Form 2THE PATENTS ACT, 1970(39 of 1970) &THE PATENTS RULES, 2003COMPLETE SPECIFICATION[See section 10 and rule 13]
1. TITLE OF THE INVENTION
"Process for preparation of optically active (S) (+) 6-(5- chloro-pyrid-2-yl)-5-
[(4-methyl -1-piperazinyl) carbonyloxy] -7-oxo-6,7-dihydro-5H-pyrrolo [3,4-
b] pyrazine"
2. APPLICANT
a) NAME: USV LIMITED
b) NATIONALITY: Indian Company incorporated under the Companies Act 1956
c) ADDRESS: B.S.D. Marg, Station Road, Govandi, Mumbai- 400 088, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field:
The present invention relates to process for preparation of dextrorotatory isomer of 6-(5-chloro-pyrid-2-yl)-5-[(4-methyl -1-piperazinyl) carbonyloxy] -7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine (Eszopiclone), Formula ( I ), a hypnotic agent. The invention further relates to recovery of key starting material (IV) from unwanted R- isomer and converting into racemic Zopiclone and further converting into Eszopiclone (I).

(I)
Background and prior art:
Zopiclone, chemically named as (±)-6-(5-chloro-pyrid-2-yl)-5-[(4-methyl-1-piperazinyl) carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine is a non-benzodiazepine with hypnotic activity. Although chemically unrelated to the benzodiazepines, Zopiclone posses a spectrum of activity analogous to that of benzodiazepines (Goa, K.L. & Heel, R.C., Drugs, 32:48-65 (1986). Zopiclone and its optically pure enantiomers are reportedly useful in the treatment of disease conditions including epilepsy, anxiety, aggressive behavior, muscle tension, behavioral disorders and depression. Recent studies (Chirality 1993, vol.5, 419) have confirmed that the dextrorotatory enantiomer of Zopiclone is approximately twice as active as the racemate whereas the levorotatory isomer is almost inactive. Moreover, according to EP0609210 the levorotatory isomer is responsible for the majority of adverse effects which are associated with the administration of the medicine. Therefore, it is much more convenient to use the optically active pure S-enantiomer of Zopiclone than the racemate.
Eszopiclone, marketed by Sepracor under the brand Lunesta (TM), is a stereoselective isomer of Zopiclone. Sepracor (the originator of Eszopiclone) has stated that the drug acts
2

rapidly, with the duration of effect lasting upto 6 hours and used for the treatment of insomnia. The recommended dosing to improve sleep onset and maintenance is 2 mg for adult patients. Clinical studies demonstrate no evidence of tolerance in any patients and also following discontinuation, there was no rebound effect observed compared with baseline on sleep maintenance. Eszopiclone produced significant improvements in sleep, decreased nocturnal awakening due to hot flashes and positively affected mood in peri-menopausal and menopausal women.
US3862149 (referred hereinafter as US '149) discloses synthesis of Zopiclone wherein solution of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo [3,4-b]pyrazine (IV) in dimethylformamide (DMF) is added to suspension of sodium hydride (in molar ratio of 1:1) in DMF. To this a solution of N-methyl piperazine carbonyl chloride (III) in DMF is added and the obtained product is subjected to column chromatography using ethyl acetate : methanol and further recrystallized with acetonitrile : diisopropylether to get racemic Zopiclone (V) in low yield. This patent involves use of column chromatography for purifying the product which is not industrially feasible. Equivalent molar ratio of sodium hydride and compound (IV) used leads to incomplete reaction. Mode of addition of reagents such as addition of compound (IV) to sodium hydride suspension results in low yield of the product and increase formation of impurities. The process described in US '149 uses an excess of solvents, results in poor yields of the final compound and increases the time period for completing the reaction. Moreover, the final product in the process was purified using column chromatography and a mixture of solvents for recrystallization. These solvents are difficult to recover, which makes the process unsuitable for use on a commercial scale. The reaction is represented by the scheme 1 as below.
Anhydrous DMF ' Nl""f- H N
0 r
(III) <200C,3hrs
NaH .
(IV) 6'
'(V) (Scheme: 1)
— CH3
3

WO9212980 equivalent to US6444673, discloses dextrorotatory isomer of Zopiclone (I) wherein racemic Zopiclone (V) is treated with D(+)-0,0-dibenzoyl tartaric acid monohydrate (VI) in dichloromethane (MDC) followed by evaporation of dichloromethane to get the compound (VII) which is further purified twice with dichloromethane: acetonitrile which gives purified D(+)-0,0-dibenzoyl tartarate salt of (S)-Zopiclone (VIII). Purified tartarate salt of Eszopiclone on basification using 2N aqueous sodium hydroxide gives Eszopiclone in crude state (IX) which on crystallization with acetonitrile gives Eszopiclone pure (I) (yield-23 %).The patent discloses use of large volume of solvents and low yield of compound (I), thus the process is not economically viable. The reaction is represented by the scheme 2 as below:



COOH
Cl ■ PtOCO-l-H 'H2° i)MDC
+ H
-QOOPh COOH (VI)
N—€H3
— CH,
(via)
2N Aq.NaOH
MDC '.m{a
'Cijstaliatbn
N-CH3
) Two Purifications MDC:8,45x2wl& ACN :9.38x2vol
Acetoritiie
Eszopiclone pure '(I)

0

COOH H OCOPh
COOH

(Scheme: 2)

(IX)

US6864257 (hereinafter referred as US '257) which is a divisional of US6444673, describes S (+) Zopiclone prepared from the corresponding racemate by methods such as chiral-phase chromatography, resolution of an optically active salt, stereoselective enzymatic catalysis by means of an appropriate microorganism or asymmetric synthesis. More especially the dextrorotatory isomer of Zopiclone is obtained by resolution of Zopiclone by means of an optically active acid like D(+)-0,0-dibenzoyl tartaric acid with yield of 23%. This invention also relates to pharmaceutical compositions containing dextrorotatory isomer of Zopiclone or its pharmaceutically acceptable salts. The patent US '257 also describes recovery of R-isomer of Zopiclone (example 1) from the mother liquor of tartarate salt of Zopiclone by concentrating to dryness under reduced pressure to
4

get the salt of R-isomer which on alkalinization using sodium hydroxide gives levorotatory isomer which is recrystallized in acetonitrile (yield-13.9%).
ES2101653 discloses (+)-6-(5-chloropyridyl-2-yl)-7-oxo-vinyloxycarbonyloxy-5,6-dihydro-pyrrolo [3,4-b] pyrazine and its use in a process for the preparation of (+)-6-(5-chloropyrid-2-yl)-5-(4- methylpiperazin-l-yl)-carbonyloxy-7-oxo-5,6- dihydropyrrole (3,4b) pyrazine. The synthesis of (+)- Zopiclone from (+)-6-(5- chloropyrid-2-yl)-7-oxo-5-vinyloxycarbonyloxy-5,6- dihydropyrrole (3,4b) pyrazine is by enzymatic resolution using lipase from Candida antartica as a catalyst.
US6969767 discloses process for the preparation of (S) Zopiclone by reacting N-methylpiperazine with optically enriched carbonate namely, (S)-5-(chloromethyl oxy carbonyl oxy)-6-(5-chloropyridin-2-yl)-7-oxo-5,6-dihydro-pyrrolo [3,4-b] pyrazine. This process does not describe the recovery of R-isomer of Zopiclone.
WO/0069442 encompasses the synthesis, use and pharmaceutical compositions of (±)-N-desmethylzopiclone or optically pure enantiomers of N-desmethylzopiclone to treat or prevent diseases and conditions which are affected by the modulation of one or more central or peripheral benzodiazepine receptors. Optically pure (S) Zopiclone is treated with a - chloroethyl chloroformate to form the corresponding quaternary amine salt, which on methanolysis gives (S) desmethylzopiclone. Also disclosed is the preparation of optically pure (S) desmethylzopiclone using resolving agent such as L-N-benzoyloxycarbonyl phenylalanine (L-ZPA). (+)-N-desmethylzopiclone, and its (-) enantiomer in the mother liquor can be racemized under basic conditions (e.g. with a tertiary amine) to reform (±)-N-desmethylzopiclone. However since Zopiclone formed under these conditions is not stable, hence an alternative route for the recycling the enantiomer R-Zopiclone (X) is described as outlined in scheme 3.
5

One more approach in same application involves dynamic resolution of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo [3,4-b]pyrazine (IV) with chiral auxiliary-based chloroformate to give one major stereoisomer of the carbonate product. This carbonate stereoisomer on reaction with N-methyl piperazine gives Eszopiclone (I) represented as below scheme 4.

(Scheme: 4)
Recovery of starting material (IV) from unwanted isomer and thereby preparation of required enantiomer of Zopiclone is not mentioned clearly in WO00/69442 and hence, optimized process and yields are not available, calculated yields of all the steps are low and hence there is a need to develop cost effective as well as rugged process for preparation of Eszopiclone. Another approach in the same application is the synthesis of optically pure (+)-N-desmethylzopiclone by treating Zopiclone with diethyl azodicarboxylate and hydrolyzing the resulting product under mild conditions.
US2007054914 discloses process for the preparation of Eszopiclone by reacting Zopiclone with an enantiomerically pure di-p-toluoyl tartaric acid; and recovering solid salt by treatment with base to form Eszopiclone. This patent application also discloses reaction of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo [3,4-b] pyrazine with l-chlorocarbonyl-4-methylpiperazine hydrochloride to form Zopiclone.
The process for synthesis of Eszopiclone as mentioned in prior art are having the following drawbacks:
a) Use of equimolar amounts of sodium hydride and N-methyl piperazine carbonyl chloride as in US3862149, does not ensure completion of the reaction. Also racemic Zopiclone obtained is subjected to column chromatography, requirement of large amounts of solvents like ethyl acetate (415 volumes) and methanol (13.3 volumes). The product is
6

further recrystallized with a mixture of solvents such as acetonitrile and diisopropyl ether (7 volumes each). This method is unproductive, uneconomical and time consuming at industrial scale and results in low yield.
b) As per the process disclosed in US3862149, mode of addition of reagents, e.g. taking total amount of sodium hydride initially in the reaction vessel and adding piperazinyl acid chloride to it results in exotherm, which may lead to formation of side products thereby affecting the yield of desired compound. Method like column chromatography is required to purify the product making the process costly and industrially unsuitable.
c) WO00/69442 discloses recovery of R isomer of N-desmethylzopiclone from the mother liquor under basic conditions (eg. tertiary amine) to reform racemic Zopiclone. However racemic Zopiclone thus recovered from the undesired enantiomer is unstable and results in low yields.
d) As per the process for resolution in WO9212980, US6444673, D(+)-tartarate salt of Zopiclone is prepared by dissolving Zopiclone and the chiral acid in dichloromethane (12.88 volumes) followed by evaporation of dichloromethane. Further to get pure tartarate salt three crystallizations are required, one in 85 volumes of acetonitrile and rest of the two crystallizations are carried out in dichloromethane and acetonitrile mixture (8.45 X 2: 9.38 X 2 volumes). Total amount of dichloromethane required is 29.78 Vol. and acetonitrile required is 104.61 volumes. Due to usage of high amounts of solvents, the batch size increases and process becomes less productive. The large amount of mother liquor containing mixture of solvents poses recovery problems and the process becomes uneconomical.
f) Recovery of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo [3,4-b]pyrazine (IV) from R-Zopiclone using a base is disclosed in WO00/69442 is not preferred due to lower yield of recovered compound (IV).
The process of the present differs from the prior art mentioned in the above patents with respect to the following advantages:
7

1] Mole ratios of key raw material with respect to sodium hydride and N-methyl
piperazine carbonyl chloride free base (III) is excess to ensure completion of the
reaction.
2] Mode of addition of reagents avoids or minimize exotherms, so as to reduce side
product formation/impurities thereby improving the yield of Eszopiclone. The 0-
acylation reaction is much simpler and chances of other side products are negligible.
3] Avoids multiple crystallization and column chromatography of racemic Zopiclone (V)
as mentioned in prior art thereby making the process time consuming and reducing
solvent consumption as well as energy cost required for solvent recovery.
4] Preparation of D(+)-0,0-dibenzoyl tartarate salt (VII),
5] Purification of D(+)-0,0-dibenzoyl tartarate salt (VII).
6] Conversion of R-isomer of Zopiclone using halogenated aliphatic acid to compound
(IV) in higher yield. 7]Recovery of unwanted R- isomer of Zopiclone by simple method and reproducing
Eszopiclone in high yield.
Therefore present invention addresses the problems associated with prior art and provides a process that is simple, efficient, inexpensive, ecofriendly, robust, readily scaleable., reproducible and commercially feasible. Hence the process of the invention produces the desired compound Eszopiclone (I) with high yield and purity. Further method of recovering key starting material of compound (IV) from the unwanted R-isomer of Zopiclone is provided herein.
Object of the invention:
The main object of the present invention is to provide process for the preparation of (S)-6-(5- chloro-pyrid-2-yl)-5-[(4-methyl -1-piperazinyl) carbonyloxy] -7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine (I) with high yield and high chemical and optical purity.
Another object of the invention is to provide recovery of key starting material 6-(5-chloro pyrid-2-yl)-5-hydroxy-7-oxo- 5,6- dihydropyrrolo [3,4-b] pyrazine of formula (IV) from unwanted R- isomer and converting into racemic Zopiclone and finally to pure (S)(+) Zopiclone.
8

Another object of present invention is to provide cost effective, efficient, economical and industrially feasible process for the preparation of dextrorotatory isomer of Zopiclone (I) with high yield.
Summary of the invention:
The present invention discloses process for the preparation of (S)-6-(5- chloro-pyrid-2-yl)-5-[(4-methyl -1-piperazinyl) carbonyloxy] -7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine (I) with higher yield and high chemical and optical purity. Further disclosed herein is the recovery of key starting material of compound (IV) from unwanted R-isomer and recycling to compound of formula (I) with higher yield.
The process for the preparation of (S)(+) Zopiclone according to the present invention, comprises the steps of:
d) basifying N-methyl piperazine carbonyl chloride hydrochloride (II) by using base to obtain N-methyl piperazine carbonyl chloride as a free base of formula (HI);
e) condensing N-methyl piperazine carbonyl chloride free base (III) with 6-(5-chloro pyrid-2-yl)-5-hydroxy-7-oxo- 5,6- dihydropyrrolo [3,4-b] pyrazine (IV) in presence of molar excess of base in a dipolar aprotic solvent to obtain racemic Zopiclone (V);
f) reacting compound (V) with D(+)-0,0'-dibenzoyl tartaric acid monohydrate (VI) in acetonitrile and filtering the precipitated solid to isolate D(+)-0,0'-dibenzoyl tartarate salt of Zopiclone (VII);
g) purifying D(+)-0,0'-dibenzoyl tartaric acid salt (VII) in organic solvent and filtering the crystallized compound of formula (VIII) obtained by addition of anti-solvent;
h) breaking the tartarate salt of Zopiclone (VIII) using an aqueous solution of base
to get crude dextrorotatory isomer of Zopiclone (IX); i) purifying crude Eszopiclone (IX) in acetonitrile to obtain pure Eszopiclone (I)
substantially free of its R-isomer, j) isolating the R-isomer of Zopiclone by treating the mother liquor obtained from
9

step (c) and (d) with base; k) cleaving the isolated (R)-isomer of Zopiclone using acid to recover compound
of formula (IV) in high yield and purity and 1) converting recovered compound (IV) to Eszopiclone (I) by following the steps
(a) to step(f).
The unwanted R-isomer present in the mother liquors obtained from the preparation and purification of D(+)-0,0-dibenzoyl taratrate salt is isolated by evaporating the solvent to yields a residue, which on basification with 2N aqueous NaOH in presence of dichloromethane provides the R-isomer of Zopiclone (X).In a further aspect the R-isomer (X) of Zopiclone is cleaved to recover compound of formula (IV) in high yield and purity.
The process for cleaving the R-isomer of Zopiclone comprises:
a) treating the R-isomer of Zopiclone (X) with organic acid in organic solvent or inorganic acid in mixture of alcohol and water;
b) neutralizing the obtained reaction mixture with the base to precipitate out compound (IV); and
c) isolating the compound (IV) by filtration followed by washing with water followed by organic solvent.
The isolated compound (IV) with high yield is then converted to (S)(+) Zopiclone (I).
The present invention thus provides an efficient synthetic process for the preparation of (S)(+) Zopiclone with higher yield and purity and simple recovery and recycling of the unwanted R-isomer to prepare Eszopiclone (I).
Detailed description of the invention:
The present invention describes an efficient process for the preparation of (S) (+) 6-(5-chloro-pyrid-2-yl)-5-[(4-methyl -1-piperazinyl) carbonyloxy] -7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine (I) with high yield and high chemical and optical purity. The invention further describes recovery of key starting material of compound (IV) from the unwanted R- isomer of Zopiclone, converting into racemic Zopiclone and finally to
10

In one embodiment the invention describes process for the preparation of (S)(+) Zopiclone according to the present invention, comprises the steps of:
a) basifying N-methyl piperazine carbonyl chloride hydrochloride (II) by using base to obtain N-methyl piperazine carbonyl chloride as free base of formula (HI);
b) condensing N-methyl piperazine carbonyl chloride free base (III) with 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo [3,4-b]pyrazine (IV) in presence of molar excess of base in a dipolar aprotic solvent to obtain racemic Zopiclone (V);
c) reacting compound (V) with D(+)-0,0'-dibenzoyl tartaric acid monohydrate (VI) in acetonitrile and filtering the precipitated solid to isolate D(+)-0,0'-dibenzoyl tartarate salt of Zopiclone (VII);
d) purifying D(+)-0,0'-dibenzoyl tartaric acid salt (VII) in organic solvent and filtering the crystallized compound of formula (VIII) obtained by addition of anti-solvent;
e) breaking the tartarate salt of Zopiclone (VII) using an aqueous solution of base to dextrorotatory isomer of Zopiclone i.e. crude Eszopiclone (IX);
f) purifying crude Eszopiclone (IX) in acetonitrile to obtain pure Eszopiclone (I) substantially free of R-isomer,
g) isolating the R-isomer of Zopiclone by treating the mother liquor obtained from step (c) and (d) with base;
h) cleaving the isolated (R)-isomer of Zopiclone using acid to recover compound
of formula (IV) in high yield and purity and i) converting recovered compound (IV) to Eszopiclone (I) by following the steps
(a) to step (f)-
According to the invention, N-methylpiperazine carbonyl chloride hydrochloride salt (II) is converted to N-methyl piperazine carbonyl chloride free base (III) comprises,
a) neutralizing compound of formula (II) in organic solvent using aqueous solution of base till the pH of the reaction mixture is alkaline and
b) isolating the compound of formula (III).
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In preferred embodiment, N-methyl piperazine carbonyl chloride hydrochloride (II) is mixed with organic solvent. Further to the resulting suspension, an aqueous saturated solution of base is slowly added under stirring. During basification the N-methyl-piperazine carbonyl chloride base gets extracted in organic solvent layer, which is separated from the aqueous layer. The aqueous layer is extracted with organic solvent. The combined organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum to isolate N-methyl piperazine carbonyl chloride free base (III).
The neutralization is carried out at 0 to 20°C preferably 0 to 5°C. The alkaline pH of reaction mixture is in the range of 7.5 to 9.0, preferably 8.0.
The organic solvent used is selected from the group consisting of halogenated hydrocarbons such as dichloromethane, chloroform, or esters such as ethyl acetate or ethers such as diethyl ether, methyl t-butyl ether or mixtures thereof, preferably dichloromethane.
The base used is selected from the group consisting of alkali metal or alkaline earth metal carbonates or bicarbonates preferably bicarbonates and more preferably sodium bicarbonate.
According to further aspect of the invention, to the solution of 6-(5-chloro pyrid-2-yl)-5-hydroxy-7-oxo-5, 6-dihydropyrrolo [3,4-b] pyrazine (IV) in dipolar aprotic solvent and base is added in portions to obtain a reaction mixture. The addition is preferably carried out under cold condition. The ratio of base to compound (IV) used is in molar excess. Solution of N-methyl piperazine carbonyl chloride (NMPCC1) free base (III) in dipolar aprotic solvent is then slowly added with the stirring to the above reaction mixture. The addition is preferably carried out under cold condition. The additions are carried out at the lower temperature range of -5 to -15°C, preferably at -10°C. The mixture is stirred at temperature below 20°C, preferably 15 to 18°C for 2 to 4 hours. After completion of reaction, the reaction mixture is quenched in 3 to 10 volumes, preferably 4.5 volumes (with respect to reaction medium) of ice-water and stirred for 15 to 45 minutes, preferably
13

20 minutes during which the product gets separated, which is then isolated by filtration, washed with water followed by ether and dried to get racemic zopiclone (V). The racemic zopiclone thus obtained is further resolved to get its S-isomer.
The dipolar aprotic solvent is selected from anhydrous N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone or mixture thereof, preferably N,N-dimethylformamide.
The base is alkali metal hydride such as sodium hydride (50%- 60% suspension in mineral oil).
Sodium hydride and NMPCC1 free base (III) are used in molar excess with the respect to 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo [3,4-b] pyrazine of formula (IV). Preferably the molar ratio of compound (iV):sodium hydride : NMPCC1 free base (III) as is 1: 1.3: 1.4.
According to further aspect of the invention, racemic Zopiclone (V) is resolved by using D(+)-0,0'-dibenzoyl tartaric acid monohydrate (VI) to isolate optically enriched dextrorotarory Eszopiclone which comprises;
a) dissolving racemic Zopiclone (V) in acetonitrile.
b) adding D(+)-0,0'-dibenzoyl tartaric acid monohydrate of formula (VI).
c) stirring reaction mixture at 25 to 40°C.
d) isolating the (S)(+) enantiomer enriched Zopiclone dibenzoyl tartarate (VII).
The resolution of Zopiclone involves formation of tartarate salt by addition of chiral acid to solution of racemic Zopiclone (V) in acetonitrile. The solution is stirred at room temperature to precipitate out the chiral acid salt (Vll).the precipitated crude chiral salt of (S)(+)-Zopiclone is isolated by filtration The filtrate enriched in R-isomer is used for recovery of compound (IV).
The chiral acid is selected from substituted tartaric acid such as D-Tartaric acid, D(+)-0,0'-dibenzoyl tartaric acid monohydrate, (+)-0,0'-Di-p-toluoyl tartaric acid, preferably D(+)-0,0'-dibenzoyl tartaric acid monohydrate (VI). The amount of acetonitrile used is 20 to 80 volumes, preferably 30 volumes with respect
14

to compound of formula (V).
The amount of compound of formula (VI) is 0.5 to 1.1 molar in relation to compound of
formula (V).
In further aspect crude D(+)-0,0'-dibenzoyl tartaric acid salt (VII) is purified by the process comprising;
a) dissolving compound of formula (VII) in refluxing organic solvent;
b) slowly adding an anti-solvent;
c) stirring the reaction mixture with heating for few minutes and
d) isolating pure D(+)-0,0'-dibenzoyl tartaric acid salt of (S)(+)-Zopiclone (VIII).
The crude salt of (S)(+)-Zopiclone (VII) is dissolved in organic solvent under reflux condition. The obtained reaction mixture is filtered. To this filtrate under hot condition, an anti-solvent is added slowly, while the temperature of the mixture is gradually raised. After addition of anti solvent, the reaction mixture is heated followed by stirring at temperature of 50 to 65°C for 5 to 25 minutes, preferably at 55°C for 15 minutes. Thereafter, the mixture is allowed to cool to at temperature of 25 to 30°C and maintained at temperature of 2 to 10°C, preferably 5°C for one hour during which the product gets separated, which is then isolated. The same purification process may be repeated to get purified tartarate salt of Eszopiclone (VIII) free from unwanted R-enantiomer. The filtrate is set aside for recycle of R-isomer.
The organic solvent is selected from dichloromethane, chloroform, or their mixture thereof, preferably dichloromethane and used in 15 to 30 volumes, preferably 20 volumes with respect to compound of formula (VII).
The anti-solvent used is acetonitrile and used in 20 to 40 volumes, preferably 25 volume with respect to compound (VII).
In further aspect of the invention, dextrorotatory isomer of Zopiclone is isolated by breaking of the tartarate salt (VIII) by using aqueous solution of base in molar excess.
Preferably, purified salt of Eszopiclone (VIII) is stirred with organic solvent and water at
15

room temperature at 25 to 35°C for 5 to 15 minutes, preferably 10 minutes followed by
alkalinizing the mixture by slow addition of aqueous solution of base.
The organic layer is separated and aqueous layer is extracted thrice with the organic
solvent. The combined organic layer is washed with water, dried over anhydrous sodium
sulphate and by evaporating the solvent under reduced pressure to get Eszopiclone crude
(IX).
The base used is alkali metal hydroxide selected from sodium hydroxide, potassium hydroxide, preferably sodium hydroxide.
The organic solvent is selected from dichloromethane and chloroform or mixture thereof, preferably dichloromethane.
The volume of dichloromethane and water used for extraction is 6 to 10 volumes each, preferably 7.6 volumes.
The molar excess of sodium hydroxide used is 1.5 to 2.5 equivalents, preferably 2.1 equivalents with respect to compound (IV).
In further aspect, purification of the isolated (S)(+) Zopiclone (X) to get ICH passing material alongwith higher optical purity involves crystallization of 6-(5- chloro-2-pyridyl)-5-[(4-methyl -1-piperazinyl) carbonyloxy] -7-oxo-6,7-dihydro-5(S)H-pyrrolo [3,4-b] pyrazine (IX) in acetonitrile.
The crystallization process involves dissolution of crude Eszopiclone (IX) in acetonitrile under reflux condition for 5 to 15 minutes to get a clear solution. Activated charcoal (5% w/w) is added to clear solution of Eszopiclone followed by filtration of the mixture through hyflo bed. The filtered solution is stirred and allowed to reach room temperature and then cooled at temperature of 5 to 15°C for 15 to 60 minutes. The crystalline solid obtained is then filtered, washed with cold acetonitrile and dried with suction at temperature range of 55 to 65°C for 4 hours to get highly pure Eszopiclone (I).
Eszopiclone obtained in a highly pure with unwanted (R)-isomer (X) and N-desmethylzopiclone (XI) less than 0.1% and with chemical purity of more than 99.5 %
16

by HPLC.
o v—<
(XI)
Acetonitrile used is preferably 9.5 to 12 volumes, preferably 10 volumes.
The term "chemical purity" as described herein refers to purity of Eszopiclone more than 99.5 %.
The term "chiral purity" as described herein refers to the purity of Eszopiclone with unwanted R- isomer less than 0.1%.
Another important embodiment of the invention encompasses method of recovery of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo [3,4-b]pyrazine (IV) from the unwanted R-isomer (X), which is an inventive synthetic process.
Recovery of 6-(5-chloro pyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo [3,4-b] pyrazine (IV) from unwanted (R)-Zopiclone (X) involves combining all the mother liquors enriched in (R)-Zopiclone D(+)-0,0'-dibenzoyl tartarate salt and isolating the crude solid by evaporating the solvent.
Preferably, breaking of the tartarate salt of (R)-Zopiclone by using aqueous solution of inorganic base to get (R)-Zopiclone (X) involves stirring the tartarate salt of (R)-Zopiclone with organic solvent and water at room temperature. The mixture is stirred at temperature of 25 to 35°C for 5 to 15 minutes, preferably 10 minutes. Addition of the 2N solution of base is continued till alkaline pH, preferably pH of 11 is achieved. During addition, the temperature is maintained at 0 to 15°C for 5 to 15 minutes, preferably at 5°C for 5 minutes. The reaction mixture is transferred to a separator. The organic layer is separated and aqueous layer is extracted thrice with the organic solvent. The combined organic layer is washed with water, dried over anhydrous sodium sulphate and the solvent
17

evaporated under reduced pressure to get (R)-Zopiclone (X).
The base used is selected from sodium hydroxide, potassium hydroxide, preferably sodium hydroxide. The molar excess of sodium hydroxide is 1.5 to 2.5 equivalents, preferably 2.1 equivalents.
The organic solvent is selected from dichloromethane, chloroform, or mixtures thereof, preferably dichloromethane.
The volumes of dichloromethane and water are in 6 to 10 volumes, preferably 7.6 volumes each.
In further embodiment (R)-Zopiclone is cleaved to obtain compound (IV) comprising:
a) treating the R-isomer of Zopiclone (X) with organic acid in organic solvent or inorganic acid in mixture of alcohol and water;
b) neutralizing the obtained reaction mixture with the base to precipitate out compound (IV); and
c) isolating the compound (IV) by filtration followed by washing with water followed by organic solvent.
Preferably, (R)-Zopiclone is cleaved in the presence of acid in organic solvent under reflux condition for 10 to 30 hours, preferably at temperature of 38°C for 22 hours and then quenched in ice-water mixture. The pH of the reaction mixture is made slightly alkaline by addition of aqueous saturated solution of base till pH between 7.0 to 11, preferably 7.5 to 8.0 is achieved at temperature 0 to 15°C, preferably at 5°C to precipitate out compound, 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo [3,4-b]pyrazine (IV) which is filtered, washed with water and organic solvent and dried at temperature of 55 to 65°C for 2 to 20 hours, preferably at 60°C for 10 hours.
The compound (IV) thus recovered is in high yield as compared to methods disclosed in the prior art, thereby making the process economically viable.
In another embodiment, (R)- Zopiclone (X) is stirred with a mixture of acid, water and alcohol at temperature 41°C for 11 hours. The obtained reaction mixture is cooled 10 to 15°C and then neutralized with saturated solution of sodium bicarbonate. Solid
18

precipitated out is filtered, washed with water and organic solvent to get compound (IV) in high yield.
The acid used for cleavage of the R-isomer is selected from organic acid such as trifluoroacetic acid, trichloroacetic acid , preferably trifluoroacetic acid and the inorganic acid is hydrochloric acid.
Organic solvent is selected from dichloromethane, chloroform, ethylene dichloride, 1,1,1-trichloroethane, chlorobenzene or mixture thereof, preferably dichloromethane and the alcohol is selected from methanol, ethanol, isopropanol preferably methanol. The base used is selected from the group consisting carbonate or bicarbonate of alkali metal or alkaline earth metal, more preferably sodium bicarbonate.
In another aspect of the invention the recovered 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo [3,4-b]pyrazine (IV) is converted to Eszopiclone of desired optical and chemical purity by the process as described in the current invention.
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 included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention.
Example: 1
Conversion of N-methyl piperazine carbonyl chloride hydrochloride salt (II) to N-
methyl piperazine carbonyl chloride base (III):
250 g (1. 25 M) N-methyl-piperazine carbonyl chloride hydrochloride was stirred in 1574 ml of dichloromethane while the temperature being maintained at 5 to 10°C. The mixture was then neutralized by slow addition of 1574 ml of saturated solution of sodium bicarbonate till pH of 7.5 to 8.0 was achieved. During addition, the temperature was maintained at 5°C. After complete addition of sodium bicarbonate, reaction mixture was stirred for 30 minutes and then transferred to a separator. Bottom layer of dichloromethane was separated and the aqueous layer extracted with 2 x 800 ml of
19

dichloromethane. Dichloromethane layers were combined and washed with 1000 ml of water, dried over anhydrous sodium sulphate and evaporated under reduced pressure to get N-methyl piperazine carbonyl chloride base (III). Yield; 133 g, 65.14 %.
Example 2
Synthesis of racemic Zopiclone (V):
150 g (0.57 M) of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo [3,4-b]pyrazine (IV) was dissolved in 4.5 liter (30 volumes) of anhydrous N,N-dimethylformamide at 25 to 35°C and mixture was stirred for 20 minutes. The solution was then cooled and 29.62 gm (0.74 M) of sodium hydride (50 to 60 % suspension in mineral oil) was added in portions to the cooled solution with stirring. During addition, the temperature was maintained at -10°C. After complete addition, the reaction mixture was stirred at same temperature for evolution of H2 gas. A solution of 131 gm (0.8 M) of N-methyl piperazine carbonyl chloride (NMPCC1 base) (III) in anhydrous N,N-dimethylformamide was slowly added. The addition was carried out at temperature of -10°C. After complete addition of NMPCC1 base, the temperature was allowed to rise gradually. The mixture was stirred at temperature below 20°C for three hours. The mixture was then quenched in 18.6 Kg of ice-water and stirred for 20 minutes. Solid precipitated out was filtered off, washed with 2 liter of water, then with 1250 ml of diisopropyl ether. The product was dried at temperature of 65°C for 18 hrs. Yield; 175 g, 78.81 %.
Example 3
Preparation of D(+)-0,0-dibenzoyl tartarate of Zopiclone (VII):
175 g (0.45 M) of racemic Zopiclone (V) was dissolved in 5250 ml of acetonitrile at temperature of 25 to 35°C with stirring. 169.37 g (0.45 M) of D(+)-0,0-dibenzoyl tartaric acid monohydrate was then added to the above solution of Zopiclone with stirring. The reaction mixture was stirred at temperature of 25 to 35°C for 6 to 7 hrs. The solid precipitated out was filtered off and washed with 2 x 200 ml of acetonitrile. The crude D(+)-0,0'- dibenzoyl tartarate salt of (S)-Zopiclone thus obtained was dried at 60 to 65°C for 10 hours. Yield = 298 g, 86.63%.
20

Example 4
Purification of D(+)-0,0-tartarate salt of Eszopiclone (VII):
The D(+)-0,0-dibenzoyl tartarate of Eszopiclone was subjected to two consecutive purifications as follows.
A] 298 g of D(+) -0,0-dibenzoyl tartarate of (S)-Zopiclone was dissolved in 5960 ml of dichloromethane under reflux. The mixture was filtered to remove any inorganic matter. The filtrate was then refluxed for 5 minutes and to it 7301 ml of acetonitrile was slowly added. Reaction mixture was maintained at temperature of 50 to 55°C for 15 minutes and then allowed to reach room temperature. The mixture was then maintained at 5°C for 1 hour. The crystallized product was filtered off, washed with 2 x 450 ml of acetonitrile and suck dried.
B] The crystallized D(+)-0,0-dibenzoyl tartaric acid salt of Eszopiclone thus obtained was crystallized again in the same solvents, however the solution of salt in dichloromethane was not filtered at this stage. Purified D(+)-0,0-dibenzoyl tartaric acid salt of Eszopiclone. m.p. Of 160 to 165°C (with decomposition), the optical rotation [a]2o = 102° (c = 0.5; acetone). Yield; 154.47 g, 44.85 %.
Example 5
Isolation of crude Eszopiclone (IX) from purified D(+)-0,0-dibenzoyl tartarate salt
of(S)-Zopiclone(VIII):
154.47 g (0.2 M) of purified D(+)-0,0-dibenzoyl tartarate salt of Eszopiclone (VIII) was dissolved in 1174 ml of water in the presence of 1174 ml of dichloromethane. The mixture was alkalinized till to attain pH 11 by slowly adding 2N aqueous sodium hydroxide solution. The aqueous phase was separated from the organic phase and extracted with 2 x 500 ml of dichloromethane. The combined organic phases were washed with 3 x 1000 ml of water and dried over sodium sulphate, evaporated to get crude Eszopiclone (IX). m.p.200 ± 5°C, the optical rotation [a]2o = 135 ± 3° (c = 1.0; acetone). Yield; 69.62g, 44.34 %.
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Example 6
Crystallization of Eszopiclone (IX):
69 g of Eszopiclone (IX) was dissolved in 696 ml of acetonitrile under reflux and 3.48 g of activated charcoal was added to the obtained solution with stirring. The hot solution was filtered through hyflobed and the filtrate stirred at 10°C. The crystalline solid obtained is then filtered, washed with cold acetonitrile and dried at temperature of 55 to 65°C for 4 hours. The pure dextrorotatory Eszopiclone (I) was obtained as colorless crystals, m.p. 206 ± 5°C, with optical rotation of which [ct]2o = 135 ± 3° (c - 1.0; acetone). Yield; 60.44 g, 34.53 %.
Example 7
Isolation of R(-) Zopiclone:
191.47 g (0. 25 M) of 0,0-dibenzoyl tartarate salt of the levorotatory isomer of Zopiclone (obtained from the filtrates of the tartarate salt of (S)(+) isomer of Example 3,4 and 5) was dissolved in 1456 ml of water in the presence of 1456 ml of dichloromethane. The mixture was alkalinized to attain pH of 11 by slowly adding 2N aqueous sodium hydroxide solution. The aqueous phase was separated and extracted with dichloromethane (2 x 700 ml). The combined organic phases were washed with 3 x 1200 ml of water, dried over sodium sulphate and evaporated to obtain R-(-)Zopiclone (X). m.p. 185°C, the optical rotation [-o
N >H
0 f—V_N N-CB,
0

Formula (X)
g) isolating the R-isomer of Zopiclone by treating the residue obtained from
evaporation of mother liquor obtained from step (c) and (d) with base; h) cleaving the isolated (R)-isomer of Zopiclone using acid to recover compound
of formula (IV) in high yield and purity and i) converting the recovered compound (IV) to pure Eszopiclone (I) by following
the steps (a) to step (f).
2. The process as claimed in claim 1, wherein free base of compound (II) is liberated by neutralizing compound (II) in organic solvent in presence of aqueous solution of base.
3. The process as claimed in claim 2, wherein the reaction is carried out at low temperature below 25°C, preferably 0 to 5°C for a period of 5 to 60 minutes till the pH of the reaction mixture is in the range of 7.5 to 9.0.
4. The process as claimed in claim 2, wherein the organic solvent is selected from halogenated solvent such as dichloromethane, chloroform or esters such as ethyl acetate or ethers such as diethyl ether, methyl t-butyl ether or mixtures thereof, preferably dichloromethane.
5. The process as claimed in claim 2, wherein the base used is selected from alkali metal carbonates or bicarbonates, preferably bicarbonates and more preferably sodium bicarbonate.
6. The process as claimed in claim 1, wherein the base used in step (b) is an alkali metal hydride such as sodium hydride.
7. The process as claimed in claim 1 and 6, wherein base and N-methyl piperazine carbonyl chloride free base (III) are used in molar excess with the respect to compound (IV).
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8. The process as claimed in claim 1 step (b), wherein the dipolar aprotic solvent is selected from such as anhydrous N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl pyrrolidone, taken alone or mixture thereof, preferably anhydrous N,N- dimethylformamide.
9. The process as claimed in claim 1, wherein reaction of step (b) is carried out at the low temperature in the range of-15 to 0°C, preferably -10°C.
10. The process as claimed in claim 1 step (c), wherein tartarate salt of Eszopiclone (VII) is obtained by;
a) dissolving the racemic Zopiclone (V) in acetonitrile;
b) reacting with D(+)-0,0'-dibenzoyl tartaric acid monohydrate (VI) and stirring for 4 to 24 hours at temperature range of 25 to 35° C to precipitate out the solid;
c) isolating compound (VII) by filtration.

11. The process as claimed in claim 10, wherein acetonitrile is used in an amount of 20 to 80 volumes, preferably 30 volumes.
12. The process as claimed in claim 1 step (d), wherein the purification of 0,0'-DBTA salt of Eszopiclone (VII) comprises;

a) refluxing compound of formula (VII) in organic solvent;
b) stirring the reaction mixture followed by addition of acetonitrile;
c) heating the reaction mixture at temperature of 50 to 65°C for few minutes and
d) isolating the compound of formula (VIII).
13. The process as claimed in claim 12 step (a), wherein the organic solvent is
selected from dichloromethane, chloroform or mixture thereof, preferably
dichloromethane.
14. The process as claimed in claim 13, wherein the amount of dichloromethane used
is 15 to 30 volumes, preferably 20 volumes.
15. The process as claimed in claim 12, wherein the amount of acetonitrile used is 20 to 40 volumes, preferably 25 volumes.
16. The process as claimed in claim 1, wherein the base used in step (e) is alkali metal hydroxide selected from sodium hydroxide, potassium hydroxide, preferably sodium hydroxide.
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17. The process as claimed in claim 1, wherein cleaving of isolated (R)-Zopiclone
comprising of
a) treating the R-isomer of Zopiclone (X) with acid in organic solvent or in mixture of alcohol and water;
b) neutralizing the obtained reaction mixture with the base to precipitate out compound (IV);
c) isolating the compound (IV) by filtration followed by washing with water followed by organic solvent.

18. The process as claimed in claim 17, wherein the acid is selected from inorganic or organic acid.
19. The process as claimed in claim 17 and 18, wherein the organic acid is selected from trifluoroacetic acid, trichloroacetic acid , preferably trifluoroacetic acid.
20. The process as claimed in claim 17, wherein the inorganic acid is hydrochloric acid.
21. The process as claimed in claim 17, wherein the organic solvent is selected from dichloromethane, chloroform, ethylene dichloride, 1,1,1-trichloroethane, chlorobenzene or mixture thereof, preferably dichloromethane.
22. The process as claimed in claim 17, wherein the alcohol is selected from methanol, ethanol, isopropanol, preferably methanol.
23. The process as claimed in claim 17, wherein the base is selected from alkali metal carbonates or bicarbonates, preferably bicarbonates and more preferably sodium bicarbonate.
24. The process as claimed in claim 1, wherein Eszopiclone obtained in a highly pure with unwanted (R)-isomer (X) and N-Desmethylzopiclone (XI) are less than 0.1% and with chemical purity of more than 99.5 %.
25. The process for preparation of optically pure Eszopiclone substantially as herein
described with reference to foregoing examples 1 to 10.

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Abstract:
(I)
Disclosed herein is the process for preparation of 6-(5- chloro-pyrid-2-yl)-5-[(4-methyl -1-piperazinyl) carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine (Zopiclone), its resolution to get the dextrorotatory isomer of formula (I) substantially free of R (-) enantiomer and recovery of key raw material i.e. 6-(5-chloro pyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo [3,4-b] pyrazine (IV) from the R-isomer of Zopiclone followed by conversion of the recovered compound (IV) to get enantiomerically enriched Eszopiclone (I) in high yield.