Novel crystal forms of Buddhist nun and preparation method thereof is replaced according to ShandongArt
The present invention relates to chemical medicine, particularly relate to novel crystal forms replacing Buddhist nun according to Shandong and preparation method thereof.
Background technology
1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidinesBase]-2-propylene-1-ketone (compound shown in formula I) is by biopharmaceutical company of the U.S. (Pharmacyclics)Exploitation, on November 13rd, 2013 single as jacket cell lymphatic cancer of FDA's approvedMedicine.This compound (according to Shandong for Buddhist nun, Ibrutinib) is a kind of targeting preparation, optionally presses downBruton's tyrosine kinase processed (BTK), this enzyme is important Jie of at least three kinds of crucial B-cells survival mechanismMatter.This multiple action of bruton's tyrosine kinase can make it command B-cell malignancies to carry out into pouringBar tissue, enable tumor cell contact necessity microenvironment and existence.FDA (Food and Drug Adminstration)(FDA) this compound (Ibrutinib) " breakthrough " status has been authorized for two kinds of B-malignant for the treatment ofTumor.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-base]-piperidino] A without hydrate crystal forms of-2-propylene-1-ketone, crystal formation B, crystal formation CAnd solvate crystal formation D, crystal formation E, crystal formation F.The X-ray diffractogram of crystal formation A is in 2-Theta valueIt is, 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 °, there is spyLevy peak；The X-ray diffractogram of crystal formation B 2-Theta value be 5.2 ± 0.1 °, 10.2 ± 0.1 °, 16.5 ± 0.1 °,At 18.5 ± 0.1 ° and 20.8 ± 0.1 °, there is characteristic peak；The X-ray diffractogram of crystal formation C in 2-Theta value is7.0±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°、At 22.1 ± 0.1 ° and 22.9 ± 0.1 °, there is characteristic peak；Crystal formation D is methyl isobutyl ketone solvent compound；Crystal formation EFor 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]-piperidino] novel crystal forms of-2-propylene-1-ketone, named crystal formation II in the present invention, crystal formation III, brilliantType IV, crystal formation V, crystal formation VI, crystal form VII, crystal formation VIII.
Further, the crystal formation II that the present invention provides is without hydrate, and crystal formation III is hydrate, crystal formation IVFor oxolane (THF) solvate, crystal formation V, crystal formation VI, crystal form VII are chloroform solvent and closeThing.
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 °,At 9.9 ± 0.2 °, there is characteristic peak.
Further, the crystal formation II that the present invention provides, its x-ray diffraction pattern in 2theta value is also23.3±0.2°、12.4±0.2°、13.3±0.2°、11.4±0.2°、15.1±0.2°、14.2±0.2°、20.3±0.2°Place has characteristic peak, as shown in Figure 1.
Further, the crystal formation II that the present invention provides, its differential scanning calorimetry (DSC) is analyzed and is being addedThere is first endothermic peak near initial temperature 104.6 DEG C in heat, occurs near peak temperature 134.6 DEG CSecond endothermic peak, as shown in Figure 2.
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-, and [[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] is phonetic for (3R)-3-Pyridine-1-base]-piperidino] preparation method of-2-propylene-1-ketone crystal formation II, comprise the steps: by1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-piperidino]-2-The powder of propylene-1-ketone is dissolved in methanol/water mixed solvent, obtains suspension, stirring analysis under the conditions of 50 DEG CCrystalline substance, obtains crystal formation II.
Further, described methanol/water mixed solvent, preferred 1:1 to the 4:1 of volume ratio of methanol and water itBetween, 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 °,At 23.1 ± 0.2 °, there is characteristic peak.
Further, the crystal formation III that the present invention provides, its x-ray diffraction pattern in 2theta value is also20.8±0.2°、20.6±0.2°、20.3±0.2°、13.6±0.2°、12.0±0.2°、24.1±0.2°、18.7±0.2°Place has characteristic peak, as shown in Figure 4.
Further, the crystal formation III that the present invention provides, its differential scanning calorimetry (DSC) is analyzed and is being addedThere is first endothermic peak near initial temperature 35.5 DEG C in heat, is being heated near initial temperature 99.4 DEG C going outExisting second endothermic peak, is being heated near peak temperature 116.7 DEG C occurring the 3rd endothermic peak, such as Fig. 5Shown in.
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]-piperidino] 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]-piperidino]-2-propylene-1-ketonePowder is dissolved in the mixed solvent of methanol/water, obtains suspension, and stirring and crystallizing under room temperature condition obtains crystalline substanceType III.
Further, described methanol/water mixed solvent, preferred 1:1 to the 4:1 of volume ratio of methanol and water itBetween, more preferably ratio is 2:1.
The crystal formation IV that the present invention provides, its x-ray diffraction pattern 2theta value be 6.3 ± 0.2 °, 18.0 ± 0.2 ° withAt 10.2 ± 0.2 °, there is characteristic peak.
Further, the crystal formation IV that the present invention provides, its x-ray diffraction pattern in 2theta value is also19.5 ± 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 °Place has characteristic peak, as shown in Figure 7.
Further, the crystal formation IV that the present invention provides, its differential scanning calorimetry (DSC) is analyzed and is being addedHeat, to occurring first endothermic peak near initial temperature 95.7 DEG C, occurs the near initial temperature 129.5 DEG CTwo endothermic peaks, as shown in Figure 8.
Further, the crystal formation IV that the present invention provides, it is heated to when 115 DEG C the weightlessness with about 6.3%,Having again the weightlessness of about 0.4% when being heated to 143 DEG C, 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]-piperidino] 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]-piperidino]-2-propylene-1-ketonePowder is dissolved in the mixed solvent of ethanol/water, obtains suspension, stirring and crystallizing under room temperature condition, collects solidBody is re-dissolved in the mixed solvent of thf/n-heptane, obtains suspension, is first risen by gained suspensionTemperature is to about 50 DEG C, then slow cooling is to about 5 DEG C, obtains crystal formation IV.
Further, the mixed solvent of described ethanol/water, the preferred 1:1 of ratio of second alcohol and water；Described fourThe preferred 1:1 of volume ratio of hydrogen furan/normal heptane mixed solvent, oxolane and normal heptane.
The crystal formation V that the present invention provides, its x-ray diffraction pattern is 21.0 ± 0.2 °, 22.3 ± 0.2 ° in 2theta valueAt 6.2 ± 0.2 °, there is characteristic peak.
Further, the crystal formation V that the present invention provides, its x-ray diffraction pattern in 2theta value is also19.3 ± 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 °Place has characteristic peak, as shown in Figure 10.
Further, the crystal formation V that the present invention provides, its differential scanning calorimetry (DSC) is analyzed and is being addedHeat, to occurring first endothermic peak near initial temperature 47.1 DEG C, occurs the near peak temperature 61.3 DEG CTwo endothermic peaks, occur the 3rd endothermic peak near initial temperature 93.3 DEG C, attached peak temperature 132.3 DEG CThere is the 4th endothermic peak in part, 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, there is 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-, and [[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] is phonetic for (3R)-3-Pyridine-1-base]-piperidino] preparation method of-2-propylene-1-ketone crystal formation V, comprise the steps: by1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-piperidino]-2-The powder of propylene-1-ketone is dissolved in the mixed solvent of chloroform/normal heptane, obtains suspension, first at 50 DEG CUnder the conditions of stand, until solution clarify after, under the conditions of-20 DEG C place 20 hours, obtain crystal formation V.
Further, described chloroform/normal heptane mixed solvent, chloroform and the volume of normal heptaneRatio preferably 1:3.
The crystal formation VI that the present invention provides, its x-ray diffraction pattern is 20.6 ± 0.2 °, 21.1 ± 0.2 ° in 2theta valueAt 22.4 ± 0.2 °, there is characteristic peak.
Further, the crystal formation VI that the present invention provides, its x-ray diffraction pattern in 2theta value is also22.2 ± 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 °Place has characteristic peak, as shown in figure 13.
Further, the crystal formation VI that the present invention provides, its differential scanning calorimetry (DSC) is analyzed and is being addedHeat, to occurring first endothermic peak time near initial temperature 46.9 DEG C, occurs the near peak temperature 61.6 DEG CTwo endothermic peaks, occur the 3rd endothermic peak near peak temperature 73.4 DEG C, attached initial temperature 95.3 DEG C4th endothermic peak occurs, as shown in figure 14 time near.
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, there is 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]-piperidino] preparation method of-2-propylene-1-ketone crystal formation VI, comprise the steps: 1-[(3R)-3-[4-Amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-piperidino]-2-propylene-1-ketone crystalline substanceStand under the conditions of the solid room temperature of type V and i.e. obtain crystal formation VI；Or by 1-[(3R)-3-[4-amino-3-(4-phenoxy groupPhenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-piperidino] solid of-2-propylene-1-ketone crystal formation V is heated to50 DEG C also obtain crystal formation VI.
The crystal form VII that the present invention provides, its x-ray diffraction pattern is 19.4 ± 0.2 °, 17.7 ± 0.2 ° in 2theta valueAt 22.8 ± 0.2 °, there is characteristic peak.
Further, the crystal form VII that the present invention provides, its x-ray diffraction pattern in 2theta value is alsoAt 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 °There is characteristic peak, as shown in figure 16.
Further, the crystal form VII that the present invention provides, its differential scanning calorimetry (DSC) is analyzed and is being addedHeat, to occurring first endothermic peak time near initial temperature 93.5 DEG C, occurs near initial temperature 129.4 DEG CSecond endothermic peak, as shown in figure 17.
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]-piperidino] preparation method of-2-propylene-1-ketone crystal form VII, comprise the steps: 1-[(3R)-3-[4-Amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-piperidino]-2-propylene-1-ketone crystalline substanceThe solid of type V or crystal formation VI is heated to 90 DEG C and i.e. obtains crystal form VII.
The crystal formation VIII that the present invention provides, its x-ray diffraction pattern 2theta value be 22.4 ± 0.2 °, 23.3 ± 0.2 ° withAt 10.2 ± 0.2 °, there is characteristic peak.
Further, the crystal formation VIII that the present invention provides, its x-ray diffraction pattern in 2theta value is also17.0 ± 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 °Place has characteristic peak, as shown in figure 19.
The present invention provides a kind of 1-, and [[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] is phonetic for (3R)-3-Pyridine-1-base]-piperidino] preparation method of-2-propylene-1-ketone crystal formation VIII, comprise the steps: by1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-piperidino]-2-The powder of propylene-1-ketone is dissolved in the mixed solvent of ethanol/water, obtains suspension, stirs under room temperature conditionCrystallize, collects solid and is re-dissolved in methanol/water mixed solvent, obtain suspension, by gained suspension firstIt is warming up to about 50 DEG C, then slow cooling is to about 5 DEG C, obtains crystal formation VIII.
Further, the mixed solvent of described ethanol/water, the preferred 1:1 of ratio of second alcohol and water；Described firstAlcohol/water mixed solvent, between preferred 1:1 to the 4:1 of volume ratio of methanol/water.
Accompanying drawing explanation
Fig. 1 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidinesBase] X-ray powder diffraction (XRPD) figure of-2-propylene-1-ketone crystal formation II
Fig. 2 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperazinePiperidinyl] means of differential scanning calorimetry (DSC) figure of-2-propylene-1-ketone crystal formation II
Fig. 3 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidinesBase] thermogravimetric analysis (TGA) figure of-2-propylene-1-ketone crystal formation II
Fig. 4 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidinesBase] X-ray powder diffraction (XRPD) figure of-2-propylene-1-ketone crystal formation III
Fig. 5 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperazinePiperidinyl] means of differential scanning calorimetry (DSC) figure of-2-propylene-1-ketone crystal formation III
Fig. 6 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidinesBase] thermogravimetric analysis (TGA) figure of-2-propylene-1-ketone crystal formation III
Fig. 7 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidinesBase] X-ray powder diffraction (XRPD) figure of-2-propylene-1-ketone crystal formation IV
Fig. 8 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperazinePiperidinyl] means of differential scanning calorimetry (DSC) figure of-2-propylene-1-ketone crystal formation IV
Fig. 9 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperidinesBase] thermogravimetric analysis (TGA) figure of-2-propylene-1-ketone crystal formation IV
Figure 10 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperazinePiperidinyl] X-ray powder diffraction (XRPD) figure of-2-propylene-1-ketone crystal formation V
Figure 11 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperazinePiperidinyl] means of differential scanning calorimetry (DSC) figure of-2-propylene-1-ketone crystal formation V
Figure 12 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperazinePiperidinyl] thermogravimetric analysis (TGA) figure of-2-propylene-1-ketone crystal formation V
Figure 13 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperazinePiperidinyl] X-ray powder diffraction (XRPD) figure of-2-propylene-1-ketone crystal formation VI
Figure 14 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperazinePiperidinyl] means of differential scanning calorimetry (DSC) figure of-2-propylene-1-ketone crystal formation VI
Figure 15 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperazinePiperidinyl] thermogravimetric analysis (TGA) figure of-2-propylene-1-ketone crystal formation VI
Figure 16 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperazinePiperidinyl] X-ray powder diffraction (XRPD) figure of-2-propylene-1-ketone crystal form VII
Figure 17 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperazinePiperidinyl] means of differential scanning calorimetry (DSC) figure of-2-propylene-1-ketone crystal form VII
Figure 18 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperazinePiperidinyl] thermogravimetric analysis (TGA) figure of-2-propylene-1-ketone crystal form VII
Figure 19 is 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-piperazinePiperidinyl] X-ray powder diffraction (XRPD) figure of-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 the protection of the present inventionScope.Preparation method and use instrument can be made improvements by those skilled in the art within the scope of the claims,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 with appendedClaim is as the criterion.
In following embodiment, except as otherwise noted, described test method is generally according to normal condition or manufactureCondition recommended by the 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 is at Panalytical Empyrean X-ray powder diffractionGather on 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 present inventionThe method parameter that described means of differential scanning calorimetry (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.Heat of the present inventionThe method parameter of weight analysis (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:
1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-piperidino]-2-The preparation method of propylene-1-ketone crystal formation II:
By 48.6mg 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-Base]-piperidino] powder of-2-propylene-1-ketone is dissolved in the methanol/water mixed solvent that 0.5mL volume ratio is 2:1In, obtain 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 °,At 20.3 °, there is characteristic peak.
Embodiment 2:
1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-piperidino]-2-The preparation method of propylene-1-ketone crystal formation III:
By 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine of 99.9mg-1-base]-piperidino] powder of-2-propylene-1-ketone is dissolved in the mixing of the methanol/water that 0.6mL volume ratio is 2:1In solvent, 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 characterised in that2theta value be 4.5 °, 16.8 °, 23.0 °, 20.8 °, 20.6 °, 20.3 °, 13.5 °, 12.0 °, 24.1 °,At 18.7 °, there is characteristic peak.
Embodiment 3:
1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-piperidino]-2-The preparation method of propylene-1-ketone crystal formation IV:
By 98.1mg 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-Base]-piperidino] to be dissolved in the methanol/water mixing that 2.5mL volume ratio is 2:1 molten for the powder of-2-propylene-1-ketoneIn agent, stirring 24 hours and separate out to solid under room temperature condition, collection solid takes 46.5mg and is dissolved in 0.6mLVolume ratio is in the thf/n-heptane mixed solvent of 1:1, obtains suspension, is first risen by gained suspensionTemperature is to 50 DEG C, then with the speed slow cooling of 0.1 DEG C/min to 5 DEG C, obtains crystal formation IV.
The crystal formation IV obtained, its X-ray powder diffraction figure (XRPD) is as shown in Figure 7, it is characterised in that,2theta value be 6.3 °, 18.0 °, 19.5 °, 10.3 °, 23.0 °, 19.2 °, 20.6 °, 17.3 °, 24.2 °,At 22.3 °, there is characteristic peak.
Embodiment 4:
1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-piperidino]-2-The preparation method of propylene-1-ketone crystal formation V:
By 350.9mg 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-Base]-piperidino] powder of-2-propylene-1-ketone is dissolved in the chloroform that volume ratio is 1:3 of 18mL/justIn heptane mixed solvent, place under the conditions of 50 DEG C 1 hour and clarify to solution, then gained clear liquor is placed inUnder the conditions of-20 DEG C, after standing 3 days, i.e. can get crystal formation V.
The crystal formation V obtained, as shown in Figure 10, its feature exists its X-ray powder diffraction figure (XRPD)In, it is 21.0 °, 22.3 °, 6.2 °, 19.3 °, 20.4 °, 21.9 °, 19.0 °, 20.6 °, 31.7 ° in 2theta valueAt 23.5 °, there is characteristic peak.
Embodiment 5:
1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-piperidino]-2-The preparation method of propylene-1-ketone crystal formation VI:
Method one:
By 10mg 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-Base]-piperidino] solid of-2-propylene-1-ketone crystal formation V is heated to the speed of 10 DEG C/min in TGA50 DEG C, then naturally cool to room temperature and i.e. can get crystal formation VI.
Method two:
By 10mg 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-Base]-piperidino]-2-propylene-1-ketone crystal formation V solid room temperature under the conditions of place within 4 hours, i.e. can get crystal formationⅥ。
The crystal formation VI obtained, as shown in figure 13, its feature exists its X-ray powder diffraction figure (XRPD)In, it is 20.6 °, 21.1 °, 22.4 °, 22.2 °, 21.3 °, 19.2 °, 31.9 °, 25.5 °, 12.8 ° in 2theta valueAt 23.7 °, there is characteristic peak.
Embodiment 6:
1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-piperidino]-2-The preparation method of propylene-1-ketone crystal form VII:
By 10mg 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-Base]-piperidino] solid of-2-propylene-1-ketone crystal formation V is heated to the speed of 10 DEG C/min in TGA90 DEG C, naturally cool to room temperature and i.e. can get crystal form VII.
The crystal form VII obtained, as shown in figure 16, its feature exists its X-ray powder diffraction figure (XRPD)In, it is 19.4 °, 17.7 °, 22.9 °, 18.1 °, 7.5 °, 24.4 °, 20.7 °, 6.3 °, 15.9 ° in 2theta valueAt 9.7 °, there is characteristic peak.
Embodiment 7:
1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-piperidino]-2-The preparation method of propylene-1-ketone crystal formation VIII:
By 101.1mg 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-Base]-piperidino] powder of-2-propylene-1-ketone is dissolved in the ethanol/water that volume ratio the is 1:1 mixing of 1mLIn solvent, room temperature stirs under conditions 24 hours and separates out to solid, and collection solid takes 4mg and is dissolved in 1mLVolume ratio is in the methanol/water mixed solvent of 2:1, obtains 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, as shown in figure 19, its feature exists its X-ray powder diffraction figure (XRPD)In, 2theta value be 22.4 °, 23.3 °, 10.2 °, 22.6 °, 21.2 °, 21.4 °, 23.0 °, 11.7 °,At 24.7 ° and 20.8 °, there is characteristic peak.