Background of the Invention
Zopiclone, a non-benzodiazepine sedative-hypnotic useful for treating insomnia, is a
racemate having a chemical name of (±)-4-methyl-l-piperazinecarboxylic acid 6-(5-
chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl ester, represented
by formula 1.

Eszopiclone, which is the S-enantiomer of zopiclone (dextrorotary isomer), possessing
more activity and less toxicity than the racemic zopiclone and represented by formula 2.
US Pat. No. 3,862,149 describes a process for preparing zopiclone (1) by the reaction of
6-(5-chloropyridin-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine-5-one (5-
OH-Py) (3) with l-chlorocarbonyl-4-methylpiperazine (CMP) (4) in the presence of N,N-
dimethyl-formamide as a solvent and sodium hydride as a base for more than 3 hours
[Column 4, lines 4 to 36]. After chromatographic purification and recrystallization from a
mixture of acetonitrile and diisopropyl ether, zopiclone is obtained with a yield of 14.7%.
2


The process as described in U.S. Pat. No. 3,862,149 involves the purification of the crude
product by column chromatography, followed by crystallization, which not only makes
the process cumbersome, but yield 14.7% of zopiclone (1) that is relatively very low.
The publication Claude Jeanmart et al, Rhone-Poulenc Rech., France, Comptes Rendus
des Sciences del' Academie des Sciences, Series C: Sciences Chimiques (1978), 287(9),
377-378 discloses the use of triethylamine and pyridine in the process for the preparation
of zopiclone (1) by reacting 5-OH-Py (3) with CMP (4) hydrochloride salt in
dichloromethane. On repeating this reaction, the present inventors obtained zopiclone in
62% yield having a purity of 99.6% by HPLC.
The patent application US2007/0054914 discloses preparation of zopiclone (1) by the
reaction of 5-OH-Py (3) and CMP (4) hydrochloride salt in the presence of either
potassium carbonate and t-butyl ammonium bromide, or N,N-dimethylformamide and
sodium hydride for more than 18 hours, yielding 50.49% of zopiclone with a purity of
99.65%. These reaction conditions require longer time for completion of the reaction,
moreover the yield of zopiclone is poor.
The patent application US 2008/0015197 discloses the preparation of zopiclone (1) by the
reaction of 5-OH-Py (3) with CMP (4) or its acid addition salt in 4-N,N-dimethylamino-
pyridine (DMAP) and a base such as triethylamine for more than 6 hours yielding
3

zopiclone in 97.42% yield with a purity of 98.69%. Although the yield of this process is
better, but the purity is below 99.0%.
Thus the prior art methods for the preparation of zopiclone (1) that are discussed above
suffer from the following disadvantages:
i) low purity,
ii) low yield,
iii) cumbersome purification process for the removal of impurities,
iv) hazardous reagent such as sodium hydride, and
v) requires longer reaction time.
Thus, there exist a need for the development of an economical process for the preparation
of zopiclone that is easy to operate on industrial scale to obtain highly pure zopiclone (1)
in better yield.
Summary of the Invention
The present invention relates to a novel process for the preparation of zopiclone (1) that
involves the reaction of 6-(5-chloropyridin-2-yl)-5-hydroxy-7-oxo-5,6-
dihydropyrrolo[3,4-b]pyrazine-5-one (5-OH-Py) (3) with chloro-carbonyl-4-methyl-
piperazine (CMP) free base (4) or as an acid addition salt in the presence of
diazabicylo[5.4.0]undec-7-ene (DBU) or a mixture of DBU and other bases.
Detailed Description of the Invention
The present invention relates to a novel process for the preparation of zopiclone (1) that
involves the reaction of 6-(5-chloropyridin-2-yl)-5-hydroxy-7-oxo-5,6-
dihydropyrrolo[3,4-b]pyrazine-5-one (5-OH-Py) (3) with chloro-carbonyl-4-methyl-
piperazine (CMP) free base (4) or as an acid addition salt in the presence of
diazabicylo[5.4.0]undec-7-ene (DBU) or a mixture of DBU and other bases.
4

The process of the present invention can be carried out in an organic solvent that include
aromatic hydrocarbons like benzene, toluene and xylene; esters like ethyl acetate and
isopropyl acetate; ethers such as ethyl ether, methyl t-butyl ether, di-isopropyl ether and
tetrahydrofuran; amides such as formamide, dimethylforamide and N-methyl-
pyrrolidone; nitriles such as acetonitrile and propionitrile; ketones such as acetone and
ethylmethyl ketone; chlorinated hydrocarbons such as dichloromethane, ethylene
dichloride and chloroform and mixtures thereof. The most preferred solvent is benzene
and dichloromethane.
Suitable bases that can be used along with DBU in the reaction include but are not limited
to: organic bases such as triethylamine, diethylamine, methyl amine, pyridine and
imidazoles; inorganic bases such as alkali hydroxides likes sodium hydroxide, its
carbonates likes sodium carbonate, its hydrides likes sodium hydride and its bicarbonates
sodium bicarbonate. The most preferred base is pyridine.
The reaction can be carried out at the temperatures selected from 0°C to 100°C,
preferably 10°C to 40°C and most preferably 20°C - 30°C.
Molar ratio of the 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-dihydro-7-hydroxy-5H-
pyrrolo[3,4-b]pyrazine-5-one (1) to that DBU in the range of 1:0.1 to 1:10, preferably
1:1 to 1:5.
The aforementioned process for the preparation of zopiclone has the following
advantages:
i) purity is greater than 99.0%,
ii) yield is greater than 80%,
iii) simple process,
iv) easy to scale up and
v) economical process.
5

The following examples illustrate the present invention and they should not be construed
to limit the scope of the invention in any respect.
Example-1
To a mixture of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-
b]pyrazine (100 g), DBU (173.9 g), pyridine (90.25 g) and dichloromethane (1000 ml), 1-
chlorocarbonyl-4-methylpiperazine hydrochloride (151.56 g) was added and stirred for 5
hours at 20-25 °C. On completion of the reaction, chilled water (1000 ml) was added to it
to form a biphasic mixture and the organic phase was extracted. The aqueous phase was
further extracted with dichloromethane (1000 ml). The organic phases were combined,
washed with water (5 x 1000 ml) and evaporated under vacuum. The resultant solid
residue was dissolved in acetonitrile (500 ml), charcoalized with activated carbon (5
gms), filtered on celite bed and washed with acetonitrile (2 x 50 ml). The filtrate and the
acetonitrile washings were combined, cooled, stirred for 2 hours at 5 - 10°C, filtered and
dried to obtain zopiclone. (Yield: 81%; Purity: 99.65% by HPLC).
Example-2
To a mixture of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-
b]pyrazine (50 g), DBU (115.94 mg) and dichloromethane (500 ml), l-chlorocarbonyl-4-
methylpiperazine hydrochloride (75.78 g) was added and stirred for 6 hours at 20-25 °C.
On completion of the reaction, chilled water (500 ml) was added to it to form a biphasic
mixture and the organic phase was extracted. The aqueous phase was further extracted
with dichloromethane (500 ml). The organic phases were combined, washed with water
(5 x 500 ml) and evaporated under vacuum. The resultant solid residue was dissolved in
acetonitrile (250 ml), charcoalized with activated carbon (2.5 gms), filtered on celite bed
and washed with acetonitrile (2 x 25 ml). The filtrate and the acetonitrile washings were
combined, cooled, stirred for 2 hours at 5 - 10°C, filtered and dried to obtain zopiclone
(Yield: 74.3%; Purity: 99.65% by HPLC).
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Example-3
To a mixture of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-
bjpyrazine (5 g), DBU (8.69 g), potassium hydroxide (3.19 g) and dichloromethane (50
ml), l-chlorocarbonyl-4-methylpiperazine hydrochloride (7.58 g) was added and stirred
for 5 hours at 20-25 °C. On completion of the reaction, chilled water (50 ml) was added
to it to form a biphasic mixture and the organic phase was extracted. The aqueous phase
was further extracted with dichloromethane (50 ml). The organic phases were combined,
washed with water (5 x 50 ml) and evaporated under vacuum. The resultant solid residue
was dissolved in acetonitrile (25 ml), charcoalized with activated carbon (0.25 gms),
filtered on celite bed and washed with acetonitrile (2 x 25 ml). The filtrate and the
acetonitrile washings were combined, cooled, stirred for 2 hours at 5 - 10°C, filtered and
dried to obtain zopiclone. (Yield: 32.4%; Purity: 96.90% by HPLC).
Example-4
To a mixture of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-
bjpyrazine (5 g), triethylamine (5.76 g), pyridine (4.5 g) and dichloromethane (50 ml), 1-
chlorocarbonyl-4-methylpiperazine hydrochloride (7.58 g) was added and stirred for 5
hours at 20-25 °C. On completion of the reaction, chilled water (50 ml) was added to it to
form a biphasic mixture and the organic phase was extracted. The aqueous phase was
further extracted with dichloromethane (50 ml). The organic phases were combined,
washed with water (5 x 50 ml) and evaporated under vacuum. The resultant solid residue
was dissolved in acetonitrile (25 ml), charcoalized with activated carbon (0.25 gms),
filtered on celite bed and washed with acetonitrile (2 x 10 ml). The filtrate and the
acetonitrile washings were combined, cooled, stirred for 2 hours at 5 - 10°C, filtered and
dried to obtain zopiclone. (Yield: 62.1%; Purity: 99.62% by HPLC).


Dated this 13th day of February 2008

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The present invention relates to a novel process for the preparation of zopiclone (1) that
involves the reaction of 6-(5-chloropyridin-2-yl)-5-hydroxy-7-oxo-5,6-
dihydropyrrolo[3,4-b]pyrazine-5-one (5-OH-Py) (3) with chloro-carbonyl-4-methyl-
piperazine (CMP) free base (4) or as an acid addition salt in the presence of
diazabicylo[5.4.0]undec-7-ene (DBU) or a mixture of DBU and other bases.