CN106279170A - Anhydrous crystal forms of 5-fluoro-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) propyl group)-3H-quinazoline-4-one and preparation method thereof - Google Patents
Anhydrous crystal forms of 5-fluoro-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) propyl group)-3H-quinazoline-4-one and preparation method thereof Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title claims abstract description 19
- 239000002904 solvent Substances 0.000 claims abstract description 16
- 230000015572 biosynthetic process Effects 0.000 claims description 49
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 14
- 239000012296 anti-solvent Substances 0.000 claims description 8
- 229930195733 hydrocarbon Natural products 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 7
- 239000004215 Carbon black (E152) Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 150000008282 halocarbons Chemical class 0.000 claims description 6
- 150000002430 hydrocarbons Chemical class 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 150000004292 cyclic ethers Chemical class 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- -1 nitroparaffin hydro carbons Chemical class 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 15
- 238000000034 method Methods 0.000 abstract description 8
- 238000005516 engineering process Methods 0.000 abstract description 5
- 239000012453 solvate Substances 0.000 abstract description 4
- 238000005457 optimization Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000000725 suspension Substances 0.000 description 9
- 238000002411 thermogravimetry Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IFSDAJWBUCMOAH-HNNXBMFYSA-N idelalisib Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)CC)=NC2=CC=CC(F)=C2C(=O)N1C1=CC=CC=C1 IFSDAJWBUCMOAH-HNNXBMFYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 108091007960 PI3Ks Proteins 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- 229960003445 idelalisib Drugs 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 2
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 2
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 230000000306 recurrent effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
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- 238000010998 test method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 102000038030 PI3Ks Human genes 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
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- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
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- 238000003760 magnetic stirring Methods 0.000 description 1
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- 239000002994 raw material Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
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- 229940095188 zydelig Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of directly 5-fluoro-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) propyl group)-3H-quinazoline-4-one anhydrous crystal forms that crystallize obtains from solvent and preparation method thereof.The anhydrous crystal forms that the present invention provides has good stability, and draws moist relatively low, and preparation method needs not move through solvate removing process, and preparation technology is simple to operate, with low cost, and optimization and exploitation to this medicine following have important value.
Description
Art
The present invention relates to chemical medicine, particularly relate to anhydrous crystal forms of 5-fluoro-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) propyl group)-3H-quinazoline-4-one and preparation method thereof.
Background technology
5-fluoro-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) propyl group)-3H-quinazoline-4-one (compound shown in formula I), have another name called Idelalisib, it it is the breakthrough PTS researched and developed by lucky moral (Gilead), U.S. food Drug Administration (FDA) approval is formally obtained on July 24th, 2014, list with trade name Zydelig, can be used for three indications: with the chronic lymphocytic leukemia (CLL) of Rituximab (Rituxan) therapeutic alliance recurrence, as single therapy recurrent follicular B cells non-Hodgkin lymphoma (FL) and recurrent small lymphocyte lymphoma (SLL).Idelalisib is that first selectivity is administered orally phosphoinositide 3-kinase delta inhibitor, phosphoinositide 3-kinase delta (PI3K-delta) is a kind of PI3K protein subtype of specific overactivation in B cell lymphoma, plays a crucial role tumor growth.Idelalisib chemical structural formula is as follows:
Polymorphism is widely present in medicine.The different crystal forms of same medicine has significant difference at aspects such as dissolubility, fusing point, density, stability, thus affects the stability of medicine, homogeneity, bioavailability, efficacy and saferry to some extent.Therefore, medicament research and development carries out comprehensive and systematic screening polymorph, select to be best suitable for the crystal formation of exploitation, be one of very important important research content.
Patent WO2013134288A1 discloses 2 kinds of anhydrous crystal forms (crystal formation I, crystal formation II) and preparation method thereof.
Patent WO2015014315A1 discloses 4 kinds of anhydrous crystal forms (crystal formation II, crystal formation III, crystal formation IV, crystal formation VIII).After deliberation, it is crystal formation I and the mixed crystal of crystal formation II that the crystal formation II of this patent report is crystal formation I in patent WO2013134288A1, crystal formation III.And these 4 kinds of anhydrous crystal forms are both needed to be obtained by solvate desolventizing, it is unfavorable for that commercial production is developed.
Summary of the invention
The invention provides a kind of 5-fluoro-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) propyl group)-3H-quinazoline-4-one anhydrous crystal forms that directly crystallize obtains from solvent, named crystal formation B in the present invention.This crystal formation can directly obtain from dicyandiamide solution, it is not necessary to through solvate removing process.Preparation technology is simple to operate, with low cost.Further, the anhydrous crystal forms prepared has good stability, relatively low draws moist, and optimization and exploitation to this medicine following have important value.
It is an object of the present invention to provide a kind of directly from solvent crystallize obtain the anhydrous crystal forms of 5-fluoro-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) propyl group)-3H-quinazoline-4-one, named crystal formation B.
On the one hand, the crystal formation B that the present invention provides, it is characterised in that its X-ray powder diffraction figure 2theta value be 9.3 ° ± 0.2 °, 11.2 ° ± 0.2 °, there is characteristic peak at 18.5 ° ± 0.2 °.
Further, the crystal formation B that the present invention provides, be further characterized in that, its X-ray powder diffraction figure 2theta value be 12.5 ° ± 0.2 °, 14.9 ° ± 0.2 °, there is characteristic peak at 20.3 ° ± 0.2 °.
Further, the crystal formation B that the present invention provides, be further characterized in that, its X-ray powder diffraction figure 2theta value be 21.5 ° ± 0.2 °, 25.8 ° ± 0.2 °, there is characteristic peak at 16.5 ° ± 0.2 °.
Further, the crystal formation B that the present invention provides, it is further characterized in that, its X-ray powder diffraction figure is the most as shown in Figure 1.
On the other hand, the crystal formation B that the present invention provides, it is characterised in that being heated near 182 DEG C starting exothermic peak occur, be heated near 251 DEG C starting endothermic peak occur, its differential scanning calorimetric thermogram is the most as shown in Figure 2.
On the other hand, the crystal formation B that the present invention provides, it is characterised in that when being heated to 240 DEG C, has the weight loss gradient of about 1.0%, and its thermogravimetric analysis figure is the most as shown in Figure 3.
It is a further object to provide the preparation method of anhydrous crystal forms B of 5-fluoro-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) propyl group)-3H-quinazoline-4-one, it is characterized in that, make 5-fluoro-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) propyl group)-3H-quinazoline-4-one alcohols, ketone, esters, aromatic hydrocarbon, halogenated hydrocarbons, nitrile, nitroparaffin hydro carbons, cyclic ethers class, fat hydrocarbon one or more dicyandiamide solutions in react direct crystallize and obtain anhydrous crystal forms B.
Described Crystallization method preferably suspend stirring, volatilize, heat cooling, anti-solvent add crystallize.
Further, after described heating cooling crystallize is heated to preference temperature, obtaining settled solution, be cooled to 25～0 DEG C and separate out to solid, described preference temperature preferably 40 DEG C is to solvent boiling point.The described heating cooling preferred halogenated hydrocarbons of crystallize solvent for use, fat hydrocarbon solvent or its mixed solvent.
Further, it is to make 5-fluoro-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) propyl group)-3H-quinazoline-4-one mix with positive solvent that described anti-solvent adds crystallize, obtain settled solution, then mix with anti-solvent to solid precipitation.The described preferred halogenated hydrocarbons of positive solvent, described anti-solvent preferred fat hydrocarbon.
The invention have the benefit that
Preparation method of the present invention is to obtain anhydrous crystal forms by crystallization the most in a solvent, and preparation technology is simple to operate, with low cost, and preparation process avoids the appearance of solvate crystalline form, is more beneficial for formulation development.
The anhydrous crystal forms that preparation method of the present invention obtains has good stability.Stable crystal formation is significant for improving drug quality, medicine can be prevented effectively from store and development process occur turn crystalline substance, thus avoid the change of drug solubility, dissolution rate, bioavailability and drug effect, reduce polymorph medicine owing to turning the change that crystalline substance causes the efficacy and saferry of medicine.
The anhydrous crystal forms that preparation method of the present invention obtains has relatively low draws moist, without special drying condition in preparation process, simplifies preparation and the aftertreatment technology of medicine, it is easy to industrialized production.Further, this crystal formation moisture under the conditions of different humidity is held essentially constant, it is simple to the long-term storage of medicine.Owing to condition of storage is required the harshest, greatly reduce material storing and quality control cost, there is the strongest economic worth.
Accompanying drawing explanation
Fig. 1 is the XRPD figure of crystal formation B
Fig. 2 is the DSC figure of crystal formation B
Fig. 3 is the TGA figure of crystal formation B
Fig. 4 is the DVS figure of crystal formation B
Fig. 5 is crystal formation B's1H NMR schemes
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.
In following embodiment, the condition that described test method is generally advised according to normal condition or manufacturer is implemented.
Being explained as follows of abbreviation used in the present invention:
XRPD:X ray powder diffraction
DSC: differential scanning calorimetric analysis
TGA: thermogravimetric analysis
DVS: dynamic water is adsorbed
1H NMR: liquid nucleus magnetic hydrogen spectrum
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: Cu, K α
Kα11.540598；Kα21.544426
K α 2/K α 1 intensity: 0.50
Voltage: 45 KVs (kV)
Electric current: 40 milliamperes (mA)
Sweep limits: from 3.0 to 40.0 degree
Differential scanning calorimetric analysis of the present invention (DSC) figure gathers on TA Q2000.The method parameter of differential scanning calorimetric analysis of the present invention (DSC) is as follows:
Sweep speed: 10 DEG C/min
Protective gas: nitrogen
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:
Sweep speed: 10 DEG C/min
Protective gas: nitrogen
Dynamic water of the present invention absorption (DVS) figure gathers on the Intrinsic dynamic water adsorption instrument produced by SMS company (Surface Measurement Systems Ltd.).The method parameter of described dynamic water adsorption instrument is as follows:
Temperature: 25 DEG C
Carrier gas, flow velocity: N2, 200 ml/min
Unit interval mass change: 0.002%/minute
RH range: 0%RH-95%RH
Embodiment 1
The preparation method of crystal formation B:
Fluoro-for 501.6mg 5-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) propyl group)-3H-quinazoline-4-one is added in 5.0mL dichloromethane and obtain suspension, this suspension is stirred at room temperature 24 hours, centrifuging and taking lower floor solid, being placed in 25 DEG C of freeze-day with constant temperature overnight, gained solid is anhydrous crystal forms B.
The X-ray powder diffraction data of the crystal formation that the present embodiment obtains are as shown in table 1.Its XRPD figure such as Fig. 1, its DSC figure such as Fig. 2, its TGA figure such as Fig. 3, its DVS figure such as Fig. 4, its1H-NMR schemes such as Fig. 5.
The product of the crystal formation B that said method prepares, its1H NMR appraising datum is as follows:
1H NMR(400MHz,DMSO-d6)δ12.92(s,1H),8.30-8.05(m,2H),7.86-7.67(m,2H),7.66-7.41(m,6H),7.27(dd,J1=10.6, J2=8.4Hz, 1H), 4.59-4.78 (m, 1H),
1.80-2.04 (m, 2H), 0.74 (t, J=7.2Hz, 3H)
Table 1
| 2theta | D is spaced | Intensity % |
| 4.77 | 18.51 | 1.31 |
| 6.35 | 13.93 | 1.62 |
| 7.92 | 11.17 | 3.66 |
| 9.25 | 9.56 | 100.00 |
| 9.36 | 9.45 | 71.90 |
| 9.67 | 9.15 | 7.67 |
| 11.16 | 7.93 | 52.87 |
| 11.43 | 7.74 | 9.81 |
| 12.16 | 7.28 | 43.10 |
| 12.47 | 7.10 | 44.80 |
| 14.47 | 6.12 | 11.79 |
| 14.75 | 6.00 | 39.70 |
| 14.86 | 5.96 | 35.41 |
| 15.73 | 5.63 | 8.93 |
| 15.92 | 5.57 | 6.14 |
| 16.47 | 5.38 | 19.90 |
| 16.69 | 5.31 | 18.83 |
| 17.81 | 4.98 | 18.73 |
| 18.52 | 4.79 | 49.12 |
| 18.77 | 4.73 | 10.31 |
| 19.16 | 4.63 | 4.20 |
| 20.33 | 4.37 | 32.34 |
| 21.03 | 4.22 | 12.25 |
| 21.51 | 4.13 | 23.33 |
| 21.79 | 4.08 | 13.39 |
| 22.42 | 3.97 | 6.56 |
| 22.95 | 3.88 | 10.81 |
| 23.19 | 3.84 | 11.69 |
| 23.59 | 3.77 | 3.71 |
| 24.20 | 3.68 | 8.38 |
| 24.57 | 3.62 | 5.10 |
| 25.10 | 3.55 | 18.09 |
[0063] [0063]
| 25.42 | 3.50 | 13.15 |
| 25.81 | 3.45 | 23.04 |
| 26.04 | 3.42 | 16.92 |
| 26.34 | 3.38 | 8.61 |
| 26.64 | 3.35 | 7.02 |
| 27.02 | 3.30 | 13.46 |
| 27.24 | 3.27 | 10.80 |
| 28.01 | 3.19 | 7.77 |
| 28.34 | 3.15 | 6.44 |
| 29.15 | 3.06 | 3.70 |
| 30.49 | 2.93 | 1.85 |
| 31.29 | 2.86 | 1.43 |
| 31.88 | 2.81 | 1.85 |
| 32.57 | 2.75 | 1.67 |
| 33.60 | 2.67 | 1.36 |
| 34.41 | 2.61 | 1.56 |
| 34.78 | 2.58 | 1.64 |
| 36.46 | 2.46 | 1.78 |
| 38.12 | 2.36 | 0.96 |
Embodiment 2
The preparation method of crystal formation B:
Fluoro-for 9.9mg 5-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) propyl group)-3H-quinazoline-4-one is added in 0.5mL normal heptane and obtain suspension, this suspension is placed in 90 DEG C of baking ovens stirring 48 hours, centrifuging and taking lower floor solid, being placed in 25 DEG C of freeze-day with constant temperature overnight, gained solid is anhydrous crystal forms B.
The X-ray powder diffraction data of the crystal formation that the present embodiment obtains are as shown in table 2.
Table 2
| 2theta | D is spaced | Intensity % |
| 9.25 | 9.56 | 100.00 |
| 9.37 | 9.44 | 74.08 |
[0070] [0070]
| 11.17 | 7.92 | 52.19 |
| 12.16 | 7.28 | 34.40 |
| 12.48 | 7.09 | 35.73 |
| 14.76 | 6.00 | 26.32 |
| 14.89 | 5.95 | 23.43 |
| 15.79 | 5.61 | 8.50 |
| 16.47 | 5.38 | 20.41 |
| 16.69 | 5.31 | 17.71 |
| 17.83 | 4.98 | 20.38 |
| 18.52 | 4.79 | 38.27 |
| 20.30 | 4.37 | 24.80 |
| 21.50 | 4.13 | 12.40 |
| 23.07 | 3.86 | 5.64 |
| 24.18 | 3.68 | 8.66 |
| 25.08 | 3.55 | 11.17 |
| 25.80 | 3.45 | 18.56 |
| 27.01 | 3.30 | 12.29 |
| 29.26 | 3.05 | 2.01 |
Embodiment 3
The preparation method of crystal formation B:
Fluoro-for 9.7mg 5-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) propyl group)-3H-quinazoline-4-one is added in 2.0mL dichloromethane, filter to obtain settled solution, this clear liquor is placed on magnetic stirring apparatus and stirs with the speed of 500 turns per minute, dropping 1.5mL normal heptane, obtain suspension, be stirred at room temperature 48 hours, centrifuging and taking lower floor solid, being placed in 25 DEG C of freeze-day with constant temperature overnight, gained solid is anhydrous crystal forms B.
The X-ray powder diffraction data of the crystal formation that the present embodiment obtains are as shown in table 3.
Table 3
| 2theta | D is spaced | Intensity % |
| 4.45 | 19.85 | 1.58 |
| 7.91 | 11.17 | 1.95 |
[0077] [0077]
| 9.25 | 9.56 | 100.00 |
| 9.36 | 9.45 | 73.41 |
| 9.66 | 9.15 | 4.14 |
| 11.15 | 7.93 | 18.84 |
| 11.87 | 7.45 | 6.37 |
| 12.16 | 7.28 | 15.60 |
| 12.48 | 7.10 | 12.90 |
| 14.73 | 6.01 | 13.54 |
| 14.90 | 5.94 | 10.12 |
| 15.91 | 5.57 | 3.91 |
| 16.69 | 5.31 | 13.50 |
| 17.62 | 5.03 | 10.83 |
| 18.36 | 4.83 | 10.69 |
| 18.53 | 4.79 | 17.57 |
| 18.77 | 4.73 | 5.66 |
| 20.33 | 4.37 | 6.13 |
| 21.03 | 4.22 | 3.15 |
| 21.51 | 4.13 | 11.24 |
| 21.78 | 4.08 | 7.97 |
| 22.48 | 3.95 | 1.45 |
| 22.94 | 3.88 | 3.59 |
| 23.20 | 3.83 | 4.98 |
| 25.09 | 3.55 | 8.90 |
| 25.42 | 3.50 | 7.12 |
| 25.81 | 3.45 | 17.53 |
| 26.04 | 3.42 | 13.69 |
| 27.03 | 3.30 | 4.91 |
| 27.24 | 3.27 | 6.20 |
| 28.03 | 3.18 | 3.88 |
| 28.35 | 3.15 | 3.94 |
| 29.15 | 3.06 | 1.36 |
| 32.52 | 2.75 | 1.25 |
| 33.63 | 2.67 | 0.47 |
Embodiment 4
The preparation method of crystal formation B:
Fluoro-for 34.4mg 5-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) propyl group)-3H-quinazoline-4-one is added in 1.0mL dichloromethane and obtain suspension, this suspension is placed in 50 DEG C of constant incubators stirring 100 minutes, filter to obtain settled solution, with 0.1 DEG C of speed slow cooling per minute to 5 DEG C, centrifuging and taking lower floor solid, being placed in 25 DEG C of freeze-day with constant temperature overnight, gained solid is anhydrous crystal forms B.
The X-ray powder diffraction data of the crystal formation that the present embodiment obtains are as shown in table 4.
Table 4
| 2theta | D is spaced | Intensity % |
| 9.25 | 9.56 | 100.00 |
| 9.34 | 9.47 | 71.22 |
| 11.17 | 7.92 | 73.80 |
| 11.42 | 7.75 | 9.20 |
| 12.15 | 7.28 | 49.99 |
| 12.48 | 7.09 | 67.52 |
| 14.75 | 6.01 | 40.95 |
| 14.87 | 5.96 | 36.44 |
| 15.74 | 5.63 | 14.55 |
| 16.45 | 5.39 | 29.23 |
| 17.07 | 5.19 | 4.85 |
| 17.81 | 4.98 | 30.30 |
| 18.51 | 4.79 | 60.77 |
| 20.32 | 4.37 | 40.07 |
| 21.03 | 4.22 | 9.79 |
| 21.50 | 4.13 | 20.91 |
| 21.77 | 4.08 | 7.87 |
| 22.45 | 3.96 | 2.56 |
| 22.95 | 3.88 | 7.75 |
| 23.18 | 3.84 | 9.28 |
| 24.18 | 3.68 | 14.33 |
| 25.10 | 3.55 | 14.27 |
| 25.41 | 3.51 | 9.27 |
[0084] [0084]
| 25.80 | 3.45 | 14.83 |
| 26.03 | 3.42 | 12.03 |
| 26.99 | 3.30 | 15.81 |
| 27.97 | 3.19 | 5.29 |
| 29.17 | 3.06 | 3.22 |
| 34.36 | 2.61 | 2.70 |
| 36.45 | 2.47 | 3.19 |
| 38.14 | 2.36 | 1.32 |
Embodiment 5
The preparation method of crystal formation B:
Fluoro-for 503.4mg 5-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) propyl group)-3H-quinazoline-4-one is added in 8.0mL dichloromethane and obtain suspension, this suspension is stirred 24 hours at 50 DEG C, centrifuging and taking lower floor solid, being placed in 25 DEG C of freeze-day with constant temperature overnight, gained solid is anhydrous crystal forms B.
The X-ray powder diffraction data of the crystal formation that the present embodiment obtains are as shown in table 5.
Table 5
| 2theta | D is spaced | Intensity % |
| 9.25 | 9.56 | 100.00 |
| 9.39 | 9.42 | 83.49 |
| 11.18 | 7.91 | 45.67 |
| 12.15 | 7.28 | 34.10 |
| 12.48 | 7.09 | 35.71 |
| 14.74 | 6.01 | 27.52 |
| 14.91 | 5.94 | 26.26 |
| 15.73 | 5.63 | 4.60 |
| 16.48 | 5.38 | 14.70 |
| 16.75 | 5.29 | 15.21 |
| 17.84 | 4.97 | 12.38 |
| 18.56 | 4.78 | 36.96 |
| 20.37 | 4.36 | 20.56 |
[0091] [0091]
| 21.04 | 4.22 | 6.37 |
| 21.52 | 4.13 | 17.73 |
| 21.83 | 4.07 | 9.77 |
| 23.24 | 3.83 | 7.12 |
| 24.20 | 3.68 | 5.99 |
| 25.11 | 3.55 | 14.34 |
| 25.46 | 3.50 | 10.57 |
| 25.84 | 3.45 | 19.71 |
| 26.09 | 3.42 | 15.16 |
| 27.06 | 3.30 | 9.75 |
| 27.26 | 3.27 | 7.95 |
| 28.03 | 3.18 | 5.35 |
| 29.22 | 3.06 | 1.88 |
Embodiment 6
Crystal formation B draws moist research:
Taking crystal formation B prepared by the present invention and carry out dynamic water absorption (DVS) test, its dynamic water absorption (DVS) is as shown in Figure 4.
Result shows, crystal formation B places under 80% relative humidities, reach balance after weightening finish be 0.63%, belong to slightly draw moist.
About drawing moist feature description and that draws moist weightening finish defines (Chinese Pharmacopoeia version annex XIX J medicine in 2010 draws moist test direction principle, experiment condition: 25 DEG C ± 1 DEG C, 80% relative humidity):
Deliquescence: absorb enough water and divide formation liquid
Great draw moist: draw wet weightening finish not less than 15%
Have draw moist: draw wet weightening finish less than 15% but not less than 2%
Slightly draw moist: draw wet weightening finish less than 2% but not less than 0.2%
Nothing or moist almost without drawing: draw wet weightening finish less than 0.2%.
Claims (10)
1. 5-fluoro-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) third that directly crystallize obtains from solvent
Base)-3H-quinazoline-4-one anhydrous crystal forms, named crystal formation B, it is characterised in that its X-ray powder diffraction
Figure 2theta value be 9.3 ° ± 0.2 °, 11.2 ° ± 0.2 °, there is characteristic peak at 18.5 ° ± 0.2 °.
Crystal formation B the most according to claim 1, is further characterized in that, its X-ray powder diffraction figure is at 2theta
Value is 12.5 ° ± 0.2 °, 14.9 ° ± 0.2 °, there is characteristic peak at 20.3 ° ± 0.2 °.
Crystal formation B the most according to claim 2, is further characterized in that, its X-ray powder diffraction figure is at 2theta
Value is 21.5 ° ± 0.2 °, 25.8 ° ± 0.2 °, there is characteristic peak at 16.5 ° ± 0.2 °.
Crystal formation B the most according to claim 1, it is characterised in that its X-ray powder diffraction figure is substantially such as figure
Shown in 1.
5. 5-fluoro-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) propyl group)-3H-quinazoline-4-one crystal formation B
Preparation method, it is characterised in that make 5-fluoro-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) propyl group)-3H-
Quinazoline-4-one and alcohols, ketone, esters, aromatic hydrocarbon, halogenated hydrocarbons, nitrile, nitroparaffin hydro carbons, cyclic ethers
Class, one or more solvents of fat hydrocarbon mix direct crystallize and obtain crystal formation B.
Crystallization method the most according to claim 5, it is characterised in that described Crystallization method preferably suspend stirring,
Volatilization, heating cooling, anti-solvent are added.
Crystallization method the most according to claim 6, it is characterised in that described heating cooling crystallize is heated to fit
Preferably after temperature, obtain settled solution, be cooled to 25～0 DEG C and separate out to solid, described preference temperature preferably 40 DEG C
To solvent boiling point.
Preparation method the most according to claim 7, it is characterised in that described heating cooling crystallize solvent for use is preferred
Halogenated hydrocarbons, fat hydrocarbon solvent or its mixed solvent.
Crystallization method the most according to claim 6, it is characterised in that it is to make 5-fluorine that described anti-solvent adds crystallize
-3-phenyl-2-((1S)-1-(9H-purine-6-base amino) propyl group)-3H-quinazoline-4-one mixes with positive solvent, obtains
Settled solution, then mix with anti-solvent to solid precipitation.
Crystallization method the most according to claim 9, the described preferred halogenated hydrocarbons of positive solvent, the preferred fat of described anti-solvent
Fat hydrocarbon.
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