Crystal of crystal form AB, and preparation method, pharmaceutical composition and application thereof

Abstract

The invention relates to the technical field of pharmacy, and provides a crystal of a compound 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl) carbamoyl] cyclopropanecarbonyl] amino] phenoxy]-6-methoxy-7-quinolyl] oxy] hexanoic acid crystal form AB for treating protein kinase AXL and / or VEGFR2 related diseases as well as a preparation method, a pharmaceutical composition and application of the crystal of the compound 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl) carbamoyl] cyclopropanecarbonyl] amino] phenoxy]-6-methoxy-7-quinolyl] oxy] hexanoic acid crystal form AB. The crystal provided by the invention not only has large particle size and uniform particle size distribution, greatly shortens the separation and purification time of the compound, but also has the advantages of less solvent inclusion, high purity, high tap density and high compressibility. Comparative study shows that if the particle size is lower than the numerical range, the defect of difficult separation still exists, and if the particle size is higher than the numerical range, the solvent in the crystal is seriously wrapped and cannot be removed by a drying method.

Description

[0001] This application requires:

[0002] The priority right of the prior application, patent application number 202311433883.0, entitled “Crystals of Form AB and preparation methods, pharmaceutical compositions, and applications thereof”, filed with the State Intellectual Property Office of China on October 31, 2023;

[0003] The entire content of this prior application is incorporated into this application by reference. Technical Field

[0004] The present application relates to the field of pharmaceutical technology, and specifically to a crystal of the crystalline form AB of the compound 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoic acid and a preparation method thereof, a pharmaceutical composition containing the crystal, and use of the crystal in treating diseases caused by abnormal activity of protein kinase AXL and / or VEGFR2. Background Art

[0005] 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoic acid is an anti-tumor drug that mainly acts on AXL and vascular endothelial growth factor receptor 2 (VEGFR2 or KDR). It is a new type of multi-target receptor tyrosine kinase inhibitor and is suitable for a variety of clinical indications such as acute myeloid leukemia, colon cancer, gastric cancer, lung cancer, thyroid cancer, prostate cancer, hepatocellular carcinoma, and kidney cancer. The chemical structure of 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoic acid is shown in the following compound 1.

[0006]

[0007] International application WO2018 / 072614A1 discloses compound 1 as an inhibitor of protein kinase AXL and / or VEGFR2, and Chinese application CN112119062A discloses crystalline form AB of compound 1, which can be used to treat diseases (such as tumors, etc.) caused by abnormal activity of these two kinases.

[0008] However, during the engineering scale-up production process of the above-mentioned crystal form, the particle size of crystal form AB is very small and the particle size distribution is uneven, which makes the subsequent post-processing filtration and drying very difficult. Usually, the separation and filtration operation alone takes several days, which becomes a key rate-limiting step affecting the preparation of the drug. Therefore, it is necessary to further study the crystal form AB of compound 1. Summary of the invention

[0009] In view of this, the present application provides crystals of form AB of the compound 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoic acid and their preparation methods, pharmaceutical compositions, and applications, in order to solve the problems of small particle size, uneven distribution, and difficult separation of existing form AB particles.

[0010] In a first aspect, the present application provides a crystal of Form AB of Compound 1, wherein the crystal satisfies the following characteristics:

[0011]

[0012] The crystals are spherical or quasi-spherical, and the particle size D90 of the crystals is 114 μm to 153 μm;

[0013] The X-ray powder diffraction pattern of the crystalline form AB expressed in 2θ angle has diffraction peaks at 4.6±0.1°, 6.7±0.1°, 10.7±0.1°, 16.2±0.1°, 17.0±0.1°, 17.4±0.1°, 19.5±0.1°, 20.7±0.1°, 21.9±0.1°, 22.5±0.1°, 23.8±0.1°, and 25.1±0.1°;

[0014] The X-ray powder diffraction pattern of the crystal form AB expressed in 2θ angles is as follows Figure 1 shown.

[0015] In combination with the first aspect, the angle of repose of the crystals is 39.45° to 40.22°; and the tap density of the crystals is 0.207 mg / mL to 0.247 mg / mL.

[0016] In a second aspect, the present application provides a method for preparing a crystal of Form AB of Compound 1, the method comprising the following steps:

[0017] Under cooling conditions and first stirring conditions, a solution containing compound 1 and a solution containing seed crystals of form AB of compound 1 are mixed to obtain a mixture, and the mixture is stirred and crystallized under second stirring conditions, and solid-liquid separation and drying are performed to obtain crystals;

[0018] The cooling temperature of the cooling condition is -20°C to 0°C, preferably -15°C to 0°C;

[0019] The rotation speed of the first stirring condition is 300 rpm to 1000 rpm, preferably 300 rpm to 700 rpm;

[0020] The rotation speed of the second stirring condition is 60 rpm to 200 rpm, preferably 70 rpm to 170 rpm;

[0021] The mass of the added seed crystals is 0.3% to 2.5% of the mass of the added compound 1.

[0022] In some embodiments, the preparation method comprises the following steps:

[0023] Under cooling conditions and first stirring conditions, mixing seed crystals of the crystalline form AB of compound 1 and solvent B to obtain a suspension containing seed crystals, and then adding the solution containing compound 1 to the suspension to obtain a mixture;

[0024] The time for stirring and crystallizing the mixture under the second stirring condition is 8 hours to 48 hours.

[0025] In some embodiments, after all the solution containing compound 1 is added to the suspension to obtain a mixture, the stirring speed is kept unchanged, and the obtained mixture is continuously stirred for 10 min to 120 min, preferably for 30 min to 120 min, and then stirred and crystallized under the second stirring condition.

[0026] In some embodiments, the solvent B is selected from at least one of a C2-C4 alcohol solvent, a C2-C4 ketone solvent, and a C2-C4 ester solvent; the mass volume ratio (g / mL) of the seed crystal of the crystalline form AB of the compound 1 to the solvent B is 1:(20-100).

[0027] In some embodiments, the solution containing Compound 1 is prepared according to the following method:

[0028] Dissolving the compound 1 in solvent A to obtain a solution containing the compound 1;

[0029] The solvent A comprises at least one of a C1-C4 halogenated alkane solvent, a C1-C2 alcohol solvent, a C3-C6 cyclic ether solvent and water; preferably, the solvent A is a mixed solution of dichloromethane / methanol, and the volume ratio of dichloromethane to methanol in the mixed solution of dichloromethane / methanol is (10-1):1;

[0030] The mass volume ratio (g / mL) of the compound 1 to the solvent A is 1:(4-40).

[0031] In some embodiments, the solid-liquid separation method is selected from at least one of filtration and centrifugation; the drying method is selected from vacuum drying; and the drying temperature is 30°C to 60°C.

[0032] In a third aspect, the present application provides a pharmaceutical composition, comprising the crystals described in the first aspect or the crystals prepared in the second aspect and a pharmaceutically acceptable carrier.

[0033] In a fourth aspect, the present application provides use of the crystals described in the first aspect or the crystals prepared in the second aspect and the pharmaceutical composition described in the third aspect in the preparation of a drug for treating diseases caused by abnormal activity of protein kinase AXL and / or VEGFR2.

[0034] This application has the following beneficial effects:

[0035] The crystals of the crystal form AB of the present application are spherical or quasi-spherical agglomerates formed by the agglomeration of small-diameter crystal particles, which have good chemical stability during subsequent processing. The particles are large in size, evenly distributed, and have good fluidity and compressibility. They can improve the filtration, separation and drying efficiency of the crystals, improve production efficiency while reducing preparation costs, and enhance the application development scenarios of the crystal form AB for finished preparations.

[0036] The crystals of the present application are placed at 65°C ± 2°C for 3 months, and both physical and chemical stability are good.

[0037] The preparation method of the crystals of the present application is simple and easy, can be stably and mass-produced, and is conducive to popularization and application. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 is the XRPD pattern of Form AB of Compound 1;

[0039] Figure 2 is a SEM image of the crystal of Form AB of Compound 1;

[0040] Figure 3 The XRPD pattern of the crystals prepared in Example 3;

[0041] Figure 4 These are the TGA and DSC spectra of the crystals prepared in Example 3. DETAILED DESCRIPTION

[0042] In order to better understand the technical solution of the present application, the embodiments of the present application are described in detail below with reference to the accompanying drawings.

[0043] It should be clear that the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present application.

[0044] The terms used in the embodiments of the present application are only for the purpose of describing specific embodiments, and are not intended to limit the present application. The singular forms "a", "said" and "the" used in the embodiments of the present application and the appended claims are also intended to include plural forms, unless the context clearly indicates other meanings.

[0045] It should be understood that the term "and / or" used in this article is only a description of the association relationship of associated objects, indicating that there can be three relationships. For example, A and / or B can represent: A exists alone, A and B exist at the same time, and B exists alone. In addition, the character " / " in this article generally indicates that the associated objects before and after are in an "or" relationship.

[0046] The crystalline form AB of 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoic acid (hereinafter referred to as compound 1) is disclosed in CN112119062A.

[0047] The X-ray powder diffraction pattern of the crystal form AB of the present application expressed in 2θ angles has diffraction peaks at 4.6±0.1°, 6.7±0.1°, 10.7±0.1°, 16.2±0.1°, 17.0±0.1°, 17.4±0.1°, 19.5±0.1°, 20.7±0.1°, 21.9±0.1°, 22.5±0.1°, 23.8±0.1°, and 25.1±0.1°;

[0048] Preferably, the X-ray powder diffraction pattern of Form AB expressed in 2θ angle is 4.6±0.1°, 6.7±0.1°, 9.3±0.1°, 9.7±0.1°, 10.7±0.1°, 11.6±0.1°, 13.4±0.1°, 13.8±0.1°, 15.3±0.1°, 16.2±0.1°, 17.0±0.1°, 17.4±0.1°, 18.6±0.1°, 19. .5±0.1°, 20.7±0.1°, 21.9±0.1°, 22.3±0.1°, 22.5±0.1°, 23.4±0.1°, 23.8±0.1°, 24.4±0.1°, 25.1±0.1°, 26.0±0.1°, 26.8±0.1°, 27.7±0.1°, 29.7±0.1°, 32.8±0.1°, and 33.1±0.1° have diffraction peaks;

[0049] More preferably, the X-ray powder diffraction pattern of Form AB expressed in 2θ angles is as follows Figure 1 shown.

[0050] However, during the subsequent research on Form AB, the inventors found that the crystal particles of Form AB were too small, the particle size distribution was extremely uneven, and the fluidity was poor, making it extremely difficult to filter and purify Form AB. In the scale-up process, the filtration step alone required several days. Such a long solid-liquid coexistence state caused uncontrollable phenomena in the system, which became the key rate-limiting step in the preparation of the drug.

[0051] After numerous experiments, the inventor unexpectedly obtained a crystal of AB crystal form. The experimental characterization proved that the crystal is an agglomerate of AB crystal form, spherical or quasi-spherical in shape, with a rounded morphology and a particle size D90 of 114μm to 153μm. Compared with the AB crystal form particles prepared in the prior art, the crystal has the following extremely excellent properties: not only the particle size is large and the particle size distribution is uniform, which greatly shortens the separation and purification time of the compound, but also it has less solvent inclusions, high purity, and high tap density and compressibility. Comparative studies have shown that if the particle size is lower than the above numerical range, there is still a defect of difficulty in separation, and if it is higher than the above numerical range, the solvent inclusions inside the crystal are serious and cannot be removed by drying methods.

[0052] In some embodiments, the particle size D90 of the crystals is 114 μm to 153 μm, specifically 114 μm, 120 μm, 125 μm, 128 μm, 133 μm, 138 μm, 143 μm, 148 μm, 150 μm or 153 μm, etc., and of course other values ​​within the above range, which are not limited in this application. D90 refers to the particle size corresponding to when the cumulative particle size distribution number of the sample reaches 90%. The particle size D90 of the crystals is limited to the above range, indicating that the proportion of crystals with a particle size of 114 μm to 153 μm is 90%, indicating that the crystals of the present application have a larger particle size and are evenly distributed.

[0053] In some embodiments, the angle of repose of the crystal is 39.45° to 40.22°, specifically 39.45°, 39.55°, 39.60°, 39.75°, 39.88°, 40.00°, 40.15° or 40.22°, etc. Of course, it can also be other values ​​within the above range, and the present application does not limit it here. The angle of repose, also known as the angle of repose, is the minimum angle with the horizontal surface when the inclined plane makes the object placed on it in a critical state of sliding down the inclined plane (that is, as the inclination angle increases, the object on the inclined plane will slide more easily; when the object reaches the state of starting to slide, the angle of the critical state is called the angle of repose). The angle of repose of the crystals of the present application is within the above range, indicating that the fluidity of the crystals of the present application is relatively strong. When the crystals are pressed into tablets or prepared as capsules, the crystals can flow freely during the production process, which is conducive to material molding and improves the uniformity of material distribution of the crystals in the process of preparing the medicine. In some embodiments, the crystals of the present application can be directly compressed into tablets during post-processing, and the drying and granulation steps can be omitted, greatly improving the industrial production efficiency of the crystals.

[0054] In some embodiments, the tap density of the crystal is 0.207 mg / mL to 0.247 mg / mL, specifically 0.207 mg / mL, 0.215 mg / mL, 0.228 mg / mL, 0.232 mg / mL, 0.238 mg / mL or 0.247 mg / mL, and of course other values ​​within the above range, which are not limited in this application. Within the above-defined range, it is shown that the crystal of the present application has good fluidity and significant tapping effect, which is conducive to improving the processing efficiency of the crystal in preparing finished pharmaceutical products.

[0055] The present application also provides a method for preparing the above-mentioned crystal, comprising the following steps:

[0056] Step S100: adding compound 1 into solvent A to dissolve it, thereby obtaining a first precursor.

[0057] In some embodiments, Compound 1 can be dissolved in Solvent A with the aid of heating.

[0058] In some embodiments, solvent A includes at least one of a C1-C4 halogenated alkane solvent, a C1-C2 alcohol solvent, a C3-C6 cyclic ether solvent and water; preferably, solvent A includes a mixture of one or more of dichloromethane, methanol, ethanol, tetrahydrofuran and water, and more preferably a mixed solution of dichloromethane / methanol. The above solvents have good solubility for compound 1. Among them, the volume ratio of dichloromethane and methanol in the mixed solution of dichloromethane / methanol is (10-1):1, specifically 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 and 1:1, etc., preferably (8-1):1, more preferably (5-1):1, and more preferably (4-2):1.

[0059] In some embodiments, the mass volume ratio (g / mL) of compound 1 and solvent A is 1:(4-40), specifically 1:4, 1:5, 1:6, 1:7, 1:10, 1:15, 1:20, 1:30 or 1:40, etc., and of course, it can also be other values ​​within the above range, which is not limited in this application. Preferably, it is 1:(5-20), more preferably 1:(6-15), and more preferably 1:(7-10).

[0060] Step S200: Under cooling conditions and first stirring conditions, the seed crystals of the crystalline form AB of compound 1 and solvent B are mixed to obtain a suspension containing the seed crystals, and then the first precursor in step S100 is added to the suspension to obtain a mixture, and the mixture is stirred and crystallized under second stirring conditions.

[0061] In some embodiments, the first precursor is added to the suspension by dropping or pumping with a feeding pump.

[0062] In some embodiments, after all the materials obtained in step S100 are added to the suspension to obtain a mixture, the stirring speed is kept unchanged, the obtained mixture is continuously stirred for 10 min to 120 min, and then stirred under the second stirring condition.

[0063] In the above steps, the stirring time may be 10 min, 30 min, 50 min, 80 min, 100 min, 120 min, etc., and may be other values ​​within the above range, which are not limited in the present application. Preferably, it is 30 min to 90 min, and more preferably, it is 30 min to 60 min.

[0064] In some embodiments, the rotation speed of the first stirring condition is 300 rpm to 1000 rpm, specifically 300 rpm, 400 rpm, 500 rpm, 600 rpm, 700 rpm, 800 rpm, 900 rpm or 1000 rpm, etc., and of course, other values ​​within the above range are also possible, and the present application does not limit this. Preferably, it is 300 rpm to 700 rpm, and more preferably, it is 300 rpm to 500 rpm.

[0065] In some embodiments, the rotation speed of the second stirring condition is 60 rpm to 200 rpm, specifically 60, 70 rpm, 100 rpm, 120 rpm, 150 rpm, 170 rpm or 200 rpm, etc., and of course other values ​​within the above range are also possible, and the present application does not limit this. Preferably, it is 70 rpm to 170 rpm, and more preferably, it is 70 rpm to 150 rpm.

[0066] The rotation speed of the first stirring condition of the present application is greater than the rotation speed of the second stirring condition, that is, the present application mixes compound 1 and the seed crystals of crystal form AB under higher stirring speed and then reduces the stirring speed. Such a setting is conducive to the agglomeration of small-size particles to form spherical agglomerates.

[0067] In some embodiments, the time for stirring and crystallizing the mixture under the second stirring condition is 8 hours to 48 hours, specifically 8 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours and 48 hours, etc., and of course other values ​​within the above range can also be used, and the present application does not limit this. Preferably, it is 12 hours to 36 hours, and more preferably, it is 18 hours to 30 hours.

[0068] In some embodiments, the cooling temperature of the cooling condition is -20°C to 0°C, specifically -20°C, -15°C, -10°C, -5°C, -3°C and 0°C, etc., and of course, other values ​​within the above range can also be used, and the present application does not limit this. Preferably, it is -15°C to 0°C, and more preferably, it is -15°C to -5°C.

[0069] In some embodiments, the mass of the added seed crystal is 0.3% to 2.5% of the mass of the added compound 1, specifically 0.3%, 0.4%, 0.8%, 1.0%, 1.5%, 2.0% and 2.5%, etc., and of course, it can also be other values ​​within the above range, which are not limited in this application. Preferably, it is 0.4% to 2.0%, more preferably 0.4% to 1.5%, and more preferably 0.4% to 1.0%.

[0070] In some embodiments, solvent B is selected from at least one of C2-C4 alcohol solvents, C2-C4 ketone solvents and C2-C4 ester solvents, preferably ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, ethyl acetate, and more preferably ethanol, n-propanol and isopropanol.

[0071] In some embodiments, the mass volume ratio (g / mL) of the seed crystal of the crystalline form AB of compound 1 to the solvent B is selected from 1: (20-100), specifically 1: 20, 1: 40, 1: 60, 1: 80, 1: 85, 1: 90 and 1: 100, etc., and of course, it can also be other values ​​within the above range, which are not limited in this application. Preferably, it is 1: (40-90), more preferably 1: (60-85), and more preferably 1: (65-80).

[0072] Step S300: The material obtained in step S200 is subjected to solid-liquid separation and drying to obtain crystals.

[0073] In some embodiments, the solid-liquid separation method includes one of filtration and centrifugation.

[0074] In some embodiments, the drying method is vacuum drying.

[0075] In some embodiments, the drying temperature is 30°C to 60°C, specifically 30°C, 35°C, 40°C, 45°C, 50°C, 55°C or 60°C, etc., and of course other values ​​within the above range are also possible, and the present application does not limit this. Preferably, it is 45°C to 50°C.

[0076] In some embodiments, the drying time is 16 h to 24 h, specifically 16 h, 18 h, 20 h, 22 h or 24 h, etc. Of course, it can also be other values ​​within the above range, and the present application does not limit it here.

[0077] The present application provides a pharmaceutical composition, which comprises the above-mentioned crystal or the crystal prepared by the above-mentioned preparation method and a pharmaceutically acceptable carrier.

[0078] The present application also provides the use of the above crystal or the crystal prepared by the above preparation method or the above pharmaceutical composition containing the crystal in the preparation of a drug for treating a disease (such as a tumor or cancer) caused by abnormal activity of protein kinase AXL and / or VEGFR2. Specifically, the above crystal or the crystal prepared by the above preparation method or the above pharmaceutical composition containing the crystal can be used to treat thyroid cancer (including medullary thyroid cancer), gastric cancer, esophageal cancer, kidney cancer (including renal carcinoma), liver cancer (including hepatocellular carcinoma), ovarian cancer, cervical cancer, colorectal cancer, small intestine cancer, brain cancer (including astrocytic tumors, including: malignant glioma, giant cell malignant glioma, gliosarcoma and malignant glioma with oligodendroglial components), leukemia, lung cancer (including non-small cell lung cancer), bone cancer, prostate cancer (including castration-resistant prostate cancer), pancreatic cancer, skin cancer, lymphoma, solid tumor, Hodgkin's disease or non-Hodgkin's lymphoma. The present application also provides a method for treating a disease caused by abnormal activity of protein kinase AXL and / or VEGFR2, the method comprising administering the above crystal or the crystal prepared by the above preparation method or the above pharmaceutical composition comprising the crystal to a subject.

[0079] The pharmaceutical composition described in the present application can be prepared into various dosage forms, including but not limited to various oral preparations; preferably, the pharmaceutical composition is a tablet or capsule.

[0080] The present application is further described below through specific embodiments.

[0081] Example 1

[0082] The preparation method of compound 1 is shown in Example 9 of compound patent WO 2018 / 072614 A1. Specifically, the preparation method of compound 1 is as follows.

[0083]

[0084] Under stirring, NaOH (4.4 g, 110 mmol) was added dropwise to a solution of methyl 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoate (IV-1, 35.0 g, 55.2 mmol, prepared according to the method described in WO2013 / 040801A1) in ethanol (350 mL). After the addition was complete, water (50 mL) was added. The resulting mixture was stirred at 20-25°C for 18 h, the reaction solution was diluted with water (100 mL), stirred for 20 min, and the pH was adjusted to 3-4 with 1N HCl. The reaction mixture was concentrated under reduced pressure to distill off about 300 mL of ethanol. The solid product was collected by filtration to give 28.4 g of crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate:methanol = 1:1, v / v) to give 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoic acid (Compound 1), 9.6 g (yield: 28.1%).

[0085] Analytical data of compound 1: molecular weight 619.61; H-NMR spectrum data are as follows:

[0086] 1 H-NMR(δ,DMSO-d6,400MHz):12.03(s,1H,OH),10.40(s,1H,NH),10.02(s,1H,NH),8.47~8.46(d,J=4,1 H,CH),7.89-7.92(d,J=12,1H,CH),7.63-7.67(d,J=16,2H,2CH),7.51-7.52(d,J=4,2H,2CH),7.39-7. 43(t,2H,2CH),7.13-7.17(t,2H,2CH),6.41-6.42(d,J=4,1H,CH),4.12-4.15(t,2H,CH2),3.95(s,3H, CH3),2.24-2.28(t,2H,CH2),1.78-1.85(m,2H,CH2),1.57-1.64(m,2H,CH2),1.43-1.51(m,6H,3CH2).

[0087] Example 2

[0088] The preparation method of the crystalline form AB of compound 1 can be found in Example 2 or 3 of the crystalline form patent CN112119062A. Specifically, the preparation method of the crystalline form AB of compound 1 is as follows.

[0089] 200.0 g of compound 1 prepared according to the method of Example 1 was weighed and added to 11 L of anhydrous ethanol. The mixture was mechanically stirred and heated to 75-80° C. to dissolve compound 1. The mixture was cooled to -10° C. to precipitate solids. The mixture was stirred at -10±2° C. for 4 h. A large amount of solids precipitated. The mixture was filtered under reduced pressure and the filter cake was vacuum dried at 55-60° C. for 10 h to obtain 170.0 g of crystals.

[0090] Weigh 2.0 g of compound 1, add it to 12 mL of a mixed solvent of tetrahydrofuran / water (95v:5v), heat to reflux until all the solids are dissolved, then cool the solution to 40±2°C, and the resulting solution is referred to as solution A. Add 80 mL of ethanol to the reaction flask, cool it to -10±2°C, and then add the crystals obtained above to ethanol and stir to form a solid-liquid suspension B. Add solution A dropwise to the solid-liquid suspension B, and control the temperature during the addition process within the range of -10 to -5°C; after the addition is complete, stir and crystallize at a temperature of -10 to -5°C for about 4 hours. Filter under reduced pressure and dry to obtain 1.45 g of crystals, which are form AB, and its X-ray powder diffraction (XRPD) spectrum is shown below: Figure 1 shown.

[0091] The crystal form AB obtained by the above method is irregular crystalline particles with extremely uneven particle size distribution. Experimental tests show that its D90 is 24μm, the angle of repose is 47.14°, and the tap density is 0.187mg / mL. Because the crystalline particles are too small and there are a large number of nano-sized crystal particles, it is extremely difficult to filter under reduced pressure and the filtration device is repeatedly blocked. Later, during the pilot scale-up process according to this method, it was found that only the filtration operation step took several days to complete, which led to the generation of uncontrollable factors in the process.

[0092] Example 3

[0093] Preparation of Form AB of Compound 1

[0094] (1) About 20.0 g of the compound 1 of Example 1 was taken, 170 mL of a dichloromethane / methanol mixed solvent with a volume ratio of 3:1 was added, and heated to dissolve.

[0095] (2) Add 1440 mL of isopropanol to the crystallizer, then cool to -13°C, add 0.1 g of AB crystal seed of Example 2, stir at 300 rpm for 30 min, then add the material obtained in step (1) dropwise to the crystallizer, stir for 30 min, then reduce the stirring to 70 rpm, and stir at a constant temperature for 24 h.

[0096] (3) The suspension obtained in step (2) was filtered. The filtration was relatively smooth without clogging the filter device. The obtained solid product was dried under reduced pressure in a vacuum drying oven at 40° C. for 24 h. The obtained dried solid particles were crystals.

[0097] The SEM image of the crystal prepared in Example 3 is as follows: Figure 2 As shown, Figure 2 It can be seen that the crystals prepared in Example 3 have a spherical appearance. After measurement, D90 is 153 μm, the angle of repose is 37.65°, and the tap density is 0.247 mg / mL.

[0098] The crystals prepared in Example 3 were measured using a powder X-ray diffraction (PXRD) instrument to obtain the following Figure 3 The XRPD spectrum shows that the diffraction peaks of the crystals prepared in Example 3 and the crystal form AB are the same. The crystals prepared in Example 3 were measured by differential scanning calorimetry, and the following results were obtained: Figure 4 The TGA spectrum and DSC spectrum of the crystalline form AB are shown. The above characterization data indicate that the crystalline form prepared in Example 3 is a high-purity AB crystalline form.

[0099] Example 4

[0100] Preparation of Form AB of Compound 1

[0101] (1) About 5.0 g of the compound 1 of Example 1 was taken, 42 mL of a dichloromethane / methanol mixed solvent with a volume ratio of 3:1 was added, and heated to dissolve.

[0102] (2) Add 360 mL of isopropanol to the crystallizer, then cool to -15°C, add 0.025 g of AB crystal seed of Example 2, stir at 500 rpm for 10 min, then add the material obtained in step (1) dropwise to the crystallizer, stir for 5 min, then reduce the stirring to 150 rpm, and stir at a constant temperature for 24 h.

[0103] (3) The suspension obtained in step (2) was filtered. The filtration was relatively smooth without clogging the filter device. The obtained solid product was dried under reduced pressure in a vacuum drying oven at 40° C. for 24 h. The obtained dried solid particles were crystals.

[0104] The crystals prepared in this example are spherical in appearance, and after measurement, D90 is 114 μm, the angle of repose is 39.45°, and the tap density is 0.207 mg / mL. The crystal form prepared in Example 4 is identified as a high-purity AB crystal form.

[0105] Example 5

[0106] Preparation of Form AB of Compound 1

[0107] (1) About 5.0 g of the compound 1 of Example 1 was taken, 42 mL of a dichloromethane / methanol mixed solvent with a volume ratio of 3:1 was added, and heated to dissolve.

[0108] (2) Add 360 mL of isopropanol to the crystallizer, then cool to -14°C, add 0.025 g of AB crystal seed of Example 2, stir at 400 rpm for 3 min, then add the material obtained in step (1) dropwise to the crystallizer, stir for 5 min, then reduce the stirring to 100 rpm, and stir at a constant temperature for 24 h.

[0109] (3) The suspension obtained in step (2) was filtered. The filtration was relatively smooth without clogging the filter device. The obtained solid product was dried under reduced pressure in a vacuum drying oven at 40° C. for 24 h. The obtained dried solid particles were crystals.

[0110] The crystals prepared in this example are spherical in appearance, and after measurement, D90 is 133 μm, the angle of repose is 40.22°, and the tap density is 0.223 mg / mL. The crystal form prepared in Example 5 is identified as a high-purity AB crystal form.

[0111] Example 6

[0112] The difference from Example 3 is that step (2) is:

[0113] 1440 mL of isopropanol was added to the crystallizer, and then the temperature was lowered to -13°C. 0.1 g of AB crystal seed of Example 2 was added, and the mixture was stirred at 300 rpm for 30 min. The material obtained in step (1) was then added dropwise to the crystallizer. After stirring for 30 min, the stirring was reduced to 80 rpm and stirred at a constant temperature for 24 h.

[0114] The crystal prepared in Example 6 is spherical in appearance, with a D90 of 145 μm, a repose angle of 39.52°, and a tap density of 0.230 mg / mL. The crystal prepared in Example 6 is identified as a high-purity AB crystal.

[0115] Comparative Example 1

[0116] The difference from Example 3 is that step (2) is:

[0117] 1440 mL of isopropanol was added to the crystallizer, and then the temperature was lowered to -13°C. 0.1 g of AB crystal seed of Example 2 was added, and the mixture was stirred at 200 rpm for 30 min. The material obtained in step (1) was then added dropwise to the crystallizer. After stirring for 30 min, the stirring was reduced to 70 rpm and stirred at a constant temperature for 24 h.

[0118] The crystals prepared in Comparative Example 1 had an irregular appearance and contained a large number of fine crystal particles. The filtration time was relatively long and the filtration device was blocked. The D90 was measured to be 56 μm, the angle of repose was 58.12°, and the tap density was 0.198 mg / mL.

[0119] Comparative Example 2

[0120] The difference from Example 3 is that step (2) is:

[0121] 1440 mL of isopropanol was added to the crystallizer, and then the temperature was lowered to -13°C. 0.6 g of AB crystal seed of Example 2 was added, and the mixture was stirred at 300 rpm for 30 min. The material obtained in step (1) was then added dropwise to the crystallizer. After stirring for 30 min, the stirring was reduced to 70 rpm and stirred at a constant temperature for 24 h.

[0122] The crystals prepared in Comparative Example 2 had an irregular appearance and contained a large number of fine crystal particles. The filtration time was relatively long and the filtration device was blocked. The D90 was measured to be 44 μm, the angle of repose was 63.12°, and the tap density was 0.190 mg / mL.

[0123] Comparative Example 3

[0124] The difference from Example 3 is that step (2) is:

[0125] 1440 mL of isopropanol was added to the crystallizer, and then the temperature was lowered to -13°C. 0.04 g of AB crystal seed of Example 2 was added, and the mixture was stirred at 300 rpm for 30 min. The material obtained in step (1) was then added dropwise to the crystallizer. After stirring for 30 min, the stirring was reduced to 70 rpm and stirred at a constant temperature for 24 h.

[0126] The crystals prepared in Comparative Example 3 had an irregular appearance and contained fine crystal particles. The filtration time was relatively long and the filtration device was blocked. The D90 was measured to be 90 μm, the angle of repose was 38.42°, and the tap density was 0.196 mg / mL.

[0127] Comparative Example 4

[0128] The difference from Example 3 is that step (2) is:

[0129] 1440 mL of isopropanol was added to the crystallizer, and then the temperature was lowered to -13°C. 0.1 g of AB crystal seed of Example 2 was added, and the mixture was stirred at 300 rpm for 30 min. The material obtained in step (1) was then added dropwise to the crystallizer. After stirring for 30 min, the stirring was reduced to 50 rpm and stirred at a constant temperature for 24 h.

[0130] The crystals prepared in Comparative Example 4 have an irregular spherical appearance, with a measured D90 of 303 μm, an angle of repose of 37.80°, and a tap density of 0.203 mg / mL. Although the crystals are relatively easy to separate, they are severely entrapped by solvents, and the entrapped solvent cannot be removed in the subsequent drying step.

[0131] Comparative Example 5

[0132] The difference from Example 3 is that step (2) is:

[0133] 1440 mL of isopropanol was added to the crystallizer, and then the temperature was lowered to -13°C. 0.1 g of AB crystal seed of Example 2 was added, and the mixture was stirred at 300 rpm for 30 min. The material obtained in step (1) was then added dropwise to the crystallizer. After stirring for 30 min, the stirring speed was maintained at 300 rpm and stirred at a constant temperature for 24 h.

[0134] The crystals prepared in Comparative Example 5 had an irregular appearance and contained a large number of fine crystal particles. The filtration time was relatively long and the filtration device was blocked. The D90 was measured to be 86 μm, the angle of repose was 42.34°, and the tap density was 0.185 mg / mL.

[0135] Comparative Example 6

[0136] The difference from Example 3 is that step (2) is:

[0137] 1440 mL of isopropanol was added to the crystallizer, and then the temperature was lowered to -13°C. 0.1 g of AB crystal seed of Example 2 was added, and the mixture was stirred at 300 rpm for 30 min. The material obtained in step (1) was then added dropwise to the crystallizer. After stirring for 30 min, the stirring speed was increased to 800 rpm, and the mixture was stirred at a constant temperature for 24 h.

[0138] The crystals prepared in Comparative Example 6 had an irregular appearance and contained a large number of fine crystal particles. The filtration time was relatively long and the filtration device was blocked. The D90 was measured to be 52 μm, the angle of repose was 44.17, and the tap density was 0.174 mg / mL.

[0139] Table 1 shows the crystal particle size data, repose angle, tap density and crystal purity generated at different stirring rates in step (2) in Examples 3 to 6 and Comparative Examples 4 to 6:

[0140]

[0141] According to Table 1, under the preferred crystallization conditions of the present application, the obtained crystals have a reasonable particle size, a rounded spherical or quasi-spherical shape, a high tap density, and are high-purity AB crystals. As the stirring rate of the second stirring condition in step (2) increases, the particle size of the product gradually becomes smaller, the shape is irregular, and the tap density decreases; while too low a stirring rate leads to severe solvent inclusion.

[0142] Stability test

[0143] The stability of the crystals of Form AB of Compound 1 provided in the present application was tested below (the test results were calculated based on the weight of Compound 1 in each test group).

[0144] Experimental methods:

[0145] Accelerated test: The samples of Examples 3 to 5 and the AB crystal sample were placed in a culture dish, and the culture dish was placed in an open state at 65°C ± 2°C for 3 months, and a small amount of samples were taken for testing at 0, 1, 2, and 3 months. The test results are shown in Table 2.

[0146] Table 2. Accelerated test results of crystals prepared in Examples 2, 3, 4, and 5

[0147]

[0148] The above experimental results show that the crystals obtained in the present application not only have high purity, but also have better stability than the AB crystal particles prepared by the prior art under accelerated experimental conditions, indicating that the crystals prepared in the present application have better physical stability and chemical stability. At the same time, in the process of scaled-up production, compared with the AB crystal particles in the prior art, it has incomparable production convenience, and its appearance, particle size, etc. are more suitable for drug preparation.

[0149] Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the claims. Any technical personnel in this field may make several possible changes and modifications without departing from the concept of the present application. Therefore, the scope of protection of the present application shall be based on the scope defined by the claims of the present application.

Claims

1. A crystal of Form AB of Compound 1, characterized in that: The crystals satisfy the following characteristics: The crystals are spherical or quasi-spherical, and the particle size D90 of the crystals is 114 μm to 153 μm; The X-ray powder diffraction pattern of the crystalline form AB expressed in 2θ angle has diffraction peaks at 4.6±0.1°, 6.7±0.1°, 10.7±0.1°, 16.2±0.1°, 17.0±0.1°, 17.4±0.1°, 19.5±0.1°, 20.7±0.1°, 21.9±0.1°, 22.5±0.1°, 23.8±0.1°, and 25.1±0.1°; The X-ray powder diffraction pattern of the crystal form AB expressed in 2θ angles is shown in FIG1 .

2. The crystal according to claim 1, characterized in that The repose angle of the crystal is 39.45° to 40.22°; The tap density of the crystals is 0.207 mg / mL to 0.247 mg / mL.

3. A method for preparing a crystal of the crystalline form AB of compound 1 according to any one of claims 1 to 2, characterized in that: The method comprises the following steps: Under cooling conditions and first stirring conditions, a solution containing compound 1 and a solution containing seed crystals of form AB of compound 1 are mixed to obtain a mixture, and the mixture is stirred and crystallized under second stirring conditions, and solid-liquid separation and drying are performed to obtain crystals; The cooling temperature of the cooling condition is -20°C to 0°C, preferably -15°C to 0°C; The rotation speed of the first stirring condition is 300 rpm to 1000 rpm, preferably 300 rpm to 700 rpm; The rotation speed of the second stirring condition is 60 rpm to 200 rpm, preferably 70 rpm to 170 rpm; The mass of the added seed crystals is 0.3% to 2.5% of the mass of the added compound 1.

4. The preparation method according to claim 3, characterized in that: Under cooling conditions and first stirring conditions, mixing seed crystals of the crystalline form AB of compound 1 and solvent B to obtain a suspension containing seed crystals, and then adding the solution containing compound 1 to the suspension to obtain a mixture; The time for stirring and crystallizing the mixture under the second stirring condition is 8 hours to 48 hours.

5. The preparation method according to claim 4, characterized in that: After all the solution containing compound 1 is added to the suspension to obtain a mixture, the stirring speed is kept unchanged, and the obtained mixture is continuously stirred for 10 min to 120 min, preferably for 30 min to 120 min, and then stirred and crystallized under the second stirring condition.

6. The preparation method according to claim 4, characterized in that: The solvent B is selected from at least one of a C2-C4 alcohol solvent, a C2-C4 ketone solvent and a C2-C4 ester solvent; The mass volume ratio (g / mL) of the seed crystals of the crystalline form AB of the compound 1 to the solvent B is 1:(20-100).

7. The preparation method according to claim 3 or 4, characterized in that: The solution containing compound 1 is prepared according to the following method: Dissolving the compound 1 in solvent A to obtain a solution containing the compound 1; The solvent A comprises at least one of a C1-C4 halogenated alkane solvent, a C1-C2 alcohol solvent, a C3-C6 cyclic ether solvent and water; preferably, the solvent A is a mixed solution of dichloromethane / methanol, and the volume ratio of dichloromethane to methanol in the mixed solution of dichloromethane / methanol is (10-1):1; The mass volume ratio (g / mL) of the compound 1 to the solvent A is 1:(4-40).

8. The preparation method according to claim 3, characterized in that: The solid-liquid separation method is selected from at least one of filtration and centrifugation; The drying method is selected from vacuum drying; The drying temperature is 30°C to 60°C.

9. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the crystal according to any one of claims 1 to 2 or the crystal prepared by the preparation method according to any one of claims 3 to 8 and a pharmaceutically acceptable carrier.

10. Use of the crystal according to any one of claims 1 to 2 and the pharmaceutical composition according to claim 9 in the preparation of a drug for treating a disease caused by abnormal activity of protein kinase AXL and / or VEGFR2.

Images