CN105198905A - Method for preparing ultrapure marbofloxacin through purification - Google Patents
Method for preparing ultrapure marbofloxacin through purification Download PDFInfo
- Publication number
- CN105198905A CN105198905A CN201510659646.5A CN201510659646A CN105198905A CN 105198905 A CN105198905 A CN 105198905A CN 201510659646 A CN201510659646 A CN 201510659646A CN 105198905 A CN105198905 A CN 105198905A
- Authority
- CN
- China
- Prior art keywords
- marbofloxacin
- ultrapure
- impurity
- purification
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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
Abstract
The invention relates to a method for preparing ultrapure marbofloxacin through purification and aims at providing a simple and easy method to remove disubstituted impurities and obtain a high-purity marbofloxacin crude drug. The method comprises the three steps of firstly, dispersing crude marbofloxacin into water, adding a proper amount of organic acids, accurately regulating the pH value to 3.0-3.5, and dissolving a solid; secondly, sufficiently standing the obtained solution for 24 hours until a small number of floccules are separated out; and thirdly, filtering to remove the floccules, adding weak base to regulate the pH value of the system to 6.0-6.5, separating out a great number of products, filtering and drying to obtain the ultrapure marbofloxacin.
Description
Technical field
Medicinal chemistry arts of the present invention, relates to a kind of preparation method of ultrapure Marbofloxacin.
Background technology
Marbofloxacin (MAB) is another third generation carbostyril family antibacterial drugs after Enrofloxacin (Enrofloxacin), danofloxacin (Danofloxacin), sarafloxacin (Sarafloxacin) etc., it is the novel fluoroquinolone antibacterial agent of animal specific, formulated by Roche Holding Ag of Switzerland, Vetoquinol company of France develops further and goes on the market in Britain in nineteen ninety-five, subsequently in succession in France, US and European listing.Marbofloxacin has anti-microbial activity have very excellent dynamic characteristic widely, and sterilizing power is strong, and absorb fast, distribution in vivo is extensive, and with other antimicrobial drugs without cross resistance, easy to use, untoward reaction is little.Pharmacokinetic studies shows, Marbofloxacin removes long half time in animal body, and bioavailability is close to 100%, and almost do not remain in the blood of animal, ight soil and tissue, be well suited for clinically to the requirement of veterinary antibiotic, its structural formula is as follows:
Containing methylpiperazine substituting group on Marbofloxacin aromatic ring structure, this substituent formation is all use N methyl piperazine and halogenated aryl hydrocarbon to carry out nucleophilic substitution reaction formation.Select an in the end step to use methylpiperazine to replace in US4801584 and directly generate target product:
In ZL94190968.9 be then after intermediate steps obtains methylpiperazine substituent by following formula, then through hydrolysis, ring closure reaction synthesis Marbofloxacin:
And WO2011/61292 and CN101619068A all have selected by the obtained methylpiperazine substituting group intermediate of following reaction, then obtain Marbofloxacin through hydrolysis cyclization:
In a word, all carry out substitution reaction formation by methylpiperazine and halogenated aryl hydrocarbon in all synthesis paths, but inevitably all contain a small amount of piperazine in commercially available methylpiperazine, piperazine participates in reaction then can be made to replace impurity containing two in final finished, namely has:
This impurity contains the functional group similar with product, and conventional purification process all cannot be removed, and its molecular weight is comparatively large, even if only contain this impurity of 0.01%, product also can be caused in making injection process to separate out floss, have a strong impact on the preparation of preparation.There is the impact made preparation in the existence and the trace thereof that also refer to this impurity in WO2011/61292, is to be separated with preparative chromatography to obtain ultrapure Marbofloxacin (two replace impurity is less than 5ppm) in this patent, but this kind of method cannot realize suitability for industrialized production.Up to now, in Marbofloxacin, two control replacing impurity is substantially all by selecting the methylpiperazine of high-quality to realize (two replace impurity is less than 100ppm), not having report more effectively to remove the method for this impurity.For improving bulk drug quality, facilitate the preparation of injection, exploitation is a kind of simple, and the method being applicable to the ultrapure Marbofloxacin of preparation (two replace impurity is less than 5ppm) of suitability for industrialized production is extremely important.
The object of the present invention is to provide a kind of simple method, remove two replacement impurity, obtain highly purified Marbofloxacin bulk drug.
Summary of the invention
For amine substance, structural difference makes different amine have different alkalescence, and often its difference is also little, but water miscible difference after utilizing its salify ability or salify, and carrying out separation and purification is a kind of effectively separation means.
Two replacement impurity is with Marbofloxacin similar, but still there is difference in it, containing methylpiperazine substituting group in Marbofloxacin structure, wherein N-methyl structural is tertiary amine, there is stronger alkalescence, the easier salify of Marbofloxacin more two replacement impurity is dissolved, and two replacement impurity is not containing this tertiary amine, alkalescence is more weak, and molecule itself is larger, comparatively the more difficult salify of Marbofloxacin is dissolved in the water, and the present invention utilizes impurity and Marbofloxacin to be dissolved in difference in the ability of water to carry out purifies and separates at salify cleverly.
The object of the present invention is to provide a kind of simple method, remove two replacement impurity, obtain highly purified Marbofloxacin bulk drug.
The method comprises the steps:
The first step: be dispersed in water by Marbofloxacin crude product, adds appropriate organic acid, accurately regulates pH to 3.0 ~ 3.5, dissolved solids.
Second step: by gained solution sufficient standing 24h, have a small amount of floss to separate out.
3rd step: filter filtering floss, adding weak base regulation system pH value is 6.0 ~ 6.5, separates out large-tonnage product, filters, dry ultrapure Marbofloxacin.
Above-mentioned method used, organic acid is the low molecular weight organic acid such as formic acid, acetic acid.Weak base used is the weak base such as ammoniacal liquor, sodium bicarbonate, saleratus.
Experiment shows, when acidity is excessive, two replacement impurity also can with sour salify after be dissolved in the water, the object filtering impurity cannot be reached, and during acid deficiency, product dissolves abundant not, when filtering and impurity removing matter, product can be lost, therefore the pH value of the strict hierarchy of control is particularly important, can guarantee yield, because two replacement foreign matter content is very low in crude product while guarantee product quality, according to said method process and lose product hardly, high-quality Marbofloxacin can be obtained efficiently.If selection inorganic acid, the pH of system is easy to too low, and two replacement impurity also fully dissolves, and does not reach the effect of clarification.And when selecting the organic monoacid such as formic acid, acetic acid, the salt formed with Marbofloxacin is weak acid and mild base salt, and this weak acid and mild base salt and weak acid itself form buffer system, facilitates the pH value of the hierarchy of control.By leaving standstill for a long time, separating out two insoluble replacement impurity, crossing and filter.
Same, because product is also simultaneously containing carboxyl, when Marbofloxacin is separated out in neutralization, the selection also particularly important of alkali, alkaline excessive time, carboxyl salify is soluble in water, still have product to be that salt of weak acid is soluble in water during hypoalkalinity, all can affect productive rate, only have suitable pH value that product can be made fully to separate out.When selecting the weak base such as ammoniacal liquor, sodium bicarbonate, saleratus, conveniently regulate pH, even if pH value is slightly too high, be also easy to pull back to target ph with weak acid again.
Use above-mentioned method, can the ultrapure Marbofloxacin of high efficiency acquisition, the method is simple, raw materials used low price, and yield is high, solves the problem that crystallization purifying cannot remove impurity, is applicable to large production operation completely.
Embodiment
Can understand the present invention more specifically by the following examples, but it illustrates instead of limits the scope of the invention.
Two replace impurity analysis detection means:
Adopt liquid chromatography/mass spectrometry (HPLC/MS) method, detect micro-dipolymer in MAB.
Chromatographic condition:
Chromatographic column: phenomenexSynergi4uFusion-RP80A, 2.0*100mm
Detected temperatures: 40 DEG C of flow velocitys: 0.25mL/min sample size: 15 μ L
Moving phase:
A: distilled water (0.1%TFA) B: acetonitrile (0.1%TFA)
| 0min | 20min | 20.5min | 25.4min | 25.5min | 35 min | |
| A | 90 | 20 | 0 | 0 | 90 | Stop |
| B | 10 | 80 | 100 | 100 | 10 |
MS condition:
ESIPositiveDetectorVoltage:1.5kV
SIM:M/Z(352)
embodiment 1
Get 40g Marbofloxacin crude product, add 500mLH
2o, dripping about 8mL first acid for adjusting pH is that 3.2(pH meter detects), dissolution of solid has micro-insolubles, leaves standstill 12h, can see flocks, filter, filtrate added drop-wise ammoniacal liquor regulates pH=6.0, a large amount of solid is separated out, and cryosel bath is cooled to 0 DEG C, filters, dry ultrapure Marbofloxacin 37.5g.HPLC/MS detects two replacement impurity and does not detect.
embodiment 2
Get 40g Marbofloxacin crude product, add 500mLH
2o, dripping about 10mL vinegar acid for adjusting pH is that 3.5(pH meter detects), dissolution of solid has micro-insolubles, leaves standstill 12h, can see flocks, filter, filtrate added drop-wise ammoniacal liquor regulates pH=6.0, a large amount of solid is separated out, and cryosel bath is cooled to 0 DEG C, filters, dry ultrapure Marbofloxacin 36.5g.HPLC/MS detects two replacement impurity and does not detect.
embodiment 3
Get 40g Marbofloxacin crude product, add 500mLH
2o, dripping about 8mL first acid for adjusting pH is that 3.2(pH meter detects), dissolution of solid has micro-insolubles, leave standstill 12h, can flocks have been seen, filter, filtrate added drop-wise sodium hydrogen carbonate solution regulates pH=6.2, a large amount of solid is separated out, and cryosel bath is cooled to 0 DEG C, filters, dry ultrapure Marbofloxacin 37.2g.HPLC/MS detects two replacement impurity and does not detect.
embodiment 4: crude product and ultrapure Marbofloxacin injection make control experiment
The ultrapure Marbofloxacin got 10g crude product Marbofloxacin respectively and obtain by above-described embodiment 1 ~ 3, by injection Making programme configuration pin agent solution, leaves standstill and observes:
Claims (3)
1. the method for the ultrapure Marbofloxacin of purification: Marbofloxacin crude product is dispersed in water, add appropriate organic acid, accurate adjustment pH to 3.0 ~ 3.5, dissolved solids, by gained solution sufficient standing 24h, has a small amount of floss to separate out, filter filtering floss, adding weak base regulation system pH value is 6.0 ~ 6.5, separates out large-tonnage product, filters, dry ultrapure Marbofloxacin.
2. the method for claim 1, the low molecular weight organic acid such as organic tart flavour formic acid, acetic acid used.
3. the method for claim 1, weak base used is ammoniacal liquor, sodium bicarbonate, saleratus etc.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510659646.5A CN105198905A (en) | 2015-10-14 | 2015-10-14 | Method for preparing ultrapure marbofloxacin through purification |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510659646.5A CN105198905A (en) | 2015-10-14 | 2015-10-14 | Method for preparing ultrapure marbofloxacin through purification |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105198905A true CN105198905A (en) | 2015-12-30 |
Family
ID=54946897
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510659646.5A Pending CN105198905A (en) | 2015-10-14 | 2015-10-14 | Method for preparing ultrapure marbofloxacin through purification |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105198905A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107056811A (en) * | 2017-04-20 | 2017-08-18 | 山东方明邦嘉制药有限公司 | A kind of process for purification of Marbofloxacin |
| CN107445977A (en) * | 2017-07-13 | 2017-12-08 | 江西傲新生物科技有限公司 | A kind of water-soluble Marbofloxacin and preparation method and application |
| CN110283186A (en) * | 2019-07-19 | 2019-09-27 | 海门慧聚药业有限公司 | A kind of crystal form of Marbofloxacin and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4801584A (en) * | 1986-09-12 | 1989-01-31 | Hoffmann-La Roche Inc. | Pyrido(3,2,1-IJ)-1,3,4 benzoxadiazine derivatives |
| CN102060860A (en) * | 2011-01-07 | 2011-05-18 | 安徽美诺华药物化学有限公司 | Preparation method of Marbofloxacin |
| CN102712598A (en) * | 2009-11-19 | 2012-10-03 | 新梅斯托克尔卡·托瓦纳·兹德拉维尔公司 | A process for a preparation of marbofloxacin and intermediate thereof |
-
2015
- 2015-10-14 CN CN201510659646.5A patent/CN105198905A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4801584A (en) * | 1986-09-12 | 1989-01-31 | Hoffmann-La Roche Inc. | Pyrido(3,2,1-IJ)-1,3,4 benzoxadiazine derivatives |
| CN102712598A (en) * | 2009-11-19 | 2012-10-03 | 新梅斯托克尔卡·托瓦纳·兹德拉维尔公司 | A process for a preparation of marbofloxacin and intermediate thereof |
| CN102060860A (en) * | 2011-01-07 | 2011-05-18 | 安徽美诺华药物化学有限公司 | Preparation method of Marbofloxacin |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107056811A (en) * | 2017-04-20 | 2017-08-18 | 山东方明邦嘉制药有限公司 | A kind of process for purification of Marbofloxacin |
| CN107445977A (en) * | 2017-07-13 | 2017-12-08 | 江西傲新生物科技有限公司 | A kind of water-soluble Marbofloxacin and preparation method and application |
| CN107445977B (en) * | 2017-07-13 | 2019-08-09 | 江西傲新生物科技有限公司 | A kind of water solubility Marbofloxacin and the preparation method and application thereof |
| CN110283186A (en) * | 2019-07-19 | 2019-09-27 | 海门慧聚药业有限公司 | A kind of crystal form of Marbofloxacin and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102040675B (en) | Method for preparing hydroxypropyl-beta-cyclodextrin | |
| CN101381756B (en) | Purification method of super tylosin | |
| CN105198905A (en) | Method for preparing ultrapure marbofloxacin through purification | |
| CN103087079B (en) | Crystallization method of piperacillin | |
| CN104231016A (en) | Etimicin sulfate preparation method | |
| CN102617489B (en) | Preparation method of sulfaclozine sodium | |
| CN102285907B (en) | The preparation method of aztreonam monocycle parent nucleus | |
| CN101805359B (en) | Method for preparing biapenem with high purity | |
| CN102603603B (en) | Method for preparing (S)-oxiracetam | |
| CN104231044A (en) | Process for purifying nosiheptide by passing through column | |
| CN106279197A (en) | The purification of isosorbide reaction solution and crystallization processes | |
| CN102617327B (en) | Dexibuprofen compound and preparation method thereof | |
| CN102746324B (en) | Purification method of cefotiam hydrochloride and aseptic powder injection of cefotiam hydrochloride | |
| US8871927B2 (en) | Method for purifying Ceftizoxime sodium | |
| CN104230984B (en) | Preparation method for trihydrate 3-amino propyl aminoethyl thiophosphoric acid | |
| CN101768164B (en) | Naloxone hydrochloride compound with high purity | |
| CN104163773B (en) | A kind of process for purification of tsiklomitsin | |
| CN104610283B (en) | A kind of cefepime hydrochloride compound and its pharmaceutical composition | |
| CN104926926B (en) | A kind of refining methd of enramycin | |
| CN103570573A (en) | Method for extracting alpha-aminoadipic acid from enzymatic waste liquor | |
| JP6126102B2 (en) | Pure S-(−)-9-fluoro-6,7-dihydro-8- (4-hydroxypiperidin-1-yl) -5-methyl-1-oxo-1H, 5H-benzo [i, j] quinolidine -2-carboxylic acid L-arginine salt tetrahydrate and process for producing the same | |
| CN103724249B (en) | A kind of preparation method of (S)-oxiracetam | |
| CN115417819B (en) | Preparation method of phentolamine mesylate | |
| CN106928290A (en) | A kind of preparation method of high content rutin | |
| CN102432532B (en) | High-purity torasemide compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20151230 |