CN103923084B - Several crystal formations and preparation method thereof - Google Patents
Several crystal formations and preparation method thereof Download PDFInfo
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- CN103923084B CN103923084B CN201410043636.4A CN201410043636A CN103923084B CN 103923084 B CN103923084 B CN 103923084B CN 201410043636 A CN201410043636 A CN 201410043636A CN 103923084 B CN103923084 B CN 103923084B
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- crystal formation
- phenoxyphenyl
- pyrazolo
- piperidyl
- pyrimidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-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
Abstract
The present invention provide 1 [(3R) 3 [4 amino 3 (4 Phenoxyphenyl) 1H pyrazolo [3,4 D] pyrimidine 1 base] 1 piperidyl] 2 propylene 1 ketone without hydrate, hydrate and solvate novel crystal forms and preparation method thereof.Several novel crystal forms that the present invention provides, can be used for treating various disease conditions, can be particularly used for treating the illness of jacket cell lymph cancer.
Description
Art
The present invention relates to chemical medicine, particularly relate to novel crystal forms of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone and preparation method thereof.
Background technology
1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone (compound shown in formula I) is to be developed by biopharmaceutical company of the U.S. (Pharmacyclics), on November 13rd, 2013, FDA's approved was as the single medicine of jacket cell lymph cancer.This compound (Ibrutinib) is a kind of targeting preparation, optionally suppresses bruton's tyrosine kinase (BTK), and this enzyme is the important medium of at least three kinds of crucial B-cells survival mechanism.This multiple action of bruton's tyrosine kinase can make it command B-cell malignancies to carry out into lymphoid tissue, enables tumour cell to contact the microenvironment of necessity and existence.FDA (Food and Drug Adminstration) (FDA) has authorized this compound (Ibrutinib) " breakthrough " status for two kinds of B-cell malignancies for the treatment of.The structure of this compound is as follows:
WO2013184572A1 discloses 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-the base]-1-piperidyl] A without hydrate crystal forms of-2-propylene-1-ketone, crystal formation B, crystal formation C and solvate crystal formation D, crystal formation E, crystal formation F.The X-ray diffractogram of crystal formation A is to have characteristic peak at 5.7 ± 0.1 °, 13.6 ± 0.1 °, 16.1 ± 0.1 °, 18.9 ± 0.1 °, 21.3 ± 0.1 ° and 21.6 ± 0.1 ° in 2-Theta value；The X-ray diffractogram of crystal formation B is to have characteristic peak at 5.2 ± 0.1 °, 10.2 ± 0.1 °, 16.5 ± 0.1 °, 18.5 ± 0.1 ° and 20.8 ± 0.1 ° in 2-Theta value；The X-ray diffractogram of crystal formation C is to have characteristic peak at 7.0 ± 0.1 °, 14.0 ± 0.1 °, 15.7 ± 0.1 °, 18.2 ± 0.1 °, 19.1 ± 0.1 °, 19.5 ± 0.1 °, 20.3 ± 0.1 °, 22.1 ± 0.1 ° and 22.9 ± 0.1 ° in 2-Theta value；Crystal formation D is methyl isobutyl ketone solvent compound；Crystal formation E is toluene solvate；Crystal formation F is Methanol solvate.
Summary of the invention
The present invention provides 7 kinds of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl] novel crystal forms of-2-propylene-1-ketone, named crystal formation II, crystal formation III, crystal formation IV, crystal formation V, crystal formation VI, crystal form VII, crystal formation VIII in the present invention.
Further, the crystal formation II that the present invention provides is without hydrate, and crystal formation III is hydrate, and crystal formation IV is oxolane (THF) solvate, and crystal formation V, crystal formation VI, crystal form VII are chloroform solvate.
The crystal formation II that the present invention provides, its x-ray diffraction pattern 2theta value be 4.9 ± 0.2 °, 20.8 ± 0.2 °, there is characteristic peak at 9.9 ± 0.2 °.
Further, the crystal formation II that the present invention provides, its x-ray diffraction pattern also 2theta value be 23.3 ± 0.2 °, 12.4 ± 0.2 °, 13.3 ± 0.2 °, 11.4 ± 0.2 °, 15.1 ± 0.2 °, 14.2 ± 0.2 °, there is characteristic peak, as shown in Figure 1 at 20.3 ± 0.2 °.
Further, the crystal formation II that the present invention provides, its differential scanning calorimetry (DSC) is analyzed and is being heated near initial temperature 104.6 DEG C occurring first endothermic peak, second endothermic peak occurs, as shown in Figure 2 near peak temperature 134.6 DEG C.
Further, the crystal formation II that the present invention provides, it is heated to when 85 DEG C the weightlessness with about 1.3%, its thermogravimetric analysis figure (TGA) is as shown in Figure 3.
The present invention provides a kind of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl] preparation method of-2-propylene-1-ketone crystal formation II, comprise the steps: 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl] powder of-2-propylene-1-ketone is dissolved in methanol/water mixed solvent, obtain suspension, stirring and crystallizing under the conditions of 50 DEG C, obtains crystal formation II.
Further, described methanol/water mixed solvent, between preferred 1:1 to the 4:1 of volume ratio of methyl alcohol and water, more preferably ratio is 2:1.
The crystal formation III that the present invention provides, its x-ray diffraction pattern 2theta value be 4.5 ± 0.2 °, 16.8 ± 0.2 °, there is characteristic peak at 23.1 ± 0.2 °.
Further, the crystal formation III that the present invention provides, its x-ray diffraction pattern also 2theta value be 20.8 ± 0.2 °, 20.6 ± 0.2 °, 20.3 ± 0.2 °, 13.6 ± 0.2 °, 12.0 ± 0.2 °, 24.1 ± 0.2 °, there is characteristic peak, as shown in Figure 4 at 18.7 ± 0.2 °.
Further, the crystal formation III that the present invention provides, its differential scanning calorimetry (DSC) is analyzed and is being heated near initial temperature 35.5 DEG C occurring first endothermic peak, it is being heated near initial temperature 99.4 DEG C occurring second endothermic peak, it is being heated near peak temperature 116.7 DEG C occurring the 3rd endothermic peak, as shown in Figure 5.
Further, the crystal formation III that the present invention provides, it is heated to when 60 DEG C the weightlessness with about 5.9%, its thermogravimetric analysis figure (TGA) is as shown in Figure 6.
The present invention provides 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl] preparation method of-2-propylene-1-ketone crystal formation III, comprise the steps: 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl] powder of-2-propylene-1-ketone is dissolved in the mixed solvent of methanol/water, obtain suspension, stirring and crystallizing under room temperature condition, obtains crystal formation III.
Further, described methanol/water mixed solvent, between preferred 1:1 to the 4:1 of volume ratio of methyl alcohol and water, more preferably ratio is 2:1.
The crystal formation IV that the present invention provides, its x-ray diffraction pattern is to have characteristic peak at 6.3 ± 0.2 °, 18.0 ± 0.2 ° and 10.2 ± 0.2 ° in 2theta value.
Further, the crystal formation IV that the present invention provides, its x-ray diffraction pattern is also to have characteristic peak, as shown in Figure 7 at 19.5 ± 0.2 °, 23.0 ± 0.2 °, 13.4 ± 0.2 °, 20.6 ± 0.2 °, 17.3 ± 0.2 °, 15.8 ± 0.2 ° and 22.3. ± 0.2 ° in 2theta value.
Further, the crystal formation IV that the present invention provides, its differential scanning calorimetry (DSC) is analyzed and is being heated near initial temperature 95.7 DEG C occurring first endothermic peak, second endothermic peak occurs, as shown in Figure 8 near initial temperature 129.5 DEG C.
Further, the crystal formation IV that the present invention provides, it is heated to when 115 DEG C the weightlessness with about 6.3%, when being heated to 143 DEG C, has again the weightlessness of about 0.4%, its thermogravimetric analysis figure (TGA) is as shown in Figure 9.
The present invention provides 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3, 4-D] pyrimidine-1-base]-1-piperidyl] preparation method of-2-propylene-1-ketone crystal formation IV, comprise the steps: 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3, 4-D] pyrimidine-1-base]-1-piperidyl] powder of-2-propylene-1-ketone is dissolved in the mixed solvent of ethanol/water, obtain suspension, stirring and crystallizing under room temperature condition, collect solid to be re-dissolved in the mixed solvent of thf/n-heptane, obtain suspension, gained suspension is first warming up to about 50 DEG C, slow cooling is to about 5 DEG C again, obtain crystal formation IV.
Further, the mixed solvent of described ethanol/water, the preferred 1:1 of ratio of second alcohol and water；The preferred 1:1 of volume ratio of described thf/n-heptane mixed solvent, oxolane and normal heptane.
The crystal formation V that the present invention provides, its x-ray diffraction pattern is to have characteristic peak at 21.0 ± 0.2 °, 22.3 ± 0.2 ° and 6.2 ± 0.2 ° in 2theta value.
Further, the crystal formation V that the present invention provides, its x-ray diffraction pattern is also to have characteristic peak, as shown in Figure 10 at 19.3 ± 0.2 °, 20.4 ± 0.2 °, 21.9 ± 0.2 °, 19.0 ± 0.2 °, 20.6 ± 0.2 °, 31.7 ± 0.2 ° and 23.5 ± 0.2 ° in 2theta value.
Further, the crystal formation V that the present invention provides, its differential scanning calorimetry (DSC) is analyzed and is being heated near initial temperature 47.1 DEG C occurring first endothermic peak, second endothermic peak occurs near peak temperature 61.3 DEG C, 3rd endothermic peak occurs near initial temperature 93.3 DEG C, at 132.3 DEG C of annexes of peak temperature, the 4th endothermic peak occurs, as shown in figure 11.
Further, the crystal formation V that the present invention provides, it is heated to when 90 DEG C the weightlessness with about 22.1%, when being heated to 200 DEG C, has again the weightlessness of about 6.6%.Its thermogravimetric analysis figure (TGA) is as shown in figure 12.
The present invention provides a kind of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3, 4-D] pyrimidine-1-base]-1-piperidyl] preparation method of-2-propylene-1-ketone crystal formation V, comprise the steps: 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3, 4-D] pyrimidine-1-base]-1-piperidyl] powder of-2-propylene-1-ketone is dissolved in the mixed solvent of chloroform/normal heptane, obtain suspension, first stand under the conditions of 50 DEG C, after solution is clarified, place 20 hours under the conditions of-20 DEG C, obtain crystal formation V.
Further, described chloroform/normal heptane mixed solvent, chloroform is preferably 1:3 with the volume ratio of normal heptane.
The crystal formation VI that the present invention provides, its x-ray diffraction pattern is to have characteristic peak at 20.6 ± 0.2 °, 21.1 ± 0.2 ° and 22.4 ± 0.2 ° in 2theta value.
Further, the crystal formation VI that the present invention provides, its x-ray diffraction pattern is also to have characteristic peak, as shown in figure 13 at 22.2 ± 0.2 °, 17.4 ± 0.2 °, 19.2 ± 0.2 °, 17.8 ± 0.2 °, 25.5 ± 0.2 °, 12.8 ± 0.2 ° and 23.7 ± 0.2 ° in 2theta value.
Further, the crystal formation VI that the present invention provides, its differential scanning calorimetry (DSC) is analyzed there is first endothermic peak when being heated near initial temperature 46.9 DEG C, second endothermic peak occurs near peak temperature 61.6 DEG C, 3rd endothermic peak occurs near peak temperature 73.4 DEG C, 4th endothermic peak occurs, as shown in figure 14 time near initial temperature 95.3 DEG C.
Further, the crystal formation VI that the present invention provides, it is heated to when 65 DEG C the weightlessness with about 16.6%, when being heated to 125 DEG C, has again the weightlessness of about 12.3%.Its thermogravimetric analysis figure (TGA) is as shown in figure 15.
The present invention provides 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl] preparation method of-2-propylene-1-ketone crystal formation VI, comprise the steps: i.e. to obtain crystal formation VI by standing under the conditions of the solid room temperature of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation V；Or the solid of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation V is heated to 50 DEG C also obtains crystal formation VI.
The crystal form VII that the present invention provides, its x-ray diffraction pattern is to have characteristic peak at 19.4 ± 0.2 °, 17.7 ± 0.2 ° and 22.8 ± 0.2 ° in 2theta value.
Further, the crystal form VII that the present invention provides, its x-ray diffraction pattern is also to have characteristic peak, as shown in figure 16 at 18.1 ± 0.2 °, 7.4 ± 0.2 °, 24.3 ± 0.2 °, 20.7 ± 0.2 °, 6.2 ± 0.2 °, 15.9 ± 0.2 ° and 9.6 ± 0.2 ° in 2theta value.
Further, the crystal form VII that the present invention provides, its differential scanning calorimetry (DSC) is analyzed there is first endothermic peak when being heated near initial temperature 93.5 DEG C, second endothermic peak occurs, as shown in figure 17 near initial temperature 129.4 DEG C.
Further, the crystal form VII that the present invention provides, it is heated to when 130 DEG C the weightlessness with about 9.8%, its thermogravimetric analysis figure (TGA) is as shown in figure 18.
The present invention provides 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl] preparation method of-2-propylene-1-ketone crystal form VII, comprise the steps: that the solid of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation V or crystal formation VI is heated to 90 DEG C i.e. obtains crystal form VII.
The crystal formation VIII that the present invention provides, its x-ray diffraction pattern is to have characteristic peak at 22.4 ± 0.2 °, 23.3 ± 0.2 ° and 10.2 ± 0.2 ° in 2theta value.
Further, the crystal formation VIII that the present invention provides, its x-ray diffraction pattern is also to have characteristic peak, as shown in figure 19 at 17.0 ± 0.2 °, 21.2 ± 0.2 °, 21.4 ± 0.2 °, 23.0 ± 0.2 °, 11.7 ± 0.2 °, 24.7 ± 0.2 ° and 15.2 ± 0.2 ° in 2theta value.
The present invention provides a kind of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3, 4-D] pyrimidine-1-base]-1-piperidyl] preparation method of-2-propylene-1-ketone crystal formation VIII, comprise the steps: 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3, 4-D] pyrimidine-1-base]-1-piperidyl] powder of-2-propylene-1-ketone is dissolved in the mixed solvent of ethanol/water, obtain suspension, stirring and crystallizing under room temperature condition, collect solid to be re-dissolved in methanol/water mixed solvent, obtain suspension, gained suspension is first warming up to about 50 DEG C, slow cooling is to about 5 DEG C again, obtain crystal formation VIII.
Further, the mixed solvent of described ethanol/water, the preferred 1:1 of ratio of second alcohol and water；Described methanol/water mixed solvent, between preferred 1:1 to the 4:1 of volume ratio of methanol/water.
Accompanying drawing explanation
Fig. 1 is X-ray powder diffraction (XRPD) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation II
Fig. 2 is means of differential scanning calorimetry (DSC) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation II
Fig. 3 is thermogravimetric analysis (TGA) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation II
Fig. 4 is X-ray powder diffraction (XRPD) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation III
Fig. 5 is means of differential scanning calorimetry (DSC) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation III
Fig. 6 is thermogravimetric analysis (TGA) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation III
Fig. 7 is X-ray powder diffraction (XRPD) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation IV
Fig. 8 is means of differential scanning calorimetry (DSC) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation IV
Fig. 9 is thermogravimetric analysis (TGA) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation IV
Figure 10 is X-ray powder diffraction (XRPD) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation V
Figure 11 is means of differential scanning calorimetry (DSC) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation V
Figure 12 is thermogravimetric analysis (TGA) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation V
Figure 13 is X-ray powder diffraction (XRPD) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation VI
Figure 14 is means of differential scanning calorimetry (DSC) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation VI
Figure 15 is thermogravimetric analysis (TGA) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation VI
Figure 16 is X-ray powder diffraction (XRPD) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal form VII
Figure 17 is means of differential scanning calorimetry (DSC) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal form VII
Figure 18 is thermogravimetric analysis (TGA) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal form VII
Figure 19 is X-ray powder diffraction (XRPD) figure of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation VIII
Detailed description of the invention
Hereinafter the present invention will be expanded on further by specific embodiment, but be not limited to protection scope of the present invention.Preparation method and use instrument can be made improvements by those skilled in the art within the scope of the claims, and these improvement also should be regarded as protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
In following embodiment, except as otherwise noted, the condition that described test method is generally advised according to normal condition or manufacturer is implemented；Shown raw material, reagent all can obtain by the way of commercially available purchase.
X-ray powder diffraction figure of the present invention gathers on Panalytical Empyrean x-ray powder diffraction instrument.The method parameter of X-ray powder diffraction of the present invention is as follows:
X ray reflection parameter: CuKa
1.540598；1.544426
K α 2/K α 1 intensity: 0.50
Voltage: 45 KVs (kV)
Electric current: 40 milliamperes (mA)
Divergent slit: automatically
Scan pattern: continuously
Sweep limits: from 3.0 to 40.0 degree
Sampling step length: 0.013 degree
Every pacing amount time: 17.85 seconds/step
Means of differential scanning calorimetry of the present invention (DSC) analysis chart gathers on TA Q2000.The method parameter that means of differential scanning calorimetry of the present invention (DSC) is analyzed is as follows:
Temperature range: room temperature-250 DEG C
Sweep speed: 10 DEG C/min
Protective gas: nitrogen 50 ml/min
Thermogravimetric analysis of the present invention (TGA) figure gathers on TA Q5000.The method parameter of thermogravimetric analysis of the present invention (TGA) is as follows:
Temperature range: room temperature-300 DEG C
Sweep speed: 10 DEG C/min
Protective gas: nitrogen 60 ml/min
Embodiment 1:
The preparation method of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation II:
By 48.6mg1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl] powder of-2-propylene-1-ketone is dissolved in the methanol/water mixed solvent that 0.5mL volume ratio is 2:1, obtains suspension.Stir 24 hours under the conditions of 50 DEG C, collect solid and i.e. obtain crystal formation II.
The crystal formation II obtained, its X-ray powder diffraction figure (XRPD) is as shown in Figure 1, it is characterised in that, 2theta value be 4.9 °, 20.7 °, 23.0 °, 23.3 °, 9.9 °, 22.7 °, 11.4 °, 15.1 °, 17.1 °, there is characteristic peak at 20.3 °.
Embodiment 2:
The preparation method of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation III:
By 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3 of 99.9mg, 4-D] pyrimidine-1-base]-1-piperidyl] powder of-2-propylene-1-ketone is dissolved in the mixed solvent of the methanol/water that 0.6mL volume ratio is 2:1, obtaining suspension, under room temperature condition, stirring i.e. can get crystal formation III in 5 hours.
The crystal formation III obtained, its X-ray powder diffraction figure (XRPD) is as shown in Figure 4, it is characterized in that, 2theta value be 4.5 °, 16.8 °, 23.0 °, 20.8 °, 20.6 °, 20.3 °, 13.5 °, 12.0 °, 24.1 °, there is characteristic peak at 18.7 °.
Embodiment 3:
The preparation method of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation IV:
By 98.1mg1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl] powder of-2-propylene-1-ketone is dissolved in the methanol/water mixed solvent that 2.5mL volume ratio is 2:1, stir under room temperature condition 24 hours and separate out to solid, collection solid takes 46.5mg and is dissolved in the thf/n-heptane mixed solvent that 0.6mL volume ratio is 1:1, obtain suspension, gained suspension is first warming up to 50 DEG C, again with the speed slow cooling of 0.1 DEG C/min to 5 DEG C, obtain crystal formation IV.
The crystal formation IV obtained, its X-ray powder diffraction figure (XRPD) is as shown in Figure 7, it is characterized in that, 2theta value be 6.3 °, 18.0 °, 19.5 °, 10.3 °, 23.0 °, 19.2 °, 20.6 °, 17.3 °, 24.2 °, there is characteristic peak at 22.3 °.
Embodiment 4:
The preparation method of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation V:
By 350.9mg1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl] powder of-2-propylene-1-ketone is dissolved in the chloroform that volume ratio the is 1:3/normal heptane mixed solvent of 18mL, place under the conditions of 50 DEG C 1 hour and clarify to solution, under the conditions of again gained clarified solution being placed in-20 DEG C, after standing 3 days, i.e. can get crystal formation V.
The crystal formation V obtained, its X-ray powder diffraction figure (XRPD) is as shown in Figure 10, it is characterized in that, be, at 21.0 °, 22.3 °, 6.2 °, 19.3 °, 20.4 °, 21.9 °, 19.0 °, 20.6 °, 31.7 ° and 23.5 °, there is characteristic peak in 2theta value.
Embodiment 5:
The preparation method of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation VI:
Method one:
By 10mg1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl] solid of-2-propylene-1-ketone crystal formation V is heated to 50 DEG C with the speed of 10 DEG C/min in TGA, and then naturally cool to room temperature and i.e. can get crystal formation VI.
Method two:
Within 4 hours, crystal formation VI is i.e. can get by placing under the conditions of the solid room temperature of 10mg1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation V.
The crystal formation VI obtained, its X-ray powder diffraction figure (XRPD) is as shown in figure 13, it is characterized in that, be, at 20.6 °, 21.1 °, 22.4 °, 22.2 °, 21.3 °, 19.2 °, 31.9 °, 25.5 °, 12.8 ° and 23.7 °, there is characteristic peak in 2theta value.
Embodiment 6:
The preparation method of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal form VII:
By 10mg1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl] solid of-2-propylene-1-ketone crystal formation V is heated to 90 DEG C with the speed of 10 DEG C/min in TGA, and naturally cool to room temperature and i.e. can get crystal form VII.
The crystal form VII obtained, its X-ray powder diffraction figure (XRPD) is as shown in figure 16, it is characterised in that be to have characteristic peak at 19.4 °, 17.7 °, 22.9 °, 18.1 °, 7.5 °, 24.4 °, 20.7 °, 6.3 °, 15.9 ° and 9.7 ° in 2theta value.
Embodiment 7:
The preparation method of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl]-2-propylene-1-ketone crystal formation VIII:
By 101.1mg1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidyl] powder of-2-propylene-1-ketone is dissolved in the ethanol/water mixed solvent that volume ratio is 1:1 of 1mL, room temperature stirs under conditions 24 hours and separates out to solid, collection solid takes 4mg and is dissolved in the methanol/water mixed solvent that 1mL volume ratio is 2:1, obtain suspension, gained suspension is first warming up to 50 DEG C, again with the speed slow cooling of 0.1 DEG C/min to 5 DEG C, obtain crystal formation VIII.
The crystal formation VIII obtained, its X-ray powder diffraction figure (XRPD) is as shown in figure 19, it is characterized in that, be, at 22.4 °, 23.3 °, 10.2 °, 22.6 °, 21.2 °, 21.4 °, 23.0 °, 11.7 °, 24.7 ° and 20.8 °, there is characteristic peak in 2theta value.
Claims (2)
1. 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-
Piperidyl] anhydrous crystal forms II of-2-propylene-1-ketone, it is characterised in that its x-ray diffraction pattern in 2theta value is
4.9±0.2°、9.9±0.2°、11.4±0.2°、12.4±0.2°、13.3±0.2°、14.2±0.2°、15.1±0.2°、
20.3 ± 0.2 °, 20.8 ± 0.2 °, there is characteristic peak at 23.3 ± 0.2 °.
Crystal formation II the most according to claim 1, it is characterised in that its X-ray diffraction (XRPD)
Scheme substantially consistent with Fig. 1.
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