WO2020063368A1 - 吗啉基喹唑啉类化合物的晶型、其制备方法及应用 - Google Patents

吗啉基喹唑啉类化合物的晶型、其制备方法及应用 Download PDF

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WO2020063368A1
WO2020063368A1 PCT/CN2019/105688 CN2019105688W WO2020063368A1 WO 2020063368 A1 WO2020063368 A1 WO 2020063368A1 CN 2019105688 W CN2019105688 W CN 2019105688W WO 2020063368 A1 WO2020063368 A1 WO 2020063368A1
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formula
morpholinoquinazoline
compound represented
crystalline form
compound
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PCT/CN2019/105688
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English (en)
French (fr)
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许祖盛
楼杨通
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上海璎黎药业有限公司
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Priority to EP19864074.0A priority Critical patent/EP3858830B1/en
Priority to US17/279,185 priority patent/US11168072B2/en
Priority to JP2021516990A priority patent/JP7071588B2/ja
Priority to AU2019345706A priority patent/AU2019345706B2/en
Priority to BR112021006026-0A priority patent/BR112021006026A2/pt
Priority to EA202190880A priority patent/EA202190880A1/ru
Priority to CA3114260A priority patent/CA3114260A1/en
Priority to SG11202103118PA priority patent/SG11202103118PA/en
Priority to MX2021003576A priority patent/MX2021003576A/es
Priority to KR1020217012398A priority patent/KR20210069664A/ko
Publication of WO2020063368A1 publication Critical patent/WO2020063368A1/zh

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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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • 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

Definitions

  • the invention relates to a crystalline form of a morpholinyl quinazoline compound, a preparation method and an application thereof.
  • a morpholino quinazoline compound having the structure shown in Formula A (Hereinafter referred to as a morpholinoquinazoline compound represented by Formula A) has an activity to inhibit phosphatidylinositol 3-kinase ⁇ (PI3K ⁇ ).
  • PI3K ⁇ is an intracellular phosphoinositide kinase that catalyzes the phosphorylation of the 3-position hydroxyl group of phosphatidyl alcohol.
  • PI3K can be divided into class I, II and III kinases, and the most widely studied is class I PI3K that can be activated by cell surface receptors.
  • Type I PI3K in mammalian cells is further classified into types Ia and Ib according to their structure and receptors, and they transmit signals from tyrosine kinase-coupled receptors and G protein-coupled receptors, respectively.
  • Type Ia PI3K includes PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ subtypes
  • type Ib PI3K includes PI3K ⁇ subtypes
  • Class Ia PI3K is a dimeric protein composed of catalytic subunit p110 and regulatory subunit p85, which has dual activities of lipid kinase and protein kinase (Nat. Rev. Cancer 2002, 2, 489-501), and is considered to be associated with cell proliferation. It is related to cancer, immune diseases and diseases involving inflammation.
  • Patent WO2015055071A1 discloses a morpholinoquinazoline compound as shown in Formula A and a preparation method thereof.
  • the crystalline form of the morpholinoquinazoline compound shown in Formula A has a crucial effect on the stability of the drug during production, processing, storage, and transportation.
  • polymorphism The phenomenon that a substance can exist in two or more different crystal structures is called a polymorphism. And different solid forms of compounds often show different physical and chemical properties. For drugs, this polymorphism may affect the absorption of drugs, and then affect the bioavailability of drugs, thus showing different clinical efficacy and toxic and side effects. In view of this, it is of great significance to develop a crystalline form of a morpholinoquinazoline compound represented by Formula A with superior properties.
  • the technical problem to be solved by the present invention is to provide a crystalline form, preparation method and application of a morpholinoquinazoline compound represented by formula A.
  • the preparation method of the crystalline form is simple, suitable for industrial production, and not easy to absorb moisture. Good stability has important value for the optimization and development of drugs.
  • the present invention solves the above technical problems through the following technical solutions.
  • the present invention provides a morpholinoquinazoline-based compound represented by Formula A, which is an X-ray powder diffraction pattern represented by an angle of 2 ⁇ at 7.7 ⁇ 0.2 °, 9.7 ⁇ 0.2 °, 12.4 There are diffraction peaks at ⁇ 0.2 °, 15.4 ⁇ 0.2 °, 17.4 ⁇ 0.2 °, 18.0 ⁇ 0.2 ° and 18.4 ⁇ 0.2 °;
  • the X-ray powder diffraction pattern of the morpholinoquinazoline-based compound represented by Formula A as shown in Formula A at a 2 ⁇ angle may also have a diffraction peak at one or more of the following 2 ⁇ angles: 11.0 ⁇ 0.2 °, 11.3 ⁇ 0.2 °, 19.5 ⁇ 0.2 °, 20.1 ⁇ 0.2 °, 21.8 ⁇ 0.2 °, 22.6 ⁇ 0.2 °, 23.2 ⁇ 0.2 °, 23.6 ⁇ 0.2 °, 24.3 ⁇ 0.2 °, 25.8 ⁇ 0.2 °, and 28.7 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the morpholinoquinazoline-type compound represented by Formula A as represented by a 2 ⁇ angle may be 7.7 ⁇ 0.2 °, 9.7 ⁇ 0.2 °, There were diffraction peaks at 11.0 ⁇ 0.2 °, 12.4 ⁇ 0.2 °, 15.4 ⁇ 0.2 °, 17.4 ⁇ 0.2 °, 18.0 ⁇ 0.2 °, 18.4 ⁇ 0.2 °, 23.6 ⁇ 0.2 °, and 24.3 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the morpholinoquinazoline-based compound I represented by Formula A represented by a 2 ⁇ angle is 7.7 ⁇ 0.2 °, 9.7 ⁇ 0.2 °, 11.0 ⁇ 0.2 °, 11.3 ⁇ 0.2 °, 12.4 ⁇ 0.2 °, 15.4 ⁇ 0.2 °, 17.4 ⁇ 0.2 °, 18.0 ⁇ 0.2 °, 18.4 ⁇ 0.2 °, 19.5 ⁇ 0.2 °, 20.1 ⁇ 0.2 °, 21.8 ⁇ 0.2 °, 22.6
  • the X-ray powder diffraction pattern of the morpholinoquinazoline compound represented by a 2 ⁇ angle, and the diffraction peaks and peak height percentages thereof can also be shown in Table Shown as 1:
  • the X-ray powder diffraction pattern represented by a 2 ⁇ angle and its diffraction peak, peak width value, and peak height percentage
  • the peak area percentage can also be shown in Table 3:
  • the X-ray powder diffraction pattern of the morpholinoquinazoline-based compound represented by Formula A at a 2 ⁇ angle can also be substantially as shown in FIG. 1.
  • the X-ray powder diffraction patterns are all measured using a K ⁇ line of a Cu target.
  • the infrared absorption spectrum (IR) of the crystalline form I of the morpholinoquinazoline compound represented by Formula A may also have characteristic peaks at the following positions: 3445cm -1 , 3246cm -1 , 3018cm -1, 3001cm -1, 2972cm -1 , 2953cm - 1, 2924cm -1, 2910cm -1, 2891cm -1, 2850cm -1, 1604cm -1, 1589cm -1, 1552cm -1, 1506cm - 1, 1489cm - 1, 1458cm -1, 1413cm -1, 1365cm -1, 1155cm -1 and 775cm -1.
  • the characteristic peaks, vibration types, groups, and absorption peak intensities in the infrared absorption spectrum of the morpholinoquinazoline-based compound of Formula I shown in Formula A may also be shown in Table 4:
  • the infrared absorption spectrum of the morpholinoquinazoline-based compound of Formula I shown in Formula A may also be substantially as shown in FIG. 2.
  • thermogravimetric analysis chart (TGA) of the crystalline form I of the morpholinoquinazoline compound represented by Formula A can also be substantially as shown in FIG. 3.
  • the differential scanning calorimetry (DSC) of the morpholinoquinazoline-based compound of Formula A shown in Formula A may further have an absorption peak at 204.3 ⁇ 3 ° C, and the heat of fusion is 98.70J / g.
  • the differential scanning calorimetry of the crystalline form I of the morpholinoquinazoline-based compound represented by Formula A may also be substantially as shown in FIG. 4.
  • the increased mass of the crystalline form I is also larger than the initial mass, and It can increase the weight by 0.23% in the range of 0% to 90% relative humidity, and increase the mass of the crystal form I by 0.34% in the range of 0% to 95% relative humidity.
  • the dynamic moisture adsorption diagram of the crystal form I may also be substantially as shown in FIG. 5.
  • the present invention also provides a method for preparing a morpholino quinazoline compound of Form I as shown in Formula A; it is Method 1 or Method 2;
  • Method 1 Form a morpholinoquinazoline compound represented by formula A in a solvent to form a thermally saturated solution, and then cool.
  • the solvent is selected from acetonitrile, 2-methyltetrahydrofuran, acetone, ethyl acetate, and ethanol And one or more of isopropyl alcohol.
  • the thermally saturated solution is filtered before the cooling step.
  • the filtering method may be a conventional filtering method for such operations in the art, and preferably is a hot filtering method.
  • the thermal filtration is a filtration membrane filtration.
  • the pore diameter of the filter membrane is preferably 0.45 microns.
  • the cooling method may be a cooling method commonly used in such operations in the art, and is preferably a rapid cooling method or a slow cooling method.
  • the final temperature of the cooling is -15 to -25 ° C, such as -20 ° C.
  • the cooling rate is 5 to 15 ° C / h, such as 10 ° C / h.
  • the cooling may further include a post-processing step: filtering and drying.
  • the filtration may be conventional conditions and operations of such operations in the art, and preferably is reduced pressure filtration.
  • the drying may be conventional conditions and operations of such operations in the art, preferably vacuum drying.
  • Method 2 Mix the morpholinoquinazoline compound shown in formula A in solvent A and solvent B, dissolve and crystallize, and then
  • the solvent A is selected from tetrahydrofuran, 1,4-dioxane, ethanol, ethyl acetate, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC), and diamine.
  • the solvent B is selected from one or more of n-heptane, n-hexane, cyclohexane, cyclopentane, n-pentane, petroleum ether and water .
  • the solvent B is selected from n-heptane, n-hexane, cyclo One or more of hexane, cyclopentane, n-pentane, and petroleum ether.
  • the solvent A is selected from one of N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC) and dimethyl sulfoxide (DMSO), or Various kinds of the solvent B are water.
  • DMF N, N-dimethylformamide
  • DMAC N, N-dimethylacetamide
  • DMSO dimethyl sulfoxide
  • the manner of crystallization may be a conventional manner of such operations in the art. It is preferable to crystallize by natural cooling to room temperature.
  • the dissolving conditions may be conventional conditions for such operations in the art.
  • the dissolving condition is heating; more preferably, heating and stirring.
  • the heating temperature is generally the boiling point of a solvent in which the morpholinoquinazoline compound shown in Formula A is dissolved, preferably 40-90 ° C, such as 50 ° C.
  • the stirring speed may be 200-350 rpm, for example, 260 rpm.
  • the dissolving step may further include a filtering step.
  • the filtration may be a conventional filtration method for such operations in the art, preferably a filtration membrane filtration.
  • the pore diameter of the filter membrane is preferably 0.45 microns.
  • the method 2 is further preferred.
  • the morpholinoquinazoline compound represented by formula A is dissolved in the solvent A to obtain a mixed solution, and the solvent B is added to the mixed solution to analyze Crystal.
  • the adding manner may be a dropping manner.
  • the crystallization may further include the following post-processing steps: filtering and drying.
  • the filtration may be conventional conditions and operations of such operations in the art, and preferably is reduced pressure filtration.
  • the drying may be conventional conditions and operations of such operations in the art, preferably vacuum drying.
  • the invention also provides an application of the crystalline form I of the morpholinoquinazoline compound represented by formula A in the preparation of a PI3 kinase inhibitor.
  • the PI3 kinase inhibitor may be a kinase inhibitor in vivo or in vitro.
  • the kinase is preferably a p110 ⁇ subtype of PI3 kinase (PI3K).
  • the invention also provides an application of the crystalline form I of the morpholinoquinazoline compound represented by formula A in the preparation of a medicament, and the medicament is used for preventing and / or treating PI3 kinase-related disease.
  • the kinase is preferably a p110 ⁇ isoform of PI3 kinase (PI3K).
  • the diseases related to PI3 kinase include, but are not limited to, one or more of cancer, immune disease, metabolic and / or endocrine dysfunction, cardiovascular disease, viral infection and inflammation, and neurological disease. , Preferably cancer and / or immune disease.
  • the immune diseases include, but are not limited to, one or more of rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease, and systemic lupus erythematosus; the cardiovascular diseases include, but not Limited to hematological tumors; the viral infections and inflammations include, but are not limited to, asthma and / or specific dermatitis.
  • the invention also provides an application of the crystalline form I of the morpholinoquinazoline compound represented by formula A in the preparation of a medicament, the medicament is used for preventing and / or treating a disease, and the
  • the disease is one or more of cancer, immune disease, metabolic and / or endocrine dysfunction, cardiovascular disease, viral infection, inflammation, and neurological disease.
  • the immune disease the cardiovascular disease, the viral infection and inflammation are the same as described above.
  • the present invention also provides an application of the crystalline form I of the morpholinoquinazoline compound represented by formula A in the preparation of a medicament, and the medicament is used in combination with another therapeutic agent for prevention and / or control and / or Treatment of diseases related to PI3 kinase.
  • the diseases related to PI3 kinase are the same as described above.
  • the another therapeutic agent can be used for preventing and / or treating diseases related to PI3 kinase.
  • the disease may be cancer, immune disease (e.g. rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease and systemic lupus erythematosus), metabolic and / or endocrine dysfunction, cardiovascular disease (e.g. blood Tumors), viral infections, inflammation (eg, asthma and / or specific dermatitis), and neurological diseases.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline form I of the morpholinoquinazoline compound represented by Formula A, and a pharmaceutically acceptable carrier.
  • the invention also provides an application of the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating diseases related to PI3 kinase.
  • the crystalline form I of the morpholinoquinazoline compound represented by formula A may also be used in combination with one or more other active ingredients; when used in combination, the active ingredients may be separate combinations Substances for simultaneous administration in the treatment by the same or different routes of administration or separate administration at different times, or they can also be administered together in the same pharmaceutical composition.
  • the method of administering the pharmaceutical composition is not particularly limited, and various dosage forms can 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; injections can be administered alone, or intravenously mixed with injection delivery solutions (such as glucose solutions and amino acid solutions); suppositories are administered to the rectum.
  • the crystalline form I of the morpholinoquinazoline compound represented by Formula A is not prepared with one or more pharmaceutically acceptable carriers and / or excipients and / or diluents. Conversion occurs when formulated.
  • the crystalline form I of the morpholinoquinazoline compound represented by Formula A can be dissolved when it is made into a pharmaceutical composition.
  • the present invention also provides a method for treating a disease, which comprises the steps of: administering to a subject in need of treatment a therapeutically effective amount of the above-mentioned morpholinoquinazoline-based compound of Formula A as shown in Formula A or the above-mentioned Pharmaceutical composition; said disease is a disease related to PI3 kinase.
  • the disease is preferably one or more of cancer, immune disease, metabolic and / or endocrine dysfunction, cardiovascular disease, viral infection, inflammation and neurological disease.
  • the subject is a person suffering from a disease related to the PI3 kinase described above.
  • control means “prevention”.
  • Prevention refers to a reduced risk of acquiring or developing a disease or disorder (i.e., at least one of the clinical symptoms of a disease that does not occur in a subject that may be exposed to a disease agent or a disease susceptible to pre-onset disease).
  • treatment refers to the improvement of a disease or disorder (ie, preventing the disease or reducing the manifestation, the degree or severity of its clinical symptoms); or, improving at least one physical parameter that may not be noticed by the subject; or slowing down Disease progression.
  • the crystalline form of the present invention can 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. Those skilled in the art know that the peak intensity and / or peak condition of X-ray powder diffraction may be different due to different experimental conditions. At the same time, due to the different accuracy of the instrument, the measured 2 ⁇ value will have an error of about ⁇ 0.2 °. The relative intensity value of the peak is more dependent on certain properties of the sample being measured than the position of the peak, such as the size of the crystal and the purity, so the measured peak intensity may have a deviation of about ⁇ 20%.
  • the term "rapid cooling” refers to placing a saturated hot solution directly at a temperature far below the boiling point of the solvent in the saturated solution (for example, -20 ° C) for cooling, and the process has a fast cooling rate.
  • slow cooling means that the saturated hot solution is cooled to room temperature at a rate of 5 to 15 ° C / h (for example, 10 ° C / h), and the process has a slow cooling rate.
  • room temperature means “10 to 30 ° C”.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention lies in that the morpholinoquinazoline compound Form I provided by the present invention as shown in Formula A is simple in preparation method, has good stability, and is not easy to absorb moisture. Development has important value.
  • FIG. 1 is an X-ray powder diffraction pattern of the morpholinoquinazoline-based compound I obtained in Example 1 in the form I.
  • FIG. 2 is an infrared absorption spectrum diagram of the morpholinoquinazoline compound of Form I obtained in Example 1 according to Formula 1.
  • FIG. 2 is an infrared absorption spectrum diagram of the morpholinoquinazoline compound of Form I obtained in Example 1 according to Formula 1.
  • FIG. 3 is a thermogravimetric analysis chart of Example 1 to obtain the morpholinoquinazoline compound of the crystalline form I shown in Formula A.
  • FIG. 3 is a thermogravimetric analysis chart of Example 1 to obtain the morpholinoquinazoline compound of the crystalline form I shown in Formula A.
  • FIG. 4 is a differential scanning calorimetry diagram of the morpholino quinazoline-based compound I obtained in Example 1 in the form I.
  • FIG. 4 is a differential scanning calorimetry diagram of the morpholino quinazoline-based compound I obtained in Example 1 in the form I.
  • FIG. 5 is a dynamic moisture adsorption diagram of the morpholinoquinazoline compound Form I obtained in Formula A in Example 1; 1 is a dehumidification curve, and 2 is a moisture absorption curve.
  • FIG. 6 is an X-ray powder diffraction pattern of the morpholinoquinazoline-based compound Form II obtained by Formula A in Comparative Example 1.
  • FIG. 6 is an X-ray powder diffraction pattern of the morpholinoquinazoline-based compound Form II obtained by Formula A in Comparative Example 1.
  • FIG. 7 is a thermogravimetric analysis chart of Comparative Example 1 to obtain the morpholinoquinazoline-based compound Form II shown in Formula A.
  • FIG. 7 is a thermogravimetric analysis chart of Comparative Example 1 to obtain the morpholinoquinazoline-based compound Form II shown in Formula A.
  • FIG. 8 is a differential scanning calorimetry diagram of the morpholinoquinazoline compound Form II obtained by Formula A in Comparative Example 1.
  • FIG. 8 is a differential scanning calorimetry diagram of the morpholinoquinazoline compound Form II obtained by Formula A in Comparative Example 1.
  • FIG. 9 is a dynamic moisture adsorption diagram of the morpholinoquinazoline compound Form II shown in Formula A obtained in Comparative Example 1; 1 is a dehumidification curve, and 2 is a moisture absorption curve.
  • FIG. 10 is an amorphous X-ray powder diffraction pattern of a morpholinoquinazoline compound shown in Formula A according to the method of patent WO2015055071A1.
  • Powder X-Ray Diffraction Analysis CuK light source, 40KV / 40mA X-ray intensity, Theta-theta scanning mode, scanning angle range of 4 ° to 40 °, step size of 0.05 °, scanning speed of 0.5 seconds /step.
  • IR Infrared absorption spectrum analysis
  • DSC Differential Scanning Calorimetry
  • TGA Thermal weight loss analysis
  • Dynamic Moisture Absorption Analysis Take about 10mg of sample, set the temperature at 25 °C, and dry for 60 minutes under the condition of 0% RH, test the moisture absorption characteristics of the sample when the humidity changes from 0% RH to 95% RH, and the humidity from Dehumidification characteristics of the sample when the 95% RH ⁇ 0% RH change, the humidity change step is 5% RH, when the value of the mass change rate dm / dt is less than 0.002%, it is regarded as the balance of the balance, and the mass change rate is less than 0.01 within 5 minutes % / Min is the equilibrium standard during the test, and the maximum equilibration time is 2 hours. The characteristics of isothermal adsorption / desorption water under the test conditions were measured, and XRPD detection was performed on the samples after the DVS test.
  • Example 10 According to the synthesis method of Example 10 in the patent WO2015055071A1, a morpholinoquinazoline compound represented by formula A is prepared, which is characterized by XRPD to be amorphous, and the XRPD chart thereof is shown in FIG. 10.
  • the obtained sample was determined to be Form I by X-ray powder diffraction pattern.
  • the X-ray powder diffraction pattern is shown in Figure 1.
  • the X-ray powder diffraction represented by the 2 ⁇ angle is 7.7 ⁇ 0.2 °, 9.7 ⁇ 0.2 °, 11.0 ⁇ 0.2 °, 11.3 ⁇ 0.2 °, 12.4 ⁇ 0.2 °, 15.4 ⁇ 0.2 °, 17.4 ⁇ 0.2 °, 18.0 ⁇ 0.2 °, 18.4 ⁇ 0.2 °, 19.5 ⁇ 0.2 °, 20.1 ⁇ 0.2 °, 21.8 ⁇ 0.2 °, 22.6 ⁇ 0.2 °, 23.2 ⁇ 0.2 °, 23.6 ⁇ 0.2 °, There were diffraction peaks at 24.3 ⁇ 0.2 °, 25.8 ⁇ 0.2 ° and 28.7 ⁇ 0.2 °.
  • the IR shown in Figure 2 for the IR 3445cm -1, 3246cm -1, 3018cm -1 , 3001cm -1, 2972cm -1, 2953cm -1, 2924cm -1, 2910cm -1, 2891cm -1, 2850cm -1 , 1604cm -1, 1589cm -1, 1552cm -1, 1506cm -1, 1489cm -1, 1458cm -1, 1413cm -1, 1365cm -1, 1155cm -1, characteristic peaks at 775cm -1.
  • the TGA diagram is shown in Figure 3. It can be seen from FIG. 3 that the crystal form I is an anhydrous substance and does not contain water or a solvent.
  • the DVS diagram is shown in Figure 5.
  • the increased mass of the Form I is 0.23% in the range of 0% to 90% relative humidity, and in the range of 0% to 95% relative humidity compared to the initial mass. Gain 0.34%.
  • Example 2 The method was the same as in Example 2.
  • the solvent was changed to 2-methyltetrahydrofuran, acetone, ethyl acetate, ethanol, and isopropanol.
  • the precipitated solid was filtered to obtain a sample.
  • the X-ray powder diffraction pattern of the sample obtained by this method was compared with the sample pattern of Example 1 to determine the crystal form I.
  • the method is the same as in Example 5.
  • the solvent tetrahydrofuran was changed to dioxane, the poor solvent was n-heptane, and the volume multiple of the dropwise addition was 13 times.
  • the X-ray powder diffraction pattern of the sample obtained by this method was compared with the sample pattern of Example 1 to determine the crystal form I.
  • a morpholinoquinazoline compound represented by Formula A was added with 5.5 mL of DMSO to dissolve, 5 mL of water was slowly added to precipitate a solid, filtered, and dried under vacuum at less than 85 ° C. for 17 hours to obtain a sample.
  • the X-ray powder diffraction pattern of the sample obtained by this method was compared with the sample pattern of Example 1 to determine the crystal form I.
  • the TGA diagram is shown in Figure 7. It can be seen from FIG. 7 that the morpholinoquinazoline compound Form II shown in Formula A is an anhydrous substance.
  • the DSC chart is shown in Figure 8.
  • the differential scanning calorimetry of the morpholinoquinazoline compound Form II shown in Formula A has an absorption peak at 202.83 ⁇ 3 ° C, and the heat of fusion is 83.42 J / g.
  • the DVS diagram is shown in Figure 9. As shown in the dynamic moisture adsorption diagram of the morpholinoquinazoline compound Form II shown in Formula A, the weight gain was 6.237% in the range of 0% to 95% relative humidity.
  • the solvent includes water, methanol, ethanol, ethyl acetate, acetone, methyl tert-butyl ether, acetonitrile, n-hexane, isopropanol, n-heptane, toluene, methyl ethyl ketone, isopropyl ether, isopropyl acetate, N-butanol, aqueous solution of methanol (90%, 75%, 50%, 10%), aqueous solution of acetone (95%, 85%, 15%).
  • the morpholine quinazoline compound Form I is left in water and organic solvents for a long period of time at room temperature and at high temperature. There is no change. It can be seen that it has a relatively good effect in water and organic solvents. Good stability.
  • the crystalline form I of the morpholinoquinazoline compound shown in Formula A has good stability under high temperature, high humidity, and light conditions.
  • the DVS of the morpholinoquinazoline-based compound Form I shown in Formula A shows that the increased mass of Form I increases in the range of 0 to 90% relative humidity compared to the initial mass. It weighs 0.23% and gains 0.34% in the range of 0% to 95% relative humidity.
  • the DVS of the morpholinoquinazoline compound Form II shown in Formula A shows that the increased mass of the morpholinoquinazoline compound Form II shown in Formula A is increased compared to The initial mass increased 6.2377% in the range of 0-95% relative humidity.
  • the morpholinoquinazoline compound Form II as shown in Formula A has a weight increase of 18 times that of the morpholinoquinazoline compound Form I as shown in Formula A. It can be seen that the morpholinoquinazoline-based compound Form I shown in Formula A has less hygroscopicity.
  • the crystalline form I of the morpholinoquinazoline compound of the present invention as shown in Formula A has good stability and extremely low hygroscopicity.

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Abstract

一种如下式A所示吗啉基喹唑啉化合物的晶型I、其制备方法及应用。该晶型I具有较好的稳定性、不易吸湿性，且制备方法简单，适合工业化生产。

Description

吗啉基喹唑啉类化合物的晶型、其制备方法及应用
本申请要求申请日为2018年9月27日的中国专利申请2018111317028的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及吗啉基喹唑啉类化合物的晶型、其制备方法及应用。
背景技术
一种吗啉基喹唑啉类化合物，其结构如式A所示
Figure PCTCN2019105688-appb-000001
(以下简称如式A所示的吗啉基喹唑啉类化合物)，具有抑制磷脂酰肌醇3-激酶δ(PI3Kδ)的活性。
PI3Kδ是一种胞内磷酸酰肌醇激酶，可催化磷脂酰醇的3位羟基磷酸化。PI3K可分为I类、II类和III类激酶，而研究最广泛的是能被细胞表面受体所激活的I类PI3K。哺乳动物细胞中I类PI3K根据结构和受体又分为Ia类和Ib类，它们分别传递来自酪氨酸激酶-偶联受体和G蛋白-偶联受体的信号。Ia类PI3K包括PI3Kα、PI3Kβ、PI3Kδ亚型，Ib类PI3K包括PI3Kγ亚型(Trends.Biochem.Sci.,1997,22,267-272)。Ia类PI3K是由催化亚单位p110和调节亚单位p85所组成的二聚体蛋白，具有类脂激酶和蛋白激酶的双重活性(Nat.Rev.Cancer 2002,2,489-501)，被认为与细胞增殖和癌症发生，免疫疾病和涉及炎症的疾病相关。
专利WO2015055071A1公开了如式A所示的吗啉基喹唑啉类化合物及其制备方法。如式A所示的吗啉基喹唑啉类化合物的晶型对药物在生产、加工、储存、运输时的稳定性有至关重要的影响。
物质可以以两种或两种以上不同的晶体结构存在的现象称为多晶型现象。而化合物不同的固体形式往往表现出不同的物理和化学性质。对于药物而言，这种多晶型现象可能会影响到药物的吸收，进而影响药物的生物利用度，从而表现出不同的临床疗效和毒副作用。鉴于此，开发具有优势性能的如式A所示的吗啉基喹唑啉类化合物的晶型具有十分重要的意义。
发明内容
本发明所要解决的技术问题是提供一种如式A所示的吗啉基喹唑啉类化合物的晶型、制备方法及应用，该晶型制备方法简单，适合工业化生产，且不易吸湿，具有较好的稳定性，对药物的优化和开发具有重要的价值。
本发明通过以下技术方案解决上述技术问题。
本发明提供了一种如式A所示的吗啉基喹唑啉类化合物的晶型I，其以2θ角表示的X-射线粉末衍射图，在7.7±0.2°、9.7±0.2°、12.4±0.2°、15.4±0.2°、17.4±0.2°、18.0±0.2°和18.4±0.2°处有衍射峰；
Figure PCTCN2019105688-appb-000002
所述如式A所示的吗啉基喹唑啉类化合物的晶型I，其以2θ角表示的X-射线粉末衍射图，还可在如下一个或多个2θ角处有衍射峰：11.0±0.2°、11.3±0.2°、19.5±0.2°、20.1±0.2°、21.8±0.2°、22.6±0.2°、23.2±0.2°、23.6±0.2°、24.3±0.2°、25.8±0.2°和28.7±0.2°。
较佳地，所述如式A所示的吗啉基喹唑啉类化合物的晶型I，其以2θ角表示的X-射线粉末衍射图，可在7.7±0.2°、9.7±0.2°、11.0±0.2°、12.4±0.2°、15.4±0.2°、17.4±0.2°、18.0±0.2°、18.4±0.2°、23.6±0.2°和24.3±0.2°处有衍射峰。
更佳地，所述如式A所示的吗啉基喹唑啉类化合物的晶型I，其以2θ角表示的X-射线粉末衍射图，在7.7±0.2°、9.7±0.2°、11.0±0.2°、11.3±0.2°、12.4±0.2°、15.4±0.2°、17.4±0.2°、18.0±0.2°、18.4±0.2°、19.5±0.2°、20.1±0.2°、21.8±0.2°、22.6±0.2°、23.2±0.2°、23.6±0.2°、24.3±0.2°、25.8±0.2°和28.7±0.2°处有衍射峰。
本发明中，所述如式A所示的吗啉基喹唑啉类化合物的晶型I中，其以2θ角表示的X-射线粉末衍射图，其衍射峰和峰高百分比还可如表1所示：
表1
编号 2θ(±0.2°) 峰高百分比(％)
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
本发明中，所述如式A所示的吗啉基喹唑啉类化合物的晶型I中，其以2θ角表示的X-射线粉末衍射图，其衍射峰和峰面积百分比还可如表2所示：
表2
编号 2θ(±0.2°) 峰面积百分比(％)
1 7.239 6.4
2 7.666 15.5
3 9.732 37.4
4 10.962 18.9
5 11.318 4.3
6 12.385 52.4
7 15.377 64.0
8 17.404 76.1
9 17.971 87.3
10 18.382 100.0
11 19.516 11.1
12 20.111 20.6
13 21.795 43.6
14 22.551 11.1
15 23.191 18.1
16 23.564 60.9
17 24.300 26.6
18 25.799 14.5
19 28.684 24.2
本发明中，所述如式A所示的吗啉基喹唑啉类化合物的晶型I中，其以2θ角度表示的X-射线粉末衍射图，其衍射峰、峰宽值、峰高百分比和峰面积百分比还可如表3所示：
表3
编号 2θ(±0.2°) d(A) 峰高百分比(％) 峰面积百分比(％)
1 7.239 12.2016 5.5 6.4
2 7.666 11.5230 18.4 15.5
3 9.732 9.0805 34.5 37.4
4 10.962 8.0645 25.7 18.9
5 11.318 7.8119 5.4 4.3
6 12.385 7.1407 89.2 52.4
7 15.377 5.7574 65.5 64.0
8 17.404 5.0912 100.0 76.1
9 17.971 4.9319 99.4 87.3
10 18.382 4.8225 89.6 100.0
11 19.516 4.5448 11.0 11.1
12 20.111 4.4117 24.6 20.6
13 21.795 4.0743 36.0 43.6
14 22.551 3.9395 15.8 11.1
15 23.191 3.8322 16.5 18.1
16 23.564 3.7724 53.2 60.9
17 24.300 3.6597 30.5 26.6
18 25.799 3.4505 13.9 14.5
19 28.684 3.1096 21.5 24.2
本发明中，所述如式A所示的吗啉基喹唑啉类化合物的晶型I以2θ角表示的X-射线粉末衍射图还可基本上如图1所示。
本发明中，所述的X-射线粉末衍射图均使用Cu靶的Kα谱线测得。
本发明中，所述如式A所示的吗啉基喹唑啉类化合物的晶型I的红外吸收光谱图(IR)还可在以下位置处有特征峰：3445cm -1、3246cm -1、3018cm -1、3001cm -1、2972cm -1、2953cm - 1、2924cm -1、2910cm -1、2891cm -1、2850cm -1、1604cm -1、1589cm -1、1552cm -1、1506cm - 1、1489cm -1、1458cm -1、1413cm -1、1365cm -1、1155cm -1和775cm -1。
本发明中，所述如式A所示的吗啉基喹唑啉类化合物的晶型I的红外吸收图谱中的特征峰、振动类型、基团和吸收峰强度还可如表4所示：
表4
Figure PCTCN2019105688-appb-000003
本发明中，所述如式A所示的吗啉基喹唑啉类化合物的晶型I的红外吸收光谱图还可基本上如图2所所示。
本发明中，所述如式A所示的吗啉基喹唑啉类化合物的晶型I的热重分析图(TGA)还可基本上如图3所示。
本发明中，所述如式A所示的吗啉基喹唑啉类化合物的晶型I的差示扫描量热图 (DSC)中还可在204.3±3℃处有吸收峰，熔化热为98.70J/g。
本发明中，所述如式A所示的吗啉基喹唑啉类化合物的晶型I的差示扫描量热图还可基本上如图4所示。
本发明中，所述如式A所示的吗啉基喹唑啉类化合物的晶型I的动态水分吸附图(DVS)中，所述晶型I增加的质量相比于初始的质量，还可在0％～90％相对湿度范围内增重了0.23％，在0％～95％相对湿度范围内所述晶型I的质量增重了0.34％。
本发明中，所述晶型I的动态水分吸附图还可基本上如图5所示。
本发明还提供了一种如式A所示的吗啉基喹唑啉类化合物的晶型I的制备方法；其为方法1或方法2；
方法1：将式A所示的吗啉基喹唑啉类化合物在溶剂中形成热饱和溶液，冷却，即可；所述溶剂选自乙腈、2-甲基四氢呋喃、丙酮、乙酸乙酯、乙醇和异丙醇中的一种或多种。
所述热饱和溶液的配置方法可参考本领域的常规配置方法，较佳地，在所述的冷却步骤前，所述热饱和溶液经过滤处理。所述过滤处理的方式可为本领域此类操作常规的过滤方式，较佳地为热过滤。所述热过滤为滤膜过滤。所述滤膜的孔径较佳地为0.45微米。
所述冷却的方式可为本领域此类操作的常规所用的冷却方式，较佳地为快速冷却的方式或缓慢冷却的方式。
较佳地，当所述冷却的方式为快速冷却时，所述冷却的最终温度为-15～-25℃，例如-20℃。
较佳地，当所述冷却的方式为缓慢冷却时，所述冷却的速率为5～15℃/h，例如10℃/h。
本发明中，所述冷却后还可包括后处理步骤：过滤和干燥。
所述过滤可为本领域此类操作的常规条件和操作，较佳地为减压过滤。所述干燥可为本领域此类操作的常规条件和操作，较佳地为真空干燥。
方法2：将如式A所示的吗啉基喹唑啉类化合物在溶剂A和溶剂B中混合，溶解，析晶，即可；
所述溶剂A选自四氢呋喃、1,4-二氧六环、乙醇、乙酸乙酯、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMAC)和二甲基亚砜(DMSO)中的一种或多种；所述溶剂B选自正庚烷、正己烷、环己烷、环戊烷、正戊烷、石油醚和水中的一种或多种。
较佳地，当所述溶剂A选自四氢呋喃、1,4-二氧六环、乙醇和乙酸乙酯中的一种或多 种时，所述溶剂B选自正庚烷、正己烷、环己烷、环戊烷、正戊烷和石油醚中的一种或多种。
较佳地，当所述溶剂A选自N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMAC)和二甲基亚砜(DMSO)中的一种或多种，所述溶剂B为水。
所述析晶的方式可为本领域此类操作的常规方式。较佳地为自然冷却至室温析晶的方式。
所述溶解的条件，可为本领域此类操作的常规条件。较佳地，所述溶解的条件为加热；更佳为加热并搅拌。
所述加热的温度一般为溶解如式A所示的吗啉基喹唑啉类化合物的溶剂的沸点，较佳地为40～90℃，例如50℃。
所述搅拌的转速可为200～350rpm，例如260rpm。
较佳地，所述溶解之后还可包括过滤步骤。所述过滤可为本领域此类操作常规的过滤方式，较佳地为滤膜过滤。所述滤膜的孔径较佳地为0.45微米。
所述方法2进一步优选，将所述如式A所示的吗啉基喹唑啉类化合物溶解在所述溶剂A中，得到混合溶液，将所述溶剂B加入至所述混合溶液中，析晶，即可。
较佳地，所述加入的方式可为滴加的方式。
本发明中，所述析晶之后还可包括以下后处理步骤：过滤和干燥。
所述过滤可为本领域此类操作的常规条件和操作，较佳地为减压过滤。所述干燥可为本领域此类操作的常规条件和操作，较佳地为真空干燥。
本发明还提供了一种所述如式A所示的吗啉基喹唑啉类化合物的晶型I在制备PI3激酶抑制剂中的应用。
其中，所述的PI3激酶抑制剂可以为体内或体外激酶抑制剂。
其中，所述的激酶优选PI3激酶(PI3K)的p110δ亚型。
本发明还提供了一种所述如式A所示的吗啉基喹唑啉类化合物的晶型I在制备药物中的应用，所述的药物用于防治和/或治疗与PI3激酶有关的疾病。
本发明中，所述激酶优选PI3激酶(PI3K)的p110δ亚型。
本发明中，所述的与PI3激酶有关的疾病包括但不限于：癌症、免疫疾病、代谢和/或内分泌功能障碍、心血管疾病、病毒感染和炎症，和神经疾病中的一种或多种，优选癌症和/或免疫疾病。
其中，所述的免疫疾病包括但不限于类风湿性关节炎、牛皮癣、溃疡性结肠炎、克罗恩病和全身性红斑狼疮中的一种或多种；所述的心血管疾病包括但不限于血液肿瘤；所 述的病毒感染和炎症包括但不限于哮喘和/或特异性皮炎。
本发明还提供了一种所述如式A所示的吗啉基喹唑啉类化合物的晶型I在制备药物中的应用，所述的药物用于防治和/或治疗疾病，所述的疾病为癌症、免疫疾病、代谢和/或内分泌功能障碍、心血管疾病、病毒感染、炎症和神经疾病中的一种或多种。
其中，所述的免疫疾病、所述的心血管疾病、所述的病毒感染和炎症均同上所述。
本发明还提供了一种所述如式A所示的吗啉基喹唑啉类化合物的晶型I在制备药物中的应用，所述的药物与另一治疗剂联合用于防治和/或治疗与PI3激酶有关的疾病。
其中，所述的与PI3激酶有关的疾病均同前所述。
其中，所述的另一治疗剂可以用于防治和/或治疗与PI3激酶有关的疾病。所述的疾病可以为癌症、免疫疾病(例如类风湿性关节炎、牛皮癣、溃疡性结肠炎、克罗恩病和全身性红斑狼疮)、代谢和/或内分泌功能障碍、心血管疾病(例如血液肿瘤)、病毒感染、炎症(例如哮喘和/或特异性皮炎)和神经疾病中的一种或多种。
本发明还提供了一种药物组合物，其包含所述如式A所示的吗啉基喹唑啉类化合物的晶型I，和药学上可接受的载体。
本发明还提供了一种上述药物组合物在制备用于防治和/或治疗与PI3激酶有关的疾病的药物中的应用。
其中，所述的与PI3激酶有关的疾病同前所述。
本发明中，所述如式A所示的吗啉基喹唑啉类化合物的晶型I也可以与一种或多种其他活性成分组合使用；当组合使用时，活性成分可以是分开的组合物，用于在治疗中通过相同或不同的施用途径同时施用或者在不同时间分别施用，或者它们也可以在同一药物组合物中一起施用。
本发明中，所述药物组合物的给药方法没有特殊限制，可根据病人年龄、性别和其它条件及症状，选择各种剂型的制剂给药；例如，片剂、丸剂、溶液、悬浮液、乳液、颗粒剂或胶囊口服给药；针剂可以单独给药，或者和注射用输送液(如葡萄糖溶液及氨基酸溶液)混合进行静脉注射；栓剂为给药到直肠。
在一些实例中，所述如式A所示的吗啉基喹唑啉类化合物的晶型I不会在与一种或多种药学上可接受的载体和/或辅料和/或稀释剂制成制剂时发生转化。
在另一些实例中，所述如式A所示的吗啉基喹唑啉类化合物的晶型I在制成药物组合物时可以被溶解。本发明还提供了一种疾病的治疗方法，其包括以下步骤：给需要治疗的对象，施用治疗有效量的上述的如式A所示的吗啉基喹唑啉类化合物的晶型I或上述的药物组合物；所述的疾病为与PI3激酶有关的疾病。
其中，所述的疾病优选为癌症、免疫疾病、代谢和/或内分泌功能障碍、心血管疾病、病毒感染、炎症和神经疾病中的一种或多种。
在本发明一实施方案中，所述的对象是患有与上述的与PI3激酶有关的疾病的人。
本发明中，“防治”指“预防”。“预防”是指获得或发生疾病或障碍的风险降低(即导致可能暴露于导致疾病试剂或疾病发作前易感疾病的受试者中未发生疾病的临床症状的至少一种)。
本发明中，“治疗”指改善疾病或障碍(即阻止疾病或减少表现、其临床症状的程度或严重性)；或者，改善至少一种身体参数，其可能不被受试者察觉；或者减缓疾病进展。
本发明的晶型可以通过一种或几种固态分析方法进行鉴定。如X射线粉末衍射、单晶X-射线衍射、红外吸光光谱、差示扫描量热、热重曲线等。本领域技术人员知道，X射线粉末衍射的峰强度和/或峰情况可能会因为实验条件不同而不同。同时由于仪器不同的精确度，测得的2θ值会有约±0.2°的误差。而峰的相对强度值比峰的位置更依赖于所测定样品的某些性质，如晶体的尺寸大小，纯度高低，因此测得的峰强度可能出现约±20％的偏差。尽管存在试验误差、仪器误差和取向优先等，本领域技术人员还是可以从本专利提供的X射线粉末衍射数据获得足够的鉴别各个晶型的信息。在红外光谱测定中，由于各种型号的仪器性能不同、供试品制备时研磨程度的差异或吸水程度不同等原因，对光谱的形状及吸收峰的位置均会有一定程度的影响。而在DSC测量中，根据加热速率、晶体形状和纯度和其它测量参数，实测获得的吸热峰的初始温度、最高温度和熔化热数据均具有一定程度的可变性。
本发明中，术语“快速冷却”是指将饱和热溶液直接放置在远低于该饱和溶液中的溶剂的沸点的温度下(例如-20℃)，进行冷却，该过程冷却速度快。
本发明中，术语“缓慢冷却”是指饱和热溶液以5～15℃/h的速率(例如10℃/h)冷却至室温，该过程冷却速度慢。
本发明中，“室温”是指“10～30℃”。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明提供的如式A所示的吗啉基喹唑啉类化合物晶型I制备方法简单，且具有较好的稳定性，且不易吸湿，对药物的优化和开发具有重要的价值。
附图说明
图1为实施例1得到如式A所示的吗啉基喹唑啉类化合物的晶型I的X-射线粉末衍射图。
图2为实施例1得到如式A所示的吗啉基喹唑啉类化合物的晶型I的红外吸收光谱图。
图3为实施例1得到如式A所示的吗啉基喹唑啉类化合物的晶型I的热重分析图。
图4为实施例1得到如式A所示的吗啉基喹唑啉类化合物的晶型I的差示扫描量热图。
图5为实施例1得到如式A所示的吗啉基喹唑啉类化合物的晶型I的动态水分吸附图；其中1为去湿曲线，2为吸湿曲线。
图6为对比实施例1得到如式A所示的吗啉基喹唑啉类化合物的晶型II的X-射线粉末衍射图。
图7为对比实施例1得到如式A所示的吗啉基喹唑啉类化合物的晶型II的热重分析图。
图8为对比实施例1得到如式A所示的吗啉基喹唑啉类化合物的晶型II的差示扫描量热图。
图9为对比实施例1得到如式A所示的吗啉基喹唑啉类化合物的晶型II的动态水分吸附图；其中1为去湿曲线，2为吸湿曲线。
图10为根据专利WO2015055071A1方法得到如式A所示的吗啉基喹唑啉类化合物的无定型的X-射线粉末衍射图。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
检测方法
仪器
仪器 型号 厂家
粉末X-射线衍射仪 D8ADVANCE BRUKER
傅里叶变换红外光谱仪 Presitage 21 Shimadzu
差示扫描量热仪 Q1000 TA
热失重分析仪 Q500 TA
动态水分吸附分析 Advantage SMS
粉末X-射线衍射分析(XRPD)：光源为CuK，X-射线强度为40KV/40mA，扫描模式为Theta-theta，扫描角度范围4°～40°，步长为0.05°，扫描速度为0.5秒/步。
红外吸收光谱分析(IR)：依据中国药典2015年版四部通则0402红外分光光度法，采用溴化钾压片法制备供试品，在4000～400cm -1波数范围内采集红外吸收光谱。供试品的扫描次数为45次，仪器分辨率为4cm -1。
差示扫描量热分析(DSC)：称取样品2～4mg，置于非密闭铝盘中，氮气流(50mL/min)环境中，样品在25℃平衡，然后以10℃/min的升温速率从25℃加热至300℃或400℃。
热失重分析(TGA)：称取样品8～12mg，置于铂金样品盘中，氮气流(50mL/min)环境中，以10℃/min的升温速率从25℃加热至300℃或400℃。
动态水分吸附分析(DVS)：取样品约10mg，温度设定25℃，湿度0％RH条件下干燥60分钟后，测试湿度从0％RH～95％RH变化时样品的吸湿特征，以及湿度从95％RH～0％RH变化时样品的去湿特征，湿度变化步长5％RH，当质量变化率dm/dt的值小于0.002％时视为天平平衡，当5分钟内质量变化率小于0.01％/分钟为检测过程中的平衡标准，最长平衡时间为2小时。测定该测试条件下的等温吸附/脱附水的特征，并对DVS测试后的样品进行XRPD检测。
根据专利WO2015055071A1中实施例10的合成方法，制备得到如式A所示的吗啉基喹唑啉类化合物，经XRPD表征为无定型，其XRPD图如图10所示。
实施例1 如式A所示的吗啉基喹唑啉类化合物的晶型I的制备
称取约20mg如式A所示的吗啉基喹唑啉类化合物到小瓶中，往小瓶中加入一定体积的乙腈，超声2分钟，将样品瓶置于磁力加热搅拌器上，控制温度为50℃，转速为260rpm，加热促进样品溶解，若溶液已澄清，则添加一定量的固体样品，继续加热促溶，保证最后得到样品过饱和溶液，趁热用0.45微米滤膜过滤并转移到新的小瓶中。将小瓶立即放到-20℃冰箱中，析出固体过滤得到样品。
经X-射线粉末衍射图谱测定所得样品为晶型I。X-射线粉末衍射图如图1所示，其以2θ角表示的X-射线粉末衍射，在7.7±0.2°，9.7±0.2°，11.0±0.2°，11.3±0.2°，12.4±0.2°，15.4±0.2°，17.4±0.2°，18.0±0.2°，18.4±0.2°，19.5±0.2°，20.1±0.2°，21.8±0.2°，22.6±0.2°，23.2±0.2°，23.6±0.2°，24.3±0.2°，25.8±0.2°和28.7±0.2°处 有衍射峰。
其IR图如图2所示，IR为3445cm -1，3246cm -1，3018cm -1，3001cm -1，2972cm -1，2953cm -1，2924cm -1，2910cm -1，2891cm -1，2850cm -1，1604cm -1，1589cm -1，1552cm -1，1506cm -1，1489cm -1，1458cm -1，1413cm -1，1365cm -1，1155cm -1，775cm -1处有特征峰。
TGA图如图3所示。由图3可知，晶型I为无水物，不含水或溶剂。
DSC图如图4所示。晶型I的差示扫描量热中在204.3±3℃处有吸收峰，熔化热为98.70J/g。
DVS图如图5所示。晶型I的动态水分吸附图中，所述晶型I增加的质量相比于初始的质量，在0％～90％相对湿度范围内增重0.23％，在0％～95％相对湿度范围内增重0.34％。
实施例2 如式A所示的吗啉基喹唑啉类化合物的晶型I的制备
称取约20mg如式A所示的吗啉基喹唑啉类化合物到小瓶中，往小瓶中加入一定体积的乙腈，超声2分钟，将样品瓶置于磁力加热搅拌器上，控制温度为50℃，转速为260rpm，加热促进样品溶解，若溶液已澄清，则添加一定量的固体样品，继续加热促溶，保证最后得到样品过饱和溶液，趁热用0.45微米滤膜过滤并转移到新的小瓶中。以10℃/h的速率缓慢降温至室温(25℃)并在室温下搅拌过夜，析出固体过滤得到样品。此方法所得样品的X射线粉末衍射图谱经与实施例1样品图谱比对，确定为晶型I。
实施例3 如式A所示的吗啉基喹唑啉类化合物的晶型I的制备
方法同实施例2，将溶剂改为2-甲基四氢呋喃、丙酮、乙酸乙酯、乙醇、异丙醇，析出固体过滤得到样品。此方法所得样品的X射线粉末衍射图谱经与实施例1样品图谱比对，确定为晶型I。
实施例4 如式A所示的吗啉基喹唑啉类化合物的晶型I的制备
称取约1g如式A所示的吗啉基喹唑啉类化合物，加5mL丙酮，在加热下溶解，停止加热，放置过夜。第二天，过滤，干燥得到样品。此方法所得样品的X射线粉末衍射图谱经与实施例1样品图谱比对，确定为晶型I。
实施例5 如式A所示的吗啉基喹唑啉类化合物的晶型I的制备
称取约20mg如式A所示的吗啉基喹唑啉类化合物到小瓶中，往小瓶中加入一定体积的四氢呋喃，超声2分钟，将样品瓶置于磁力加热搅拌器上，控制温度为50℃，转速为260rpm，加热促进样品溶解，若溶液已澄清，则添加一定量的固体样品，继续加热促溶，保证最后得到样品呈过饱和溶液，趁热用0.45微米滤膜过滤并转移到新的小瓶中，向瓶中缓慢滴加10倍体积的正庚烷并保持缓慢搅拌，析出固体过滤得到样品。此方法所得样品的X射线粉末衍射图谱经与实施例1样品图谱比对，确定为晶型I。
实施例6 如式A所示的吗啉基喹唑啉类化合物的晶型I的制备
方法同实施例5，将溶剂四氢呋喃改为将二氧六环，不良溶剂为正庚烷，滴加的体积倍数为13倍。此方法所得样品的X射线粉末衍射图谱经与实施例1样品图谱比对，确定为晶型I。
实施例7 如式A所示的吗啉基喹唑啉类化合物的晶型I的制备
在室温下，将1g如式A所示的吗啉基喹唑啉类化合物溶解于5.5mL的DMF中，搅拌下慢慢加入1mL水，析出固体过滤得到样品。此方法所得样品的X射线粉末衍射图谱经与实施例1样品图谱比对，确定为晶型I。
实施例8 如式A所示的吗啉基喹唑啉类化合物的晶型I的制备
往10g如式A所示的吗啉基喹唑啉类化合物中加入500mL乙醇，在加热下完全溶解，趁热过滤，滤液浓缩至50-70mL后，室温搅拌过夜，加入正庚烷析晶到大量固体析出，过滤，在小于85℃真空干燥5-6小时，得到样品。此方法所得样品的X射线粉末衍射图谱经与实施例1样品图谱比对，确定为晶型I。
实施例9 如式A所示的吗啉基喹唑啉类化合物的晶型I的制备
往5g如式A所示的吗啉基喹唑啉类化合物中加入25mL乙醇和25mL正庚烷，回流16小时后，冷却至室温，过滤，小于85℃真空干燥16小时，得到约4g样品。此方法所得样品的X射线粉末衍射图谱经与实施例1样品图谱比对，确定为晶型I。
实施例10 如式A所示的吗啉基喹唑啉类化合物的晶型I的制备
在室温下，往5g如式A所示的吗啉基喹唑啉类化合物中加入5.5mL的DMSO溶解，慢慢加入5mL水析出固体，过滤，小于85℃真空干燥17小时，得到样品。此方法所得样品的X射线粉末衍射图谱经与实施例1样品图谱比对，确定为晶型I。
实施例11 如式A所示的吗啉基喹唑啉类化合物的晶型I的制备
在室温下，往6g如式A所示的吗啉基喹唑啉类化合物中加入乙酸乙酯360g溶解，浓缩到一半体积，加入约60g正庚烷，析出固体，过滤。小于85℃真空干燥48小时，得到样品。此方法所得样品的X射线粉末衍射图谱经与实施例1样品图谱比对，确定为晶型I。
对比实施例1 如式A所示的吗啉基喹唑啉类化合物的晶型II的制备
称取30mg如式A所示的吗啉基喹唑啉类化合物到小瓶中，往小瓶中加入1,4-二氧六环/异丙醚(v/v＝1:1)，超声促使样品溶解，若溶液已澄清，则继续添加一定量的固体样品，并超声促溶，保证最后得到样品为过饱和溶液，用0.45微米滤膜过滤并转移到新的小瓶，将小瓶敞口放置，室温下自然挥发溶剂，得到固体即为如式A所示的吗啉基喹唑 啉类化合物的晶型II。
如式A所示的吗啉基喹唑啉类化合物的晶型II的X-射线粉末衍射图谱如图6所示，其中2θ、d(A)、峰高数和峰面积如下表5所示：
表5
Figure PCTCN2019105688-appb-000004
TGA图如图7所示。由图7可知，如式A所示的吗啉基喹唑啉类化合物晶型II为无水物。
DSC图如图8所示。如式A所示的吗啉基喹唑啉类化合物晶型II的差示扫描量热中在202.83±3℃处有吸收峰，熔化热为83.42J/g。
DVS图如图9所示。如式A所示的吗啉基喹唑啉类化合物晶型II的动态水分吸附图中，在0％～95％相对湿度范围内增重6.237％。
效果实施例1 稳定性
1如式A所示的吗啉基喹唑啉类化合物的晶型I在水和有机溶剂中的稳定性
1.1如式A所示的吗啉基喹唑啉类化合物的晶型I在水和有机溶剂中室温放置10天的稳定性
分别称取约20mg如式A所示的吗啉基喹唑啉类化合物晶型I固体样品到小瓶子，分别往小瓶中加入1mL的水或有机溶剂，超声5分钟得到混悬液。将混悬液在室温下旋转10天，过滤后的湿样品用XRPD表征。结果显示，各种溶剂下，晶型都没有发生变化，仍为晶型I。所述的溶剂包括水、甲醇，乙醇，乙酸乙酯，丙酮，甲基叔丁基醚，乙腈，正己烷，异丙醇，正庚烷，甲苯，甲乙酮，异丙醚，乙酸异丙酯，正丁醇，甲醇的水溶液 (90％，75％，50％，10％)，丙酮的水溶液(95％，85％，15％)。
1.2如式A所示的吗啉基喹唑啉类化合物的晶型I在有机溶剂中高温打浆18小时的稳定性
往5g如式A所示的吗啉基喹唑啉类化合物晶型I固体中加入乙醇10g，异丙醇10g，正庚烷10g。混合物在80℃打浆18小时，冷却至室温，过滤，小于85℃真空干燥16小时，得到约4g样品。此方法所得样品的X-射线粉末衍射图谱与实施例1中所得晶型I样品的衍射峰一致。
如式A所示的吗啉基喹唑啉类化合物的晶型I在水和有机溶剂中经过长时间的室温放置，以及高温放置均没有发生变化，可见，其在水和有机溶剂中具有较好的稳定性。
2如式A所示的吗啉基喹唑啉类化合物的晶型I在高温、高湿、光照条件下的稳定性
将适量的如式A所示的吗啉基喹唑啉类化合物的晶型I的样品置于培养皿上，分别于高温(40±2℃和60±2℃)、高湿(25℃，RH75±5％和RH90±5％)和光照(4500±500Lux，25℃)条件下敞开放置。于5天、10天、1月取样试验，结果见下表6～8：
将适量的如式A所示的吗啉基喹唑啉类化合物无定型样品和如式A所示的吗啉基喹唑啉类化合物晶型II的样品分别置于培养皿上，分别于高温(60±2℃)、高湿(25℃，RH75±5％)和光照(4500±500Lux，25℃)条件下敞开放置。于5天、10天取样试验，结果见下表9～10：
表6 影响因素高温(40±2℃、60±2℃)试验结果
Figure PCTCN2019105688-appb-000005
表7 影响因素高湿(25℃，RH75±5％、RH90±5％)试验结果
Figure PCTCN2019105688-appb-000006
Figure PCTCN2019105688-appb-000007
表8 影响因素光照(4500Lux±500Lux，25℃)试验结果
Figure PCTCN2019105688-appb-000008
表9 影响因素高温(60±2℃)、光照(4500Lux±500Lux，25℃)、高湿(25℃，RH75±5％)试验结果
Figure PCTCN2019105688-appb-000009
表10 影响因素高温(60±2℃)、光照(4500Lux±500Lux，25℃)、高湿(25℃，RH75±5％)试验结果
Figure PCTCN2019105688-appb-000010
由上述表6～8数据表明，如式A所示的吗啉基喹唑啉类化合物的晶型I在高温、高湿、光照条件下，其化学纯度和晶型均没有发生改变，具有较好的稳定性。
如式A所示的吗啉基喹唑啉类化合物的无定型样品分别在光照(4500±500Lux，25℃)、高温(60℃)和高湿(25℃，RH75％)条件下放置10天，性状无明显变化。由上述表9数据表明，由上表可知样品在高温(60℃)和高湿(25℃，RH75％)条件下总杂含量略有增加；在光照(4500±500Lux，25℃)条件下，总杂含量显著增大，样品在光照条件下不稳定。
获得如式A所示的吗啉基喹唑啉类化合物的晶型II难度较大，纯度也稍差。样品分 别在光照(4500±500Lux，25℃)、高温(60℃)和高湿(25℃，RH75％)条件下放置10天，性状无明显变化。由上述表10数据表明，样品在高温(60℃)和高湿(25℃，RH75％)条件下总杂含量略有增加；在光照(4500±500Lux，25℃)条件下，总杂含量显著增大，样品在光照条件下不稳定。
可见，如式A所示的吗啉基喹唑啉类化合物的晶型I在高温、高湿、光照条件下，均具有较好的稳定性。
效果实施例2 吸湿性
取样品约10mg，温度设定25℃，湿度0％RH条件下干燥60分钟后，测试湿度从0％RH～95％RH变化时样品的吸湿特征，以及湿度从95％RH～0％RH变化时样品的去湿特征，湿度变化步长5％RH，当质量变化率dm/dt的值小于0.002％时视为天平平衡，当5分钟内质量变化率小于0.01％/分钟为检测过程中的平衡标准，最长平衡时间为2小时。测定该测试条件下的等温吸附/脱附水的特征，并对DVS测试后的样品进行XRPD检测。
由图5如式A所示的吗啉基喹唑啉类化合物的晶型I的DVS可知，所述晶型I增加的质量相比于初始的质量，在0～90％相对湿度范围内增重0.23％，在0％～95％相对湿度范围内增重0.34％。
由图9如式A所示的吗啉基喹唑啉类化合物的晶型II的DVS可知，所述如式A所示的吗啉基喹唑啉类化合物晶型II增加的质量相比于初始的质量，在0～95％相对湿度范围内增重6.237％。
在0～95％相对湿度范围内如式A所示的吗啉基喹唑啉类化合物晶型II增重量为如式A所示的吗啉基喹唑啉类化合物晶型I的18倍，可见如式A所示的吗啉基喹唑啉类化合物晶型I具有较小的吸湿性。
可见，本发明的如式A所示的吗啉基喹唑啉类化合物的晶型I具有较好的稳定性和极低的吸湿性。
应当理解，本文所述的实施例仅用于说明目的，通过实施例将有助于进一步理解本发明，但不用于限制本发明的内容。对于本领域技术人员而言，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施，这些改变或改进包括在本申请的主旨和范围以及所附权利要求的范围内。

Claims (16)

  1. 一种如式A所示的吗啉基喹唑啉类化合物的晶型I，其以2θ角表示的X-射线粉末衍射图，在7.7±0.2°、9.7±0.2°、12.4±0.2°、15.4±0.2°、17.4±0.2°、18.0±0.2°和18.4±0.2°处有衍射峰；
    Figure PCTCN2019105688-appb-100001
  2. 如权利要求1所述如式A所示的吗啉基喹唑啉类化合物的晶型I，其特征在于，其以2θ角表示的X-射线粉末衍射图，还在如下一个或多个2θ角处有处有衍射峰：11.0±0.2°、11.3±0.2°、19.5±0.2°、20.1±0.2°、21.8±0.2°、22.6±0.2°、23.2±0.2°、23.6±0.2°、24.3±0.2°、25.8±0.2°和28.7±0.2°。
  3. 如权利要求1所述如式A所示的吗啉基喹唑啉类化合物的晶型I，其特征在于，其以2θ角表示的X-射线粉末衍射图，在7.7±0.2°、9.7±0.2°、11.0±0.2°、12.4±0.2°、15.4±0.2°、17.4±0.2°、18.0±0.2°、18.4±0.2°、23.6±0.2°和24.3±0.2°处有衍射峰；
    和/或，所述如式A所示的吗啉基喹唑啉类化合物的晶型I的红外吸收光谱图中在以下位置处有特征峰：3445cm -1、3246cm -1、3018cm -1、3001cm -1、2972cm -1、2953cm -1、2924cm - 1、2910cm -1、2891cm -1、2850cm -1、1604cm -1、1589cm -1、1552cm -1、1506cm -1、1489cm - 1、1458cm -1、1413cm -1、1365cm -1、1155cm -1和775cm -1；
    和/或，所述如式A所示的吗啉基喹唑啉类化合物的晶型I的差示扫描量热图中在204.3±3℃处有吸收峰，熔化热为98.70J/g；
    和/或，所述如式A所示的吗啉基喹唑啉类化合物的晶型I的动态水分吸附图中，所述晶型I增加的质量相比于初始的质量，在0％～90％相对湿度范围内增重了0.23％，在0％～95％相对湿度范围内增重了0.34％。
  4. 如权利要求3所述如式A所示的吗啉基喹唑啉类化合物的晶型I，其特征在于，其以2θ角表示的X-射线粉末衍射图，在7.7±0.2°、9.7±0.2°、11.0±0.2°、11.3±0.2°、12.4±0.2°、15.4±0.2°、17.4±0.2°、18.0±0.2°、18.4±0.2°、19.5±0.2°、20.1±0.2°、21.8±0.2°、22.6±0.2°、23.2±0.2°、23.6±0.2°、24.3±0.2°、25.8±0.2°和28.7±0.2°处有衍射峰；
    和/或，所述如式A所示的吗啉基喹唑啉类化合物的晶型I的红外吸收图谱中特征峰、振动类型、基团和吸收峰强度如下表所示：
    Figure PCTCN2019105688-appb-100002
    和/或，所述如式A所示的吗啉基喹唑啉类化合物的晶型I的热重分析图基本上如图3所示；
    和/或，所述如式A所示的吗啉基喹唑啉类化合物的晶型I的差示扫描量热图基本上如图4所示；
    和/或，所述如式A所示的吗啉基喹唑啉类化合物的晶型I的动态水分吸附图基本上如图5所示。
  5. 如权利要求1～4中至少一项所述如式A所示的吗啉基喹唑啉类化合物的晶型I，其特征在于，其以2θ角表示的X-射线粉末衍射图，其衍射峰和峰高百分比如下表所示：
    编号 2θ(±0.2°) 峰高百分比(％) 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
    。
  6. 如权利要求5所述如式A所示的吗啉基喹唑啉类化合物的晶型I，其特征在于，其以2θ角表示的X-射线粉末衍射图基本上如图1所示；
    和/或，所述如式A所示的吗啉基喹唑啉类化合物的晶型I的红外吸收光谱图还基本上如图2所示。
  7. 如权利要求1～6中至少一项所述如式A所示的吗啉基喹唑啉类化合物的晶型I的制备方法，其特征在于，其为方法1或方法2：
    方法1：将式A所示的吗琳基喹唑啉类化合物在溶剂中形成热饱和溶液，冷却，即可；所述溶剂选自乙腈、2-甲基四氢呋喃、丙酮、乙酸乙酯、乙醇和异丙醇中的一种或多种；
    方法2：将如式A所示的吗啉基喹唑啉类化合物在溶剂A和溶剂B中混合，溶解，析晶，即可；
    所述溶剂A选自四氢呋喃、1,4-二氧六环、乙醇、乙酸乙酯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜中的一种或多种；所述溶剂B选自正庚烷、正己烷、环己烷、环戊烷、正戊烷、石油醚和水中的一种或多种。
  8. 如权利要求7所述如式A所示的吗啉基喹唑啉类化合物的晶型I的制备方法，其特征在于，方法1中，所述冷却的方式为快速冷却或缓慢冷却，当所述冷却的方式为快速冷却为快速冷却时，所述冷却的最终温度为-15～-25℃；当所述冷却的方式为缓慢冷却 时，所述冷却的速率为5～15℃/h；
    和/或，方法2中，当所述溶剂A选自四氢呋喃、1,4-二氧六环、乙醇和乙酸乙酯中的一种或多种时，所述溶剂B选自正庚烷、正己烷、环己烷、环戊烷、正戊烷和石油醚中的一种或多种；
    和/或，方法2中，当所述溶剂A选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和二甲基亚砜时中的一种或多种，所述溶剂B为水；
    和/或，所述方法2，其包括以下步骤：将所述如式A所示的吗啉基喹唑啉类化合物溶解在所述溶剂A中，得到混合溶液，将所述溶剂B加入至所述混合溶液中，析晶，即可。
  9. 一种如权利要求1～6中至少一项所述如式A所示的吗啉基喹唑啉类化合物的晶型I在制备PI3激酶抑制剂中的应用。
  10. 一种如权利要求1～6中至少一项所述如式A所示的吗啉基喹唑啉类化合物的晶型I在制备药物中的应用，所述的药物用于防治和/或治疗与PI3激酶有关的疾病。
  11. 如权利要求10所述的应用，其特征在于，所述的与PI3激酶有关的疾病为癌症、免疫疾病、代谢和/或内分泌功能障碍、心血管疾病、病毒感染和炎症，和神经疾病中的一种或多种。
  12. 如权利要求10所述的应用，其特征在于，所述的免疫疾病为类风湿性关节炎、牛皮癣、溃疡性结肠炎、克罗恩病和全身性红斑狼疮中的一种或多种；
    和/或，所述的心血管疾病为血液肿瘤；
    和/或，所述的病毒感染和炎症包为哮喘和/或特异性皮炎。
  13. 一种如权利要求1～6中至少一项所述如式A所示的吗啉基喹唑啉类化合物的晶型I在制备药物中的应用，所述的药物与另一治疗剂联合用于防治和/或治疗与PI3激酶有关的疾病。
  14. 一种药物组合物，其包含如权利要求1～6中至少一项所述如式A所示的吗啉基喹唑啉类化合物的晶型I，和药学上可接受的载体。
  15. 一种疾病的治疗方法，其包括以下步骤：给需要治疗的对象，施用治疗有效量的如权利要求1～6中至少一项所述如式A所示的吗啉基喹唑啉类化合物的晶型I或如权力要求13所述的药物组合物；所述的疾病为与PI3激酶有关的疾病。
  16. 如权利要求15所述的治疗方法，其特征在于，所述的疾病为癌症、免疫疾病、代谢和/或内分泌功能障碍、心血管疾病、病毒感染、炎症和神经疾病中的一种或多种。
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