided in Pharmazie, 19(10), 677 (1964). Furo[3,4-b]pyrazine-5,7-dione of Formula IV is reacted with amino-5-chloropyridine in the presence of an organic solvent. The organic solvent is selected from the group consisting of amides, nitriles, ethers, aliphatic or aromatic hydrocarbons, halogenated hydrocarbons, ketones, alcohols,
and esters. The organic solvent is preferably dimethylformamide or acetonitrile. The organic solvent is more preferably dimethylformamide. The reaction is carried out at a temperature of about 35°C or below, preferably of about 0°C to about 30°C, more preferably of about 25°C to about 30°C. The formation of 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic acid of Formula V may be facilitated by stirring the reaction mixture. The compound of Formula V is not isolated from the reaction mixture and it is directly cyclized to obtain 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I. The cyclization is carried out in the presence of acetic anhydride. The acetic anhydride may be added to the reaction mixture comprising the compound of Formula V or the reaction mixture comprising the compound of Formula V may be added to acetic anhydride. The cylization may be facilitated by heating the reaction mixture to a temperature of about 60°C to about 100°C. 6-(5-Chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I can be isolated from the reaction mixture by the methods including layer separation, concentration, precipitation, filtration, or a combination thereof.
A fourth aspect of the present invention provides a process for the preparation of 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I,
(Formula Removed)
wherein the process comprises, a) reacting furo[3,4-b]pyrazine-5,7-dione of Formula IV,
(Formula Removed)
with 2-amino-5-chloropyridine in the presence of acetic anhydride to obtain 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I, and

b) isolating 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I from the reaction mixture thereof.
Furo[3,4-b]pyrazine-5,7-dione of Formula IV used as a starting material can be prepared according to the method provided in Chem. Ber, 40, 4850 (1907). 2-amino-5-chloropyridine can be prepared according to the method provided in Pharmazie, 19(10), 677 (1964). Furo[3,4-Jb]pyrazine-5,7-dione of Formula IV is reacted with amino-5-chloropyridine in the presence acetic anhydride. The reaction mixture can also contain an organic solvent. The organic solvent is selected from the group consisting of amides, nitriles, ethers, aliphatic or aromatic hydrocarbons, halogenated hydrocarbons, ketones, alcohols, and esters. The reaction is carried out at a temperature of about 10°C to about 90°C, preferably of about 60°C to about 85°C, more preferably of about 80°C to about 85°C. The reaction may be facilitated by stirring the reaction mixture. The reaction mixture is subsequently cooled to about 30°C or below and optionally quenched with water. 6-(5-Chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I is isolated from the reaction mixture by the methods including layer separation, concentration, precipitation, filtration, or a combination thereof.
6-(5-Chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I obtained according to the previous aspects of the invention is further converted into zopiclone and eszopiclone. 6-(5-Chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I is reduced to obtain 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one of Formula VI.
(Formula Removed)
The reduction is carried out in the presence of a reducing agent and water or an organic solvent, or a mixture thereof. The reducing agent is preferably potassium borohydride or sodium borohydride. The organic solvent is preferably a water miscible organic solvent. The organic solvent is more preferably dioxane. The

compound of Formula VI is reacted with 1-chlorocarbonyl-4-methylpiperazine to obtain zopiclone of Formula III.
(Formula Removed)

1-Chlorocarbonyl-4-methylpiperazine can be used as a free base or as an acid addition salt. The reaction is preferably carried out in the presence of sodium hydride and an organic solvent. The organic solvent is preferably an amide, more preferably dimethylformamide. Zopiclone of Formula III is resolved to obtain eszopiclone of Formula II.
(Formula Removed)
The resolution can be carried out by using optically active acids, chiral chromatography, or enzymatic methods. The resolution is preferably carried out by using an optically acid in the presence of an organic solvent. The organic solvent is selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbon, halogenated hydrocarbons, alcohols and nitriles. The optically active acid is preferably D(+)-O,O'-dibenzoyltartaric acid. The salt of eszopiclone so obtained is isolated by crystallization and treated with a base to obtain eszopiclone in the presence of water or an organic solvent or a mixture thereof. The base is preferably an alkali metal hydroxide. The organic solvent is preferably a halogenated hydrocarbon or an ester. Eszopiclone can be isolated from the reaction mixture by the methods including layer separation, precipitation, concentration, filtration or a combination 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.
COMPARATIVE EXAMPLE (According to US 3,862,149)
PREPARATION OF 6-(5-CHLOROPYRID-2-YL)-5, 7-DIOXO-5.6-
DIHYDROPYRROLO[3,4-B]PYRAZINE
A) A suspension of 2-amino-5-chloropyridine (100 g) and pyrazine -2,3-dicarboxylic
acid anhydride (58.5 g) in acetonitrile (1.17 L) was heated at reflux temperature for
1.5 h. The reaction mixture was cooled, filtered and washed with Acetonitrile (350
ml). The solid material so obtained was dried and washed with 1N hydrochloride
(330ml).
B) A suspension of the solid obtained from step 1) (100 g) in thionyl chloride (500 ml)
was heated at reflux temperature for 1 h. The solution so obtained was evaporated
to dryness under reduced pressure. The resultant residue was treated with diethyl
ether (250 ml) and the insoluble product was filtered off. The solid so obtained was
dried and suspended in a mixture of water (910 ml) and chloroform (3.8 L). The
suspension was stirred for 1 h at 20°C. The organic layer was separated, dried on
sodium sulfate and concentrated to dryness to obtain the title compound.
Yield: 72 g HPLC Purity: 95%
EXAMPLE 1
PREPARATION OF 6-(5-CHLOROPYRID-2-YL)-5, 7-DIOXO-5.6-
DIHYDROPYRROLO[3,4-B]PYRAZINE
Pyrazine-2,3-dicarboxylic acid anhydride (100 g) was added to dimethylformamide (300 ml), followed by the addition of 2-amino-5-chloro pyridine (100 g). The reaction mixture was stirred for 1 h at 25° to 30°C. Acetic anhydride (125 ml) was subsequently added to the reaction mixture and heated to 80° to 84°C for 1 h. The

reaction mixture was cooled to about 25°C and poured into chilled water (1.5 L). The solid product was filtered and washed with water (1 L) to obtain the title compound.
Yield: 170 g HPLC Purity: 98%
EXAMPLE 2
PREPARATION OF 6-(5-CHLOROPYRID-2-YL)-5, 7-DIOXO-5.6-
DIHYDROPYRROLO[3,4-B]PYRAZINE
A) Preparation of 3-{[(5-chloropyridin-2-yl)amino]carbonyl}pyrazine-2-
carboxylic acid:
Pyrazine-2,3-dicarboxylic acid anhydride (100 g) was added to dimethylformamide (300 ml), followed by the addition of 2-amino-5-chloro pyridine (100 g). The reaction mixture was stirred for 1 h at 25° to 30°C. After the completion of the reaction, the reaction mixture was added to de-ionised water (1500 ml). The mixture was stirred at 20° to 25°C for 30 minutes and the solid was filtered to obtain the title compound.
Yield: 175g
B) Preparation of 6-(5-chloropyrid-2-yl)-5, 7-dioxo-5,6-dihydropyrrolo[3,4-
bjpyrazine:
3-{[(5-chloropyridin-2-yl)amino]carbonyl}pyrazine-2-carboxylic acid (100 g) obtained from step A) was dissolved in dimethylformamide (500 ml) at 20° to 25°C and acetic anhydride (73 ml) was added to the solution. The reaction mixture was stirred at 80° to 85°C for 1 h. After the completion of the reaction, the reaction mixture was quenched by adding de-ionised water. The precipitated solid was isolated by filtration, washed with water (500 ml) and dried at 50° to 55°C to obtain the title compound.
Yield: 80 g
HPLC Purity: 99.5%
EXAMPLE 3
PREPARATION OF 6-(5-CHLOROPYRID-2-YL)-5, 7-DIOXO-5.6-
DIHYDROPYRROLO[3,4-B]PYRAZINE

A) Preparation of 3-{[(5-chloropyridin-2-yl)amino]carbonyl}pyrazine-2-
carboxylic acid:
Pyrazine-2,3-dicarboxylic acid anhydride (100 g) was added to dimethylformamide (300 ml), followed by the addition of 2-amino-5-chloro pyridine (100 g). The reaction mixture was stirred for 1 h at 25° to 30°C. After the completion of the reaction, the reaction mixture was added to de-ionised water (1500 ml). The mixture was stirred at 20° to 25°C for 30 minutes and the solid was filtered to obtain the title compound.
Yield: 175 g
B) Preparation of 6-(5-chloropyrid-2-yl)-5, 7-dioxo-5,6-dihydropyrrolo[3,4-
b]pyrazine:
3-{[(5-chloropyridin-2-yl)amino]carbonyl}pyrazine-2-carboxylic acid (100 g) obtained from step A) was added to acetic anhydride (500 ml) at 25° to 30°C and heated to
80° to 85°C. After stirring at 80° to 85°C for 1 h, the reaction mixture was cooled to 25° to 30°C and quenched by adding de-ionised water. The precipitated solid was isolated by filtration, washed with water (500 ml) and dried at 50° to 55°C to obtain the title compound.
Yield: 80 g
HPLC Purity: 98%
EXAMPLE 4
PREPARATION OF 6-(5-CHLOROPYRID-2-YL)-5, 7-DIOXO-5.6-
DIHYDROPYRROLO[3,4-B]PYRAZINE
Pyrazine-2,3-dicarboxylic acid anhydride (100 g) and 2-amino-5-chloropyridine (80 g) were added to acetic anhydride (500 ml). The reaction mixture was stirred for 1 h at 80° to 85°C. The reaction mass is subsequently cooled to 20° to 25°C and quenched by adding to de-ionised water (2500 ml). The mixture was stirred at 20° to 25°C for 30 minutes and filtered. The isolated solid was dried at 50° to 55°C to obtain the title compound.
Yield: 120g

WE CLAIM:
1. A process for the preparation of 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I,

(Formula Removed)
wherein the process comprises,
a) reacting furo[3,4-b]pyrazine-5,7-dione of Formula IV,
(Formula Removed)
with 2-amino-5-chloropyridine at about 35°C or below to obtain 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic acid of Formula V,
(Formula Removed)
b) cyclizing 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic
acid of Formula V to obtain 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-
5,7(6H)-dione of Formula I, and
c) isolating 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of
Formula I from the reaction mixture thereof.
2. A process for the preparation of 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I,

(Formula Removed)
wherein the process comprises,
a) reacting furo[3,4-b]pyrazine-5,7-dione of Formula IV,
(Formula Removed)
with 2-amino-5-chloropyridine to obtain 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic acid of Formula V,


(Formula Removed)
b) cyclizing 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic
acid of Formula V in the presence of acetic anhydride to obtain 6-(5-
chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I, and
c) isolating 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of
Formula I from the reaction mixture thereof.
3. A process according to any one of the preceding claims, wherein step a) is
carried out in the presence of an organic solvent.
4. A process according to claim 3, wherein the organic solvent is selected from
the group consisting of amides, nitriles, ethers, aliphatic or aromatic
hydrocarbons, halogenated hydrocarbons, ketones, alcohols, and esters.
5. A process according to claim 4, wherein the organic solvent is
dimethylformamide or acetonitrile.

6. A process for the preparation of 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I,

(Formula Removed)

wherein the process comprises,
a) reacting furo[3,4-b]pyrazine-5,7-dione of Formula IV,
(Formula Removed)
with 2-amino-5-chloropyridine to obtain 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic acid of Formula V,


(Formula Removed)
b) cyclizing 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic
acid of Formula V to obtain 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-
5,7(6H)-dione of Formula I, and
c) isolating 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-B]pyrazine-5,7(6H)-dione of
Formula I from the reaction mixture thereof,
wherein the process is characterized by the fact that 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic acid of Formula V is not isolated from the reaction mixture before step c).
7. A process according to claim 6, wherein step b) is carried out in the presence of acetic anhydride.

8. A process for the preparation of 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I,
(Formula Removed)
wherein the process comprises, a) reacting furo[3,4-b]pyrazine-5,7-dione of Formula IV,
(Formula Removed)
with 2-amino-5-chloropyridine in the presence of acetic anhydride to obtain 6-
(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I,
and
b) isolating 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of
Formula I from the reaction mixture thereof.
9. A process according to claim 8, wherein step a) is carried out at a
temperature of about 10°C to about 90°C.
10. A process according to any one of the preceding claims wherein 6-(5-
chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I is
further converted into eszopiclone.