CN103910696B - Cabazitaxel isopropyl ether compound and crystallization thereof - Google Patents
Cabazitaxel isopropyl ether compound and crystallization thereof Download PDFInfo
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- CN103910696B CN103910696B CN201210596353.3A CN201210596353A CN103910696B CN 103910696 B CN103910696 B CN 103910696B CN 201210596353 A CN201210596353 A CN 201210596353A CN 103910696 B CN103910696 B CN 103910696B
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- isopropyl ether
- cabazitaxel
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- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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Abstract
The present invention relates to Cabazitaxel isopropyl ether compound and crystallization thereof, specifically, the present invention relates to Cabazitaxel isopropyl ether compound and crystallization thereof, prepare the method for this isopropyl ether compound and crystallization thereof, pharmaceutical composition containing this isopropyl ether compound and crystallization thereof and its preparing the purposes in antitumor drug.Cabazitaxel isopropyl ether compound of the present invention and crystallization thereof have physico-chemical property excellence, good stability, preparation technology easy, be more suitable for industrially scalable and the advantage such as prepare.
Description
Technical field
The present invention relates to medicinal chemistry art, in particular to the isopropyl ether compound of anti-malignant tumor compound Cabazitaxel, the invention still further relates to its crystallization.
Technical background
Bearing taxanes has very strong anti-tumor activity, at present this compounds list marketing existing, and as taxol, Docetaxel and Cabazitaxel etc., they have good inhibit activities to various solid tumor cell.Wherein, Cabazitaxel, i.e. 4-acetoxyl group-2 α-benzoyloxy-5 β, 20-epoxy group(ing)-1-hydroxyl-7 β, 10 β-dimethoxy-9-oxo Japanese yew-11-alkene-13 α-Ji (2R, 3S)-3-tertbutyloxycarbonylamino-PLA ester (structure is shown below), match by France the taxane anti-tumor medicament that Norfin, Inc develops listing, this medicine is better to prostate cancer patients with terminal curative effect, compared with other antitumor drug, this medicine can significantly improve the vitality of prostate cancer 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-propyl alcohol compound, propyl carbinol compound, the crystallization of 1-propyl alcohol compound.
But applicant studies discovery, Cabazitaxel disclosed in prior art and solvate thereof are stable not, and preparation method is complicated, industrialization cost is higher.
Summary of the invention
The present invention is surprisingly found out that Cabazitaxel isopropyl ether compound and crystallization thereof, successfully solves the deficiency that prior art exists, its have physico-chemical property excellence, good stability, preparation technology easy, be more suitable for industrially scalable and the advantage such as prepare.
One aspect of the present invention provides the Cabazitaxel isopropyl ether compound that formula I represents,
Wherein, x is 0.1 ~ 2.0, is preferably 0.3 ~ 1.5, is more preferably 0.7 ~ 1.0.
As another aspect of the present invention, the invention provides the synthetic method of Cabazitaxel isopropyl ether compound.
Method of the present invention comprises: Cabazitaxel is dissolved in acetic acid by (a), and (b) adds isopropyl ether in the solution of step a, and (c) separates out Cabazitaxel isopropyl ether compound.
In above-mentioned steps (a), the amount of acetic acid can all be dissolved as suitable with Cabazitaxel.Solvent temperature is 0 ~ 60 DEG C, is preferably 10 ~ 40 DEG C, is more preferably room temperature.
In above-mentioned steps (b), the ratio of the volume and acetic acid volume that add isopropyl ether is 1 ~ 8: 1, is preferably 2 ~ 4: 1.
In above-mentioned steps (c), the temperature separating out Cabazitaxel isopropyl ether compound is 0 ~ 40 DEG C, is preferably room temperature.
Another aspect provides the pharmaceutical composition comprising Cabazitaxel isopropyl ether compound, in this pharmaceutical composition, comprise treatment significant quantity above-mentioned Cabazitaxel isopropyl ether compound.In addition, can also contain in this pharmaceutical composition or not contain pharmaceutically acceptable auxiliary material.
Another aspect provides Cabazitaxel isopropyl ether compound or Cabazitaxel isopropyl ether compound pharmaceutical composition is preparing the purposes in anti-tumor drug, the purposes preferably in the medicine preparing anti-prostate cancer.
The invention provides the crystallization of Cabazitaxel isopropyl ether compound, in its powder x-ray diffraction collection of illustrative plates, be 7.70 at angle of diffraction 2 θ, 8.55, 10.07, 14.09, 14.96, there is diffraction peak at 19.82 degree of places, preferred is 7.70 at angle of diffraction 2 θ, 8.55, 10.07, 14.09, 14.96, 17.39, 18.50, 19.15, 19.82, there is diffraction peak at 23.29 degree of places, preferred is 7.70 at angle of diffraction 2 θ, 8.55, 10.07, 13.48, 14.09, 14.96, 15.75, 16.28, 16.92, 17.39, 18.50, 19.15, 19.82, 21.71, there is diffraction peak at 23.29 degree of places, most preferred is 7.70 at angle of diffraction 2 θ, 8.55, 10.07, 12.55, 13.23, 13.48, 14.09, 14.96, 15.75, 16.28, 16.92, 17.39, 17.72, 18.50, 19.15, 19.82, 20.78, 21.71, 21.99, 22.30, there is diffraction peak at 23.29 degree of places.
As a preferred embodiment of the present invention, in the powder x-ray diffraction collection of illustrative plates of Cabazitaxel isopropyl ether compound of the present invention crystallization, the peak position of typical peaks and intensity are represented by following table:
| Numbering | 2 θ (degree) | Relative intensity |
| 1 | 7.70 | 100.00 |
| 2 | 8.55 | 9.56 |
| 3 | 10.07 | 21.72 |
| 4 | 12.55 | 6.78 |
| 5 | 13.23 | 4.54 |
| 6 | 13.48 | 9.58 |
| 7 | 14.09 | 13.98 |
| 8 | 14.96 | 8.82 |
| 9 | 15.75 | 5.85 |
| 10 | 16.28 | 4.38 |
| 11 | 16.92 | 6.18 |
| 12 | 17.39 | 11.75 |
| 13 | 17.72 | 6.25 |
| 14 | 18.50 | 5.01 |
| 15 | 19.15 | 5.29 |
| 16 | 19.82 | 12.76 |
| 17 | 20.78 | 3.53 |
| 18 | 21.71 | 9.50 |
| 19 | 21.99 | 7.35 |
| 20 | 22.30 | 2.82 |
| 21 | 23.29 | 9.31 |
As an embodiment of the invention, Cabazitaxel isopropyl ether compound of the present invention crystallization has powder x-ray diffraction collection of illustrative plates as shown in Figure 1.
As an embodiment of the invention, Cabazitaxel isopropyl ether compound of the present invention crystallization has DSC collection of illustrative plates as shown in Figure 3, and temperature rise rate is 10 DEG C/min.In DSC collection of illustrative plates, starting temperature is about 149 DEG C, and peak temperature is about 153 DEG C.
As an embodiment of the invention, Cabazitaxel isopropyl ether compound of the present invention crystallization has TGA collection of illustrative plates as shown in Figure 4, and temperature rise rate is 10 DEG C/min.
For any given crystallized form, due to the preferred orientation that the factors such as such as crystal habit cause, the relative intensity of diffraction peak can change, and this is known in crystallography art.There is the place of preferred orientation impact, peak intensity changes, but the characteristic peak positions of crystal formation cannot change.In addition, for any given crystal formation, may there is slight errors in the position at peak, and this is also known in crystallography art.Such as, because the change of temperature during analytic sample, sample move or the demarcation etc. of instrument, the position at peak can be moved, and the error at measurment of 2 θ values is about sometimes ± and 0.2 °.Therefore, when determining often kind of crystalline texture, this error should be taken into account.
As a preferred embodiment of the present invention, in Cabazitaxel isopropyl ether compound of the present invention crystallization, in every mole of Cabazitaxel, the content of isopropyl ether is 0.1 ~ 2.0mol, more preferably in every mole of Cabazitaxel, the content of isopropyl ether is 0.3 ~ 1.5mol, and most preferably in every mole of Cabazitaxel, the content of isopropyl ether is 0.7 ~ 1.0mol.
The invention provides the preparation method of Cabazitaxel isopropyl ether compound crystallization, method of the present invention comprises: Cabazitaxel is dissolved in acetic acid by (a), b () adds isopropyl ether in the solution of step a, (c) separates out the crystallization of Cabazitaxel isopropyl ether compound.
In above-mentioned steps (a), the amount of acetic acid can all be dissolved as suitable with Cabazitaxel.Solvent temperature is 0 ~ 60 DEG C, is preferably 10 ~ 40 DEG C, is more preferably room temperature.
In above-mentioned steps (b), the ratio of the volume and acetic acid volume that add isopropyl ether is 1 ~ 8: 1, is preferably 2 ~ 4: 1.
In above-mentioned steps (c), the temperature separating out the crystallization of Cabazitaxel isopropyl ether compound is 0 ~ 40 DEG C, is preferably room temperature.
Another aspect of the present invention there are provided a kind of Cabazitaxel isopropyl ether compound crystal composition, wherein the crystallization of Cabazitaxel isopropyl ether compound accounts for more than 50% of crystal composition weight, be better more than 80%, be more preferably more than 90%, preferably more than 95%.
The present invention provides the pharmaceutical composition comprising the compound crystallization of Cabazitaxel isopropyl ether or Cabazitaxel isopropyl ether compound crystal composition on the other hand, comprises treatment significant quantity above-mentioned Cabazitaxel isopropyl ether compound crystallization or Cabazitaxel isopropyl ether compound crystal composition in this pharmaceutical composition.In addition, can also contain in this pharmaceutical composition or not contain pharmaceutically acceptable auxiliary material.
Another aspect of the invention provides the crystallization of Cabazitaxel isopropyl ether compound, Cabazitaxel isopropyl ether compound crystal composition or Cabazitaxel isopropyl ether compound crystalline drug composition and is preparing the purposes in anti-tumor drug, the purposes preferably in the medicine preparing anti-prostate cancer.
Cabazitaxel used in the present invention is commercially available or obtains according to the Chinese patent literature of publication number CN1179776A.
Accompanying drawing explanation
Fig. 1: the powder x-ray diffraction collection of illustrative plates of Cabazitaxel isopropyl ether compound prepared by the embodiment of the present invention 1.
Fig. 2: the powder x-ray diffraction collection of illustrative plates of Cabazitaxel isopropyl ether compound prepared by the embodiment of the present invention 2.
Fig. 3: the DSC collection of illustrative plates of Cabazitaxel isopropyl ether compound prepared by the embodiment of the present invention 1.
Fig. 4: the TGA collection of illustrative plates of Cabazitaxel isopropyl ether compound prepared by the embodiment of the present invention 1.
Embodiment
Specific embodiment below, its objective is and make those skilled in the art more clearly understand and to implement the present invention.They should not be considered to limiting the scope of the invention, and are exemplary illustration of the present invention and Typical Representative.
Embodiment 1:
Be dissolved in 20ml acetic acid by Cabazitaxel (2g), drip isopropyl ether 60ml under stirring at room temperature, stir 2h, suction filtration, solid isopropyl ether washs, and vacuum-drying (55 DEG C) obtains 1.5g white solid in about 3 hours.The mass percentage that gas Chromatographic Determination obtains isopropyl ether in product is 9.65%.
Embodiment 2:
Be dissolved in 10ml acetic acid by Cabazitaxel (2g), drip isopropyl ether 30ml under stirring at room temperature, stir 2h, suction filtration, solid isopropyl ether washs, and vacuum-drying (55 DEG C) obtains 1.55g white solid in about 3 hours.The mass percentage that gas Chromatographic Determination obtains isopropyl ether in product is 9.24%.
Embodiment 3:
Be dissolved in 30ml acetic acid by Cabazitaxel (2g), drip isopropyl ether 90ml under stirring at room temperature, stir 2h, suction filtration, solid isopropyl ether washs, and vacuum-drying (55 DEG C) obtains 1.51g white solid in about 3 hours.The mass percentage that gas Chromatographic Determination obtains isopropyl ether in product is 9.68%.
Embodiment 4:
Be dissolved in 20ml acetic acid by Cabazitaxel (2g), drip isopropyl ether 40ml under stirring at room temperature, stir 2h, suction filtration, solid isopropyl ether washs, and vacuum-drying (55 DEG C) obtains 1.0g white solid in about 3 hours.The mass percentage that gas Chromatographic Determination obtains isopropyl ether in product is 8.71%.
Embodiment 5:
Be dissolved in 20ml acetic acid by Cabazitaxel (2g), drip isopropyl ether 80ml under stirring at room temperature, stir 2h, suction filtration, solid isopropyl ether washs, and vacuum-drying (55 DEG C) obtains 1.6g white solid in about 3 hours.The mass percentage that gas Chromatographic Determination obtains isopropyl ether in product is 10.12%.
Embodiment 6: stability analysis
With reference to Chinese Pharmacopoeia version in 2010 two annex VD, the Cabazitaxel acetone compound got appropriate embodiment 1 gained Cabazitaxel isopropyl ether compound and prepare according to patent WO2005028462 method, by following condition test, experimental result sees the following form.
HPLC condition:
Instrument: Agilent1100
Chromatographic column: C18,4.6 × 150mm, 5 μm
Column temperature: 25 DEG C
Determined wavelength: 230nm
Moving phase: acetonitrile: water (60: 40-80: 20)
Flow velocity: 1.0ml/min
The acceleration of isopropyl ether compound and acetone compound and long-term stable experiment result
Gas-chromatography test of the present invention 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: starting temperature is 50 DEG C, keeps 3 minutes; With the ramp to 80 DEG C of per minute 10 DEG C, keep 3 minutes, with the ramp to 150 DEG C of per minute 30 DEG C, keep 9 minutes.
Injector temperature: 200 DEG C of detector (FID) temperature: 250 DEG C
Carrier gas: nitrogen flow rate: 3ml/min splitting ratio: 10: 1
Sample: the DMSO solution of product, concentration 100mg/ml, sampling volume: 1 μ l.
Powder x-ray diffraction test of the present invention is all carried out according to following condition:
BrukerD8ADVANCE instrument is adopted 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, continuous sweep; Sweep limit: 3 ° ~ 45 °, sweep velocity 8 °/min.
Claims (14)
1. Cabazitaxel isopropyl ether compound crystallization, in its powder x-ray diffraction collection of illustrative plates, be that 7.70,8.55,10.07,14.09,14.96,19.82 degree of places have diffraction peak at angle of diffraction 2 θ, in every mole of Cabazitaxel, the content of isopropyl ether is 0.3 ~ 1.5mol.
2. crystallization according to claim 1, in its powder x-ray diffraction collection of illustrative plates, is that 7.70,8.55,10.07,14.09,14.96,17.39,18.50,19.15,19.82,23.29 degree of places have diffraction peak at angle of diffraction 2 θ.
3. crystallization according to claim 2, in its powder x-ray diffraction collection of illustrative plates, be that 7.70,8.55,10.07,13.48,14.09,14.96,15.75,16.28,16.92,17.39,18.50,19.15,19.82,21.71,23.29 degree of places have diffraction peak at angle of diffraction 2 θ.
4. crystallization according to claim 3, in its powder x-ray diffraction collection of illustrative plates, be that 7.70,8.55,10.07,12.55,13.23,13.48,14.09,14.96,15.75,16.28,16.92,17.39,17.72,18.50,19.15,19.82,20.78,21.71,21.99,22.30,23.29 degree of places have diffraction peak at angle of diffraction 2 θ.
5. the crystallization described in any one of claim 1-4, is characterized in that the content of isopropyl ether in every mole of Cabazitaxel is 0.7 ~ 1.0mol.
6. prepare the method for crystallization described in any one of claim 1-5, comprising:
A Cabazitaxel is dissolved in acetic acid by ();
B () adds isopropyl ether in the solution of step a
C () separates out the crystallization of Cabazitaxel isopropyl ether compound.
7. method according to claim 6, wherein the volume of isopropyl ether is 1 ~ 8:1 with the ratio of acetic acid volume.
8. method according to claim 7, wherein the volume of isopropyl ether is 2 ~ 4:1 with the ratio of acetic acid volume.
9. crystal composition, the Cabazitaxel isopropyl ether compound crystallization wherein described in any one of claim 1-5 accounts for more than 50% of crystal composition weight.
10. crystal composition according to claim 9, the Cabazitaxel isopropyl ether compound crystallization wherein described in any one of claim 1-5 accounts for more than 80% of crystal composition weight.
11. crystal compositions according to claim 10, the Cabazitaxel isopropyl ether compound crystallization wherein described in any one of claim 1-5 accounts for more than 90% of crystal composition weight.
12. crystal compositions according to claim 11, the Cabazitaxel isopropyl ether compound crystallization wherein described in any one of claim 1-5 accounts for more than 95% of crystal composition weight.
13. pharmaceutical compositions, it comprises the crystallization described in any one of claim 1-5 or the crystal composition described in any one of claim 9-12.
Crystallization described in 14. any one of claim 1-5, the crystal composition described in claim 9-12 or pharmaceutical composition according to claim 13 are preparing the purposes in anti-tumor drug.
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| CN1849311A (en) * | 2003-09-19 | 2006-10-18 | 安万特医药股份有限公司 | Acetone solvate of dimethoxy docetaxel and its process of preparation |
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| CN1849311A (en) * | 2003-09-19 | 2006-10-18 | 安万特医药股份有限公司 | Acetone solvate of dimethoxy docetaxel and its process of preparation |
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