CN106008515A - New crystal form of ibrutinib and preparation method of new crystal form - Google Patents
New crystal form of ibrutinib and preparation method of new crystal form Download PDFInfo
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- CN106008515A CN106008515A CN201610347335.XA CN201610347335A CN106008515A CN 106008515 A CN106008515 A CN 106008515A CN 201610347335 A CN201610347335 A CN 201610347335A CN 106008515 A CN106008515 A CN 106008515A
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- crystal formation
- base
- pyrazolo
- propylene
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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 invention relates to a new crystal form of ibrutinib and a preparation method of the new crystal form. The new crystal form is named as a crystal form V; an X-ray powder diffraction pattern of the new crystal form V has characteristic peaks at parts with 2theta values of 19.3+/-0.2 degrees, 20.4+/-0.2 degrees, 21.9+/-0.2 degrees, 19.0+/-0.2 degrees, 20.6+/-0.2 degrees, 31.7+/-0.2 degrees and 23.5+/-0.2 degrees. The structural formula is shown in the description.
Description
Art
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-piperidines
Base]-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 approved
Medicine.This compound (according to Shandong for Buddhist nun, Ibrutinib) is a kind of targeting preparation, optionally presses down
Bruton's tyrosine kinase processed (BTK), this enzyme is important Jie of at least three kinds of crucial B-cells survival mechanism
Matter.This multiple action of bruton's tyrosine kinase can make it command B-cell malignancies to carry out into pouring
Bar 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 of
Tumor.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 C
And solvate crystal formation D, crystal formation E, crystal formation F.The X-ray diffractogram of crystal formation A is in 2-Theta value
It 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 spy
Levy 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 is
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°、
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 E
For 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, brilliant
Type 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 IV
For oxolane (THF) solvate, crystal formation V, crystal formation VI, crystal form VII are chloroform solvent and close
Thing.
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 °,
9.9 there is characteristic peak at ± 0.2 °.
Further, the crystal formation II that the present invention provides, its x-ray diffraction pattern in 2theta value is also
23.3±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 added
There is first endothermic peak near initial temperature 104.6 DEG C in heat, occurs near peak temperature 134.6 DEG C
Second 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: by
1-[(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 C
Crystalline 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 it
Between, 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 also
20.8±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 added
There is first endothermic peak near initial temperature 35.5 DEG C in heat, is being heated near initial temperature 99.4 DEG C going out
Existing second endothermic peak, is being heated near peak temperature 116.7 DEG C occurring the 3rd endothermic peak, such as Fig. 5
Shown 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-ketone
Powder is dissolved in the mixed solvent of methanol/water, obtains suspension, and stirring and crystallizing under room temperature condition obtains crystalline substance
Type III.
Further, described methanol/water mixed solvent, preferred 1:1 to the 4:1 of volume ratio of methanol and water it
Between, 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 ° with
At 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 also
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 °
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 added
Heat, to occurring first endothermic peak near initial temperature 95.7 DEG C, occurs the near initial temperature 129.5 DEG C
Two 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-ketone
Powder is dissolved in the mixed solvent of ethanol/water, obtains suspension, stirring and crystallizing under room temperature condition, collects solid
Body is re-dissolved in the mixed solvent of thf/n-heptane, obtains suspension, is first risen by gained suspension
Temperature 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 four
The 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 value
At 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 also
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 °
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 added
Heat, to occurring first endothermic peak near initial temperature 47.1 DEG C, occurs the near peak temperature 61.3 DEG C
Two endothermic peaks, occur the 3rd endothermic peak near initial temperature 93.3 DEG C, attached peak temperature 132.3 DEG C
There 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: by
1-[(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 C
Under 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 heptane
Ratio 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 value
At 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 also
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 °
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 added
Heat, to occurring first endothermic peak time near initial temperature 46.9 DEG C, occurs the near peak temperature 61.6 DEG C
Two endothermic peaks, occur the 3rd endothermic peak near peak temperature 73.4 DEG C, attached initial temperature 95.3 DEG C
4th 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 substance
Stand 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 group
Phenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-piperidino] solid of-2-propylene-1-ketone crystal formation V is heated to
50 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 value
At 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 also
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 °
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 added
Heat, to occurring first endothermic peak time near initial temperature 93.5 DEG C, occurs near initial temperature 129.4 DEG C
Second 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 substance
The 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 ° with
At 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 also
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 °
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: by
1-[(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 condition
Crystallize, collects solid and is re-dissolved in methanol/water mixed solvent, obtain suspension, by gained suspension first
It 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 first
Alcohol/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-piperidines
Base] 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-piperazine
Piperidinyl] 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-piperidines
Base] 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-piperidines
Base] 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-piperazine
Piperidinyl] 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-piperidines
Base] 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-piperidines
Base] 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-piperazine
Piperidinyl] 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-piperidines
Base] 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-piperazine
Piperidinyl] 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-piperazine
Piperidinyl] 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-piperazine
Piperidinyl] 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-piperazine
Piperidinyl] 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-piperazine
Piperidinyl] 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-piperazine
Piperidinyl] 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-piperazine
Piperidinyl] 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-piperazine
Piperidinyl] 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-piperazine
Piperidinyl] 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-piperazine
Piperidinyl] 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 invention
Scope.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 appended
Claim is as the criterion.
In following embodiment, except as otherwise noted, described test method is generally according to normal condition or manufacture
Condition 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 diffraction
Gather 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 invention
The 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 invention
The 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 2:1
In, 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 2:1
In 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 that
2theta 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-ketone
In agent, stirring 24 hours and separate out to solid under room temperature condition, collection solid takes 46.5mg and is dissolved in 0.6mL
Volume ratio is in the thf/n-heptane mixed solvent of 1:1, obtains suspension, is first risen by gained suspension
Temperature 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/just
In heptane mixed solvent, place under the conditions of 50 DEG C 1 hour and clarify to solution, then gained clear liquor is placed in
Under 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 value
At 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 TGA
50 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 formation
Ⅵ。
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 value
At 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 TGA
90 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 value
At 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 1mL
In solvent, room temperature stirs under conditions 24 hours and separates out to solid, and collection solid takes 4mg and is dissolved in 1mL
Volume 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.
Claims (3)
1. 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-D] pyrimidine-1-base]-1-
Piperidyl] the solvate crystal formation V of-2-propylene-1-ketone, it is characterised in that its x-ray diffraction pattern is at 2theta
Value is to have characteristic peak at 21.0 ± 0.2 °, 22.3 ± 0.2 ° and 6.2 ± 0.2 °.
Crystal formation V the most according to claim 1, is further characterized in that, its x-ray diffraction pattern is at 2theta
Value is 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 °
Place has characteristic peak.
Crystal formation V the most according to claim 1, it is characterised in that its X-ray diffraction (XRPD)
Scheme substantially consistent with Figure 10.
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