MTL-II crystal form of miindoptoline as well as preparation method and application of MTL-II crystal form

Abstract

The invention relates to an MTL-II crystal form of miindoprine as well as a preparation method and application of the MTL-II crystal form. The X-ray powder diffraction pattern of the MTL-II crystal form of miindopturin has characteristic diffraction peaks at the following angles of 2theta (degrees): 7.5 + / -0.2 degrees, 9.6 + / -0.2 degrees, 11.1 + / -0.2 degrees, 14.3 + / -0.2 degrees, 15.1 + / -0.2 degrees, 16.2 + / -0.2 degrees, 18.4 + / -0.2 degrees, 18.6 + / -0.2 degrees, 20.5 + / -0.2 degrees and 23.1 + / -0.2 degrees. The MTL-II crystal form of miindoprine is a non-solvate, the solvent residue is less, and meanwhile, the preparation method of miindoprine is simple and convenient to operate and easy for industrial production and application.

Description

Technical Field

[0001] The present application relates to the technical field of drug crystal forms, and in particular to an MTL-II crystal form of midostaurin and a preparation method and application thereof. Background Art

[0002] Midostaurin is an active derivative obtained by structural modification of staurosporine, an indolecarbazole alkaloid isolated from the culture medium of Streptomyces. Its Chinese name is 4'-N-benzamido-staurosporine. Midostaurin is a tyrosine kinase inhibitor, which is clinically used for targeted therapy of acute myeloid leukemia (AML). It also has good efficacy in treating aggressive systemic mastocytosis (ASM), systemic mastocytosis with hematological neoplasms (SM-AHN) and mast cell leukemia (MCL).

[0003] Midostaurin is a drug approved for marketing by the FDA in 2017, and its compound preparation methods and various crystal forms have been reported in many reports in the field. However, different crystal forms have different physical and chemical properties, which may have different effects on the drugability of the drug. In addition, most of the crystal forms of midostaurin reported so far are solvates or contain high solvent residues, including Class II solvents, which are difficult to be actually used in preparations. In addition, the preparation methods of these crystal forms also have problems such as difficulty in industrial production, complex processes, and high costs. Summary of the invention

[0004] Based on this, the present application provides a MTL-II crystal form of midostaurin and a preparation method thereof. The MTL-II crystal form of midostaurin is a non-solvate with little residual solvent, and the preparation method of midostaurin is simple to operate and easy to apply in industrial production.

[0005] In a first aspect of the present application, there is provided a MTL-II crystal form of midostaurin, whose X-ray powder diffraction (XRPD) spectrum has characteristic diffraction peaks at the following 2θ (°) angles:

[0006] 7.5±0.2°, 9.6±0.2°, 11.1±0.2°, 14.3±0.2°, 15.1±0.2°, 16.2±0.2°, 18.4±0.2°, 18.6±0.2°, 20.5±0.2° and 23.1±0.2°.

[0007] In some embodiments, the X-ray powder diffraction pattern of the MTL-II crystal form of midostaurin has a characteristic diffraction peak at at least one of the following 2θ (°) angles:

[0008] 13.0±0.2°, 13.7±0.2°, 13.9±0.2°, 14.8±0.2°, 17.1±0.2°, 17.3±0.2°, 23.9±0.2° and 26.2±0.2°.

[0009] In some embodiments, the 2θ (°) angle and relative intensity of the characteristic diffraction peak in the X-ray powder diffraction pattern of the MTL-II crystal form of midostaurin are as follows:

[0010] The 2θ (°) angle is 7.5 ± 0.2° and the relative intensity is 89.0;

[0011] The 2θ (°) angle is 9.6 ± 0.2° and the relative intensity is 100.0;

[0012] The 2θ(°) angle is 11.1±0.2° and the relative intensity is 11.8;

[0013] The 2θ(°) angle is 13.0±0.2° and the relative intensity is 4.6;

[0014] The 2θ(°) angle is 13.7±0.2° and the relative intensity is 7.7;

[0015] The 2θ(°) angle is 13.9±0.2° and the relative intensity is 7.3;

[0016] The 2θ (°) angle is 14.3 ± 0.2° and the relative intensity is 23.0;

[0017] The 2θ(°) angle is 14.8±0.2° and the relative intensity is 7.1;

[0018] The 2θ(°) angle is 15.1±0.2° and the relative intensity is 16.8;

[0019] The 2θ(°) angle is 16.2±0.2° and the relative intensity is 19.9;

[0020] The 2θ(°) angle is 17.1±0.2° and the relative intensity is 5.6;

[0021] The 2θ(°) angle is 17.3±0.2° and the relative intensity is 5.7;

[0022] The 2θ(°) angle is 18.4±0.2° and the relative intensity is 27.4;

[0023] The 2θ (°) angle is 18.6 ± 0.2° and the relative intensity is 14.8;

[0024] The 2θ (°) angle is 20.5 ± 0.2° and the relative intensity is 21.6;

[0025] The 2θ (°) angle is 23.1 ± 0.2° and the relative intensity is 14.0;

[0026] The 2θ(°) angle is 23.9±0.2° and the relative intensity is 6.3;

[0027] The 2θ(°) angle was 26.2±0.2° and the relative intensity was 7.8.

[0028] In some of the embodiments, the X-ray powder diffraction pattern of the MTL-II crystal form of midostaurin is substantially as follows Figure 1 As shown, and / or, the thermogravimetric analysis (TGA) spectrum is substantially as shown Figure 2 shown.

[0029] In some embodiments, the MTL-II crystal form of midostaurin is a non-solvate compound crystal form.

[0030] In some embodiments, the MTL-II crystalline form of midostaurin has one or more of the following characteristics:

[0031] (1) The total residual solvent is less than 500 ppm;

[0032] (2) The moisture content is less than 1 wt%.

[0033] In some embodiments, the melting point of the MTL-II crystalline form of midostaurin is 269±1°C.

[0034] The second aspect of the present application provides a method for preparing the MTL-II crystal form of midostaurin described in the first aspect, comprising the following steps:

[0035] Mixing midostaurin with a first solvent, and subjecting the mixture to pulping or heating for dissolution to precipitate a solid, to prepare a first solvate of midostaurin; wherein the first solvent is one or both of acetone and ethyl acetate;

[0036] The first solvate of midostaurin is mixed with a second solvent, heated to dissolve, and then cooled to crystallize to prepare the MTL-II crystal form of midostaurin; the second solvent is ethanol.

[0037] In some of these embodiments,

[0038] In the step of preparing the first solvate of midostaurin, the temperature of heating and dissolving is 30° C. to 80° C., the mass volume ratio of midostaurin to the first solvent is 1 g: (5 to 30) mL, and the time for precipitating the solid is 0.5 h to 3 h; and / or,

[0039] In the step of preparing the MTL-II crystal form of midostaurin from the first solvate of midostaurin, the mass volume ratio of the first solvate of midostaurin to the second solvent is 1g: (10-30)mL, and the specific steps of heating to dissolve and then cooling to crystallize are heating to 60°C-80°C to dissolve, and then naturally cooling to crystallize.

[0040] The third aspect of the present application provides the use of the MTL-II crystal form of midostaurin described in the first aspect in the preparation of a tyrosine kinase inhibitor.

[0041] The fourth aspect of the present application provides the use of the MTL-II crystal form of midostaurin described in the first aspect in the preparation of a drug having the efficacy of preventing or treating aggressive systemic mastocytosis (ASM), systemic mastocytosis associated with hematological tumors (SM-AHN) or mast cell leukemia (MCL).

[0042] The present application has found that the midostaurin crystal form MTL-II has a specific 2θ (°) angle characteristic peak in its X-ray powder diffraction pattern, and it is a new crystal form when compared with the midostaurin crystal form obtained by the traditional method. At the same time, the midostaurin crystal form MTL-II is a non-solvate with low residual solvent content, high purity and low impurity content, which is conducive to its application in preparations. In addition, the midostaurin crystal form MTL-II also has good stability.

[0043] In addition, the preparation method of the midostaurin crystal form MTL-II has simple process, simple equipment requirements, high crystallization yield, high product purity, recyclable solvent, low production cost, and can realize industrial mass production. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 The XRPD spectrum of the MTL-II crystal form of midostaurin prepared in Example 1;

[0045] Figure 2 This is the TGA spectrum of the MTL-II crystal form of midostaurin prepared in Example 1;

[0046] Figure 3 This is the nuclear magnetic resonance spectrum of the MTL-II crystal form of midostaurin prepared in Example 1. DETAILED DESCRIPTION

[0047] The MTL-II crystal form of midostaurin of the present application and its preparation method and application are further described in detail below in conjunction with specific examples. The present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present application more thorough and comprehensive.

[0048] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0049] Herein, "at least one" refers to any one, any two, or any two or more of the listed items.

[0050] In this application, "first aspect", "second aspect", "third aspect", "fourth aspect", etc. are used only for descriptive purposes and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first", "second", "third", "fourth", etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity.

[0051] In the present application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0052] In this application, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0053] The percentage contents involved in this application, unless otherwise specified, refer to mass percentage for solid-liquid mixing and solid-solid mixing, and refer to volume percentage for liquid-liquid mixing.

[0054] The percentage concentrations mentioned in this application, unless otherwise specified, refer to the final concentration, which refers to the percentage of the added component in the system after the addition of the component.

[0055] The temperature parameters in this application, unless otherwise specified, allow for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range of instrument control.

[0056] In this application, the "X-ray powder diffraction pattern is basically as Figure 1 The “substantially” in “shown” means that as long as it can be determined as a whole that a certain X-ray powder diffraction pattern is substantially consistent with the X-ray powder diffraction pattern described in this application, it should be considered to fall within the scope of protection of this application. The same applies to the “substantially” in the thermogravimetric analysis spectrum.

[0057] The room temperature in the present application generally refers to 4°C to 30°C, preferably 20±5°C.

[0058] Some examples of the present application provide a MTL-II crystal form of midostaurin, whose X-ray powder diffraction (XRPD) spectrum has characteristic diffraction peaks at the following 2θ (°) angles:

[0059] 7.5±0.2°, 9.6±0.2°, 11.1±0.2°, 14.3±0.2°, 15.1±0.2°, 16.2±0.2°, 18.4±0.2°, 18.6±0.2°, 20.5±0.2° and 23.1±0.2°.

[0060] In some examples, the X-ray powder diffraction pattern of the MTL-II crystal form of midostaurin has a characteristic diffraction peak at at least one of the following 2θ (°) angles:

[0061] 13.0±0.2°, 13.7±0.2°, 13.9±0.2°, 14.8±0.2°, 17.1±0.2°, 17.3±0.2°, 23.9±0.2° and 26.2±0.2°.

[0062] In some of these examples, their X-ray powder diffraction patterns have characteristic diffraction peaks at the following 2θ (°) angles:

[0063] : 7.5±0.2°, 9.6±0.2°, 11.1±0.2°, 14.3±0.2°, 15.1±0.2°, 16.2±0.2°, 18.4±0.2°, 18.6±0.2°, 20.5±0.2°, 23.1±0.2°, 13.0±0.2°, 13.7±0.2°, 13.9±0.2°, 14.8±0.2°, 17.1±0.2°, 17.3±0.2°, 23.9±0.2° and 26.2±0.2°.

[0064] In some of the examples, the 2θ (°) angle and relative intensity of the characteristic diffraction peaks in the X-ray powder diffraction pattern of the MTL-II crystal form of midostaurin are shown in Table 1 below:

[0065] Table 1

[0066] Peak number 2θ Relative Strength 1 7.5±0.2° 89.0 2 9.6±0.2° 100.0 3 11.1±0.2° 11.8 4 13.0±0.2° 4.6 5 13.7±0.2° 7.7 6 13.9±0.2° 7.3 7 14.3±0.2° 23.0 8 14.8±0.2° 7.1 9 15.1±0.2° 16.8 10 16.2±0.2° 19.9 11 17.1±0.2° 5.6 12 17.3±0.2° 5.7 13 18.4±0.2° 27.4 14 18.6±0.2° 14.8 15 20.5±0.2° 21.6 16 23.1±0.2° 14.0 17 23.9±0.2° 6.3 18 26.2±0.2° 7.8

[0067] In some of these examples, the X-ray powder diffraction pattern of the MTL-II crystalline form of midostaurin is substantially as follows: Figure 1 shown.

[0068] In some of the examples, the thermogravimetric analysis (TGA) spectrum of the MTL-II crystal form of midostaurin is substantially as follows: Figure 2 shown.

[0069] In some examples, the MTL-II crystal form of midostaurin is a non-solvent compound crystal form. Figure 3 The NMR shown in the figure verifies that the spectrum of the MTL-II crystal form of midostaurin does not contain the characteristic hydrogen and characteristic carbon peaks of the solvent used for crystallization.

[0070] In some of the examples, the total residual solvent in the MTL-II crystal form of midostaurin is less than 500 ppm. The residual solvent can be detected by GC. At the same time, it can be understood that because the GC spectrum is complex, the same sample involves multiple sheets, and the residual solvent is calculated in combination with the spectrum, the GC spectrum itself cannot directly show the residual solvent, so the GC spectrum is omitted.

[0071] In some examples, the water content of the MTL-II crystalline form of midostaurin is less than 1 wt %.

[0072] In some examples, the melting point of the MTL-II crystal form of midostaurin is 269±1° C. Further, the melting point of the MTL-II crystal form of midostaurin is 269° C.

[0073] Some other examples of the present application provide a method for preparing the MTL-II crystal form of midostaurin as described above, comprising the following steps:

[0074] S1: mixing midostaurin with a first solvent, and precipitating a solid after pulping or heating to dissolve, to prepare a first solvate of midostaurin; the first solvent is one or both of acetone and ethyl acetate;

[0075] S2: mixing the first solvate of midostaurin with a second solvent, heating to dissolve and then cooling to crystallize, to prepare the MTL-II crystal form of midostaurin; the second solvent is ethanol.

[0076] It can be understood that S1 and S2 do not represent the order of the steps, but are only used to facilitate the detailed description of the preparation method of the present application and should not be understood as a limitation on the technical solution.

[0077] Furthermore, step S1 is a crystal conversion step, in which midostaurin is converted into a first solvate of midostaurin.

[0078] In some examples, the temperature for heating and dissolving may be 30° C. to 80° C. Specifically, the temperature for heating and dissolving includes, but is not limited to, 30° C., 35° C., 40° C., 45° C., 50° C., 55° C., 60° C., 65° C., 70° C., 75° C., 80° C., or any two of the foregoing.

[0079] It is understandable that crystallization can continue for a period of time after solids are precipitated after pulping or heating and dissolving. In some examples, the time for solid precipitation is 0.5h to 3h. Furthermore, after solids are precipitated after pulping or heating and dissolving or after crystallization is completed, the steps of solid-liquid separation and drying are also included.

[0080] In some examples, the mass volume ratio of midostaurin to the first solvent is 1 g: (5-30) mL. Specifically, the mass volume ratio of midostaurin to the first solvent includes but is not limited to: 1 g: 5 mL, 1 g: 10 mL, 1 g: 15 mL, 1 g: 20 mL, 1 g: 25 mL, 1 g: 30 mL, or any two of the foregoing.

[0081] Further, step S2 is a recrystallization step, in which the first solvate of midostaurin is prepared into the MTL-II crystal form of midostaurin. Specifically, the first solvate of midostaurin is mixed with the second solvent, heated to dissolve, and then cooled to crystallize, to prepare the MTL-II crystal form of midostaurin.

[0082] In some examples, the mass volume ratio of the first solvate of midostaurin to the second solvent is 1 g: (10-30) mL. Specifically, the mass volume ratio of the first solvate of midostaurin to the second solvent includes but is not limited to: 1 g: 10 mL, 1 g: 15 mL, 1 g: 20 mL, 1 g: 25 mL, 1 g: 30 mL, or any two of the foregoing.

[0083] In some examples, the specific steps of heating to dissolve and then cooling to crystallize are heating to 60°C to 80°C to dissolve, and then cooling naturally to crystallize. Specifically, the heating temperature includes but is not limited to: 60°C, 65°C, 70°C, 75°C, 80°C or any two of the foregoing.

[0084] In some examples, after cooling and crystallization, the steps of solid-liquid separation and drying are also included. Furthermore, the specific step of drying is drying at a temperature of 80°C to 110°C. Specifically, the drying temperature includes but is not limited to: 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C or any two of the foregoing.

[0085] Some other examples of the present application provide the use of the MTL-II crystal form of midostaurin as described above in the preparation of tyrosine kinase inhibitors.

[0086] Some other examples of the present application provide the use of the MTL-II crystal form of midostaurin as described above in the preparation of a medicament having the efficacy of preventing or treating aggressive systemic mastocytosis (ASM), systemic mastocytosis with hematological tumors (SM-AHN) or mast cell leukemia (MCL).

[0087] For experimental parameters not specified in the following specific embodiments, reference is made to the instructions given in the present application document, and reference may also be made to experimental manuals in the art or other experimental methods known in the art, or to experimental conditions recommended by manufacturers.

[0088] The “stirring” in the following specific embodiments may be carried out by conventional methods in the art, for example, the stirring method includes magnetic stirring, mechanical stirring, and the stirring speed may be 50-400 rpm / min, specifically 250 rpm / min.

[0089] The raw materials and reagents involved in the following specific examples can be obtained from commercial sources, or can be prepared by those skilled in the art according to known methods.

[0090] The crude midostaurin used in the following specific examples is commercially available, or can be prepared by reacting staurosporine with benzoyl chloride or benzoic anhydride according to existing literature methods.

[0091] The X-ray powder diffraction (XRPD) instrument and test conditions involved in the following specific embodiments are as follows: The XRPD test uses an Empyrean X-ray diffractometer from Panalytical. On a single crystal silicon sample plate, a copper target is used and the XRPD test is performed according to the parameters in Table 2 below:

[0092] Table 2

[0093] Step length [°2Th.]: 0.0263 Preset time [s]: 46.65 Working current and voltage: 40mA, 45kV Scanning range [°2Th.]: 3-40

[0094] The melting point instrument model involved in the following specific embodiments is: WRS-2 microcomputer melting point instrument.

[0095] The thermogravimetric analyzer (TGA) and test conditions involved in the following specific embodiments are: the TGA model is Mettler TGA2; the test conditions are: heating rate 10°C / min, temperature range 40°C to 400°C.

[0096] The HPLC purity test conditions of the MTL-II crystal form of midostaurin involved in the following specific examples are:

[0097] Octadecyl bonded silica gel was used as filler (Agilent Eclipse Plus C18, 4.6*250mm, 5μm), mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: acetonitrile; diluent: acetonitrile; detection wavelength: 292m; flow rate: 1.0ml / min; column temperature 35℃; injection volume 10μL, gradient elution was performed as shown in Table 3 below:

[0098] Table 3

[0099] Time (minutes) A(％) B(％) 0 50 50 25 50 50 75 100 0 85 100 0

[0100] The GC solvent residual detection conditions of the MTL-II crystal form of midostaurin involved in the following specific embodiments are determined according to the residual solvent determination method (Method 0861, Part IV, General Rules, 2020 Edition of the Chinese Pharmacopoeia), and the specific chromatographic conditions are: a capillary chromatographic column with 5-phenyl-95-methylpolysiloxane as the stationary phase; programmed temperature rise: initial temperature 55°C, maintained for 1 minute, heated to 145°C at a rate of 10°C / min, and then heated to 200°C at a rate of 55°C / min, maintained for 5.0 minutes; the injection port temperature is 200°C; the detector is a hydrogen flame detector, and the detector temperature is 250°C; the column flow is 2.3 mL per minute, the split ratio is 8:1, and the injection is 1uL.

[0101] Preparation Example 1

[0102] This example is the preparation of the MTL-II crystal form of midostaurin, and the steps are as follows:

[0103] (1) Crystallization: Pour 10 g of crude midostaurin into 200 mL of acetone and heat to 35° C. with stirring. The yellow-green solid quickly dissolves and white particles quickly precipitate. The mixture cools to room temperature and continues to crystallize for 2 hours. The product is filtered, the filter cake is washed with a small amount of acetone, and dried with nitrogen.

[0104] (2) Recrystallization: The white solid obtained in step (1) was directly poured into 200 mL of anhydrous ethanol and heated to 70°C while stirring. The solid was completely dissolved. The heating was removed and the temperature was naturally reduced to crystallize. When the temperature was lowered to room temperature, a large amount of white solid precipitated. The solid was filtered and the filter cake was dried with nitrogen and then moved to a 100°C oven for drying. The vacuum was turned on for 4 hours and the solid was taken out. The solid weight was 8.7 g and stored in an aluminum-plastic ziplock bag.

[0105] The MTL-II crystal form of midostaurin prepared in Example 1 was subjected to XRPD test, melting point test and TGA test. The test results of XRPD test and TGA test are as follows: Figure 1 and Figure 2 As shown, according to Figure 1 The 2θ (°) angle and relative intensity of the characteristic diffraction peak are shown in Table 4 below. The melting point test result is 269°C.

[0106] Table 4

[0107] Peak number 2θ Relative Strength 1 7.5° 89.0 2 9.6° 100.0 3 11.1° 11.8 4 13.0° 4.6 5 13.7° 7.7 6 13.9° 7.3 7 14.3° 23.0 8 14.8° 7.1 9 15.1° 16.8 10 16.2° 19.9 11 17.1° 5.6 12 17.3° 5.7 13 18.4° 27.4 14 18.6° 14.8 15 20.5° 21.6 16 23.1° 14.0 17 23.9° 6.3 18 26.2° 7.8

[0108] In addition, the MTL-II crystal form of midostaurin prepared in Example 1 was subjected to nuclear magnetic resonance detection (the solvent was deuterated DMSO), and the results were as follows: Figure 3 As shown, it can be seen that there are no characteristic hydrogen and characteristic carbon spectral peaks of the solvent anhydrous ethanol used for crystallization in the figure.

[0109] Preparation Example 2

[0110] This example is the preparation of the MTL-II crystal form of midostaurin, and the steps are as follows:

[0111] (1) Crystallization: Pour 10 g of crude midostaurin into 250 mL of ethyl acetate and heat to 70° C. with stirring. The yellow-green solid gradually dissolves and yellow particles precipitate. The temperature is naturally cooled to room temperature and crystallization is continued for 1 hour. The product is filtered, the filter cake is washed with a small amount of ethyl acetate, and blown dry with nitrogen;

[0112] (2) Recrystallization: The white solid obtained in step (1) was directly poured into 180 mL of anhydrous ethanol and heated to 75° C. while stirring. The solid was completely dissolved. The heating was removed and the temperature was naturally reduced to crystallize. When the temperature was reduced to room temperature, a large amount of white solid precipitated. The solid was filtered and the filter cake was dried with nitrogen and then moved to a 100° C. oven for drying. The vacuum was turned on for 4 hours and the solid was taken out and weighed to obtain a solid weight of 8.7 g. The solid was stored in an aluminum-plastic ziplock bag.

[0113] Test Example 1

[0114] This test example is a GC solvent residue test of the MTL-II crystal form of midostaurin, and the steps are as follows:

[0115] (1) Take about 0.5 g of the MTL-II crystal form and the crystal form II (the crystal form II described in the original patent CN101048416A) of midostaurin prepared in Examples 1 and 2, accurately weigh them, put them in a 5 mL volumetric flask, accurately add N,N-dimethylacetamide to dissolve them, and make up to volume to prepare the test solution.

[0116] (2) Take appropriate amounts of ethanol, acetone, dichloromethane and ethyl acetate respectively, and use N,N-dimethylacetamide to quantitatively prepare a solution containing approximately 500 μg of ethanol, 500 μg of acetone, 60 μg of dichloromethane and 500 μg of ethyl acetate per mL. Seal the solution and use it as the reference solution.

[0117] (3) Determine according to the residual solvent determination method (Method 3 of Part IV General Rules 0861 of the 2020 edition of the Chinese Pharmacopoeia) and calculate the solvent residue by peak area using the external standard method.

[0118] The results are shown in Table 5. It can be seen that there is a high amount of residual solvent in the crystal form II, while the residual solvent of the MTL-II crystal form of Examples 1 to 2 is below 0.050%, which is more suitable for the application of preparations.

[0119] Table 5

[0120] Ethanol acetone Dichloromethane Ethyl acetate Benzyl alcohol Example 1 0.020％ 0.002％ Not detected Not detected Not detected Example 2 0.050％ Not detected Not detected Not detected Not detected Crystal form II Not detected Not detected Not detected Not detected 4.237％

[0121] Test Example 2

[0122] This test example is the impurity content and accelerated stability test of the MTL-II crystal form of midostaurin, and the steps are as follows:

[0123] The impurity content of the samples of the MTL-II crystal form of midostaurin prepared in Examples 1 and 2 and the crystal form II (the crystal form II described in the original research patent CN101048416A) was detected and used as the sample purity at month 0. Then, the samples were placed in a stability test box at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%, and the temperature and humidity conditions were maintained for 6 months, and the sample purity at month 6 was detected.

[0124] The results are shown in Table 6. It can be seen that the purity of Form II and the MTL-II Form of Examples 1-2 did not change significantly, the moisture content was still within the control range, and the stability was good, but the impurity content of Form II was significantly higher than that of the MTL-II Form of Examples 1-2.

[0125] Table 6

[0126]

[0127] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0128] The above-described embodiments only express several implementation methods of the present application, which is convenient for understanding the technical solution of the present application in detail, but it cannot be understood as limiting the scope of protection of the patent application. It should be pointed out that for ordinary technicians in this field, without departing from the concept of the present application, several modifications and improvements can be made, which all belong to the scope of protection of the present application. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided in the present application are all within the scope of protection of the claims attached to the present application. Therefore, the scope of protection of the patent of this application shall be based on the content of the attached claims, and the description can be used to interpret the content of the claims.

Claims

1. A MTL-II crystal form of midostaurin, characterized in that: Its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ (°) angles: 7.5±0.2°, 9.6±0.2°, 11.1±0.2°, 14.3±0.2°, 15.1±0.2°, 16.2±0.2°, 18.4±0.2°, 18.6±0.2°, 20.5±0.2° and 23.1±0.2°.

2. The MTL-II crystal form of midostaurin according to claim 1, characterized in that Its X-ray powder diffraction spectrum has a characteristic diffraction peak at at least one of the following 2θ (°) angles: 13.0±0.2°, 13.7±0.2°, 13.9±0.2°, 14.8±0.2°, 17.1±0.2°, 17.3±0.2°, 23.9±0.2° and 26.2±0.2°.

3. The MTL-II crystal form of midostaurin according to claim 2, characterized in that The 2θ(°) angle and relative intensity of the characteristic diffraction peak in its X-ray powder diffraction spectrum are shown below: The 2θ (°) angle is 7.5 ± 0.2° and the relative intensity is 89.0; The 2θ (°) angle is 9.6 ± 0.2° and the relative intensity is 100.0; The 2θ(°) angle is 11.1±0.2° and the relative intensity is 11.8; The 2θ(°) angle is 13.0±0.2° and the relative intensity is 4.6; The 2θ(°) angle is 13.7±0.2° and the relative intensity is 7.7; The 2θ(°) angle is 13.9±0.2° and the relative intensity is 7.3; The 2θ (°) angle is 14.3 ± 0.2° and the relative intensity is 23.0; The 2θ (°) angle is 14.8 ± 0.2° and the relative intensity is 7.1; The 2θ(°) angle is 15.1±0.2° and the relative intensity is 16.8; The 2θ(°) angle is 16.2±0.2° and the relative intensity is 19.9; The 2θ(°) angle is 17.1±0.2° and the relative intensity is 5.6; The 2θ(°) angle is 17.3±0.2° and the relative intensity is 5.7; The 2θ (°) angle is 18.4 ± 0.2° and the relative intensity is 27.4; The 2θ (°) angle is 18.6 ± 0.2° and the relative intensity is 14.8; The 2θ (°) angle is 20.5 ± 0.2° and the relative intensity is 21.6; The 2θ (°) angle is 23.1 ± 0.2° and the relative intensity is 14.0; The 2θ(°) angle is 23.9±0.2° and the relative intensity is 6.3; The 2θ(°) angle was 26.2±0.2° and the relative intensity was 7.

8.

4. The MTL-II crystal form of midostaurin according to claim 3, characterized in that Its X-ray powder diffraction spectrum is substantially as shown in FIG1 , and / or its thermogravimetric analysis spectrum is substantially as shown in FIG2 .

5. The MTL-II crystal form of midostaurin according to any one of claims 1 to 4, characterized in that The MTL-II crystal form of midostaurin is a non-solvent compound crystal form.

6. The MTL-II crystal form of midostaurin according to any one of claims 1 to 4, characterized in that The MTL-II crystal form of midostaurin has one or more of the following characteristics: (1) The total residual solvent is less than 500 ppm; (2) The moisture content is less than 1 wt%.

7. The MTL-II crystal form of midostaurin according to any one of claims 1 to 4, characterized in that Its melting point is 269±1℃.

8. The method for preparing the MTL-II crystal form of midostaurin according to any one of claims 1 to 7, characterized in that: The steps include: Mixing midostaurin with a first solvent, and subjecting the mixture to pulping or heating for dissolution to precipitate a solid, to prepare a first solvate of midostaurin; wherein the first solvent is one or both of acetone and ethyl acetate; The first solvate of midostaurin is mixed with a second solvent, heated to dissolve, and then cooled to crystallize to prepare the MTL-II crystal form of midostaurin; the second solvent is ethanol.

9. The method for preparing the MTL-II crystal form of midostaurin according to claim 8, characterized in that: In the step of preparing the first solvate of midostaurin, the temperature of heating and dissolving is 30° C. to 80° C., the mass volume ratio of midostaurin to the first solvent is 1 g: (5 to 30) mL, and the time for precipitating the solid is 0.5 h to 3 h; and / or, In the step of preparing the MTL-II crystal form of midostaurin from the first solvate of midostaurin, the mass volume ratio of the first solvate of midostaurin to the second solvent is 1g: (10-30)mL, and the specific steps of heating to dissolve and then cooling to crystallize are heating to 60°C-80°C to dissolve, and then naturally cooling to crystallize.

10. Use of the MTL-II crystal form of midostaurin according to any one of claims 1 to 7 in the preparation of tyrosine kinase inhibitors.

11. Use of the MTL-II crystal form of midostaurin according to any one of claims 1 to 7 in the preparation of a medicament for preventing or treating aggressive systemic mastocytosis, systemic mastocytosis associated with hematological tumors, or mast cell leukemia.

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