MXPA04005196A - Methods for the purification of levofloxacin. - Google Patents
Methods for the purification of levofloxacin.Info
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- 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
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- 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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Abstract
Levofloxacin has been purified by dissolving levofloxacin in a polar solvent at an elevated temperature and crystallizing purified levofloxacin. Preferably, an antioxidant is added to increase the purity.
Description
METHODS FOR THE PURIFICATION OF LEVOFLOXACIN
FIELD OF THE INVENTION
The present invention relates to methods for purifying levofloxacin. In a preferred embodiment, levofloxacin is prepared with antioxidants.
BACKGROUND OF THE INVENTION
Levofloxacin is a broad-spectrum synthetic antibiotic. Levofloxacin is the S-enantiomer of the racemate, ofloxacin, a fluoroquinolone antimicrobial agent. The antimicrobial activity of ofloxacin lies mainly in the S enantiomer. The mechanism of action of levofloxacin and other fluoroquinolone antimicrobials consists of the inhibition of DNA gyrase (bacterial topoisomerase II), an enzyme required for replication, transcription repair and recombination of the DNA Levofloxacin is available as LE AQUIN® that can be administered orally or intravenously.
Levofloxacin is a chiral fluorinated carboxyquinolone. Its chemical name is (S) -9-fluoro-2, 3-dihydro-3-methyl-10 (4-methyl-l-piperazinyl) -7-oxo-7H-pyrido [1,2,3-de] -1, 4-benzoxazin-6-
carboxylic hemihydrate (CAS Registry No. 100986-85-4). The chemical structure of levofloxacin is shown as Formula I.
Formula I
U.S. Patent No. 4,382,892 relates to pyrido [1, 2, 3-de] [1,4] benzoxazine derivatives and methods for purifying them.
U.S. Patent No. 5,053,407 relates to optically active pyridobenzoxazine derivatives, to processes for their preparation, and intermediates useful for preparing such derivatives.
U.S. Patent No. 5,051,505 relates to processes for preparing piperazinyl quinolone derivatives. The process comprises reacting dihaloquinolones with piperazine derivatives and tetraalkyl ammonium halides in the presence of a solvent
polar such as acetonitrile, dimethylformamide, pyridine, sulfolone and dimethyl sulfoxide.
U.S. Patent No. 5,155,223 relates to the preparation of quinolinecarboxylic acids.
U.S. Patent No. 5,545,737 discloses the selective production of levofloxacin hemihydrate or monohydrate by controlling the water content of an aqueous solvent in which levofloxacin dissolves during crystallization. Arutia et al, Arzneimittelforschung (October 1998) 48 (10): 1024-7, states that racemic mixture ofloxacin has an antioxidant property.
A disadvantage of prior art methods for purifying levofloxacin is that they often produce an unsatisfactory yield. For example, yields of 45% -65% are typical. There remains a need for novel methods for purifying levofloxacin, particularly purified preparations having reduced impurities, such as anti-levofloxacin, desmethyl levofloxacin, N-oxide levofloxacin, defluoro-levofloxacin and / or decarboxy-levofloxacin.
EXTRACT OF THE INVENTION
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 it crystallizes to form levofloxacin. In one embodiment, the solvent is anhydrous. In another embodiment, an antioxidant is added, which results in a purer levofloxacin product.
DETAILED DESCRIPTION OF THE INVENTION
Crude and semi-crude preparations can be prepared by methods known in the art. Alternatively, levofloxacin 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 to 80 ° C, 87.5 g (0.31 mol) of (S) - (-) - 9, 10-difluoro acid are charged. - 3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1, 2, 3-de] [1,4] benzoxazine-6-carboxylic acid, 61.3 ml of DMSO and 86.3 ml ( 0.77 mol) of N-methylpiperazine. The suspension is stirred at a speed of 250 rpm under a nitrogen atmosphere at 80 ° C until the reaction is complete (monitoring
by HPLC). The suspension is then cooled to 75 ° C and a mixture of isopropanol (675 ml) and water (25 ml) is added dropwise at this temperature for 2 hours. The suspension is then cooled to 5 ° C for 4 hours, kept at this temperature for 2 hours and filtered under vacuum at this temperature. The solid is then washed with 175 ml of isopropanol (2 rinses) and dried under vacuum to obtain crude levofloxacin.
In one embodiment of the present invention, the crude levofloxacin is purified. As used here, "purified levofloxacin" is a relative term that means more pure. As used herein, "crude levofloxacin" refers to levofloxacin that has not gone through a 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 raised to improve the dissolution of the levofloxacin in the solvent. Generally, elevated temperatures are in the range of 80 ° C to 110 ° C. Preferably, the mixture is refluxed. Preferably, once the levofloxacin is dissolved in the solvent, the mixture is filtered while hot. The purified levofloxacin is then precipitated, preferably by slow cooling, and is preferably recovered. The purified levofloxacin
preferably it has a purity of 99% or more, more preferably 99.5% or more.
Polar solvents are generally adequate. Preferably, the solvent is DMSO, methyl ethyl ketone, butanol, acetonitrile, mixtures thereof, or aqueous mixtures thereof. As used herein, the term "polar solvent" is a relative term that means relatively more polar than another solvent.
The solvent may be anhydrous or may contain a small amount of water. The solvent is preferably used to contain water when a water-soluble antioxidant, such as sodium metabisulfite. The amount of water must be less than 20% (v / v) and preferably 10% or less. Larger amounts of water tend to decrease performance. n-BuOH: H20 (9: 1) and acetonitrile: H20 (99: 1) are examples of suitable water-containing solvents. Acetonitrile and acetonitrile: H20 (99: 1) are the most preferred solvents for purifying levofloxacin.
In another embodiment, an antioxidant is added to the mixture before precipitation. The antioxidant can be any that prevents the formation of N-oxide levofloxacin, particularly during crystallization. Examples of it include ascorbic acid, sodium ascorbate, calcium ascorbate, palmitate
ascorbic, butylated hydroxyanisole, butylated hydroxytoluene, 2, 4, 5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, guaiac gum, propyl gallate, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone , tocopherols (such as vitamin E), and pharmacologically acceptable salts and mixtures thereof. Preferably, the antioxidant includes sodium metabisulfite or ascorbic acid.
An antioxidant, if used, can be added at several points in the purification process. For example, in one embodiment, an antioxidant is mixed with levofloxacin before or during the crystallization step or before the dissolution step. In another embodiment, an antioxidant is mixed with (S) - (-) - 9, 10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] acid [1,4] benzoxazin-6-carboxylic acid, a precursor of levofloxacin, before its conversion to levofloxacin at an elevated temperature.
The amount of antioxidant, when present, is preferably 0.2% to 5% by weight, more preferably 0.2% to 1%.
The function and advantages of these and other embodiments of the present invention will be more fully understood from
of the following of the following examples. The following examples are intended to illustrate the benefits of the present invention, but not to exemplify the full scope of the invention.
EXAMPLES
The following table summarizes the results of the experiments described in the following Examples. The percentage of each component of Table 1 was determined by HPLC using a method based on the European Pharmacopoeia method for related substances in Ofloxacin.
Table 1: Purification during Crystallization
Ex. System Profile of Impurities of Purified Crude Oil Solvent Levo Imp.D Imp. E. Imp. F Levo Imp.D Imp. E. Imp. F Anti DesMe N- Anti DesMe Oxide Oxide
1 n-Bu-OH 99, 44 ND 0.119 0.19 99, 60 ND 0.09 0.19
n-BuOH 99, 58 ND 0.11, 0.21 99, 78 ND 0.08 ND Ascorbic acid (2.4%) n-BuOH 99, 58 ND 0, 11 0, 21 99, 85 ND 0.08 ND Na2S205 (0.6%) ACN 99, 44 ND 0, 11 0, 19 99, 67 ND 0, 04 0, 15
ACN: H20 99, 64 0, 08 0, 09 < 0, 03 99, 85 ND 0, 06 < 0, 03
ACN: H20 99, 77 < 0, 03 0, 05 < 0, 03 99, 93 ND < 0.03 ND Na2S205 (0.2%) ACN 99, 58 ND 0.11 0.21 99, 70 ND 0.06 0.1 Na2S205 (0.5%) DMSO: H20 99.44 ND 0.11 0 , 19 99, 75 ND 0, 06 0, 13
MEK 99.44 ND 0, 11 0, 19 99, 58 ND ND 0.26
ACN: H20 99, 58 ND 0, 11 0.21 99, 69 ND 0.08 ND (90: 10) Na2S2Os (0.5%)
11 ACN: H20 99, 58 ND 0, 11 0.21 99, 74 ND 0.06 ND (95: 5) Na2S205 (0.5%) 12 ACN: H20 99, 58 ND 0.111 0.21 99, 81 ND 0, 08 ND (95: 5) Na2S205 (0.2%) 13 DMSO 99, 80 ND 0.03 0.02 Ascorbic acid (0.6%) 14 DMSO 99, 77 0, 04 0, 10 < 0, 03 Na2S205 ND = not detected
Example 1: n-BuOH
1 g of crude levofloxacin was placed 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 room temperature over a period of 2.5 hours. The precipitate was filtered under vacuum, washed with n-BuOH and dried
60 ° C in a vacuum oven to give 810 mg (81%) of purified levofloxacin hemihydrate.
Example 2: n-BuOH / Ascorbic acid
1.5 g of pure levofloxacin and 36 mg of ascorbic acid were suspended in 9.5 ml of n-BuOH under an inert atmosphere. The mixture was heated to reflux temperature and hot filtration was performed. The solution was then evaporated to dryness and n-BuOH (10 mL) was added. The mixture was heated to reflux temperature until completely dissolved and then cooled to room temperature over a period of 1.5 hours. The precipitate was filtered 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: .H20 (9: 1) / Metabisulfite
1.5 g of crude levofloxacin and 10 mg of sodium metabisulfite were suspended in 6 ml of a mixture of n-BuOH: H20 (9: 1) under a nitrogen atmosphere. The mixture was heated to reflux temperature until complete dissolution of the material.
Then the solution was cooled to room temperature for a period of 1.5 hours. The precipitate was filtered under vacuum, washed
with a mixture of n-BuOH: H20 (9: 1) (4 ml) and dried at 60 ° C in a vacuum oven to give 1.2 g (81%) of purified levofloxacin hemihydrate. The purified hemihydrated levofloxacin contained virtually no N-oxide levofloxacin.
Example 4: ACN
1.5 g of crude levofloxacin was placed 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 for a period of 20 minutes. The precipitate was filtered 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 in the crude sample.
Example 5: ACN: H2Q (99: 1)
25 g of crude wet levofloxacin (22.17 g of dry levofloxacin) was placed in suspension in 225 ml of a mixture of ACN: H20 (99: 1) under a nitrogen atmosphere. The mixture was refluxed for 1 hour and then filtered under vacuum with Hyflow.
when it was still hot The solution was then heated again to reflux and cooled to 0 ° C for a period of 1 hour. The precipitate was filtered under vacuum, washed with ACN: H20 (2x12 ml) and dried in a vacuum oven to give 18.6 g (84%) of purified levofloxacin hemihydrate. The purified hemihydrated levofloxacin contained approximately one third less desmethyl levofloxacin than in the crude sample.
Example 6: ACN: H20 (99: 1) / Metabisulfite
8 g of crude wet levofloxacin (5.6 g of dry levofloxacin) and 14 mg of sodium metabisulfite were suspended in 39 ml of a mixture of ACN: H20 (99: 1) under a nitrogen atmosphere. The mixture was refluxed for 1 hour, 0.65 g of Hyflow was added and the reflux continued for another half hour. The mixture was filtered under vacuum while it was still hot. Then the solution was cooled to 3 ° C over a period of 30 minutes. The precipitate was then filtered under vacuum, washed with a mixture of ACN: H20 (99: 1) (5 ml) and dried at 60 ° C in a vacuum oven to give 1.77 g (31%) of levofloxacin. purified. Technical problems that occurred during hot filtration reduced performance.
Example 7: ACN / Metabisulfite
1.5 g of crude levofloxacin and 8 mg of sodium metabisulfite were suspended in 10.5 ml of ACN under a nitrogen atmosphere. The mixture was heated to reflux temperature and hot filtration was performed. Then the solution was heated again to reflux temperature until the material was completely dissolved. The solution was then cooled to 0 ° C over a period of 30 minutes. The precipitate was filtered 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 in the crude sample.
Example 8: DMSO / H20
1 g of crude levofloxacin was suspended in 1.5 ml of D SO. The mixture was heated to 108 ° C until complete dissolution of the material. Then H20 was added for 10 minutes and the mixture was cooled to room temperature. The precipitate was filtered under vacuum, washed with 1 ml of a mixture of D S0: H20 1: 5 and dried at 60 ° C in an air-flow oven to give 840 mg (84%) of purified levofloxacin hemihydrate.
Example 9: MEK
1.5 g of crude levofloxacin was placed 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 filtered 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
1.5 g of crude levofloxacin and 8 mg of sodium metabisulfite were suspended in 10.5 ml of a mixture of ACN: H20 9: 1 under a nitrogen atmosphere. The mixture was heated to reflux temperature until complete dissolution of the material. Then the solution was cooled to room temperature over a period of 30 minutes. The precipitate was filtered under vacuum, washed with a mixture of ACN: H20 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: H2Q (95: 5) / Metabisulfite (8 mg)
1.5 g of pure levofloxacin and 8 mg of sodium metabisulfite was suspended in 10.5 ml of a mixture of ACN: H20 95: 5 under a nitrogen atmosphere. The mixture was heated to reflux temperature and hot filtration was performed. The solution was heated again to reflux temperature then cooled to 3 ° C in 30 minutes. The precipitate was filtered 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)
1.5 g of crude levofloxacin and 4 mg of sodium metabisulfite were suspended in 15 ml of a mixture of ACN: H20 95: 5 under a 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 filtered 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 In a three-necked flask equipped with a condenser were suspended in 3.5 ml of DMSO at 80 ° C under a nitrogen atmosphere 5 g (17.8 mmol) of acid (S) - (-) -9, 10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-
de] [1,4] benzoxazin-6-carboxylic acid, 4.46 g (44.6 mmol), 31 mg (0.17 mmol) of ascorbic acid. The reaction mixture was heated to this temperature (4 h 30) until the end 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 filtered under vacuum, washed with IPA (10 ml) and dried at 60 ° C in a vacuum oven to give 5.63 g (87.6%) of pure levofloxacin.
Example 14: D SO / Metabisulfite In a three-necked flask equipped with a condenser were suspended in 7 ml of DMSO at 80 ° C under a nitrogen atmosphere 10 g (35.5 mmol) of (S) - ( -) -9, 10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [2,3-de] [1,4] benzoxazine-6-carboxylic acid, 9.0 g (90 mmol), 34 mg (0.17 mmol) of sodium metabisulfite. The reaction mixture was heated to this temperature (5h30) until the end 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 filtered under vacuum, washed with IPA (10 ml) and dried at 60 ° C in a vacuum oven to give 11.8 g (92.4%) of pure levofloxacin.
Claims (42)
1. A process for preparing levofloxacin having a purity of 99% or greater, comprising: dissolving levofloxacin in a polar solvent at an elevated temperature, and crystallizing the purified levofloxacin.
2. The process according to claim 1, wherein the purity of the purified levofloxacin is 99.5% by weight or greater.
3. The process according to claim 1, wherein the elevated temperature is in the range of 80 ° C to 110 ° C.
4. The process according to claim 1, wherein the elevated temperature is the reflux temperature of the solution.
5. The process according to claim 1, wherein the polar solvent is selected from the group consisting of dimethyl sulfoxide, methyl ethyl ketone, acetonitrile, buanol, mixtures thereof and aqueous mixtures thereof.
6. The process according to claim 1, wherein the solvent is acetonitrile.
7. The process according to claim 1, wherein the solvent is a mixture of acetonitrile and water, wherein the amount of water in the solvent is 10% or less.
8. The process according to claim 1, wherein the amount of dimethyl levofloxacin in the purified levofloxacin is at least one third less than the amount in the initial levofloxacin.
9. The process according to claim 1, further comprising adding an antioxidant prior to the crystallization step.
10. The process according to claim 9, 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, guaiac gum, propyl gallate, tiodipripionic acid, dilauryl thiodipripionate, tere- butylhydroquinone, tocopherols, and pharmaceutically acceptable salts thereof.
11. The process according to the antioxidant claim is sodium metabisulfite.
12. The process according to the antioxidant claim is ascorbic acid.
13. The process according to claim 9, wherein the amount of N-oxide levofloxacin in the purified levofloxacin is at least one third less than the amount in the initial levofloxacin.
14. The process according to claim 9, wherein the amount of N-oxide levofloxacin in the purified levofloxacin is 0.1% or less.
15. The process according to claim 9, wherein the purity of the purified levofloxacin is 99.5% by weight or more.
16. The process according to claim 9, further comprising a step of determining whether the initial levofloxacin contains an amount of N-oxide levofloxacin that is detectable by HPLC.
17. The process according to claim 9, wherein the solvent is acetonitrile and wherein the purified levofloxacin is substantially pure levofloxacin hemihydrate.
18. The process according to claim 1, wherein the purified levofloxacin is substantially pure levofloxacin hemihydrate.
19. A process for preparing levofloxacin hemihydrate having a purity of 99% or greater, comprising: dissolving levofloxacin in a polar solvent at an elevated temperature and crystallizing levofloxacin hemihydrate.
20. The process according to claim 19, wherein the elevated temperature is in the range of 80 ° C to 110 ° C.
21. The process according to claim 19, wherein the elevated temperature is the reflux temperature of the solution.
22. The process according to claim 19, wherein the solvent is selected from the group consisting of acetonitrile, dimethyl sulfoxide: H20, methyl ethyl ketone, butanol and mixtures thereof.
23. The process according to claim 19, wherein the solvent is dimethyl sulfoxide: H20 in a ratio of 1: 5 ..
24. The process according to claim 19, wherein the solvent is methyl ethyl ketone.
25. The process according to claim 19, wherein the solvent is n-butanol.
26. The process according to claim 19, wherein the solvent is acetonitrile.
27. The product of the process according to claim 1.
28. The product of the process according to claim 9.
29. The product of the process according to claim 19.
30. A process for preparing levofloxacin having a purity of 99% or greater, comprising: dissolving levofloxacin in a polar solvent; add an antioxidant; and crystallizing the purified levofloxacin, wherein the passage of the aggregate occurs before or after the dissolution step and before the crystallization step.
31. The process according to claim 9, wherein the antioxidant is in the range of 0.2% to 5% by weight of the levofloxacin.
32. The process according to claim 9, wherein the antioxidant is added to the levofloxacin before the dissolution step.
33. The process according to claim 1, further comprising adding an antioxidant during the crystallization step.
34. A process for preparing levofloxacin having a purity of 99% or greater, which comprises converting (S) - (-) - 9, 10 -difluoro-3-methyl-7-??? - 2,3-dihydro-7H acid [2,3-de] [1,4] benzoxazine-6-carboxylic acid to levofloxacin at an elevated temperature in the presence of an antioxidant.
35. The process according to claim 34, wherein the purity of the levofloxacin is 99.9% by weight or greater.
36. The process according to claim 34, wherein the amount of N-oxide levofloxacin in the levofloxacin is 0.1% or less.
37. A process for preparing levofloxacin hemihydrate, comprising: dissolving levofloxacin in a solvent selected from the group consisting of acetonitrile, acetonitrile: H20, dimethyl sulfoxide: H20, methyl ethyl ketone, butanol, butanol: H20, and mixtures thereof; and crystallize the hemihydrated levofloxacin.
38. The process according to claim 37, wherein the solvent consists essentially of butanol: H20 in a ratio of 9: 1 or acetonitrile: H20 in a ratio of 99: 1.
39. The process according to claim 38, wherein the solvent consists essentially of acetonitrile: H20 in a ratio of 99: 1.
40. The process according to claim 37, wherein the temperature of the solvent is raised to a temperature higher than 80 ° C and lower than 110 ° C.
41. The process according to claim 37, wherein the step of dissolving comprises refluxing the solvent.
42. The process according to claim 37, further comprising drying the hemihydrated levofloxacin at 60 ° C.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US33431601P | 2001-11-29 | 2001-11-29 | |
US35493902P | 2002-02-11 | 2002-02-11 | |
US26296502A | 2002-10-03 | 2002-10-03 | |
US10/263,192 US7629458B2 (en) | 2001-10-03 | 2002-10-03 | Preparation of levofloxacin and hemihydrate thereof |
PCT/US2002/038182 WO2003045329A2 (en) | 2001-11-29 | 2002-11-27 | Methods for the purification of levofloxacin |
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CA2462023A1 (en) | 2001-10-03 | 2003-04-10 | Teva Pharmaceutical Industries Ltd. | Preparation of levofloxacin and forms thereof |
CN1735620A (en) * | 2002-12-16 | 2006-02-15 | 兰贝克赛实验室有限公司 | Pure levofloxacin hemihydrate and processes for preparation thereof |
KR100704641B1 (en) * | 2004-07-21 | 2007-04-06 | 주식회사유한양행 | Methods for the preparation of levofloxacin having a high purity |
JP2006273718A (en) * | 2005-03-28 | 2006-10-12 | Shiono Chemical Co Ltd | Method for producing levofloxacin-1/2 hydrate |
CN1321121C (en) * | 2005-04-21 | 2007-06-13 | 浙江医药股份有限公司新昌制药厂 | Post processing method for preparing levo-ofloxacin |
US7964723B2 (en) * | 2008-08-02 | 2011-06-21 | Apeloa-Kangyu | And practical process for exclusively producing (S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido-[1,2,3,de][1,4]benzoxazine-6-carboxylic acid hemihydrate |
CN102070650B (en) * | 2011-01-28 | 2012-06-27 | 山东省药品检验所 | Preparation method for levofloxacin-N-oxide |
US20120251685A1 (en) * | 2011-04-04 | 2012-10-04 | Martek Biosciences Corporation | Oil-in-Water Emulsions Comprising a Polyunsaturated Fatty Acid and Methods of Making the Same |
CN105823851A (en) * | 2015-12-15 | 2016-08-03 | 浙江海洋学院 | Detection method for ofloxacin enantiomer in seawater |
CN108218892A (en) * | 2018-03-16 | 2018-06-29 | 乐山职业技术学院 | A kind of purification process of lavo-ofloxacin |
CN114507242B (en) * | 2022-01-26 | 2023-05-19 | 上虞京新药业有限公司 | Preparation method of levofloxacin with high optical purity |
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---|---|---|---|---|
NO166131C (en) * | 1985-06-20 | 1991-06-05 | Daiichi Seiyaku Co | ANALOGUE PROCEDURE FOR THE PREPARATION OF S (-) - PYRIDOBENZOKSAZINE COMPOUNDS. |
US5237060A (en) * | 1985-12-10 | 1993-08-17 | Bayer Aktiengesellschaft | Process of preparing enantiomerically pure 1,8-bridged 4-quinolone-3-carboxylic acids |
TW208013B (en) * | 1990-03-01 | 1993-06-21 | Daiichi Co Ltd | |
US5521310A (en) * | 1992-10-07 | 1996-05-28 | Derivados Del Etilo, S.A. | Process to obtain benzoxazines to be used for the synthesis of ofloxazine, levofloxazine and derivatives |
KR0125115B1 (en) * | 1994-03-22 | 1997-12-05 | 김은영 | Process for preparing piperazinyl quinolone derivatives |
KR100309871B1 (en) * | 1999-02-24 | 2001-10-29 | 윤종용 | Process for Preparing (-)Pyridobenzoxazine Carboxylic Acid Derivatives |
CA2462023A1 (en) * | 2001-10-03 | 2003-04-10 | Teva Pharmaceutical Industries Ltd. | Preparation of levofloxacin and forms thereof |
-
2002
- 2002-11-27 PL PL02374558A patent/PL374558A1/en not_active Application Discontinuation
- 2002-11-27 CN CNA028236440A patent/CN1596256A/en active Pending
- 2002-11-27 EP EP02791339A patent/EP1460997A4/en not_active Withdrawn
- 2002-11-27 CA CA002466860A patent/CA2466860A1/en not_active Abandoned
- 2002-11-27 HU HU0500285A patent/HUP0500285A3/en unknown
- 2002-11-27 WO PCT/US2002/038182 patent/WO2003045329A2/en active Application Filing
- 2002-11-27 IL IL16217202A patent/IL162172A0/en unknown
- 2002-11-27 AU AU2002365416A patent/AU2002365416A1/en not_active Abandoned
- 2002-11-27 JP JP2003546834A patent/JP2005527484A/en active Pending
- 2002-11-27 MX MXPA04005196A patent/MXPA04005196A/en not_active Application Discontinuation
-
2004
- 2004-05-27 IS IS7288A patent/IS7288A/en unknown
- 2004-06-15 HR HR20040546A patent/HRP20040546A2/en not_active Application Discontinuation
- 2004-06-29 NO NO20042731A patent/NO20042731L/en not_active Application Discontinuation
-
2006
- 2006-05-01 JP JP2006127862A patent/JP2006219496A/en not_active Withdrawn
-
2007
- 2007-08-22 JP JP2007216178A patent/JP2008007517A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
JP2005527484A (en) | 2005-09-15 |
AU2002365416A1 (en) | 2003-06-10 |
CA2466860A1 (en) | 2003-06-05 |
HUP0500285A2 (en) | 2005-06-28 |
NO20042731L (en) | 2004-06-29 |
EP1460997A4 (en) | 2005-06-15 |
WO2003045329A3 (en) | 2004-02-19 |
JP2008007517A (en) | 2008-01-17 |
HRP20040546A2 (en) | 2004-10-31 |
WO2003045329A2 (en) | 2003-06-05 |
JP2006219496A (en) | 2006-08-24 |
EP1460997A2 (en) | 2004-09-29 |
HUP0500285A3 (en) | 2009-03-30 |
CN1596256A (en) | 2005-03-16 |
IS7288A (en) | 2004-06-21 |
PL374558A1 (en) | 2005-10-31 |
IL162172A0 (en) | 2005-11-20 |
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