WO2020007219A1 - 一种egfr抑制剂的晶型及其制备方法 - Google Patents
一种egfr抑制剂的晶型及其制备方法 Download PDFInfo
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- WO2020007219A1 WO2020007219A1 PCT/CN2019/092987 CN2019092987W WO2020007219A1 WO 2020007219 A1 WO2020007219 A1 WO 2020007219A1 CN 2019092987 W CN2019092987 W CN 2019092987W WO 2020007219 A1 WO2020007219 A1 WO 2020007219A1
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- 0 Cc(c(Cl)ccc1)c1Nc1c(cc(c(OC)c2)N(CC3(*)CN(C)C3)C(O)=O)c2ncn1 Chemical compound Cc(c(Cl)ccc1)c1Nc1c(cc(c(OC)c2)N(CC3(*)CN(C)C3)C(O)=O)c2ncn1 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
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- the invention relates to a crystalline form of an EGFR inhibitor and a preparation method thereof, and also includes the application of the crystalline form in the preparation of a medicine for treating non-small cell lung cancer, especially a medicine for brain metastasis of non-small cell lung cancer.
- EGFR epidermal growth factor receptor
- HER1 epidermal growth factor receptor
- HER2 erbB2
- HER3 erbB3
- HER4 erbB4
- EGFR is a glycoprotein that is a receptor for epidermal growth factor (EGF) cell proliferation and signal transduction. It is a tyrosine kinase-type receptor with a cell membrane penetrating and located on the cell membrane surface.
- the receptor After the ligand binds to the epidermal growth factor receptor (EGFR), the receptor undergoes dimerization, and EGFR dimerization can activate its kinase pathway located in the cell. This autophosphorylation can direct downstream phosphorylation, including the MAPK, Akt, and JNK pathways, and induce cell proliferation.
- EGFR epidermal growth factor receptor
- AZD3759 was developed by AstraZeneca and is currently in clinical Phase I / II to address central nervous system (CNS) metastases, such as brain metastasis (BM: Brain Metastasis) and choroid meninges, in patients with EGFR mutation-positive non-small cell lung cancer.
- CNS central nervous system
- BM Brain Metastasis
- LM Leptomenigeal Metastasis
- LM Leptomenigeal Metastasis
- the clinical response rate is high. It has obvious effect on extracranial and intracranial patients;
- Erlotinib is used as the initial (first-line) treatment for patients with metastatic non-small cell lung cancer (NSCLC) who have been approved by the FDA to test for the presence of specific epidermal growth factor receptor (EGFR) activating mutations in their tumors.
- NSCLC metastatic non-small cell lung cancer
- EGFR epidermal growth factor receptor
- the drug has also been approved for patients with advanced NSCLC who have had tumors that have spread or grown after at least one chemotherapy regimen (second- or third-line treatment).
- the invention provides the crystal form A of the compound of formula (II), n is 0, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 5.18 ⁇ 0.2 °, 7.06 ⁇ 0.2 °, 15.24 ⁇ 0.2 °, 17.36 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above-mentioned Form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.18 ⁇ 0.2 °, 7.06 ⁇ 0.2 °, 7.67 ⁇ 0.2 °, 15.24 ⁇ 0.2 °, 17.36 ⁇ 0.2 °, 18.30 ⁇ 0.2 °, 18.99 ⁇ 0.2 °, 20.96 ⁇ 0.2 °, 24.00 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above-mentioned Form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.18 ⁇ 0.2 °, 7.06 ⁇ 0.2 °, 7.67 ⁇ 0.2 °, 13.67 ⁇ 0.2 °, 15.24 ⁇ 0.2 °, 17.36 ⁇ 0.2 °, 18.30 ⁇ 0.2 °, 18.99 ⁇ 0.2 °, 20.96 ⁇ 0.2 °, 22.19 ⁇ 0.2 °, 22.76 ⁇ 0.2 °, 24.00 ⁇ 0.2 °, 26.78 ⁇ 0.2 °, 27.46 ⁇ 0.2 °.
- the XRPD pattern of the above-mentioned Form A is shown in FIG. 1.
- the differential scanning calorimetry curve of the above-mentioned Form A has starting points of endothermic peaks at 39.36 ° C ⁇ 3 ° C and 154.14 ° C ⁇ 3 ° C.
- the DSC spectrum of the above-mentioned Form A is shown in FIG. 2.
- thermogravimetric analysis curve of the above-mentioned Form A has a weight loss of 1.153% at 59.57 ° C ⁇ 3 ° C.
- the TGA spectrum of the above-mentioned Form A is shown in FIG. 3.
- the present invention also provides a method for preparing a crystal form of the compound (II), comprising:
- step (b) dissolving maleic acid in a solvent, slowly adding the solution obtained in step (a), and stirring at 60-70 ° C for 1-2 hours;
- the solvent is methanol.
- the present invention provides the B crystal form of the compound of formula (II), n is 0, 0.5, 1, 1.5 or 2, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 5.97 ⁇ 0.2 °, 11.30 ⁇ 0.2 ° , 18.83 ⁇ 0.2 °, 20.00 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above-mentioned Form B has characteristic diffraction peaks at the following 2 ⁇ angles: 5.97 ⁇ 0.2 °, 11.30 ⁇ 0.2 °, 14.26 ⁇ 0.2 °, 18.00 ⁇ 0.2, 18.83 ⁇ 0.2 °, 20.00 ⁇ 0.2 °, 22.11 ⁇ 0.2 °, 24.99 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above-mentioned Form B has characteristic diffraction peaks at the following 2 ⁇ angles: 5.97 ⁇ 0.2 °, 7.17 ⁇ 0.2 °, 11.30 ⁇ 0.2 °, 14.26 ⁇ 0.2 °, 18.00 ⁇ 0.2 °, 18.83 ⁇ 0.2 °, 20.00 ⁇ 0.2 °, 22.11 ⁇ 0.2 °, 22.56 ⁇ 0.2 °, 24.99 ⁇ 0.2 °, 25.62 ⁇ 0.2 °, 27.91 ⁇ 0.2 °.
- the XRPD pattern of the above-mentioned Form B is shown in FIG. 4.
- the differential scanning calorimetry curve of the above-mentioned Form B has a starting point of an endothermic peak at 210.69 ° C ⁇ 3 ° C.
- the DSC pattern of the above-mentioned Form B is shown in FIG. 5.
- thermogravimetric analysis curve of the above-mentioned Form B has a thermogravimetric analysis curve with a weight loss of 0.738% at 68.75 ° C ⁇ 3 ° C.
- the TGA spectrum of the above-mentioned Form B is shown in FIG. 6.
- the invention also provides a method for preparing the crystal form B of the compound of formula (II), comprising:
- the solvent is a mixed solvent of methanol and water, and the volume ratio of methanol to H 2 O in the mixed solvent is 10/1.
- the invention also provides the crystal form C of the compound of formula (II), n is 0, 0.5, 1, 1.5 or 2, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 5.89 ⁇ 0.2 °, 12.88 ⁇ 0.2 °, 16.58 ⁇ 0.2 °, 19.44 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above-mentioned Form C has characteristic diffraction peaks at the following 2 ⁇ angles: 5.89 ⁇ 0.2 °, 12.38 ⁇ 0.2 °, 12.88 ⁇ 0.2 °, 16.58 ⁇ 0.2 °, 19.44 ⁇ 0.2 °, 22.30 ⁇ 0.2 °, 23.35 ⁇ 0.2 °, 24.38 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above-mentioned crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 5.89 ⁇ 0.2 °, 12.38 ⁇ 0.2 °, 12.88 ⁇ 0.2 °, 16.58 ⁇ 0.2 °, 17.61 ⁇ 0.2 °, 18.67 ⁇ 0.2 °, 19.44 ⁇ 0.2 °, 20.43 ⁇ 0.2 °, 22.30 ⁇ 0.2 °, 23.35 ⁇ 0.2 °, 24.38 ⁇ 0.2 °, 25.91 ⁇ 0.2 °.
- the XRPD pattern of the crystal form C is shown in FIG. 7.
- the differential scanning calorimetry curve of the above-mentioned Form C has a starting point of an endothermic peak at 45.31 ° C. ⁇ 3 ° C. and 150.75 ° C. ⁇ 3 ° C.
- the DSC pattern of the above-mentioned crystal form C is shown in FIG. 8.
- thermogravimetric analysis curve of the above-mentioned Form C has a thermogravimetric analysis curve with a weight loss of 3.720% at 83.74 ° C ⁇ 3 ° C.
- the TGA spectrum of the above-mentioned crystal form C is shown in FIG. 9.
- the present invention also provides a method for preparing the crystal form C of the compound of formula (II), including:
- the solvent is selected from a mixed solvent of ethanol and water, and the volume ratio of ethanol and water in the mixed solvent is 10/1.
- the invention also provides the D crystal form of the compound of formula (II), n is 0, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.39 ⁇ 0.2 °, 14.28 ⁇ 0.2 °, 14.77 ⁇ 0.2 °, 17.69 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above D form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.28 ⁇ 0.2 °, 7.39 ⁇ 0.2 °, 13.39 ⁇ 0.2 °, 14.28 ⁇ 0.2 °, 14.77 ⁇ 0.2 °, 17.69 ⁇ 0.2 °, 20.11 ⁇ 0.2 °, 21.53 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above D form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.28 ⁇ 0.2 °, 7.39 ⁇ 0.2 °, 13.39 ⁇ 0.2 °, 14.28 ⁇ 0.2 °, 14.77 ⁇ 0.2 °, 17.69 ⁇ 0.2 °, 20.11 ⁇ 0.2 °, 21.53 ⁇ 0.2 °, 24.95 ⁇ 0.2 °, 25.95 ⁇ 0.2 °, 27.06 ⁇ 0.2 °, 28.42 ⁇ 0.2 °.
- the XRPD pattern of the D crystal form is shown in FIG. 10.
- the XRPD pattern of the D crystal form is shown in FIG. 10.
- the differential scanning calorimetry curve of the D crystal form has starting points of endothermic peaks at 41.54 ° C ⁇ 3 ° C and 140.93 ° C ⁇ 3 ° C.
- the DSC pattern of the D crystal form is shown in FIG. 11.
- thermogravimetric analysis curve of the D-form mentioned above has a thermogravimetric analysis curve with a weight loss of 2.120% at 84.38 ° C ⁇ 3 ° C.
- the TGA spectrum of the D crystal form is shown in FIG. 12.
- the invention also provides a method for preparing a crystal form D of the compound of formula (II), comprising:
- the solvent is selected from a mixed solvent of isopropyl alcohol and water, and the volume ratio of isopropyl alcohol to H 2 O in the mixed solvent is 10/1.
- the invention also provides the E-form of the compound of formula (II), where n is 0, 0.5, 1, 1.5 or 2, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 5.09 ⁇ 0.2 °, 7.12 ⁇ 0.2 °, 14.55 ⁇ 0.2 °, 21.81 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above-mentioned E-form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.09 ⁇ 0.2 °, 7.12 ⁇ 0.2 °, 14.55 ⁇ 0.2 °, 16.56 ⁇ 0.2 °, 17.75 ⁇ 0.2 °, 21.24 ⁇ 0.2 °, 21.81 ⁇ 0.2 °, 23.39 ⁇ 0.2 °.
- the X-ray powder diffraction pattern of the above-mentioned E-form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.09 ⁇ 0.2 °, 7.12 ⁇ 0.2 °, 14.55 ⁇ 0.2 °, 16.56 ⁇ 0.2 °, 17.75 ⁇ 0.2 °, 18.56 ⁇ 0.2 °, 21.24 ⁇ 0.2 °, 21.81 ⁇ 0.2 °, 23.39 ⁇ 0.2 °, 26.29 ⁇ 0.2 °, 27.23 ⁇ 0.2 °, 28.16 ⁇ 0.2 °.
- the XRPD pattern of the above-mentioned E crystal form is shown in FIG. 13.
- the differential scanning calorimetry curve of the above E-form has a starting point of an endothermic peak at 35.41 ° C ⁇ 3 ° C and 145.45 ⁇ 3 ° C.
- the DSC spectrum of the E-form is shown in FIG. 14.
- thermogravimetric analysis curve of the above E-form has a thermogravimetric analysis curve with a weight loss of 1.917% at 76.77 ° C ⁇ 3 ° C.
- the TGA spectrum of the aforementioned E-form is shown in FIG. 15.
- the invention also provides a method for preparing the crystal form E of the compound of formula (II), including:
- the solvent is ethyl acetate or acetone.
- the compound of the present invention has better PK properties and oral absorption rate, its crystal form is relatively stable, its solubility is good, its hygroscopicity is appropriate, and its influence on light and heat is small.
- the compounds of the present invention show excellent inhibitory activity against EGFR with sensitive mutations and brain metastases, and have high selectivity for wild-type EGFR.
- the compounds of the present invention may provide a more effective therapeutic effect on diseases caused by abnormalities of the enzymes of the epidermal growth factor receptor, especially brain metastases of non-small cell lung cancer.
- the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
- Well-known equivalent alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
- the present invention uses the following abbreviations: rt stands for room temperature; THF stands for tetrahydrofuran; CDI stands for carbonyldiimidazole; DCM stands for dichloromethane; DMF stands for N, N-dimethylformamide; MeOH stands for methanol; acetone stands for acetone; NIS Stands for N-iodosuccinimide; HPLC stands for high performance liquid chromatography; TLC stands for thin layer chromatography. Compound by hand or Software naming. Commercially available compounds use supplier catalog names.
- Tube voltage 40kV
- tube current 40mA
- Anti-scattering slit 7.10mm
- Test conditions Take a sample (0.5 ⁇ 1mg) and place it in a DSC aluminum pan for testing. The method is: room temperature ⁇ 250 °C, heating rate is 10 °C / min.
- Test conditions Take a sample (2-5 mg) and place it in a TGA platinum pot for testing.
- the method is: room temperature to 300 ° C, and the heating rate is 10 ° C / min.
- Figure 1 is the XRPD spectrum of Form A.
- Figure 2 is a DSC spectrum of Form A.
- Figure 3 is a TGA spectrum of Form A.
- Figure 4 is an XRPD spectrum of Form B.
- Figure 5 is a DSC spectrum of Form B.
- Figure 6 is a TGA spectrum of Form B.
- Figure 7 is an XRPD spectrum of Form C.
- Figure 8 is a DSC spectrum of Form C.
- Figure 9 is a TGA spectrum of Form C.
- FIG. 10 is an XRPD spectrum of the D crystal form.
- FIG. 11 is a DSC spectrum of the D crystal form.
- FIG. 12 is a TGA spectrum of the D crystal form.
- FIG. 13 is an XRPD spectrum of the E-form.
- Fig. 14 is a DSC spectrum of the E-form.
- FIG. 15 is a TGA spectrum of the E-form.
- Figure 16 is the tumor growth curve of Form A in the PC-9-Luc brain metastasis model.
- FIG. 17 is the survival curve of animal A in the PC-9-Luc brain metastasis model.
- FIG. 18 is an XRPD spectrum of a Form A after a TGA heating experiment.
- step 1
- CDI (1.32 kg, 8.16 mol) was placed in tetrahydrofuran (30 liters), the temperature was lowered to -10 ° C, and compound c (1.5 kg, 7.42 mol, 1.0 equivalent) was slowly added in portions, and the control temperature was -5--10 ° C Stir for 0.5 hours, slowly raise the temperature to 10 ° C, and continue stirring for 15.5 hours. HPLC and TLC showed the reaction was complete. Ethyl acetate (15 liters) was added, and the reaction solution was quenched by adding 1.0 mol / liter of dilute hydrochloric acid for a total of 15 liters.
- the organic phase was 0.5 mol / liter of dilute hydrochloric acid (10 liters), saturated sodium bicarbonate (2 liters), and Wash with saturated brine (3 liters) and collect the organic phase.
- the aqueous phase was extracted with ethyl acetate (10 liters), and the organic phase was washed with 0.5 mol / liter of dilute hydrochloric acid (4 liters), saturated sodium bicarbonate (1 liter), and saturated brine (2 liters).
- the organic phases were combined, The organic phase was dried over anhydrous sodium sulfate.
- the cake was washed with 10 liters of purified water, the filter cake was collected, 24 liters of ethyl acetate was added to beat at room temperature for 2 hours, and the filter cake was filtered under reduced pressure.
- the filter cake was washed with 6 liters of ethyl acetate, and dried in a vacuum oven at 50 ° C to a constant weight to obtain Compound j.
- Aqueous ammonia: water 1: 1 (V / V) was added to the filtrate for a total of 24.6 liters, and a large amount of white solid precipitated in the solution. After filtration, the filter cake was beaten with 30 liters of purified water at 20-30 ° C for 2 hours, filtered, and the filter cake was dried under vacuum at 50 ° C to constant weight. A compound of formula (I) is obtained.
- Example 5 Solubility test of the crystal form of compound A of formula (II) in different pH media
- the solubility of this product is pH-dependent, showing high solubility in buffer solutions below pH 6.8, and high solubility in purified water, simulated gastric juice, simulated satiety fluid, and simulated fasting fluid.
- Lung cancer PC-9-Luc cells were cultured in monolayer in vitro.
- the culture conditions were RPMI-1640 (medium) plus 10% fetal bovine serum, 100 U / ml penicillin and 100 ⁇ g / ml streptomycin, and incubated at 37 ° C and 5% CO 2. Box culture. Passage with conventional digestion treatment with trypsin-EDTA twice a week. When the cell saturation is 80% -90% and the number reaches the requirements, the cells are collected, counted, and seeded.
- mice Female, 6-8 weeks old, weighing 18-22 grams. Provided by Shanghai Xipuer-Bikai Laboratory Animal Co., Ltd. or other qualified suppliers.
- mice Female BALB / c nude mice were anesthetized with sodium pentobarbital. Buprenorphine was injected subcutaneously 30 minutes before surgery and 6 hours after surgery. Sagittal incisions were made with a sterile scalpel, the skull was exposed and cleaned with a cotton swab. Before injecting the cells, use a sharp needle to perforate the skull on the right side of the anterior halo and on the front side of the coronal suture. Slowly inject the cell suspension. After the injection, clean the skull with hydrogen peroxide and wipe with a dry cotton swab, reset the scalp with tweezers, close the incision, and continue to observe the animal until it is fully awake.
- mice inoculated in situ were injected intraperitoneally with luminin according to their weight, and the mice were pre-anesthetized with a mixed gas of oxygen and isoflurane. After the mice were deeply anesthetized, they were moved to the imaging chamber of IVIS (Lumina II) to start bioluminescence detection. Detect and record all bioluminescence signals and generated image information in animals (tumor in situ and metastases).
- IVIS Lumina II
- mice were prepared on day 6 after vaccination. Before grouping, all animals were tested for bioluminescence, and the signal intensity and weight were used as parameters to randomly group and start administration. The bioluminescent signal intensity of mice was measured twice a week after the administration for a total of 3 weeks.
- the experimental indicator is whether tumor growth can be delayed or inhibited. After the tumor inoculation, the bioluminescence signals of the animals were detected twice a week for a total of 3 weeks. Measure body weight twice a week.
- the antitumor efficacy of the compound of the present invention is significantly better than that of AZD3759 and erlotinib. It has the potential to treat tumor brain metastases, and can significantly prolong the median survival time.
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Abstract
Description
Claims (44)
- 根据权利要求1所述的A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.18±0.2°,7.06±0.2°,7.67±0.2°,15.24±0.2°,17.36±0.2°,18.30±0.2°,18.99±0.2°,20.96±0.2°,24.00±0.2°。
- 根据权利要求2所述的A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.18±0.2°,7.06±0.2°,7.67±0.2°,13.67±0.2°,15.24±0.2°,17.36±0.2°,18.30±0.2°,18.99±0.2°,20.96±0.2°,22.19±0.2°,22.76±0.2°,24.00±0.2°,26.78±0.2°,27.46±0.2°。
- 根据权利要求3所述的A晶型,其XRPD图谱如图1所示。
- 根据权利要求1-4任意一项所述的A晶型,其差示扫描量热曲线在39.36℃±3℃和154.14℃±3℃处具有吸热峰的起始点。
- 根据权利要求5所述的A晶型,其DSC图谱如图2所示。
- 根据权利要求1-4任意一项所述的A晶型,其热重分析曲线在59.57℃±3℃时失重达1.153%。
- 根据权利要求7所述的A晶型,其TGA图谱如图3所示。
- 根据权利要求1-8任意一项所述式(II)化合物A晶型的制备方法,包括:(a)将式(I)化合物加入溶剂中,升温至60-70℃;(b)将马来酸溶于溶剂中,缓慢加入步骤(a)所得溶液,60-70℃下搅拌1-2小时;(c)降温至20-30℃,N 2保护下减压抽滤,干燥;其中,所述溶剂为甲醇。
- 根据权利要求10所述的B晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.97±0.2°,11.30±0.2°,14.26±0.2°,18.00±0.2,18.83±0.2°,20.00±0.2°,22.11±0.2°,24.99±0.2°。
- 根据权利要求11所述的B晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.97±0.2°,7.17±0.2°,11.30±0.2°,14.26±0.2°,18.00±0.2°,18.83±0.2°,20.00±0.2°,22.11±0.2°,22.56±0.2°,24.99±0.2°,25.62±0.2°,27.91±0.2°。
- 根据权利要求12所述的B晶型,其XRPD图谱如图4所示。
- 根据权利要求10-13任意一项所述的B晶型,其差示扫描量热曲线在210.69℃±3℃处具有吸热峰的起始点。
- 根据权利要求14所述的B晶型,其DSC图谱如图5所示。
- 根据权利要求10-13任意一项所述的B晶型,其热重分析曲线在68.75℃±3℃时失重达0.738%。
- 根据权利要求16所述的B晶型,其TGA图谱如图6所示。
- 根据权利要求18所述的C晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.89±0.2°,12.38±0.2°,12.88±0.2°,16.58±0.2°,19.44±0.2°,22.30±0.2°,23.35±0.2°,24.38±0.2°。
- 根据权利要求19所述的C晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.89±0.2°,12.38±0.2°,12.88±0.2°,16.58±0.2°,17.61±0.2°,18.67±0.2°,19.44±0.2°,20.43±0.2°,22.30±0.2°,23.35±0.2°,24.38±0.2°,25.91±0.2°。
- 根据权利要求20所述的C晶型,其XRPD图谱如图7所示。
- 根据权利要求18-21任意一项所述的C晶型,其差示扫描量热曲线在45.31℃±3℃和150.75℃±3℃处具有吸热峰的起始点。
- 根据权利要求22所述的C晶型,其DSC图谱如图8所示。
- 根据权利要求18-21任意一项所述的C晶型,其热重分析曲线在在83.74℃±3℃时失重达3.720%。
- 根据权利要求24所述的C晶型,其TGA图谱如图9所示。
- 根据权利要求26所述的D晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.28±0.2°,7.39±0.2°,13.39±0.2°,14.28±0.2°,14.77±0.2°,17.69±0.2°,20.11±0.2°,21.53±0.2°。
- 根据权利要求27所述的D晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.28±0.2°,7.39±0.2°,13.39±0.2°,14.28±0.2°,14.77±0.2°,17.69±0.2°,20.11±0.2°,21.53±0.2°,24.95±0.2°,25.95±0.2°,27.06±0.2°,28.42±0.2°。
- 根据权利要求28所述的D晶型,其XRPD图谱如图10所示。
- 根据权利要求26-29任意一项所述的D晶型,其差示扫描量热曲线在41.54℃±3℃和140.93℃±3℃处具有吸热峰的起始点。
- 根据权利要求30所述的D晶型,其DSC图谱如图11所示。
- 根据权利要求26-29任意一项所述的D晶型,其热重分析曲线在84.38℃±3℃时失重达2.120%。
- 根据权利要求32所述的D晶型,其TGA图谱如图12所示。
- 根据权利要求34所述的E晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.09±0.2°,7.12±0.2°,14.55±0.2°,16.56±0.2°,17.75±0.2°,21.24±0.2°,21.81±0.2°,23.39±0.2°。
- 根据权利要求35所述的E晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:5.09±0.2°,7.12±0.2°,14.55±0.2°,16.56±0.2°,17.75±0.2°,18.56±0.2°,21.24±0.2°,21.81±0.2°,23.39±0.2°,26.29±0.2°,27.23±0.2°,28.16±0.2°。
- 根据权利要求36所述的E晶型,其XRPD图谱如图13所示。
- 根据权利要求34-37任意一项所述的E晶型,其差示扫描量热曲线在35.41℃±3℃和145.45±3℃处具有吸热峰的起始点。
- 根据权利要求38所述的E晶型,其DSC图谱如图14所示。
- 根据权利要求34-37任意一项所述的E晶型,其热重分析曲线在76.77℃±3℃时失重达1.917%。
- 根据权利要求40所述的E晶型,其TGA图谱如图15所示。
- 根据权利要求1-8、10-41任意一项所述的晶型或根据权利要求9所述的制备方法得到的晶型在制备治疗癌症药物中的应用。
- 根据权利要求42所述的应用,其中,所述癌症是指非小细胞肺癌。
- 根据权利要求43所述的应用,其中,所述非小细胞肺癌是指非小细胞肺癌脑转移。
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