Title of Invention	AN IMPROVED PROCESS FOR PREPARATION OF S-ZOPICLONE (II)
Abstract	The invention is directed to preparation of optically active isomer of 6-(5-chloro-2-pyridinyl)-6, 7-dihydro-7-oxo-5H-pyrrolo-[3, 4-b]-pyrazine-5-yl-4-methyl piperazine-1-carboxylate. The current embodiment describes a process which is industrially feasible, cost effective and reduces the time cycle.

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FORM 2 THE PATENT ACT, 1970 (39 OF 1970) & THE PATENT RULES, 2003 COMPLETE SPECIFICATION [See section 10 and rule 13] 1. TITLE OF THE INVENTION: AN IMPROVED PROCESS FOR THE MANUFACTURE OF PYRAZINE DERIVATIVE 2. APPLICANT (a) Name (b) Nationality (c) Address Emcure Pharmaceuticals Ltd. India R&D Center II, 12/2 F - II Block, M.LD.C. Pimpri, Pune - 411018, Maharashtra 3. PREAMBLE TO THE DESCRIPTION PROVISIONAL The following specification describes the Invention. ü COMPLETE The following specification particularly describes the invention and the manner in which it is to be performed. 4. DESCRIPTION (Description starts from next page.) 5. CLAIMS (not applicable for provisional specification.) 6. DATE AND SIGNATURE (to be given at the end of the last page of specification) 7. ABSTRACT OF THE INVENTION (to be given along with complete specification on separate page) Note: - * Repeat boxes in case of more than one entry *To be signed by the applicant(s) or by the authorized registered patent agent. *Name of the applicants should be given in full, family name in the beginning "Complete address of the applicant should be given stating the postal index no./code, state and country. "Strike out the column which is/are not applicable. AN IMPROVED PROCESS FOR MANUFACTURE OF PYRAZINE DERIVATIVE FIELD OF THE INVENTION The present invention relates to an industrial process for the synthesis of 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo-[3,4-b]-pyrazine-5-yl-4-methyl piperazine-1 -carboxylate with higher yields and economical feasibility. BACKGROUND OF THE INVENTION 6-(5-Chloro-2-pyridinyl)-6, 7-dihydro-7-oxo-5H-pyrrolo-[3,4-b]-pyrazine-5-yl-4-methyl piperazine-1-carboxylate i.e. Zopiclone (I) is a non benzodiazepine, which belongs to the group of medicines called as the central nervous system (CNS) depressants. Zopiclone, a cyclopyrrolone derivative, is a short-acting hypnotic agent (Ref: US 5,786,357). Zopiclone belongs to a novel chemical class, which is structurally unrelated to existing hypnotics. Zopiclone belongs to the class of pyrrolopyrazine, which is known to possess hypnotic properties. (Ref: http://www.fda.gov/cder/foi/nda/2004/ 021476 Lunesta prntlbl.PDF). Zopiclone is used to cure people with insomnia. 1 In a racemic compound it is known that one of the two enantiomers is more active. The dextro isomer of Zopiclone (II) is twice as active as the racemate, whereas the laevorotatory isomer is almost inactive. Further, the dextrorotatory isomer also has the lower toxicity as compared to the racemate (Ref: US 6,319,926). The use and preparation of the optically active isomer of Zopiclone is described in US 6,319, 926 Bl. US 5,786,357 is a patent, which discloses the method of treatment by making use of the (+) enantiomer of Zopiclone. WO2004/037212 and US 2004147521 disclose the preparation of Zopiclone derivatives. US 3, 862, 149 discloses a process for the preparation of Zopiclone. The reaction sequence includes the reaction of 2-amino-5-chloropyridine and pyrazine 2,3-dicarboxylic acid anhydride at reflux temperature to yield 3-(5-chloropyrid-2-yl) carbomyl pyrazine-2-carboxylic acid. Further, 3-(5-chloropyrid-2-yl) carbomyl pyrazine -2-carboxylic acid is cyclised using thionyl chloride to yield 6-(5- chloropyrid -2-yl)-5,7-dioxo-5,6-dihydropyrolo-[3,4-b]-pyrazine, which is further treated with potassium borohydride to yield 6-(5- chloropyrid -2-yl)-5-hydroxy-7-oxo-5,6-dihydro pyrrolo-[3,4-b]-pyrazine. The obtained 6-(5- chloropyrid -2-yl)-5-hydroxy-7-oxo-5,6-dihydro pyrrolo-[3,4-b]-pyrazine is reacted with l-chlorocarbonyl-4-methylpiperazine using sodium hydride to give 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo-[3,4-b]-pyrazine-5-yl-4-methyl piperazine -1-carboxylate (I), which is purified using column chromatographic technique to get pure Zopiclone. 2 However, this prior art process has following limitations: 1. The l-chlorocarbonyl-4-methyl piperazine used is moisture sensitive. 2. It is also a strong skin irritant. 3. The use of sodium hydride makes the process hazardous to explosion. 4. The overall yield of the reaction is low, thus making the process industrially unfeasible. 5. The purification of the final product is carried out by making use of chromatographic technique and hence the process is not industrially feasible. US 6,339,086, US 6,506,753 and US 6,458,791 discloses the preparation of Zopiclone as shown in Scheme (I). The compound (III) is reacted with the chiral auxiliary-based chloroformate (IV) to yield compound of formula (V), which is further reacted with base (VI) to yield S-Zopiclone (II). Alternatively, Zopiclone is also prepared as shown in Scheme (II). The amino alcohol (III) is reacted with the ester (VII) in the presence of an enzyme to give compound of formula (VIII), which is further treated with base (VI) to yield S-Zopiclone (II). . Scheme (I): Process for preparation of S-Zopiclone as per US 6,339,086 Scheme (II): Process for preparation of Zopiclone as per US 6,339,086 However, this process has disadvantages, which limit its scope on an industrial scale. The process disclosed in US 6,339,086 makes use of a chiral auxiliary based chloroformate. The chiral auxiliary based chloroformate is not readily available, which needs reaction step(s), to generate the chiral auxiliary based chloroformate. This increases additional number of steps, thus increasing the time cycle, utilities, cost, manpower etc. This chloroformate is difficult to handle and moisture sensitive. Further, the Scheme (II) makes use of an enzyme in its process, which is industrially not feasible. The cost involved in the enzymatic process is high. Enzyme catalyzed reactions require more lead time for a chemical conversion than the typical conventional chemicals. Enzymes are sensitive to pH, temperature, humidity and contaminants. Storage of these enzymes is more difficult as they have a shorter shelf life than most chemicals. There should be a careful study and planning regarding the availibility of enzymes on hand, as it is not readily available in the market (Ref: http://www.aatcc.org/magazine/files/enzvmes aatccreview.pdf) 4 US 6,444,673 discloses a process for the resolution of racemic Zopiclone by making use of D (+)-0,0'-dibenzoyltartaric acid and dichloromethane. The crude salt obtained is recrystallised in acetonitrile. The product obtained is further dissolved in dichloromethane and further acetonitrile is added. The final product is recrystallised again to obtain a pure compound. However, this method has following disadvantages: a) More steps are required to reach the final purity of the product. b) Larger amount of solvents are required. Especially acetonitrile, which is costly solvent, is used in the ratio of 1:18 (Wt/ vol) with respect to the racemic Zopiclone tartarate. c) Further as the steps increase, the yield decreases, thus making the process costly. d) The time cycle required for the process is also more. In view of the above shortcomings, it was necessary to develop alternate synthetic route, which would give compound of formula (II) with use of limited volumes of acetonitrile as well as dichloromethane. The present inventors have developed a synthetic route for preparation of Zopiclone, by a process which not only suppresses the need for complicated purification of racemic Zopiclone, but also gives Zopiclone in good yields. The present inventors have also made an approach to prepare (S)-Zopiclone by avoiding the highly explosive base sodium hydride. In the present invention, an approach to prepare (S)-Zopiclone by avoiding the highly moisture sensitive reagent i.e. l-chlorocarbonyl-4-methylpiperazine. The present inventors have also developed a process for the preparation of (S) Zopiclone of desired purity by reducing the steps, making use of less amount of solvents, reducing the time cycle and thus making the entire process cost effective and industrially feasible. 5 OBJECT OF THE INVENTION First object of the present invention is to provide an improved process for the preparation of (S)-Zopiclone of formula (II) by a synthetic route, which is novel from the routes disclosed in prior art. Second object of the invention is to provide (S)-Zopiclone by avoiding the highly moisture sensitive and skin irritating reagent i.e. l-chlorocarbonyl-4-methylpiperazine. Third object of the invention is to prepare Zopiclone by avoiding the use of sodium hydride, which is explosive and difficult to handle on an industrial scale. Fourth object of the invention is to provide optically active form of Zopiclone in appreciable yields. Fifth object of the invention is to provide optically active form of Zopiclone by making use of lesser amount of solvents, especially acetonitrile. Sixth object of the invention is to provide a simple, industrially feasible, economical and safe method to prepare optically active Zopiclone. SUMMARY OF THE INVENTION: According to the present invention the optically active Zopiclone is prepared by making use of l-chlorocarbonyl-4-methyl piperazine hydrochloride. The present invention also makes use of less hazardous base. This current embodiment also discloses the resolution of racemic Zopiclone by making use of less amount of solvents especially acetonitrile, thus decreasing the cost and the time cycle of the process. 6 DETAILED DESCRIPTION OF THE INVENTION: Optically active Zopiclone i.e. (S)-Zopiclone is prepared as per Scheme (III) disclosed below: The present embodiment describes the preparation of optically active Zopiclone as per the reaction sequence disclosed in Scheme (III). The reaction sequence includes the reaction of pyrazine-2, 3-dicarboxylic acid anhydride (IX) and 2-amino-5-chloropyridine (X), to yield 3-(5-chloropyrid-2yl) carbomyl pyrazine-2-carboxylic acid (XI). This compound (XI) is cyclised using thionyl chloride to yield 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo-[3,4-b]-pyrazine (XII), which is reduced using potassium borohydride to give 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydro pyrrolo-[3,4-b]- 7 pyrazine i.e. (XIII). Further, the compound (XIII) is reacted with l-chlorocarbonyl-4-methylpiperazine hydrochloride (XIV) in the presence of dimethyl amino pyridine and tri ethyl amine to produce racemic Zopiclone (I). This racemic compound is treated with D (+) di-benzoyl tartaric acid to yield the racemic tartarate salt (XV), which on crystallization in the single step using methylene dichloride and acetonitrile yields the (S) (+) Zopiclone tartarate salt (XVI). This optically active tartarate salt is then basified using sodium hydroxide to yield (S) Zopiclone (II). The current invention makes use of l-chlorocarbonyl-4-methylpiperazine hydrochloride (XIV). This compound is easy to handle. It is less moisture sensitive and is a safe reagent. Further, it also does not cause any skin reactions. The base used in the reaction is 4-dimethyl amino pyridine and triethylamine. This combination of base used, requires less stringent conditions and hence make the reaction conditions less hazardous as compared to the use of sodium hydride, otherwise used for the said reaction. The current embodiment makes use of a process in which the purification step is faster and quick. A single step crystallization, for resolution of Zopiclone, is carried out, which requires lesser amount of solvents and thus decreases the cost of the entire process. The solvents used in the crystallization step are methylene dichloride and acetonitrile. Methylene dichloride used is in the ratio of 1 : 4 to 1 : 8 wt / vol (w.r.t. wt. of Zopiclone). Acetonitrile used is in the ratio of 1 : 8 to 1 : 12 wt / vol. In the preferred embodiment, methylene dichloride used is in the ratio of 1 : 4 to 1 : 6 wt / vol (w.r.t. wt. of Zopiclone) and acetonitrile used is in the ratio of 1 : 9 to 1 : 11 wt / vol. The improved method of crystallization according to the instant invention reduces the load on utilities, reactor occupancy, manpower, time cycle etc. A further result to this is the increase in the yield of the final product. 8 Thus, the current embodiment makes use of a process, which is advantageous in following ways: 1) Use of l-Chlorocarbonyl-4-methylpiperazine hydrochloride, being less moisture sensitive. 2) Easy to handle. 3) Avoids skin irritation. 4) Use of safe and non explosive base. 5) Cost effective and industrially feasible process. 6) High yields. 7) Avoiding use of column chromatography. 8) Reduction in the time cycle of the process. The invention is described in detail here below with respect to the following examples, which are provided merely for illustration and are not intended to restrict the scope of the invention in any manner. Any embodiments that may be apparent to a person skilled in the art are deemed to fall within the scope of the present invention. 9 EXAMPLES: Example 1: Preparation of 3-(5-chloropyrid-2-yl)carbomylpyrazine-2-carboxylic acid (XI) Acetonitrile (10 L) was charged to pyrazine-2, 3-dicarboxylic acid anhydride (590 g) and 2-amino-5-chloropyridine (1000 g) while stirring. The reaction mixture was refluxed. The reaction mixture was cooled. The solid was filtered and washed with acetonitrile. Further, the solid was suspended in water and IN hydrochloric acid was added till pH of the reaction reached 1.0. The reaction mixture was stirred for 15 minutes. The solid was filtered and washed with water and dried. Yield =1.0 Kg. Example 2: Preparation of 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo-[3,4-b]-pyrazine (XII) Thionyl chloride (5.0 L) was added to 3-(5-chloropyrid-2-yl)carbomyl pyrazine-2-carboxylic acid (1000 g) while stirring. The reaction mixture was further refluxed for 5 hours. After completion of the reaction the thionyl chloride was distilled out and the residue was cooled while stirring. The solid was filtered and dried. Yield = 0.85 Kg. Example 3: Preparation of 6-(5-chloropyrid-2yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo-[3,4-b]-pyrazine(XIII) 6-(5-Chloropyrid-2yl)-5,7-dioxo-5,6-dihydropyrrolo-[3,4-b]-pyrazine was charged in dioxane and water. The reaction mixture was cooled to 10 - 13°C. Potassium borohydride (154 g) was added maintaining the temperature below 13°C. The reaction mixture was stirred, maintaining the temperature. The reaction mixture was poured over water. Acetic acid was added. The solid was filtered washed and suck dried. The solid was suspended in chloroform and stirred. The solid was filtered, washed and dried. Yield = 0.75 Kg 10 Example 4: Preparation of 6-(5-chloropyrid-2yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo-[3,4-b]-pyrazine (I) Dichloromethane (10 L), imino alcohol (XIII) (1000 g; 0.2626 moles) and piperazine carbamoyl chloride hydrochloride (1140 gm) were taken in a round bottom flask. The reaction mixture was stirred. Triethyl amine (3.22 L) was added slowly maintaining the temperature between 25-30°C within 30 minutes. 4-Dimethylaminopyridine (25g) was added. The reaction mixture was refluxed for 1.0-1.5 hours. After completion of the reaction heating was stopped and the reaction mixture was cooled. The organic layer was washed with water. Charcoal was added and stirred. The reaction mixture was filtered and washed with methylene chloride. The organic layer was concentrated. Methanol (1 L) was added and stirred. The methanol was distilled out to remove final traces of methylene chloride. Further methanol (4 L) was added and cooled to 0-10°C and stirred. The solid was filtered and washed with chilled methanol. The solid obtained was dried. Yield=l.lKg Example 5: Preparation of Zopiclone tartarate salt (XV) Methanol (16 L) was charged to racemic Zopiclone (1000 g) at 25-32 °C. A solution of D-(+)-dibenzoyltartaric acid in methanol (967g) (16L) was added and the reaction mixture was heated to reflux. The reaction mixture was cooled. The solid was filtered and washed with 1.0 L methanol. The solid obtained was dried Yield =1.8 Kg Example 6: Preparation of (S) Zopiclone tartarate salt (XV) Acetonitrile (5 L) and methylene chloride (10 L) as added to racemic Zopiclone tartarate salt (1000 g). The reaction mixture was heated. The reaction mixture was cooled. The reaction mixture was stirred and filtered. The solid was dried washed with mixture of methylene chloride and acetonitrile solution (1 L) (2:1) and dried well. Yield = 0.50 Kg 11 Example 7: Preparation of (S) Zopiclone (II) (+)-Zopiclone tartarate salt (1000 g), water (5 L) and methylene dichloride (5L) were added to a round bottom flask. The reaction mixture was cooled. 10% sodium hydroxide solution (100G in 1 L) was added drop wise at 15-20°C. The reaction mixture was further stirred. pH was maintained between 11.0 to 11.5. The organic layer was separated. The aqueous layer was extracted with methylene chloride 2.5 L twice. The organic layer was concentrated. Cyclohexane 2 L was added and the reaction mixture was stirred. The solid was filtered and washed with Cyclohexane. The solid was dried well. Yield = 0.31 Kg Optical Rotation: +129.3° in c= 1% dimethyl formamide Chiral Purity: 99.98% RS Purity: 99.99% 12 CLAIMS 1) A process for the preparation of S-Zopiclone (II) comprising the steps of: a) coupling pyrazine-2,3-dicarboxylic acid anhydride (EX) and 2-amino-5-chloropyridine (X) to get 3(-5-chloropyrid-2yl) carbomyl pyrazine-2-carboxylic acid (XI), b) cyclizing the acid of formula (XI) in the presence of SOCI2, to get 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo-[3,4-b]-pyrazine (XII), c) reducing the dihydropyrrolo compound of formula (XII) in the presence of potassium borohydride to yield compound (XIII), (XIV) d) reacting the compound (XIII) with 1 -chlorocarbonyl-4-methylpiperazine hydrochloride (XIV) in the presence of mixture of base to yield racemic Zopiclone (I), .0 (I) e) preparing racemic Zopiclone tartarate by making use of (D)-(+)-dibenzoyl tartaric acid, to get compound (XV), f) isolating (S) Zopiclone tartarate and g) converting of (S) Zopiclone tartarate to (S) Zopiclone free base. A process according to claim 1, wherein mixture of the base used for reacting the compound (XIII) with 1 -chlorocarbonyl-4-methylpiperazine hydrochloride (XIV) to yield racemic Zopiclone (I) is dimethyl amino pyridine and triethyl amine. ) 3) A process according to claim 1, wherein the (S) Zopiclone tartarate salt is prepared from the racemic Zopiclone tartarate salt by making use of a fixed ratio of acetonitrile and methylene dichloride. 4) A process according to claim 3, wherein methylene dichloride used is in the ratio of 1 : 4 to 1 : 8 wt / vol. 5) A process according to claim 3, wherein methylene dichloride used is preferably in the ratio of 1 : 4 to 1 : 6 wt / vol. 6) A process according to claim 3, wherein acetonitrile used is in the ratio of 1 : 8 to 1 : 12 wt / vol. 7) A process according to claim 3, wherein acetonitrile used is preferably in the ratio of 1 : 9 to 1 :11 wt / vol. 8) A process for preparing optically pure Zopiclone substantially as described in foregoing examples. 15 ABSTRACT The invention is directed to preparation of optically active isomer of 6-(5-chloro-2-pyridinyl)-6, 7-dihydro-7-oxo-5H-pyrrolo-[3, 4-b]-pyrazine-5-yl-4-methyl piperazine-1-carboxylate. The current embodiment describes a process which is industrially feasible, cost effective and reduces the time cycle.

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