43200-80-2

Basic information

• Product Name: Zopiclone
• Synonyms: 4-Methyl-1-piperazinecarboxylic acid ester with 6-(5-chloro-2-pyridyl)-6,7-dihydro-7-hydroxy-5H-pyrrolo[3,4-b]pyrazin-5-one;6-(5-Chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-methyl-1-piperazinecarboxylate;Amoban;Amovane;Imovance;oxo-5h-pyrrolo(3,4-b)pyrazin-5-ylester;RP-27267;Sopivan
• CAS NO: 43200-80-2
• Molecular Formula: C₁₇H₁₇ClN₆O₃
• Molecular Weight: 388.81
• EINECS: 256-138-9
• Product Categories: Active Pharmaceutical Ingredients;Sedative, Hypnotic;Intermediates & Fine Chemicals;Pharmaceuticals;Isotope Labeled Compounds;GABA;Isotopically Labeled Pharmaceutical Reference Standard;BUPHENYL;Other APIs
• Mol File: 43200-80-2.mol

Chemical Properties

• Melting Point: 1780C
• Boiling Point: 580.7 °C at 760 mmHg
• Flash Point: 2℃
• Appearance: Crystalline solid
• Density: 1.1105 (estimate)
• Vapor Pressure: 1.78E-13mmHg at 25°C
• Storage Temp.: Store at RT
• Solubility: DMSO: 2 mg/mL
• PKA: pKa ﹣1.5±0.1(10% ACN in aq. H2SO4 t = 25.0) (Uncertain)
• CAS DataBase Reference: Zopiclone(CAS DataBase Reference)
• NIST Chemistry Reference: Zopiclone(43200-80-2)
• EPA Substance Registry System: Zopiclone(43200-80-2)

Safety Data

• Hazard Codes: Xn,Xi,F
• Statements: 20/21/22-36/37/38-62-36-11
• Safety Statements: 26-36-36/37-16
• RIDADR: UN 1648 3 / PGII
• WGK Germany: 3
• RTECS: TL1425000
• Hazardous Substances Data: 43200-80-2(Hazardous Substances Data)

Usage

References

[1] Stuart Noble, Heather D. Langtry and Harriet M. Lamb, Drugs, 1998, vol. 55, 277-302 [2] G. Hajak, W. E. Müller, H. U. Wittchen, D. Pittrow, W. Kirch, Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data, Addiction, 2003, vol. 98, 1371-1378

Chemical Properties

Crystalline Solid

Uses

Different sources of media describe the Uses of 43200-80-2 differently. You can refer to the following data:
1. antihyperammonemic,antineoplastic
2. inhibits tyrosinase and prevents melanin formation used to whiten and lighten skin
3. Cyclopyrrolone member of a family of non-benzodiazepine GABAA receptor agonists. This is a controlled substance (depressant) in the US but not in Canada. Sedative, hypnotic

Definition

ChEBI: A pyrrolo[3,4-b]pyrazine compound having a 4-methylpiperazine-1-carboxyl group at the 5-position, a 5-chloropyridin-2-yl group at the 6-position and an oxo-substituent at the 7-position.

Manufacturing Process

Producing of 6-(5-chloropyrid-2-yl)-5-(4-methylpiperazin-1-yl)-carbonyloxy-7- oxo-5,6-dihydropyrrolo[3,4-b]pyrazine by two methods. 1). A solution of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6- dihydropyrrolo[3,4-b]pyrazine (12.0 g) in anhydrous dimethylformamide (360 ml) is added to a suspension of sodium hydride (50% dispersion in mineral oil) (2.4 g) in anhydrous dimethylformamide (60 ml), whilst maintaining the temperature at about -10°C. When the evolution of gas has ceased, a solution of 1-chlorocarbonyl-4-methylpiperazine (8.1 g) in anhydrous dimethylformamide (20 ml) is added, whilst maintaining the temperature at about -10°C. The reaction mixture is stirred for a further 3 h whilst allowing it to heat up gradually to a temperature of about 20°C, and then it is poured into ice-water (1540 ml). The product which crystallizes is filtered off, washed with water (150 ml) and then with diisopropyl ether (100 ml). After drying, a product is obtained and is dissolved in ethyl acetate (600 ml). The solution obtained is filtered through silica gel (250.0 g). Elution is then carried out with ethyl acetate (3200 ml) followed by a mixture of ethyl acetate and methanol The eluates are combined and concentrated to dryness under reduced pressure. So 8.3 g of the 6-(5-chloropyrid-2-yl)-5-(4-methylpiperazin-1-yl)- carbonyloxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine are obtained, melting point 178°C (recrystallisation from a mixture of acetonitrile and diisopropyl ether 1:1; 190 ml). 2). 1-Methylpiperazine (155.0 g) is added to a suspension of 6-(5-chloropyrid- 2-yl)-7-oxo-5-phenoxycarbonyloxy-5,6-dihydropyrrolo[3,4-b]pyrazine (194.0 g) in acetone (970 ml) cooled to a temperature of about 3°C. The reaction mixture is stirred for 3 h at a temperature of about 3°C and is then poured into water (5000 ml). The product which precipitates is filtered off and then washed with water (600 ml) and dried. This product is treated with methylene chloride (1100 ml) at a temperature of about 20°C. The insoluble material is filtered off and then the filtrate is washed with 1 N sodium hydroxide solution (3x200 ml) and with water (3x200 ml). The organic phase is treated with decolorizing charcoal (10.0 g), dried over potassium carbonate, filtered and then concentrated to dryness under reduced pressure. The oily residue obtained is dissolved in boiling acetonitrile (500 ml). The 101.0 g of 6-(5- chloropyrid-2-yl)-5-(4-methylpiperazin-l-yl)carbonyloxy-7-oxo-5,6- dihydropyrrolo[3,4-b]-pyrazine are obtained, melting point 178°C (washed with ice cold acetonitrile, 50 ml, and then crystallizes with diisopropyl ether, 50 ml).

Brand name

IMOVANE

Therapeutic Function

Sedative, Hypnotic

World Health Organization (WHO)

Zopiclone was introduced as a sedative in 1985. It remains registered in several countries and the World Health Organization is not aware of any other country that has refused registration.

Clinical Use

Hypnotic

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: metabolism inhibited by erythromycin; concentration significantly reduced by rifampicin. Antipsychotics: enhanced sedative effects. Antivirals: concentration possibly increased by ritonavir.

Metabolism

Zopiclone is extensively metabolised in the liver via the cytochrome P450 isoenzyme CYP3A4 and, to a lesser extent, CYP2C8; the 2 major metabolites, the less active zopiclone N-oxide and the inactive N-desmethylzopiclone, are excreted mainly in the urine. About 50% of a dose is converted by decarboxylation to inactive metabolites, which are partly eliminated via the lungs as carbon dioxide.

InChI:InChI=1/C17H17ClN6O3/c1-22-6-8-23(9-7-22)17(26)27-16-14-13(19-4-5-20-14)15(25)24(16)12-3-2-11(18)10-21-12/h2-5,10,16H,6-9H2,1H3/p+1/t16-/m0/s1

Upstream product

• 43200-83-5 3-((5-chloropyridin-2-yl)carbamoyl)pyrazine-2-carboxylic acid 
• 1072-98-6 5-chloro-2-pyridylamine 
• 4744-50-7 2,3-pyrazinedicarboxylic anhydride 
• 138729-47-2 eszopiclone 
• 109-01-3 1-methyl-piperazine 
• 43200-88-0 6-(5-chloro-pyridin-2-yl)-7-phenoxycarbonyloxy-6,7-dihydro-pyrrolo[3,4-b]pyrazin-5-one 
• 39539-66-7 4-methyl-piperazine-1-carbonyl chloride 
• 43200-81-3 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one 
• 138680-08-7 (-)-Zopiclone 
• 55112-42-0 4-methylpiperazine-1-carbonyl chloride monohydrochloride 

Downstream Products

• 1020156-02-8 D(+)-O,O-dibenzoyl tartarate of zopiclone 
• 945843-90-3 eszopiclone di-p-toluoyl-L-tartaric acid salt 
• 43200-81-3 6-(5-chloropyridin-2-yl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one 
• 144025-94-5 (R)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate D-(+)-O,O'-dibenzoyltartaric acid salt 
• 59878-63-6 N-Desmethylzopiclone 
• 138680-08-7 (-)-Zopiclone 
• 138729-47-2 eszopiclone 
• 1225275-18-2 eszopiclone di-p-anisolyl-L-tartaric acid salt 
• 144025-93-4 eszopiclone dibenzoyl-D-tartrate 
• 928655-45-2 (+)-6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)-carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine di-p-toluyl-D-tartate 

Relevant articles and documents

Preparation method of zopiclone intermediate

The invention provides a preparation method of zopiclone. According to the method, anhydride is used as a reaction solvent, pyrazine-2,3-dianhydride and 2-amino-5-chloropyridine are synthesized into 6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine in one step, so that the process is simplified, the obtained product is high in yield and purity, production conditions and environment friendliness are achieved, and the method is suitable for industrial production.

A method for producing zopiclone

The invention relates to a preparation method of zopiclone for improving sleeping, belonging to the field of medicines. In the preparation process of 6-(5-chlro-2-pyridyl)-5, 7-dioxo-5, 6-dihydropyrrolo[3, 4-b] pyrazine, namely a compound 3, by taking DMAP (dimethylaminopyridine) as a catalyst, in the presence of triethylamine, cyclization is directly carried out to synthesize an intermediate 3. The crude product yield is 85%, the yield is improved, the operation is simplified, and irritant reagents such as acetic anhydride, thionyl chloride, ethyl chloroformate and the like are not used, thereby facilitating production, facilitating recovery of xylene as a solvent and reducing emission of three wastes. Zopiclone is further synthesized by the compound 3. The method is concise in whole line, simple and convenient to operate and more suitable for industrialized production.

A racemization method of zopiclone

The invention relates to a racemization method of eszopiclone. According to the invention, tetramethylguanidine which is cheap and easily available is used as a racemization agent. The method provided by the invention is simple to operate, is safe and stable, has advantages of high yield and good product quality, and is suitable for industrial production.

CRYSTALLINE POLYMOPHIC FORMS OF ZOPICLONE, PROCESSES FOR THEIR PREPARATION AND THEIR PHARMACEUTICAL COMPOSITIONS

Disclosed are processes for the preparation of crystalline polymorphic forms of zopiclone and their pharmaceutical compositions for use as a sedative.

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)

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 from the R-isomer of Zopiclone followed by conversion of the recovered compound to get pure Eszopiclone (I) in high yield and high purity.

PROCESS FOR PREPARATION OF DEXTROROTATORY ISOMER OF 6-(5-CHLORO-PYRID-2-YI)-5-[(4-METHYL -1-PIPERAZINYL) CARBONYLOXY]-7-OXO-6,7-DIHYDRO-5H-PYRROLO [3,4-B] PYRAZINE (ESZOPICLONE)

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 from the R-isomer of Zopiclone followed by conversion of the recovered compound to get pure Eszopiclone (I) in high yield and high purity.

A NEW METHOD FOR PREPARATION OF ZOPICLONE AND ITS POLYMORPHS

A process for the preparation of crystalline Zopiclone comprising i) suspending zopiclone in a mixture of acetonitrile and diisopropyl ether, filtering and drying the resulting solid; ii) dissolving the solid in step i) in N,N-dimethylformamide to get a clear solution; iii) heating and then precipitating solid; iv) filtering and drying the solid to get crystalline zopiclone. Crystalline zopiclone Form C. Crystalline Zopiclone Form D characterized by an X-ray powder diffraction pattern that comprises peaks with 2theta values of at least 14.8, 19.8, 21.3, 27.3 °2θ ± 0.2 °2θ. A process for preparation of crystalline Zopiclone Form D comprising dissolving Zopiclone in N,N-dimethylformamide and filtering; washing clear filtrate with an alkali solution; separating and concentrating the organic layer, adding isopropyl alcohol thereto and concentrating further to get a slurry; filtering the slurry and drying the resultant solid to get crystalline Zopiclone form D. Pharmaceutical composition comprising crystalline forms of Zopiclone.

Racemization process of R-zopiclone

In one of the embodiments, the present invention provides a racemization process comprising: removing the organic solvent from a mother liquor comprising R-zopiclone malate, eszopiclone malate and an organic solvent to obtain a mixture of R-zopiclone malate and eszopiclone malate; mixing the mixture with water to obtain a solution; neutralizing R-zopiclone malate and eszopiclone malate in the solution to obtain a precipitate of R-zopiclone and eszopiclone; filtering the precipitate; mixing the precipitate of R-zopiclone and eszopiclone with DBU and an organic inert solvent having a boiling point of at least 80° C.; heating; and cooling to obtain a zopiclone racemate.

A NOVEL PROCESS FOR THE PREPARATION OF ESZOPICLONE

The present invention is related to a novel process for the preparation of eszopiclone (II), that comprises the following steps: (a) preparation of zopiclone (I) by reaction of 6-(5-chloropyridin-2-yl)-5-hydroxy-7-oxo- 5,6-dihydropyrrolo[3,4-b]pyrazine-5-one (5-OH-Py) (III) with chloro-carbonyl-4- methyl-piperazine (CMP) free base (IV) or its acid addition salt in the presence of diazabicylo [5.4.0]undec-7-ene (DBU) or a mixture of DBU and other bases; (b) resolution of racemic zopiclone with dibenzoyl-D-tartaric acid in suitable solvent wherein dibenzoyl-D-tartaric acid addition salt of eszopiclone is separated by the addition of a nitrile solvent; (c) optional purification of dibenzoyl-D-tartaric acid addition salt of eszopiclone by dissolution in solvent selected from alcohols, ketones or mixture thereof followed by the precipitation by adding a nitrile solvent; (d) conversion of the dibenzoyl-D-tartaric acid addition salt of eszopiclone to obtain the eszopiclone free base (II) by treating with an alkaline solution; (e) purification of eszopiclone by dissolving in nitrile solvent followed by addition of ketonic solvent. The eszopiclone (II) obtained by the process of the present invention has chiral purity greater than 99.9% and less amounts of organic volatile impurities. The present invention further provides novel crystalline form B of eszopiclone- Dibenzoyl-D-tartarate salt (V) and its preparation.

IMPROVED PROCESS FOR THE PREPARATION OF ZOPICLONE AND IT'S ENANTIOMERICALLY ENRICHED ISOMER

Present invention relates to an improved process for the preparation of Zopiclone and its enantiomerically enriched isomer (Eszopiclone). 6-(5-Chloropyridin-2- yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo [3,4-b] pyrazine is reacted with 1-chloro- carbonyl-4-methylpiperazine in the presence of alkali earth metal carbonates, hydroxides or oxides in a solvent medium to give Zopiclone. It is reacted with optically active acid in a mixture of water and water miscible organic solvent followed by work up to give Eszopiclone. The present invention also relates to process for the conversion of (R) or (S) Zopiclone to 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydro- pyrrolo- [3,4-b] - pyrazine of the intermediate which can be converted to racemic Zopiclone.