FORM 2
THE PATENTS ACT, 1970;
[39 of 1970]
&
THE PATENTS RULES, 2003
PROVISIONAL SPECIFICATION: [SECTION-10; RULE 13]
IMPROVED PROCESS OF THE MANUFACTURE OF ZOPICLONE AND A PRODUCT DERIVED THEREFROM
CENTAUR CHEMICALS PVT. LTD., a Company incorporated under the Companies Act, 1956, having regd. office at "Centaur House", Shanti Nagar, Vakola, Santacruz (East), Mumbai -400055, Maharashtra State, India;
The following specification describes the invention:

This invention relates to an improved process for the manufacture of Zopiclone and a product derived out of the said process.
Field of the Invention
The invention relates to an improved process for
synthesis of Zopiclone, chemically named as 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo-[3,4b] pyrazin-5-yl-
4-methyl piperazine-l-carboxylate, is a non - benzodiazepine hypnotic which has following structure.

Background of the Invention
Zopiclone, 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo-[3,4b] pyrazin-5-yl-4-methyl piperazine-1-carboxylate is a non - benzodiazepine hypnotic and its uses are described in US patent nos. 3,862,149 and 4,220,646.
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Prior Art
1) The US patent 3,862,149 describes the condensation of l-chlorocarbonyl-4-methylpiperazine with 6-(5-chloropyridyl-2-yl)-5-hydroxy-7-oxo-5,6-dihydro-5H-pyrrolo[3,4b] pyrazine in anhydrous dimethylformamide and sodium hydride [50% dispersion in mineral oil] to get zopiclone.
2) The Indian patent 645/ Mum/ 2004 describes the formation of zopiclone, by reaction of 6-(5-chloropyridyl-2-yl)-5-hydroxy-7-oxo-5,6-dihydro-5H-pyrrolo [3,4b] pyrazine and 4-chlorocarbonyl-4-methylpiperazine in methylene chloride using pyridine as a base.
3) The US patent 2007/ 0054914 Al describes the reaction of 6-(5-chloropyridyl-2-yl)-5-hydroxy-7r oxo-5,6-dihydro-5H-pyrrolo [3,4b] pyrazine and l-chlorocarbonyl4-methylpiperazine hydrochloride using inorganic base, potassium carbonate and phase transfer catalyst such as tetrabutylammonium bromide in MIBK / water mixture at 25-35°C
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The main disadvantages of prior art are
1) Use of sodium hydride, which has potential hazard of handling on large scale.
2) Use of l-chlorocarbonyl-4-methylpiperazine as base on commercial scale has potential problem of unstability (Ref. US patent 2007/0054914 Al) as well as its commercial availability.
3) Use of pyridine on large scale has potential environmental hazards.
Objective of Invention
The present invention describes the process having the final product with better quality, more environment friendly with cost effectiveness.
Summary of Invention
The present invention describes the synthesis of Zopiclone, which comprises of
a) a reaction of 6-(5-chloropyridyl-2-yl)-5-hydroxy-7-oxo-5,6-dihydro-5H-pyrrolo[3,4b] pyrazine with-1-chlorocarbonyl-4-methylpiperazine hydrochloride using triethyl amine and dimethylamino pyridine in methylene chloride /
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N,N-dimethylformamide at 5-10°C followed by heating at 38-42°C.
b) The isolation of crude Zopiclone from reaction mixture and its crystallization using ethyl acetate followed by purification in isopropanol.
Detail Description of Invention
The process for producing racemic zopiclone is given in Scheme I hereunder:

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In accordance with the scheme I, 6-(5-chloropyridyl-2-yl)-5-hydroxy-7K)xo-5,6-dihydro--5H-pyrrolo [3,4b] pyrazine and l-chlorocarbonyl-4-methylpiperazine hydrochloride were reacted in organic solvent such as methylene chloride or dimethylformamide, in presence of combination of bases such as triethyl amine and N,N-dimethylamino pyridine. The isolated product was further purified in ethyl acetate and isopropanol. The zopiclone isolated from such process is of very high HPLC purity and good yields. The use of combination of triethyl amine and N, N-dimethylamino pyridine provides distinct advantage in terms of operational safety on large scale.
Process
Charged 1.0 Kg (3.81 moles) of 6-(5-chloropyridyl-2-yl)-5-hydroxy-7-oxo-5,6-dihydro-5H-pyrrolo [3,4b] pyrazine in 10.0 Ltrs. of methylene chloride and cooled the reaction mixture to 5-10°C. 1.0 Kg of l-chlorocarbonyl-4-methylpiperazine hydrochloride was added at same temperature. 1.22 Kg (12 moles) of triethyl amine was added to the reaction mixture followed by addition of N, N-dimethylamino pyridine (0.35Kg) at temperature 5-10°C in two lots. Reaction mixture was heated to reflux and maintained for 2 hrs. Reaction mixture was cooled to room temperature and 4.5 Ltrs. of water was added at 25°C. The organic layer was separated and aqueous phase was extracted
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with methylene chloride (2.0 Ltrs.). The combined organic phase was washed with water (2.0 Ltrs.). The organic phase was separated and concentrated at atmospheric pressure to obtain crude Zopiclone. It was recrystallised from ethyl acetate and further purified from isopropanol (Yield: 1.0-1.2 Kg).
1) In accordance with the invention the process for the synthesis of zopiclone by reacting 6-(5-chloropyridyl-2-yl)-5-hydroxy-7-oxo-5,6-dihydro-5H-pyrrolo[3,4b] pyrazine with l-chloroCarbonyl-4-methylpiperazine hydrochloride at 5-10°C followed by heating at 38-42°C using combination of bases such as triethyl amine and N,N-dimethylamino pyridine in methylene chloride.
2) The same reaction as mentioned under serial No. 1 hereinabove is carried out in N, N-dimethylformamide.
Dated this 3rd day of May, 2007.

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