CN1596256A - Methods for the purification of levofloxacin - Google Patents
Methods for the purification of levofloxacin Download PDFInfo
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- CN1596256A CN1596256A CNA028236440A CN02823644A CN1596256A CN 1596256 A CN1596256 A CN 1596256A CN A028236440 A CNA028236440 A CN A028236440A CN 02823644 A CN02823644 A CN 02823644A CN 1596256 A CN1596256 A CN 1596256A
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- Prior art keywords
- levofloxacin
- described method
- purifying
- solvent
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- 229960003376 levofloxacin Drugs 0.000 title claims abstract description 111
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 title claims abstract description 110
- 238000000034 method Methods 0.000 title claims description 50
- 238000000746 purification Methods 0.000 title description 3
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 19
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 19
- 239000002798 polar solvent Substances 0.000 claims abstract description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 102
- 239000000203 mixture Substances 0.000 claims description 45
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 39
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 20
- 235000006708 antioxidants Nutrition 0.000 claims description 18
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 17
- 238000010992 reflux Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical group [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 12
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 11
- -1 levofloxacin N-oxide compound Chemical class 0.000 claims description 11
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical group OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 6
- 230000017858 demethylation Effects 0.000 claims description 6
- 238000010520 demethylation reaction Methods 0.000 claims description 6
- CFLBIADORGSMCX-UHFFFAOYSA-N 2h-1,4-benzoxazine-6-carboxylic acid Chemical compound O1CC=NC2=CC(C(=O)O)=CC=C21 CFLBIADORGSMCX-UHFFFAOYSA-N 0.000 claims description 4
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 4
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Chemical group OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 4
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 3
- SRUQARLMFOLRDN-UHFFFAOYSA-N 1-(2,4,5-Trihydroxyphenyl)-1-butanone Chemical compound CCCC(=O)C1=CC(O)=C(O)C=C1O SRUQARLMFOLRDN-UHFFFAOYSA-N 0.000 claims description 2
- CIWBSHSKHKDKBQ-DUZGATOHSA-N D-isoascorbic acid Chemical compound OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 0.000 claims description 2
- GHKOFFNLGXMVNJ-UHFFFAOYSA-N Didodecyl thiobispropanoate Chemical compound CCCCCCCCCCCCOC(=O)CCSCCC(=O)OCCCCCCCCCCCC GHKOFFNLGXMVNJ-UHFFFAOYSA-N 0.000 claims description 2
- 241000147041 Guaiacum officinale Species 0.000 claims description 2
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 claims description 2
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 235000010385 ascorbyl palmitate Nutrition 0.000 claims description 2
- 235000010376 calcium ascorbate Nutrition 0.000 claims description 2
- 229940047036 calcium ascorbate Drugs 0.000 claims description 2
- 239000011692 calcium ascorbate Substances 0.000 claims description 2
- BLORRZQTHNGFTI-ZZMNMWMASA-L calcium-L-ascorbate Chemical compound [Ca+2].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] BLORRZQTHNGFTI-ZZMNMWMASA-L 0.000 claims description 2
- 229940091561 guaiac Drugs 0.000 claims description 2
- 125000000687 hydroquinonyl group Chemical group C1(O)=C(C=C(O)C=C1)* 0.000 claims description 2
- KWUZCAVKPCRJPO-UHFFFAOYSA-N n-ethyl-4-(6-methyl-1,3-benzothiazol-2-yl)aniline Chemical compound C1=CC(NCC)=CC=C1C1=NC2=CC=C(C)C=C2S1 KWUZCAVKPCRJPO-UHFFFAOYSA-N 0.000 claims description 2
- 229920001206 natural gum Polymers 0.000 claims description 2
- 235000010388 propyl gallate Nutrition 0.000 claims description 2
- 239000000473 propyl gallate Substances 0.000 claims description 2
- 229940075579 propyl gallate Drugs 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 2
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 2
- 229960005055 sodium ascorbate Drugs 0.000 claims description 2
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 2
- 235000010384 tocopherol Nutrition 0.000 claims description 2
- 229930003799 tocopherol Chemical group 0.000 claims description 2
- 239000011732 tocopherol Chemical group 0.000 claims description 2
- 229960001295 tocopherol Drugs 0.000 claims description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical group OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims 3
- 230000003647 oxidation Effects 0.000 claims 3
- 238000007254 oxidation reaction Methods 0.000 claims 3
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical class COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 description 19
- 238000003828 vacuum filtration Methods 0.000 description 16
- 238000010438 heat treatment Methods 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- 238000001291 vacuum drying Methods 0.000 description 14
- 206010013786 Dry skin Diseases 0.000 description 13
- 238000001035 drying Methods 0.000 description 13
- 238000005406 washing Methods 0.000 description 11
- 239000012299 nitrogen atmosphere Substances 0.000 description 10
- 239000002994 raw material Substances 0.000 description 8
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 5
- 229960001699 ofloxacin Drugs 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229940124307 fluoroquinolone Drugs 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XNIVKSPSCYJKBL-UHFFFAOYSA-N 2h-1,2-benzoxazine-6-carboxylic acid Chemical compound O1NC=CC2=CC(C(=O)O)=CC=C21 XNIVKSPSCYJKBL-UHFFFAOYSA-N 0.000 description 2
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 2
- NVKWWNNJFKZNJO-YFKPBYRVSA-N Ofloxacin impurity a Chemical compound N1([C@@H](C)CO2)C=C(C(O)=O)C(=O)C3=C1C2=C(F)C(F)=C3 NVKWWNNJFKZNJO-YFKPBYRVSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000003139 biocide Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 description 1
- CMLFRMDBDNHMRA-UHFFFAOYSA-N 2h-1,2-benzoxazine Chemical class C1=CC=C2C=CNOC2=C1 CMLFRMDBDNHMRA-UHFFFAOYSA-N 0.000 description 1
- QDEJGQKJMKXYLM-UHFFFAOYSA-N 2h-pyrido[2,3-h][1,2]benzoxazine Chemical class C1=CC2=NC=CC=C2C2=C1C=CNO2 QDEJGQKJMKXYLM-UHFFFAOYSA-N 0.000 description 1
- VRPQEKUZCDCTNO-UHFFFAOYSA-N 3-piperazin-1-yl-1h-quinolin-2-one Chemical class O=C1NC2=CC=CC=C2C=C1N1CCNCC1 VRPQEKUZCDCTNO-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 1
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940089519 levaquin Drugs 0.000 description 1
- MVLAUMUQGRQERL-JTQLQIEISA-N levofloxacin n-oxide Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CC[N+](C)([O-])CC1 MVLAUMUQGRQERL-JTQLQIEISA-N 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
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
Abstract
Levofloxacin has been purified by dissolving levofloxacin in a polar solvent at an elevated temperature and crystallizing purified levofloxacin. Preferably, an antioxidant is added to increase the purity.
Description
The application is that the sequence number of submitting on October 3rd, 2002 is 10/262, the part continuation application of 965 patent application, the sequence number that described patent application requires submit to October 3 calendar year 2001 is 60/326,958, the sequence number of submitting to November 29 calendar year 2001 is 60/334, the sequence number that submit to 316 and 2002 year February 11 is 60/354, the sequence number of submitting in 939 provisional application and on October 3rd, 2002 is the right of priority of 10/263,192 patent application.In the lump support for referencial use at this each full content of these applications.
Invention field
The present invention relates to the method for purifying levofloxacin (levofloxacin).In a preferred embodiment, levofloxacin prepares with antioxidant.
Background of invention
Levofloxacin is a kind of wide spectrum synthetic antibiotic.Levofloxacin is the S enantiomorph of racemize Ofloxacine USP 23 (ofloxaxin), and Ofloxacine USP 23 is a kind of fluoroquinolone (fluoroquinolone) class biocide.The anti-microbial activity of Ofloxacine USP 23 mainly belongs to the S enantiomorph.The mechanism of action of levofloxacin and other fluoroquinolones biocides relates to the inhibition of NDA gyrase (bacterium topoisomerase II), and dna gyrase is dna replication dna, transcribes and repair and the essential a kind of enzyme of recombinating.Levofloxacin can have been bought as LEVAQUIN , and the latter can be taken orally or intravenously administrable.
Levofloxacin is a kind of fluorinated carboxyquinolone of chirality.Its chemical name is (S)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid semihydrate (CAS registration number 100986-85-4).The chemical structure of levofloxacin is suc as formula shown in the I.
Formula I
U.S. Patent No. 4,382,892 relate to pyrido [1,2,3-de] [1,4] benzo-oxazine derivative and their method of preparation.
U.S. Patent No. 5,053,407 relate to pyrido-benzoxazine derivative, its preparation method of optically-active, and the useful intermediates for preparing these derivatives.
U.S. Patent No. 5,051,505 relate to the method for preparing the piperazinyl Carbostyril derivative.This method is included under the situation of polar solvent such as acetonitrile, dimethyl formamide, pyridine, tetramethylene sulfone and methyl-sulphoxide existence, and dihalo-quinolone and bridged piperazine derivatives and quaternary alkylammonium halides are reacted.
U.S. Patent No. 5,155,223 relate to quinoline carboxylic acid's preparation.
U.S. Patent No. 5,545,737 disclose by being controlled at the water-content that dissolves a kind of water-containing solvent of levofloxacin during the crystallization therein and have optionally produced Levofloxacin semihydrate or monohydrate.People such as Arutla (Arzneimittelforschung (in October, 1998) 48 (10): 1024-7) assert that racemic mixture ofloxacin has the character of antioxidant.
A shortcoming of the art methods of purifying levofloxacin is that their productive rate usually can not be satisfactory.For example, productive rate is generally 45%～65%.Still the novel method that needs the purifying levofloxacin, especially the purifying goods that reduce such as trans levofloxacin (anti-levofloxacin), demethylation levofloxacin (desmethyllevofloxaxin), levofloxacin N-oxide compound (N-oxide levofloxaxin), defluorinate levofloxacin (desfluoro-levofloxacin) and/or decarboxylation levofloxacin impurity such as (decarboxy-levofloxacin).
Summary of the invention
The invention provides the novel method of purifying levofloxacin.Levofloxacin is dissolved in a kind ofly is in pyritous polar solvent and crystallization to form levofloxacin, preferably, described polar solvent is selected from DMSO, methyl ethyl ketone, acetonitrile, alcohol (preferred butanols), ketone, their mixture and their aqueous mixture.In one embodiment, described solvent is anhydrous.In another embodiment, added a kind of antioxidant, the result has produced purer levofloxacin product.
Detailed Description Of The Invention
The crude product of levofloxacin or half pure product can prepare by methods known in the art.Or, crude preparation of levofloxacin can be passed through, for example, following method preparation: (S)-(-)-9 of in 1 liter of reactor 80 ℃ of heating, that be equipped with mechanical stirrer, condenser and thermometer, loading 87.5g (0.31mol), 10-two fluoro-3-methyl-7-oxos-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid, 61.3mlDMSO and 86.3ml (0.77mol) N methyl piperazine.Stirring slurries with 250rpm speed under 80 ℃ and nitrogen atmosphere (detects by HPLC) till reacting completely.Slurries are cooled to 75 ℃ then, and in this temperature through dripping the mixture of Virahol (675ml) and water (25ml) in 2 hours.Then slurries were cooled to 5 ℃ through 4 hours, kept 2 hours in this temperature, and vacuum filtration under this temperature.Use 175ml washed with isopropyl alcohol (2 rinsings) solid and vacuum-drying to obtain crude preparation of levofloxacin then.
In one embodiment of the invention, purifying thick levofloxacin.As used in this, " levofloxacin of purifying " is a relative terms that expression is purer.As used in this, " thick levofloxacin " refers to the levofloxacin without the purified crystals step.Crude preparation of levofloxacin is mixed to form a kind of mixture of normally suspension with a kind of The suitable solvent.The temperature that improves this mixture then is to increase the dissolving of levofloxacin in this solvent.Typically, this high temperature (elevated temperature) is about 80 ℃～about 110 ℃.Preferred this mixture that refluxes.Preferably, in a single day levofloxacin dissolves in solvent, with regard to the filtered while hot mixture.The levofloxacin of deposition and purification preferably by slowly cooling, and preferably reclaims then.The levofloxacin of purifying preferably has about 99% or higher purity, and more preferably from about 99.5% or higher.
In general polar solvent suits.Solvent is DMSO, methyl ethyl ketone, butanols, acetonitrile, their mixture or their aqueous mixture preferably.As used in this, term " polar solvent " be as expression than another solvent phase to relative terms of polar more.
This solvent can be anhydrous, maybe can contain a spot of water.When using water soluble antioxidant (as Sodium Pyrosulfite), this solvent preferably contains water.The amount of water should be less than about 20% (v/v), and preferred about 10% or still less.The water of more amount often reduces productive rate.Propyl carbinol: water (9: 1) and acetonitrile: water (99: 1) is the example of the water-containing solvent that suits.Acetonitrile and acetonitrile: water (99: 1) is the most preferred solvent of purifying levofloxacin.
In another embodiment, before precipitation, a kind of antioxidant is added in the described mixture.This antioxidant can be that any levofloxacin N-oxide compound that prevents forms, and particularly prevents the antioxidant that levofloxacin N-oxide compound forms during crystallisation process.Example comprises xitix, sodium ascorbate, calcium ascorbate, ascorbyl palmitate, butylated hydroxy anisole (BHA), Yoshinox BHT, 2,4,5-trihydroxybutyrophenone, 4-methylol-2, acceptable salt and mixture on 6-two-tert.-butyl phenol, saccharosonic acid, heal sore natural gum (gum guaiac), propyl gallate, thio-2 acid, Tyox B, tertiary butylated hydroquinone, tocopherol (as vitamin-E) and their pharmacology.Preferably, antioxidant comprises Sodium Pyrosulfite or xitix.
If the use antioxidant can add in each stage of purge process.For example, in one embodiment, before the crystallisation step or during, or before dissolving step, antioxidant is mixed with levofloxacin.In another embodiment, in (S)-(-)-9,10-two fluoro-3-methyl-7-oxos-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid (precursor of levofloxacin) at high temperature is converted into before the levofloxacin, and antioxidant is mixed with it.
When existing, preferably about 0.2%～about 5% (weight) of the amount of antioxidant, more preferably from about 0.2%～about 1%.
Can more fully understand the function and the advantage of these or other embodiment of the present invention from the following examples.The following example is in order to illustrate benefit of the present invention, but illustration four corner of the present invention not.
Embodiment
Following table 1 has been summarized the result of experiment described in the embodiment hereinafter.The percentage composition of every kind of component is to use European Pharmacopoeia method based on related substances in the Ofloxacine USP 23, measure by HPLC in the table 1.
Table 1: the purifying during crystallization
| Embodiment | Solvent systems | The impurity analysis data | |||||||
| Crude product | The purifying product | ||||||||
| Levofloxacin | Impurity D: trans levofloxacin | Impurity E: demethylation levofloxacin | Impurity F: levofloxacin N oxide compound | Levofloxacin | Impurity D: trans levofloxacin | Impurity E: demethylation levofloxacin | Impurity F: levofloxacin N oxide compound | ||
| ????1 | Propyl carbinol | ????99.44 | ????ND | ????0.11 | ????0.19 | ??99.60 | ????ND | ????0.09 | ????0.19 |
| ????2 | Propyl carbinol xitix (2.4%) | ????99.58 | ????ND | ????0.11 | ????0.21 | ??99.78 | ????ND | ????0.08 | ????ND |
| ????3 | Propyl carbinol/H 2O Na 2SO 5(0.6％) | ????99.58 | ????ND | ????0.11 | ????0.21 | ??99.85 | ????ND | ????0.08 | ????ND |
| ????4 | CAN | ????99.44 | ????ND | ????0.11 | ????0.19 | ??99.67 | ????ND | ????0.04 | ????0.15 |
| ????5 | ACN∶H 2O | ????99.64 | ????0.08 | ????0.09 | ????＜0.03 | ??99.85 | ????ND | ????0.06 | ????＜0.03 |
| ????6 | ACN∶H 2O Na 2S 2O 5(0.2％) | ????99.77 | ????＜0.03 | ????0.05 | ????＜0.03 | ??99.93 | ????ND | ????＜0.03 | ????ND |
| ????7 | CAN Na 2S 2O 5(0.5％) | ????99.58 | ????ND | ????0.11 | ????0.21 | ??99.70 | ????ND | ????0.06 | ????0.1 |
| ????8 | DMSO∶H 2O | ????99.44 | ????ND | ????0.11 | ????0.19 | ??99.75 | ????ND | ????0.06 | ????0.13 |
| ????9 | MEK | ????99.44 | ????ND | ????0.11 | ????0.19 | ??99.58 | ????ND | ????ND | ????0.26 |
| ????10 | ACN∶H 2O (90∶10) Na 2S 2O 5(0.5％) | ????99.58 | ????ND | ????0.11 | ????0.21 | ??99.69 | ????ND | ????0.08 | ????ND |
| ????11 | ACN∶H 2O (95∶5) Na 2S 2O 5(0.5％) | ????99.58 | ????ND | ????0.11 | ????0.21 | ??99.74 | ????ND | ????0.06 | ????ND |
| ????12 | ACN∶H 2O (95∶5) Na 2S 2O 5(0.25％) | ????99.58 | ????ND | ????0.11 | ????0.21 | ??99.81 | ????ND | ????0.08 | ????ND |
| ????13 | DMSO xitix (0.6%) | ????99.80 | ????ND | ????0.03 | ????0.02 | ??- | ????- | ????- | ????- |
| ????14 | DMSO Na 2S 2O 5(0.5 eq.) | ????99.77 | ????0.04 | ????0.10 | ????＜0.03 | ??- | ????- | ????- | ????- |
The ND=undetermined
Embodiment 1: propyl carbinol
The 1g crude preparation of levofloxacin is put into the 7ml propyl carbinol make suspension.With mixture heating up to reflux temperature till raw material dissolves fully.Through 2.5 hours solution is cooled to room temperature then.To precipitate vacuum filtration, with propyl carbinol washing and in vacuum drying oven in 60 ℃ of dryings, thereby obtain the Levofloxacin semihydrate of 810mg (81%) purifying.
Embodiment 2: propyl carbinol/xitix
Under inert atmosphere, 1.5g crude preparation of levofloxacin and 36mg xitix are put into the 9.5ml propyl carbinol and make suspension.With mixture heating up to reflux temperature and carry out heat filtering.Solution evaporation is extremely done, and added propyl carbinol (10ml).Mixture heating up is refluxed up to dissolving fully, then through being cooled to room temperature in 1.5 hours.To precipitate vacuum filtration, with propyl carbinol (4ml) washing and in vacuum drying oven in 60 ℃ of dryings, thereby obtain the Levofloxacin semihydrate of 840mg (56%) purifying.
Embodiment 3: propyl carbinol: H
2O (9: 1)/pyrosulfite
Under nitrogen atmosphere, 1.5g crude preparation of levofloxacin and 10mg Sodium Pyrosulfite are put into 6ml propyl carbinol: H
2Make suspension in O (9: the 1) mixture.With mixture heating up to reflux temperature till raw material dissolves fully.Through 1.5 hours solution is cooled to room temperature then.To precipitate vacuum filtration, use propyl carbinol: H
2O (9: 1) mixture (4ml) washing and in vacuum drying oven in 60 ℃ of dryings, thereby obtain the Levofloxacin semihydrate of 1.2g (81%) purifying.In fact the Levofloxacin semihydrate of this purifying does not contain levofloxacin N-oxide compound.
Embodiment 4:ACN (acetonitrile)
The 1.5g crude preparation of levofloxacin is put into 10.5ml ACN make suspension.With mixture heating up to reflux temperature till raw material dissolves fully.Through time of 20 minutes solution is cooled to 0 ℃ then.To precipitate vacuum filtration, with ACN (1.5ml) washing and in vacuum drying oven in 30 ℃ of dryings, thereby obtain the levofloxacin (semihydrate/monohydrate mixture) of 1.15g (77%) purifying.The Levofloxacin semihydrate of this purifying contains the demethylation levofloxacin of half amount in the crude samples approximately.
Embodiment 5:ACN: H
2O (99: 1)
Crude preparation of levofloxacin (levofloxacin that about 22.17g does) under nitrogen atmosphere that 25g is wet is put into 225ml ACN: H
2Make suspension in O (99: the 1) mixture.Mixture heating up to refluxing 1 hour, is used the vacuum filtration of Hyflow strainer while hot.Then solution is heated to once more backflow and was cooled to 0 ℃ through 1 hour.To precipitate vacuum filtration, use ACN: H
2O washing (2 times, each 12ml) is also dry in vacuum drying oven, thereby obtains the Levofloxacin semihydrate of 18.6g (84%) purifying.The demethylation levofloxacin that the Levofloxacin semihydrate of this purifying contains is than approximately lacking 1/3rd in the crude samples.
Embodiment 6:ACN: H
2O (99: 1)/pyrosulfite
Under nitrogen atmosphere that 8g is wet crude preparation of levofloxacin (levofloxacin that about 5.6g does) and 14mg Sodium Pyrosulfite are put into 39ml ACN: H
2Form suspension in O (99: the 1) mixture.Mixture heating up was refluxed 1 hour, add 0.65g Hyflo (diatomite), and continue the half an hour of refluxing.The filtered while hot mixture.Through 30 minutes solution is cooled to 3 ℃ then.To precipitate vacuum filtration, use ACN: H
2O (99: 1) mixture (5ml) washing in 60 ℃ of dryings, obtains the levofloxacin of 1.77g (31%) purifying in vacuum drying oven.Technical problem during heat filtering has reduced productive rate.
Embodiment 7:ACN/ Sodium Pyrosulfite
Under nitrogen atmosphere, 1.5g crude preparation of levofloxacin and 8mg Sodium Pyrosulfite are put into 10.5ml ACN and form suspension.With mixture heating up to reflux temperature and carry out heat filtering.Then solution reheat to reflux temperature is dissolved fully up to raw material.Through 30 minutes solution is cooled to 0 ℃ then.To precipitate vacuum filtration and in vacuum drying oven in 60 ℃ of dryings, obtain the levofloxacin of 1.04g (69%) purifying.The levofloxacin N-oxide compound that the levofloxacin of this purifying contains is about half in the crude samples.
Embodiment 8:DMSO (methyl-sulphoxide)/H
2O
The 1g crude preparation of levofloxacin is put into 1.5ml DMSO form suspension.Mixture heating up to 108 ℃ is dissolved fully up to raw material.Then through 10 minutes interpolation H
2O (7.5ml) also is cooled to room temperature with mixture.To precipitate vacuum filtration and go out precipitation, with the DMSO of 1ml: H
2O (1: 5) mixture washing, and in convection oven in 60 ℃ of dryings, obtain the Levofloxacin semihydrate of 840mg (84%) purifying.
Embodiment 9:MEK (methyl ethyl ketone)
The 1.5g crude preparation of levofloxacin is put into 15ml MEK form suspension.Mixture heating up to reflux temperature is dissolved fully up to raw material.Through 3 hours solution is cooled to-5 ℃ then.To precipitate vacuum filtration, with the MEK of 1.5ml washing, and in vacuum drying oven in 30 ℃ of dryings, obtain the Levofloxacin semihydrate of 840mg (84%) purifying.
Embodiment 10:ACN: H
2O (9: 1)/pyrosulfite
Under nitrogen atmosphere, 1.5g crude preparation of levofloxacin and 8mg Sodium Pyrosulfite are put into 10.5mlACN: H
2Form suspension in O (9: the 1) mixture.Heated mixt to reflux temperature dissolves fully up to raw material.Through 30 minutes solution is cooled to room temperature then.To precipitate vacuum filtration, use ACN: H
2O (9: 1) mixture (4ml) washing, and in vacuum drying oven in 60 ℃ of dryings, obtain the pure levofloxacin of 1.16g (77%).
Embodiment 11:ACN: H
2O (95: 5)/pyrosulfite (8mg)
Under nitrogen atmosphere, 1.5g crude preparation of levofloxacin and 8mg Sodium Pyrosulfite are put into 10.5mlACN: H
2Form suspension in O (95: the 5) mixture.With mixture heating up to reflux temperature and carry out heat filtering.Once more solution is heated to reflux temperature, then at 30 minutes internal cooling to 3 ℃.To precipitate vacuum filtration and in vacuum drying oven in 60 ℃ of dryings, obtain the pure levofloxacin of 500mg (33%).
Embodiment 12:ACN: H
2O (95: 5)/pyrosulfite (4mg)
Under nitrogen atmosphere, 1.5g crude preparation of levofloxacin and 4mg Sodium Pyrosulfite are put into 15ml ACN: H
2Form suspension in O (95: the 5) mixture.With mixture heating up to reflux temperature till raw material dissolves fully.Through 2 hours solution is cooled to 3 ℃ then.To precipitate vacuum filtration and in vacuum drying oven in 60 ℃ of dryings, obtain the pure levofloxacin of 1.3g (86%).
Embodiment 13:DMSO/ xitix
In the three-necked flask of condenser is housed, under 80 ℃ and nitrogen atmosphere with 5g (17.8mmol) (S)-(-)-9,10-two fluoro-3-methyl-7-oxos-2,3-dihydro-7H-pyrido [1,2,3-de] [form suspension among the DMSO of 1,4] benzoxazine-6-carboxylic acid, 4.46g (44.6mmol), 31mg (0.17mmol) xitix adding 3.5ml.Heating (4 hours 30 minutes) reaction mixture is till reacting completely under this temperature.Then solution is cooled to 70 ℃ and drip IPA (40ml).In 1 hour, mixture is cooled to 0 ℃, under this temperature, stirred 30 minutes then.To precipitate vacuum filtration, with IPA (10ml) washing and in vacuum drying oven in 60 ℃ of dryings, obtain the pure levofloxacin of 5.63g (87.6%).
Embodiment 14:DMSO/ Sodium Pyrosulfite
In the three-necked flask of condenser is housed, under 80 ℃ and nitrogen atmosphere with 10g (35.5mmol) (S)-(-)-9,10-two fluoro-3-methyl-7-oxos-2,3-dihydro-7H-pyrido [1,2,3-de] [form suspension among the DMSO of 1,4] benzoxazine-6-carboxylic acid, 9g (90mmol), 34mg (0.17mmol) Sodium Pyrosulfite adding 3.5ml.Heating (5 hours 30 minutes) reaction mixture is till reacting completely under this temperature.Then solution is cooled to 70 ℃ and drip IPA (40ml).In 1 hour, mixture is cooled to 0 ℃, under this temperature, stirred 30 minutes then.To precipitate vacuum filtration, with IPA (10ml) washing and in vacuum drying oven in 60 ℃ of dryings, obtain the pure levofloxacin of 11.8g (92.4%).
Claims (36)
1. one kind prepares and has about 99% or the method for more highly purified levofloxacin, comprising: at high temperature be dissolved in levofloxacin in the polar solvent; With the levofloxacin crystallization that makes purifying.
2. the described method of claim 1, the purity of the levofloxacin of wherein said purifying is about 99.5% (weight) or higher.
3. the described method of claim 1, wherein said high temperature is about 80 ℃～about 110 ℃.
4. the described method of claim 1, wherein said high temperature is the reflux temperature of described solution.
5. the described method of claim 1, wherein said polar solvent is selected from methyl-sulphoxide, methyl ethyl ketone, acetonitrile, butanols, their mixture and their aqueous mixture.
6. the described method of claim 1, wherein said solvent is an acetonitrile.
7. the described method of claim 1, wherein said solvent is the mixture of acetonitrile and water, wherein the water yield in described solvent is about 10% or still less.
8. the described method of claim 1, wherein the amount of demethylation levofloxacin in the levofloxacin of described purifying lacks 1/3rd than the amount in initial levofloxacin at least.
9. the described method of claim 1 further is included in described crystallisation step and adds antioxidant before.
10. the described method of claim 9, wherein said antioxidant is selected from xitix, sodium ascorbate, calcium ascorbate, ascorbyl palmitate, butylated hydroxyanisol, Yoshinox BHT, 2,4,5-trihydroxybutyrophenone, 4-methylol-2, acceptable salt and mixture on 6-two-tert.-butyl phenol, saccharosonic acid, heal sore natural gum (gum guaiac), propyl gallate, thio-2 acid, Tyox B, tertiary butylated hydroquinone, tocopherol and their pharmacology.
11. the described method of claim 9, wherein said antioxidant is a Sodium Pyrosulfite.
12. the described method of claim 9, wherein said antioxidant is an xitix.
13. the described method of claim 9, wherein the amount of levofloxacin N-oxide compound in the levofloxacin of described purifying lacks 1/3rd than the amount in initial levofloxacin at least.
14. the described method of claim 9, wherein the amount of levofloxacin N-oxide compound in the levofloxacin of described purifying is about 0.1% or still less.
15. the described method of claim 9, the purity of the levofloxacin of wherein said purifying are about 99.5% (weight) or higher.
16. the described method of claim 9, but comprise is further measured the levofloxacin N-oxide compound whether initial levofloxacin contains the HPLC quantitation.
17. the described method of claim 9, wherein said solvent is an acetonitrile, and the levofloxacin of wherein said purifying is pure Levofloxacin semihydrate basically.
18. the described method of claim 1, the levofloxacin of wherein said purifying are pure Levofloxacin semihydrate basically.
19. one kind prepares and has about 99% or the method for more highly purified Levofloxacin semihydrate, comprising: at high temperature be dissolved in levofloxacin in the polar solvent; With the Levofloxacin semihydrate crystallization that makes purifying.
20. the described method of claim 19, wherein said high temperature are about 80 ℃～about 110 ℃.
21. the described method of claim 19, wherein said high temperature are the reflux temperature of described solution.
22. the described method of claim 19, wherein said polar solvent is selected from acetonitrile, methyl-sulphoxide: H
2O, methyl ethyl ketone, butanols and their mixture.
23. the described method of claim 19, wherein said solvent are the methyl-sulphoxide that ratio was about 1: 5: H
2O.
24. the described method of claim 19, wherein said solvent is a methyl ethyl ketone.
25. the described method of claim 19, wherein said solvent is a propyl carbinol.
26. the described method of claim 19, wherein said solvent is an acetonitrile.
27. the product of the described method of claim 1.
28. the product of the described method of claim 9.
29. the product of the described method of claim 19.
30. one kind prepares and has about 99% or the method for more highly purified levofloxacin, comprising: levofloxacin is dissolved in the polar solvent; Add antioxidant; With the levofloxacin crystallization that makes purifying, wherein said interpolation step occurs in before or after the described dissolving step, and before described crystallisation step.
31. the described method of claim 9, wherein said oxidation inhibitor are about 0.2%～about 0.5% of levofloxacin weight.
32. the described method of claim 9, wherein said oxidation inhibitor is added in the levofloxacin before described dissolving step.
33. the described method of claim 1 adds oxidation inhibitor during further being included in described crystallisation step.
34. one kind prepares and has about 99% or the method for more highly purified levofloxacin, this method is included in high temperature and has under the situation of antioxidant existence, with (S)-(-)-9,10-two fluoro-3-methyl-7-oxos-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid transforms into levofloxacin.
35. the described method of claim 34, the purity of wherein said levofloxacin are about 99.5% (weight) or higher.
36. the described method of claim 34, wherein the amount of levofloxacin N-oxide compound in described levofloxacin is about 0.1% or still less.
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33431601P | 2001-11-29 | 2001-11-29 | |
| US60/334,316 | 2001-11-29 | ||
| US35493902P | 2002-02-11 | 2002-02-11 | |
| US60/354,939 | 2002-02-11 | ||
| US26296502A | 2002-10-03 | 2002-10-03 | |
| US10/263,192 | 2002-10-03 | ||
| US10/263,192 US7629458B2 (en) | 2001-10-03 | 2002-10-03 | Preparation of levofloxacin and hemihydrate thereof |
| US10/262,965 | 2002-10-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1596256A true CN1596256A (en) | 2005-03-16 |
Family
ID=31892240
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA028236440A Pending CN1596256A (en) | 2001-11-29 | 2002-11-27 | Methods for the purification of levofloxacin |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP1460997A4 (en) |
| JP (3) | JP2005527484A (en) |
| CN (1) | CN1596256A (en) |
| AU (1) | AU2002365416A1 (en) |
| CA (1) | CA2466860A1 (en) |
| HR (1) | HRP20040546A2 (en) |
| HU (1) | HUP0500285A3 (en) |
| IL (1) | IL162172A0 (en) |
| IS (1) | IS7288A (en) |
| MX (1) | MXPA04005196A (en) |
| NO (1) | NO20042731L (en) |
| PL (1) | PL374558A1 (en) |
| WO (1) | WO2003045329A2 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1321121C (en) * | 2005-04-21 | 2007-06-13 | 浙江医药股份有限公司新昌制药厂 | Post processing method for preparing levo-ofloxacin |
| CN102070650A (en) * | 2011-01-28 | 2011-05-25 | 山东省药品检验所 | Preparation method for levofloxacin-N-oxide |
| CN105823851A (en) * | 2015-12-15 | 2016-08-03 | 浙江海洋学院 | Detection method for ofloxacin enantiomer in seawater |
| CN108218892A (en) * | 2018-03-16 | 2018-06-29 | 乐山职业技术学院 | A kind of purification process of lavo-ofloxacin |
| CN114507242A (en) * | 2022-01-26 | 2022-05-17 | 上虞京新药业有限公司 | Preparation method of high-optical-purity levofloxacin |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL161164A0 (en) | 2001-10-03 | 2004-08-31 | Teva Pharma | Preparation of levofloxacin and forms thereof |
| WO2004055025A1 (en) * | 2002-12-16 | 2004-07-01 | Ranbaxy Laboratories Limited | Pure levofloxacin hemihydrate and processes for preparation thereof |
| KR100704641B1 (en) * | 2004-07-21 | 2007-04-06 | 주식회사유한양행 | Methods for the preparation of levofloxacin having a high purity |
| JP2006273718A (en) * | 2005-03-28 | 2006-10-12 | Shiono Chemical Co Ltd | Method for producing levofloxacin-1/2 hydrate |
| 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 |
| 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 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK170473B1 (en) * | 1985-06-20 | 1995-09-11 | Daiichi Seiyaku Co | S (-) - pyridobenzoxazinforbindelser |
| US5237060A (en) * | 1985-12-10 | 1993-08-17 | Bayer Aktiengesellschaft | Process of preparing enantiomerically pure 1,8-bridged 4-quinolone-3-carboxylic acids |
| TW208013B (en) * | 1990-03-01 | 1993-06-21 | Daiichi Co Ltd | |
| CA2125287A1 (en) * | 1992-10-07 | 1994-04-14 | Juan Carlos Carretero Gonzalvez | Process to obtain benzoxazines to be used for the synthesis of ofloxazine, levofloxazine and derivatives |
| KR0125115B1 (en) * | 1994-03-22 | 1997-12-05 | 김은영 | Process for preparing piperazinyl quinolone derivatives |
| KR100309871B1 (en) * | 1999-02-24 | 2001-10-29 | 윤종용 | Process for Preparing (-)Pyridobenzoxazine Carboxylic Acid Derivatives |
| IL161164A0 (en) * | 2001-10-03 | 2004-08-31 | Teva Pharma | Preparation of levofloxacin and forms thereof |
-
2002
- 2002-11-27 EP EP02791339A patent/EP1460997A4/en not_active Withdrawn
- 2002-11-27 WO PCT/US2002/038182 patent/WO2003045329A2/en active Application Filing
- 2002-11-27 AU AU2002365416A patent/AU2002365416A1/en not_active Abandoned
- 2002-11-27 CN CNA028236440A patent/CN1596256A/en active Pending
- 2002-11-27 IL IL16217202A patent/IL162172A0/en unknown
- 2002-11-27 JP JP2003546834A patent/JP2005527484A/en active Pending
- 2002-11-27 MX MXPA04005196A patent/MXPA04005196A/en not_active Application Discontinuation
- 2002-11-27 PL PL02374558A patent/PL374558A1/en not_active Application Discontinuation
- 2002-11-27 HU HU0500285A patent/HUP0500285A3/en unknown
- 2002-11-27 CA CA002466860A patent/CA2466860A1/en not_active Abandoned
-
2004
- 2004-05-27 IS IS7288A patent/IS7288A/en unknown
- 2004-06-15 HR HR20040546A patent/HRP20040546A2/en not_active Application Discontinuation
- 2004-06-29 NO NO20042731A patent/NO20042731L/en not_active Application Discontinuation
-
2006
- 2006-05-01 JP JP2006127862A patent/JP2006219496A/en not_active Withdrawn
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2007
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1321121C (en) * | 2005-04-21 | 2007-06-13 | 浙江医药股份有限公司新昌制药厂 | Post processing method for preparing levo-ofloxacin |
| CN102070650A (en) * | 2011-01-28 | 2011-05-25 | 山东省药品检验所 | Preparation method for levofloxacin-N-oxide |
| CN102070650B (en) * | 2011-01-28 | 2012-06-27 | 山东省药品检验所 | Preparation method for levofloxacin-N-oxide |
| CN105823851A (en) * | 2015-12-15 | 2016-08-03 | 浙江海洋学院 | Detection method for ofloxacin enantiomer in seawater |
| CN108218892A (en) * | 2018-03-16 | 2018-06-29 | 乐山职业技术学院 | A kind of purification process of lavo-ofloxacin |
| CN114507242A (en) * | 2022-01-26 | 2022-05-17 | 上虞京新药业有限公司 | Preparation method of high-optical-purity levofloxacin |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003045329A3 (en) | 2004-02-19 |
| IL162172A0 (en) | 2005-11-20 |
| HRP20040546A2 (en) | 2004-10-31 |
| JP2008007517A (en) | 2008-01-17 |
| NO20042731L (en) | 2004-06-29 |
| MXPA04005196A (en) | 2005-11-23 |
| AU2002365416A1 (en) | 2003-06-10 |
| JP2005527484A (en) | 2005-09-15 |
| CA2466860A1 (en) | 2003-06-05 |
| WO2003045329A2 (en) | 2003-06-05 |
| EP1460997A2 (en) | 2004-09-29 |
| IS7288A (en) | 2004-06-21 |
| PL374558A1 (en) | 2005-10-31 |
| EP1460997A4 (en) | 2005-06-15 |
| JP2006219496A (en) | 2006-08-24 |
| HUP0500285A3 (en) | 2009-03-30 |
| HUP0500285A2 (en) | 2005-06-28 |
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