The present invention relates to a process for the preparation of 6-(5-
chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one of
Formula I.
(Formula Removed)
The present invention further relates to a process for the preparation of eszopiclone using 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one 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)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-6]pyrazin-5-one of
Formula I as an intermediate.
(Formula Removed)
The process provided in US '149 patent for preparing 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5/-/-pyrrolo[3,4-/b]pyrazin-5-one of Formula I involves reducing 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula IV.
(Formula Removed)
The reduction in US '149 patent is carried out by using 0.75 molar equivalents of potassium borohydride in a solvent mixture of dioxan and water. After reduction, the reaction mixture is poured into water and neutralized with acetic acid. The product which crystallizes out is isolated by filtration and it is further purified by suspending in chloroform. The suspension is stirred, filtered and washed with
chloroform to obtain 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one of Formula I.
The present inventors have observed that the excessive use of potassium borohydride results in the formation of the impurity of Formula V in 10% to 15% along with the desired compound of Formula I.

(Formula Removed)
Formation of the impurity of Formula V in such high amounts necessitates the employment of additional purification steps and it also affects the yield.
The present inventors have developed an advantageous process for the preparation of 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5/-/-pyrrolo[3,4-6]pyrazin-5-one of Formula I. The present process requires only about 0.1 to about 0.4 molar equivalents of reducing agent and thereby substantially minimizes the formation of impurity of Formula V. Further, the present inventors have observed that the purification of 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-(b]pyrazin-5-one of Formula I by suspending in a mixture of dichloromethane and C1-3 alkanol also improves the purity of said compound. The present process also improves the yield of 6-(5-chloropyridin-2-yl)-5/-/-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 simple, economic and industrially preferable manner.

A first aspect of the present invention provides a process for the preparation of 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-6]pyrazin-5-one of Formula I,
(Formula Removed)
wherein the process comprises,
a) reducing 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of
Formula IV by using about 0.25 to about 0.4 molar equivalents of a reducing
agent,
(Formula Removed)
and
b) isolating 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5/-/-pyrrolo[3,4-
b]pyrazin-5-one of Formula I from the reaction mixture thereof.
The compound of Formula IV used as a starting material can be prepared according to the method provided in US 3,862,149. The compound of Formula IV is reduced by using about 0.25 to about 0.4 molar equivalents of a reducing agent in the presence of water or a mixture of water and an organic solvent. The reducing agent is preferably potassium borohydride, sodium borohydride, lithium aluminium hydride, lithium borohydride, lithium-tri-ethyl borohydride or lithium-tri-sec-butyl borohydride. The reducing agent is more preferably potassium borohydride. The reducing agent is preferably used in about 0.3 molar equivalents to the quantity of the compound of Formula IV. The organic solvent is selected from the group consisting of ethers, aliphatic hydrocarbons, aromatic
hydrocarbons, halogenated hydrocarbon, nitriles, amides, esters, and ketones. The organic solvent is preferably a cyclic ether, more preferably 1,4-dioxane. The reduction process is carried out at a temperature of about 40°C or below. Preferably the reduction is carried out at a temperature of about 5°C to about 20°C. The reduction may be facilitated by stirring. Subsequent to reduction, the compound of Formula I is isolated from the reaction mixture by the methods including layer separation, concentration, neutralization, precipitation, filtration, or a combination thereof.
A second aspect of the present invention provides a process for the preparation of 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-6]pyrazin-5-one
of Formula I,
(Formula Removed)
wherein the process comprises,
a) reducing 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-£i]pyrazine-5,7(6/-/)-dione of
Formula IV by using a reducing agent,
(Formula Removed)
to obtain 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5/-/-pyrrolo[3,4-/)]pyrazin-5-one of Formula I,
b) suspending 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-
b]pyrazin-5-one of Formula I in a mixture of dichloromethane and C1-3 alkanol,
and
b) isolating 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5/-/-pyrrolo[3,4-6]pyrazin-5-one of Formula I from the mixture thereof.
The compound of Formula IV used as a starting material can be prepared according to the method provided in US 3,862,149. The compound of Formula IV is reduced by using a reducing agent in the presence of water or a mixture of water and an organic solvent. The reducing agent is preferably potassium borohydride, sodium borohydride, lithium aluminium hydride, lithium borohydride, lithium-tri-ethyl borohydride or lithium-tri-sec-butyl borohydride. The reducing agent is more preferably potassium borohydride. The organic solvent is selected from the group consisting of ethers, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbon, nitriles, amides, esters, and ketones. The organic solvent is preferably a cyclic ether, more preferably 1,4-dioxane. The reduction process is carried out at a temperature of about 40°C or below. Preferably the reduction is carried out at a temperature of about 5°C to about 20°C. The reduction may be facilitated by stirring. After reduction, the compound of Formula I is isolated from the reaction mixture by the methods including layer separation, concentration, precipitation, filtration, or a combination thereof. Preferably the compound of Formula I is isolated by contacting the reaction mixture with water, adjusting the pH to about 6 to about 7 and filtering. An organic acid is preferably used for pH adjustment. The isolated compound of Formula I is optionally washed with water. The compound of Formula I is suspended in a mixture of dichloromethane and C1-3 alkanol to form a slurry. The C1-3 alkanol is preferably methanol. The slurry is stirred to effect the removal of impurities and filtered to obtain the compound of Formula I.
6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one of Formula I obtained according to the previous aspects of the invention is further converted into zopiclone and eszopiclone. The compound of Formula I 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 active 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,0'-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-CHLOROPYRIDIN-2-YL)-7-HYDROXY-6,7-DIHYDRO-5H-PYRROLO[3,4-B]PYRAZIN-5-ONE
Potassium borohydride (3.75g) was added to a suspension of 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-b]pyrazine (25 g) in a mixture of dioxane and water (19:1 by volume; 253 ml) with vigorous stirring at 13°C. After stirring for 6 minutes, the reaction mixture was poured into water (1.2 L) and subsequently neutralized with acetic acid (12 ml). The product which crystallized out was filtered, washed with water (60ml) and dried to obtain a crude product having 15% of impurity of Formula V. The crude product was suspended in chloroform (160 ml) and stirred for 30 minutes. The solid was filtered and dried at 40° to 45°C for 4 to 5 h to obtain the title compound.
Yield: 16 g
HPLC Purity: 99.0%
Impurity of Formula V: 1%
EXAMPLE
PREPARATION OF 6-(5-CHLOROPYRIDIN-2-YL)-7-HYDROXY-6,7-DIHYDRO-5H-PYRROLO[3,4-B]PYRAZIN-5-ONE
6-(5-Chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione (100 g) was added to a mixture of 1,4-dioxane (500 ml) and water (50 ml) at 25° to 30°C. The reaction mixture was cooled to 0° to 5°C and potassium borohydride (16.14 g; 0.3

molar equivalents) was added to the reaction mixture in 15 minutes time at 0° to 5°C. The reaction mixture was stirred for 30 minutes at 0° to 5°C and the reaction mixture was added into cool water (5° to 10°C; 3.65 L). The pH of the reaction mixture was adjusted to 6 to 7 by adding acetic acid (100 ml) and stirred for 30 minutes at 20° to 25°C. The solid was filtered, washed with water (1 L) and dried in hot air oven at 50° to 55°C for 5 to 8 h. The solid was suspended in a 9:1 mixture of dichloromethane and methanol (500 ml). The solid was filtered and dried under vacuum at 50° to 55°C for 8 to 10 h to obtain the title compound.
Yield: 70 g
HPLC Purity: 99.5%
Impurity of Formula V: Not detectable

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

wherein the process comprises,
a) reducing 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b)]pyrazine-5,7(6/-/)-dione of
Formula IV by using about 0.1 to about 0.4 molar equivalents of a reducing
agent,
(Formula Removed)

and
b) isolating 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-
b]pyrazin-5-one of Formula I from the reaction mixture thereof.
2. A process according to claim 1, wherein step a) is carried out in the presence
of water or a mixture of water and an organic solvent.
3. A process according to claim 2, wherein the organic solvent is selected from
the group consisting of ethers, aliphatic hydrocarbons, aromatic hydrocarbons,
halogenated hydrocarbon, nitriles, amides, esters, and ketones.
4. A process according to claim 3, wherein the organic solvent is a cyclic ether.

5. A process according to claim 4, wherein the organic solvent is 1,4-dioxane.
6. A process according to claim 1, wherein the reducing agent preferably
potassium borohydride, sodium borohydride, lithium aluminium hydride, lithium
borohydride, lithium-tri-ethyl borohydride or lithium-tri-sec-butyl borohydride.
7. A process according to claim 6, wherein the reducing agent is potassium
borohydride.
8. A process for the preparation of 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-
dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one of Formula I,

(Formula Removed)
wherein the process comprises,
a) reducing 6-(5-chloropyridin-2-yl)-5/-/-pyrrolo[3,4-/3]pyrazine-5,7(6/-/)-dione of
Formula IV by using a reducing agent,
(Formula Removed)

to obtain 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5/-/-pyrrolo[3,4-£)]pyrazin-
5-one of Formula I,
b) suspending 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5/-/-pyrrolo[3,4-
6]pyrazin-5-one of Formula I in a mixture of dichloromethane and d-3 alkanol,
and
b) isolating 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-
ib]pyrazin-5-one of Formula I from the mixture thereof.
12

9. A process according to claim 8, wherein the C1-3 alkanol is methanol.
10. A process according to any one of the preceding claims, wherein 6-(5-
chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one of
Formula I is further converted into eszopiclone.