CN103910697B - Cabazitaxel acetic acid compound and crystallization thereof - Google Patents
Cabazitaxel acetic acid compound and crystallization thereof Download PDFInfo
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- CN103910697B CN103910697B CN201210596354.8A CN201210596354A CN103910697B CN 103910697 B CN103910697 B CN 103910697B CN 201210596354 A CN201210596354 A CN 201210596354A CN 103910697 B CN103910697 B CN 103910697B
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- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
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Abstract
The present invention relates to Cabazitaxel acetic acid compound and crystallization thereof, specifically, the present invention relates to Cabazitaxel acetic acid compound and crystallization thereof, prepare this acetic acid compound and the method for crystallization thereof, containing this acetic acid compound and the pharmaceutical composition of crystallization thereof and its purposes in preparing antitumor drug.The Cabazitaxel acetic acid compound of the present invention and crystallization thereof have physicochemical property excellence, good stability, preparation technology is easy, be more suitable for industrially scalable the advantage such as prepares.
Description
Technical field
The present invention relates to medicinal chemistry art, in particular to the acetic acid compound of anti-malignant tumor compound Cabazitaxel, the invention still further relates to its crystallization.
Technical background
Bearing taxanes has the strongest anti-tumor activity, has this compounds list marketing at present, and such as paclitaxel, Docetaxel and Cabazitaxel etc., they have good inhibitory activity to various solid tumor cells.Wherein, Cabazitaxel, i.e. 4-acetoxyl group-2 α-benzoyloxy-5 β, 20-epoxy radicals-1-hydroxyl-7 β, 10 β-dimethoxy-9-oxo Ramulus et folium taxi cuspidatae-11-alkene-13 α-base (2R, 3S)-3-tertbutyloxycarbonylamino-PLA ester (structure is shown below), it is by the taxane anti-tumor medicament of match Norfin, Inc of France exploitation listing, this medicine is preferable to carcinoma of prostate patients with terminal curative effect, compared with other antitumor drug, this medicine can significantly improve the vitality of carcinoma of prostate patients with terminal, extends patient vitals.
Prior art discloses the solvate of multiple Cabazitaxel.As WO2005028462 discloses the acetone compound of Cabazitaxel, this solvate was approved listing by U.S. FDA in 2010；WO2009115655 discloses Cabazitaxel ethanolates, the different solvate of ethanol/water, monohydrate and dihydrate；WO2012142117 discloses Cabazitaxel toluene compound, methyl tributyl etherate, 2-propanol compound, n-butyl alcohol compound, the crystallization of 1-propanol compound.
But, applicant studies discovery, and disclosed in prior art, Cabazitaxel and solvate thereof are not sufficiently stable, and preparation method is complicated, industrialization is relatively costly, additionally, above-mentioned partial solvent compound has certain toxicity, for medicine and non-best choice.
Summary of the invention
Present invention has surprisingly found that Cabazitaxel acetic acid compound and crystallization thereof, successfully solve the deficiency that prior art exists, it has physicochemical property excellence, good stability, preparation technology simplicity, is more suitable for industrially scalable and the advantage such as prepares.
One aspect of the present invention provides the Cabazitaxel acetic acid compound that Formulas I represents,
Wherein, x is 0.1～2.0, preferably 0.2～1.0, more preferably 0.4～0.8.
As another aspect of the present invention, the invention provides the preparation method of Cabazitaxel acetic acid compound.
The method comprise the steps that Cabazitaxel is dissolved in acetic acid by (a), (b) adds water in the solution of step a, and (c) separates out Cabazitaxel acetic acid compound.
In above-mentioned steps (a), the amount of acetic acid can all be dissolved with Cabazitaxel and is advisable.Solution temperature is 0～60 DEG C, preferably 10～40 DEG C, more preferably room temperature.
In above-mentioned steps (b), adding the volume of water with the ratio of acetic acid volume is 0.5～4: 1, preferably 1～2: 1.
In above-mentioned steps (c), the temperature separating out Cabazitaxel acetic acid compound is 0～40 DEG C, preferably room temperature.
Another aspect provides the pharmaceutical composition comprising Cabazitaxel acetic acid compound, this pharmaceutical composition comprises therapeutically effective amount above-mentioned Cabazitaxel acetic acid compound.Additionally, this pharmaceutical composition can also contain or not contain pharmaceutically acceptable adjuvant.
Another aspect provides Cabazitaxel acetic acid compound or Cabazitaxel acetic acid compound pharmaceutical composition purposes in preparing anti-tumor drug, the preferably purposes in the medicine preparing anti-prostate cancer.
nullThe invention provides the crystallization of Cabazitaxel acetic acid compound，In its powder x-ray diffraction collection of illustrative plates，It is 4.06 at angle of diffraction 2 θ、7.24、8.13、10.19、12.20、14.13、Diffraction maximum is had at 20.49 degree，Preferred is 4.06 at angle of diffraction 2 θ、7.24、8.13、10.19、10.74、12.20、13.68、14.13、15.26、15.89、17.39、Diffraction maximum is had at 20.49 degree，Preferred angle of diffraction 2 θ is 4.06、7.24、8.13、10.19、10.74、11.72、12.20、12.89、13.68、14.13、15.26、15.89、17.39、19.11、20.49、Diffraction maximum is had at 21.46 degree，Most preferably angle of diffraction 2 θ is 4.06、7.24、8.13、9.26、10.19、10.74、11.72、12.20、12.89、13.68、14.13、14.70、15.26、15.89、17.39、17.74、19.11、20.08、20.49、21.46、24.73、Diffraction maximum is had at 25.78 degree.
As a preferred embodiment of the present invention, in the powder x-ray diffraction collection of illustrative plates of the Cabazitaxel acetic acid compound crystallization of the present invention, peak position and the intensity of typical peaks are represented by following table:
| Numbering | 2 θ (spend) | Relative intensity |
| 1 | 4.06 | 15.29 |
| 2 | 7.24 | 11.29 |
| 3 | 8.13 | 100.00 |
| 4 | 9.26 | 2.66 |
| 5 | 10.19 | 21.10 2 --> |
| 6 | 10.74 | 9.10 |
| 7 | 11.72 | 7.15 |
| 8 | 12.20 | 18.54 |
| 9 | 12.89 | 6.19 |
| 10 | 13.68 | 12.07 |
| 11 | 14.13 | 20.89 |
| 12 | 14.70 | 4.12 |
| 13 | 15.26 | 14.22 |
| 14 | 15.89 | 8.81 |
| 15 | 17.39 | 21.10 |
| 16 | 17.74 | 13.51 |
| 17 | 19.11 | 9.25 |
| 18 | 20.08 | 8.23 |
| 19 | 20.49 | 20.06 |
| 20 | 21.46 | 8.56 |
| 21 | 24.73 | 4.82 |
| 22 | 25.78 | 6.42 |
As a preferred embodiment of the present invention, the Cabazitaxel acetic acid compound crystallization of the present invention has powder x-ray diffraction collection of illustrative plates as shown in Figure 1.
For any given crystal form, the preferred orientation caused due to factors such as such as crystal habits, the relative intensity of diffraction maximum can change, and this is known in crystallography art.There is the place of preferred orientation impact, peak intensity is to change, but the characteristic peak positions of crystal formation cannot change.Additionally, for any given crystal formation, the position at peak there may be slight errors, this is also known in crystallography art.Such as, owing to the change of temperature when analyzing sample, sample move or the demarcation etc. of instrument, the position at peak can be moved, and the evaluated error of 2 θ values is about ± 0.2 ° sometimes.Therefore, when determining every kind of crystalline texture, it should this error is taken into account.
As a preferred embodiment of the present invention, in the Cabazitaxel acetic acid compound crystallization of the present invention, in every mole of Cabazitaxel, the content of acetic acid is 0.1～2.0mol, in preferably every mole Cabazitaxel, the content of acetic acid is 0.2～1.0mol, and in more preferably every mole Cabazitaxel, the content of acetic acid is 0.4～0.8mol.
The invention provides the preparation method of Cabazitaxel acetic acid compound crystallization, the method comprise the steps that Cabazitaxel is dissolved in acetic acid by (a), b () adds water in the solution of step a, (c) separates out the crystallization of Cabazitaxel acetic acid compound.
In above-mentioned steps (a), the amount of acetic acid can all be dissolved with Cabazitaxel and is advisable.Solution temperature is 0～60 DEG C, preferably 10～40 DEG C, more preferably room temperature.
In above-mentioned steps (b), adding the volume of water with the ratio of acetic acid volume is 0.5～4: 1, preferably 1～2: 1.
In above-mentioned steps (c), the temperature separating out the crystallization of Cabazitaxel acetic acid compound is 0～40 DEG C, preferably room temperature.
Another aspect of the present invention there are provided a kind of Cabazitaxel acetic acid compound crystal composition, and wherein Cabazitaxel acetic acid compound crystallizes and accounts for more than the 50% of crystal composition weight, and preferably more than 80%, more preferably more than 90%, preferably more than 95%.
Another aspect of the present invention provides and comprises the crystallization of Cabazitaxel acetic acid compound or the pharmaceutical composition of Cabazitaxel acetic acid compound crystal composition, this pharmaceutical composition comprises the crystallization of therapeutically effective amount above-mentioned Cabazitaxel acetic acid compound or Cabazitaxel acetic acid compound crystal composition, additionally, this pharmaceutical composition can also contain or not contain pharmaceutically acceptable adjuvant.
Another aspect of the invention provides the crystallization of Cabazitaxel acetic acid compound, Cabazitaxel acetic acid compound crystal composition or Cabazitaxel acetic acid compound crystalline drug compositions purposes in preparing anti-tumor drug, the especially purposes in the medicine preparing anti-prostate cancer.
Cabazitaxel used in the present invention is commercially available or Chinese patent literature according to publication number CN1179776A prepares.
Accompanying drawing explanation
The powder x-ray diffraction collection of illustrative plates of the Cabazitaxel acetic acid compound of Fig. 1: the embodiment of the present invention 1 preparation.
The powder x-ray diffraction collection of illustrative plates of the Cabazitaxel acetic acid compound of Fig. 2: the embodiment of the present invention 2 preparation.
Detailed description of the invention
Following specific embodiment, its objective is to make those skilled in the art can be more clearly understood that and implement the present invention.They are not considered as limiting the scope of the invention, and the simply exemplary illustration of the present invention and Typical Representative.
Embodiment 1:
Being dissolved in 20ml acetic acid by Cabazitaxel (2g), lower dropping purified water 30ml is stirred at room temperature, separate out solid, stir 1h, sucking filtration, solid purified water is washed, and vacuum drying (40 DEG C) about 3 hours obtains 1.9g white solid.It is 4.85% that gas Chromatographic Determination obtains the weight/mass percentage composition of acetic acid in product.
Embodiment 2:
Being dissolved in 10ml acetic acid by Cabazitaxel (2g), lower dropping purified water 15ml is stirred at room temperature, separate out solid, stir 1h, sucking filtration, solid purified water is washed, and vacuum drying (40 DEG C) about 3 hours obtains 1.92g white solid.It is 2.87% that gas Chromatographic Determination obtains the weight/mass percentage composition of acetic acid in product.
Embodiment 3:
Being dissolved in 30ml acetic acid by Cabazitaxel (2g), lower dropping purified water 45ml is stirred at room temperature, separate out solid, stir 1h, sucking filtration, solid purified water is washed, and vacuum drying (40 DEG C) about 3 hours obtains 1.85g white solid.It is 3.95% that gas Chromatographic Determination obtains the weight/mass percentage composition of acetic acid in product.
Embodiment 4:
Being dissolved in 20ml acetic acid by Cabazitaxel (2g), lower dropping purified water 20ml is stirred at room temperature, separate out solid, stir 1h, sucking filtration, solid purified water is washed, and vacuum drying (40 DEG C) about 3 hours obtains 1.5g white solid.It is 2.97% that gas Chromatographic Determination obtains the weight/mass percentage composition of acetic acid in product.
Embodiment 5:
Being dissolved in 20ml acetic acid by Cabazitaxel (2g), lower dropping purified water 40ml is stirred at room temperature, separate out solid, stir 1h, sucking filtration, solid purified water is washed, and vacuum drying (40 DEG C) about 3 hours obtains 1.91g white solid.It is 3.02% that gas Chromatographic Determination obtains the weight/mass percentage composition of acetic acid in product.
Embodiment 6: stability analysis
With reference to Chinese Pharmacopoeia two annex VD of version in 2010, taking appropriate embodiment 1 gained Cabazitaxel acetic acid compound and the Cabazitaxel acetone compound prepared according to patent WO2005028462 method, by following condition test, experimental result see table.
HPLC condition:
Instrument: Agilent1100
Chromatographic column: C18,4.6 × 150mm, 5 μm
Column temperature: 25 DEG C
Detection wavelength: 230nm
Flowing phase: acetonitrile: water (60: 40-80: 20)
Flow velocity: 1.0ml/min
Acetic acid compound and the long-term stable experiment result of acetone compound
Gas chromatogram of the present invention test is carried out according to following condition:
Instrument: Agilent 7890A type gas chromatograph；
Chromatographic column: DB-WAX capillary column (30m × 0.53mm × 1.0 μm)
Column temperature: initial temperature is 50 DEG C, keeps 3 minutes；With the ramp of 10 DEG C per minute to 80 DEG C, keep 3 minutes, with the ramp of 30 DEG C per minute to 150 DEG C, keep 9 minutes.
Injector temperature: 200 DEG C of detector (FID) temperature: 250 DEG C
Carrier gas: nitrogen flow rate: 3ml/min split ratio: 10: 1
Sample: the DMSO solution of product, concentration 100mg/ml, sampling volume: 1 μ l.
Powder x-ray diffraction of the present invention test is all carried out according to following condition:
BrukerD8ADVANCE instrument is used to measure.Condition determination is as follows: light source: CuK α 40kV40mA, graphite monochromator, divergent slit (DS): 1 °；Antiscatter slits (SS): 1 °；LynxEye detector array, scan mode: θ/θ, scans continuously；Sweep limits: 3 °～45 °, 8 °/min of scanning speed.
Claims (2)
1. the method for the Cabazitaxel acetic acid compound of formula I, including:
A Cabazitaxel is dissolved in acetic acid by ()；
B () adds water in the solution of step a；
C () separates out Cabazitaxel acetic acid compound,
Wherein, x is 0.4～0.8, and in step b, the volume of water is 1～2:1 with the ratio of acetic acid volume.
2. the preparation method of Cabazitaxel acetic acid compound crystallization, including:
A Cabazitaxel is dissolved in acetic acid by ()；
B () adds water in the solution of step a；
C () separates out the crystallization of Cabazitaxel acetic acid compound,
Wherein, in the powder x-ray diffraction collection of illustrative plates of described Cabazitaxel acetic acid compound crystallization, it is to have diffraction maximum at 4.06,7.24,8.13,9.26,10.19,10.74,11.72,12.20,12.89,13.68,14.13,14.70,15.26,15.89,17.39,17.74,19.11,20.08,20.49,21.46,24.73,25.78 degree at angle of diffraction 2 θ, in the crystallization of described Cabazitaxel acetic acid compound, in every mole of Cabazitaxel, the content of acetic acid is 0.4～0.8mol, and in step b, the volume of water is 1～2:1 with the ratio of acetic acid volume.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101918385A (en) * | 2008-01-17 | 2010-12-15 | 安万特医药股份有限公司 | Crystalline forms of dimethoxy docetaxel and methods for preparing same |
| CN103814018A (en) * | 2011-09-09 | 2014-05-21 | 台湾神隆股份有限公司 | Crystalline forms of cabazitaxel |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101918385A (en) * | 2008-01-17 | 2010-12-15 | 安万特医药股份有限公司 | Crystalline forms of dimethoxy docetaxel and methods for preparing same |
| CN103814018A (en) * | 2011-09-09 | 2014-05-21 | 台湾神隆股份有限公司 | Crystalline forms of cabazitaxel |
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