CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefits of U.S. Provisional Application Nos. 60/793,303 filed Apr. 20, 2006 and 60/884,109 filed Jan. 9, 2007, the disclosures of which are incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to methods for preparing eszopiclone crystalline Form A, substantially pure eszopiclone, optically enriched eszopiclone and eszopiclone with a low concentration of residual solvent(s).

BACKGROUND

Zopiclone, a non-benzodiazepine which can be used to induce a sedative, hypnotic or tranquilizing effect, useful for treating insomnia, is a racemate having a chemical name of 4-methyl-1-piperazinecarboxylic acid 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl ester, (Â±)-6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl-4-methylpiperazine-1-carboxylate, or 6-(5-chloropyrid-2-yl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine, represented with formula I below.

Eszopiclone is the S-enantiomer of zopiclone and is more active and less toxic than the racemic zopiclone according to U.S. Pat. No. 6,444,673 B1. This drug has been marketed in the United States by Sepracorâ„¢ under the name LunestaÂ®, formerly known as EstorraÂ®, having a CAS Registry Number of 138729-47-2. Eszopiclone has a chemical name of (+)-6-(5-chloro-2-pyridinyl)-7(S)-(4-methylpiperazin-1-yl-carbonyloxy)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine-5-one and is represented with formula II below.

Eszopiclone in free base form and salt forms are disclosed in U.S. Pat. Nos. 6,444,673 and 6,864,257.

Eszopiclone can be prepared by optical resolution of racemic zopiclone. Blaschke, G. et al., Chirality (1993) 5:419-421 discloses preparation of eszopiclone free of its enantiomer using 0.5 equivalent D-(+)-Malic acid. By this procedure the diastereomeric salt is crystallized from a mixture of methanol-acetone, the salt is then neutralized and the free base is extracted in CH₂Cl₂/ethyl acetate and precipitated by concentration of the solution. The preparation of eszopiclone by optical resolution of racemic zopiclone using malic acid was improved in U.S. Pat. No. 6,339,086 using one equivalent D-(+)-Malic acid. In another method for optical resolution of racemic zopiclone, a semi-preparative HPLC method is described in C. F. F. Gimenez et. al., Chirality (1995) 7:267-271. A capillary electrophoresis method for zopiclone enantiomer separation is disclosed in High, J. Resolution Chromatography (2000) 23(6):413-429. Alternatively, US 2005/0043311A1 discloses eszopiclone separated from the racemic zopiclone using D-(+)-O,Oâ€²-dibenzoyl-tartaric acid. According to this method, eszopiclone is crystallized from acetonitrile.

These methods described afford eszopiclone in a free base form or salt forms, containing the unwanted enantiomer. Thus, there is a need in the art for improved processes for improving the optical purity of eszopiclone in diastereomeric salts or free base form.

Zopiclone exits in a few crystalline forms; these forms are characterized in Chem. Commun. (2001) 2204-2205 and J. Phys. IV France 11 (2001) pr10-93-pr10-97, and mentioned in Drug Development and Industrial Pharmacy (2000) 26(5):531-537. The crystalline forms are monoclinic dihydrate Form I, monoclinic anhydrous Form II and orthorhombic Form III.

Eszopiclone Form A, which has an X-ray diffraction (XRD) pattern equivalent to that of Form III of Zopiclone disclosed in the Chem. Commun. publication, is characterized by the following main XRD peaks: 5.1, 10.1, 11.3, 12.6, 16.1, 18.1, 19.1, 20.2, 21.4, 25.7, 27.7 Â±0.2 degrees 2 theta. Form III is a racemic conglomerate suggesting that the same X-ray diffraction (XRD) pattern is exhibited also by a single enantiomer. It has been found that crystallization of eszopiclone free base in acetonitrile or ethylacetate in accordance with the disclosures of U.S. Pat. No. 6,444,673 and U.S. Pat. No. 6,339,086 produces polymorphic Form A.

However, acetonitrile is expensive and the solubility of eszopiclone in ethylacetate is low and a large volume of the solvent is required to induce complete dissolution. In addition, in order to recover eszopiclone from the solution in ethylacaetate concentration is required in order to induce eszopiclone precipitation. There is a need in the art for a method allowing industrial preparation of eszopiclone Form A using more practical solvents.

SUMMARY OF THE INVENTION

The present invention provides a method for preparing eszopiclone Form A comprising crystallizing eszopiclone free base from a solvent selected from the group consisting of isopropanol (IPA), methyl isobutyl ketone (MIBK), acetone, n-butanol, isobutanol, 2-butanol, tetrahydrofuran (THF), dimethyl carbonate, methanol, ethanol, ethyl lactate, dimethylformamide (DMF), carbon tetrachloride, toluene, isobutyl acetate and mixtures thereof.

The present invention provides a method of preparing substantially chemically pure eszopiclone, comprising crystallizing eszopiclone free base from a solvent selected from the group consisting of methyl isobutyl ketone, isobutyl acetate, acetone, isobutanol, isopropanol (IPA), THF, toluene, ethanol:water (preferably in a volume ratio of about 1:1), n-butanol, 2-butanol and isopropanol:water (preferably in a volume ratio ranging from about 3:1 to about 10:1, e.g., about 3:1, about 5:1, about 7:1 or about 10:1).

The present invention is further directed to a method for optical enrichment of eszopiclone free base comprising crystallizing eszopiclone free base from a solvent selected from the group consisting of n-butanol, 2-butanol, isobutyl acetate, isobutanol, isopropanol (IPA), toluene, acetone, isopropanol:water (preferably in a volume ratio of about 3:1 to about 10:1), ethanol:water (preferably in a volume ratio of about 1:1 to about 1:27) and acetone:water (preferably in a volume ratio of about 1:1).

Another embodiment of the present invention provides eszopiclone free base with low level(s) of residual solvent(s).

Another embodiment of the present invention provides a method for preparing eszopiclone free base with low level(s) of residual solvent(s), comprising crystallizing eszopiclone from a solvent selected from the group consisting of: toluene, isobutyl acetate, isopropanol:water in a volume ratio of about 3:1 to about 10:1, and ethanol:water in a volume ratio of about 1:1 to about 95:5.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, â€œeszopicloneâ€ refers to eszopiclone free base.

As used herein, â€œeszopiclone Form Aâ€ is crystalline eszopiclone characterized by the following main XRD peaks: 5.1, 10.1, 11.3, 12.6, 16.1, 18.1, 19.1, 20.2, 21.4, 25.7, 27.7 Â±0.2 degrees 2 theta.

As used herein, â€œambient temperatureâ€ refers to room temperature and is meant to indicate a temperature of about 18 to about 25Â° C., e.g., about 20 to about 22Â° C.

As used herein, â€œsubstantially chemically pureâ€ refers to more than about 97%, e.g., at least about 99%, chemical purity as measured by HPLC.

As used herein, â€œsubstantially optically pureâ€ in reference to eszopiclone means having at least about 97% of the (S)-enantiomer of zopiclone, as measured by chiral HPLC.

As used herein, eszopiclone free base with â€œlow level(s) of residual solvent(s)â€ means that the eszopiclone contains residual solvent(s) in a content of no more than about 5000 ppm of isobutyl acetate, isopropanol or ethanol, and/or no more than about 1400 ppm of toluene, by weight of the eszopiclone product, wherein the residual solvent(s) is the solvent(s) used to crystallize the eszopiclone that remains associated with the eszopiclone product after crystallization.

As used herein, the solution of eszopiclone free base may be prepared, for example, by heating to a temperature of about 50Â° C. to about reflux. In addition, admixing additional solvent can aid in dissolution. The volume of solvent used may be determined based on the solubility of eszopiclone in each specific solvent.

The present invention provides a method for preparing eszopiclone Form A comprising crystallizing eszopiclone free base from a solvent selected from the group consisting of isopropanol (IPA), methyl isobutyl ketone (MIBK), acetone, n-butanol, isobutanol, 2-butanol, tetrahydrofuran (THF), dimethyl carbonate, methanol, ethanol, ethyl lactate, dimethylformamide (DMF), carbon tetrachloride, toluene, isobutyl acetate and mixtures thereof. Alternatively, eszopiclone free base may be slurried in a solvent selected from the group described above.

Stirring during crystallization of the eszopiclone Form A is preferred.

The precipitating step may be done by either cooling the solution or the slurry, or adding an anti-solvent to the solution or slurry.

Preferably, prior to the precipitation of the eszopiclone Form A, heating is performed. Preferably the heating is to a temperature ranging from ambient temperature to about reflux temperature.

Typically, the cooling is to a temperature ranging from about âˆ’10Â° C. to about ambient temperature.

The anti-solvent is preferably a non-polar solvent like ether, aromatic hydrocarbon and aliphatic hydrocarbon. More preferably, the anti-solvent is selected from the group consisting of: n-hexane, n-heptane, methyl tert-butyl ether (MTBE) and water. The volume of the anti-solvent added to a solution of eszopiclone can range from about 1 to about 50 volumes of the solution of eszopiclone.

The obtained crystalline form of eszopiclone Form A may be further recovered. Recovery of eszopiclone Form A may be by any means known to a skilled artisan such as by filtering, washing and drying, for example, in a vacuum oven.

Preferably, the obtained eszopiclone Form A is substantially chemically pure.

Preferably, the obtained eszopiclone Form A is substantially optically pure.

The present invention provides a method of preparing substantially chemically pure eszopiclone, comprising crystallizing eszopiclone free base from a solvent selected from the group consisting of methyl isobutyl ketone, isobutyl acetate, acetone, isobutanol, isopropanol (IPA), THF, toluene, ethanol:water (preferably in a volume ratio of about 1:1), n-butanol, 2-BuOH and isopropanol:water (preferably in a volume ratio ranging from about 3:1 to about 10:1, e.g., about: 3:1, 5:1, 7:1 or 10:1). Alternatively, eszopiclone free base may be slurried in a solvent selected from the group described above.

The process parameters are as described above. Preferably, the solvent is selected from the group consisting of MIBK, isopropyl alcohol, THF, toluene, ethanol/water in a volume ratio of about 1:1, acetone, 2-butanol, isopropyl alcohol/water in a volume ratio of about 3:1, about 5:1, about 7:1 or about 10:1, and isobutyl acetate.

The obtained eszopiclone is preferably eszopiclone Form A.

Preferably, the substantially chemically pure eszopiclone obtained by this process has a chemical purity of more than about 98%, more preferably more than about 99%, even more preferably more than about 99.5% and most preferably about 99.9% or higher, by HPLC.

The present invention is further directed to a method for optical enrichment of eszopiclone free base comprising crystallizing eszopiclone free base from a solvent selected from the group consisting of n-butanol, 2-butanol, isobutyl acetate, isobutanol, isopropanol (IPA), toluene, acetone, IPA/H₂O (preferably in a volume ratio of about 3:1 to about 10:1), ethanol:water (preferably in a volume ratio of about 1:1 to about 1:27) and acetone:water (preferably in a volume ratio of about 1:1). Alternatively, eszopiclone free base may be slurried in a solvent selected from the group described above.

The process parameters are as described above.

Preferably, the solvent is selected from the group consisting of toluene, isopropyl alcohol, n-butanol, isopropyl alcohol/water in a volume ratio of about 3:1, about 5:1, about 7:1 or about 10:1, and isobutyl acetate.

More preferably, the isopropyl alcohol to water volume ratio is of about 7:1 to 10:1.

Typically, the obtained substantially optically pure solid eszopiclone is eszopiclone Form A.

Preferably, the eszopiclone is optically enriched by 0.5%, more preferably optically enriched by 4% and most preferably optically enriched by 7%, compared with the starting eszopiclone. For instance, eszopiclone optically enriched by 4% means that the optical purity of the eszopiclone product is 4% higher than the optical purity of the starting eszopiclone as determined by chiral HPLC.

The obtained eszopiclone is substantially optically pure. The substantially optically pure eszopiclone obtained by this method can have an optical purity of preferably more than about 98%, more preferably more than about 99%, more preferably more than about 99.5% and most preferably, at least about 99.9%, by chiral HPLC.

When the mixture of isopropanol and water used has a volume ratio of about 5:1 or 10:1, the residual solvent(s) in the final eszopiclone product is no more than about 5000 ppm, preferably no more than about 800 ppm, and more preferably no more than about 700 ppm. This method is advantageous over the process disclosed in U.S. Pat. No. 6,339,086 in that the residual solvent content of the eszopiclone product is lower.

Preferably, the method comprises dissolving eszopiclone in a mixture of isopropanol and water; heating; and cooling to obtain a precipitate. Preferably, the heating is to a temperature of about ambient temperature to about reflux temperature, more preferably, to about reflux temperature. Preferably, the cooling is to a temperature ranging from about 0Â° C. to about room temperature, more preferably, to a temperature of about 10Â° C. Preferably, after cooling, a slurry is obtained. Preferably, the slurry is stirred. Preferably, the stirring is for about 30 minutes to about 20 hours.

Preferably, the obtained eszopiclone is eszopiclone Form A.

In some of the embodiments of the method, the obtained eszopiclone is optically enriched by at least about 0.1%, preferably optically enriched by at least about 4% and more preferably optically enriched by 4.5% compared with the starting eszopiclone as determined by chiral HPLC. For instance, the obtained eszopiclone can be optically enriched by about 0.1% or about 4%.

Preferably, the precipitate of the eszopiclone product is further recovered.

Recovery of eszopiclone, preferably Form A, in any of the above processes can be performed by any means known in the art for example by filtering, washing, and drying in vacuum. Preferably, the washing is with the same solvent used in the process. Preferably, when the solvent used in the process is IPA/water, the washing is with IPA. Preferably, the drying is at a temperature of about 30Â° C. to about 70Â° C., more preferably, at about 50Â° C. to about 60Â° C., and most preferably, at about 50Â° C.

Another embodiment of the present invention provides eszopiclone free base with low level(s) of residual solvent(s).

Another embodiment of the present invention provides a method for preparing eszopiclone free base with low level(s) of residual solvent(s), comprising crystallizing eszopiclone from a solvent selected from the group consisting of: toluene, isobutyl acetate, isopropanol:water in a volume ratio of about 3:1 to about 10:1, and ethanol:water in a volume ratio of about 1:1 to about 95:5. Alternatively, a mixture of these solvents can be used in the method.

The eszopiclone free base with low level(s) of residual solvent(s) preferably contains no more than about 1350 ppm toluene (more preferably no more than about 890 ppm toluene), no more than about 600 ppm isobutyl acetate or no more than about 800 ppm (more preferably no more than about 700 ppm) isopropanol.

Preferably, the process comprises providing a solution of eszopiclone free base in a solvent selected from the group consisting of: toluene, isobutyl acetate, isopropanol:water in a volume ratio of about 3:1 to about 10:1, and ethanol:water in a volume ratio of about 1:1 to about 95:5, and precipitating the eszopiclone. The eszopiclone can be precipitated from the solution by cooling or solvent removal via evaporation such as evaporation under vacuum.

Preferably, the process comprises combining eszopiclone free base with a solvent selected from the group consisting of: toluene, isobutyl acetate, isopropanol:water in a volume ratio of about 3:1 to about 10:1, and ethanol:water in a volume ratio of about 1:1 to about 95:5; heating; and cooling.

Preferably, the heating is to a temperature of about 30Â° C. to about 90Â° C., more preferably, to about 60Â° C. to about 80Â° C. Preferably, the cooling is to a temperature of less than about ambient temperature.

Preferably, the isopropanol:water volume ratio is of about 7:1 to 10:1

Preferably, the ethanol:water volume ratio is of about 3:1 to about 10:1, more preferably, of about 95:5.

Preferably, the obtained eszopiclone is substantially chemically pure.

Preferably, the obtained eszopiclone is substantially optically pure.

Preferably, the obtained eszopiclone is eszopiclone Form A.

The use of isopropanol:water and ethanol:water in a solution of eszopiclone with a limited volume of water is advantageous because it enables using a low amount of the organic solvent.

The identity of the eszopiclone Form A obtained by the processes of the invention is confirmed by analysis of the powder X-ray diffraction (XRD) pattern obtained by methods known in the art using a Scintag X-ray powder diffractometer having a variable goniometer, an X-Ray tube with Cu target anode (Cu radiation Î»=1.5418 â„«), a solid state detector and a round standard aluminum sample holder.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

HPLC method (with regard to the optical purity)Column & packing:Chiralcel OD-H 4.6 Ã— 250 mm, 5 Î¼m CN 14325Eluent:0.1% DEA in EthanolStop time:25 minFlow:0.7 ml/minDetector:306 nmInjection volume:20 Î¼l.Diluent:EthanolColumn temperature:25Â° C.Autosampler10Â° C.temperature:Run time:R-ZP: 12.9 min; S-ZP: 18.4 min

HPLC method (with regard to the chemical purity)Column & packing:Inertsil ODS 3 V 250*4.6 mm 5Î¼ C.N5020-01802Buffer preparation:0.01M Sodium dihydrogen phosphateadjusted to pH = 7.0 with 1N NaOHEluent A:66% Buffer:34% AcetonitrileEluent B:AcetonitrileGradient of Eluent:Time (min)Eluent A (%)Eluent B (%)â€‚0 min100013 min100023 min406033 min4060Stop time:33 minEquilibration time:7 minFlow:1.0 ml/minDetector:306 nm.Injection volume:20 Î¼l.Diluent:50% Acetonitrile:50% BufferColumn temperature:25Â° C.Autosampler temp.:5Â° C.

Example 1 Preparation of Eszopiclone Form A from Ethyl Acetate [Comparative Example]

To eszopiclone free base (1 g) was added ethyl acetate (AR grade) (20 ml) and the slurry was heated to reflux. At reflux, an additional 10 ml of ethyl acetate were added to complete dissolution of the solid. Heating was stopped and the solution was cooled in ice-acetone bath to a temperature of about âˆ’10Â° C. in 15 min. Precipitation started at 60Â° C. The mixture was stirred at about âˆ’10Â° C. for 1 h. The solid was filtered, washed with 2 ml EtOAc and dried in a vacuum oven at 60Â° C. to yield eszopiclone Form A. Yield 80%.

Example 2 Preparation of Eszopiclone Form A from MIBK

To eszopiclone free base (1.5 gr) was added MIBK (CP grade) (6 ml) and the obtained slurry was heated to reflux. During heating an additional 6 ml of MIBK were added. At reflux additional solvent (9 ml) was added to induce complete dissolution of the solid. Heating was stopped and the solution was cooled to the room temperature. Precipitation started at 80Â° C. After this the mixture was cooled to 26Â° C. in 45 min. and stirred at room temperature for 2 h. The solid was filtered, washed with 2 ml MIBK and dried in vacuum oven at 65Â° C. The wet material was Eszopiclone Form A. Yield 80%. (Chemical Purity 99.96% by HPLC).

Example 3 Preparation of Eszopiclone Form A from N-Butanol

To eszopiclone free base (1.5 gr.) was added n-BuOH(CP grade) (6 ml) and the obtained slurry was heated to reflux. At reflux (114Â° C.), additional 4 ml of n-BuOH were added to slurry till full dissolution of the solid. Then heating was stopped and solution was cooled to the room temperature. Precipitation of solid started at 100Â° C. The mixture was cooled to 29Â° C. in about 40 min. and then stirred at room temperature (26Â° C.-29Â° C.) for 1 h. The solid was filtered, washed with 3 ml n-BuOH and dried in a vacuum oven at 65Â° C. and 7 mm Hg. Yield 90% (Chemical Purity 100% by HPLC).

Example 4 Preparation of Eszopiclone Form A from Isobutanol

To eszopiclone free base (1 gr) was added i-BuOH(CP grade) (6 ml) and the obtained slurry was heated to reflux. At reflux (106Â° C.), additional 4 ml of i-BuOH were added to slurry till full dissolution of the solid. Then heating was stopped and the solution was cooled to the room temperature. Precipitation of solid started at 97Â° C. The mixture was cooled to 24Â° C. in Ëœ35 min. and then stirred at room temperature (Ëœ24Â° C.) for 2 h. The solid was filtered, washed with 2 ml i-BuOH and dried in a vacuum oven at 60Â° C. and 7 mm Hg. Yield 71% (Chemical Purity 97.37% by HPLC).

Example 5 Preparation of Eszopiclone Form A from Isopropanol

To eszopiclone free base (1.5 gr) was added IPA (HPLC grade) (3 ml) and the obtained slurry was heated to reflux. During heating additional 6 ml of IPA were added. At reflux (82Â° C.), additional 62 ml of IPA were added to slurry till full dissolution of the solid. Then heating was stopped and solution was cooled to room temperature. Precipitation of solid started at 60Â° C. The mixture was cooled to 25Â° C. in Ëœ40 min. and then stirred at room temperature (about 26Â° C.-29Â° C.) for 2 h. The solid was filtered, washed with 3 ml IPA and dried on a shelf over weekend. Then solid was dried at 60Â° C. Yield 80% (Chemical Purity 99.94% by HPLC).

Example 6 Preparation of Eszopiclone Form A from THF

To eszopiclone free base (1.5 gr) were added THF (extra dry) (7.5 ml) and slurry was heated to reflux. At reflux, additional 16 ml THF were added to full dissolution of solid. Heating was stopped and the solution was cooled to room temperature. Precipitation started at 45Â° C. The mixture was cooled to 27Â° C. in Ëœ1 h and then stirred at room temperature for 2 h. The solid was filtered, washed with 3 ml THF and dried in vacuum oven at 60Â° C. Yield 60% (Chemical Purity 99.93% by HPLC).

Example 7 Preparation of Eszopiclone Form A from Toluene

To eszopiclone free base (0.9 gr) was added toluene (extra dry) (4.5 ml) and slurry was heated to reflux. At reflux, additional toluene (4 ml) was added to complete dissolution of solid. Heating was stopped and solution was cooled to room temperature. Precipitation started at 70Â° C. The mixture was cooled to 26Â° C. in Ëœ50 min. and then stirred at room temperature for 2 h. The solid was filtered, washed with 1.5 ml toluene and dried in vacuum oven at 65Â° C. Yield 70% (Chemical Purity 99.72% by HPLC).

Example 8 Preparation of Eszopiclone Form A from EtOH/H₂O (1:1)

To eszopiclone free base (1.5 gr) was added a 1:1, based on volume, mixture of EtOH/H₂O (15 ml) and slurry was heated to reflux. At 76Â° C. complete dissolution of solid was observed. Heating was stopped at 80Â° C. and slurry was cooled to room temperature. Precipitation started at 68Â° C. The mixture was cooled to 28Â° C. in Ëœ50 min. and then stirred at room temperature for 2 h. The solid was filtered, washed with 3 ml solvents mixture and dried in a vacuum oven at 60Â° C. Yield 67% (Chemical Purity 99.65% by HPLC).

Example 9 Preparation of Eszopiclone Form A from I-BuOAc

To eszopiclone free base (1.5 gr) was added i-BuOAc (AR grade) (7.5 ml) and slurry was heated to reflux. At reflux, additional 18 ml of i-BuOAc were added to complete dissolution of solid. Heating was stopped and the solution was cooled to room temperature. Precipitation started at 85Â° C. The mixture was cooled to 28Â° C. in Ëœ50 min. and then stirred at room temperature for 2 h. The solid was filtered, washed with 3 ml i-BuOAc and dried in a vacuum oven at 50Â° C. Yield 93% (Chemical Purity by HPLC 99.95%).

Table Summarizing Results of Example 2-9

Solventvolume inml pergram ofChemicalstartingPurityExampleSolventeszopicloneYieldXRDby HPLC2MIBK1480%(wet)99.96%Form A3n-BuOH6.790%(wet)NotForm Aanalyzed4i-BuOH1071%(wet)â€‚97.3% Form A5IPA4780%(wet)99.94%Form A6THF15.760%99.93%7toluene9.570%Form A99.72%8EtOH/1067%(wet)99.65%H₂OForm A(1:1)9i-BuOAc1793%(wet)NotForm Aanalyzed

Examples 10-20 Preparation of Eszopiclone Form A from Other Solvents by Method Described in Examples 2-9

Eszopiclone Form A was also prepared using other solvents shown in the table below with a method corresponding to that described in Examples 2-9.

Solventvolume inml pergram ofChemicalstartingPurityExampleSolventeszopicloneYieldXRDby HPLC10acetone4458%(wet)^â€ƒ100%Form A11EtOH/H₂O27/175%(wet)NotForm Aanalyzed12dimethyl1060%(wet)NotcarbonateForm Aanalyzed13MeOH1054%(wet)NotForm Aanalyzed14Ethyl649%Notlactateanalyzed15DMF563%Form ANotanalyzed16CCl₄7853%Form ANotanalyzed17Acetone/7051%Form ANotH₂O(1:1)analyzed18EtOAc/H₂O22.536%Form ANot(3% H₂O)analyzed192-BuOH2887%99.66%20EtOAc/H₂O3056%Form ANot(1.5% H₂O)analyzed

Example 21 Preparation of Eszopiclone Form A from THF as Solvent and MTBE as Anti-Solvent

To eszopiclone free base (0.8 gr) was added THF extra dry (12.5 ml) and the obtained slurry was heated to reflux. At reflux, the solid was dissolved to give a clear solution. To the solution was added MTBE (CP grade), until a solid started to precipitate. With MTBE addition, the temperature of the solution dropped. After 8 ml of MTBE were added, precipitation started at a temperature of about 60Â° C., heating was stopped and the slurry was cooled to room temperature. The mixture was cooled to 28Â° C. in 25 min and then stirred at 28Â° C. for 2 h. The solid was filtered, washed with 1.5 ml of MTBE and dried in a vacuum oven at 60Â° C. Yield 75%.

Examples 22-26 Preparation of Eszopiclone Form A from Other Solvent/Anti-Solvent by Method Described in Example 21

Eszopiclone Form A was also prepared using other solvents/antisolvents shown in the table below with a method corresponding to that described in Example 21.

Volume Ratioof Solvent/ExampleSolvent/AntisolventAntisolventYieldXRD22Toluene/n-Heptane9.5/1.7^â€ƒ73%Form A23n-BuOH/MTBE11.1/7.2â€ƒâ€‰87%Form A24Acetone/MTBE40/55.557%Form A25THF/MTBE15.6/10â€ƒâ€‚75%Form A26IPA/H₂O47/62.550%Form A

Example 27-31 Preparation of Optically Enriched Eszopiclone Form A by Method Described in Examples 2-9

OpticalOpticalSolvent volumepurity ofpurity ofin ml per gramstartingcrystallizedExam-of startingEszopicloneEszopicloneYieldpleSolventEszopiclone(by HPLC)(by HPLC)(%)27toluene9.592.5%99.9%78%28i-BuOAc1792.5%96.66%â€‚88%29Isopropyl4792.5%97.4%88%alcohol30isobutanol1092.5%93.4%86%31n-Butanol1092.5%97.2%90%

Examples 32-35 Preparation of Eszopiclone Form A from IPA/Water

Eszopiclone (2.0 g, optical purity 95.5-98.5%) was dissolved in aqueous isopropanol (â€œIPAâ€ ) by heating at reflux. The solution was cooled with stirring to room temperature for an hour and stirred for additional hour at room temperature. The solid was filtered, washed with aqueous isopropanol, dried under vacuum at 50Â° C. overnight resulting in Eszopiclone crystalline form A with yield 85-95%.

VolumeIPA/water(ml pergram ofVolumeHPLC purity %ResidualExam-startingratioChemicalOpticalsolventpleeszopiclone)IPA:waterpuritypurity(ppm)32393:199.9699.91Notanalyzed33285:199.9399.97676343910:1â€‚99.9710077035307:1100100Notanalyzed

Example 36 Preparation of Eszopiclone Form A from IPA/Water by Cooling to 10Â° C.

Eszopiclone (7 g, optical purity 98.45%) was dissolved in aqueous isopropanol 10:1 (136.5 ml) by heating at reflux. The solution was cooled with stirring to about 10Â° C. during one hour and stirred for additional two hours at that temperature. The solid was filtered, washed with aqueous iso-propanol, dried under vacuum at 50Â° C. overnight and gave Eszopiclone, having crystalline form A with yield 89.5%. (Optical purity: 99.91% by HPLC, Chemical purity: 99.4% by HPLC)

Example 37 Repetition of Example 2 from U.S. Pat. No. 6,339,086

To a mixture of Eszopiclone malate (2.0 g, 3.74 mmol, purity profile 99.96% by HPLC and optical purity 96% by HPLC) in water (4 ml) and ethyl acetate (20 ml), 40% aqueous potassium carbonate (1.6 g, 4.64 mmol) was added slowly with stirring at 30Â° C. Then the mixture was heated at 60Â° C., and the organic phase was isolated and washed with 20 ml of water. The mixture was concentrated to 2/3 volume of the organic solvent. The resulted slurry was cooled to 5Â° C. and stirred at the same temperature for additional 2 hours. The solid was filtered, washed with cold ethyl acetate, dried at 50Â° C. under vacuum overnight (the first drying) yielding Eszopiclone containing residual ethyl acetate at a level of 7534 ppm (GC) with an optical purity of 96.35% by HPLC. The Eszopiclone was further dried at 75Â° C. under vacuum for 18 hours (the second drying) yielding Eszopiclone containing residual ethyl acetate at a level of 7360 ppm (GC).

Example 38 Using Other Organic Solvents to Conduct a Process Similar to the Process in Example 2 of U.S. Pat. No. 6,339,086

To a mixture of Eszopiclone malate (2.0 g, 3.74 mmol, purity profile 99.96% by HPLC and optical purity 96%) in water (4 ml) and one of the organic solvents shown in the table below, 40% aqueous potassium carbonate (1.6 g, 4.64 mmol) was added slowly with stirring at 30Â° C. Then the mixture was heated, and the organic phase was isolated and washed with 20 ml of water. The mixture was concentrated. The resulted slurry was cooled to 5Â° C. and stirred at the same temperature for additional 2 hours. The solid was filtered, washed with cold organic solvent (as used before), dried at 50Â° C. under vacuum overnight (the first drying) to obtain Eszopiclone containing a residual solvent. The Eszopiclone was further dried at 75Â° C. under vacuum for 18 hours (the second drying) resulting in Eszopiclone containing a residual solvent.

The results of Examples 37 and 38 (involving preparation of eszopiclone from eszopiclone malate by neutralization, extraction with organic solvent and precipitation) are shown in the table below.

HeatingVolume of organictemperatureResidualResidualsolvent in ml per(during theChemicalOpticalsolvent (ppm)solvent (ppm)Organicgram of startingextraction)YieldRecovery*puritypurityAfter 1^stAfter 2^ndSolventeszopiclone(Â° C.)(%)(%)(%)(%)dryingdryingEthyl20608096.3575347360acetateButyl548073NotNot96.467336468acetatecheckedanalyzedToluene258075Not99.9596.880257478checkedisobutyl6480608399.94**99.1577997578acetate
*The â€œRecoveryâ€ relates to the total amount of Eszopiclone (in its solid form and in the mother liquor)

**Material balance of Eszopiclone: Yield of the solid and the material in mother liquids in these experiments was less than 83%, while the purity profile of the material dissolved in mother liquids was about 95%, indicating decomposition of eszopiclone. In the water phase, eszopiclone was absent.

Example 39 Preparation of Eszopiclone from Eszopiclone Malate by Neutralization in Water Filtration and Crystallization from Organic Solvent

Example 39 was conducted using the procedure described in Example 38 using different solvents. The results of this experiment are shown in the table below.

Residual solvent in Eszopiclone prepared by crystallizationSolvent,volume in relation toChemical purityOptical purityOptical purityResidualstarting EszopicloneYieldof Eszopicloneof startingof Eszopiclonesolvent(ml/gr)(%)product (%)Eszopiclone (%)product (%)(ppm)toluene (9)9099.9798.8599.961349isobutyl acetate (27)8099.9598.8599.97568isopropanol/water,8599.9795.599.91676volume ratio 5:1, (14)