43200-80-2

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

Provided is a process for the preparation of zopiclone, an intermediate in the synthesis of eszopiclone. The present invention provides a process for preparing zopiclone by combining 6-(5-chloro-2-pyridinyl]-6,7-dihydro-7-hydroxy-5H-pyrroIo[3,4-b]pyrazine-5-one (7-OH-Py) having the formula (I), with chloro-carbonyl-4-methyl-piperazine (CMP) as a free base or an acid addition salt having the formula (II), 4-N,N-dimethylamino-Pyridine (DMAP) catalyst and a base in the presence of a polar solvent.

The invention relates to a process for making of 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo-[3,4-b] pyrazin-5-yl-4-methyl piperazine-1-carboxylate, also known as zopiclone. The invention further describes an effective method for resolving of zopiclone into its enantiomers (eszopiclone and (R)-zopiclone) and also provides a method of recycling of (R)-zopiclone.

The invention is directed to compositions comprising, and methods of using, racemic N-desmethylzopiclone, optically pure (+)-N-desmethylzopiclone, and optically pure (?)-N-desmethylzopiclone in the treatment and prevention of diseases and conditions in mammals. The invention is further directed to novel methods of preparing N-desmethylzopiclone, optically pure (+)-N-desmethylzopiclone, and optically pure (?)-N-desmethylzopiclone.