Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF LEVOFLOXACIN HEMIHYDRATE.
Abstract	The present invention relates to an improved process for the preparation of levofloxacin hemihydrate by reacting (s)-(-)9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7h-pyrido(1,2,3-de) (1,4)benzoxazine-6-carboxylic acid with n-methly piperazine in a polar solvent followed by crystallizing the obtained crude product in isopropanol with moisture content of 12%to20% affords levofloxacin hemihydrate.

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Field of the Invention: The present invention relates to a process for the preparation of Levofloxacin hemihydrate. Background of the Invention: Levofloxacin, (S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-l-piperazinyl)-7-oxo-7H-pyrido[ 1,2,3-de]-l54-benzoxazine-6-carboxylic acid has the formula as given below Levofloxacin is the S-enantiomer of Ofloxacin, a fluoroquinolone antibacterial agent. The mechanism of action of Levofloxacin and other fluoroquinolone antibacterials involves the inhibition of DNA gyrase (bacterial topolsomerase II), an enzyme required for DNA replication, transcription repair and recombination. U.S. Patent No. 4,383,892 discloses the pyrido[ 1,2,3-de][1,4] benzoxazine derivatives and methods for preparation of them. U.S. patent No.5,053,407 discloses the optically active pyridobenzoxazine derivatives, intermediates useful for preparation of pyridobenzoxazine derivatives and the process. U.S. Patent No. 5,051,505 discloses the process for preparation of piperazinyl quinolone derivatives by reaction of dihaloquinolones with piperazine derivatives and tetra alkyl ammonium halides in presence of a polar solvent such as acetonitrile, DMF, pyridine, sulfolane and DMSO. U.S. Patent No. 5,155,223 discloses the process for preparation of quinoline carboxylic acids. Three polymorphic forms of Levofloxacin i.e anhydrous Levofloxacin form α, β, y and two hydrate forms i.e hemihydrate and monohydrate are reported in the literature. U.S. Patent Application No.2003/130507 discloses the process for preparation of Levofloxacin by reaction of (S)-(-) 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4] benzoxazine -6-carboxylic acid with N-methyl piperazine in a polar solvent or as a neat mixture at an elevated temperature of 70°C to 120°C and recovering Levofloxacin by using the techniques well known in the art. The Application further discloses the polymorphic or pseudomorphic forms (form-A, form-B, form-C, form-F, form-G, form-H) of Levofloxacin and the processes for their preparation. EP Patent No. 444,678 and U.S. patent No. 5,545,737 are particularly disclosed the processes for preparation of hemihydrate free of monohydrate by crystallizing crude Levofloxacin in aqueous ethanol containing 2-10% moisture content and process for monohydrate free of hemihydrate by crystallizing crude Levofloxacin in aqueous ethanol containing 10% or more than 10% moisture content. Surprisingly the inventors observed that when the water content is varied or by addition of water to slurry of Levofloxacin in a polar solvent at reflux temperature of solvent resulted the Levofloxacin hemihydrate free of monohydrate. Summary of the invention: The main object of the present invention is to provide an alternate process for the preparation of Levofloxacin hemihydrate free of Levofloxacin monohydrate. The process for the preparation of Levofloxacin hemihydrate is shown in the following scheme. Accordingly in the present invention reacting (S)-(-)9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-p3n:ido[l52,3-de][l,4] benzoxazine -6-carboxylic acid with N-methyl piperazine yields crude Levofloxacin. Suspending crude Levofloxacin in isopropanol, addition of known quantity of water to make-up the water content to about 12% to about 20% followed by precipitation affords the Levofloxacin hemihydrate. The prepared Levofloxacin hemihydrate is identical with the reported Levofloxacin hemihydrate by its X-ray diffraction pattern. Detailed description of the invention: Thus in accordance with the present invention Levofloxacin hemihydrate is prepared by reacting (S)-(-)9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4] benzoxazine-6-carboxylic acid with N-methyl piperazine in a polar solvent preferably n-Butanol at temperature of 120°C to 125°C for about 5 hrs to 12 hrs followed by removing the solvent by vacuum distillation at temperature below 100°C. Toluene is added to the reaction mass followed by chloroform and mixed for about 30 min at temperature of 20°C to 40°C. Removed the insolubles by filtration and the solvent mixture is removed by distillation at temperature below 60°C. Isopropanol is added to the reaction mass, cooled, mixed for about 30 min to about 4 hrs at temperature of 20°C to 40°C and isolated the Levofloxacin crude. Levofloxacin crude is dissolved in mixture of toluene-chloroform at temperature of 20°C to 40°C by mixing for about 30 min to 2 hrs. Removed the insolubles by filtration, treated the clear solution with carbon and distilled off the toluene-chloroform at temperature below 60°C. Isopropanol is added to the mass, temperature is raised to 65°C to 90°C, known quantity of water preferably to make-up the water content about 12% to about 20%, more selectively about 15%) is added to the reaction mass at temperature of 60°C to 90°C, mixed for about 5 min to 30 min, cooled to 15°C to about 35°C, mixed for about 30 min to 4 hrs, isolated and dried at temperature of 45°C to 85°C preferably at 60°C to 70°C gives the Levofloxacin hemihydrate. The required (S)-(-) 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4] benzoxazine-6-carboxylic acid is prepared by the reported method. The present invention is further illustrated with the following example. Example : Preparation of Levofloxacin hemihydrate Step-1 (S)-(-)9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4] benzoxazine-6-carboxylic acid (100 g) is suspended in n-Butanol (80 ml),N-methyl piperazine (80 g) is added and the temperature is raised to 120°C-125°C. Reaction mass is maintained at temperature of 120°C-125°C for 6 hrs and cooled to below 100°C, distilled off the solvent under vacuum at temperature below 100°C. Toluene (100 ml) is added and again distilled off under vacuum to remove traces of n-Butanol. Reaction mass is cooled to 60°C - 65°C, toluene (200 ml) and chloroform (1000 ml) are added and mixed for about 60 min at 25°C - 30°C. The reaction mass is filtered to remove insolubles. Clear filtrate is collected and the solvents are distilled off under vacuum at temperature below 65°C. Isopropanol (500ml) is added to the reaction mass, temperature is raised to reflux and maintained at reflux temperature for about 15 min at 75°C-80°C. Reaction mass is cooled to 25°C-30°C, maintained for 1 hr at 25°C - 30°C,the product is filtered and washed the wet cake with isopropanol (50 ml). The weight of the wet cake is about 150 g and the wet cake as such is proceeded to next step without drying. Step-2 The above-obtained wet cake (150 g) is dissolved in a mixture of toluene (500 ml) and chloroform (2000 ml). Activated carbon (10g) is added and stirred for about 30 min at 25°C - 30°C. The reaction mass is filtered, filtrate is collected and distilled off the solvents under vacuum at temperature below 60°C-Isopropanol (50 ml) is added to the mass and distilled off under vacuum at temperature below 60°C, Isopropanol (425 ml) is added to the mass and temperature of reaction mass is raised to reflux. Water (75 ml) is added slowly over 15 min and maintained for about 15 min at reflux temperature. Reaction mass is cooled to 30°C and maintained for about 30 min at 25°C - 30°C, Product is filtered and dried at 60°C - 70°C till constant weight. The dry weight of Levofloxacin hemihydrate is 90 g (68.5%) The water content is 2.54% (by KF) The IR and XRD of the product are identical with the reported data of Levofloxacin hemihydrate. We claim: 1. A process for the preparation of Levofloxacin hemihydrate comprising the steps of; Reacting (S)-(-)9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de] [1,4] benzoxazine-6-carboxylicacid with N-methyl piperazine in a polar solvent at temperature of 120°C to 125°C Removing the solvent under vacuum below 100°C to get residue Dissolving the residue in a mixture of toluene - chloroform and removing insolubles Removing the toluene-chloroform mixture and adding isopropanol Cooling and isolating crude Levofloxacin Dissolving the crude Levofloxacin in a mixture of toluene- chloroform and removing the insolubles Removing the toluene-chloroform mixture and adding isopropanol Adding known quantity of water and mixing for about 5 min to about 30 min Cooling to a temperature of about 15°C to about 35°C Isolating and drying the product 2. The process as claimed in claim 1, wherein the polar solvent is n-Butanol. 3. The process as claimed in claim 1, wherein the mixture of toluene-chloroform is removed under vacuum below 60°C. 4. The process as claimed in claim 1, wherein the crude Levofloxacin is isolated at 20°C to 30°C. 5. The process as claimed in claim 1, wherein water is added at 60°C to 90°C 6. The process as claimed in claim 1, wherein the quantity of water is equivalent to 12% to 20% of the isopropanol. 7. The process as claimed in claim 1, wherein the drying is carried out at temperature of 45°C to 85°C.

Documents:

931-che-2004 correspondence others 12-04-2011.pdf

931-che-2004 form-1 12-04-2011.pdf

931-CHE-2004 FORM-1.pdf

931-CHE-2004 FORM-13 30-11-2010.pdf

931-che-2004-abstract.pdf

931-che-2004-claims duplicate.pdf

931-che-2004-claims original.pdf

931-che-2004-correspondnece-others.pdf

931-che-2004-correspondnece-po.pdf

931-che-2004-description(complete) duplicate.pdf

931-che-2004-description(complete) original.pdf

931-che-2004-form 1.pdf

931-che-2004-form 19.pdf

931-che-2004-form 3.pdf

931-che-2004-pct.pdf