CN101440098B - Crystal of oxacephem - Google Patents
Crystal of oxacephem Download PDFInfo
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- CN101440098B CN101440098B CN2008101816721A CN200810181672A CN101440098B CN 101440098 B CN101440098 B CN 101440098B CN 2008101816721 A CN2008101816721 A CN 2008101816721A CN 200810181672 A CN200810181672 A CN 200810181672A CN 101440098 B CN101440098 B CN 101440098B
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- Prior art keywords
- crystal
- flomoxef
- methyl
- methyl acetate
- solvate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- 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
- A61K31/5365—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 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D505/10—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D505/12—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7
- C07D505/14—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7 with hetero atoms directly attached in position 7
- C07D505/16—Nitrogen atoms
- C07D505/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
- C07D505/20—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D505/24—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen further substituted by doubly-bound nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
Provided are a hydrate of flomoxef or a solvate of flomoxef with methyl acetate, and crystals of these. They are advantageous from an environmental standpoint and for formulation into pharmaceutical preparations, etc. The invention relates to a flomoxef crystal.
Description
The application divides an application, its female case be the applying date be February 18, application number in 2005 be 200580005415.7 and denomination of invention be the application of " crystal of oxacephem ".
[technical field]
The present invention relates to oxacephem (Oxacephem) crystal, it can be used as biocide.
[background technology]
Flomoxef with formula (I)
[Chemical formula 1]
Can be used as the oxacephem biocide.Comprise the form that the freeze-dried preparation of its sodium salt can injection preparation and on market, obtain (trade(brand)name: Flumarin, Shionogi ﹠amp; Co., Ltd.).This class freeze-dried preparation makes as base substance and mixed chlorinated sodium and stablizer by using flomoxef.(seeing patent document 1).
The flomoxef crystal also is known, and for example, this crystal is in the presence of methylene dichloride and methyl-phenoxide, with Lewis acid (TiCl
4Or
) handle the protected material of corresponding 4-carboxylic acid after, from ethyl acetate, crystallized out (see patent document 2, embodiment 3).In another well-known method, in the presence of methyl-phenoxide, used Lewis acid (SnCl at 4-carboxylic acid and the protected intermediate product of 3-terminal hydroxyl
4) do similar processing, crystallization from methylene dichloride and acetone afterwards (non-patent document 1). there is not to find description about these crystalline forms.But,, obtain to contain the crystal of methylene dichloride by the method for in these files, describing according to the further research that the inventor did.
[patent document 1]
Japanese unexamined patent publication JP-A 60-45514
[patent document 2]
Japanese unexamined patent publication JP-A 59-139385
[non-patent document 1]
The microbiotic magazine, (The Journal of Amtibiotics) (April, P466-476,1985)
[summary of the invention]
[problem that this patent will solve]
The flomoxef crystal that comprises methylene dichloride faces the difficulty that removes methylene dichloride with common drying means.As the formulation method in actual production, freeze-drying is used for sterilization equally, and it carries out according to described in the patent document 1, is not comprised the sodium salt of methylene dichloride thus.Yet freeze-drying needs high production cost usually, and, aspect maintenance of the equipment, need very big workload.So, recently need to use non-freeze dried method as much as possiblely, as to the more effective commercial run of injection sterilization preparation. do not comprise at flomoxef under the situation of methylene dichloride, flomoxef itself just can be used as active pharmaceutical ingredients and uses. therefore, flomoxef is required new crystal, this new crystal does not contain methylene dichloride, more has superiority in preparation.
[means of dealing with problems]
As the result who considers that the problems referred to above are conscientiously studied, the present inventor has found to comprise the new solvate of flomoxef crystalline, and has finished the present invention of following detailed description.
(1) hydrate or the hydrate crystal of compound shown in Xia Mian the chemical formula (I):
[Chemical formula 2]
(2) according to the hydrate or the hydrate crystal of above-mentioned (1), it is a monohydrate.
(3) according to the hydrate crystal of above-mentioned (1) or (2), it has main peaks in powder x-ray diffraction figure, is positioned at spacing d=8.31,7.00,6.11,5.43,4.47,4.35,4.19,4.15,3.95,3.81,3.50,3.32,2.96 (unit: dust).
(4) the methyl acetate solvate of compound shown in Xia Mian the chemical formula (I) or methyl acetate solvate crystal:
[chemical formula 3]
(5) according to the methyl acetate solvate or the methyl acetate solvate crystal of above-mentioned (4), it is 0.5 methyl acetate solvate.
(6) according to the methyl acetate solvate crystal of above-mentioned (4) or (5), it has main peaks in powder x-ray diffraction figure, be positioned at spacing d=10.42,6.32,4.96,4.62,4.56,4.36,4.23,3.97,3.93,3.79,3.47,2.79 (units: dust).
[effect of the present invention]
The novel solvent thing of flomoxef of the present invention is crystal preferably, therefore, is being excellent aspect stability and the operability, and is having superiority in preparation.Particularly, hydrate crystal has the possibility that directly is mixed with injectable usefulness preparation with power filling method, because they do not comprise the organic solvent such as methylene dichloride. further, methyl acetate solvate crystal is compared with the crystal that comprises methylene dichloride, having superiority aspect safety and the environment, making that flomoxef can be with the high-level efficiency suitability for industrialized production.In other words, these crystal can be produced intermediate as active pharmaceutical ingredients or its.
[brief description of drawings]
The powder x-ray diffraction figure of the flomoxef monohydrate crystal that obtains among [Fig. 1] embodiment 1.
The flomoxef 0.5 methyl acetate solvate crystalline powder x-ray diffraction figure that obtains among [Fig. 2] embodiment 3.
[implementing best mode of the present invention]
To make an explanation below according to each solvate of the present invention and its crystal.
(1) hydrate
Preferred each the molecule flomoxef of the hydrate of flomoxef comprises a part water.This hydrate is crystal preferably.The main peaks that such crystal preferably has in powder x-ray diffraction figure is positioned at spacing d=8.31,7.00,6.11,5.43,4.47,4.35,4.19,4.15,3.95,3.81,3.50,3.32,2.96 (unit: dust) etc., more specifically be presented in the table 1 or Fig. 1 that will be described later. (X-ray diffraction condition determination: used in cathode-ray tube CuK alpha-ray, tube voltage 40Kv, tube current 30mA, dsin θ=n λ (n is an integer, and θ is a diffraction angle)).
In this manual, the value of spacing d is to have high-intensity relatively peak, and it can be selected as main peaks from X-ray peak easily, still, should be appreciated that crystalline structure is necessary to be limited by these values.Promptly, can comprise peak in addition, above-mentioned peak. usually, when measuring crystal by x-ray analysis, owing to determining instrument, condition determination, adhere to existence of solvent or the like, (less) measuring error may appear in the peak. therefore, when confirming crystalline structure and any crystal property to the similar substantially X-ray diagram of the above-mentioned figure that belongs to the scope of the invention, this less error should be considered.
Above-mentioned hydrate is passable, for example, by dissolving flomoxef under room temperature or warm (preferred about 20 to 40 ℃) condition or according to JP-A 59-139385 or microbiotic magazine (TheJournal of Antibiotics) (April, P466-476,1985) its dichloromethane solvent thing that the method described in obtains is in a spot of soluble solvent. afterwards in room temperature or at a certain amount of water of ice-cooled introducing down, the amount of water should be greater than the amount of soluble solvent, arrive room temperature at about 0 ℃ then, preferably stir or leave standstill, continue to obtain over a few hours to one day in about 5 to 25 ℃ temperature.The flomoxef of per 1 gram, the usage quantity of soluble solvent be preferably from 0.1 to 10ml, and preferred 0.5 to 5ml, more preferably 1 to 3ml.The flomoxef of per 1 gram, the usage quantity of water be preferably from 1 to 100ml, and preferred 5 to 50ml, more preferably 10 to 30ml.
The example of soluble solvent comprises for example methyl alcohol of alcohols, ethanol, 2-propyl alcohol, 2-methyl cellosolve, ethylene glycol, methyl cellosolve, glycerol and propylene glycol; Ethers is diox for example, tetrahydrofuran (THF), glycol dimethyl ether and Diethylene Glycol-dimethyl ether; Ketone is acetone for example, methyl ethyl ketone, and methyl iso-butyl ketone (MIBK); The ester class is methyl-formiate for example, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, methyl propionate, ethyl propionate; The organic halogenation hydro carbons is methylene dichloride for example, chloroform, tetracol phenixin, 1,2-ethylene dichloride, trichloroethane, chlorobenzene and dichlorobenzene; Nitrile is acetonitrile and propionitrile for example; Dimethyl formamide; Dimethyl sulfoxide (DMSO); N,N-DIMETHYLACETAMIDE; N-Methyl pyrrolidone; Quinoline; Pyridine; And triethylamine.These solvents can be separately or two or more unite use.
Utilize well-known separation method (for instance, filtering centrifugal or similar approach), can from solvent, separate the crystal of acquisition like this, be purified by well-known method (washing, dry air, drying under reduced pressure for instance) afterwards.
Above-mentioned solvate can be dissolved in the warm water by will comprise the flomoxef that obtains or the extraction residue of its organic solvent thing from the reaction soln of flomoxef intermediate deprotection equally, and prepares to a couple of days in 0-10 ℃ of temperature range stirred for several hour.
(2) methyl acetate solvate
Preferred each the molecule flomoxef of the methyl acetate solvate of flomoxef comprises 0.5 to 1.0 molecule, preferably comprises the methyl acetate of 0.5 molecule.The methyl acetate solvate is crystal preferably.This crystal preferably has main peaks in powder x-ray diffraction figure, be positioned at spacing d=10.42, and 6.32,4.96,4.62,4.56,4.36,4.23,3.97,3.93,3.79,3.47,2.79 (units: dust) etc., more specifically be presented in the table 3 or Fig. 2 that will be described later.
The methyl acetate solvate can, for example, prepare in order to following method.Warm (preferably about 20 to 40 ℃) down after dissolving flomoxef or its dichloromethane solvent thing, distill solvent in methyl acetate.At warm (preferably about 20 to 40 ℃) down, after the dissolution residual substance, solution stirs under room temperature at 0 ℃ in methyl acetate, continues a few hours to a couple of days. and the crystal that is settled out is filtered, and washing is preferably with cold methyl acetate washing, then at air drying.To the flomoxef of per 1 gram, the each usage quantity of first and second methyl acetates is preferably from 0.1 to 20ml, preferably from 0.5 to 15ml, more preferably from 1 to 10ml.To the flomoxef of per 1 gram, the water usage quantity is preferably from 1 to 100ml, preferably from 5 to 50ml, is more preferably from 10 to 30ml.
Above-mentioned methyl acetate solvate also can be with the preparation of above-described method, and promptly the extraction residue of the reaction soln by using flomoxef intermediate deprotection is as starting raw material.
Above-mentioned hydrate or methyl acetate solvate can be converted to other and want the solvate or the crystal that obtain.By freeze drying process, power filling method or the like, preparation can single composition or with the pH regulator agent, stablizer or the like is formed together. particularly, hydrate has very big advantage in preparation, because it is preferably prepared by power filling method.
Reference example 1
[chemical formula 4]
(wherein, Me=methyl; The BH=diphenyl-methyl)
With the flomoxef intermediate (in this compound; protected by diphenyl-methyl for 4 of flomoxef; 3 hydroxyls of tetrazolium are by to the protection of methyl carbobenzoxy-(Cbz)) (405mg) (described (microbiotic magazine (The Journal of Amtibiotics) (April in above-mentioned non-patent document 1; P466-476; 1985))), the mixture of methylene dichloride (2.5ml) and Nitromethane 99Min. (0.5ml) is cooled to-30 ℃, adds the dichloromethane solution (2ml) that contains methyl-phenoxide (0.11ml) and tin tetrachloride (0.17ml) afterwards.After the stirring, the temperature of reaction soln progressively was elevated to-10 ℃ in 3.5 hours.Final reaction soln is dumped into 1N hydrochloric acid, in the mixture of ethyl acetate and methyl ethyl ketone, then isolated organic phase is mixed with sodium bicarbonate aqueous solution, make water become acidity with concentrated hydrochloric acid, the mixture with ethyl acetate and methyl ethyl ketone extracts afterwards.Dried over mgso is used in extract saturated common salt water washing, drying under reduced pressure afterwards, and residue is extracted in the reaction that obtains steeping the dichloromethane solvent thing that comprises flomoxef of last form.
Embodiment 1
Under thermal condition, after residue is extracted in the reaction that obtains in the dissolving 1000mg reference example 1 in 20mL water, solution was stirred 1 day down at 5 ℃.The crystal that is settled out is filtered, use the 10mL cold water washing afterwards.Carry out air drying and drying under reduced pressure (condition: 50Pa, 5 to 10 hours), obtain the flomoxef monohydrate crystal of 803mg (77%).IR (whiteruss): 3539,3198,2924,2854,1776,1711,1685,1645,1534,1450,1387,1267,1130,1062,1039,997,861,665cm
-1 1H NMR (DMSO-d6): δ 3.36 (3H, unimodal), 3.59 (1H, doublet, J=15.3Hz), 3.66 (1H, doublet, J=15.3Hz), 3.73 (2H, triplets, J=5.1Hz), 4.18 (1H, doublet, J=13.5Hz), 4.23 (1H, doublet, J=13.5Hz), 4.31 (2H, triplet, J=5.1Hz), (4.52 2H, unimodal), 5.06 (2H, wide unimodal), 7.30 (1H, triplet, J=56.4Hz), 9.25 (1H, unimodal).Ultimate analysis: for C
15H
18N
6O
7F
2S
2.H
2O
Calculated value: C35.02, H3.92, N16.33, F7.39, S12.46
Measured value: C35.05, H3.93, N16.39, F7.22, S12.32
Moisture content
Calculated value (monohydrate): 3.50%
Measure with Ka Er-Fei Sheer moisture titration apparatus (KF): 3.52%
Fusing point: 94 ℃
Powder x-ray diffraction figure is presented among table 1 and Fig. 1.
[table 1]
| 2 θ d value relative intensities |
| 10.64 8.30 1312.64 7.00 1014.48 6.11 1416.30 5.43 1216.56 5.34 419.04 4.66 619.86 4.47 2420.40 4.35 1721.18 4.19 1321.38 4.15 2322.48 3.95 1323.30 3.81 1323.88 3.72 524.62 3.61 525.46 3.50 1325.64 3.47 826.86 3.31 2027.24 3.27 828.36 3.14 529.62 3.01 630.20 2.96 1331.24 2.86 732.36 2.76 533.50 2.67 633.66 2.66 733.84 2.65 635.04 2.56 535.78 2.51 536.20 2.48 6 |
Embodiment 2
Below shown in the table 2 under the condition, residue is extracted in the reaction that obtains in the reference example 1 under room temperature or warm situation, is dissolved in the soluble solvent, under room temperature or ice-cooled condition, add entry then. be reflected at 5 to 25 ℃ left standstill or stirred for several hour by 1 day.The all crystals that obtains confirms not contain organic solvent through nucleus magnetic resonance like this, confirms it is monohydrate through ultimate analysis.They also show the powder x-ray diffraction figure identical with embodiment 1.
[table 2]
| Sequence number | Initial crystal | Soluble solvent mL | Water (mL) |
| 1234567891011121314151617181920212223 | 100mg″″″″1000mg″″″″″″″″″″″″″″″″″ | Methyl alcohol 0.2 ethanol 0.2 ethanol 0.3 acetone 0.2 methyl alcohol 2 ethanol 22-propyl alcohol 22-methyl cellosolves 2 ethylene glycol 2 acetic acid first 2 ethyl acetate 2 oxolanes 2 diox 22-Ethyl Methyl Ethers 2 diethylene glycols-dimethyl 2 acetone 2 methyl ethyl ketones 2 acetonitriles 2 dimethyl sulfoxide (DMSO)s 2 dimethyl formamides 2 dimethylacetylamide 2N-methyl pyrrolidones 2 | 1.30.30.21.31.5181818181818181818181818181818181818 |
Embodiment 3
Residue is extracted in the reaction that obtains in the 1000mg reference example 1 be dissolved under thermal condition in the 5mL methyl acetate, solvent is removed in distillation then.Under thermal condition, residue is dissolved in the methyl acetate of 2mL, stirred 1 day down at 5 ℃ then.The crystal that is settled out is filtered, and the cold methyl acetate with 2mL washs afterwards.After the dry air, obtain 784mg (82%) 0.5 methyl acetate solvate crystal.IR (whiteruss): 3493,3249,3041,2925,2853,1765,1737,1711,1668,1643,1543,1457,1441,1420,1392,1376,1248,1231,1080,1062,1042,1030,805,751cm
-1 1H NMR (DMSO-d6): δ 3.36 (3H, unimodal), 3.59 (1H, doublet, J=15.3Hz), 3.66 (1H, doublet, J=15.3Hz), 3.73 (2H, triplets, J=5.1Hz), 4.18 (1H, doublet, J=13.5Hz), 4.23 (1H, doublet, J=13.5Hz), 4.31 (2H, triplet, J=5.1Hz), (4.51 2H, unimodal), 5.06 (2H, wide unimodal), 7.30 (1H, triplet, J=56.4Hz), 9.25 (1H, unimodal).
In NMR, observe the methyl acetate peak 1.98 (3H, unimodal) of 0.5 molecule, 3.55 (3H, unimodal)
Ultimate analysis: for C
15H
18N
6O
7F
2S
2.1/2AcOMe
Calculated value: C37.15, H3.97, N15.75, F7.12, S12.02
Measured value: C36.96, H3.92, N15.55, F6.98, S11.96
Fusing point: 78 ℃
Powder x-ray diffraction figure is presented among table 3 and Fig. 2.
[table 3]
| 2 θ d value relative intensities |
| 8.48 10.42 3811.34 7.80 611.70 7.56 514.00 6.32 1016.94 5.23 717.86 4.96 1519.20 4.62 1419.46 4.56 2320.00 4.44 820.36 4.36 3321.00 4.23 1722.36 3.97 1522.62 3.93 1223.48 3.79 1224.50 3.63 625.66 3.47 1826.78 3.32727.02 3.30 927.42 3.25 627.823.20930.80 2.90 931.70 2.82 832.04 2.79 10 |
Embodiment 4
Residue is extracted in the reaction that obtains in the 1000mg reference example 1 be dissolved under thermal condition in the 5mL acid methyl esters, solvent is removed in distillation then.Under thermal condition, residue being dissolved in the methyl acetate of 2mL, stirring 1 day down at 5 ℃ then. the crystal that is settled out is filtered, and the cold methyl acetate with 2mL washs afterwards. after the dry air, obtain 838mg (78%) 0.5 methyl acetate solvate crystal, similar to embodiment 3.
Claims (1)
1. the monohydrate crystal of compound (I) shown in the following chemical formula,
It has powder x-ray diffraction figure as shown in Figure 1.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004043824 | 2004-02-20 | ||
| JP2004-043824 | 2004-02-20 | ||
| JP2004043824 | 2004-02-20 | ||
| JP2004053283 | 2004-02-27 | ||
| JP2004053283 | 2004-02-27 | ||
| JP2004-053283 | 2004-02-27 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005800054157A Division CN100509819C (en) | 2004-02-20 | 2005-02-18 | Crystal of oxacephem |
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|---|---|
| CN101440098A CN101440098A (en) | 2009-05-27 |
| CN101440098B true CN101440098B (en) | 2011-07-13 |
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| CNB2005800054157A Expired - Fee Related CN100509819C (en) | 2004-02-20 | 2005-02-18 | Crystal of oxacephem |
| CN2008101816721A Expired - Fee Related CN101440098B (en) | 2004-02-20 | 2005-02-18 | Crystal of oxacephem |
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| JP (1) | JP4530287B2 (en) |
| KR (1) | KR100832757B1 (en) |
| CN (2) | CN100509819C (en) |
| TW (1) | TWI338008B (en) |
| WO (1) | WO2005058914A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP1680079A4 (en) | 2003-10-24 | 2008-01-02 | Adhesives Res Inc | Rapidly disintegrating films for delivery of pharmaceutical or cosmetic agents |
| CN102952149B (en) * | 2012-11-09 | 2015-06-24 | 浙江新和成股份有限公司 | One-pot synthesis method of flomoxef intermediate |
| KR101314500B1 (en) | 2012-12-28 | 2013-10-07 | 제일약품주식회사 | Oxacephem preparations with improved stability and preparation method thereof |
| CN105801601B (en) * | 2016-04-02 | 2018-01-26 | 丽珠医药集团股份有限公司 | A kind of Flomoxef Sodium synthetic method |
| CN108424418A (en) * | 2017-02-15 | 2018-08-21 | 山东致纯医药科技有限公司 | A kind of Flomoxef sodium impurity |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0128536A1 (en) * | 1983-06-14 | 1984-12-19 | Shionogi & Co., Ltd. | Fluoromethylthiooxacephalosporin derivatives |
| US4532233A (en) * | 1982-12-23 | 1985-07-30 | Shionogi & Co., Ltd. | Fluoromethylthiooxacephalosporins |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03279329A (en) * | 1990-03-27 | 1991-12-10 | Banyu Pharmaceut Co Ltd | Antibiotic comprising cephamycin and cephalosporin |
| JP3279329B2 (en) * | 1991-11-01 | 2002-04-30 | クルップ・プレスタ・アーゲー | Camshaft manufacturing equipment |
-
2005
- 2005-02-18 KR KR1020067016586A patent/KR100832757B1/en active IP Right Grant
- 2005-02-18 CN CNB2005800054157A patent/CN100509819C/en not_active Expired - Fee Related
- 2005-02-18 TW TW094104742A patent/TWI338008B/en not_active IP Right Cessation
- 2005-02-18 CN CN2008101816721A patent/CN101440098B/en not_active Expired - Fee Related
- 2005-02-18 WO PCT/JP2005/002607 patent/WO2005058914A1/en active Application Filing
- 2005-02-18 JP JP2005516398A patent/JP4530287B2/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4532233A (en) * | 1982-12-23 | 1985-07-30 | Shionogi & Co., Ltd. | Fluoromethylthiooxacephalosporins |
| EP0128536A1 (en) * | 1983-06-14 | 1984-12-19 | Shionogi & Co., Ltd. | Fluoromethylthiooxacephalosporin derivatives |
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| Publication number | Publication date |
|---|---|
| KR100832757B1 (en) | 2008-05-27 |
| TWI338008B (en) | 2011-03-01 |
| CN101440098A (en) | 2009-05-27 |
| CN1922191A (en) | 2007-02-28 |
| TW200533672A (en) | 2005-10-16 |
| WO2005058914A1 (en) | 2005-06-30 |
| KR20060120253A (en) | 2006-11-24 |
| CN100509819C (en) | 2009-07-08 |
| JP4530287B2 (en) | 2010-08-25 |
| JPWO2005058914A1 (en) | 2007-07-12 |
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