CN103910698B - Cabazitaxel acetone compound and crystallization thereof - Google Patents

Abstract

The present invention relates to cabazitaxel acetonide and crystals thereof, specifically, the present invention relates to cabazitaxel acetonide and crystals thereof, a method for preparing the acetonide and crystals thereof, and a product containing the acetonide and crystals thereof Pharmaceutical composition and its use in the preparation of antitumor drugs. The cabazitaxel acetonide and its crystals of the present invention have the advantages of excellent physical and chemical properties, good stability, simple and convenient preparation process, and are more suitable for industrial scale preparation.

Description

Cabazitaxel Acetonide and Its Crystals

technical field

The invention relates to the field of medicinal chemistry, in particular to the acetonide compound of the anti-malignant tumor compound cabazitaxel, and also relates to its crystallization.

technical background

Taxane compounds have strong anti-tumor activity, and such compounds are currently on the market, such as paclitaxel, docetaxel and cabazitaxel, etc., which have good inhibitory activity on various solid tumor cells. Among them, cabazitaxel, namely 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1-hydroxy-7β, 10β-dimethoxy-9-oxotaxane-11 -en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxyl-3-phenylpropionate (structure shown in the following formula), developed and marketed by Sanofi, France Taxane anti-tumor drugs, the drug has better curative effect on patients with advanced prostate cancer. Compared with other anti-tumor drugs, this drug can significantly improve the vitality of patients with advanced prostate cancer and prolong the life of patients.

The prior art discloses various solvates of cabazitaxel. For example, WO2005028462 discloses the monoacetonate of cabazitaxel, which has been approved by the US FDA in 2010; WO2009115655 discloses cabazitaxel ethanolate, ethanol/water isosolvate, monohydrate, and dihydrate Hydrate; WO2012142117 discloses cabazitaxel toluene, methyl tributyl etherate, 2-propanolate, n-butanolate, 1-propanolate crystals.

However, the applicant found that the cabazitaxel and its solvates disclosed in the prior art are not stable enough, and the preparation method is complicated and the cost of industrialization is high.

Contents of the invention

The present invention surprisingly discovers cabazitaxel-0.75 acetonate and its crystallization, which successfully solves the deficiencies in the prior art. It has excellent physical and chemical properties, good stability, simple and convenient preparation process, and is more suitable for industrial scale preparation. Etc.

One aspect of the present invention provides cabazitaxel acetonide, wherein the content of acetone per mole of cabazitaxel is 0.75 mole.

As another aspect of the present invention, the present invention provides a method for synthesizing the above-mentioned cabazitaxel acetonide.

The method of the present invention comprises: (a) dissolving cabazitaxel in a solvent containing acetone, (b) adding anti-solvent to the solution in step a, (c) separating out cabazitaxel acetonide; wherein, step b The above anti-solvent is C _5-12 aliphatic hydrocarbon, or C _2-5 alkyl-OC _2-5 alkyl ether solvent.

As a preferred embodiment of the present invention, the acetone-containing solvent in the above step (a) refers to a solvent with acetone volume percentage of 50-100%, preferably an acetone solvent or a miscible solvent of acetone and butanone, more preferably an acetone solvent; The amount of the acetone-containing solvent should be such that the cabazitaxel can be completely dissolved; the dissolution temperature is 0-60°C, preferably 10-40°C, more preferably room temperature.

As a preferred embodiment of the present invention, the anti-solvent in the above step (b) is a C ₅ -C ₁₂ aliphatic hydrocarbon, preferably n-pentane, n-hexane, cyclohexane, n-heptane, more preferably n-hexane.

As a preferred embodiment of the present invention, the temperature for precipitation of cabazitaxel acetonide in the above step (c) is 0-40° C., preferably room temperature.

Another aspect of the present invention provides a pharmaceutical composition comprising the above-mentioned cabazitaxel acetonide, and the pharmaceutical composition contains a therapeutically effective amount of the above-mentioned cabazitaxel acetonide. In addition, the pharmaceutical composition may or may not contain pharmaceutically acceptable auxiliary materials.

Another aspect of the present invention provides the use of the above-mentioned cabazitaxel acetonide or the pharmaceutical composition of cabazitaxel acetonide in the preparation of anti-tumor drugs, preferably in the preparation of anti-prostate cancer drugs.

Another aspect of the present invention provides cabazitaxel acetonide crystals, wherein the content of acetone per mole of cabazitaxel is 0.75 moles, and in its powder X-ray diffraction pattern, the diffraction angles 2θ are 7.50, 7.90, 10.15, There are diffraction peaks at 14.37, 15.79, and 19.82 degrees. Preferably, there are diffraction peaks at diffraction angles 2θ of 7.50, 7.90, 8.86, 10.15, 13.50, 14.37, 15.00, 15.79, 17.64, and 19.82 degrees. The more preferred diffraction angle 2θ is There are diffraction peaks at 7.50, 7.90, 8.86, 10.15, 12.81, 13.50, 14.37, 15.00, 15.79, 17.64, 18.18, 19.15, 19.82, 21.75, 22.96 degrees, and the most preferred diffraction angle 2θ is 7.50, 7.90, 8.86, 10.15, There are diffraction peaks at 12.58, 12.81, 13.50, 14.37, 15.00, 15.79, 16.60, 17.64, 18.18, 18.51, 19.15, 19.82, 21.75, 22.17, 22.96, and 23.79 degrees.

As a preferred embodiment of the present invention, the peak position and intensity of the typical peaks in the powder X-ray diffraction spectrum of the cabazitaxel acetonide crystallization of the present invention are represented by the following table:

Numbering 2θ (degrees) Relative Strength 1 7.50 17.32 2 7.90 100.00 3 8.86 4.63 4 10.15 11.09 5 12.58 3.93 6 12.81 5.31 7 13.50 4.53 8 14.37 11.78 9 15.00 7.64

10 15.79 8.70 11 16.60 2.32 12 17.64 4.40 13 18.18 3.17 14 18.51 2.05 15 19.15 2.82 16 19.82 9.13 17 21.75 3.46 18 22.17 2.54 19 22.96 3.76 20 23.79 2.84

As an embodiment of the present invention, the cabazitaxel acetonate crystal of the present invention has a powder X-ray diffraction pattern as shown in FIG. 1 .

It is well known in the art of crystallography that, for any given crystalline form, the relative intensities of diffraction peaks can vary due to preferred orientations due to factors such as crystal morphology. Where there is an effect of preferred orientation, the peak intensity is changed, but the position of the characteristic peak of the crystal form cannot be changed. Furthermore, for any given crystalline form, there may be slight errors in the position of the peaks, as is well known in the art of crystallography. For example, due to temperature changes, sample movement, or instrument calibration when analyzing samples, the position of the peak can move, and the measurement error of the 2θ value is sometimes about ±0.2°. Therefore, this error should be taken into account when determining each crystal structure.

As an embodiment of the present invention, the crystallization of cabazitaxel acetonide of the present invention has a DSC spectrum as shown in FIG. 2 , and the heating rate is 10° C./min.

As another aspect of the present invention, the present invention provides a method for preparing the above-mentioned cabazitaxel acetonide crystals.

The method of the present invention comprises: (a) dissolving cabazitaxel in a solvent containing acetone, (b) adding an anti-solvent to the solution in step a, (c) separating out cabazitaxel acetonide crystals; wherein, step b The anti-solvent is C _5-12 aliphatic hydrocarbon, or C _2-5 alkyl-OC _2-5 alkyl ether solvent.

As a preferred embodiment of the present invention, the acetone-containing solvent in the above step (a) refers to a solvent with acetone volume percentage of 50-100%, preferably an acetone solvent or a miscible solvent of acetone and butanone, more preferably an acetone solvent; The amount of the acetone-containing solvent should be such that the cabazitaxel can be completely dissolved; the dissolution temperature is 0-60°C, preferably 10-40°C, more preferably room temperature.

As a preferred embodiment of the present invention, the anti-solvent in the above step (b) is a C5-C12 aliphatic hydrocarbon, preferably n-pentane, n-hexane, cyclohexane, n-heptane, more preferably n-hexane.

As a preferred embodiment of the present invention, the temperature for precipitation of cabazitaxel acetonide crystals in the above step (c) is 0-40° C., preferably room temperature.

Another aspect of the present invention is to provide a crystalline composition of cabazitaxel acetonide, wherein the acetonide crystals of cabazitaxel account for more than 50% of the weight of the crystalline composition, preferably more than 80%, more preferably 90% % or more, preferably more than 95%.

Another aspect of the present invention provides a pharmaceutical composition comprising cabazitaxel acetonide crystals or a composition of cabazitaxel acetonide crystals, the pharmaceutical composition comprising a therapeutically effective amount of the above cabazitaxel acetonide crystals or cabazitaxel The cyproketone crystalline composition, in addition, the pharmaceutical composition may or may not contain pharmaceutically acceptable auxiliary materials.

Another aspect of the present invention provides the use of cabazitaxel acetonide crystals or the pharmaceutical composition of cabazitaxel acetonide crystals in the preparation of anti-tumor drugs, preferably in the preparation of anti-prostate cancer drugs.

The content of acetone in the product of the present invention is analyzed, and it is found that when the drying temperature is higher than 70° C., the content of acetone in the product will gradually decrease as the drying time prolongs. Therefore, when drying, the preferred temperature is 30-60°C, more preferably 40°C. When the preferred drying temperature of the present invention is adopted, the content of acetone in the product is basically stable at about 0.75 mol of acetone per mole of cabazitaxel.

Cabazitaxel used in the present invention is commercially available or prepared according to the Chinese patent document with publication number CN1179776A.

Description of drawings

Figure 1: Powder X-ray diffraction pattern of cabazitaxel acetonide prepared in Example 1 of the present invention.

Figure 2: DSC spectrum of the cabazitaxel acetonide prepared in Example 1 of the present invention

detailed description

The purpose of the following specific examples is to enable those skilled in the art to understand and implement the present invention more clearly. They should not be considered as limiting the scope of the invention, but as illustrations and typical representatives of the invention.

Example 1:

Dissolve cabazitaxel (5 g) in 50 ml of acetone, heat to reflux, add 100 ml of n-hexane dropwise with stirring, cool to room temperature after the drop, stir for 1 h, filter with suction, wash with n-hexane, and dry in vacuum at 40°C overnight to obtain 4.2 g white solid. The purity as measured by HPLC is 99.97%, and the mass percentage of acetone as measured by gas chromatography is 4.95%.

Example 2:

Dissolve cabazitaxel (1g) in 5ml acetone and 5ml butanone, heat to 50°C, add 20ml of n-hexane dropwise under stirring, cool to room temperature after dropping, stir for 1h, filter with suction, wash with n-hexane, vacuum at 40°C Drying overnight gave 0.5 g of a white solid. The purity as measured by HPLC is 99.91%, and the mass percentage of acetone as measured by gas chromatography is 4.85%.

Example 3:

Dissolve Cabazitaxel (1g) in 10ml of acetone, heat to 50°C, add dropwise 20ml of cyclohexane under stirring, cool to room temperature after dropping, stir for 1h, filter with suction, wash with cyclohexane, and dry overnight at 40°C under vacuum 0.6 g of white solid were obtained. The purity as measured by HPLC is 99.93%, and the mass percentage of acetone as measured by gas chromatography is 4.9%.

Example 4:

Dissolve Cabazitaxel (1g) in 10ml of acetone, heat to 50°C, add 20ml of n-heptane dropwise under stirring, cool to room temperature after the drop, stir for 1h, filter with suction, wash with n-heptane, and dry overnight at 40°C under vacuum 0.8 g of white solid were obtained. The purity as measured by HPLC is 99.95%, and the mass percentage of acetone as measured by gas chromatography is 4.9%.

Example 5:

Cabazitaxel (1 g) was dissolved in 10 ml of acetone, and 20 ml of n-heptane was added dropwise with stirring. After the dripping was completed, it was stirred for 1 h, filtered with suction, washed with n-heptane, and dried under vacuum at 40° C. overnight to obtain 0.7 g of a white solid. The purity as measured by HPLC is 99.92%, and the mass percentage of acetone as measured by gas chromatography is 4.8%.

Embodiment 6: stability analysis

Referring to Appendix VD of Part Two of the Chinese Pharmacopoeia 2010 Edition, appropriate amounts of cabazitaxel acetonide obtained in Example 1 and cabazitaxel monoacetonate prepared according to the method of patent WO2005028462 were taken and tested according to the following conditions. The experimental results are shown in the table below.

HPLC conditions:

Instrument: Agilent1100

Chromatographic column: C18, 4.6×150mm, 5μm

Column temperature: 25°C

Detection wavelength: 230nm

Mobile phase: acetonitrile: water (60:40-80:20)

Flow rate: 1.0ml/min

Comparison of accelerated and long-term stability test results

Gas chromatography test of the present invention is carried out according to the following conditions:

Instrument: Agilent 7890A gas chromatograph;

Chromatographic column: DB-624 capillary column (30m×0.53mm×3.0μm)

Column temperature: the initial temperature is 40°C, keep for 5 minutes; increase the temperature to 200°C at a rate of 40°C per minute, and keep for 2 minutes.

Inlet temperature: 250°C Detector (FID) temperature: 300°C

Carrier gas: Nitrogen Flow rate: 3ml/min Split ratio: 10:1

Sample: DMSO solution of the product, concentration 100mg/ml, injection volume: 1μl.

The powder X-ray diffraction test of the present invention is carried out according to the following conditions:

Measured by Bruker D8 ADVANCE instrument. The measurement conditions are as follows: light source: CuKα 40kV 40mA, graphite monochromator, divergence slit (DS): 1°; anti-scatter slit (SS): 1°; LynxEye array detector, scanning mode: θ/θ, continuous scanning; scanning Range: 3°～45°, scanning speed 8°/min.

Claims (12)

1. Cabazitaxel acetone compound crystallization, wherein in every mole of Cabazitaxel, the content of acetone is 0.75 mole, in its powder x-ray diffraction collection of illustrative plates, is that 7.50,7.90,10.15,14.37,15.79,19.82 degree of places have diffraction peak at angle of diffraction 2 θ.

2. crystallization according to claim 1, in its powder x-ray diffraction collection of illustrative plates, is that 7.50,7.90,8.86,10.15,13.50,14.37,15.00,15.79,17.64,19.82 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 7.50,7.90,8.86,10.15,12.81,13.50,14.37,15.00,15.79,17.64,18.18,19.15,19.82,21.75,22.96 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 7.50,7.90,8.86,10.15,12.58,12.81,13.50,14.37,15.00,15.79,16.60,17.64,18.18,18.51,19.15,19.82,21.75,22.17,22.96,23.79 degree of places have diffraction peak at angle of diffraction 2 θ.

5. prepare the method for the crystallization described in any one of claim 1-4, comprising:

A Cabazitaxel is dissolved in the solvent containing acetone by (),

B () adds anti-solvent in the solution of step a,

C () separates out the crystallization of Cabazitaxel acetone compound;

Wherein, the anti-solvent described in step b is C _5-12aliphatic hydrocarbon or C _2-5alkyl-O-C _2-5the ether solvents of alkyl.

6. method according to claim 5, the anti-solvent wherein described in step b is Skellysolve A, normal hexane, normal heptane.

7. crystal composition, the Cabazitaxel acetone compound crystallization wherein described in any one of claim 1-4 accounts for more than 50% of crystal composition weight.

8. crystal composition according to claim 7, the Cabazitaxel acetone compound crystallization wherein described in any one of claim 1-4 accounts for crystal composition weight more than 80%.

9. crystal composition according to claim 8, the Cabazitaxel acetone compound crystallization wherein described in any one of claim 1-4 accounts for crystal composition weight more than 90%.

10. crystal composition according to claim 9, the Cabazitaxel acetone compound crystallization wherein described in any one of claim 1-4 accounts for crystal composition weight more than 95%.

11. pharmaceutical compositions, it comprises the crystallization described in any one of claim 1-4 or the crystal composition described in any one of claim 7-10.

Crystallization described in 12. any one of claim 1-4, the crystal composition described in claim 7-10 or pharmaceutical composition according to claim 11 are preparing the purposes in anti-tumor drug.