Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/06—Peri-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• the present invention relates to methods for purifying levofloxacin.
• the levofloxacin is prepared with anitoxidants.
• Levofloxacin is a broad spectrum synthetic antibiotic.
• Levofloxacin is the S- enantiomer of the racemate, ofloxacin, a fluoroquinolone antimicrobial agent.
• the antibacterial activity of ofloxacin resides primarily in the S-enantiomer.
• the mechanism of action of levofloxacin and other fluoroquinolone antimicrobials involves the inhibition of DNA gyrase (bacterial topoisomerase II), an enzyme required for DNA replication, transcription repair and recombination.
• Levofloxacin is available as LEVAQUIN ® which may be orally administered or administered intravenously.
• Levofloxacin is a chiral fluorinated carboxyquinolone. Its chemical name is (S)-9-fluoro-2,3
• U.S. Patent No. 5,053,407 is directed toward optically active pyridobenzoxazine derivatives, processes for preparing the same, and intermediates useful for preparing such derivatives.
• U.S. Patent No. 5,051 ,505 is directed toward processes for preparing piperazinyl quinolone derivatives.
• the process comprises reacting dihaloquinolones with piperazine derivatives and tetraalkyl ammonium halides in the presence of a polar solvent such as acetonitrile, dimethylformamide, pyridine, sulfolane and dimethyl sulfoxide.
• a polar solvent such as acetonitrile, dimethylformamide, pyridine, sulfolane and dimethyl sulfoxide.
• U.S. Patent No. 5,155,223 is directed toward the preparation of quinolinecarboxylic acids.
• U.S. Patent No. 5,545,737 discloses selectively producing a levofloxacin hemihydrate or monohydrate by controlling the water content of an aqueous solvent in which levofloxacin is dissolved during a crystallization.
• the present invention provides novel processes for purifying levofloxacin.
• Levofloxacin is dissolved in a polar solvent, preferably one selected from the group consisting of DMSO, methyl ethyl ketone, acetonitrile, an alcohol (preferably butanol), a ketone, mixtures thereof, and aqueous mixtures thereof, at an elevated temperature and crystallized to form levofloxacin.
• a polar solvent preferably one selected from the group consisting of DMSO, methyl ethyl ketone, acetonitrile, an alcohol (preferably butanol), a ketone, mixtures thereof, and aqueous mixtures thereof, at an elevated temperature and crystallized to form levofloxacin.
• the solvent is anhydrous.
• an antioxidant is added, resulting in a more pure levofloxacin product.
• levofloxacin crude can be prepared, for example, by the following method: In a 1 -liter reactor equipped with a mechanical stirrer, a condenser and a thermometer, heated at 80°C is charged 87.5g (0.31 mole) of (S)-(-)-9,10-difluoro-3- methyl-7-oxo-2,3-dihydro-7H-pyrido[ 1 ,2,3-de] [ 1 ,4]benzoxazine-6-carboxylic acid, 61.3mL DMSO and 86.3 mL (0.77 mole) of N-methylpiperazine.
• purified levofloxacin is a relative term meaning more pure.
• crude levofloxacin refers to levofloxacin that has not undergone a purifying crystallization step.
• a crude preparation of levofloxacin is mixed with a suitable solvent to form a mixture that is typically a suspension.
• the temperature of the mixture is then elevated to enhance dissolution of the levofloxacin in the solvent.
• the elevated temperature ranges from about 80 °C to about 110 °C.
• the mixture is refluxed.
• the mixture is filtrated while hot.
• Purified levofloxacin is then precipitated, preferably by slow cooling, and preferably recovered.
• the purified levofloxacin preferably has a purity of about 99% or greater, more preferably about 99.5% or greater.
• Polar solvents are generally suitable.
• the solvent is DMSO, methyl ethyl ketone, butanol, acetonitrile, mixtures thereof, or aqueous mixtures thereof.
• polar solvent is intended as a relative term to mean relatively more polar than another solvent.
• the solvent may be anhydrous or may contain a small amount of water.
• the solvent preferably contains water when a water-soluble antioxidant, such as sodium metabisulfite, is used.
• the amount of water should be less than about 20% (v/v) and preferably about 10% (v/v) or less. Greater amounts of water tends to decrease the yield.
• n-BuOH:H 2 O (9:1) and acetonitrile:H 2 O (99:1) are examples of suitable water-containing solvents.
• Acetonitrile and acetonitrile:H 2 O (99:1) are the most preferred solvents for purifying levofloxacin.
• an antioxidant is added to the mixture prior to precipitation.
• the antioxidant may be any that prevents the formation of N-oxide levofloxacin, particularly during crystallization.
• examples include ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbic palmitate, butylated hydroxyanisole, butylated hydroxytoluene, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, gum guaiac, propyl gallate, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, tocopherols (such as vitamin E), and pharmaceutically acceptable salts and mixtures thereof.
• the antioxidant includes sodium metabisulfite or ascorbic acid.
• An antioxdiant if used, can be added at various points in the purification process.
• an antioxidant is admixed with levofloxacin before or during the crystallization step or before the dissolution step.
• an antioxidant is admixed with (S)-(-)-9,10-Difluoro-3-Methyl-7-oxo-2,3-Dihydro-7H-
• the amount of antioxidant, when present, is preferably about 0.2% to about 5% by weight, more preferably about 0.2% to about 1 %.
• Table 1 summarizes the results of the experiments described in the Examples below.
• the percentage of each component in Table 1 was determined by HPLC using a method based on the European Pharmacopea method for related substances in Ofloxacin.
• Example 11 ACN:H2O (95:5) / Metabisulfite (8 mg) [030] 1.5 g of levofloxacin crude and 8 mg of sodium metabisulfite were put in suspension in 10.5 ml of a mixture ACN:H 2 O 95:5 under nifrogen atmosphere. The mixture was heated to reflux temperature and a hot filtration was performed. The solution was heated again to reflux temperature then cooled to 3°C in 30 minutes. The precipitate was filtrated under vacuum and dried at 60°C in a vacuum oven to give 500 mg (33%) of pure levofloxacin.
• Example 12 ACN:H2O (95:5) / Metabisulfite (4 mg) [031 ] 1.5 g of levofloxacin crude and 4 mg of sodium metabisulfite were put in suspension in 15 ml of a mixture ACN:H 2 O 95:5 under nitrogen atmosphere. The mixture was heated to reflux temperature until complete dissolution of the material. Then the solution was cooled to 3°C over a period of 2 hours. The precipitate was filtrated under vacuum and dried at 60°C in a vacuum oven to give 1.3 g (86.7%) of pure Levofloxacin.
• Example 13 DMSO / Ascorbic Acid

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• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Epoxy Compounds (AREA)

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• 2002
  • 2002-11-27 MX MXPA04005196A patent/MXPA04005196A/es not_active Application Discontinuation
  • 2002-11-27 CA CA002466860A patent/CA2466860A1/en not_active Abandoned
  • 2002-11-27 AU AU2002365416A patent/AU2002365416A1/en not_active Abandoned
  • 2002-11-27 HU HU0500285A patent/HUP0500285A3/hu unknown
  • 2002-11-27 JP JP2003546834A patent/JP2005527484A/ja active Pending
  • 2002-11-27 WO PCT/US2002/038182 patent/WO2003045329A2/en active Application Filing
  • 2002-11-27 IL IL16217202A patent/IL162172A0/xx unknown
  • 2002-11-27 CN CNA028236440A patent/CN1596256A/zh active Pending
  • 2002-11-27 PL PL02374558A patent/PL374558A1/xx not_active Application Discontinuation
  • 2002-11-27 EP EP02791339A patent/EP1460997A4/de not_active Withdrawn
• 2004
  • 2004-05-27 IS IS7288A patent/IS7288A/is unknown
  • 2004-06-15 HR HR20040546A patent/HRP20040546A2/hr not_active Application Discontinuation
  • 2004-06-29 NO NO20042731A patent/NO20042731L/no not_active Application Discontinuation
• 2006
  • 2006-05-01 JP JP2006127862A patent/JP2006219496A/ja not_active Withdrawn
• 2007
  • 2007-08-22 JP JP2007216178A patent/JP2008007517A/ja active Pending

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