EP1460997A2 - Procedes de purification de levofloxacine - Google Patents

Procedes de purification de levofloxacine

Info

Publication number
EP1460997A2
EP1460997A2 EP02791339A EP02791339A EP1460997A2 EP 1460997 A2 EP1460997 A2 EP 1460997A2 EP 02791339 A EP02791339 A EP 02791339A EP 02791339 A EP02791339 A EP 02791339A EP 1460997 A2 EP1460997 A2 EP 1460997A2
Authority
EP
European Patent Office
Prior art keywords
levofloxacin
solvent
purified
antioxidant
amount
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02791339A
Other languages
German (de)
English (en)
Other versions
EP1460997A4 (fr
Inventor
Valerie Niddam-Hildesheim
Neomi Gershon
Eduard Schwartz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Pharmaceutical Industries Ltd
Original Assignee
Teva Pharmaceutical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/263,192 external-priority patent/US7629458B2/en
Application filed by Teva Pharmaceutical Industries Ltd filed Critical Teva Pharmaceutical Industries Ltd
Publication of EP1460997A2 publication Critical patent/EP1460997A2/fr
Publication of EP1460997A4 publication Critical patent/EP1460997A4/fr
Withdrawn legal-status Critical Current

Links

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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Epoxy Compounds (AREA)

Abstract

Selon l'invention, la levofloxacine est purifiée par dissolution de celle-ci dans un solvant polaire à une température élevée et par cristallisation de la levofloxacine purifiée. De préférence, un antioxydant est ajouté aux fins d'augmenter sa pureté.
EP02791339A 2001-11-29 2002-11-27 Procedes de purification de levofloxacine Withdrawn EP1460997A4 (fr)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
US33431601P 2001-11-29 2001-11-29
US334316P 2001-11-29
US35493902P 2002-02-11 2002-02-11
US354939P 2002-02-11
US26296502A 2002-10-03 2002-10-03
US263192 2002-10-03
US262965 2002-10-03
US10/263,192 US7629458B2 (en) 2001-10-03 2002-10-03 Preparation of levofloxacin and hemihydrate thereof
PCT/US2002/038182 WO2003045329A2 (fr) 2001-11-29 2002-11-27 Procedes de purification de levofloxacine

Publications (2)

Publication Number Publication Date
EP1460997A2 true EP1460997A2 (fr) 2004-09-29
EP1460997A4 EP1460997A4 (fr) 2005-06-15

Family

ID=31892240

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02791339A Withdrawn EP1460997A4 (fr) 2001-11-29 2002-11-27 Procedes de purification de levofloxacine

Country Status (13)

Country Link
EP (1) EP1460997A4 (fr)
JP (3) JP2005527484A (fr)
CN (1) CN1596256A (fr)
AU (1) AU2002365416A1 (fr)
CA (1) CA2466860A1 (fr)
HR (1) HRP20040546A2 (fr)
HU (1) HUP0500285A3 (fr)
IL (1) IL162172A0 (fr)
IS (1) IS7288A (fr)
MX (1) MXPA04005196A (fr)
NO (1) NO20042731L (fr)
PL (1) PL374558A1 (fr)
WO (1) WO2003045329A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7629458B2 (en) 2001-10-03 2009-12-08 Teva Pharmaceutical Industries Ltd. Preparation of levofloxacin and hemihydrate thereof

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1735620A (zh) * 2002-12-16 2006-02-15 兰贝克赛实验室有限公司 纯的左氧氟沙星半水合物和它的制备方法
KR100704641B1 (ko) * 2004-07-21 2007-04-06 주식회사유한양행 고순도의 레보플록사신 제조방법
JP2006273718A (ja) * 2005-03-28 2006-10-12 Shiono Chemical Co Ltd レボフロキサシン・１／２水和物の製法
CN1321121C (zh) * 2005-04-21 2007-06-13 浙江医药股份有限公司新昌制药厂 左氧氟沙星制备及后处理方法
US7964723B2 (en) 2008-08-02 2011-06-21 Apeloa-Kangyu And practical process for exclusively producing (S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido-[1,2,3,de][1,4]benzoxazine-6-carboxylic acid hemihydrate
CN102070650B (zh) * 2011-01-28 2012-06-27 山东省药品检验所 左氧氟沙星-n-氧化物的制备方法
US20120251685A1 (en) * 2011-04-04 2012-10-04 Martek Biosciences Corporation Oil-in-Water Emulsions Comprising a Polyunsaturated Fatty Acid and Methods of Making the Same
CN105823851A (zh) * 2015-12-15 2016-08-03 浙江海洋学院 一种检测海水中氧氟沙星对映体的方法
CN108218892A (zh) * 2018-03-16 2018-06-29 乐山职业技术学院 一种左氧氟沙星的纯化方法
CN114507242B (zh) * 2022-01-26 2023-05-19 上虞京新药业有限公司 高光学纯度左氧氟沙星的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003028664A2 (fr) * 2001-10-03 2003-04-10 Teva Pharmaceutical Industries Ltd. Préparation de lévofloxacine et formes à base de cette substance

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Publication number Priority date Publication date Assignee Title
NO166131C (no) * 1985-06-20 1991-06-05 Daiichi Seiyaku Co Analogifremgangsmaate for fremstilling av s(-)-pyridobenzoksazinforbindelser.
US5237060A (en) * 1985-12-10 1993-08-17 Bayer Aktiengesellschaft Process of preparing enantiomerically pure 1,8-bridged 4-quinolone-3-carboxylic acids
TW208013B (fr) * 1990-03-01 1993-06-21 Daiichi Co Ltd
KR0131914B1 (ko) * 1992-10-07 1998-04-17 조아퀸 가리데 센트멘나트 오플로옥사진, 레보플로옥사진과 이 유도체의 합성에 이용될 수 있는 벤조옥사진의 수득과정
KR0125115B1 (ko) * 1994-03-22 1997-12-05 김은영 (-)피페라진 벤즈옥사진 유도체의 제조방법
KR100309871B1 (ko) * 1999-02-24 2001-10-29 윤종용 (-)피리도벤즈옥사진 카르복실산 유도체의 제조방법

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003028664A2 (fr) * 2001-10-03 2003-04-10 Teva Pharmaceutical Industries Ltd. Préparation de lévofloxacine et formes à base de cette substance
WO2003028665A2 (fr) * 2001-10-03 2003-04-10 Teva Pharmaceutical Industries Ltd. Techniques de purification de la lévofloxacine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO03045329A2 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7629458B2 (en) 2001-10-03 2009-12-08 Teva Pharmaceutical Industries Ltd. Preparation of levofloxacin and hemihydrate thereof

Also Published As

Publication number Publication date
WO2003045329A2 (fr) 2003-06-05
CA2466860A1 (fr) 2003-06-05
JP2008007517A (ja) 2008-01-17
JP2006219496A (ja) 2006-08-24
PL374558A1 (en) 2005-10-31
WO2003045329A3 (fr) 2004-02-19
HUP0500285A3 (en) 2009-03-30
HRP20040546A2 (en) 2004-10-31
IS7288A (is) 2004-06-21
EP1460997A4 (fr) 2005-06-15
MXPA04005196A (es) 2005-11-23
JP2005527484A (ja) 2005-09-15
NO20042731L (no) 2004-06-29
IL162172A0 (en) 2005-11-20
AU2002365416A1 (en) 2003-06-10
CN1596256A (zh) 2005-03-16
HUP0500285A2 (hu) 2005-06-28

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