ZA200403672B - Methods for the purification of levofloxacin - Google Patents
Methods for the purification of levofloxacin Download PDFInfo
- Publication number
- ZA200403672B ZA200403672B ZA200403672A ZA200403672A ZA200403672B ZA 200403672 B ZA200403672 B ZA 200403672B ZA 200403672 A ZA200403672 A ZA 200403672A ZA 200403672 A ZA200403672 A ZA 200403672A ZA 200403672 B ZA200403672 B ZA 200403672B
- Authority
- ZA
- South Africa
- Prior art keywords
- levofloxacin
- polar solvent
- acetonitrile
- antioxidant
- butanol
- Prior art date
Links
- 229960003376 levofloxacin Drugs 0.000 title claims description 99
- 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 description 98
- 238000000034 method Methods 0.000 title claims description 73
- 238000000746 purification Methods 0.000 title description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 75
- 230000008569 process Effects 0.000 claims description 63
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 53
- 239000000203 mixture Substances 0.000 claims description 51
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 44
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 36
- 239000002798 polar solvent Substances 0.000 claims description 35
- 230000003078 antioxidant effect Effects 0.000 claims description 26
- 239000003963 antioxidant agent Substances 0.000 claims description 25
- 235000006708 antioxidants Nutrition 0.000 claims description 25
- SUIQUYDRLGGZOL-RCWTXCDDSA-N levofloxacin hemihydrate Chemical compound O.C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1.C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 SUIQUYDRLGGZOL-RCWTXCDDSA-N 0.000 claims description 20
- 238000010992 reflux Methods 0.000 claims description 19
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 18
- 238000004090 dissolution Methods 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical group [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 10
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 10
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 10
- 150000001204 N-oxides Chemical class 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 235000010323 ascorbic acid Nutrition 0.000 claims description 8
- 239000011668 ascorbic acid Substances 0.000 claims description 8
- 229960005070 ascorbic acid Drugs 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 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 claims description 5
- HNURKXXMYARGAY-UHFFFAOYSA-N 2,6-Di-tert-butyl-4-hydroxymethylphenol Chemical compound CC(C)(C)C1=CC(CO)=CC(C(C)(C)C)=C1O HNURKXXMYARGAY-UHFFFAOYSA-N 0.000 claims description 4
- WKRSSAPQZDHYRV-VIFPVBQESA-N Ofloxacin impurity e Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCNCC1 WKRSSAPQZDHYRV-VIFPVBQESA-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
- 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
- ODJQKYXPKWQWNK-UHFFFAOYSA-N 3,3'-Thiobispropanoic acid Chemical compound OC(=O)CCSCCC(O)=O ODJQKYXPKWQWNK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004255 Butylated hydroxyanisole Substances 0.000 claims description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 claims description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 2
- CIWBSHSKHKDKBQ-DUZGATOHSA-N D-araboascorbic acid Natural products OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-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
- 235000000072 L-ascorbyl-6-palmitate Nutrition 0.000 claims description 2
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims description 2
- BGNXCDMCOKJUMV-UHFFFAOYSA-N Tert-Butylhydroquinone Chemical compound CC(C)(C)C1=CC(O)=CC=C1O BGNXCDMCOKJUMV-UHFFFAOYSA-N 0.000 claims description 2
- 239000003490 Thiodipropionic acid Substances 0.000 claims description 2
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 2
- 229940043253 butylated hydroxyanisole Drugs 0.000 claims description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 claims description 2
- 235000010376 calcium ascorbate Nutrition 0.000 claims description 2
- 239000011692 calcium ascorbate Substances 0.000 claims description 2
- 229940047036 calcium ascorbate Drugs 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
- 235000010350 erythorbic acid Nutrition 0.000 claims description 2
- 239000004318 erythorbic acid Substances 0.000 claims description 2
- 229940091561 guaiac Drugs 0.000 claims description 2
- 229940026239 isoascorbic acid Drugs 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
- 239000004250 tert-Butylhydroquinone Substances 0.000 claims description 2
- 235000019281 tert-butylhydroquinone Nutrition 0.000 claims description 2
- 235000019303 thiodipropionic acid Nutrition 0.000 claims description 2
- 239000011732 tocopherol Substances 0.000 claims description 2
- 229930003799 tocopherol Natural products 0.000 claims description 2
- 235000019149 tocopherols Nutrition 0.000 claims description 2
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- GHKOFFNLGXMVNJ-UHFFFAOYSA-N Didodecyl thiobispropanoate Chemical compound CCCCCCCCCCCCOC(=O)CCSCCC(=O)OCCCCCCCCCCCC GHKOFFNLGXMVNJ-UHFFFAOYSA-N 0.000 claims 1
- 239000003508 Dilauryl thiodipropionate Substances 0.000 claims 1
- 235000019304 dilauryl thiodipropionate Nutrition 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- JYVLIDXNZAXMDK-UHFFFAOYSA-N methyl propyl carbinol Natural products CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 239000000725 suspension Substances 0.000 description 15
- 239000002244 precipitate Substances 0.000 description 14
- 239000012299 nitrogen atmosphere Substances 0.000 description 10
- 239000000463 material Substances 0.000 description 7
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 description 6
- 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 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229960001699 ofloxacin Drugs 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-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
- 150000004682 monohydrates Chemical class 0.000 description 2
- 210000003739 neck Anatomy 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- -1 tetraalkyl ammonium halides Chemical class 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
- PVTXJGJDOHYFOX-UHFFFAOYSA-N 2h-1,4-benzoxazine Chemical class C1=CC=C2N=CCOC2=C1 PVTXJGJDOHYFOX-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
- ODJQKYXPKWQWNK-UHFFFAOYSA-L 3-(2-carboxylatoethylsulfanyl)propanoate Chemical compound [O-]C(=O)CCSCCC([O-])=O ODJQKYXPKWQWNK-UHFFFAOYSA-L 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
- 108010054814 DNA Gyrase Proteins 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 1
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940124307 fluoroquinolone Drugs 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
- 239000012535 impurity Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940089519 levaquin Drugs 0.000 description 1
- 230000008774 maternal effect Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 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 class C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 1
- 239000003306 quinoline derived antiinfective agent Substances 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000007787 solid Substances 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
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
METHODS FOR THE PURIFICATION OF
LEVOFLOXACIN
[001] This application is a continuation-in-part application of patent application serial number 10/262,965, filed October 3, 2002, which claims the priority of provisional application serial numbers 60/326,958, filed October 3, 2001, 60/334,316, filed November 29, 2001 and 60/354,939, filed February 11, 2002, and patent application serial no. 10/263,192, filed October 3, 2002. The entire content of each of these applications is incorporated herein by reference.
[002] The present invention relates to methods for purifying levofloxacin. In a preferred embodiment, the levofloxacin is prepared with anitoxidants.
[003] 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.
[004] Levofloxacin is a chiral fluorinated carboxyquinolone. Its chemical name is (S)-9-fluoro-2,3 -dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]- 1,4-benzoxazine- 6-carboxylic acid hemihydrate (CAS Registry No. 100986-85-4). The chemical structure of levofloxacin is shown as Formula I.
~Y gn -
SNA "
OL
F
0 OH
Formula I
[005] U.S. Patent No. 4,382,892 is directed toward pyrido[1,2,3-de][1,4]benzoxazine derivatives and methods of preparing them.
[006] 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.
[007] 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.
[008] U.S. Patent No. 5,155,223 is directed toward the preparation of quinolinecarboxylic acids.
[009] 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. Arutla et al,
Arzneimittelforschung (October 1998) 48(10):1024-7, asserts that the racemic mixture ofloxacin has an antioxidant property.
One disadvantage of the prior art methods for purifying levofloxacin is that they often produce an unsatisfactory yield. For example, 45-65% yields are typical. There remains a . need for novel methods for purifying levofloxacin, particularly purified preparations having diminished impurities, such as anti-levofloxacin, desmethyl levofloxacin, N-oxide ‘ levofloxacin, desfluoro-levofloxacin and/or decarboxy-levofloxacin.
[010] 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. In one embodiment, the solvent is anhydrous. In another embodiment, an antioxidant is added, resulting in a more pure levofloxacin product.
[011] Crude and semi-pure preparations of levofloxacin can be prepared by methods known in the art. Alternatively, 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-7-0x0-2,3-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. The slurry is stirred at a rate of 250 rpm under nitrogen atmosphere at 80°C until completion of the reaction (monitoring by HPLC). Then the slurry is cooled to 75°C and a mixture of isopropanol (675 mL) and water (25 mL) is added dropwise at this temperature over 2 hours. The slurry is then cooled to S "C over 4 hours, maintained at this temperature for 2 hours and filtrated under vacuum at this temperature. The solid is then washed with 175 mL of isopropanol (2 rinses) and dried under vacuum to obtain levofloxacin crude.
[012] In one embodiment of the present invention, crude levofloxacin is purified. As used herein, “purified levofloxacin” is a relative term meaning more pure. As used herein, “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. Typically, the elevated temperature ranges from about 80 “C to about 110 "C. Preferably, the mixture is refluxed.
Preferably, once the levofloxacin is dissolved in the solvent, 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.
[013] Polar solvents are generally suitable. Preferably, the solvent is DMSO, methyl ethyl ketone, butanol, acetonitrile, mixtures thereof, or aqueous mixtures thereof. As used ‘ herein, the term “polar solvent” is intended as a relative term to mean relatively more polar than another solvent.
[014] 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,O (9:1) and acetonitrile:H,0 (99:1) are examples of suitable water-containing solvents. Acetonitrile and acetonitrile:H,O (99:1) are the most preferred solvents for purifying levofloxacin.
[015] In another embodiment, 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, dilaury! thiodipropionate, tert-butylhydroquinone, tocopherols (such as vitamin E), and pharmaceutically acceptable salts and mixtures thereof. Preferably, the antioxidant includes sodium metabisulfite or ascorbic acid.
[016] An antioxdiant, if used, can be added at various points in the purification process.
For example, in one embodiment, an antioxidant is admixed with levofloxacin before or during the crystallization step or before the dissolution step. In another embodiment, an antioxidant is admixed with (S)-(-)-9,10-Difluoro-3-Methyl-7-0x0-2,3-Dihydro-7H-
Pyrido(1,2,3-de][ 1 ,4]Benzoxazine-6-Carboxylic Acid, a levofloxacin precursor, prior to its conversion to levofloxacin at an elevated temperature.
[017] The amount of antioxidant, when present, is preferably about 0.2% to about 5% by weight, more preferably about 0.2% to about 1 %.
[018] The function and advantages of these and other embodiments of the present invention will be more fully understood from the examples below. The following examples are intended to illustrate the benefits of the present invention, but do not exemplify the full scope of the invention.
[019] The following 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.
Table 1: Purification During Crystallization
CTT TTT EI IRE LT TIT em
SE RES i Gop rede CE .
EE TT 1 ¥ BlsLevo | tmp. D-fimp. £7 Imp: Fil sev formp:D | 1mpE=] 1mp.-
EE LR 9. | Ant [DesMe IPN. TLET Eid Anti | DesMez| CF
SY = EES RERUN a fo) [TI CERRS Ee BRE SEE od Like IESE EERE EEC SEE ee BE “Oxide - 1 [amon [mar] wo | on | ow [we | wo | ow on. 2 | n-BuOH 99.58 0.21 99.78 ND 0.08
Asc. acid (2.4%) 3 | n-BuOH/H,0 ] 99.58 0.21 99.85 0.08 ND
Na,S,0; (0.6%) «Joon Joss] wo [on [ow [oes | w | oor [oss
ACN:H,0 99.77 | <0.03 0.05 <0.03 99.93 <0.03
Na,S,0, (0.2%) 7 J ACN 99.58 ND 0.21 99.70 ND
Na,S,0, (0.5%) + [owsoms [maa] wo [on [on [oom | 0 | ow [om 9 fue fosas| wo | ou | 019 | oss
ACN:H,0 99.58 0.21 99.69 0.08 ND (90:10)
Na,S,0, (0.5%)
ACN:H,0 99.58 ND 0.11 0.21 99.74 ND ND (95:5)
Na,S,0; (0.5%) 12 | ACN:H,0 99.58 ND 0.11 0.21 99.81 ND 0.08 ND (95:5)
Na,S,0, (0.25%) 13 | DMSO 99.80 0.03 0.02
Asc. Acid (0.6%) 14 | DMSO 99.77 <0.03
Na,S,0; (0.5 eq.)
ND = Not detected.
Example 1: n-BuOH
[020] 1g of levofloxacin crude was put in suspension in 7 ml of n-BuOH. The mixture was heated to reflux temperature until complete dissolution of the material. Then the solution was cooled to RT over a period of 2.5 hours. The precipitate was filtrated under vacuum, washed with n-BuOH and dried at 60°C in a vacuum oven to give 810 mg (81%) of purified levofloxacin hemihydrate.
Example 2: n-BuOH / Ascorbic acid
[021] 1.5 g of levofloxacin crude and 36 mg of ascorbic acid were put in suspension in 9.5 ml of n-BuOH under inert atmosphere. The mixture was heated to reflux temperature and a hot filtration was performed. The solution was then evaporated to dryness and n-
BuOH (10 ml) was added. The mixture was heated to reflux until complete dissolution and then cooled to RT over a period of 1.5 hour. The precipitate was filtrated under vacuum, washed with n-BuOH (4 ml) and dried at 60°C in a vacuum oven to give 840 mg (56%) of purified levofloxacin hemihydrate.
Example 3: n-BuOH:H,0 (9:1) / Metabisulfite
[022] 1.5 goflevofloxacin crude and 10 mg of sodium metabisulfite were put in suspension in 6 ml of a mixture n-BuOH:H,0 (9:1) under nitrogen atmosphere. The mixture was heated to reflux temperature until complete dissolution of the material. Then the solution was cooled to RT over a period of 1.5 hours. The precipitate was filtrated under vacuum, washed with a mixture n-BuOH:H,0 (9:1) (4 ml) and dried at 60°C in a vacuum oven to give 1.2 g (81%) of punfied levofloxacin hemihydrate. The purified levofloxacin hemihydrate contained virtually no N-oxide levofloxacin.
Example 4: ACN
[023] 1.5g of levofloxacin crude was put in suspension in 10.5 ml of ACN. The mixture was heated to reflux temperature until complete dissolution of the material. Then the solution was cooled to 0°C over a period of 20 minutes. The precipitate was filtrated under vacuum, washed with ACN (1.5 ml) and dried at 30°C in a vacuum oven to give 1.15 g (77%) of purified levofloxacin (hemihydrate/monohydrate mixture). The purified levofloxacin contained approximately half the amount of desmethyl levofloxacin as that in the crude sample.
Example 5: ACN: H,0 (99:1)
[024] 25 g of wet levofloxacin crude (about 22.17g or dry levofloxacin) was put in suspension in 225 mL of mixture ACN:H,O (99:1) under nitrogen atmosphere. The mixture was heated to reflux during 1 hour and then filtrated under vacuum with Hyflow when still hot. Then the solution was heated again to reflux and cooled to 0°C over a period of 1 hour. The precipitate was filtrated under vacuum, washed with ACN:H,0(2x12 mL) and dried in a vacuum oven to give 18.6 g (84%) of purified levofloxacin hemihydrate. The purified levofloxacin hemihydrate contained approximately one-third less desmethyl levofloxacin than in the crude sample.
Example 6: ACN:H,0 (99:1) / Metabisulfite
[025] 8 g of wet levofloxacin crude (about 5.6g of dry levofloxacin) and 14 mg of sodium metabisulfite were put in suspension in 39 ml of a mixture ACN:H,0 (99:1) under nitrogen atmosphere. The mixture was heated to reflux during 1 hour, 0.65 g of Hyflo was added and the reflux was continued for an additional half an hour. The mixture was , filtrated under vacuum when still hot. Then the solution was cooled to 3°C over a period of 30 minutes. The precipitate was filtrated under vacuum, washed with a mixture
ACN:H,0 (99:1) (5 ml) and dried at 60°C in a vacuum oven to give 1.77 g (31%) of purified levofloxacin. Technical problems during the hot filtration decreased the yield.
Example 7: ACN / Metabisulfate
[026] 1.5 g of levofloxacin crude and 8 mg of sodium metabisulfite were put in suspension in 10.5 ml of ACN under nitrogen atmosphere. The mixture was heated to reflux temperature and a hot filtration was performed. Then the solution was heated again to reflux temperature until complete dissolution of the maternal. The solution was then cooled to 0°C over a period of 30 minutes. The precipitate was filtrated under vacuum and dried at 60°C in a vacuum oven to give 1.04 g (69%) of purified levofloxacin. The purified levofloxacin contained approximately half the amount of N-oxide levofloxacin as that in the crude sample.
Example 8: DMSO/H,0
[027] 1g of levofloxacin crude was put in suspension in 1.5 ml of DMSO. The mixture was heated to 108°C until complete dissolution of the material. Then H,0 (7.5 ml) was added over 10 minutes and the mixture was cooled to RT. The precipitate was filtrated under vacuum, washed with 1 ml of a mixture DMSO:H,0 1:5 and dried at 60°C in an air- flow oven to give 840 mg (84%) of purified levofloxacin hemihydrate.
Example 9: MEK
[028] 1.5g of levofloxacin crude was put in suspension in 15 ml of MEK. The mixture was heated to reflux temperature until complete dissolution of the material. Then the solution was cooled to -5°C over a period of 3 hours. The precipitate was filtrated under vacuum, washed with 1.5 ml of MEK and dried at 30°C in a vacuum oven to give 840 mg (84%) of purified levofloxacin hemihydrate.
Example 10: ACN:H20 (9:1) / Metabisulfite
[029] 1.5 gof levofloxacin crude and 8 mg of sodium metabisulfite were put in suspension in 10.5 ml of a mixture ACN:H,O 9:1 under nitrogen atmosphere. The mixture was heated to reflux temperature until complete dissolution of the material. Then the solution was cooled to RT over a period of 30 minutes. The precipitate was filtrated under vacuum, washed with a mixture ACN:H,0 9:1 (4 ml) and dried at 60°C in a vacuum oven . to give 1.16 g (77%) of pure levofloxacin.
Example 11: ACN:H20 (95:5) / Metabisulfite (8 mg)
[030] 1.5 gof levofloxacin crude and 8 mg of sodium metabisulfite were put in suspension in 10.5 ml of a mixture ACN:H,O 95:5 under nitrogen 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:H20 (95:5) / Metabisulfite (4 mg)
[031] 1.5 gof levofloxacin crude and 4 mg of sodium metabisulfite were put in suspension in 15 ml of a mixture ACN:H,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
[032] In a three necks flask equipped of a condenser were put in suspension in 3.5 ml of
DMSO at 80°C under nitrogen atmosphere Sg (17.8 mmol) of (S)-(-)-9,10-Difluoro-3-
Methyl-7-0x0-2,3-Dihydro-7H-Pyrido[1,2,3-de][ 1,4]Benzoxazine-6-Carboxylic Acid, 4.46g (44.6 mmol), 31 mg (0.17 mmol) of ascorbic acid. The reaction mixture was heated at this temperature (4h30) until completion of the reaction. Then the solution was cooled to 70°C and IPA (40 ml) was added dropwise. The mixture was cooled to 0°C in 1 hour and then stirred at this temperature for 30 minutes. The precipitate was filtrated under vacuum, washed with IPA (10ml) and dried at 60°C in a vacuum oven to give 5.63 g (87.6%) of pure levofloxacin.
Example 14: DMSO / Metabisulfite
[033] In a three necks flask equipped of a condenser were put in suspension in 7 ml of
DMSO at 80°C under nitrogen atmosphere 10 g (35.5 mmol) of (S)-(-)-9,10-Difluoro-3-
Methyl-7-0x0-2,3-Dihydro-7H-Pyrido[1,2,3-de][ 1,4]Benzoxazine-6-Carboxylic Acid, 9.0g (90 mmol), 34 mg (0.17 mmol) of sodium metabisulfite. The reaction mixture was heated at this temperature (Sh30) until completion of the reaction. Then the solution was cooled to 70°C and IPA (40 ml) was added dropwise. The mixture was cooled to 0°C in 1 hour and then stirred at this temperature for 30 minutes. The precipitate was filtrated under vacuum, washed with IPA (10m!) and dried at 60°C in a vacuum oven to give 11.8 g (92.4%) of pure levofloxacin.
Claims (1)
- What is claimed is:l. A process for preparing levofloxacin having a purity of about 99% or greater, comprising: dissolving levofloxacin in at least one polar solvent at an elevated temperature; and crystallizing purified levofloxacin, wherein the at least one polar solvent is selected from the group consisting of dimethyl sulfoxide, methyl ethyl ketone, acetonitrile, butanol, mixtures thereof, and aqueous mixtures thereof.2. The process of claim 1, wherein the purity of the purified levofloxacin is about99.5% by weight or greater.3. The process of claim 1, wherein the elevated temperature ranges from about 80°C to about 110°C.4. The process of claim 1, wherein the elevated temperature is the reflux temperature of the solution.5. The process of claim 1, wherein the at least one polar solvent is acetonitrile.6. The process of claim 1, wherein the at least one polar solvent is a mixture of acetonitrile and water, wherein the amount of water in the at least one solvent is about 10% or less.7. The process of claim 1, wherein the amount of desmethyl levofloxacin in the purified levofloxacin is at least one-third less than the amount in the initial levofloxacin.8. The process of claim 1, further comprising adding an antioxidant prior to the crystallizing step. Amended Sheet: 6 December 20059. The process of claim 8, wherein the antioxidant is selected from the group consisting of 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, and pharmaceutically acceptable salts and mixtures thereof.10. The process of claim 8, wherein the antioxidant is sodium metabisulfite.11. The process of claim 8, wherein the antioxidant is ascorbic acid.12. The process of claim 8, wherein the amount of N-oxide levofloxacin in the purified levofloxacin is at least one-third less than the amount in the initial levofloxacin.13. The process of claim 8, wherein the amount of N-oxide levofloxacin in the purified levofloxacin is about 0.1% or less.14. The process of claim 8, wherein the purity of the purified levofloxacin is about99.5% by weight or greater.15. The process of claim 8, further comprising a step of determining whether the initial levofloxacin contains an amount of N-oxide levofloxacin that is detectable by HPLC.16. The process of claim 8, wherein the at least one polar solvent is acetonitrile and wherein the purified levofloxacin is substantially pure levofloxacin hemihydrate.17. The process of claim 1, wherein the purified levofloxacin is substantially pure levofloxacin hemihydrate. 11 Amended Sheet: 6 December 200518. A process for preparing levofloxacin hemihydrate having a purity of about 99% or greater, comprising: dissolving levofloxacin in at least one polar solvent at an elevated temperature; and crystallizing levofloxacin hemihydrate, wherein the at least one polar solvent is selected from the group consisting of acetonitrile, dimethyl sulfoxide, methyl ethyl ketone, butanol, mixtures thereof, and aqueous mixtures thereof.19. The process of claim 18, wherein the elevated temperature ranges from about 80°C to about 110°C.20. The process of claim 18, wherein the elevated temperature is the reflux temperature of the solution.21. The process of claim 18, wherein the at least one polar solvent is dimethyl sulfoxide:H,O in a ratio of about 1:5.22. The process of claim 18, wherein the at least one polar solvent is methyl ethyl ketone.23. The process of claim 18, wherein the at least one polar solvent is n-butanol.24. The process of claim 18, wherein the at least one polar solvent is acetonitrile.25. The product of the process of claim 1.26. The product of the process of claim 8.27. The product of the process of claim 18. 12 Amended Sheet: 6 December 200528. A process for preparing levofloxacin having a purity of about 99% or greater, comprising: dissolving levofloxacin in at least one polar solvent; adding an antioxidant; and crystallizing purified levofloxacin, wherein the adding step occurs before or after the dissolving step and before the crystallizing step.29. The process of claim 8, wherein the antioxidant ranges from about 0.2% to about 5% by weight levofloxacin.30. The process of claim 8, wherein the antioxidant is added to the levofloxacin before the dissolving step. 31 The process of claim 1, further comprising adding an antioxidant during the crystallization step.31. A process for preparing levofloxacin having a purity of about 99% or greater comprising converting (S)-(-)-9,10-Difluoro-3-Methyl-7-0x0-2,3-Dihydro-7H- Pyrido[1,2,3-de][1,4]Benzoxazine-6-Carboxylic Acid to levofloxacin at an elevated temperature in the presence of an antioxidant.32. The process of claim 32, wherein the purity of the levofloxacin is about 99.5% by weight or greater.34. The process of claim 32, wherein the amount of N-oxide levofloxacin in the levofloxacin is about 0.1% or less.35. The process of claim 19, wherein the mixture of levofloxacin and the at least one polar solvent is filtered when hot before the crystallizing step. 13 Amended Sheet: 6 December 200536. The process of claim 20, wherein the at least one polar solvent is selected from the group consisting of acetonitrile, acetonitrile:H,O, dimethyl sulfoxide:H,0, methyl ethyl ketone, butanol, butanol:H,O, and mixtures thereof.37. The process of claim 18, wherein the at least one polar solvent is selected from the group consisting of acetonitrile, acetonitrile:H,O, dimethyl sulfoxide, dimethyl sulfoxide:H,0, methyl ethyl ketone, methyl ethyl ketone:H,O, butanol, butanol:H,0, and mixtures thereof.38. The process of claim 37, wherein the at least one polar solvent consists essentially of butanol:H,O in a ratio of about 9:1 or acetonitrile:H,O in a ratio of about 99:1.39. The process of claim 38, wherein the at least one polar solvent consists essentially of acetonitrile:H,O in a ratio of about 99:1.40. The process of claim 18, further comprising adding an antioxidant prior to the crystallizing step.41. The process of claim 18, wherein the amount of N-oxide levofloxacin in the purified levofloxacin is about 0.1% or less.42. The process of claim 18, wherein the purity of the purified levofloxacin is about99.5% by weight or greater.43. The process of claim 18, wherein the levofloxacin hemihydrate is prepared with a yield of about 80% or greater.44. The process of claim 38, wherein the levofloxacin hemihydrate is prepared with a yield of about 80% or greater. 14 Amended Sheet: 6 December 200545. A process for preparing levofloxacin hemihydrate, comprising: dissolving levofloxacin in at least one polar solvent selected from the group consisting of acetonitrile, acetonitrile:H,0, dimethyl sulfoxide:H,O, methyl ethyl ketone, butanol, butanol:H,0, and mixtures thereof at an elevated temperature; and crystallizing levofloxacin hemihydrate.46. The process of claim 45, wherein the at least one polar solvent consists essentially of butanol:H,0 in a ratio of about 9:1 or acetonitrile:H,O in a ratio of about 99:1.47. The process of claim 46, wherein the at least one polar solvent consists essentially of acetonitrile:H,O in a ratio of about 99:1.48. The process of claim 45, wherein the mixture of levofloxacin and at least one polar solvent is filtered when hot before the crystallizing step.49. The process of claim 45, wherein the dissolution step comprises refluxing the at least one polar solvent.50. The process of claim 44, further comprising drying the crystallized levofloxacin hemihydrate at about 60°C.51. The process of claim 18, wherein the at least one polar solvent comprises butanol:H,O.52. The process of claim 18, wherein the at least one polar solvent comprises acetonitrile: H,O.53. The process of claim 18, wherein the at least one polar solvent comprises dimethyl sulfoxide:HO0.54. The process of claim 53, wherein the at least one polar solvent comprises dimethyl sulfoxide:H,O in a ratio of about 1:5. Amended Sheet: 6 December 200555. The process of claim 18, wherein the at least one polar solvent comprises butanol.56. The process of claim 18, wherein the at least one polar solvent comprises acetonitrile.57. The process of claim 18, wherein the at least one polar solvent comprises dimethyl sulfoxide.58. The process of claim 18, wherein the at least one polar solvent comprises methyl ethyl ketone.59. The process of claim 18, wherein the at least one polar solvent comprises acetonitrile, dimethyl sulfoxide, methyl ethyl ketone or butanol.60. The process of claim 18, further comprising (a) mixing an antioxidant with levofloxacin before the dissolving step, (b) adding an antioxidant during the dissolving step, (c) adding the antioxidant between the dissolving step and crystallizing step, or (d) adding an antioxidant during the crystallizing step.61. The process of claim 60, wherein the antioxidant used in (a), (b), (c) or (d) ranges from about 0.2% to about 5% by weight of the levofloxacin used in the dissolving step.62. The process of claim 60, wherein the antioxidant is mixed with the levofloxacin before the dissolving step.63. The process of claim 60, wherein the antioxidant is added during the crystallization step.64. The process of claim 45, wherein the crystallized levofloxacin hemihydrate has a purity of about 99% or greater. 16 Amended Sheet: 6 December 2005
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US33431601P | 2001-11-29 | 2001-11-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200403672B true ZA200403672B (en) | 2006-05-31 |
Family
ID=38116116
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200403672A ZA200403672B (en) | 2001-11-29 | 2004-05-13 | Methods for the purification of levofloxacin |
Country Status (1)
Country | Link |
---|---|
ZA (1) | ZA200403672B (en) |
-
2004
- 2004-05-13 ZA ZA200403672A patent/ZA200403672B/en unknown
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2008007517A (en) | Method for purification of levofloxacin | |
WO2003028665A2 (en) | Methods for the purification of levofloxacin | |
US20050124629A1 (en) | Methods for the purification of levofloxacin | |
JP2544375B2 (en) | Alkyl-substituted benzoxazinorifamycin derivatives | |
HU187449B (en) | Process for producing new quiniline-carboxylic acid derivatives and pharmaceutical compositions containing them as active agents | |
EP0109284B1 (en) | 6,7-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1h,5h-benzo(ij)quinolizine-2-carboxylic acid and derivatives | |
WO2015098693A1 (en) | Alkoxycarbonyl hemiacetal-type ester prodrug of pyridone carboxylic acid antibacterial drug | |
WO2012126147A1 (en) | Purification method of cefmetazole sodium | |
ZA200403672B (en) | Methods for the purification of levofloxacin | |
US20070244318A1 (en) | Process for the Preparation of Levofloxacin Hemihydrate | |
CA2573129C (en) | Process for preparing levofloxacin or its hydrate | |
NO167456B (en) | ANALOGUE PROCEDURE FOR PREPARING THE THERAPEUTIC ACTIVE COMPOUND 7- (3-AMINO-1-PYRROLIDINYL) -8-BROMO-1-CYCLOPROPYL-6-FLUORO-1,4-DIHYDRO-4-OXO-3-QUINOLINE | |
US20040152701A1 (en) | Novel anhydrous crystalline form of Levofloxacin and process for preparation there of | |
US5773449A (en) | Thioquinolone compounds which have useful pharmaceutical activity | |
KR20040058336A (en) | Methods for the purification of levofloxacin | |
EP0267432B1 (en) | Antibacterially active pyrido-benzothiazine derivatives with long term action | |
KR910009334B1 (en) | Benzoxazine cenboxylic acid derivatives and the preparation process there of | |
WO2006004561A1 (en) | Process for the preparation of gatifloxacin and regeneration of degradation products | |
EA029363B1 (en) | Pharmaceutical formulations containing 3-(4-cinnamyl-1-piperazinyl) amino derivatives of 3-formyl rifamycin sv and 3-formyl rifamycin s and a process of their preparation | |
Uno et al. | Synthesis of antimicrobial agents. 5. In vivo metabolism of 7-(4-hydroxypiperazin-1-yl) quinolones | |
CN110343120B (en) | Preparation method of 3-methyl cefdinir | |
CN1358183A (en) | Quinolinecarboxylic acid derivative or salts thereof | |
WO1990012799A1 (en) | Antibacterial pyrido(1,2,3-de)-1,4-benzoxazinone agents | |
JPH04364185A (en) | Pyridobenzoxazine derivative | |
US4585868A (en) | Precursors of 6,7-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid |