CN113444073A - Crystal form III of morpholinyl quinazoline compound, preparation method and application thereof - Google Patents
Crystal form III of morpholinyl quinazoline compound, preparation method and application thereof Download PDFInfo
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- CN113444073A CN113444073A CN202010222069.4A CN202010222069A CN113444073A CN 113444073 A CN113444073 A CN 113444073A CN 202010222069 A CN202010222069 A CN 202010222069A CN 113444073 A CN113444073 A CN 113444073A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Abstract
The invention discloses a crystal form III of a morpholinyl quinazoline compound, and a preparation method and application thereof. The crystal form III of the morpholinyl quinazoline compound provided by the invention has better thermal stability and solubility, particularly has higher equilibrium solubility in an aqueous medium with the pH value of 1.0 to 8.0, and has important values for promoting the dissolution and absorption of a medicament and improving the bioavailability of the medicament.
Description
Technical Field
The invention relates to a morpholinyl quinazoline compound crystal form III, a preparation method and application thereof.
Background
The structure is shown as formula A
The morpholinyl quinazoline compound has activity of inhibiting phosphatidylinositol 3-kinase delta (PI3K delta).
PI3K δ is an intracellular phosphoinositide kinase that catalyzes the phosphorylation of the hydroxyl group at the 3-position of phosphatidylols. PI3K can be divided into class i, ii and iii kinases, with class iii PI3K being the most widely studied one that is activated by cell surface receptors. Class iii PI3K in mammalian cells is further classified by structure and receptor into class iiia and class iiib, which transmit signals from tyrosine kinase-coupled receptors and G protein-coupled receptors, respectively. Class IIIa PI3K includes the PI3K α, PI3K β, PI3K δ subtypes, class IIIb PI3K includes the PI3K γ subtype (trends biochem. Sci.,1997,22, 267-272). IIIa-class PI3K is a dimeric protein consisting of a catalytic subunit p110 and a regulatory subunit p85, has dual activity of lipid kinase and protein kinase (Nat. Rev. cancer 2002,2,489-501), and is thought to be associated with cell proliferation and carcinogenesis, immune disorders and diseases involving inflammation.
WO2015055071A1 discloses morpholinyl quinazoline compounds shown in formula A and a preparation method thereof. The crystal form of the morpholinyl quinazoline compound shown as the formula A has a crucial influence on the stability of the medicament during production, processing, storage and transportation.
The phenomenon in which a substance exists in two or more different crystal structures is called polymorphism. Different crystalline forms of a compound may often exhibit different physical and chemical properties. In the case of drugs, the polymorphism may affect the dissolution and absorption of the drugs, and further affect the bioavailability of the drugs, thereby showing different clinical effects and toxic and side effects. In view of this, it is very important to develop a crystal form of the morpholinyl quinazoline compound shown in the formula A, which has advantageous properties.
Disclosure of Invention
The invention aims to overcome the defect that a morpholinyl quinazoline compound shown as a formula A has few crystal forms, and provides a morpholinyl quinazoline compound crystal form III, a preparation method and an application thereof. The crystal form has good thermal stability and good solubility in an aqueous medium with the pH value of 1.0 to 8.0, is favorable for dissolution and absorption of a medicament, and improves the bioavailability of the medicament.
The invention solves the technical problems through the following technical scheme.
The invention provides a crystal form III of a morpholinyl quinazoline compound shown as a formula A, which has an X-ray powder diffraction pattern expressed by a 2 theta angle, wherein diffraction peaks exist at 7.1 +/-0.2 degrees, 8.1 +/-0.2 degrees, 11.4 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.2 +/-0.2 degrees, 18.9 +/-0.2 degrees and 20.4 +/-0.2 degrees;
in a preferred embodiment of the present invention, the morphous form iii of the morpholinyl quinazoline compound represented by the formula a has an X-ray powder diffraction pattern expressed by 2 θ angle, and further has diffraction peaks at one or more of the following 2 θ angles: 12.7 +/-0.2 degrees, 13.7 +/-0.2 degrees, 14.4 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.6 +/-0.2 degrees, 20.9 +/-0.2 degrees, 23.1 +/-0.2 degrees, 24.7 +/-0.2 degrees and 28.1 +/-0.2 degrees.
In a preferred embodiment of the present invention, the morphous form iii of the morpholinyl quinazoline compound represented by the formula a has diffraction peaks at 7.1 ± 0.2 °, 8.1 ± 0.2 °, 11.4 ± 0.2 °, 12.7 ± 0.2 °, 13.7 ± 0.2 °, 14.4 ± 0.2 °, 15.9 ± 0.2 °, 17.2 ± 0.2 °, 18.6 ± 0.2 °, 18.9 ± 0.2 °, 19.6 ± 0.2 °, 20.4 ± 0.2 °, 20.9 ± 0.2 °, 23.1 ± 0.2 °, 24.7 ± 0.2 ° and 28.1 ± 0.2 ° in an X-ray powder diffraction pattern represented by 2 θ.
In a preferred embodiment of the present invention, in the crystal form iii of the morpholinyl quinazoline compound represented by the formula a, the diffraction peaks and peak height percentages are shown in table 1 in the X-ray powder diffraction diagram expressed by 2 θ angle:
TABLE 1
| Numbering | 2θ(±0.2°) | Percentage of peak height (%) |
| 1 | 7.126 | 17.8 |
| 2 | 8.110 | 28.9 |
| 3 | 11.426 | 32.1 |
| 4 | 12.726 | 5.9 |
| 5 | 13.678 | 5.3 |
| 6 | 14.388 | 7.7 |
| 7 | 15.925 | 55.2 |
| 8 | 17.228 | 42.2 |
| 9 | 18.591 | 63.5 |
| 10 | 18.904 | 100.0 |
| 11 | 19.578 | 12.4 |
| 12 | 20.445 | 73.0 |
| 13 | 20.914 | 9.4 |
| 14 | 23.069 | 37.2 |
| 15 | 24.746 | 38.6 |
| 16 | 28.063 | 13.3 |
。
In a preferred embodiment of the invention, the morphous form iii of the morpholinyl quinazoline compound represented by the formula a has an X-ray powder diffraction pattern represented by 2 θ angle substantially as shown in fig. 1.
In the present invention, the X-ray powder diffraction patterns are all measured by using the Ka line of the Cu target.
In a preferred embodiment of the invention, the morphotyl III of the morpholinyl quinazoline compound shown in the formula A has an infrared absorption spectrum (IR) with characteristic peaks at the following positions: 3460cm-1、3335cm-1、2957cm-1、2851cm-1、2797cm-1、1605cm-1、1587cm-1、1557cm-1、1470cm-1、1447cm-1、1408cm-1、1341cm-1、1260cm-1、1153cm-1、1109cm-1、1013cm-1、851cm-1And 768cm-1。
In a preferred embodiment of the present invention, the infrared absorption spectrum of the crystal form iii of the morpholinyl quinazoline compound represented by the formula a is also substantially as shown in fig. 2.
In a preferred embodiment of the invention, the thermogravimetric analysis (TGA) of the crystalline form iii of the morpholinyl quinazoline compound according to formula a shows substantially no weight loss before heating to 150 ℃, which indicates that it is a non-solvated species, and the weight loss above 150 ℃ is due to decomposition.
In a preferred embodiment of the present invention, the thermogravimetric analysis diagram of the crystal form iii of the morpholinyl quinazoline compound represented by the formula a is also substantially as shown in fig. 3.
In a preferred embodiment of the invention, the morphotyl quinazoline compound shown in the formula A has a Differential Scanning Calorimetry (DSC) chart with an endothermic peak at 159.32 deg.C (peak temperature).
In a preferred embodiment of the present invention, the differential scanning calorimetry diagram of the crystal form iii of the morpholinyl quinazoline compound shown in the formula a is also substantially as shown in fig. 4.
In a preferred embodiment of the invention, the crystal form III of the morpholinyl quinazoline compound shown in the formula A is DMSO-d6Liquid nuclear magnetic hydrogen spectrum as solvent (1H NMR) substantially as shown in figure 5,1the H NMR chart shows no residual crystallization solvent in form iii. The water content was determined to be 0.02% by Karl Fischer method.
In summary, form iii is a non-solvated crystalline solid having a melting point of about 159.3 ± 3 ℃ (obtained from a differential scanning calorimetry trace) and is an anhydrous form of a morpholino quinazoline compound represented by formula a.
The invention provides a preparation method of a crystal form III of a morpholinyl quinazoline compound shown as a formula A, which comprises a scheme I or a scheme II;
scheme one, it includes the following steps: distilling a solution of the morpholinyl quinazoline compound shown in the formula A and an organic solvent to remove the organic solvent, and collecting the crystal form III of the morpholinyl quinazoline compound shown in the formula A;
scheme two, it includes the following steps: drying the crystal form IV of the morpholino quinazoline compound shown in the formula A to remove moisture to obtain the crystal form III of the morpholino quinazoline compound shown in the formula A.
In the first embodiment, the organic solvent may be an alcohol solvent (e.g., methanol), or a mixed solvent of an alcohol solvent (e.g., methanol) and one or more of a ketone solvent (e.g., acetone), a nitrile solvent (e.g., acetonitrile), and a halogenated hydrocarbon solvent (e.g., dichloromethane); for example, an alcohol solvent (e.g., methanol), or a mixed solvent of an alcohol solvent (e.g., methanol) and one of a ketone solvent (e.g., acetone), a nitrile solvent (e.g., acetonitrile), and a halogenated hydrocarbon solvent (e.g., dichloromethane); when the organic solvent is a mixed solvent formed by an alcohol solvent and one or more of a ketone solvent, a nitrile solvent and a halogenated hydrocarbon solvent, the volume ratio of the alcohol solvent to the one or more of the ketone solvent, the nitrile solvent and the halogenated hydrocarbon solvent is 1:1 (for example, methanol: acetone (1:1), methanol: acetonitrile (1:1) or methanol: dichloromethane (1: 1)).
In the first scheme, the morpholinyl quinazoline compound shown in the formula A and an organic solvent are in solution; the preparation method is conventional in the field, and the preparation method preferably comprises the following steps: carrying out ultrasonic treatment on a morpholinyl quinazoline compound shown as a formula A in an organic solvent until a solid is not dissolved any more, and filtering with a filter membrane; the obtained filtrate is the solution. The filter membrane may be a 0.45 micron filter membrane.
In the first embodiment, the solution of the morpholinyl quinazoline compound represented by the formula a and the organic solvent may be a saturated solution.
In the first embodiment, the distillation method may be a method conventional in the art, for example, concentration under reduced pressure may be performed in a rotary evaporator; wherein, the vacuum degree of the reduced pressure concentration can be-0.09 MPa; the temperature of the reduced pressure concentration can be 28-42 ℃ (for example, 30 +/-2 ℃ and 40 +/-2 ℃); the rotation speed of the reduced pressure concentration can be 50-60 rpm (for example, 50rpm, 55rpm, 60 rpm).
In the second embodiment, the drying method may be a drying method conventional in the art, such as drying under reduced pressure or drying under atmospheric pressure; without limitation, the vacuum degree of the reduced pressure drying can be-0.09 MPa; the temperature of the reduced pressure drying can be 28-62 ℃, and is further preferably 35-45 ℃ (for example 40 +/-2 ℃). The drying time is 1 hour to overnight, namely 1 to 24 hours. Without limitation, the drying under normal pressure is preferably carried out at a temperature of 38 to 142 ℃ (e.g., 40 ± 2 ℃, 60 ± 2 ℃, 80 ± 2 ℃, 100 ± 2 ℃, 120 ± 2 ℃ and 140 ± 2 ℃), more preferably at a temperature of 48 to 72 ℃, and most preferably at a temperature of 60 ± 2 ℃. The drying time is 1 hour to overnight, namely 1 to 24 hours.
In the second scheme, the crystal form iv of the morpholino quinazoline compound shown in the formula a can be obtained by a conventional preparation method in the art, and the method can comprise the following steps: and (2) slowly volatilizing the solution of the morpholinyl quinazoline compound shown in the formula A and the organic solvent to remove the organic solvent to obtain the crystal form IV of the morpholinyl quinazoline compound shown in the formula A. Wherein the solution of the morpholinyl quinazoline compound shown in the formula A and the organic solvent is the solution of the morpholinyl quinazoline compound shown in the formula A and the organic solvent in the scheme I.
The slow evaporation method may be a method conventional in the art, such as placing in a fume hood for slow evaporation, or for example, covering the container in which the saturated solution is placed with an aluminum foil with pores on the surface, and placing in a fume hood for slow evaporation of the solvent.
According to the crystal form IV of the morpholinyl quinazoline compound shown in the formula A, an X-ray powder diffraction pattern expressed by a 2 theta angle has diffraction peaks at 6.1 +/-0.2 degrees, 8.4 +/-0.2 degrees, 11.8 +/-0.2 degrees, 13.6 +/-0.2 degrees, 16.0 +/-0.2 degrees, 17.3 +/-0.2 degrees, 18.4 +/-0.2 degrees, 20.0 +/-0.2 degrees, 21.8 +/-0.2 degrees, 24.4 +/-0.2 degrees, 24.7 +/-0.2 degrees and 25.5 +/-0.2 degrees;
further, in the crystal form iv of the morpholinyl quinazoline compound shown in the formula a in the present invention, in an X-ray powder diffraction pattern represented by a 2 θ angle and a peak height percentage, diffraction peaks and peak height percentages thereof can also be shown in table 2:
TABLE 2
Without limitation, a typical example of the crystal form iv of the morpholinyl quinazoline compound represented by the formula a in the present invention has an X-ray powder diffraction pattern expressed by an angle of 2 θ as shown in fig. 6.
In the present invention, a typical example of the crystal form IV of the morpholinyl quinazoline compound shown in the formula A loses about 5.76% of volatile substances when heated to 150 ℃ in a thermogravimetric analysis chart (TGA), which confirms that the compound is a solvated substance, and the weight loss generated at the temperature of more than 150 ℃ is caused by decomposition.
Without limitation, the TGA diagram of a typical example of the crystalline form iv of the morpholinyl quinazoline compound of the formula a as described in the present invention can also be substantially as shown in fig. 7.
In the present invention, a typical example of the crystal form iv of the morpholinyl quinazoline compound shown in the formula a has two endothermic peaks in a Differential Scanning Calorimetry (DSC) chart, which are respectively at 81.26 ℃ (peak temperature) and 160.00 ℃ (peak temperature).
Without limitation, a DSC diagram of a typical example of a crystalline form iv of a morpholinyl quinazoline compound of the formula a as described herein can also be substantially as shown in figure 8.
Without limitation, a typical example of the crystal form IV of the morpholinyl quinazoline compound shown as the formula A in the invention is DMSO-d6Liquid nuclear magnetic hydrogen spectrum as solvent (1H NMR) chart is shown in fig. 9.1H NMR showed no residue of crystallization solvent in form iv. The water content was 5.7% as determined by the Karl Fischer method, which was calculated to be approximately two moles of water. According to1H NMR, TGA and moisture results prove that the crystal form IV is a dihydrate crystalline solid of the morpholinyl quinazoline compound shown in the formula A.
The invention also provides a pharmaceutical composition, which comprises the crystal form III of the morpholinyl quinazoline compound shown in the formula A and a pharmaceutically acceptable carrier. Wherein the content of the crystal form III of the morpholinyl quinazoline compound shown in the formula A is (prophylactically or therapeutically) effective amount.
The invention also provides an application of the crystal form III of the morpholinyl quinazoline compound shown as the formula A or the pharmaceutical composition in preparation of a PI3 kinase (PI3K) inhibitor.
The PI3 kinase is preferably a p110 delta subtype.
The invention also provides an application of the crystal form III of the morpholinyl quinazoline compound shown as the formula A or the pharmaceutical composition in preparation of a medicine, wherein the medicine is used for preventing and/or treating diseases related to PI3 kinase (PI 3K).
In the invention, the PI3 kinase is preferably a p110 delta subtype.
In the present invention, the diseases related to PI3 kinase include but are not limited to: cancer, immune diseases, metabolic and/or endocrine dysfunction, cardiovascular disease, viral infection and inflammation, and neurological disease, preferably cancer and/or immune disease.
Wherein the immune disease includes but is not limited to one or more of rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease and systemic lupus erythematosus. The cardiovascular disease includes but is not limited to hematological tumors. The viral infection and inflammation include, but are not limited to, asthma and/or atopic dermatitis.
The invention also provides an application of the crystal form III of the morpholinyl quinazoline compound shown as the formula A or the pharmaceutical composition in preparation of a medicament, wherein the medicament is used for preventing and/or treating diseases, and the diseases are one or more of cancers, immune diseases, metabolism and/or endocrine dysfunction, cardiovascular diseases, viral infection, inflammation and neurological diseases.
Wherein said immune disorder, said cardiovascular disorder, said viral infection and inflammation are as described above.
In the invention, the crystal form III of the morpholinyl quinazoline compound shown in the formula A can also be combined with one or more other active ingredients for use; when used in combination, the active ingredients may be separate compositions for simultaneous administration by the same or different routes of administration or for separate administration at different times in therapy, or they may be administered together in the same pharmaceutical composition.
In the present invention, the method of administration of the pharmaceutical composition is not particularly limited, and various dosage forms of the preparation may be selected for administration according to the age, sex, and other conditions and symptoms of the patient; for example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; the injection can be administered alone or mixed with infusion solution (such as glucose solution and amino acid solution) for intravenous injection; the suppository is administered to the rectum.
In some examples, the crystal form iii of the morpholinyl quinazoline compound of formula a is not transformed when formulated with one or more pharmaceutically acceptable carriers and/or excipients and/or diluents.
In the present invention, "prevention" means "prevention". "preventing" refers to obtaining or developing a disease or disorder of reduced risk (i.e., resulting in exposure to the resulting disease agent or disease before onset susceptible to disease subjects do not develop clinical symptoms of the disease at least one).
In the present invention, "treatment" refers to ameliorating a disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of its clinical symptoms); alternatively, at least one physical parameter, which may not be perceived by the subject, is improved; or slow disease progression.
The crystalline forms of the invention may be identified by one or more solid state analysis methods. Such as X-ray powder diffraction, single crystal X-ray diffraction, infrared absorption spectrum, differential scanning calorimetry, thermogravimetric curve, etc. One skilled in the art will appreciate that the peak intensity and/or peak condition of the X-ray powder diffraction may vary depending on the experimental conditions. Meanwhile, due to different accuracies of the instruments, the measured 2 theta value has an error of about +/-0.2 degrees. The relative intensity values of the peaks depend more on certain properties of the measured sample, such as the size of the crystals and the purity than the position of the peaks, so that the measured peak intensities may deviate by about + -20%. One skilled in the art can obtain sufficient information to identify each crystal form from the X-ray powder diffraction data provided herein, despite experimental errors, instrumental errors, and orientation preference, etc. In infrared spectrometry, the shape of the spectrum and the position of an absorption peak are affected to a certain extent due to different instrument performances of various models, different grinding degrees or different water absorption degrees during preparation of a test article, and the like. In DSC measurements, however, the initial temperature, maximum temperature and heat of fusion data of the endothermic peak obtained by actual measurement are subject to some degree of variability, depending on the heating rate, crystal shape and purity and other measurement parameters.
In the present invention, "room temperature" means "10 to 30 ℃.
In the invention, the environment temperature of the fume hood is 10-30 ℃, and the environment humidity is 35-80% RH.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the crystal form III of the morpholinyl quinazoline compound shown as the formula A has good thermal stability and solubility, particularly has high equilibrium solubility in an aqueous medium with the pH value of 1.0 to 8.0, and has important values for promoting the dissolution and absorption of a medicament and improving the bioavailability of the medicament.
Drawings
FIG. 1 is a typical X-ray powder diffraction pattern of a crystal form III of a morpholinyl quinazoline compound shown as a formula A.
FIG. 2 is a typical infrared absorption spectrum of a crystal form III of a morpholinyl quinazoline compound shown as a formula A.
FIG. 3 is a typical thermogravimetric analysis diagram of a crystal form III of a morpholinyl quinazoline compound shown as a formula A.
Fig. 4 is a typical differential scanning calorimetry trace of crystalline form iii of a morpholino quinazoline compound according to formula a.
FIG. 5 is a typical liquid nuclear magnetic hydrogen spectrum diagram of a crystal form III of a morpholinyl quinazoline compound shown as a formula A.
FIG. 6 is a typical X-ray powder diffraction pattern of a crystalline form IV of a morpholinyl quinazoline compound as shown in formula A.
FIG. 7 is a typical thermogravimetric analysis of a crystalline form IV of a morpholinyl quinazoline compound according to formula A.
FIG. 8 is a typical differential scanning calorimetry trace of crystalline form IV of a morpholinoquinazoline compound according to formula A.
FIG. 9 is a typical liquid nuclear magnetic hydrogen spectrum diagram of a crystal form IV of a morpholinyl quinazoline compound shown as a formula A.
FIG. 10 is an X-ray powder diffraction pattern of a crystalline form IV of a morpholinyl quinazoline compound represented by the formula A obtained in example 8 before and after vacuum drying at 40 ℃ overnight.
FIG. 11 is a thermogravimetric analysis overlay of a crystalline form IV of a morpholinyl quinazoline compound represented by the formula A obtained in example 8 before and after vacuum drying at 40 ℃ overnight.
FIG. 12 is a differential scanning thermal overlay of crystalline form IV of a morpholinoquinazoline compound of the formula A obtained in example 8 after drying in vacuum at 40 ℃ overnight.
FIG. 13 is a typical X-ray powder diffraction pattern of an amorphous morpholinyl quinazoline compound of the formula A obtained according to the method of patent WO2015055071A 1.
FIG. 14 is a typical X-ray powder diffraction pattern of a crystalline form I of a morpholinyl quinazoline compound of the formula A obtained in comparative example 1.
FIG. 15 is a typical thermogravimetric analysis of the crystalline form I of the morpholinyl quinazoline compound of the formula A obtained in comparative example 1.
FIG. 16 is a typical differential scanning calorimetry chart of form I of a morpholinoquinazoline compound of the formula A obtained in comparative example 1.
FIG. 17 is a typical liquid nuclear magnetic hydrogen spectrum of crystal form I of morpholinyl quinazoline compound shown in formula A.
FIG. 18 is an X-ray powder diffraction pattern of crystalline form III of a morpholinyl quinazoline compound according to formula A after heating at various temperatures.
FIG. 19 is an X-ray powder diffraction overlay of a crystalline form IV of a morpholinyl quinazoline compound represented by formula A after heating at various temperatures.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Detection method
Instrument for measuring the position of a moving object
X-ray powder diffraction analysis (XRPD): the light source is CuK, the X-ray intensity is 40KV/40mA, the divergence slit is 1.0mm, the cable-pulling slit is 0.4 degrees, the scanning mode is continuous scanning, the scanning angle range is 3-45 degrees or 4-40 degrees, the step length is 0.02 degrees or 0.05 degrees, the scanning speed is 8 degrees/min or 6 degrees/min, and the detector: LynxEye.
Infrared absorption spectroscopy (IR): according to the infrared spectrophotometry 0402 of the four general rules of the Chinese pharmacopoeia 2015 year edition, the potassium bromide tabletting method is adopted to prepare a test article at 4000-400 cm-1Infrared absorption spectra were collected over the wavenumber range. The number of scanning times of the sample is 45, and the resolution of the instrument is 4cm-1。
Differential Scanning Calorimetry (DSC): weighing 2-4 mg of sample, placing the sample in a non-sealed aluminum tray, balancing the sample at 25 ℃ in a nitrogen flow (50mL/min) environment, and then heating the sample from 25 ℃ to 300 ℃ at a heating rate of 10 ℃/min.
Thermogravimetric analysis (TGA): weighing 8-12 mg of sample, placing the sample in a platinum sample tray, heating the sample to 300 ℃ from 25 ℃ at a heating rate of 10 ℃/min in a nitrogen flow (50mL/min) environment.
Liquid nuclear magnetic hydrogen spectrum (1H NMR): collecting liquid nuclear magnetic hydrogen spectrum on Bruk 400MHz nuclear magnetic resonance spectrometer with DMSO-d6As a solvent.
According to the synthesis method in the patent WO2015055071A1, the morpholinyl quinazoline compound shown in the formula A is prepared, and is characterized by being amorphous by XRPD, and the XRPD pattern of the morpholinyl quinazoline compound is shown in figure 13.
When the solvents listed in the examples of the present specification are mixed solvents, the proportions thereof are volume ratios.
Example 1 preparation of morpholmyl quinazoline compound of crystal form III as shown in formula A
Weighing about 2.0g of morpholinyl quinazoline compound shown in formula A, placing the morpholinyl quinazoline compound in a 500mL round-bottom flask, adding 300mL of methanol: and (2) performing ultrasonic treatment on acetonitrile (1:1) at room temperature until the solid is not dissolved any more, filtering the mixed solution by using a 0.45-micron filter membrane, transferring the filtrate into a new round-bottom flask, setting the rotation speed of a rotary evaporator to be 55rpm, controlling the water bath temperature to be 40 +/-2 ℃, performing reduced pressure concentration under-0.09 MPa, collecting the solid obtained after the solvent is completely dried by rotation, placing the solid in a vacuum oven at 40 ℃, and performing reduced pressure drying on the solid overnight.
And the obtained sample is crystal form III through X-ray powder diffraction method determination. The X-ray powder diffraction pattern is shown in figure 1, and has diffraction peaks at 7.1 + -0.2 deg., 8.1 + -0.2 deg., 11.4 + -0.2 deg., 12.7 + -0.2 deg., 13.7 + -0.2 deg., 14.4 + -0.2 deg., 15.9 + -0.2 deg., 17.2 + -0.2 deg., 18.6 + -0.2 deg., 18.9 + -0.2 deg., 19.6 + -0.2 deg., 20.4 + -0.2 deg., 20.9 + -0.2 deg., 23.1 + -0.2 deg., 24.7 + -0.2 deg. and 28.1 + -0.2 deg. in terms of 2 theta angle.
The IR spectrum is shown in FIG. 2 at 3460cm-1、3335cm-1、2957cm-1、2851cm-1、2797cm-1、1605cm-1、1587cm-1、1557cm-1、1470cm-1、1447cm-1、1408cm-1、1341cm-1、1260cm-1、1153cm-1、1109cm-1、1013cm-1、851cm-1And 768cm-1Has characteristic peaks.
Its TGA profile is shown in FIG. 3. As can be seen in fig. 3, form iii had essentially no weight loss when heated to 150 ℃, indicating that it is a non-solvated species, with weight loss beyond 150 ℃ due to decomposition.
The DSC chart is shown in FIG. 4. The differential scanning calorimetry of form III shows an endothermic peak at 159.32 deg.C (peak temperature), which is a melting peak of form III.
It is prepared from DMSO-d6Liquid nuclear magnetic hydrogen spectrum as solvent (1H NMR) chart is shown in fig. 5.1The H NMR chart shows no residual crystallization solvent in form iii. The water content of the crystal form III is 0.02 percent by Karl Fischer method.
TGA, 1H NMR and moisture content results prove that the crystal form III is a non-solvated crystalline solid, DSC results show that the melting point of the crystal form III is about 159.3 +/-3 ℃, and the crystal form III is an anhydrous crystal form of the morpholinyl quinazoline compound shown as the formula A.
Example 2 preparation of Crystal form III of Morpholinylquinazolines Compounds of formula A
Weighing about 300mg of morpholinyl quinazoline compound shown as formula A, adding 10mL of dichloromethane: ultrasonically treating with methanol (1:1) at room temperature until the solid is not dissolved, filtering with 0.45 μm filter membrane, transferring the filtrate into round bottom flask, setting rotary evaporator at 50rpm, controlling water bath temperature at 30 + -2 deg.C, concentrating under reduced pressure of-0.09 MPa, collecting the solid obtained after the solvent is completely dried, placing in vacuum oven, and drying under reduced pressure at 40 deg.C for 1 hr. The X-ray powder diffraction pattern of the sample obtained by the method is compared with the sample pattern of the example 1 to determine the crystal form III.
Example 3 preparation of Crystal form III of Morpholinylquinazolines Compounds of formula A
Weighing about 1.0g of morpholinyl quinazoline compound shown in formula A, placing the morpholinyl quinazoline compound in a 200mL round-bottom flask, adding 90mL of methanol: acetone (1:1), ultrasonic treating at room temperature until the solid is not dissolved, filtering with 0.45 micron filter membrane, transferring the filtrate into a new round bottom flask, setting the rotation speed of a rotary evaporator at 60rpm, controlling the water bath temperature at 40 +/-2 ℃, concentrating under reduced pressure of-0.09 MPa, collecting the solid obtained after the solvent is completely dried by rotation. The X-ray powder diffraction pattern of the sample obtained by the method is compared with the sample pattern of the example 1 to determine the crystal form III.
Example 4 preparation of Crystal form III of Morpholinylquinazolines Compounds of formula A
Weighing about 100mg of morpholinyl quinazoline compound shown as formula a into a glass vial, and adding 4mL of dichloromethane into the vial: methanol (1:1), sonicated at room temperature until the solids no longer dissolved, filtered through a 0.45 micron filter and the filtrate was transferred to a new vial. The vial was covered with aluminum foil and perforated with small holes, placed in a fume hood at room temperature to slowly volatilize the solvent, after 4 days, the solvent was completely volatilized, the resulting solid was collected, and dried under reduced pressure at 40 ℃, -0.09MPa overnight. The X-ray powder diffraction pattern of the sample obtained by the method is compared with the sample pattern of the example 1 to determine the crystal form III.
Example 5 preparation of Crystal form III of Morpholinylquinazolines Compounds of formula A
Adding about 100mg of the morpholinyl quinazoline compound shown in the formula A to 20mL of methanol, or adding about 30mg of the morpholinyl quinazoline compound shown in the formula A to 2mL of methanol: acetone (1:1) was added to prepare a saturated solution according to the method of example 4, followed by filtration, the solvent was slowly evaporated, the resulting solid was collected after complete evaporation of the solvent, and dried under reduced pressure at 40 ℃ and-0.09 MPa overnight. The X-ray powder diffraction pattern of each sample obtained by the method is compared with the pattern of the sample in the example 1, and the crystal form III is determined.
The above examples show that the crystal form iii can be obtained according to the type of the organic solvent, and when the organic solvent contains methanol, the saturated solution of the morpholinyl quinazoline compound shown in the formula a in the organic solvent can be obtained by either rotary evaporation or by evaporating the solvent to the open state, and the precipitated solid is dried to obtain the crystal form iii.
Example 6 preparation of crystalline form IV of a morpholinyl quinazoline compound of formula A
Weighing about 200mg of morpholinyl quinazoline compound shown as formula a into a glass vial, and adding 20mL of methanol into the vial: acetonitrile (1:1), sonicated at room temperature until the solid no longer dissolved, filtered through a 0.45 micron filter and the filtrate was transferred to a new vial. The vial was covered with aluminum foil and pricked with several small holes, placed in a fume hood to slowly evaporate the solvent, and after 3 days, the solvent was completely evaporated and the resulting solid was collected.
The sample obtained is of a crystal form IV determined by an X-ray powder diffraction method. The X-ray powder diffraction pattern is shown in FIG. 6, and the diffraction peak (2 theta) and the peak height percentage (%) are shown in the following Table 3:
TABLE 3
Its TGA profile is shown in FIG. 7. The TGA profile shows that form iv loses about 5.76% of volatiles upon heating to 150 ℃, confirming that it is a solvated species, with weight loss beyond 150 ℃ due to decomposition.
The DSC chart is shown in FIG. 8. Form IV has two endothermic peaks on a differential scanning calorimetry chart at 81.26 deg.C (peak temperature) and 160.00 deg.C (peak temperature), respectively.
It is prepared from DMSO-d6Liquid nuclear magnetic hydrogen spectrum as solvent (1H NMR) chart is shown in fig. 9.1H NMR showed no residue of crystallization solvent in form iv. The water content was 5.7% as determined by the Karl Fischer method, which was calculated to be approximately two moles of water.
According to1H NMR, TGA and moisture results prove that the crystal form IV is dihydrate crystal solid of the morpholinyl quinazoline compound shown as the formula A.
Example 7 preparation of crystalline form IV of a morpholinyl quinazoline compound of the formula A (liquid phase diffusion method)
Weighing about 30mg of morpholinyl quinazoline compound shown as formula A, placing the morpholinyl quinazoline compound in a glass vial, adding 4mL of methanol into the vial, performing ultrasonic treatment at room temperature until the solid is not dissolved, filtering the mixture by using a 0.45 micron filter membrane, taking 2mL of filtrate, and transferring the filtrate into a new 4mL vial. Another 20mL glass bottle was added with 10mL of water, and a 4mL vial containing the filtrate was opened to a 20mL vial, and the 20mL vial was sealed and allowed to stand at room temperature. When the precipitation of solids was observed in a 4mL glass vial, the solids were collected by separation.
The X-ray powder diffraction pattern of the sample obtained by the method is compared with the pattern of the sample in the example 6 to determine the crystal form IV.
Example 8 preparation of Crystal form III of Morpholinylquinazolines Compounds of formula A
The sample of form iv obtained from the procedure of example 6 was placed in a vacuum oven set at 40 ℃ and vacuum dried overnight at-0.09 MPa and the XRPD, TGA and DSC were again determined. And comparing the X-ray powder diffraction pattern of the dried sample with the pattern of the sample in the example 1 to determine the crystal form III. After drying, the sample had essentially no weight loss on the TGA plot before heating to 150 ℃, confirming that the moisture had essentially been dried off. The endothermic peak of water at 81.26 ℃ (peak temperature) on the DSC diagram of the dried sample disappeared, leaving only the melting endothermic peak of form iii. XRPD, TGA and DSC overlay of the sample before and after drying overnight are shown in FIGS. 10-12, respectively. XRPD, TGA and DSC results prove that after the crystal form IV of the morpholinyl quinazoline compound shown in the formula A is dried in vacuum at 40 ℃ overnight, the contained two moles of moisture can be completely removed, and the crystal form IV of the morpholinyl quinazoline compound shown in the formula A is converted into the crystal form III of the morpholinyl quinazoline compound shown in the formula A.
Comparative example 1 preparation of crystalline form I of morpholinyl quinazolines of formula A
Adding 500mL of ethanol into 10g of morpholinyl quinazoline compound shown as formula A, completely dissolving under heating, filtering while hot, concentrating the filtrate to 50-70mL, stirring overnight at room temperature, adding n-heptane for crystallization until a large amount of solids are separated out, filtering, and drying in vacuum at the temperature of less than 85 ℃ for 5-6 hours to obtain the solid, namely the crystal form I of the morpholinyl quinazoline compound shown as formula A.
The X-ray powder diffraction pattern is shown in FIG. 14, which shows the diffraction peak (2. theta.) and the peak height percentage (%))As shown in table 4 below:
TABLE 4
| Numbering | 2θ(±0.2°) | Percentage of peak height (%) |
| 1 | 7.239 | 5.5 |
| 2 | 7.666 | 18.4 |
| 3 | 9.732 | 34.5 |
| 4 | 10.962 | 25.7 |
| 5 | 11.318 | 5.4 |
| 6 | 12.385 | 89.2 |
| 7 | 15.377 | 65.5 |
| 8 | 17.404 | 100.0 |
| 9 | 17.971 | 99.4 |
| 10 | 18.382 | 89.6 |
| 11 | 19.516 | 11.0 |
| 12 | 20.111 | 24.6 |
| 13 | 21.795 | 36.0 |
| 14 | 22.551 | 15.8 |
| 15 | 23.191 | 16.5 |
| 16 | 23.564 | 53.2 |
| 17 | 24.300 | 30.5 |
| 18 | 25.799 | 13.9 |
| 19 | 28.684 | 21.5 |
The TGA profile is shown in FIG. 15. As can be seen in fig. 15, form i had essentially no weight loss when heated to 150 c, indicating that it is a non-solvated species, with weight loss above 150 c due to decomposition.
The DSC chart is shown in FIG. 16. The differential scanning calorimetry of the crystal form I has an endothermic peak at 204.33 deg.C (peak temperature), which is the melting peak of the crystal form I.
It is prepared from DMSO-d6Liquid nuclear magnetic hydrogen spectrum as solvent (1H NMR) chart is shown in fig. 17.1H NMR showed no residual crystallization solvent in form i. The water content was determined to be 0.1% by Karl Fischer method.
TGA, 1H NMR and moisture content results prove that the crystal form I is a non-solvated crystalline solid, and DSC results show that the melting point of the crystal form I is about 204.3 +/-3 ℃, and the crystal form I is an anhydrous crystal form of the morpholinyl quinazoline compound shown as the formula A.
Effect example 1 stability
Stability of 1 morpholinyl quinazoline compound crystal form III shown as formula A in water and organic solvent
1.1 stability of crystal form III of morpholinyl quinazoline compound shown as formula A in organic solvent at room temperature for 6 days
Respectively taking about 10mg of a morpholinyl quinazoline compound crystal form III sample shown as a formula A, placing the morpholinyl quinazoline compound crystal form III sample into a glass vial, respectively adding 0.3mL of isopropanol, isopropyl acetate, acetone, toluene, methyl tert-butyl ether or acetonitrile into the vial, and performing ultrasonic dispersion to prepare suspension. The suspension was rotary equilibrated at room temperature for 6 days, the remaining solid wet sample was collected and the X-ray powder diffractogram was determined. The result shows that the morphotyl quinazoline compound crystal form III shown in the formula A is balanced in various solvents for 6 days at room temperature, and the crystal form is not changed and still is the crystal form III.
1.2 conversion relation between crystal form III and crystal form IV of morpholinyl quinazoline compound shown as formula A
The research result of example 8 shows that the crystal form iii can be obtained after drying and dehydrating the crystal form iv, and in order to further research the conditions for mutual transformation between the crystal form iii and the crystal form iv, a suspension equilibrium experiment of the crystal form iii in solvent systems with different water activities (aw ═ 0-1) at room temperature is set. The method comprises the following specific steps: respectively taking about 10mg of a morpholinyl quinazoline compound crystal form III sample shown as a formula A, placing the sample into a glass vial, and respectively adding 1mL of water, or 0.3mL of methanol, or 0.3mL of water into the vial: methanol (10: 90, aw-0.26), or 0.3mL of water: methanol (25: 75, aw-0.50), or 0.3ml of water: methanol (50: 50, aw-0.73), or 0.3mL of water: methanol (80: 20, aw-0.91) is ultrasonically dispersed to prepare suspension. The suspension was rotary equilibrated at room temperature for 6 days, the remaining solid wet sample was collected and the X-ray powder diffractogram was determined. The results are shown in Table 5.
TABLE 5 stability of form III at different Water Activities
| Solvent (volume ratio, water activity) | Crystal form of wet sample |
| Methanol | Ⅲ |
| Water: methanol (10: 90, aw-0.26) | Ⅲ |
| Water: methanol (25: 75, aw 0.50) | Ⅲ |
| Water: methanol (50: 50, aw 0.73) | Ⅲ |
| Water: methanol (80: 20, aw-0.91) | Ⅳ |
| Water (W) | Ⅳ |
Note: water Activity (Water Activity, also known as Water Activity, abbreviated aw) is the ratio of the equilibrium vapor pressure of Water in a product to the saturated vapor pressure of pure Water at the same temperature.
The result shows that the morpholinyl quinazoline compound crystal form III shown as the formula A is only converted into a crystal form IV in an aqueous solvent system with room temperature water activity of 0.91 or above; in an aqueous solvent system with the room-temperature water activity of below 0.73, the morpholinyl quinazoline compound crystal form III shown as the formula A cannot be combined with water molecules, and the crystal form III is a more stable crystal form.
1.3 influence of temperature change on crystal form III and crystal form IV of morpholinyl quinazoline compound shown as formula A
And (2) placing a glass small bottle filled with a proper amount of crystal form III sample of the morpholinyl quinazoline compound shown as the formula A in an electrothermal blowing oven in an open manner, setting the oven temperature to be 40 ℃, 60 ℃, 80 ℃, 100 ℃, 120 ℃ and 140 ℃ in sequence, heating for 1 hour respectively at each temperature, taking out a proper amount of sample, and determining an X-ray powder diffraction pattern.
And (2) placing a glass vial filled with a proper amount of crystal form IV sample of the morpholinyl quinazoline compound shown as the formula A in an electrothermal blowing oven in an open manner, setting the oven temperatures to be 40 ℃, 60 ℃, 80 ℃ and 100 ℃ in sequence, heating for 1 hour respectively at each temperature, taking out a proper amount of sample, and determining an X-ray powder diffraction pattern.
Fig. 18 shows an X-ray powder diffraction pattern of a crystal form iii of a morpholinoquinazoline compound represented by the formula a after heating at the above respective temperatures for 1 hour. Through X-ray powder diffraction superposition, the crystal form III of the morpholinyl quinazoline compound shown as the formula A is not subjected to crystal form transformation after being heated for 1 hour at the above temperatures, and the fact that the crystal form III of the morpholinyl quinazoline compound shown as the formula A has good thermal stability is confirmed.
An X-ray powder diffraction pattern of a crystal form iv of the morpholinyl quinazoline compound represented by the formula a after heating for 1 hour at the above respective temperatures is shown in fig. 19. Through X-ray powder diffraction superposition, the crystal form IV of the morpholinyl quinazoline compound shown as the formula A can be confirmed to be partially converted into the crystal form III after being heated for 1 hour at 40 ℃, and can be completely converted into the crystal form III after being heated for 1 hour at 60 ℃, so that the thermal stability of the crystal form III of the morpholinyl quinazoline compound shown as the formula A is better than that of the crystal form IV.
The crystal form III combines with water molecules under the condition of high water activity, the water molecules of the crystal form IV are removed under the condition of heating, and reversible transformation relation is realized between the two crystal forms, and the technical inspiration is as follows: on one hand, the morpholinyl quinazoline compound shown as the formula A in the crystal form IV is not tightly bonded with water molecules, water molecules are easily dehydrated by heating, and the thermodynamic stability of the crystal form IV is not as good as that of the crystal form III; on the other hand, the crystal form iv may exist as an intermediate in the preparation process of the crystal form iii, and when a person skilled in the art prepares a single crystal form iv or a mixture of the crystal form iii and the crystal form iv in any ratio by using the method of the embodiment of the present invention or other methods, the person skilled in the art may remove moisture by a suitable manner, for example, drying at a lower temperature under normal pressure or reduced pressure, and the like, so that the single crystal form iii disclosed in the present invention may be obtained.
Effect example 2 equilibrium solubility test of Crystal form III and Crystal form I of Morpholinylquinazoline Compound represented by formula A
The preparation method of the equilibrium solubility test medium comprises the following steps:
the preparation method of 0.1mol/L hydrochloric acid solution as medium, acetic acid-sodium acetate buffer solution (50mmol/L) with pH of 4.5, phosphate buffer solution (50mmol/L) with pH of 6.8 and phosphate buffer solution (50mmol/L) with pH of 7.4 refers to Solutions of 36 th edition of United states Pharmacopeia; the medium water is purified water.
phosphate buffer (50mmol/L) at pH 8.0:
taking 0.68g of monopotassium phosphate, adding 23.05mL of 0.2mol/L sodium hydroxide solution, diluting with water to 100mL, and measuring the pH value to be 8.00.
Simulated Gastric Fluid (SGF) preparation method:
taking 202.5mg of sodium chloride, adding 7.2mL of 1mol/L hydrochloric acid solution, and diluting with water to 100mL to obtain the sodium chloride, wherein the pH value is measured to be 1.21.
Preparation method of simulated fasting state intestinal fluid (FaSSIF):
the first step is as follows: 0.4185g of sodium hydroxide, 3.4393g of disodium hydrogen phosphate and 6.1858g of sodium chloride are taken, 900mL of water is added, the pH is adjusted to 6.50 by 0.2mol/L of sodium hydroxide solution, the solution is diluted to 1000mL by water and shaken up.
The second step is that: adding 2.2394g of FaSSIF/FeSSIF/FaSSGF powder into 500mL of the above buffer solution, and stirring until the powder is completely dissolved to obtain the final product.
A preparation method of simulated feeding state intestinal fluid (FeSSIF) comprises the following steps:
the first step is as follows: 2.0208g of sodium hydroxide, 4.3199g of glacial acetic acid and 5.9337g of sodium chloride are taken, 480mL of water is added, the pH is adjusted to 5.0 by 1mol/L of sodium hydroxide solution, the solution is diluted to 500mL by water and shaken up.
The second step is that: adding 5.6008g of FaSSIF/FeSSIF/FaSSGF powder (brand: Biorelevant) into 500mL of the buffer solution, and stirring until the powder is completely dissolved to obtain the composition.
Equilibrium solubility test:
respectively taking 9 glass vials, sequentially and respectively adding 1.5mL of prepared 0.1mol/L hydrochloric acid solution, acetic acid-sodium acetate buffer solution (50mmol/L) with pH of 4.5, phosphate buffer solution (50mmol/L) with pH of 6.8, phosphate buffer solution (50mmol/L) with pH of 7.4, water, phosphate buffer solution (50mmol/L) with pH of 8.0, simulated gastric juice (SGF), simulated fasted state intestinal juice (FaSSIF) or simulated fed state intestinal juice (FeSSIF), respectively adding excessive crystal form III or crystal form I of the morpholinyl quinazoline compound shown in the formula A into each vial, performing vortex 30-second dispersion to prepare supersaturated solution, covering and sealing each glass, wrapping aluminum foil paper on each glass, and performing rotary equilibrium at room temperature.
And after balancing for 24 hours, centrifuging at 12000rpm for 10 minutes, transferring supernatant, diluting the supernatant to a proper concentration by using methanol, measuring the concentration of the morpholinyl quinazoline compound shown as the formula A by using a high performance liquid chromatography, and calculating the equilibrium solubility of the crystal form III and the crystal form I of the morpholinyl quinazoline compound shown as the formula A in each medium according to an external standard method.
TABLE 6
As can be seen from Table 6, the equilibrium solubility of form III is higher than that of form I in 0.1mol/L hydrochloric acid solution, acetic acid-sodium acetate buffer solution (50mmol/L) at pH 4.5, phosphate buffer solution (50mmol/L) at pH 6.8, phosphate buffer solution (50mmol/L) at pH 7.4, water, phosphate salt (50mmol/L) at pH8.0, Simulated Gastric Fluid (SGF), simulated fasted state intestinal fluid (FaSSIF) and simulated fed state intestinal fluid (FeSSIF). In particular, form III is 3.1-fold, 2.7-fold, 2.3-fold, 3.0-fold, and 1.4-fold, respectively, as compared to form I in terms of equilibrium solubility data in phosphate buffer at pH 6.8 (50mmol/L), phosphate buffer at pH 7.4 (50mmol/L), phosphate buffer at pH8.0 (50mmol/L), simulated fasted state intestinal fluid (FaSSIF), and simulated fed state intestinal fluid (FeSSIF).
Claims (10)
1. A crystal form III of a morpholinyl quinazoline compound shown as a formula A is characterized in that an X-ray powder diffraction pattern expressed by a 2 theta angle measured by using a K alpha spectral line of a Cu target has diffraction peaks at 7.1 +/-0.2 degrees, 8.1 +/-0.2 degrees, 11.4 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.2 +/-0.2 degrees, 18.9 +/-0.2 degrees and 20.4 +/-0.2 degrees;
2. the crystalline form iii of the morpholinyl quinazoline compound of the formula a as claimed in claim 1, having an X-ray powder diffraction pattern expressed in terms of 2 Θ angles with diffraction peaks at one or more of the following 2 Θ angles: 12.7 +/-0.2 degrees, 13.7 +/-0.2 degrees, 14.4 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.6 +/-0.2 degrees, 20.9 +/-0.2 degrees, 23.1 +/-0.2 degrees, 24.7 +/-0.2 degrees and 28.1 +/-0.2 degrees.
3. The morphotropic form III of the morpholinyl quinazoline compound of the formula A as claimed in claim 1 or 2, wherein the diffraction peaks and the peak height percentages are shown in Table 1 in the X-ray powder diffraction diagram expressed by 2 theta angle:
TABLE 1
And/or the infrared absorption spectrogram of the crystal form III of the morpholinyl quinazoline compound shown in the formula A has characteristic peaks at the following positions: 3460cm-1、3335cm-1、2957cm-1、2851cm-1、2797cm-1、1605cm-1、1587cm-1、1557cm-1、1470cm-1、1447cm-1、1408cm-1、1341cm-1、1260cm-1、1153cm-1、1109cm-1、1013cm-1、851cm-1And 768cm-1；
And/or the morphotyl III of the morpholinyl quinazoline compound shown in the formula A has an endothermic peak at 159.3 +/-3 ℃ in a differential scanning calorimetry diagram.
4. A crystalline form iii of a morpholinyl quinazoline compound of the formula a as claimed in any of claim 3 having an X-ray powder diffraction pattern expressed in terms of 2 Θ angles substantially as shown in figure 1;
and/or the infrared absorption spectrogram of the crystal form III of the morpholinyl quinazoline compound shown in the formula A is basically shown in figure 2;
and/or the thermogravimetric analysis diagram of the crystal form III of the morpholinyl quinazoline compound shown in the formula A is basically shown in figure 3;
and/or the morphotyl III of the morpholinyl quinazoline compound shown in the formula A is shown in a differential scanning calorimetry diagram basically as shown in a figure 4;
and/or the crystal form III of the morpholinyl quinazoline compound shown as the formula A is DMSO-d6The liquid nuclear magnetic hydrogen spectrum as a solvent is substantially as shown in fig. 5.
5. A preparation method of the morpholinyl quinazoline compound as shown in the formula A in any one of claims 1 to 4, which is characterized by comprising a scheme I or a scheme II;
scheme one, it includes the following steps: distilling a solution of the morpholinyl quinazoline compound shown in the formula A and an organic solvent to remove the organic solvent, and collecting the crystal form III of the morpholinyl quinazoline compound shown in the formula A;
scheme two, it includes the following steps: drying the crystal form IV of the morpholino quinazoline compound shown in the formula A to remove moisture to obtain the crystal form III of the morpholino quinazoline compound shown in the formula A.
6. The preparation method of the crystal form III of the morpholinyl quinazoline compound as shown in the formula A in claim 5,
in the first scheme, the organic solvent is an alcohol solvent, or a mixed solvent formed by the alcohol solvent and one or more of a ketone solvent, a nitrile solvent and a halogenated hydrocarbon solvent;
and/or, in the first scheme, the solution of the morpholinyl quinazoline compound shown in the formula a and the organic solvent is prepared by a preparation method comprising the following steps: carrying out ultrasonic treatment on a morpholinyl quinazoline compound shown as a formula A in an organic solvent until a solid is not dissolved any more, and filtering with a filter membrane; the obtained filtrate is the solution;
and/or, in the first scheme, the solution of the morpholinyl quinazoline compound shown in the formula A and the organic solvent is a saturated solution;
and/or, in the first scheme, the filter membrane is a 0.45 micron filter membrane;
and/or, in the first scheme, the distillation is vacuum concentration in a rotary evaporator;
and/or, in the second scheme, the drying is reduced pressure drying or normal pressure drying;
and/or in the scheme II, the crystal form IV of the morpholinyl quinazoline compound shown in the formula A is obtained by adopting a preparation method comprising the following steps: slowly volatilizing a solution of the morpholinyl quinazoline compound shown as the formula A and an organic solvent to remove the organic solvent to obtain a crystal form IV of the morpholinyl quinazoline compound shown as the formula A;
and/or, in the second scheme, the crystal form iv of the morpholino quinazoline compound represented by the formula a has diffraction peaks at 6.1 ± 0.2 °, 8.4 ± 0.2 °, 11.8 ± 0.2 °, 13.6 ± 0.2 °, 16.0 ± 0.2 °, 17.3 ± 0.2 °, 18.4 ± 0.2 °, 20.0 ± 0.2 °, 21.8 ± 0.2 °, 24.4 ± 0.2 °, 24.7 ± 0.2 °, and 25.5 ± 0.2 ° in an X-ray powder diffraction pattern represented by 2 θ angle;
and/or in the second scheme, the morphotyl IV of the morpholinyl quinazoline compound shown in the formula A has two endothermic peaks in a differential scanning calorimetry chart, and the two endothermic peaks are respectively at 81.3 +/-3 ℃ and 160.0 +/-3 ℃.
7. The preparation method of the crystal form III of the morpholinyl quinazoline compound as shown in the formula A in claim 6,
in the first scheme, when the organic solvent contains an alcohol solvent, the alcohol solvent is methanol;
and/or, in the first scheme, when the organic solvent contains a ketone solvent, the ketone solvent is acetone;
and/or, in the first scheme, when the organic solvent contains a nitrile solvent, the nitrile solvent is acetonitrile;
and/or, in the first scheme, when the organic solvent contains a halogenated hydrocarbon solvent, the halogenated hydrocarbon solvent is dichloromethane;
and/or, in the first scheme, when the organic solvent is a mixed solvent formed by an alcohol solvent and one or more of a ketone solvent, a nitrile solvent and a halogenated hydrocarbon solvent, the volume ratio of the alcohol solvent to one or more of the ketone solvent, the nitrile solvent and the halogenated hydrocarbon solvent is 1: 1;
and/or, in the first scheme, in the preparation method of the solution of the morpholinyl quinazoline compound shown in the formula a and the organic solvent, the filter membrane is a 0.45 micron filter membrane;
and/or, in the first scheme, when the distillation is vacuum concentration in a rotary evaporator, the vacuum degree of the vacuum concentration is-0.09 MPa;
and/or, in the first scheme, when the distillation is carried out in a rotary evaporator under reduced pressure, the temperature of the reduced pressure concentration is 28-42 ℃;
and/or in the first scheme, when the distillation is carried out in a rotary evaporator under reduced pressure, the rotation speed of the reduced pressure concentration is 50-60 rpm;
and/or, in the second scheme, when the drying method is reduced pressure drying, the vacuum degree of the reduced pressure drying is-0.09 MPa;
and/or in the second scheme, when the drying method is reduced pressure drying, the temperature of the reduced pressure drying is 28-62 ℃;
and/or in the second scheme, when the drying method is normal-pressure drying, the temperature of the normal-pressure drying is 38-142 ℃;
and/or in the second scheme, in the preparation method of the crystal form IV of the morpholinyl quinazoline compound shown in the formula A, the solution of the morpholinyl quinazoline compound shown in the formula A and the organic solvent is the same as the solution of the morpholinyl quinazoline compound shown in the formula A and the organic solvent in the first scheme;
and/or in the scheme II, in the preparation method of the crystal form IV of the morpholinyl quinazoline compound shown in the formula A, the slow volatilization is that a container for placing the saturated solution is covered by an aluminum foil with small holes on the surface, and the container is placed in a fume hood to slowly volatilize the solvent;
and/or, in the second scheme, the crystal form iv of the morpholino quinazoline compound shown in the formula a has an X-ray powder diffraction pattern expressed by 2 θ angle and peak height percentage, and the diffraction peaks and peak height percentage are shown in table 2:
TABLE 2
And/or, in scheme two, the TGA diagram of the crystalline form iv of the morpholino quinazoline compound shown in formula a is substantially shown in fig. 7;
and/or in scheme II, the DSC chart of the crystal form IV of the morpholinyl quinazoline compound shown in the formula A is basically shown in figure 8;
and/or in the scheme II, the crystal form IV of the morpholinyl quinazoline compound shown as the formula A is DMSO-d6FIG. 9 shows a liquid nuclear magnetic hydrogen spectrum of the solvent.
8. A pharmaceutical composition, which comprises the crystal form III of the morpholinyl quinazoline compound shown in the formula A according to any one of claims 1 to 4 and at least one pharmaceutically acceptable carrier.
9. The application of the crystal form III of the morpholinyl quinazoline compound shown in the formula A according to any one of claims 1 to 4 or the pharmaceutical composition of claim 8 in preparing a PI3 kinase inhibitor or a medicament; the medicine is used for preventing and/or treating diseases related to PI3 kinase, or one or more of cancer, immune diseases, metabolism and/or endocrine dysfunction, cardiovascular diseases, virus infection, inflammation and nerve diseases.
10. The use of claim 9, wherein the PI3 kinase is the p110 δ subtype;
and/or, the diseases related to PI3 kinase comprise: one or more of cancer, immune disease, metabolic and/or endocrine dysfunction, cardiovascular disease, viral infection and inflammation, and neurological disease, such as cancer and/or immune disease; wherein the immune disease may include one or more of rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease and systemic lupus erythematosus; the cardiovascular disease may include hematological neoplasms; the viral infection and inflammation may include asthma and/or atopic dermatitis.
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