WO2006009374A1 - Process for preparing levofloxacin or its hydrate - Google Patents
Process for preparing levofloxacin or its hydrate Download PDFInfo
- Publication number
- WO2006009374A1 WO2006009374A1 PCT/KR2005/002294 KR2005002294W WO2006009374A1 WO 2006009374 A1 WO2006009374 A1 WO 2006009374A1 KR 2005002294 W KR2005002294 W KR 2005002294W WO 2006009374 A1 WO2006009374 A1 WO 2006009374A1
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- WO
- WIPO (PCT)
- Prior art keywords
- levofloxacin
- mixed solvent
- water
- ethyl acetate
- butanol
- Prior art date
Links
- 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 43
- 238000004519 manufacturing process Methods 0.000 title description 4
- 239000012046 mixed solvent Substances 0.000 claims abstract description 56
- 238000000034 method Methods 0.000 claims abstract description 28
- 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 23
- 150000004682 monohydrates Chemical class 0.000 claims abstract description 17
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 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 26
- 239000002244 precipitate Substances 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 238000000746 purification Methods 0.000 description 13
- 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
- -1 e.g. Substances 0.000 description 5
- 229960001699 ofloxacin Drugs 0.000 description 5
- 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
- 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 3
- 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 3
- 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
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 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 2
- 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
- 239000002798 polar solvent Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 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
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- JWEQRJSCTFBRSI-PCLIKHOPSA-N rboxylate Chemical compound COC(=O)C1C(N2C3=O)C4=CC=CC=C4OC1(C)N=C2S\C3=C\C(C=1)=CC=C(OC)C=1COC1=CC=CC=C1C JWEQRJSCTFBRSI-PCLIKHOPSA-N 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
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance 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
- 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
Definitions
- the present invention relates to a process of preparing high purity levofloxacin or its hydrate, e.g., hemihydrate or monohydrate.
- Levofloxacin may be used in its hydrate forms, such as a hemihydrate form or a monohydrate form.
- Known methods of preparing levofloxacin are disclosed in US Patent Nos. 5,053,407, 4,777,253, 4,382,892, 5,237,060 and 6,316,618.
- US Patent No. 5,545,737 discloses a process of selectively producing levofloxacin hemihydrate or monohydrate by controlling the water content of an aqueous solvent in which levofloxacin is dissolved during crystallization.
- one disadvantage of the process disclosed in US Patent No. 5,545,737 is an unsatisfactory yield. For example, a 45 - 65 % yield is typical.
- the above methods have a disadvantage in that it is difficult to remove impurities, such as decarboxy-levofloxacin (Impurity B), desfluoro-levofloxacin (Impurity C), anti-levofloxacin (Impurity D), desmethyl-levofloxacin (Impurity E), and N-oxide levofloxacin (Impurity F), which may be produced during the process for preparing levofloxacin.
- impurities such as decarboxy-levofloxacin (Impurity B), desfluoro-levofloxacin (Impurity C), anti-levofloxacin (Impurity D), desmethyl-levofloxacin (Impurity E), and N-oxide levofloxacin (Impurity F)
- US Publication Nos. 2003/0130507 and 2003/0144511 disclose processes for purifying crude levofloxacin by using a polar solvent such as n- butanol or acetonitrile; or a mixed solvent containing water and a polar solvent, such as n-butanol & water, dimethyl sulfoxide & water, and acetonitrile & water.
- a polar solvent such as n- butanol or acetonitrile
- a mixed solvent containing water and a polar solvent such as n-butanol & water, dimethyl sulfoxide & water, and acetonitrile & water.
- 2003/0130507 and 2003/0144511 require the adding of an antioxidant, such as ascorbic acid or sodium metabisulfite, in order to prevent the formation of N-oxide levofloxacin (Impurity F), which is a drawback since the antioxidant remains as an impurity in the final product, i.e., levofloxacin or its hydrate. Further, the processes have another problem in that desmethyl-levofloxacin (Impurity E) cannot be completely removed, thus remaining in the final product.
- an antioxidant such as ascorbic acid or sodium metabisulfite
- the present invention provides a process of preparing high purity levofloxacin hemihydrate or monohydrate without using additional agents, e.g., antioxidants.
- the present invention employs a novel mixed solvent system, which is allowed to completely remove any known impurities, i.e. Impurities B, C, D, E, and F.
- a process of preparing levofloxacin hemihydrate or monohydrate comprising: (a) adding crude levofloxacin to a mixed solvent (A) containing water and an organic solvent selected from the group consisting of methyl acetate, ethyl acetate, and isobutyl methyl ketone or a mixed solvent (B) containing water and two organic solvents selected from the group consisting of t-butanol, isopropyl acetate, methyl acetate, ethyl acetate, and isobutyl methyl ketone, (b) refluxing the mixture obtained in the adding the crude levofloxacin to the mixed solvent (A) or (B) to form a solution, and (c) recovering levofloxacin hemihydrate or monohydrate from the solution.
- a process of preparing levofloxacin hemihydrate or monohydrate without impurities includes purifying crude levofloxacin through re-crystallization using a novel mixed solvent.
- crude levofloxacin refers to levofloxacin before purification and may be prepared by known methods in the art, e.g., processes as disclosed in US Patent 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).
- the process of preparing levofloxacin hemihydrate or monohydrate includes (a) adding crude levofloxacin to a mixed solvent, (b) refluxing the mixture obtained in the step (a) to form a solution, and (c) recovering levofloxacin hemihydrate or monohydrate from the solution obtained in the step (b).
- the mixed solvent may be a two- or three- component system.
- a mixed solvent (A) of a two-component system includes water and an organic solvent selected from the group consisting of methyl acetate, ethyl acetate, and isobutyl methyl ketone.
- a mixed solvent (B) of a three-component system includes water and two organic solvents selected from the group consisting of t-butanol, isopropyl acetate, methyl acetate, ethyl acetate, and isobutyl methyl ketone.
- the water content in the mixed solvent (A) or (B) may be about 1.5 ⁇ 6.0 % (v/v), for example, about 3.0 % (v/v). If the amount of water in a mixed solvent is greater than 6.0 % (v/v), the yield may be decreased.
- a mixture of t-butanol, ethyl acetate, and water may be used.
- the volume ratio of t-butanol, ethyl acetate and water in the mixture may be 32.3 : 64.7 : 3.
- the refluxing may be performed using a conventional method, e.g., at about 50 0 C ⁇
- the recovering of levofloxacin hemihydrate or monohydrate may be performed using a conventional crystallization method, e.g., cooling, filtering under reduced pressure, and/or distilling under reduced pressure.
- the hydrate forms of levofloxacin may be controlled by the mixed solvent used or the water content.
- the preferable hydrate form of levofloxacin is levofloxacin hemihydrate.
- Example 5 Purification with mixed solvent containing ethyl acetate, methyl acetate, and water
- Example 6 Purification with mixed solvent containing ethyl acetate, methyl acetate, and water [34] 2.0 g of the crude levofloxacin prepared in Example 1 was added to 90 ml of a mixed solvent containing ethyl acetate, methyl acetate, and water (48.5 : 48.5 : 3). The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The resulting precipitate was filtered under reduced pressure and then washed with 4.0 ml of the mixed solvent containing ethyl acetate, methyl acetate, and water (48.5 : 48.5 : 3). The resulting wet cake was dried under reduced pressure to provide 1.7 g of lev ⁇ ofloxacin monohydrate (yield: 85 %).
- Example 7 Purification with mixed solvent containing ethyl acetate, methyl acetate, and water
- Example 8 Purification with mixed solvent containing t-butanol, ethyl acetate, and water
- Example 9 Purification with mixed solvent containing t-butanol, ethyl acetate, and water
- Example 10 Purification with mixed solvent containing t-butanol, ethyl acetate, and water
- Example 11 Purification with mixed solvent containing t-butanol, methyl acetate, and water
- Example 12 Purification with mixed solvent containing t-butanol, methyl acetate, and water
- Example 13 Purification with mixed solvent containing t-butanol, methyl acetate, and water
- levofloxacin hemihydrate or monohydrate prepared in Examples 1 - 13 were analyzed by HPLC to determine the concentration of impurities, i.e., decarboxy-lev- ofloxacin (Impurity B), desfluoro-levofloxacin (Impurity C), anti-levofloxacin (Impurity D), desmethyl-levofloxacin (Impurity E) and N-oxide levofloxacin (Impurity F).
- impurities i.e., decarboxy-lev- ofloxacin (Impurity B), desfluoro-levofloxacin (Impurity C), anti-levofloxacin (Impurity D), desmethyl-levofloxacin (Impurity E) and N-oxide levofloxacin (Impurity F).
- impurities i.e., decarboxy-lev- ofloxacin (Impurity B), desfluoro-levofloxaci
- levofloxacin hemihydrate or monohydrate may be obtained with high purity ( > 99.8%), without impurities, such as Impurities B, C, D, E, and F.
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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
The present invention provides a process of preparing levofloxacin hemihydrate or monohydrate without impurities, i.e. Impurities B, C, D, E, and F. The process comprises (a) adding crude levofloxacin to a novel mixed solvent, (b) refluxing the mixture obtained in (a) to form a solution, and (c) recovering levofloxacin hemihydrate or monohydrate from the solution obtained in (b).
Description
Description PROCESS FOR PREPARING LEVOFLOXACIN OR ITS
HYDRATE
Technical Field
[1] The present invention relates to a process of preparing high purity levofloxacin or its hydrate, e.g., hemihydrate or monohydrate.
Background Art [2] Levofloxacin, whose chemical name is
(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-l-piperazinyl)-7-oxo-7H-pyrido[l,2,3
-de]-l,4-benzoxazine-6-carboxylic acid, is known as a useful anti-bacterial agent, and is represented by the following formula (I).
[3] Levofloxacin may be used in its hydrate forms, such as a hemihydrate form or a monohydrate form. Known methods of preparing levofloxacin are disclosed in US Patent Nos. 5,053,407, 4,777,253, 4,382,892, 5,237,060 and 6,316,618.
[4] In these methods, column chromatography is performed in order to obtain a purified levofloxacin or one of its hydrates from synthesized crude levofloxacin, which makes it difficult to apply the methods to industrial-scale mass production.
[5] US Patent No. 5,545,737 discloses a process of selectively producing levofloxacin hemihydrate or monohydrate by controlling the water content of an aqueous solvent in which levofloxacin is dissolved during crystallization. However, one disadvantage of the process disclosed in US Patent No. 5,545,737 is an unsatisfactory yield. For example, a 45 - 65 % yield is typical.
[6] In addition, the above methods have a disadvantage in that it is difficult to remove impurities, such as decarboxy-levofloxacin (Impurity B), desfluoro-levofloxacin (Impurity C), anti-levofloxacin (Impurity D), desmethyl-levofloxacin (Impurity E), and N-oxide levofloxacin (Impurity F), which may be produced during the process for preparing levofloxacin.
[7] To solve these problems , US Publication Nos. 2003/0130507 and 2003/0144511 disclose processes for purifying crude levofloxacin by using a polar solvent such as n- butanol or acetonitrile; or a mixed solvent containing water and a polar solvent, such as
n-butanol & water, dimethyl sulfoxide & water, and acetonitrile & water. However, the processes disclosed in US Publication Nos. 2003/0130507 and 2003/0144511 require the adding of an antioxidant, such as ascorbic acid or sodium metabisulfite, in order to prevent the formation of N-oxide levofloxacin (Impurity F), which is a drawback since the antioxidant remains as an impurity in the final product, i.e., levofloxacin or its hydrate. Further, the processes have another problem in that desmethyl-levofloxacin (Impurity E) cannot be completely removed, thus remaining in the final product.
[8] Thus, there is a need for a novel process of purifying levofloxacin to completely remove known impurities, such as Impurities B, C, D, E, and F. Disclosure of Invention
Technical Problem
[9] The present invention provides a process of preparing high purity levofloxacin hemihydrate or monohydrate without using additional agents, e.g., antioxidants. The present invention employs a novel mixed solvent system, which is allowed to completely remove any known impurities, i.e. Impurities B, C, D, E, and F.
Technical Solution
[10] According to an aspect of the present invention, there is provided a process of preparing levofloxacin hemihydrate or monohydrate, the process comprising: (a) adding crude levofloxacin to a mixed solvent (A) containing water and an organic solvent selected from the group consisting of methyl acetate, ethyl acetate, and isobutyl methyl ketone or a mixed solvent (B) containing water and two organic solvents selected from the group consisting of t-butanol, isopropyl acetate, methyl acetate, ethyl acetate, and isobutyl methyl ketone, (b) refluxing the mixture obtained in the adding the crude levofloxacin to the mixed solvent (A) or (B) to form a solution, and (c) recovering levofloxacin hemihydrate or monohydrate from the solution.
Best Mode
[11] A process of preparing levofloxacin hemihydrate or monohydrate without impurities according to an embodiment of the present invention includes purifying crude levofloxacin through re-crystallization using a novel mixed solvent.
[12] As used herein, "crude levofloxacin" refers to levofloxacin before purification and may be prepared by known methods in the art, e.g., processes as disclosed in US Patent 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).
[13] The process of preparing levofloxacin hemihydrate or monohydrate includes (a) adding crude levofloxacin to a mixed solvent, (b) refluxing the mixture obtained in the step (a) to form a solution, and (c) recovering levofloxacin hemihydrate or
monohydrate from the solution obtained in the step (b).
[14] In the step (a), the mixed solvent may be a two- or three- component system. A mixed solvent (A) of a two-component system includes water and an organic solvent selected from the group consisting of methyl acetate, ethyl acetate, and isobutyl methyl ketone. Further, a mixed solvent (B) of a three-component system includes water and two organic solvents selected from the group consisting of t-butanol, isopropyl acetate, methyl acetate, ethyl acetate, and isobutyl methyl ketone.
[15] The water content in the mixed solvent (A) or (B) may be about 1.5 ~ 6.0 % (v/v), for example, about 3.0 % (v/v). If the amount of water in a mixed solvent is greater than 6.0 % (v/v), the yield may be decreased.
[16] Among the mixed solvents, a mixture of t-butanol, ethyl acetate, and water may be used. The volume ratio of t-butanol, ethyl acetate and water in the mixture may be 32.3 : 64.7 : 3.
[17] The refluxing may be performed using a conventional method, e.g., at about 500C ~
115°C, to produce solution of levofloxacin. Further, the recovering of levofloxacin hemihydrate or monohydrate may be performed using a conventional crystallization method, e.g., cooling, filtering under reduced pressure, and/or distilling under reduced pressure.
[18] When the process of the present embodiment is performed, high purity ( > 99.8%) levofloxacin hemihydrate or monohydrate may be obtained. As confirmed in the following Examples, all known impurities, i.e., Impurities B, C, D, E, F, are completely removed by the process of the present embodiment.
[19] The hydrate forms of levofloxacin may be controlled by the mixed solvent used or the water content. The preferable hydrate form of levofloxacin is levofloxacin hemihydrate.
[20] The present invention will now be further illustrated and described by the following examples, which are not intended to limit the scope of the invention.
[21] Example 1. Preparation of crude levofloxacin
[22] 5.1 g (11.42 mmol) of (-) potassium N-
(l-hydroxy-propy-2(S)-yl)-6-fluoro-7-(N-methylpiperazinyl)-8-nitro-4-quinolone-3-ca rboxylate was dissolved in 34 ml of methanol. 1.07 g of potassium hydroxide was added to the solution, which was then refluxed for 2.5 hours. The resulting reaction mixture was evaporated under reduced pressure to remove the solvent. 5.7 ml of 3 M acetic acid solution was added to the reaction mixture to produce a pale yellow precipitate. 10 mL of tetrahydrofuran (THF) was added to the obtained precipitate while stirring. The resultant solid was filtered, washed with water/THF (1/1, v/v), and dried to produce 3.0 g of crude levofloxacin.
[23] M. P. 226.5 0C ~ 227.2 0C
[24] 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, IH, J=I 1.2Hz & 2Hz), 4.51-4.54 (dd, IH, J=I 1.6Hz & 2Hz), 4.63 (m, IHz), 7.46 (d, IH, J= 12.8Hz), 8.38 (s, IHz)
[25] Example 2. Purification with mixed solvent containing methyl acetate and water
[26] 1.18 g of the crude levofloxacin prepared in Example 1 was added to 59 ml of a mixed solvent containing methyl acetate and water (97 : 3). The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The resulting precipitate was filtered under reduced pressure and then washed with 2.4 ml of the mixed solvent containing methyl acetate and water (97 : 3). The resulting wet cake was dried under reduced pressure to provide 1.01 g of levofloxacin hemihydrate (yield: 85.6 %).
[27] Example 3. Purification with mixed solvent containing isobutyl methyl ketone and water
[28] 1.15 g of the crude levofloxacin prepared in Example 1 was added to 35.7 ml of a mixed solvent containing isobutyl methyl ketone and water (98.5 : 1.5). The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The resulting precipitate was filtered under reduced pressure and then washed with 2.3 ml of the mixed solvent containing isobutyl methyl ketone and water (98.5 : 1.5). The resulting wet cake was dried under reduced pressure to provide 1.03 g of levofloxacin hemihydrate (yield: 89.6 %).
[29] Example 4. Purification with mixed solvent containing ethyl acetate and water
[30] 2.0 g of the crude levofloxacin prepared in Example 1 was added to 80 ml of a mixed solvent containing ethyl acetate and water (97 : 3). The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The resulting precipitate was filtered under reduced pressure and then washed with 4 ml of the mixed solvent containing ethyl acetate and water (97 : 3). The resulting wet cake was dried under reduced pressure to provide 1.8 g of levofloxacin hemihydrate (yield: 90 %).
[31] Example 5. Purification with mixed solvent containing ethyl acetate, methyl acetate, and water
[32] 2.0 g of the crude levofloxacin prepared in Example 1 was added to 90 ml of a mixed solvent containing ethyl acetate, methyl acetate, and water (19.4 : 77.6 : 3). The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The resulting precipitate was filtered under reduced pressure and then washed with 4.0 ml of the mixed solvent containing ethyl acetate, methyl acetate, and water (19.4 : 77.6 : 3). The resulting wet cake was dried under reduced pressure to provide 1.75 g of lev¬ ofloxacin monohydrate (yield: 87.5 %).
[33] Example 6. Purification with mixed solvent containing ethyl acetate, methyl acetate, and water
[34] 2.0 g of the crude levofloxacin prepared in Example 1 was added to 90 ml of a mixed solvent containing ethyl acetate, methyl acetate, and water (48.5 : 48.5 : 3). The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The resulting precipitate was filtered under reduced pressure and then washed with 4.0 ml of the mixed solvent containing ethyl acetate, methyl acetate, and water (48.5 : 48.5 : 3). The resulting wet cake was dried under reduced pressure to provide 1.7 g of lev¬ ofloxacin monohydrate (yield: 85 %).
[35] Example 7. Purification with mixed solvent containing ethyl acetate, methyl acetate, and water
[36] 1.5 g of the crude levofloxacin prepared in Example 1 was added to 75 ml of a mixed solvent containing ethyl acetate, methyl acetate, and water (77.6 : 19.4 : 3). The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The resulting precipitate was filtered under reduced pressure and then washed with 3.0 ml of the mixed solvent containing ethyl acetate, methyl acetate, and water (77.6 : 19.4 : 3). The resulting wet cake was dried under reduced pressure to provide 1.25 g of lev¬ ofloxacin monohydrate (yield: 83.3 %).
[37] Example 8. Purification with mixed solvent containing t-butanol, ethyl acetate, and water
[38] 2.0 g of the crude levofloxacin prepared in Example 1 was added to 54 ml of a mixed solvent containing t-butanol, ethyl acetate, and water (64.7 : 32.3 : 3). The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The resulting precipitate was filtered under reduced pressure and then washed with 4.0 ml of the mixed solvent containing t-butanol, ethyl acetate, and water (64.7 : 32.3 : 3). The resulting wet cake was dried under reduced pressure to provide 1.69 g of levofloxacin hemihydrate (yield: 84.5 %).
[39] Example 9. Purification with mixed solvent containing t-butanol, ethyl acetate, and water
[40] 2.0 g of the crude levofloxacin prepared in Example 1 was added to 54 ml of a mixed solvent containing t-butanol, ethyl acetate, and water (48.5 : 48.5 : 3). The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The resulting precipitate was filtered under reduced pressure and then washed with 4.0 ml of the mixed solvent containing t-butanol, ethyl acetate, and water (48.5 : 48.5 : 3). The resulting wet cake was dried under reduced pressure to provide 1.72 g of levofloxacin hemihydrate (yield: 86 %).
[41] Example 10. Purification with mixed solvent containing t-butanol, ethyl acetate, and water
[42] 2.0 g of the crude levofloxacin prepared in Example 1 was added to 64 ml of a mixed solvent containing t-butanol, ethyl acetate, water (32.3 : 64.7 : 3). The reaction
mixture was refluxed for 1 hour and then cooled to room temperature. The resulting precipitate was filtered under reduced pressure and then washed with 4.0 ml of the mixed solvent containing t-butanol, ethyl acetate, and water (32.3 : 64.7 : 3). The resulting wet cake was dried under reduced pressure to provide 1.75 g of levofloxacin hemihydrate (yield: 87.5 %).
[43] Example 11. Purification with mixed solvent containing t-butanol, methyl acetate, and water
[44] 2.0 g of the crude levofloxacin prepared in Example 1 was added to 60 ml of a mixed solvent containing t-butanol, methyl acetate, and water (64.7 : 32.3 : 3). The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The resulting precipitate was filtered under reduced pressure and then washed with 4.0 ml of the mixed solvent containing t-butanol, methyl acetate, and water (64.7 : 32.3 : 3). The resulting wet cake was dried under reduced pressure to provide 1.72 g of lev¬ ofloxacin hemihydrate (yield: 86 %).
[45] Example 12. Purification with mixed solvent containing t-butanol, methyl acetate, and water
[46] 2.0 g of the crude levofloxacin prepared in Example 1 was added to 70 ml of a mixed solvent containing t-butanol, methyl acetate, and water (48.5 : 48.5 : 3). The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The r esulting precipitate was filtered under reduced pressure and then washed with 4.0 ml of the mixed solvent containing t-butanol, methyl acetate, and water (48.5 : 48.5 : 3). The resulting wet cake was dried under reduced pressure to provide 1.69 g of levofloxacin hemihydrate (yield: 84.5%).
[47] Example 13. Purification with mixed solvent containing t-butanol, methyl acetate, and water
[48] 2.0 g of the crude levofloxacin prepared in Example 1 was added to 70 ml of a mixed solvent containing t-butanol, methyl acetate, and water (32.3 : 64.7 : 3). The reaction mixture was refluxed for 1 hour and cooled to room temperature. The resulting precipitate was filtered under reduced pressure and then washed with 4.0 ml of the mixed solvent containing t-butanol, methyl acetate, and water (32.3 : 64.7 : 3). The resulting wet cake was dried under reduced pressure to provide 1.59 g of lev¬ ofloxacin hemihydrate (yield: 79.5 %).
[49] Test Example 1.
[50] The levofloxacin hemihydrate or monohydrate prepared in Examples 1 - 13 were analyzed by HPLC to determine the concentration of impurities, i.e., decarboxy-lev- ofloxacin (Impurity B), desfluoro-levofloxacin (Impurity C), anti-levofloxacin (Impurity D), desmethyl-levofloxacin (Impurity E) and N-oxide levofloxacin (Impurity F). The results of the HPLC analysis are summarized in the following Table 1.
[51] Table 1.
[52] - : not detected [53] As shown above, according to the process of the present invention, levofloxacin hemihydrate or monohydrate may be obtained with high purity ( > 99.8%), without impurities, such as Impurities B, C, D, E, and F.
Claims
[1] A process of preparing levofloxacin hemihydrate or monohydrate, the process comprising: adding crude levofloxacin to a mixed solvent (A) containing water and an organic solvent selected from the group consisting of methyl acetate, ethyl acetate, and isobutyl methyl ketone; or a mixed solvent (B) containing water and two organic solvents selected from the group consisting of t-butanol, isopropyl acetate, methyl acetate, ethyl acetate, and isobutyl methyl ketone, refluxing the mixture obtained in the adding the crude levofloxacin to the mixed solvent (A) or (B) to form a solution, and recovering levofloxacin hemihydrate or monohydrate from the solution.
[2] The process of claim 1, wherein the water content in the mixed solvent (A) or
(B) is about 1.5 ~ 6.0 % (v/v).
[3] The process of claims 1 or 2, wherein the mixed solvent (B) contains t-butanol, ethyl acetate, and water.
[4] The process of claim 3, wherein the volume ratio of t-butanol, ethyl acetate and water is 32.3 : 64.7 : 3.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2573129A CA2573129C (en) | 2004-07-21 | 2005-07-18 | Process for preparing levofloxacin or its hydrate |
| JP2007522417A JP5065020B2 (en) | 2004-07-21 | 2005-07-18 | Process for producing levofloxacin or a hydrate thereof |
Applications Claiming Priority (2)
| 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2006009374A1 true WO2006009374A1 (en) | 2006-01-26 |
Family
ID=35785447
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2005/002294 WO2006009374A1 (en) | 2004-07-21 | 2005-07-18 | Process for preparing levofloxacin or its hydrate |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP5065020B2 (en) |
| KR (1) | KR100704641B1 (en) |
| CA (1) | CA2573129C (en) |
| WO (1) | WO2006009374A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7629458B2 (en) | 2001-10-03 | 2009-12-08 | Teva Pharmaceutical Industries Ltd. | Preparation of levofloxacin and hemihydrate thereof |
| 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 |
|---|---|---|---|---|
| US5545737A (en) * | 1990-03-01 | 1996-08-13 | Daiichi Pharmaceutical Co., Ltd. | Process for selectively producing an (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 or monohydrate |
| US6316618B1 (en) * | 1998-02-24 | 2001-11-13 | Samsung Electronics Co., Ltd. | Process for preparing (-)pyridobenzoxazine carboxylic acid derivatives |
| WO2003045329A2 (en) * | 2001-11-29 | 2003-06-05 | Teva Pharmaceutical Industries Ltd. | Methods for the purification of levofloxacin |
| WO2004055025A1 (en) * | 2002-12-16 | 2004-07-01 | Ranbaxy Laboratories Limited | Pure levofloxacin hemihydrate and processes for preparation thereof |
Family Cites Families (3)
| 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 |
| JP3105572B2 (en) * | 1990-03-01 | 2000-11-06 | 第一製薬株式会社 | Selective production of hydrate |
| JP2004099494A (en) * | 2002-09-09 | 2004-04-02 | Shiono Chemical Co Ltd | Method for producing optically active tricyclic compound |
-
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 CA CA2573129A patent/CA2573129C/en not_active Expired - Fee Related
- 2005-07-18 WO PCT/KR2005/002294 patent/WO2006009374A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5545737A (en) * | 1990-03-01 | 1996-08-13 | Daiichi Pharmaceutical Co., Ltd. | Process for selectively producing an (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 or monohydrate |
| US6316618B1 (en) * | 1998-02-24 | 2001-11-13 | Samsung Electronics Co., Ltd. | Process for preparing (-)pyridobenzoxazine carboxylic acid derivatives |
| WO2003045329A2 (en) * | 2001-11-29 | 2003-06-05 | Teva Pharmaceutical Industries Ltd. | Methods for the purification of levofloxacin |
| WO2004055025A1 (en) * | 2002-12-16 | 2004-07-01 | Ranbaxy Laboratories Limited | Pure levofloxacin hemihydrate and processes for preparation thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7629458B2 (en) | 2001-10-03 | 2009-12-08 | Teva Pharmaceutical Industries Ltd. | Preparation of levofloxacin and hemihydrate thereof |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2573129A1 (en) | 2006-01-26 |
| JP2008507507A (en) | 2008-03-13 |
| KR20060009155A (en) | 2006-01-31 |
| KR100704641B1 (en) | 2007-04-06 |
| JP5065020B2 (en) | 2012-10-31 |
| CA2573129C (en) | 2012-10-16 |
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