JP2008507507A - Process for producing levofloxacin or a hydrate thereof - Google Patents
Process for producing levofloxacin or a hydrate thereof Download PDFInfo
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- JP2008507507A JP2008507507A JP2007522417A JP2007522417A JP2008507507A JP 2008507507 A JP2008507507 A JP 2008507507A JP 2007522417 A JP2007522417 A JP 2007522417A JP 2007522417 A JP2007522417 A JP 2007522417A JP 2008507507 A JP2008507507 A JP 2008507507A
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- levofloxacin
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- ethyl acetate
- butanol
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- 229960003376 levofloxacin Drugs 0.000 title claims abstract description 52
- 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 41
- 238000000034 method Methods 0.000 title abstract description 17
- 239000012046 mixed solvent Substances 0.000 claims abstract description 56
- 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 abstract description 24
- 150000004682 monohydrates Chemical class 0.000 claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 claims abstract description 13
- 239000000203 mixture Substances 0.000 claims abstract description 5
- 238000010992 reflux Methods 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 93
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 56
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 50
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 27
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 27
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 9
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012535 impurity Substances 0.000 abstract description 27
- 239000002244 precipitate Substances 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 5
- 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 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 150000001204 N-oxides Chemical class 0.000 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 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- QEHPHWRZQAZOTI-PPHPATTJSA-N levofloxacin monohydrate Chemical compound O.C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 QEHPHWRZQAZOTI-PPHPATTJSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 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 description 1
- -1 4-methyl-1-piperazinyl Chemical group 0.000 description 1
- DCINPPZTEPFLEP-LEMICQRHSA-M C[C@@H](CO)N(C=C(C([O-])=O)C(C1=CC(F)=C2C3N(C)CCNC3)=O)C1=C2[N+]([O-])=O.[K+] Chemical compound C[C@@H](CO)N(C=C(C([O-])=O)C(C1=CC(F)=C2C3N(C)CCNC3)=O)C1=C2[N+]([O-])=O.[K+] DCINPPZTEPFLEP-LEMICQRHSA-M 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- KTUQUZJOVNIKNZ-UHFFFAOYSA-N butan-1-ol;hydrate Chemical compound O.CCCCO KTUQUZJOVNIKNZ-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Saccharide Compounds (AREA)
Abstract
本発明は不純物Ｂ、不純物Ｃ、不純物Ｄ、不純物Ｅおよび不純物Ｆのような不純物のないレボフロキサシン半水和物または一水和物の製造方法を提供する。 本発明の製造方法
は（ａ）新規混合溶媒に粗レボフロキサシンを加える段階と、（ｂ）段階（ａ）で得られた混合物を還流して溶液を形成する段階と、（ｃ）段階（ｂ）で得られた溶液からレボフロキサシン半水和物または一水和物を回収する段階とを含む。The present invention provides a process for producing levofloxacin hemihydrate or monohydrate free of impurities such as impurities B, C, D, E and F. The production method of the present invention comprises (a) adding crude levofloxacin to a new mixed solvent, (b) refluxing the mixture obtained in step (a) to form a solution, (c) step (b) Recovering levofloxacin hemihydrate or monohydrate from the solution obtained in
Description
本発明は、高純度レボフロキサシンまたはその水和物、例えば、半水和物または一水和物を製造する方法に関する。 The present invention relates to a process for producing high purity levofloxacin or a hydrate thereof, such as a hemihydrate or a monohydrate.
化学名が（Ｓ）−９−フルオロ−２，３−ジヒドロ−３−メチル−１０−（４−メチル−１−ピペラジニル）−７−オキソ−７Ｈ−ピリド［１，２，３−ｄｅ］−１，４−ベンゾキサジン−６−カルボン酸であるレボフロキサシン(Levofloxacin)は、有用な抗菌剤として周知の物質であり、下記化学式１で表示される。 The chemical name is (S) -9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-de]- Levofloxacin, a 1,4-benzoxazine-6-carboxylic acid, is a well-known substance as a useful antibacterial agent and is represented by the following chemical formula 1.
レボフロキサシンは、半水和物(hemihydrate)形態または一水和物(monohydrate)形態のような水和物形態で使われ得る。レボフロキサシンを製造する公知の方法は、特許文献１、特許文献２、特許文献３、特許文献４および特許文献５に開示されている。 Levofloxacin can be used in a hydrate form, such as a hemihydrate form or a monohydrate form. Known methods for producing levofloxacin are disclosed in Patent Literature 1, Patent Literature 2, Patent Literature 3, Patent Literature 4 and Patent Literature 5.
それらの方法は、合成された粗レボフロキサシンから純粋なレボフロキサシンまたはその水和物形態を得るためにカラムクロマトグラフィーが実施され、このことから該方法が産業的規模の量産には適用し難い。 In these methods, column chromatography is performed to obtain pure levofloxacin or a hydrate form thereof from synthesized crude levofloxacin, which makes the method difficult to apply to industrial-scale mass production.
特許文献６は、結晶化過程でレボフロキサシンを溶解させる水性溶媒中の水含有量を調節することにより、レボフロキサシンの半水和物または一水和物を選択的に製造する方法を開示している。しかし、前記特許文献６に開示された製造方法の１つの短所は、満足すべきレベルとはいえない収率である。例えば、４５〜６５％の収率が典型である。 Patent Document 6 discloses a method for selectively producing levofloxacin hemihydrate or monohydrate by adjusting the water content in an aqueous solvent in which levofloxacin is dissolved during the crystallization process. However, one disadvantage of the production method disclosed in Patent Document 6 is an unsatisfactory yield. For example, a yield of 45-65% is typical.
また、前記の方法は、レボフロキサシンの製造過程で生成されるデカルボキシ-レボフ
ロキサシン（decarboxy-levofloxacin）（不純物Ｂ）、デスフルオロ−レボフロキサシン（desfluoro-levofloxacin）（不純物Ｃ）、アンチ−レボフロキサシン（anti-levofloxacin）（不純物Ｄ）、デスメチル−レボフロキサシン（desmethyl-levofloxacin）（不純
物Ｅ）、Ｎ−オキシドレボフロキサシン（N-oxide levofloxacin）（不純物Ｆ）といった不純物を除去し難いという不利な点を有している。
In addition, the above-described method is a method of producing decarboxy-levofloxacin (impurity B), desfluoro-levofloxacin (impurity C), anti-levofloxacin (anti-levofloxacin) produced in the process of producing levofloxacin. ) (Impurity D), desmethyl-levofloxacin (impurity E), N-oxide levofloxacin (impurity F), and the like.
かかる問題を解決するために、特許文献７、特許文献８は、ｎ−ブタノールまたはアセトニトリルのような極性溶媒；またはｎ−ブタノールと水、ジメチルスルホキシドと水、アセトニトリルと水のような、水と極性溶媒とを含有する混合溶媒を使用して粗レボフロキサシンを精製する方法を開示する。しかし、前記特許文献７、特許文献８に開示された製造方法は、Ｎ−オキシドレボフロキサシン（不純物Ｆ）の生成を防止するために、アスコルビン酸またはメタ重亜硫酸ナトリウムのような酸化防止剤を加えねばならないので、前記酸化防止剤が最終生成物、すなわちレボフロキサシンまたはその水和物の不純物として残留することがあり、問題となる。また、前記方法は、デスメチル−レボフロキサシン
（不純物Ｅ）が完全に除去されずに、最終生成物に残ることとなるという問題がある。
In order to solve such a problem, Patent Document 7 and Patent Document 8 describe a polar solvent such as n-butanol or acetonitrile; or n-butanol and water, dimethyl sulfoxide and water, acetonitrile and water, water and polarity. Disclosed is a method for purifying crude levofloxacin using a mixed solvent containing a solvent. However, in the production methods disclosed in Patent Document 7 and Patent Document 8, an antioxidant such as ascorbic acid or sodium metabisulfite must be added in order to prevent the formation of N-oxide levofloxacin (impurity F). This is problematic because the antioxidant may remain as an impurity in the final product, ie levofloxacin or its hydrate. In addition, the above method has a problem that desmethyl-levofloxacin (impurity E) is not completely removed and remains in the final product.
従って、不純物Ｂ、Ｃ、Ｄ、Ｅ、およびＦのような既知不純物を完全に除去するためのレボフロキサシンの新しい精製方法に対する必要性がある。
本発明は、例えば抗酸化剤のような追加の処理剤（ａｇｅｎｔ）を使用することなく、高純度レボフロキサシン半水和物または一水和物を製造する方法を提供する。本発明は、新しい混合溶媒系を採用することにより、前述の不純物Ｂ、不純物Ｃ、不純物Ｄ、不純物Ｅおよび不純物Ｆのような既知不純物を完全に除去できる。 The present invention provides a method of producing high purity levofloxacin hemihydrate or monohydrate without the use of additional agents such as antioxidants. The present invention can completely remove known impurities such as the aforementioned impurities B, C, D, E and F by adopting a new mixed solvent system.
本発明の一態様においては、（ａ）酢酸メチル、酢酸エチルおよびイソブチルメチルケトンからなる群より選択された有機溶媒と水とを含有する混合溶媒Ａ、またはｔ−ブタノール、酢酸イソプロピル、酢酸メチル、酢酸エチルおよびイソブチルメチルケトンからなる群より選択された２種の有機溶媒と水とを含有する混合溶媒Ｂに、粗レボフロキサシンを加える段階と、（ｂ）前記粗レボフロキサシンを前記混合溶媒ＡまたはＢに加えて得られた混合物を還流して溶液を形成する段階と、（ｃ）前記溶液からレボフロキサシン半水和物または一水和物を回収する段階とを含む、レボフロキサシン半水和物または一水和物の製造方法が提供される。 In one embodiment of the present invention, (a) a mixed solvent A containing an organic solvent selected from the group consisting of methyl acetate, ethyl acetate and isobutyl methyl ketone and water, or t-butanol, isopropyl acetate, methyl acetate, Adding crude levofloxacin to a mixed solvent B containing two organic solvents selected from the group consisting of ethyl acetate and isobutyl methyl ketone and water; and (b) adding the crude levofloxacin to the mixed solvent A or B. And levofloxacin hemihydrate or monohydrate comprising: refluxing the resulting mixture to form a solution; and (c) recovering levofloxacin hemihydrate or monohydrate from said solution A method of manufacturing an article is provided.
本発明の一態様による、不純物のないレボフロキサシン半水和物または一水和物の製造方法は、新規の混合溶媒を使用して再結晶化させることにより、粗レボフロキサシンを精製する工程を含む。 According to one embodiment of the present invention, a method for producing an impurity-free levofloxacin hemihydrate or monohydrate comprises purifying crude levofloxacin by recrystallization using a novel mixed solvent.
ここで「粗レボフロキサシン」とは、精製前のレボフロキサシンを意味し、米国特許第６，３１６，６１８号明細書に開示されているような、当業界で公知の方法により製造できる。前記不純物は、デカルボキシ-レボフロキサシン（不純物Ｂ）、デスフルオロ−レ
ボフロキサシン（不純物Ｃ）、アンチ−レボフロキサシン（不純物Ｄ）、デスメチル−レボフロキサシン（不純物Ｅ）およびＮ−オキシドレボフロキサシン（不純物Ｆ）を含む。
Here, “crude levofloxacin” means levofloxacin before purification, and can be produced by a method known in the art as disclosed in US Pat. No. 6,316,618. The impurities include decarboxy-levofloxacin (impurity B), desfluoro-levofloxacin (impurity C), anti-levofloxacin (impurity D), desmethyl-levofloxacin (impurity E) and N-oxide levofloxacin (impurity F).
前記レボフロキサシン半水和物または一水和物の製造方法は、（ａ）混合溶媒に粗レボフロキサシンを加える段階と、（ｂ）段階（ａ）で得られた混合物を還流して溶液を形成する段階と、（ｃ）段階（ｂ）で得られた溶液からレボフロキサシン半水和物または一水和物を回収する段階とを含む。 The method for producing levofloxacin hemihydrate or monohydrate includes: (a) adding crude levofloxacin to a mixed solvent; and (b) refluxing the mixture obtained in step (a) to form a solution. And (c) recovering levofloxacin hemihydrate or monohydrate from the solution obtained in step (b).
前記段階（ａ）で、該混合溶媒は、ニ成分系または三成分系でありうる。ニ成分系混合溶媒Ａは、酢酸メチル、酢酸エチルおよびイソブチルメチルケトンからなる群より選択された１種の有機溶媒と水とを含む。また、三成分系混合溶媒Ｂは、ｔ−ブタノール、酢酸イソプロピル、酢酸メチル、酢酸エチルおよびイソブチルメチルケトンからなる群より選
択された２種の有機溶媒と水とを含む。
In the step (a), the mixed solvent may be a two-component system or a three-component system. The two-component mixed solvent A includes one organic solvent selected from the group consisting of methyl acetate, ethyl acetate, and isobutyl methyl ketone, and water. Further, the ternary mixed solvent B includes two organic solvents selected from the group consisting of t-butanol, isopropyl acetate, methyl acetate, ethyl acetate, and isobutyl methyl ketone, and water.
前記混合溶媒ＡまたはＢにおける水含有量は、約１．５〜６．０％（ｖ／ｖ）であり、例えば、約３．０％（ｖ／ｖ）でもよい。混合溶媒における水の含有量が６．０％（ｖ／ｖ）を超える場合、収率が低くなりうる。 The water content in the mixed solvent A or B is about 1.5 to 6.0% (v / v), for example, about 3.0% (v / v). When the content of water in the mixed solvent exceeds 6.0% (v / v), the yield can be lowered.
前記混合溶媒にあってｔ−ブタノール、酢酸エチルおよび水の混合物が使われてもよく、ｔ−ブタノール、酢酸エチルおよび水の体積比は、３２．３：６４．７：３でありうる。 A mixture of t-butanol, ethyl acetate and water in the mixed solvent may be used, and the volume ratio of t-butanol, ethyl acetate and water may be 32.3: 64.7: 3.
前記還流は、例えば約５０℃〜１１５℃で通常の方法で行ってもよく、これでレボフロキサシン溶液を形成することができる。また、レボフロキサシン半水和物または一水和物の回収は、冷却、減圧濾過、および／または減圧蒸留のような通常の結晶化方法で行える。 The reflux may be performed, for example, at a temperature of about 50 ° C. to 115 ° C. by a usual method, whereby a levofloxacin solution can be formed. In addition, levofloxacin hemihydrate or monohydrate can be recovered by a usual crystallization method such as cooling, vacuum filtration, and / or vacuum distillation.
本発明の製造方法により、レボフロキサシン半水和物または一水和物を９９．８％以上の高純度に製造できる。下記実施例で確認することができるが、本発明の製造方法により、不純物Ｂ、不純物Ｃ、不純物Ｄ、不純物Ｅおよび不純物Ｆといった既知不純物すべてが完全に除去される。 By the production method of the present invention, levofloxacin hemihydrate or monohydrate can be produced with a high purity of 99.8% or more. As can be seen in the following examples, all the known impurities such as impurity B, impurity C, impurity D, impurity E and impurity F are completely removed by the manufacturing method of the present invention.
レボフロキサシンの水和物形態は、使用される混合溶媒またはその水の含有量により調節することができる。望ましいレボフロキサシンの水和物形態は、レボフロキサシン半水和物である。 The hydrate form of levofloxacin can be adjusted by the mixed solvent used or its water content. The preferred hydrate form of levofloxacin is levofloxacin hemihydrate.
本発明を下記実施例によってさらに詳細に説明する。しかし、これが本発明の範囲を限定するものではない。 The invention is illustrated in more detail by the following examples. However, this does not limit the scope of the present invention.
粗レボフロキサシンの製造
（−）カリウム Ｎ−（１−ヒドロキシ−プロピ−２（Ｓ）−イル）−６−フルオロ−
７（Ｎ−メチルピペラジニル）−８−ニトロ−４−キノロン−３−カルボキシレート、５．１ｇ（１１．４２ｍｍｏｌ）をメタノール３４ｍＬに溶解させた。水酸化カリウム１．０７ｇを前記溶液に加えて２．５時間還流した。生成した反応混合物を減圧蒸留して溶媒を除去した。３Ｍ酢酸水溶液、５．７ｍＬを反応混合物に添加して淡黄色の沈殿物を得た。得られた沈殿物にテトラヒドロフラン（ＴＨＦ）１０ｍＬを撹拌しつつ加えた。得られた固体を濾過し、水／ＴＨＦ（１／１、ｖ／ｖ）で洗浄した後、乾燥して粗レボフロキサシン３．０ｇを得た。
M. P. 226.5℃〜227.2℃
1H-NMR (D2O, δ, ppm) 1.49 (d, 3H, J=6.8Hz), 2.93 (s, 3H), 3.38 (broad, 4H), 3.54 (m, 4H), 4.38-4.42 (dd, 1H, J=11.2Hz & 2Hz), 4.51-4.54 (dd, 1H, J=11.6Hz & 2Hz), 4.63 (m, 1Hz), 7.46 (d, 1H, J=12.8Hz), 8.38 (s, 1Hz)
Preparation of crude levofloxacin (-) potassium N- (1-hydroxy-prop-2 (S) -yl) -6-fluoro-
7 (N-methylpiperazinyl) -8-nitro-4-quinolone-3-carboxylate (5.1 g, 11.42 mmol) was dissolved in 34 mL of methanol. 1.07 g of potassium hydroxide was added to the solution and refluxed for 2.5 hours. The resulting reaction mixture was distilled under reduced pressure to remove the solvent. 5.7 mL of 3M aqueous acetic acid was added to the reaction mixture to give a pale yellow precipitate. To the resulting precipitate, 10 mL of tetrahydrofuran (THF) was added with stirring. The obtained solid was filtered, washed with water / THF (1/1, v / v) and then dried to obtain 3.0 g of crude levofloxacin.
MP 226.5 ℃ ~ 227.2 ℃
1 H-NMR (D 2 O, δ, ppm) 1.49 (d, 3H, J = 6.8Hz), 2.93 (s, 3H), 3.38 (broad, 4H), 3.54 (m, 4H), 4.38-4.42 ( dd, 1H, J = 11.2Hz & 2Hz), 4.51-4.54 (dd, 1H, J = 11.6Hz & 2Hz), 4.63 (m, 1Hz), 7.46 (d, 1H, J = 12.8Hz), 8.38 (s , 1Hz)
酢酸メチルおよび水を含有する混合溶媒で精製
実施例１で製造した粗レボフロキサシン１．１８ｇを、酢酸メチルと水とを含有する混合溶媒（９７：３）５９ｍＬに加えた。反応混合物を１時間還流した後、室温に冷却した。生成された沈殿物を減圧濾過し、酢酸メチルと水とを含有する混合溶媒（９７：３）２．４ｍＬで洗浄した。生成されたウェットケーキ（ｗｅｔ ｃａｋｅ）を減圧乾燥し、レ
ボフロキサシン半水和物１．０１ｇを製造した（収率：８５．６％）。
Purification with a mixed solvent containing methyl acetate and water 1.18 g of the crude levofloxacin produced in Example 1 was added to 59 mL of a mixed solvent (97: 3) containing methyl acetate and water. The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The produced precipitate was filtered under reduced pressure, and washed with 2.4 mL of a mixed solvent (97: 3) containing methyl acetate and water. The resulting wet cake was dried under reduced pressure to produce 1.01 g of levofloxacin hemihydrate (yield: 85.6%).
イソブチルメチルケトンおよび水を含有する混合溶媒で精製
実施例１で製造した粗レボフロキサシン１．１５ｇを、イソブチルメチルケトンと水とを含有する混合溶媒（９８．５：１．５）３５．７ｍＬに加えた。反応混合物を１時間還流した後、室温に冷却した。生成された沈殿物を減圧濾過し、イソブチルメチルケトンと水とを含有する混合溶媒（９８．５：１．５）２．３ｍＬで洗浄した。生成ウェットケーキを減圧乾燥し、レボフロキサシン半水和物１．０３ｇを製造した（収率：８９．６％）。
Purification with a mixed solvent containing isobutyl methyl ketone and water 1.15 g of the crude levofloxacin produced in Example 1 was added to 35.7 mL of a mixed solvent (98.5: 1.5) containing isobutyl methyl ketone and water. It was. The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The produced precipitate was filtered under reduced pressure, and washed with 2.3 mL of a mixed solvent (98.5: 1.5) containing isobutyl methyl ketone and water. The resulting wet cake was dried under reduced pressure to produce 1.03 g of levofloxacin hemihydrate (yield: 89.6%).
酢酸エチルおよび水を含有する混合溶媒で精製
実施例１で製造した粗レボフロキサシン２．０ｇを、 酢酸エチルと水とを含有する混
合溶媒（９７：３）８０ｍＬに加えた。反応混合物を１時間還流した後、室温に冷却した。生成された沈殿物を減圧濾過し、酢酸エチルと水とを含有する混合溶媒（９７：３）４ｍＬで洗浄した。生成されたウェットケーキを減圧乾燥し、レボフロキサシン半水和物１．８ｇを製造した（収率：９０％）。
Purification with a mixed solvent containing ethyl acetate and water 2.0 g of crude levofloxacin prepared in Example 1 was added to 80 mL of a mixed solvent (97: 3) containing ethyl acetate and water. The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The produced precipitate was filtered under reduced pressure, and washed with 4 mL of a mixed solvent (97: 3) containing ethyl acetate and water. The resulting wet cake was dried under reduced pressure to produce 1.8 g of levofloxacin hemihydrate (yield: 90%).
酢酸エチル、酢酸メチルおよび水を含有する混合溶媒で精製
実施例１で製造した粗レボフロキサシン２．０ｇを、 酢酸エチル、酢酸メチルと水と
を含有する混合溶媒（１９．４：７７．６：３）９０ｍＬに加えた。反応混合物を１時間還流した後、室温に冷却した。生成された沈殿物を減圧濾過し、酢酸エチル、酢酸メチルと水とを含有する混合溶媒（１９．４：７７．６：３）４．０ｍＬで洗浄した。生成されたウェットケーキを減圧乾燥し、レボフロキサシン一水和物１．７５ｇを製造した（収率：８７．５％）。
Purification with a mixed solvent containing ethyl acetate, methyl acetate and water 2.0 g of the crude levofloxacin prepared in Example 1 was mixed with a mixed solvent containing ethyl acetate, methyl acetate and water (19.4: 77.6: 3). ) To 90 mL. The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The produced precipitate was filtered under reduced pressure, and washed with 4.0 mL of a mixed solvent (19.4: 77.6: 3) containing ethyl acetate, methyl acetate and water. The produced wet cake was dried under reduced pressure to produce 1.75 g of levofloxacin monohydrate (yield: 87.5%).
酢酸エチル、酢酸メチルおよび水を含有する混合溶媒で精製
実施例１で製造した粗レボフロキサシン２．０ｇを、 酢酸エチル、酢酸メチルと水と
を含有する混合溶媒（４８．５：４８．５：３）９０ｍＬに加えた。反応混合物を１時間還流した後、室温に冷却した。生成された沈殿物を減圧濾過し、酢酸エチル、酢酸メチルと水とを含有する混合溶媒（４８．５：４８．５：３）４．０ｍＬで洗浄した。生成ウェットケーキを減圧乾燥し、レボフロキサシン一水和物１．７ｇを製造した（収率：８５％）。
Purification with a mixed solvent containing ethyl acetate, methyl acetate and water 2.0 g of the crude levofloxacin prepared in Example 1 was mixed with a mixed solvent containing ethyl acetate, methyl acetate and water (48.5: 48.5: 3). ) To 90 mL. The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The produced precipitate was filtered under reduced pressure, and washed with 4.0 mL of a mixed solvent (48.5: 48.5: 3) containing ethyl acetate, methyl acetate and water. The resulting wet cake was dried under reduced pressure to produce 1.7 g of levofloxacin monohydrate (yield: 85%).
酢酸エチル、酢酸メチルおよび水を含有する混合溶媒で精製
実施例１で製造した粗レボフロキサシン１．５ｇを、 酢酸エチル、酢酸メチルと水と
を含有する混合溶媒（７７．６：１９．４：３）７５ｍＬに加えた。反応混合物を１時間還流した後、室温に冷却した。生成された沈殿物を減圧濾過し、酢酸エチル、酢酸メチルと水とを含有する混合溶媒（７７．６：１９．４：３）３．０ｍＬで洗浄した。生成されたウェットケーキを減圧乾燥し、レボフロキサシン一水和物１．２５ｇを製造した（収率：８３．３％）。
Purification with a mixed solvent containing ethyl acetate, methyl acetate and water 1.5 g of the crude levofloxacin produced in Example 1 was mixed with a mixed solvent containing ethyl acetate, methyl acetate and water (77.6: 19.4: 3). ) To 75 mL. The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The produced precipitate was filtered under reduced pressure, and washed with 3.0 mL of a mixed solvent (77.6: 19.4: 3) containing ethyl acetate, methyl acetate and water. The produced wet cake was dried under reduced pressure to produce 1.25 g of levofloxacin monohydrate (yield: 83.3%).
ｔ−ブタノール、酢酸エチルおよび水を含有する混合溶媒で精製
実施例１で製造した粗レボフロキサシン２．０ｇを、ｔ−ブタノール、酢酸エチルと水とを含有する混合溶媒（６４．７：３２．３：３）５４ｍＬに加えた。反応混合物を１時間還流した後、室温に冷却した。生成された沈殿物を減圧濾過し、ｔ−ブタノール、酢酸エチルと水とを含有する混合溶媒（６４．７：３２．３：３）４．０ｍＬで洗浄した。生
成されたウェットケーキを減圧乾燥し、レボフロキサシン半水和物１．６９ｇを製造した（収率：８４．５％）。
Purification with a mixed solvent containing t-butanol, ethyl acetate and water 2.0 g of the crude levofloxacin produced in Example 1 was mixed with a mixed solvent containing t-butanol, ethyl acetate and water (64.7: 32.3). 3) Added to 54 mL. The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The produced precipitate was filtered under reduced pressure, and washed with 4.0 mL of a mixed solvent (64.7: 32.3: 3) containing t-butanol, ethyl acetate and water. The produced wet cake was dried under reduced pressure to produce 1.69 g of levofloxacin hemihydrate (yield: 84.5%).
ｔ−ブタノール、酢酸エチルおよび水を含有する混合溶媒で精製
実施例１で製造した粗レボフロキサシン２．０ｇを、ｔ−ブタノール、酢酸エチルと水とを含有する混合溶媒（４８．５：４８．５：３）５４ｍＬに加えた。反応混合物を１時間還流した後、室温に冷却した。生成された沈殿物を減圧濾過し、ｔ−ブタノール、酢酸エチルと水とを含有する混合溶媒（４８．５：４８．５：３）４．０ｍＬで洗浄した。生成されたウェットケーキを減圧乾燥し、レボフロキサシン半水和物１．７２ｇを製造した（収率：８６％）。
Purification with a mixed solvent containing t-butanol, ethyl acetate and water 2.0 g of the crude levofloxacin prepared in Example 1 was mixed with a mixed solvent containing t-butanol, ethyl acetate and water (48.5: 48.5). 3) Added to 54 mL. The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The produced precipitate was filtered under reduced pressure, and washed with 4.0 mL of a mixed solvent (48.5: 48.5: 3) containing t-butanol, ethyl acetate and water. The produced wet cake was dried under reduced pressure to produce 1.72 g of levofloxacin hemihydrate (yield: 86%).
ｔ−ブタノール、酢酸エチルおよび水を含有する混合溶媒で精製
実施例１で製造した粗レボフロキサシン２．０ｇを、ｔ−ブタノール、酢酸エチルと水とを含有する混合溶媒（３２．３：６４．７：３）６４ｍＬに加えた。反応混合物を１時間還流した後、室温に冷却した。生成された沈殿物を減圧濾過し、ｔ−ブタノール、酢酸エチルと水とを含有する混合溶媒（３２．３：６４．７：３）４．０ｍＬで洗浄した。生成されたウェットケーキ（ｗｅｔ ｃａｋｅ）を減圧乾燥し、レボフロキサシン半水和物
１．７５ｇを製造した（収率：８７．５％）。
Purification with a mixed solvent containing t-butanol, ethyl acetate and water 2.0 g of the crude levofloxacin prepared in Example 1 was mixed with a mixed solvent containing t-butanol, ethyl acetate and water (32.3: 64.7). : 3) Added to 64 mL. The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The produced precipitate was filtered under reduced pressure, and washed with 4.0 mL of a mixed solvent (32.3: 64.7: 3) containing t-butanol, ethyl acetate and water. The resulting wet cake was dried under reduced pressure to produce 1.75 g of levofloxacin hemihydrate (yield: 87.5%).
ｔ−ブタノール、酢酸メチルおよび水を含有する混合溶媒で精製
実施例１で製造した粗レボフロキサシン２．０ｇを、ｔ−ブタノール、酢酸メチルと水とを含有する混合溶媒（６４．７：３２．３：３）６０ｍＬに加えた。反応混合物を１時間還流した後、室温に冷却した。生成された沈殿物を減圧濾過し、ｔ−ブタノール、酢酸メチルと水とを含有する混合溶媒（６４．７：３２．３：３）４．０ｍＬで洗浄した。生成されたウェットケーキを減圧乾燥し、レボフロキサシン半水和物１．７２ｇを製造した（収率：８６％）。
Purification with a mixed solvent containing t-butanol, methyl acetate and water 2.0 g of the crude levofloxacin produced in Example 1 was mixed with a mixed solvent containing t-butanol, methyl acetate and water (64.7: 32.3). : 3) Added to 60 mL. The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The produced precipitate was filtered under reduced pressure, and washed with 4.0 mL of a mixed solvent (64.7: 32.3: 3) containing t-butanol, methyl acetate and water. The produced wet cake was dried under reduced pressure to produce 1.72 g of levofloxacin hemihydrate (yield: 86%).
ｔ−ブタノール、酢酸メチルおよび水を含有する混合溶媒で精製
実施例１で製造した粗レボフロキサシン２．０ｇを、ｔ−ブタノール、酢酸メチルと水とを含有する混合溶媒（４８．５：４８．５：３）７０ｍＬに加えた。反応混合物を１時間還流した後、室温に冷却した。生成された沈殿物を減圧濾過し、ｔ−ブタノール、酢酸メチルと水とを含有する混合溶媒（４８．５：４８．５：３）４．０ｍＬで洗浄した。生成されたウェットケーキを減圧乾燥し、レボフロキサシン半水和物１．６９ｇを製造した（収率：８４．５％）。
Purification with a mixed solvent containing t-butanol, methyl acetate and water 2.0 g of the crude levofloxacin produced in Example 1 was mixed with a mixed solvent containing t-butanol, methyl acetate and water (48.5: 48.5). : 3) Added to 70 mL. The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The produced precipitate was filtered under reduced pressure, and washed with 4.0 mL of a mixed solvent (48.5: 48.5: 3) containing t-butanol, methyl acetate and water. The produced wet cake was dried under reduced pressure to produce 1.69 g of levofloxacin hemihydrate (yield: 84.5%).
ｔ−ブタノール、酢酸メチルおよび水を含有する混合溶媒で精製
実施例１で製造した粗レボフロキサシン２．０ｇを、ｔ−ブタノール、酢酸メチルと水とを含有する混合溶媒（３２．３：６４．７：３）７０ｍＬに加えた。反応混合物を１時間還流した後、室温に冷却した。生成された沈殿物を減圧濾過し、ｔ−ブタノール、酢酸メチルと水とを含有する混合溶媒（３２．３：６４．７：３）４．０ｍＬで洗浄した。生成されたウェットケーキを減圧乾燥し、レボフロキサシン半水和物１．５９ｇを製造した（収率：７９．５％）。
Purification with a mixed solvent containing t-butanol, methyl acetate and water 2.0 g of the crude levofloxacin prepared in Example 1 was mixed with a mixed solvent containing t-butanol, methyl acetate and water (32.3: 64.7). : 3) Added to 70 mL. The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The produced precipitate was filtered under reduced pressure, and washed with 4.0 mL of a mixed solvent (32.3: 64.7: 3) containing t-butanol, methyl acetate and water. The produced wet cake was dried under reduced pressure to produce 1.59 g of levofloxacin hemihydrate (yield: 79.5%).
実施例１〜１３で製造したレボフロキサシン半水和物または一水和物をＨＰＬＣで分析
し、デカルボキシ-レボフロキサシン（不純物Ｂ）、デスフルオロ−レボフロキサシン（
不純物Ｃ）、アンチ−レボフロキサシン（不純物Ｄ）、デスメチル−レボフロキサシン（不純物Ｅ）、Ｎ−オキシドレボフロキサシン（不純物Ｆ）の不純物を測定した。ＨＰＬＣ分析結果を次表１に要約した。
The levofloxacin hemihydrate or monohydrate produced in Examples 1-13 was analyzed by HPLC and decarboxy-levofloxacin (impurity B), desfluoro-levofloxacin (
Impurities C), anti-levofloxacin (impurity D), desmethyl-levofloxacin (impurity E), and N-oxide levofloxacin (impurity F) were measured. The HPLC analysis results are summarized in Table 1 below.
前記に示したように、本発明の製造方法により、前述の不純物Ｂ、不純物Ｃ、不純物Ｄ、不純物Ｅおよび不純物Ｆといった不純物のないレボフロキサシン半水和物または一水和物を９９．８％以上の高純度に製造できる。 As described above, by the production method of the present invention, 99.8% or more of levofloxacin hemihydrate or monohydrate free of impurities such as impurity B, impurity C, impurity D, impurity E, and impurity F described above is contained. Can be produced with high purity.
Claims (4)
前記粗レボフロキサシンを前記混合溶媒ＡまたはＢに加えて得られた混合物を還流して溶液を形成する段階と、
前記溶液からレボフロキサシン半水和物または一水和物を回収する段階と
を含む、レボフロキサシン半水和物または一水和物の製造方法。 A mixed solvent A containing an organic solvent selected from the group consisting of methyl acetate, ethyl acetate and isobutyl methyl ketone and water, or selected from the group consisting of t-butanol, isopropyl acetate, methyl acetate, ethyl acetate and isobutyl methyl ketone Adding crude levofloxacin to mixed solvent B containing the two kinds of organic solvents and water,
Adding the crude levofloxacin to the mixed solvent A or B to reflux the resulting mixture to form a solution;
Recovering levofloxacin hemihydrate or monohydrate from the solution.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020040056637A KR100704641B1 (en) | 2004-07-21 | 2004-07-21 | Methods for the preparation of levofloxacin having a high purity |
| KR10-2004-0056637 | 2004-07-21 | ||
| PCT/KR2005/002294 WO2006009374A1 (en) | 2004-07-21 | 2005-07-18 | Process for preparing levofloxacin or its hydrate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2008507507A true JP2008507507A (en) | 2008-03-13 |
| JP5065020B2 JP5065020B2 (en) | 2012-10-31 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2007522417A Expired - Fee Related JP5065020B2 (en) | 2004-07-21 | 2005-07-18 | Process for producing levofloxacin or a hydrate thereof |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP5065020B2 (en) |
| KR (1) | KR100704641B1 (en) |
| CA (1) | CA2573129C (en) |
| WO (1) | WO2006009374A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT1451194E (en) | 2001-10-03 | 2007-01-31 | Teva Pharma | Preparation of levofloxacin hemihydrate |
| 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 |
| CN111855840A (en) * | 2020-06-30 | 2020-10-30 | 辰欣药业股份有限公司 | Method for detecting related substances in levofloxacin hydrochloride injection |
| CN116953096A (en) * | 2022-12-24 | 2023-10-27 | 华夏生生药业(北京)有限公司 | Method for detecting impurities in levofloxacin injection |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4777253A (en) * | 1986-04-25 | 1988-10-11 | Abbott Laboratories | Process for preparation of racemate and optically active ofloxacin and related derivatives |
| JPH04234890A (en) * | 1990-03-01 | 1992-08-24 | Dai Ichi Seiyaku Co Ltd | Selective production of hydrate |
| WO2003045329A2 (en) * | 2001-11-29 | 2003-06-05 | Teva Pharmaceutical Industries Ltd. | Methods for the purification of levofloxacin |
| JP2004099494A (en) * | 2002-09-09 | 2004-04-02 | Shiono Chemical Co Ltd | Method for producing optically active tricyclic compound |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW208013B (en) * | 1990-03-01 | 1993-06-21 | Daiichi Co Ltd | |
| KR100309871B1 (en) * | 1999-02-24 | 2001-10-29 | 윤종용 | Process for Preparing (-)Pyridobenzoxazine Carboxylic Acid Derivatives |
| WO2004055025A1 (en) * | 2002-12-16 | 2004-07-01 | Ranbaxy Laboratories Limited | Pure levofloxacin hemihydrate and processes for preparation thereof |
-
2004
- 2004-07-21 KR KR1020040056637A patent/KR100704641B1/en active IP Right Grant
-
2005
- 2005-07-18 JP JP2007522417A patent/JP5065020B2/en not_active Expired - Fee Related
- 2005-07-18 WO PCT/KR2005/002294 patent/WO2006009374A1/en active Application Filing
- 2005-07-18 CA CA2573129A patent/CA2573129C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4777253A (en) * | 1986-04-25 | 1988-10-11 | Abbott Laboratories | Process for preparation of racemate and optically active ofloxacin and related derivatives |
| JPH04234890A (en) * | 1990-03-01 | 1992-08-24 | Dai Ichi Seiyaku Co Ltd | Selective production of hydrate |
| WO2003045329A2 (en) * | 2001-11-29 | 2003-06-05 | Teva Pharmaceutical Industries Ltd. | Methods for the purification of levofloxacin |
| JP2004099494A (en) * | 2002-09-09 | 2004-04-02 | Shiono Chemical Co Ltd | Method for producing optically active tricyclic compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2573129C (en) | 2012-10-16 |
| JP5065020B2 (en) | 2012-10-31 |
| KR20060009155A (en) | 2006-01-31 |
| WO2006009374A1 (en) | 2006-01-26 |
| CA2573129A1 (en) | 2006-01-26 |
| KR100704641B1 (en) | 2007-04-06 |
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