CN113444073B - 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 PDF

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CN113444073B
CN113444073B CN202010222069.4A CN202010222069A CN113444073B CN 113444073 B CN113444073 B CN 113444073B CN 202010222069 A CN202010222069 A CN 202010222069A CN 113444073 B CN113444073 B CN 113444073B
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quinazoline compound
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crystal form
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CN113444073A (en
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楼杨通
唐佑海
许祖盛
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Shanghai Yingli Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

The invention discloses a crystal form III of a morpholinyl quinazoline compound, a preparation method and application thereof. The crystal form III of the morpholino quinazoline compound provided by the invention has better thermal stability and solubility, and particularly has higher equilibrium solubility in aqueous medium with pH ranging from 1.0 to 8.0, and has important value for promoting dissolution and absorption of medicines and improving bioavailability of the medicines.

Description

Crystal form III of morpholinyl quinazoline compound, preparation method and application thereof
Technical Field
The invention relates to a crystal form III of a morpholinyl quinazoline compound, a preparation method and application thereof.
Background
The structure is shown as AThe morpholino quinazoline compounds have the activity of inhibiting phosphatidylinositol 3-kinase delta (PI 3K delta).
Pi3kδ is an intracellular phosphoinositide kinase that catalyzes the phosphorylation of the hydroxyl group at the 3-position of phosphatidyl alcohol. PI3 ks can be classified as class i, class ii and class iii kinases, with class iii PI3 ks being the most widely studied ones that are activated by cell surface receptors. Class iii PI3 ks in mammalian cells are 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 PI3 ks include pi3kα, pi3kβ, pi3kδ subtypes, class iiib PI3 ks include pi3kγ subtype (trends.biochem.sci., 1997,22,267-272). Class iiia PI3K is a dimeric protein consisting of catalytic subunit p110 and regulatory subunit p85, has dual activities 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 diseases and diseases involving inflammation.
Patent WO2015055071A1 discloses morpholinyl quinazoline compounds of formula a and a method for preparing the same. The crystal form of the morpholinyl quinazoline compound shown in the formula A has a critical influence on the stability of the medicament in the process of production, processing, storage and transportation.
A phenomenon in which a substance exists in two or more different crystal structures is called polymorphism. While different crystalline forms of a compound may often exhibit different physical and chemical properties. For drugs, this polymorphism may affect dissolution and absorption of the drug, and further affect bioavailability of the drug, thereby exhibiting different clinical effects and toxic and side effects. In view of this, it is of great importance to develop crystalline forms of morpholino quinazolines of formula a which possess advantageous properties.
Disclosure of Invention
The invention aims to overcome the defect of few crystal forms of morpholinyl quinazoline compounds shown in a formula A, and provides a crystal form III of the morpholinyl quinazoline compounds, a preparation method and application thereof. The crystal form of the invention has good thermal stability and better solubility in aqueous medium with pH value ranging from 1.0 to 8.0, thereby facilitating the dissolution and absorption of the medicine and improving the bioavailability of the medicine.
The invention solves the technical problems through the following technical proposal.
The invention provides a crystal form III of a morpholino quinazoline compound shown in a formula A, wherein an X-ray powder diffraction pattern expressed by a 2 theta angle 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;
in a preferred embodiment of the present invention, the crystalline form iii of the morpholino quinazoline compound of the formula a, which has an X-ray powder diffraction pattern expressed in terms of 2θ, further has diffraction peaks at one or more of the following 2θ angles: 12.7.+ -. 0.2 °, 13.7.+ -. 0.2 °, 14.4.+ -. 0.2 °, 18.6.+ -. 0.2 °, 19.6.+ -. 0.2 °, 20.9.+ -. 0.2 °, 23.1.+ -. 0.2 °, 24.7.+ -. 0.2 ° and 28.1.+ -. 0.2 °.
In a preferred embodiment of the present invention, the crystalline form iii of the morpholino quinazoline compound of 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 expressed by 2θ.
In a preferred embodiment of the present invention, the crystalline form iii of the morpholino quinazoline compound of the formula a has a diffraction peak and a percentage of peak height in an X-ray powder diffraction pattern expressed in terms of 2θ, as shown in table 1:
TABLE 1
Numbering device 2θ(±0.2°) Peak height percentage (%)
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 present invention, the crystalline form III of the morpholino quinazoline class of compound of formula A has an X-ray powder diffraction pattern in terms of 2-theta angles substantially as shown in figure 1.
In the invention, the X-ray powder diffraction patterns are all measured by using the K alpha spectrum line of a Cu target.
In a preferred embodiment of the present invention, the morpholino quinazoline compound of formula a, form iii, 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 -1 And 768cm -1 。
In a preferred embodiment of the present invention, the infrared absorption spectrum of the crystalline form iii of the morpholino quinazoline compound of the formula a is also substantially as shown in fig. 2.
In a preferred embodiment of the invention, the crystalline form III of the morpholino quinazoline class of compound of formula A has a thermogravimetric analysis (TGA) showing substantially no weight loss prior to heating to 150 ℃, which means that it is a non-solvated material and the weight loss over 150 ℃ is due to decomposition.
In a preferred embodiment of the present invention, the crystalline form III of the morpholino quinazoline class of compound of formula A has a thermogravimetric analysis substantially as shown in FIG. 3.
In a preferred embodiment of the present invention, the crystalline form III of the morpholino quinazoline class of compound of formula A has an endothermic peak at 159.32 ℃ (peak temperature) in a Differential Scanning Calorimetry (DSC).
In a preferred embodiment of the present invention, the crystalline form III of the morpholino quinazoline class of compound of formula A is further characterized by a differential scanning calorimetry pattern substantially as depicted in FIG. 4.
In a preferred embodiment of the present invention, the morpholino quinazoline compound of formula A is crystalline form III, which is in the form of DMSO-d 6 Liquid nuclear magnetic hydrogen spectrum as solvent 1 H NMR) is substantially as shown in figure 5, 1 the H NMR chart shows that no crystallization solvent remains in form III. Karl Fischer methodThe moisture content was 0.02%.
In summary, form III is a non-solvated crystalline solid having a melting point of about 159.3 + -3deg.C (obtained from a differential scanning calorimetry) and is an anhydrous crystalline form of a morpholino quinazoline compound of formula A.
The invention provides a preparation method of a crystal form III of a morpholinyl quinazoline compound shown in a formula A, which comprises a scheme I or a scheme II;
Scheme one, it includes the following step: distilling a solution of the morpholinyl quinazoline compound shown in the formula A and an organic solvent to remove the organic solvent, and collecting a crystal form III of the morpholinyl quinazoline compound shown in the formula A;
scheme II, it includes the following step: drying the crystal form IV of the morpholino quinazoline compound shown in the formula A to remove water to obtain the crystal form III of the morpholino quinazoline compound shown in the formula A.
In the first scheme, the organic solvent may be an alcohol solvent (such as methanol), or a mixed solvent formed by the alcohol solvent (such as methanol) and one or more of a ketone solvent (such as acetone), a nitrile solvent (such as acetonitrile) and a halogenated hydrocarbon solvent (such as dichloromethane); such as 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 or 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 as the formula A is mixed with an organic solvent; it is obtained by a preparation method conventional in the art, and the method preferably comprises the following steps: carrying out ultrasonic treatment on the morpholinyl quinazoline compound shown in the formula A in an organic solvent until the solid is no longer dissolved, and filtering with a filter membrane; the obtained filtrate is the solution. The filter may be a 0.45 micron filter.
In the first scheme, the solution of the morpholinyl quinazoline compound shown in the formula A and the organic solvent can be a saturated solution.
In scheme one, the distillation method can be a conventional method in the art, for example, can be in a rotary evaporator for reduced pressure concentration; 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 rotational speed of the reduced pressure concentration may be 50 to 60rpm (e.g., 50rpm, 55rpm, 60 rpm).
In the second embodiment, the drying method may be a conventional drying method in the art, such as reduced pressure drying or normal pressure drying; without limitation, the vacuum degree of the reduced pressure drying may be-0.09 MPa; the temperature of the reduced pressure drying may be 28 to 62℃and more preferably 35 to 45℃such as 40.+ -. 2 ℃. The drying period is 1 hour to overnight, i.e. 1 to 24 hours. Without limitation, the atmospheric drying 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 48 to 72 ℃, and most preferably 60.+ -. 2 ℃. The drying period is 1 hour to overnight, i.e. 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 adopting a preparation method conventional in the art, and the preparation method comprises the following steps: slowly volatilizing a solution of the morpholinyl quinazoline compound shown in the formula A and an organic solvent to remove the organic solvent, and obtaining a 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 scheme A.
The slow evaporation method may be a conventional method in the art, for example, placing in a fume hood to evaporate slowly, and for example, placing a container containing the saturated solution in the fume hood to evaporate slowly after covering the container with aluminum foil having small holes on the surface.
In the crystal form IV of the morpholino 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 morpholino quinazoline compound shown in the formula a, in the X-ray powder diffraction pattern expressed by the 2θ angle and the peak height percentage, the diffraction peak and the peak height percentage may be shown in table 2:
TABLE 2
Without limitation, one typical example of form iv of the morpholino quinazoline class of compounds of formula a described in the present invention has an X-ray powder diffraction pattern expressed in terms of 2θ angles as shown in fig. 6.
In the present invention, a typical example of the crystalline form IV of morpholino quinazoline compounds of formula A, which loses about 5.76% of volatiles when heated to 150℃in thermogravimetric analysis (TGA), demonstrates that it is a solvated material and that the weight loss over 150℃is due to decomposition.
Without limitation, a typical example of crystalline form IV of morpholino quinazolines of formula A described in the present invention may also have a TGA profile substantially as shown in FIG. 7.
In the present invention, a typical example of the crystal form iv of the morpholino quinazoline compound shown in the formula a has two endothermic peaks in a Differential Scanning Calorimetry (DSC) at 81.26 ℃ (peak temperature) and 160.00 ℃ (peak temperature), respectively.
Without limitation, a typical example of crystalline form IV of morpholino quinazolines of formula A described in the present invention may also have a DSC chart substantially as shown in FIG. 8.
Without limitation, a typical example of form IV of morpholino quinazolines of formula A described in the present invention is as DMSO-d 6 Liquid nuclear magnetic hydrogen spectrum as solvent 1 H NMR) is shown in fig. 9. 1 H NMR showed no crystallization solvent residue in form IV. The Karl Fischer method measured a moisture content of 5.7% calculated to be approximately two moles of water. According to 1 H NMR, TGA and moisture results confirm that form iv is a crystalline solid dihydrate of the morpholino quinazoline compound of formula a.
The invention also provides a pharmaceutical composition which comprises a 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 morpholino quinazoline compound shown in the formula A is an effective (preventive or therapeutic) amount.
The invention also provides an application of the crystal form III of the morpholinyl quinazoline compound shown in the formula A or the pharmaceutical composition in the preparation of PI3 kinase (PI 3K) inhibitor.
Wherein the PI3 kinase is preferably of the p110δ subtype.
The invention also provides the application of the crystal form III of the morpholinyl quinazoline compound shown in the formula A or the pharmaceutical composition in the preparation of medicines for preventing and/or treating diseases related to PI3 kinase (PI 3K).
In the present invention, the PI3 kinase is preferably p110 delta subtype.
In the present invention, the diseases related to PI3 kinase include, but are not limited to: one or more of cancer, immune disorders, metabolic and/or endocrine dysfunctions, cardiovascular disorders, viral infections and inflammations, and neurological disorders, preferably cancer and/or immune disorders.
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 neoplasms. The viral infections and inflammations include, but are not limited to, asthma and/or atopic dermatitis.
The invention also provides the application of the crystal form III of the morpholinyl quinazoline compound shown in the formula A or the pharmaceutical composition in the preparation of medicines for preventing and/or treating diseases, wherein the diseases are one or more of cancers, immune diseases, metabolic and/or endocrine dysfunctions, cardiovascular diseases, virus infection, inflammation and nerve diseases.
Wherein said immune disorder, said cardiovascular disorder, said viral infection and said inflammation are as described above.
In the invention, the crystal form III of the morpholinyl quinazoline compound shown in the formula A can be combined with one or more other active ingredients; when used in combination, the active ingredients may be separate compositions for simultaneous administration by the same or different routes of administration in the treatment or at different times, respectively, or they may be administered together in the same pharmaceutical composition.
In the present invention, the administration method of the pharmaceutical composition is not particularly limited, and various dosage forms of preparation administration can be selected according to the age, sex and other conditions and symptoms of the patient; for example, tablets, pills, solutions, suspensions, emulsions, granules or capsules for oral administration; the injection can be administered alone or mixed with injectable delivery solution (such as glucose solution and amino acid solution) for intravenous injection; suppositories are administered into the rectum.
In some examples, form iii of the morpholino quinazoline compound of formula a does not undergo conversion when formulated with one or more pharmaceutically acceptable carriers and/or excipients and/or diluents.
In the present invention, "control" means "prevention". "preventing" refers to a reduced risk of acquiring or developing a disease or disorder (i.e., resulting in at least one of the clinical symptoms of a disease not occurring in a subject that may be exposed to a disease agent or a disease susceptible prior to onset of the disease).
In the present invention, "treating" refers to ameliorating a disease or disorder (i.e., preventing a disease or reducing its manifestation, the extent or severity of its clinical symptoms); alternatively, at least one physical parameter is improved, which may not be perceived by the subject; or slowing 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 absorbance spectra, differential scanning calorimeter, thermogravimetric curves, and the like. Those skilled in the art will appreciate that the peak intensity and/or peak condition of X-ray powder diffraction may vary depending on the experimental conditions. Meanwhile, due to different accuracies of the instrument, the measured 2 theta value has an error of about + -0.2 degrees. The relative intensity value of the peak is more dependent on certain properties of the sample to be measured, such as the size of the crystal and the purity, than the position of the peak, so that the measured peak intensity may deviate by about + -20%. Those skilled in the art can obtain sufficient information to identify individual crystalline forms from the X-ray powder diffraction data provided by this patent despite experimental error, instrumental error, orientation priority, and the like. In infrared spectrometry, the shape of the spectrum and the position of the absorption peak are affected to some extent due to different instrument performances of various types, different grinding degrees during preparation of the test sample, different water absorption degrees and the like. In contrast, in DSC measurement, the initial temperature, the maximum temperature and the heat of fusion data of the endothermic peak obtained by actual measurement have a degree of variability depending on the heating rate, the crystal shape and purity and other measurement parameters.
In the present invention, "room temperature" means "10 to 30 ℃.
In the invention, the environmental temperature of the fume hood is 10-30 ℃, and the environmental humidity is 35-80% RH.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the crystal form III of the morpholinyl quinazoline compound shown in the formula A has good thermal stability and solubility, and particularly has high equilibrium solubility in aqueous medium with the pH value of 1.0 to 8.0, and has important value for promoting dissolution and absorption of the medicine and improving bioavailability of the medicine.
Drawings
FIG. 1 is a typical X-ray powder diffraction pattern of form III of morpholino quinazolines of formula A.
FIG. 2 is a typical infrared absorption spectrum of a crystal form III of a morpholino quinazoline compound shown as a formula A.
FIG. 3 is a typical thermogravimetric analysis of crystalline form III of the morpholino quinazoline compound of formula A.
FIG. 4 is a typical differential scanning calorimetric diagram of a crystalline form III of a morpholino quinazoline compound of the formula A.
FIG. 5 is a typical liquid nuclear magnetic resonance spectrum of a crystal form III of a morpholino quinazoline compound of the formula A.
FIG. 6 is a typical X-ray powder diffraction pattern of form IV of morpholino quinazolines of formula A.
FIG. 7 is a typical thermogravimetric analysis of form IV of a morpholino quinazoline compound of formula A.
FIG. 8 is a typical differential scanning calorimetric diagram of form IV of a morpholino quinazoline compound of formula A.
FIG. 9 is a typical liquid nuclear magnetic resonance spectrum of form IV of morpholino quinazoline compounds of formula A.
FIG. 10 is an X-ray powder diffraction pattern of crystalline form IV of morpholino quinazoline compounds of the formula A obtained in example 8 before and after vacuum drying at 40℃overnight.
FIG. 11 is a thermogravimetric analysis of form IV of the morpholino quinazoline compound of formula A obtained in example 8 before and after vacuum drying at 40 ℃.
FIG. 12 is a differential scanning calorimetry thermogram of form IV of the morpholino quinazoline compound of formula A obtained in example 8 before and after vacuum drying at 40 ℃.
FIG. 13 is a typical X-ray powder diffraction pattern of an amorphous form of morpholino quinazolines of formula A obtained according to the method of patent WO2015055071A 1.
FIG. 14 is a typical X-ray powder diffraction pattern of crystalline form I of morpholino quinazolines of formula A obtained in comparative example 1.
FIG. 15 is a typical thermogravimetric analysis of form I of the morpholino quinazoline compound of formula A obtained in comparative example 1.
FIG. 16 is a typical differential scanning calorimetric diagram of form I of a morpholino quinazoline compound of the formula A obtained in comparative example 1.
FIG. 17 is a typical liquid nuclear magnetic resonance spectrum of form I of the morpholino quinazoline compound of formula A.
Figure 18 is an X-ray powder diffraction pattern of crystalline form iii of the morpholino quinazoline compound of formula a after heating at various temperatures.
FIG. 19 is an X-ray powder diffraction pattern of form IV of the morpholino quinazoline compound of formula A after heating at various temperatures.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Detection method
Instrument for measuring and controlling the intensity of light
X-ray powder diffraction analysis (XRPD): the light source is CuK, the X-ray intensity is 40KV/40mA, the divergent slit is 1.0mm, the cable-stayed 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 is: lynxEye.
Infrared absorption spectroscopy (IR): according to the Chinese pharmacopoeia 2015 edition four-part rule 0402 infrared spectrophotometry, adopting potassium bromide tabletting method to prepare test article, and making the test article be 4000-400 cm -1 Infrared absorption spectra were collected over the wavenumber range. The scanning times of the sample are 45 times, and the resolution of the instrument is 4cm -1 。
Differential scanning calorimetric analysis (DSC): 2-4 mg of the sample was weighed, placed in a non-closed aluminum pan, in an atmosphere of nitrogen flow (50 mL/min), equilibrated at 25deg.C, and then heated from 25deg.C to 300deg.C at a heating rate of 10deg.C/min.
Thermogravimetric analysis (TGA): 8-12 mg of the sample is weighed, placed in a platinum sample tray and heated from 25 ℃ to 300 ℃ in a nitrogen flow (50 mL/min) environment at a heating rate of 10 ℃/min.
Liquid nuclear magnetic hydrogen spectrum 1 H NMR): liquid nuclear magnetic hydrogen spectrum is collected on a Bruce 400MHz nuclear magnetic resonance spectrometer, DMSO-d 6 As a solvent.
Morpholino quinazoline compounds of formula a were prepared according to the synthetic method of patent WO2015055071A1 and characterized as amorphous by XRPD, the XRPD pattern of which is shown in figure 13.
When the solvents listed in the examples of the present specification are mixed solvents, the proportions thereof are all volume ratios.
Example 1 preparation of Crystal form III of morpholinyl quinazoline Compounds of formula A
About 2.0g of morpholino quinazoline compounds of formula A were weighed into a 500mL round bottom flask, 300mL of methanol was added: acetonitrile (1:1), sonicated at room temperature until the solids are no longer dissolved, filtered with a 0.45 micron filter membrane and the filtrate transferred to a new round bottom flask, set the rotational speed of the rotary evaporator at 55rpm, control the water bath temperature at 40+ -2 ℃, -0.09MPa, concentrate under reduced pressure, collect the solids obtained after complete spin-drying of the solvent, place in a vacuum oven at 40 ℃, -0.09MPa, dry under reduced pressure overnight.
The obtained sample is in a crystal form III by an X-ray powder diffraction method. The X-ray powder diffraction pattern is shown in FIG. 1, and the X-ray powder diffraction pattern expressed by 2 theta angles 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.
The IR diagram 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 -1 And 768cm -1 There is a characteristic peak.
The TGA profile is shown in fig. 3. As can be seen from fig. 3, form iii has substantially no weight loss upon heating to 150 ℃, which suggests that it is a non-solvated material, and the weight loss generated above 150 ℃ is due to decomposition.
The DSC chart is shown in FIG. 4. The differential scanning calorimeter of the crystal form III has an endothermic peak at 159.32 ℃ (peak temperature) and is a melting peak of the crystal form III.
It is in the form of DMSO-d 6 Liquid nuclear magnetic hydrogen spectrum as solvent 1 H NMR) is shown in fig. 5. 1 The H NMR chart shows that no crystallization solvent remains in form III. The Karl Fischer method determines that the water content of the crystal form III is 0.02%.
TGA, 1H NMR and moisture content results confirm that form III is a non-solvated crystalline solid, DSC results show a melting point of about 159.3 + -3deg.C, form III being an anhydrous crystalline form of morpholino quinazoline compounds of formula A.
EXAMPLE 2 preparation of Crystal form III of morpholinyl quinazoline Compounds of formula A
About 300mg of morpholino quinazoline compound of formula A was weighed and 10mL of methylene chloride was added: methanol (1:1), ultrasonic until the solid is no longer dissolved at room temperature, filtering with a 0.45 micrometer filter membrane, transferring the filtrate into a round bottom flask, setting the rotation speed of a rotary evaporator to 50rpm, controlling the water bath temperature to be 30+/-2 ℃ and the decompression concentration under-0.09 MPa, collecting the solid obtained after the solvent is completely dried by spin, and placing the solid in a vacuum oven for decompression drying at 40 ℃ for 1 hour. 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 morpholinyl quinazoline Compounds of formula A
About 1.0g of morpholino quinazoline compounds of formula A were weighed into a 200mL round bottom flask, and 90mL of methanol was added: acetone (1:1), ultrasonic until the solid is no longer dissolved at room temperature, filtering with a 0.45 micrometer filter membrane, transferring the filtrate into a new round bottom flask, setting the rotation speed of a rotary evaporator to 60rpm, controlling the water bath temperature to 40+/-2 ℃ and concentrating under reduced pressure under-0.09 MPa, and collecting the solid obtained after the solvent is completely dried by spin. 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 morpholinyl quinazoline Compounds of formula A
About 100mg of morpholino quinazoline compound of formula A was weighed into a glass vial, and 4mL of methylene chloride was added to the vial: methanol (1:1), sonicated at room temperature until the solids are no longer dissolved, filtered with a 0.45 micron filter and the filtrate transferred to a new vial. The vials were covered with aluminum foil and perforated with small holes, placed in a fume hood at room temperature to slowly evaporate the solvent, after 4 days the solvent was completely evaporated and the resulting solid was collected and dried overnight under reduced pressure at 40 ℃ and-0.09 MPa. 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 morpholinyl quinazoline Compounds of formula A
About 100mg of the morpholino quinazoline compound of formula a is added to 20mL of methanol, or about 30mg of the morpholino quinazoline compound of formula a is added to 2mL of methanol: a saturated solution was prepared in acetone (1:1) as in example 4, filtered, the solvent was slowly evaporated, and the resulting solid was collected after complete evaporation of the solvent, dried overnight at 40℃under reduced pressure of-0.09 MPa. The X-ray powder diffraction patterns of the samples obtained by the method are compared with the patterns of the samples of the example 1, and the samples are determined to be the crystal form III.
As can be seen from the above examples, the crystal form iii is obtained by using a saturated solution of the morpholino quinazoline compound of the formula a in an organic solvent, either by rotary evaporation or by using an open-top evaporation solvent, and the crystal form iii can be obtained after precipitation of a solid and drying, when the organic solvent contains methanol.
EXAMPLE 6 preparation of Crystal form IV of morpholinyl quinazoline Compounds of formula A
About 200mg of morpholino quinazoline compound of formula A was weighed into a glass vial, and 20mL of methanol was added to the vial: acetonitrile (1:1), sonicated at room temperature until the solids are no longer dissolved, filtered with a 0.45 micron filter membrane and the filtrate transferred to a new vial. The vials were covered with aluminum foil and perforated with small holes, placed in a fume hood to slowly evaporate the solvent, after 3 days the solvent was completely evaporated and the resulting solid was collected.
The obtained sample is in a crystal form IV by an X-ray powder diffraction method. The X-ray powder diffraction pattern is shown in fig. 6, and the diffraction peaks (2θ) and the peak height percentage (%) thereof are shown in table 3 below:
TABLE 3 Table 3
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The TGA profile is shown in fig. 7. TGA profile shows about 5.76% volatiles lost when form iv is heated to 150 ℃, which confirms that it is a solvated species, with weight loss exceeding 150 ℃ due to decomposition.
The DSC chart is shown in FIG. 8. Form iv has two endothermic peaks on the differential scanning calorimeter at 81.26 ℃ (peak temperature) and 160.00 ℃ (peak temperature), respectively.
It is in the form of DMSO-d 6 Liquid nuclear magnetic hydrogen spectrum as solvent 1 H NMR) is shown in fig. 9. 1 H NMR showed no crystallization solvent residue in form IV. The Karl Fischer method measured a moisture content of 5.7% calculated to be approximately two moles of water.
According to 1 H NMR, TGA and moisture results confirm that form iv is a crystalline solid dihydrate of morpholino quinazolines of formula a.
EXAMPLE 7 preparation of Crystal form IV of morpholino quinazoline Compounds of formula A (liquid phase diffusion method)
About 30mg of morpholino quinazoline compound of formula A was weighed into a glass vial, 4mL of methanol was added to the vial, sonicated at room temperature until the solid was no longer dissolved, filtered through a 0.45 μm filter and 2mL of the filtrate was transferred to a new 4mL vial. Another 20mL glass bottle was added with 10mL of water, and a 4mL vial containing the filtrate was placed in the 20mL vial with an opening, and the 20mL vial was sealed and allowed to stand at room temperature. When solids were observed to precipitate out of the 4mL glass vial, the solids were collected by isolation.
The X-ray powder diffraction pattern of the sample obtained by the method is compared with the pattern of the sample of the example 6 to determine the crystal form IV.
EXAMPLE 8 preparation of Crystal form III of morpholinyl quinazoline Compounds of formula A
The sample of form iv prepared by the method of example 6 was placed in a vacuum oven and dried overnight at a temperature of 40 ℃, -0.09MPa and then again assayed for XRPD, TGA and DSC. The X-ray powder diffraction pattern of the dried sample was compared with the pattern of the sample of example 1 to determine form iii. The TGA profile of the dried sample showed substantially no weight loss before heating to 150 c, confirming that the moisture was substantially removed by drying. The endothermic peak of water at 81.26 ℃ (peak temperature) on the DSC plot of the dried sample disappeared, leaving only the melting endothermic peak of form iii. XRPD, TGA and DSC stacks of the samples before and after drying overnight are shown in figures 10-12, respectively. XRPD, TGA and DSC results prove that after the crystal form iv of the morpholino quinazoline compound shown in the formula a is dried under vacuum at 40 ℃ overnight, the contained two moles of moisture can be completely removed, and the crystal form iii of the morpholino quinazoline compound shown in the formula a is converted.
Comparative example 1 preparation of Crystal form I of morpholino quinazoline Compounds of formula A
Adding 500mL of ethanol into 10g of morpholinyl quinazoline compounds shown in a formula A, completely dissolving under heating, filtering while the mixture is hot, concentrating 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 vacuum drying at a temperature of less than 85 ℃ for 5-6 hours to obtain solids, namely the crystal form I of the morpholinyl quinazoline compounds shown in the formula A.
The X-ray powder diffraction pattern is shown in FIG. 14, and the diffraction peak (2. Theta.) and the peak height percentage (%)As shown in table 4 below:
TABLE 4 Table 4
Numbering device 2θ(±0.2°) Peak height percentage (%)
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 from fig. 15, form i has substantially no weight loss upon heating to 150 ℃, which indicates that it is a non-solvated material, and the weight loss generated above 150 ℃ is due to decomposition.
The DSC chart is shown in FIG. 16. The differential scanning calorimeter of the crystal form I has an endothermic peak at 204.33 ℃ (peak temperature), and is a melting peak of the crystal form I.
It is in the form of DMSO-d 6 Liquid nuclear magnetic hydrogen spectrum as solvent 1 H NMR) is shown in fig. 17. 1 H NMR showed no crystallization solvent residue in form I. The Karl Fischer method measured a moisture content of 0.1%.
TGA, 1H NMR and moisture content results confirm that form I is a non-solvated crystalline solid, DSC results show a melting point of about 204.3.+ -. 3 ℃ and form I is an anhydrous crystalline form of the morpholino quinazoline compound of formula A.
Effect example 1 stability
1 stability of the crystal form III of morpholino quinazoline compounds shown as formula A in water and organic solvents
1.1 stability of Crystal form III of morpholino quinazoline Compound of formula A in organic solvent at room temperature for 6 days
About 10mg of morpholino quinazoline compound crystal form III sample shown in a formula A is respectively taken and placed in a glass small bottle, 0.3mL of isopropanol, isopropyl acetate, acetone, toluene, methyl tertiary butyl ether or acetonitrile is respectively added into the small bottle, and ultrasonic dispersion is carried out to prepare suspension. The suspension was spin equilibrated at room temperature for 6 days, and the remaining solid wet sample was collected and the X-ray powder diffraction pattern was determined. The results show that the morpholino quinazoline compound crystal form III shown in the formula A is balanced in various solvents at room temperature for 6 days, and the crystal form is unchanged and still is the crystal form III.
1.2 conversion relationship between form III and form IV of morpholino quinazoline compounds of formula A
The results of the study in example 8 show that form iii can be obtained after drying and dehydration of form iv, and in order to further study the conditions for the mutual transformation between form iii and form iv, suspension equilibrium experiments of form iii in solvent systems with different water activities (aw=0 to 1) at room temperature were set up. The method comprises the following specific steps: about 10mg of the morpholino quinazoline compound crystal form III sample shown in the formula A is respectively taken and placed in a glass small bottle, and 1mL of water, 0.3mL of methanol or 0.3mL of water is respectively added into the small bottle: methanol (10:90, aw-0.26), or 0.3mL of water: methanol (25:75, aw-0.50), or 0.3ml water: methanol (50:50, aw-0.73), or 0.3mL of water: methanol (80:20, aw-0.91) and ultrasonic dispersion to prepare suspension. The suspension was spin equilibrated at room temperature for 6 days, and the remaining solid wet sample was collected and the X-ray powder diffraction pattern 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 forms 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 and its preparation method Ⅳ
Note that: the Water Activity (Water Activity, also known as Water Activity, abbreviated aw) refers to 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 results show that the morpholino quinazoline compound crystal form III shown in the formula A is only converted into crystal form IV in an aqueous solvent system with the water activity of 0.91 and above at room temperature; in an aqueous solvent system with a water activity below 0.73 at room temperature, the morpholino quinazoline compound of the formula A, form III, is a more stable crystal form, and does not bind water molecules.
1.3 influence of temperature Change on Crystal form III and Crystal form IV of morpholinoquinazoline Compounds of formula A
Placing a glass vial containing a proper amount of a crystal form III sample of the morpholino quinazoline compound shown in a formula A in an electrothermal blowing oven at the oven temperature of 40 ℃, 60 ℃, 80 ℃, 100 ℃, 120 ℃ and 140 ℃ in sequence, respectively heating for 1 hour at each temperature, taking out a proper amount of the sample, and measuring an X-ray powder diffraction pattern.
Placing a glass vial containing a proper amount of a crystal form IV sample of the morpholino quinazoline compound shown in a formula A in an electrothermal blowing oven at the oven temperature of 40 ℃, 60 ℃, 80 ℃ and 100 ℃ in sequence, respectively heating for 1 hour at each temperature, taking out a proper amount of the sample, and measuring an X-ray powder diffraction pattern.
The X-ray powder diffraction pattern of the morpholino quinazoline compound of the formula A in the form III after heating at the above temperatures for 1 hour is shown in figure 18. Through an X-ray powder diffraction superposition graph, the crystal form III of the morpholino quinazoline compound shown in the formula A can be confirmed to have no crystal form transformation after being heated for 1 hour at the temperatures, and the crystal form III of the morpholino quinazoline compound shown in the formula A has good thermal stability.
The X-ray powder diffraction pattern of the morpholino quinazoline compound of the formula A in the form IV is shown in figure 19 after heating at the above temperatures for 1 hour. Through an X-ray powder diffraction superposition graph, the crystal form IV of the morpholino quinazoline compound shown in the formula A can be confirmed to be partially converted into the crystal form III after being heated at 40 ℃ for 1 hour, and can be completely converted into the crystal form III after being heated at 60 ℃ for 1 hour, so that the heat stability of the crystal form III of the morpholino quinazoline compound shown in the formula A is better than that of the crystal form IV.
The crystal form III is combined with water molecules under the condition of high water activity, the water molecules are removed from the crystal form IV under the heating condition, and the reversible transformation relation between the two crystal forms is realized, so that the technical teaching is as follows: on the one hand, the morpholinyl quinazoline compound shown in the formula A in the crystal form IV is not tightly combined with water molecules, the water molecules are easy to remove after being heated, and the thermodynamic stability of the crystal form IV is not as good as that of the crystal form III; on the other hand, form iv may exist as an intermediate in the preparation of form iii, and when a person skilled in the art obtains a single form iv, or a mixture of form iii and form iv in any ratio, by using the method of the embodiment of the present invention or other methods, it may be possible to obtain a single form iii as disclosed in the present invention by removing moisture by a suitable means, such as drying at a lower temperature under normal pressure or drying under reduced pressure.
Effect example 2 equilibrium solubility test of Crystal form III and Crystal form I of morpholinoquinazoline Compounds of formula A
The preparation method of the equilibrium solubility test medium comprises the following steps:
preparation methods of the medium 0.1mol/L hydrochloric acid solution, acetic acid-sodium acetate buffer solution (50 mmol/L) with pH of 4.5, phosphate buffer solution (50 mmol/L) with pH of 6.8 and phosphate buffer solution (50 mmol/L) with pH of 7.4 are referred to general rules of U.S. Pharmacopeia 36 edition Solutions; the medium water is purified water.
preparation method of phosphate buffer (50 mmol/L) with pH of 8.0:
0.68g of potassium dihydrogen phosphate is taken, 23.05mL of 0.2mol/L sodium hydroxide solution is added, and the mixture is diluted to 100mL with water, thus obtaining the product, and the pH value is measured to be 8.00.
The preparation method of Simulated Gastric Fluid (SGF) comprises the following steps:
202.5mg of sodium chloride is taken, 7.2mL of 1mol/L hydrochloric acid solution is added, and the mixture is diluted to 100mL by water, thus obtaining the pH value of 1.21.
The preparation method of simulated fasted state intestinal juice (FaSSIF) comprises the following steps:
the first step: 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 sodium hydroxide solution, the mixture is diluted to 1000mL by water, and the mixture is shaken well.
And a second step of: adding 2.2394g of FaSSIF/FeSSIF/FaSSGF powder (brand: biorelevant) into 500mL of the above buffer solution, and stirring until the powder is completely dissolved.
The preparation method of the simulated feeding state intestinal juice (FeSSIF) comprises the following steps:
the first step: 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 using 1mol/L sodium hydroxide solution, the mixture is diluted to 500mL by using water, and the mixture is shaken well.
And a second step of: adding 5.6008g of FaSSIF/FeSSIF/FaSSGF powder (brand: biorelevant) into 500mL of the above buffer solution, and stirring until the powder is completely dissolved.
Equilibrium solubility test:
taking 9 glass vials respectively, sequentially adding 1.5mL of prepared 0.1mol/L hydrochloric acid solution, acetic acid-sodium acetate buffer solution (50 mmol/L) with pH of 4.5, phosphate buffer solution (50 mmol/L) with pH of 6.8, phosphate buffer solution (50 mmol/L) with pH of 7.4, water, phosphate buffer solution (50 mmol/L) with pH of 8.0, simulated Gastric Fluid (SGF), simulated fasted state intestinal fluid (FaSSIF) or simulated fed state intestinal fluid (FeSSIF), adding excessive morpholino quinazoline compound crystal form III or crystal form I shown in formula A into each vial respectively, dispersing for 30 seconds by vortex to prepare supersaturated solution, sealing each glass vial by adding a cover, wrapping aluminum foil paper, and rotationally balancing at room temperature.
After 24 hours of equilibration, centrifuging at 12000rpm for 10 minutes, removing supernatant, diluting with methanol to a proper concentration, measuring the concentration of the morpholino quinazoline compound shown in the formula A by adopting a high performance liquid chromatography, and calculating the equilibrium solubility of the crystalline form III and the crystalline form I of the morpholino quinazoline compound shown in 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 was higher than that of form I in 0.1mol/L hydrochloric acid solution, pH 4.5 acetic acid-sodium acetate buffer (50 mmol/L), pH 6.8 phosphate buffer (50 mmol/L), pH 7.4 phosphate buffer (50 mmol/L), water, pH 8.0 phosphate (50 mmol/L), simulated Gastric Fluid (SGF), simulated fasted state intestinal fluid (FaSSIF) and simulated fed state intestinal fluid (FeSSIF). Especially in terms of equilibrium solubility data in phosphate buffer at pH 6.8 (50 mmol/L), phosphate buffer at pH 7.4 (50 mmol/L), phosphate buffer at pH 8.0 (50 mmol/L), simulated fasted state intestinal fluid (FaSSIF) and simulated fed state intestinal fluid (FeSSIF), form III is 3.1 times, 2.7 times, 2.3 times, 3.0 times and 1.4 times, respectively, that of form I.

Claims (12)

1. A crystalline form iii of a morpholino quinazoline compound of formula a, characterized by having diffraction peaks at 7.1±0.2°, 8.1±0.2°, 11.4±0.2°, 15.9±0.2°, 17.2±0.2°, 18.9±0.2° and 20.4±0.2° in an X-ray powder diffraction pattern expressed in terms of 2θ measured using a kα spectrum line of a Cu target;
2. form iii of morpholino quinazolines of formula a according to claim 1, characterized by an X-ray powder diffraction pattern expressed in terms of 2Θ angles having diffraction peaks at one or more of the following 2Θ angles: 12.7.+ -. 0.2 °, 13.7.+ -. 0.2 °, 14.4.+ -. 0.2 °, 18.6.+ -. 0.2 °, 19.6.+ -. 0.2 °, 20.9.+ -. 0.2 °, 23.1.+ -. 0.2 °, 24.7.+ -. 0.2 ° and 28.1.+ -. 0.2 °.
3. The crystalline form iii of the morpholino quinazoline compound of formula a according to claim 1 or 2, wherein the X-ray powder diffraction pattern expressed in terms of 2Θ angles has diffraction peaks and peak heights as shown in table 1:
TABLE 1
；
And/or, the morpholino quinazoline compound shown in the formula A has an infrared absorption spectrum 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 -1 And 768cm -1 ；
And/or the crystal form III of the morpholino quinazoline compound shown in the formula A has an endothermic peak at 159.3 +/-3 ℃ in a differential scanning calorimeter diagram.
4. A crystalline form iii of morpholino quinazolines of formula a according to claim 3, characterized by an X-ray powder diffraction pattern in terms of 2Θ angle substantially as shown in figure 1;
and/or, the crystal form III of the morpholino quinazoline compound shown as the formula A has an infrared absorption spectrum basically shown as figure 2;
and/or, the crystal form III of the morpholino quinazoline compound shown as the formula A has a thermogravimetric analysis chart basically shown as figure 3;
and/or, the morpholino quinazoline compound shown as the formula A is in a crystal form III, and a differential scanning calorimeter diagram of the morpholino quinazoline compound is basically shown as figure 4;
and/or, the morpholinyl quinazoline compound shown as the formula A is in a crystal form III, and the morpholinyl quinazoline compound is in a DMSO-d form 6 The liquid nuclear magnetic hydrogen spectrum as a solvent is substantially as shown in fig. 5.
5. A process for the preparation of crystalline form iii of morpholino quinazolines of formula a according to any one of claims 1 to 4, characterized in that it comprises scheme one or scheme two;
scheme one, it includes the following step: distilling a solution of the morpholinyl quinazoline compound shown in the formula A and an organic solvent to remove the organic solvent, and collecting a crystal form III of the morpholinyl quinazoline compound shown in the formula A;
Scheme II, it includes the following step: drying a crystal form IV of the morpholino quinazoline compound shown in the formula A to remove water to obtain a crystal form III of the morpholino quinazoline compound shown in the formula A;
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 ketone solvents, nitrile solvents and halogenated hydrocarbon solvents;
in a second scheme, the crystal form IV of the morpholino quinazoline compound shown in 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 degrees in an X-ray powder diffraction pattern expressed by a 2 theta angle.
6. The method for preparing the morpholinyl quinazoline compound of the formula A in the crystal form III according to claim 5, wherein,
in the scheme I, the morpholinyl quinazoline compound shown in the formula A and the solution of the organic solvent are prepared by a preparation method comprising the following steps: carrying out ultrasonic treatment on the morpholinyl quinazoline compound shown in the formula A in an organic solvent until the solid is no longer dissolved, and filtering with a filter membrane; the obtained filtrate is the solution; the organic solvent is an alcohol solvent or a mixed solvent formed by the alcohol solvent and one or more of ketone solvents, nitrile solvents and halogenated hydrocarbon solvents;
And/or, in the first scheme, the solution of the morpholinyl quinazoline compound shown as the formula A and the organic solvent is a saturated solution; the organic solvent is an alcohol solvent or a mixed solvent formed by the alcohol solvent and one or more of ketone solvents, nitrile solvents and halogenated hydrocarbon solvents;
and/or, in the first scheme, the filter membrane is a 0.45 micrometer filter membrane;
and/or, in the first scheme, the distillation is to perform reduced pressure 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 second scheme, the crystal form IV of the morpholino 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 in the formula A and an organic solvent to remove the organic solvent, so as to obtain a 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 scheme one;
and/or, in the second scheme, the crystal form IV of the morpholino quinazoline compound shown as the formula A has two endothermic peaks in a differential scanning calorimeter diagram, wherein the two endothermic peaks are respectively at 81.3+/-3 ℃ and 160.0+/-3 ℃.
7. The method for preparing the morpholinyl quinazoline compound of the formula A in the crystal form III according to claim 6, wherein,
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 ketone solvents, the ketone solvents are acetone;
and/or, in the first scheme, when the organic solvent contains nitrile solvent, the nitrile solvent is acetonitrile;
and/or, in the first scheme, when the organic solvent contains 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 one or more of an alcohol solvent, 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;
and/or, in the first scheme, in the preparation method of the morpholino quinazoline compound shown in the formula A and the solution of the organic solvent, the filter membrane is a 0.45 micrometer filter membrane;
and/or, in the first scheme, when the distillation is the reduced pressure concentration in a rotary evaporator, the vacuum degree of the reduced pressure concentration is-0.09 MPa;
And/or, in the first scheme, when the distillation is the reduced pressure concentration in a rotary evaporator, the temperature of the reduced pressure concentration is 28-42 ℃;
and/or, in the first scheme, when the distillation is the reduced pressure concentration in a rotary evaporator, 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 morpholino 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 a diffraction peak and a peak height percentage shown in table 2 in an X-ray powder diffraction diagram expressed by a 2θ angle and a peak height percentage:
TABLE 2
；
And/or, in the second scheme, the crystal form IV of the morpholino quinazoline compound shown as the formula A has a TGA diagram basically shown in figure 7;
and/or, in the second scheme, the crystal form IV of the morpholino quinazoline compound shown as the formula A has a DSC chart basically shown as figure 8;
and/or in scheme II, the morpholinyl quinazoline compound shown as the formula A is in a crystal form IV, and the morpholinyl quinazoline compound is in a DMSO-d form 6 The liquid nuclear magnetic hydrogen spectrum as a solvent is shown in fig. 9.
8. A pharmaceutical composition comprising crystalline form iii of a morpholino quinazoline compound of formula a according to any one of claims 1 to 4 and at least one pharmaceutically acceptable carrier.
9. Use of a crystalline form iii of a morpholino quinazoline compound of the formula a according to any one of claims 1 to 4, or a pharmaceutical composition according to claim 8, in the manufacture of a PI3 kinase inhibitor, or a medicament; the medicine is used for preventing and/or treating diseases related to PI3 kinase, or used for preventing and/or treating one or more diseases of cancers, immune diseases, metabolic and/or endocrine dysfunctions, cardiovascular diseases, viral infections, inflammations and nerve diseases.
10. The use of claim 9, wherein the PI3 kinase is p110 delta subtype;
and/or the PI3 kinase related diseases are one or more of cancer, immune diseases, metabolic and/or endocrine dysfunctions, cardiovascular diseases, viral infections and inflammations, and neurological diseases.
11. The use according to claim 9, wherein the PI3 kinase associated disease is cancer and/or immune disease.
12. The use according to claim 10, wherein the immune disorder is one or more of rheumatoid arthritis, psoriasis, ulcerative colitis, crohn's disease and systemic lupus erythematosus;
and/or, the cardiovascular disease is a hematological tumor;
and/or, the viral infection and inflammation is asthma and/or atopic dermatitis.
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