CN110283186A - A kind of crystal form of Marbofloxacin and preparation method thereof - Google Patents
A kind of crystal form of Marbofloxacin and preparation method thereof Download PDFInfo
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- CN110283186A CN110283186A CN201910652644.1A CN201910652644A CN110283186A CN 110283186 A CN110283186 A CN 110283186A CN 201910652644 A CN201910652644 A CN 201910652644A CN 110283186 A CN110283186 A CN 110283186A
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- marbofloxacin
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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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- 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
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Abstract
The present invention relates to crystal forms of Marbofloxacin and preparation method thereof.The crystal form of Marbofloxacin disclosed by the invention, referred to as A type.The characteristic peak of the A crystal form XRPD map is expressed as 12.82 with interplanar distance d；7.12Å；5.95Å；5.31Å；4.53Å；3.98Å；3.64Å；3.59Å;DSC map nearby has obvious exothermic peak at 295.05 DEG C.
Description
Technical field
The present invention relates to crystal forms of Marbofloxacin and preparation method thereof.
Background technique
The chemical name of Marbofloxacin (Marbofloxacin) are as follows: fluoro- 2,3- dihydro-3- methyl-1 0- (the 4- methyl-1-of 9-
Piperazinyl) -7- oxo -7H- pyridine-[3,2,1-ij] (4,1,2) benzo oxadiazines -6- carboxylic acid, molecular formula C17H19FN4O4,
Molecular weight is 362.36, and structural formula is as follows:
Marbofloxacin is fluoroquinolone antibacterial agent for animals, is developed earliest by Roche Holding Ag, and grand by method national strength and prestige
(Vetoquinol) company further develops, and lists in nineteen ninety-five in Europe.Marbofloxacin is after Enrofloxacin
(Enrofloxacin), another after Danofloxacin (Danofloxacin), sarafloxacin (Sarafloxacin) etc.
Three generations's carbostyril family antibacterial drugs, the drug is with extensive antibacterial activity and has very good dynamic characteristic, sterilization
Power is strong, absorbs fastly, widely distributed in vivo, with other antimicrobials without cross resistance, easy to use, adverse reaction is small.Pharmacy is dynamic
Mechanics study shows that Marbofloxacin removes long half time in animal body, bioavilability close to 100%, animal blood,
Almost without residual in excrement and tissue, it is well suited for the requirement clinically to veterinary antibiotic.
Drug crystal forms are this several years domestic popular directions of one for doing imitation medicine, and crystal form is different, in fusing point, solubility, close
Degree, stability etc. all might have marked difference.Specific on drug molecule, dissolution of the crystal form of drug to drug
Degree, bioavilability, stability, curative effect and safety etc. might have bigger influence.Although having many about horse
The report of wave sand star synthetic method, but there has been no crystal forms and preparation method that document refers to Marbofloxacin preparation so far, more
The spectral signature in relation to crystal form is not referred to.
Summary of the invention
The object of the present invention is to provide medicinal crystal-forms of a kind of Marbofloxacin and preparation method thereof.
The invention discloses a kind of crystal forms of Marbofloxacin, hereinafter referred to as A type.The A crystal form is radiated using Cu-K β
ConditionPowder x-ray diffraction data when 2 angle θ of Prague is 3~50 ° are as shown in table 1, wherein 2-
Theta is 2 angles θ, and d is interplanar distance, I/IoRelative intensity is represented, accounts for hundred of area under strongest line with area under a certain spectral line
Divide than indicating.Characteristic peak (I/Io> 30%) as shown in Fig. 1, characteristic peak interplanar distance d (rounds up and takes percentile) table
It is shown as
1 Marbofloxacin crystal form x-ray diffractogram of powder data of table
The Marbofloxacin A crystal form surveys infrared absorption spectrum in about 431.90cm with KBr pressed disc method-1, 546.95cm-1,
670.61cm-1, 682.97cm-1, 701.07cm-1, 747.25cm-1, 782.87cm-1, 801.65cm-1, 910.51cm-1,
919.77cm-1, 1004.34cm-1, 1055.23cm-1, 1114.05cm-1, 1292.88cm-1, 1309.53cm-1, 1388.60cm-1, 1421.82cm-1, 1438.22cm-1, 1513.97cm-1, 1541.99cm-1, 1618.87cm-1, 1723.32cm-1,
2796.91cm-1, 2928.56cm-1, 3048.15cm-1There is absorption peak at place.
Using Perkin Elmer Diamond Differential Scanning Calorimeter Auto-
Sample equipment carries out thermometric analysis to A crystal form, and temperature range is 30-400 DEG C, and heating speed is 10 DEG C/minute, as the result is shown horse
Wave sand star A crystal form nearby has obvious exothermic peak at 295.05 DEG C.
The invention also discloses the methods for preparing Marbofloxacin A crystal form.
Marbofloxacin A crystal form can be generally prepared via a method which:
(1) Marbofloxacin is placed in suitable solvent, the solvent is selected from the mixed system of alcohol and ammonia, the alcohol choosing
From or mixtures thereof methanol, ethyl alcohol, propyl alcohol, butanol, isopropanol；The ammonia is ammonium hydroxide, and methylamine water solution or other room temperature are
The aqueous solution of gaseous amine；
(2) drum nitrogen micro-vacuum deamination；
(3) it is cooled to 0-5 degree crystallization 2-5 hours, filters, cleaning, about 20-90 DEG C of filter cake vacuum drying 4-8 hours is collected
Marbofloxacin off-white color crystalline solid.
As a kind of alternative plan, the synthesis of Marbofloxacin can refer to patent CN94190968.9 progress.It will close
At good Marbofloxacin be placed in 10-20 times Marbofloxacin bulking value (1 bulking value be defined as by every 1g Marbofloxacin be added
The solvent of 1mL) solvent in.
The solvent is selected from the mixed solution of alcohol and ammonia；The alcohol can be selected from methanol, ethyl alcohol, propyl alcohol, butanol, isopropanol
Or mixtures thereof；The ammonia is ammonium hydroxide, and methylamine water solution or other room temperature are the aqueous solution of gaseous amine；Ammonia and alcohol it is mixed
Composition and division in a proportion example, the volume ratio content of ammonia are no more than 10% and are not 0.
In above-mentioned solvent, the solvent for being preferred for crystallization is ethyl alcohol.
In the step of above method (3), solution is cooled to 0-5 DEG C (preferably 2 DEG C), crystallization 2-5 hours, preferably 3 hours, mistake
It is white to collect Marbofloxacin class in 4-8 hours (preferably 5 hours) of 20-90 DEG C (preferably 40-60 DEG C) vacuum drying for filter, cleaning, filter cake
Color crystalline solid.
Marbofloxacin A type crystallization disclosed by the invention has determining structure, and crystal form is highly stable, bulk density
Well, it being sealed half a year or more in 40 DEG C of accelerated tests and 50% humidity environment, crystal form is basically unchanged, and content does not reduce,
Can under conditions of being protected from light, be shady and cool and dry long-term preservation.
Detailed description of the invention
Attached drawing 1 is the powder x-ray diffraction spectrogram of Marbofloxacin A crystal form.
Attached drawing 2 is the infrared absorption pattern of Marbofloxacin A crystal form, and wherein abscissa is wave number (wavenumbers (cm-1)), ordinate is percentage transmittance (%transmittance).
Attached drawing 3 is the differential thermal analysis map (DSC) of Marbofloxacin A crystal form.
Specific embodiment
The present invention provides a kind of selective synthetic methods.
Embodiment
1. the preparation method one of Marbofloxacin A crystal form
Ethyl alcohol (68.0g) and Marbofloxacin (12.0g) are added in reaction flask, is added 23% ammonium hydroxide (9.0g), 20-30 DEG C
30min is stirred, solid whole dissolved clarification is passed through nitrogen bubbling at 25~30 DEG C, micro-vacuum deamination 16 hours, is cooled to 0-5 DEG C of analysis
Crystalline substance, filtering, 50 DEG C of vacuum drying obtain off-white color Marbofloxacin solid (10.5g, purity 99.4%).
2. the preparation method two of Marbofloxacin A crystal form
Isopropanol (89.0g) and Marbofloxacin (12.0g) are added in reaction flask, water (24.0g) and 40% methylamine is added
Aqueous solution (8.0g), 20-30 DEG C of stirring 30min, solid whole dissolved clarification are passed through nitrogen bubbling, micro-vacuum piptonychia at 25~30 DEG C
Amine 24 hours, it is cooled to 0-5 DEG C of crystallization, is filtered, 60 DEG C of vacuum drying obtain off-white color Marbofloxacin solid (10.0g, purity
99.3%).
3. Marbofloxacin A crystal form X ray diffracting spectrum measures
Crystal powder prepared by Example 1 carries out X ray diffracting spectrum measurement, and the crystal is using Cu-K β spoke
Penetrate conditionPowder x-ray diffraction data when 2 angle θ of Prague is 3~50 ° are as shown in table 1, wherein 2-
Theta is 2 angles θ, and d is interplanar distance, I/IoRelative intensity is represented, accounts for hundred of area under strongest line with area under a certain spectral line
Divide than indicating.Characteristic peak (I/Io> 30%) as shown in Figure 1, its characteristic peak interplanar distance d (round up and take percentile) is indicated
ForBy peak as characterized above
Marbofloxacin crystal be defined as A crystal form.
4. Marbofloxacin A infrared absorption spectrum measures
Marbofloxacin A crystal form prepared by Example 1 surveys infrared absorption spectrum in about 431.90cm with KBr pressed disc method-1,
546.95cm-1, 670.61cm-1, 682.97cm-1, 701.07cm-1, 747.25cm-1, 782.87cm-1, 801.65cm-1,
910.51cm-1, 919.77cm-1, 1004.34cm-1, 1055.23cm-1, 1114.05cm-1, 1292.88cm-1, 1309.53cm-1,
1388.60cm-1, 1421.82cm-1, 1438.22cm-1, 1513.97cm-1, 1541.99cm-1, 1618.87cm-1,
1723.32cm-1, 2796.91cm-1, 2928.56cm-1, 3048.15cm-1There is absorption peak at place.Attached drawing 2 is the infrared absorption of A crystal form
Map.
5. Marbofloxacin A crystal form differential thermal analysis (DSC)
Using Perkin Elmer Diamond Differential Scanning Calorimeter Auto-
Sample equipment carries out thermometric analysis to Marbofloxacin A crystal form, and temperature range is 30-400 DEG C, and heating speed is 10 DEG C/minute, knot
Fruit, which is shown in 295.05 DEG C, nearby exothermic peak.Attached drawing 3 is the DSC map of A crystal form.
Claims (6)
1. the X ray diffracting spectrum of the A crystal form of Marbofloxacin, powder has following characteristic peak: being expressed as with interplanar distance (d) The method preparation that the crystal form includes the following steps:
(1) Marbofloxacin is placed in suitable solvent, the solvent is selected from the mixed system of alcohol and ammonia, and the alcohol is selected from first
Or mixtures thereof alcohol, ethyl alcohol, propyl alcohol, butanol, isopropanol；The ammonia is ammonium hydroxide, and methylamine water solution or other room temperature are gaseous state
Amine aqueous solution；
(2) drum nitrogen micro-vacuum deamination；
(3) it is cooled to 0-5 degree crystallization 2-5 hours, filters, Ma Bo is collected in cleaning, about 20-90 DEG C of filter cake vacuum drying 4-8 hours
Xacin-series white crystalline body.
2. the A crystal form of Marbofloxacin according to claim 1, it is characterised in that: the Marbofloxacin A crystal form infrared absorption
Spectrum is in about 431.90cm-1, 546.95cm-1, 670.61cm-1, 682.97cm-1, 701.07cm-1, 747.25cm-1,
782.87cm-1, 801.65cm-1, 910.51cm-1, 919.77cm-1, 1004.34cm-1, 1055.23cm-1, 1114.05cm-1,
1292.88cm-1, 1309.53cm-1, 1388.60cm-1, 1421.82cm-1, 1438.22cm-1, 1513.97cm-1,
1541.99cm-1, 1618.87cm-1, 1723.32cm-1, 2796.91cm-1, 2928.56cm-1, 3048.15cm-1There is absorption at place
Peak.
3. the A crystal form of Marbofloxacin according to claim 1, it is characterised in that: the differential thermal of the Marbofloxacin A crystal form point
Analysis map (DSC) nearby has exothermic peak at 295.05 DEG C.
4. the A crystal form of Marbofloxacin according to claim 1, it is characterised in that: solvent is 10- in the preparation method
20 times of Marbofloxacin bulking values.
5. the A crystal form of Marbofloxacin according to claim 1, it is characterised in that: ammonia and alcohol in the preparation method
Mixed proportion, the volume ratio content of ammonia are no more than 10% and are not 0.
6. the preparation method of the A crystal form of Marbofloxacin according to claim 1, it is characterised in that: preferred alcohols are ethyl alcohol.
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Citations (6)
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|---|---|---|---|---|
| CN101619068A (en) * | 2009-08-13 | 2010-01-06 | 浙江国邦药业有限公司 | Novel method for preparing marbofloxacin |
| 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 |
| CN105198905A (en) * | 2015-10-14 | 2015-12-30 | 海门慧聚药业有限公司 | Method for preparing ultrapure marbofloxacin through purification |
| 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 |
| CN107383058A (en) * | 2017-08-28 | 2017-11-24 | 海门慧聚药业有限公司 | Preparation of marbofloxacin |
| CN107522718A (en) * | 2017-09-14 | 2017-12-29 | 浙江国邦药业有限公司 | A kind of synthetic method of Marbofloxacin |
-
2019
- 2019-07-19 CN CN201910652644.1A patent/CN110283186A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101619068A (en) * | 2009-08-13 | 2010-01-06 | 浙江国邦药业有限公司 | Novel method for preparing marbofloxacin |
| 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 |
| CN105198905A (en) * | 2015-10-14 | 2015-12-30 | 海门慧聚药业有限公司 | Method for preparing ultrapure marbofloxacin through purification |
| 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 |
| CN107383058A (en) * | 2017-08-28 | 2017-11-24 | 海门慧聚药业有限公司 | Preparation of marbofloxacin |
| CN107522718A (en) * | 2017-09-14 | 2017-12-29 | 浙江国邦药业有限公司 | A kind of synthetic method of Marbofloxacin |
Non-Patent Citations (3)
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| JIN SHEN等: "Marbofloxacin", 《ACTA CRYSTALLOGRAPHICA. SECTION E.》 * |
| 单国洋等: "麻保沙星新合成路线研究", 《精细化工中间体》 * |
| 吕扬、杜冠华主编: "《晶型药物》", 31 October 2009 * |
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Application publication date: 20190927 |