Crystal form of a nitrogen-containing heterocyclic compound, preparation method and application thereof

Abstract

The application discloses a crystal form of a nitrogen-containing heterocyclic compound, a preparation method and application. The application provides a crystal form C of compound 1, and discloses a preparation method, a composition and application of the crystal form C in preparation of drugs. The crystal form has good stability and high bioavailability.

Description

Technical Field

[0001] This invention relates to the crystal form, preparation method, and application of a nitrogen-containing heterocyclic compound. Background Technology

[0002] A nitrogen-containing heterocyclic compound 1, chemically named (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-oxo)-3-toluene)amine)-7-ethoxyquinazoline-6-yl)-2-fluoro-3-(1-methylpyrrolidine-2-yl)acrylamide, has the molecular formula C 31 H 31 FN8O3 has the following structural formula:

[0003]

[0004] CN109422755 and WO2019042409 disclose this nitrogen-containing heterocyclic compound and its preparation method. Compound 1, prepared by the method disclosed in the patent, is a yellow, foamy solid with unsatisfactory solid-state properties. It also indicates that compound 1 is a small molecule inhibitor that either weakens or selectively targets ErbB2 and exhibits EGFR kinase inhibitory activity. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to overcome the defects of the unsatisfactory solid properties of (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-oxy)-3-toluene)amine)-7-ethoxyquinazoline-6-yl)-2-fluoro-3-(1-methylpyrrolidine-2-yl)acrylamide in the prior art, and to provide a crystal form, preparation method and application of the compound, which has high stability and good bioavailability.

[0006] The present invention solves the above-mentioned technical problems through the following technical solution:

[0007] This invention provides a crystal form C of compound 1;

[0008]

[0009] The crystalline form C, when subjected to Cu-Kα radiation, exhibits X-ray powder diffraction patterns (denoted as 2θ) with diffraction peaks at the following positions: 5.32±0.2°, 8.42±0.2°, 10.62±0.2°, 11.48±0.2°, 13.46±0.2°, 16.14±0.2°, 16.57±0.2°, 16.96±0.2°, 17.26±0.2°, and 18.11±0.2°.

[0010] In one embodiment, the X-ray powder diffraction pattern of crystal form C, expressed at an angle of 2θ, further exhibits diffraction peaks at one or more of the following positions: 19.42±0.2°, 21.26±0.2°, 22.11±0.2°, 22.73±0.2°, 23.05±0.2°, 23.45±0.2°, 25.98±0.2°, 26.71±0.2°, 26 0.89±0.2°; preferably, it also has diffraction peaks at one or more of the following positions: 12.23±0.2°, 13.00±0.2°, 14.76±0.2°, 20.33±0.2°, 24.89±0.2°, 28.50±0.2°, 31.74±0.2°, 34.46±0.2°, 35.94±0.2° and 37.67±0.2°.

[0011] In one embodiment, the X-ray powder diffraction pattern of crystal form C, expressed at a 2θ angle, has the diffraction peaks shown in the table below:

[0012]

[0013]

[0014] In one embodiment, the X-ray powder diffraction pattern of crystal form C, expressed in terms of a 2θ angle, is essentially as follows: Figure 5 As shown.

[0015] In one embodiment, the differential scanning calorimetry (DSC) of crystal form C shows an endothermic peak at 213.3 °C (initial temperature).

[0016] In one embodiment, the differential scanning calorimetry (DSC) of crystal form C shows an endothermic peak at 213.3 °C (initial temperature) and a heat of fusion of 95.16 J / g.

[0017] In one embodiment, the differential scanning calorimetry (DSC) of crystal form C is essentially as follows: Figure 6 As shown.

[0018] In one embodiment, the thermogravimetric analysis of crystal form C shows a weight loss of 2.1% when heated to 200°C; and a weight loss of 1.5% when heated further to 230°C.

[0019] In one particular scheme, the thermogravimetric analysis diagram of crystal form C is basically as follows: Figure 6 As shown.

[0020] The present invention also provides a method for preparing the above-mentioned crystal form C, which is Scheme 1 or Scheme 2;

[0021] Option 1 includes the following steps: converting the suspension of compound 1 with a solvent into crystal form C to obtain the crystal form C of compound 1;

[0022]

[0023] The compound 1 is one of crystal form B, crystal form A, crystal form G, crystal form H, crystal form I, crystal form M, and crystal form E; crystal form B is obtained by using Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ has diffraction peaks at the following positions: 7.53±0.2°, 8.83±0.2°, 12.72±0.2°, 13.98±0.2°, 14.20±0.2°, 15.05±0.2°, 15.44±0.2°, 17.68±0.2°, 18.13±0.2°, 18.38±0.2°, 18.86±0.2°, 21.24±0.2°, 22.44±0.2°, and 24.54±0.2°; crystal form A is obtained by using Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ has diffraction peaks at the following positions: 7.53±0.2°, 8.83±0.2°, 12.72±0.2°, 13.98±0.2°, 14.20±0.2°, 15.05±0.2°, 15.44±0.2°, 17.68±0.2°, 18.13±0.2°, 18.38±0.2°, 18.86±0.2°, 21.24±0.2°, 22.44±0.2°, and 24.54±0.2°; The 2θ X-ray powder diffraction pattern has diffraction peaks at the following positions: 5.97±0.2°, 12.27±0.2°, 13.30±0.2°, 14.31±0.2°, 16.08±0.2°, 16.60±0.2°, 17.93±0.2°, and 20.24±0.2°; the crystal form G is obtained using Cu-Kα radiation, and the 2θ X-ray powder diffraction pattern has diffraction peaks at the following positions: 6.41±0.2°, 6.88±0.2°, 8.75±0.2°, 12.82±0.2°, 13.38±0.2°, 13.73±0.2°, 16.74±0.2°, 17.64±0.2°, 19.24±0.2°, and 21. The crystal form H, when irradiated with Cu-Kα, exhibits diffraction peaks at the following positions in its 2θ X-ray powder diffraction pattern: 5.41±0.2°, 6.13±0.2°, 7.92±0.2°, 11.19±0.2°, 12.26±0.2°, and 21.91±0.2°; the crystal form I, when irradiated with Cu-Kα, exhibits diffraction peaks at the following positions in its 2θ X-ray powder diffraction pattern: 6.80±0.2°, 7.22±0.2°, 8.03±0.2°, 8.35±0.2°, 9.70±0.2°, 10.28±0.2°, and 19. The crystal form M, using Cu-Kα radiation, has X-ray powder diffraction peaks at the following positions in its 2θ X-ray powder diffraction pattern: 5.52±0.2°, 7.96±0.2°, 9.41±0.2°, 13.36±0.2°, 14.68±0.2°, 17.93±0.2°, 18.70±0.2°, 25.75±0.2°, 26.11±0.2°, and 26.50±0.2°; the crystal form E, using Cu-Kα radiation, has X-ray powder diffraction peaks at the following positions in its 2θ X-ray powder diffraction pattern: 6.07±0.2°, 8.97±0.2°, 9.32±0.2°, 9.87±0.2°, 13.05±0.2°, and 13.27±0.2°, 14.09±0.2°, 15.78±0.2°, 16.98±0.2°, 18.27±0.2°, 18.47±0.2°, 21.26±0.2°, 22.41±0.2°;

[0024] When the compound 1 is one of crystal form A, crystal form G, crystal form H, crystal form I, crystal form M and crystal form E, the solvent is acetone or acetone / water;

[0025] When compound 1 is crystal form B, the solvent is acetonitrile or ethanol;

[0026] Option 2 includes the following steps: crystallizing compound 1 in a solvent to obtain crystal form C of compound 1; the solvent is an alcohol solvent, preferably ethanol or isopropanol.

[0027] In the preparation method of crystal form C, when Scheme 1 is adopted, if the solvent is acetone / water, the volume ratio of acetone to water is 986:14–950:50.

[0028] In the preparation method of crystal form C, when Scheme 1 is adopted, if the compound 1 is one of crystal form A, crystal form G, crystal form H, crystal form I, crystal form M and crystal form E, the crystal transformation temperature is 20-30℃ (room temperature).

[0029] In the preparation method of crystal form C, when Scheme 1 is adopted, if compound 1 is crystal form B, the crystal transformation temperature is 20-50℃, for example 20-30℃ (room temperature).

[0030] In the preparation method of crystal form C, when using Scheme 2, the mass-volume ratio of compound 1 to solvent is 100 mg: 2 mL.

[0031] In the preparation method of crystal form C, when using Scheme 2, the crystallization temperature is 50-60℃, preferably 55℃.

[0032] In the preparation method of crystal form C, when using Scheme 2, the crystallization time is 24 hours.

[0033] The present invention also provides a pharmaceutical composition comprising the above-described crystal form C and pharmaceutical excipients.

[0034] The present invention also provides the application of the above-mentioned crystal form C in the preparation of a drug, the drug being used to treat cancer and / or diseases treated by inhibiting EGFR and / or ErbB2 receptor tyrosine kinase; for example, treating diseases treated by selectively inhibiting ErbB2 receptor tyrosine kinase; the cancer and the disease may be breast cancer, gastric cancer, ovarian cancer, lung cancer, etc.; the crystal form C may be a therapeutically effective amount.

[0035] This invention also provides the use of the above-described crystal form C in the preparation of EGFR and / or ErbB2 receptor tyrosine kinase inhibitors. The EGFR and / or ErbB2 receptor tyrosine kinase inhibitors may be selective ErbB2 receptor tyrosine kinase inhibitors.

[0036] In this invention, "room temperature" refers to 20-30℃.

[0037] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0038] The reagents and raw materials used in this invention are all commercially available.

[0039] The positive and progressive effects of this invention are as follows: it overcomes the defects of the unsatisfactory solid properties of (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-oxy)-3-toluene)amine)-7-ethoxyquinazoline-6-yl)-2-fluoro-3-(1-methylpyrrolidine-2-yl)acrylamide in the prior art, and provides a crystal form of the compound with high stability and good bioavailability. Attached Figure Description

[0040] Figure 1 XRPD spectrum of crystal form A

[0041] Figure 2 TGA / DSC spectrum of crystal form A

[0042] Figure 3 XRPD spectrum of crystal form B

[0043] Figure 4 TGA / DSC spectrum of crystal form B

[0044] Figure 5 XRPD spectrum of crystal form C

[0045] Figure 6 TGA / DSC spectrum of crystal form C

[0046] Figure 7 XRPD spectrum of crystal form D

[0047] Figure 8 XRPD spectrum of crystal form E

[0048] Figure 9 TGA / DSC spectrum of crystal form E

[0049] Figure 10 XRPD spectrum of crystal form F

[0050] Figure 11TGA / DSC spectrum of crystal form F

[0051] Figure 12 XRPD spectrum of crystal form G

[0052] Figure 13 TGA / DSC spectrum of crystal form G

[0053] Figure 14 XRPD spectrum of crystal form H

[0054] Figure 15 TGA / DSC spectrum of crystal form H

[0055] Figure 16 XRPD spectrum of crystal form I

[0056] Figure 17 TGA / DSC spectra of crystal form I

[0057] Figure 18 XRPD spectrum of crystal form J

[0058] Figure 19 XRPD spectrum of crystal form K

[0059] Figure 20 XRPD spectrum of crystal form L

[0060] Figure 21 XRPD spectrum of crystal form M

[0061] Figure 22 TGA / DSC spectrum of crystal form M

[0062] Figure 23 XRPD comparison chart of suspension competition between crystal form B and crystal form C

[0063] Figure 24 XRPD comparison chart of competing C / A / G / H / I / M / E mixture suspensions

[0064] Figure 25 XRPD comparison chart of crystal form C stability test

[0065] Figure 26 Amorphous XRPD spectrum. Detailed Implementation

[0066] The present invention will be further illustrated by way of embodiments below, but the present invention is not limited to the scope of the embodiments described herein.

[0067] The abbreviations used in this invention are explained as follows:

[0068] XPRD—X-ray Powder Diffraction

[0069] TGA—Thermogravimetric Analysis

[0070] DSC—Differential Scanning Calorimetry

[0071] DVS—Dynamic Water Adsorption-Desorption Analysis

[0072] The test conditions are as follows:

[0073] XRPD

[0074] The X-ray powder diffraction patterns described in this application were acquired using a PANalytical Empyrean X-ray powder diffractometer and a PANalytical X'Pert3 X-ray powder diffractometer.

[0075] The parameters for Empyrean-type X-ray powder diffraction are as follows:

[0076] X-ray type: Cu, Kα

[0077] 1.540598; 1.544426

[0078] Kα2 / Kα1 intensity ratio: 0.50

[0079] Voltage: 45 kV

[0080] Current: 40 milliamperes (mA)

[0081] Diverging Slit: Automatic

[0082] Scanning mode: Continuous

[0083] Scan range: from 3.0 to 40.0 degrees

[0084] Scanning time per step: 17.780 seconds

[0085] Step size: 0.0167 degrees

[0086] The parameters for PANalytical X'Pert3 type X-ray powder diffraction are as follows:

[0087] X-ray type: Cu, Kα

[0088] 1.540598; 1.544426

[0089] Kα2 / Kα1 intensity ratio: 0.50

[0090] Voltage: 45 kV

[0091] Current: 40 milliamperes (mA)

[0092] Diverging slit: 1 / 16 degree

[0093] Scanning mode: Continuous

[0094] Scan range: from 3.0 to 40.0 degrees

[0095] Scanning time per step: 46.665 seconds

[0096] Step size: 0.0263 degrees

[0097] DSC

[0098] The differential scanning calorimetry (DSC) data described in this application were acquired using TA Instruments Q200 and TA Instruments Q2000 differential scanning calorimeters. The instrument control software was Q Series, and the analysis software was UniversalAnalysis. Typically, 1–10 mg of sample was placed in a covered (unless otherwise specified) aluminum crucible and heated from room temperature to 300°C at a rate of 10°C / min under a 50 mL / min dry N2 atmosphere. The TA software recorded the heat change of the sample during the heating process. In this application, the melting point is reported based on the initial temperature.

[0099] TGA

[0100] Thermogravimetric analysis (TGA) data described in this application were acquired using TA Instruments Q500 and TA Instruments Q5000 thermogravimetric analyzers. The instrument control software was Q Series, and the analysis software was UniversalAnalysis. Typically, 2–15 mg of sample was placed in a platinum crucible, and segmented high-resolution detection was employed. The sample was heated from room temperature to 400°C at a heating rate of 10°C / min under the protection of dry N2 at a rate of 50 mL / min. Simultaneously, the TA software recorded the weight change of the sample during the heating process.

[0101] DVS

[0102] The dynamic moisture adsorption maps described in this application were acquired using SMS's Intrinsic and Intrinsic Plus dynamic moisture adsorption analyzers. The parameters of the dynamic moisture adsorption test method described in this invention are as follows:

[0103] Temperature: 25℃

[0104] Protective gas and flow rate: N2, 200 ml / min

[0105] dm / dt: 0.002% / minute

[0106] Minimum dm / dt equilibration time: 10 minutes

[0107] Maximum balancing time: 180 minutes

[0108] Relative humidity range: 0%RH-95%RH-0%RH

[0109] Relative humidity gradient: 10% (0%RH-90%RH-0%RH), 5% (90%RH-95%RH and 95%RH-90%RH)

[0110] Example of amorphous preparation of compound 1:

[0111] Example 1:

[0112] The structure of compound 1 is as follows, and its amorphous form was prepared in Example 45 of patent CN109422755 and WO2019042409.

[0113] The amorphous solid is a yellow, foamy solid with unsatisfactory solid-state properties; its XRPD is as follows: Figure 26 As shown.

[0114]

[0115] Examples of crystal form preparation:

[0116] Example 1 (Crystal form A of compound 1)

[0117] The solid XRPD obtained by suspending and stirring 100 mg of compound 1 crystal form B in 1 mL of EtOAc at room temperature for five days is as follows: Figure 1 As shown. Its TGA and DSC spectra are as follows. Figure 2 As shown, TGA data shows that the crystal form sample lost 6.4% of its weight when heated to 200℃, and there are two endothermic peaks at 137.2℃ and 214.7℃ (peak temperatures) in the DSC, indicating that the obtained solid product is the crystal form A described in this application.

[0118] Table 1 XRPD data for crystal form A

[0119]

[0120]

[0121] Example 2 (Crystal form B of compound 1)

[0122] The X-ray powder diffraction data of the solid obtained by crystallizing 100 mg of the amorphous form of compound 1 in 1 ml of acetone at room temperature for 2 h are shown in Table 2, and its XRPD pattern is shown in the figure. Figure 3 As shown, TGA / DSC Figure 4As shown, the sample lost 0.7% weight when heated from room temperature to 100°C, and 2.3% weight when heated to 220°C. There was an endothermic peak at 165.2°C (initial temperature), which is presumed to be the melting signal of the sample. The results indicate that the obtained solid product is the crystal form B described in this application.

[0123] Table 2 XRPD data for crystal form B

[0124]

[0125]

[0126] Example 3 (Crystal form C of compound 1)

[0127] The X-ray powder diffraction data of the solid obtained by crystallizing 100 mg of the amorphous form of compound 1 in 2 ml of ethanol at 50-60 °C for 24 h are shown in Table 3, and its XRPD pattern is shown in the figure. Figure 5 As shown, the TGA / DSC results are as follows: Figure 6 As shown, the sample lost 2.1% of its weight when heated from room temperature to 200°C, and lost 1.5% of its weight when heated to 230°C. There was an endothermic peak at 213.3°C (initial temperature), which is presumed to be the melting signal of the sample. The heat of fusion was 95.16 J / g. The results indicate that the obtained solid product is the crystal form C described in this application.

[0128] Table 3 XRPD data for crystal form C

[0129]

[0130]

[0131] Example 4 (Crystal Form D)

[0132] The X-ray powder diffraction data of the solid obtained by crystallizing 5 mg of the amorphous form of compound 1 in 1 ml of 2-methyltetrahydrofuran (2-MeTHF) at 50 °C for four days are shown in Table 4, and its XRPD pattern is shown in the figure. Figure 7 As shown, the results indicate that the obtained solid product is crystal form D as described in this application.

[0133] Table 4 XRPD data for crystal form D

[0134]

[0135] Implementation 5 (Crystal Form E)

[0136] The X-ray powder diffraction data of the solid prepared by repeatedly suspending and stirring 100 mg of crystal form B of compound 1 in 1 mL of Acetone / H2O (605:395, v / v) at room temperature for three days are shown in Table 5, and its XRPD pattern is shown in the figure. Figure 8As shown, the TGA / DSC results are as follows: Figure 9 As shown, the sample lost 6.0% of its weight when heated from room temperature to 135℃, and had two endothermic peaks at 85.8℃ (peak temperature) and 160.0℃ (peak temperature), indicating that the obtained solid product is the crystal form E described in this application.

[0137] Table 5 XRPD data for crystal form E

[0138]

[0139] Implementation column 6 (crystal form F)

[0140] The X-ray powder diffraction data of the solid prepared by suspending and stirring 2 mg of crystal form B of compound 1 in 1 mL of Acetone / H2O (605:395, v / v) at room temperature for one day are shown in Table 6, and its XRPD pattern is shown in the figure. Figure 10 As shown, the TGA / DSC results are as follows: Figure 11 As shown, the sample lost 13.2% of its weight when heated from room temperature to 140°C, and there was an endothermic peak at 80.7°C (initial temperature). The results indicate that the obtained solid product is the crystal form F described in this application.

[0141] Table 6 XRPD data for crystal form F

[0142]

[0143]

[0144] Implemented in column 7 (crystal form G)

[0145] Weigh 100 mg of crystal form B of compound 1, add 21 mL of CHCl3 / MeOH (1:20, v / v) to dissolve the sample, filter the sample, seal it with sealing film and poke several small holes, and place it in a fume hood to evaporate naturally at room temperature. The X-ray powder diffraction data of the obtained solid are shown in Table 7, and its XRPD pattern is shown in... Figure 12 As shown, the TGA / DSC results are as follows: Figure 13 As shown, the sample lost 9.6% of its weight when heated from room temperature to 125°C. There were two endothermic peaks at 83.0°C and 146.6°C (peak temperature), indicating that the obtained solid product is the crystal form G described in this application.

[0146] Table 7 XRPD data for crystal form G

[0147]

[0148]

[0149] Implementation column 8 (crystal form H)

[0150] The X-ray powder diffraction data of the solid prepared by suspending and stirring 100 mg of crystal form B of compound 1 in 1 mL of water at 50 °C for four days are shown in Table 8, and its XRPD pattern is shown in the figure. Figure 14 As shown, the TGA / DSC results are as follows: Figure 15 As shown, the sample lost 15.3% of its weight when heated from room temperature to 150°C; DSC results showed that the sample had an endothermic peak at 83.7°C (peak temperature), indicating that the obtained solid product was the crystal form H described in this application.

[0151] Table 8 XRPD data for crystal form H

[0152]

[0153] Implementation 9 (Crystal Form I)

[0154] Weigh 100 mg of crystal form B of compound 1, add 8 mL of CHCl3 / IPA (1:3, v / v) to dissolve the sample, filter the sample, seal it with sealing film and poke several small holes, and place it in a fume hood for natural evaporation. The X-ray powder diffraction data of the resulting solid are shown in Table 9, and its XRPD pattern is shown in... Figure 16 As shown, the TGA / DSC results are as follows: Figure 17 As shown, the sample was heated from room temperature to 150°C and lost 15.2% of its weight. DSC results showed an endothermic peak at 95.5°C (peak temperature), indicating that the obtained solid product is crystal form I as described in this application.

[0155] Table 9 XRPD data for crystal form I

[0156]

[0157]

[0158] Implemented in column 10 crystal form J

[0159] 20 mg of crystal form B of compound 1 was dissolved in 0.2 mL of dimethyl sulfoxide (DMSO). After filtering the sample, 5 mL of MIBK (4-methyl-2-pentanone) was added dropwise to the flask under magnetic stirring. The sample was allowed to evaporate at room temperature until a solid was formed. The X-ray powder diffraction data of the resulting solid are shown in Table 10, and its XRPD pattern is shown in... Figure 18 As shown, the results indicate that the obtained solid product is crystal form J as described in this application.

[0160] Table 10 XRPD data for crystal form J

[0161]

[0162] Implementing 11 crystal form K

[0163] Weigh 100 mg of crystal form B of compound 1, add 20 mL of CHCl3 / MeOH (1:20, v / v) to dissolve the sample, filter the sample and allow it to evaporate in an open container until a solid is formed. The X-ray powder diffraction data of the obtained solid are shown in Table 11, and its XRPD pattern is shown in... Figure 19 As shown, the results indicate that the obtained solid product is crystal form K as described in this application.

[0164] Table 11 XRPD data for crystal form K

[0165]

[0166]

[0167] Implementing column 12 crystal form L

[0168] The X-ray powder diffraction data of the solid obtained after purging crystal form E in Example 5 under nitrogen for ten minutes are shown in Table 12, and its XRPD pattern is shown below. Figure 20 As shown, the results indicate that the obtained solid product is the crystal form L described in this application.

[0169] Table 12 XRPD data for crystal form L

[0170]

[0171]

[0172] Implementing 13 crystal form M

[0173] The X-ray powder diffraction data of the solid prepared by suspending and stirring 100 mg of crystal form B of compound 1 in 1 mL of Acetone / H2O (605:395, v / v) at room temperature for six days are shown in Table 13, and its XRPD pattern is shown in the figure. Figure 21 As shown, the TGA / DSC results are as follows: Figure 22 As shown, the sample lost 6.9% of its weight when heated from room temperature to 135°C; there were two endothermic peaks at 81.6°C (initial temperature) and 157.6°C (initial temperature), indicating that the obtained solid product is the crystal form M described in this application.

[0174] Table 13 XRPD data for crystal form M

[0175]

[0176] Examples of crystal form transformation relationships

[0177] Example 1: Suspension Competition Test of Crystal Forms B and C

[0178] A competition test was conducted on the suspension of two crystalline forms in acetonitrile and ethanol at room temperature and 50°C. The test results are summarized in Table 14. The specific steps are as follows:

[0179] 1) Prepare saturated solutions of crystal form B in acetonitrile and ethanol at room temperature and 50°C respectively, and filter them.

[0180] 2) Add approximately 5 mg of crystal form B and crystal form C to 0.5 mL of each saturated solution: ethanol and acetonitrile solution of crystal form B respectively, and suspend and stir the resulting suspensions at room temperature and 50°C for two days respectively.

[0181] 3) Test the obtained solid XRPD, such as... Figure 23 .

[0182] Example 2: Competition among suspensions of crystalline forms C / A / G / H / I / M / E was tested.

[0183] A suspension competition experiment was conducted on the crystalline C / A / G / H / I / M / E in Acetone / H2O mixed solutions with different volume ratios (986 / 14, v / v and 950 / 50, v / v) or in acetone at room temperature. The experimental results are summarized in Table 14. The specific steps are as follows:

[0184] 1) Prepare saturated solutions of crystal forms C / A / G / H / I / M / E in each solvent system at room temperature and filter them;

[0185] 2) Add approximately 5 mg of crystalline C / A / G / H / I / M / E to each 0.5 mL saturated solution, and suspend the resulting suspension at room temperature with stirring overnight;

[0186] 3) The solid obtained from the separation was tested using XRPD, such as... Figure 24 .

[0187] Table 14 Summary of Competition Tests for Various Crystal Forms of Suspension

[0188]

[0189] Conclusion: Based on Figure 23 and Figure 24 The XRPD comparison results show that the solid samples obtained in each system are all of crystal form C, suggesting that crystal form C is a relatively stable crystal form.

[0190] Physicochemical stability assessment of crystal form C

[0191] Example 1

[0192] To assess the physicochemical stability of crystal form C, approximately 20 mg of crystal form C of compound 1 was weighed and placed in a sealed container at 60°C for one day, and then left uncovered (sealed with a sealing film with some holes punched) at 25°C / 60%RH and 40°C / 75%RH for one week. The solid samples after different conditions were tested for purity by UPLC to assess chemical stability, and for crystal form by XRPD to assess physical stability. The evaluation results are summarized in Table 15: Under all three test conditions, crystal form C did not undergo a crystal form transformation. XRPD results are shown in [Table 15]. Figure 25 As shown, the sample did not undergo significant degradation after being placed at 60℃ for one day, at 25℃ / 60%RH and at 40℃ / 75%RH for one week (see Table 16 for specific purity changes).

[0193] Table 15 Summary of Physicochemical Stability Assessment Results for Crystal Form C

[0194]

[0195]

[0196] Table 16 Summary of Impurities in Crystal Form C Stability Samples

[0197]

[0198] Conclusion: The results show that crystal form C exhibits good physical and chemical stability after being placed at 60℃ for one day, at 25℃ / 60%RH, and at 40℃ / 75%RH for one week.

[0199] Example 1: Comparison of absorption in rats after administration of different crystal forms

[0200] SD rats were administered samples of different crystalline forms via gavage. Blood samples of 0.4 mL were collected from the fundus venous plexus of the rats at 5, 15, 30, 60, 90, 120, 240, 360, 480, 600, and 1440 min before and after administration. The blood samples were centrifuged at 8000 rpm for 5 min, and the supernatant plasma was separated. 50 μL of the plasma sample was mixed with 300 μL of acetonitrile (Propranolol, 25 ng / ml) containing the internal standard to precipitate the protein. The mixture was vortexed for 10 min, centrifuged at 6000 g, 4℃ for 20 min, and 20 μL of the supernatant was diluted with 80 μL of ultrapure water. The supernatant was then centrifuged again, and 80 μL of the supernatant was injected into a 96-well plate. Plasma drug concentrations were determined by LC / MS / MS, and the corresponding pharmacokinetic parameters were calculated (see Table 17).

[0201] Table 17 Pharmacokinetic parameters of different crystal forms after gavage administration

[0202]

[0203]

[0204] Conclusion: In this experiment, rats were administered amorphous, crystalline A, crystalline B, crystalline C, and crystalline M via gavage at a dose of 8 mg / kg. The results showed that crystalline C had the best pharmacokinetic parameters.

[0205] Example 2: EGFR / ErbB2 Enzymatic Experiment

[0206] First, prepare the 1× reaction buffer required for the kinase. Dilute the 5× Enzymatic buffer (HEPES 20mM pH 7.0, NaN3 0.1%, BSA 0.05%, sodium orthovanadate 0.5mM) from the HTRF kinEASE-TK kit to a 1-fold concentration with deionized water. Simultaneously add 50nM Supplement Enzymatic buffer (SEB reagent), 1mM MnCl2, 5mM MgCl2, and 1mM DTT. The second step is to prepare the 5× compound. Take 10mM of the test compound (crystal form C prepared in Example 3) stock solution and dilute it in multiple steps with DMSO in a 96-well compound plate to obtain a compound at an initial concentration of 100×. Then, using this concentration as the first concentration, perform 3-fold serial dilutions with DMSO, for a total of 10 concentrations. Then, take 1 μl of each serial dilution and add it to 19 μl of the 1× reaction buffer to prepare the 5× compound for later use. Next, 2 μl of the 5× compound was transferred from the 96-well plate to the 384-well plate. 2 μl of the following solution was added to the control wells (1 μl of DMSO plus 19 μl of 1× reaction buffer). 2 μl of 250 mM EDTA was added to the blank control wells. In the third step of the enzyme reaction, the kinase, substrate (TK Substrate-biotin), and ATP were prepared into 2.5× enzyme / substrate mixtures and 2.5× ATP solutions using 1× reaction buffer. The final concentrations of ErbB2 kinase (Sigma E2645-500UN) were 0.06 ng / μl and 4 μM of ATP; the final concentrations of EGFR kinase (Carna 08-016) were 0.06 units / μl and 1.65 μM of ATP. 4 μl of a 2.5× enzyme / substrate mixture was added to each well of a 384-well plate and incubated at room temperature for 5 minutes. Then, 4 μl of a 2.5× ATP solution was added to each well and the reaction was incubated at room temperature for 30 minutes. In the fourth step, to terminate the reaction, a 2× mixture of TK Antibody-Eu(K) and Sa-XL665 was prepared using HTRF Detection buffer, with 5 μl of TK Antibody-Eu(K) used per well. After 30 minutes of enzyme reaction, 10 μl of the above solution was added to each well of the 384-well plate and the reaction was incubated at room temperature for 1 hour. Data measurements were performed on EnVision™, using a 337 nm wavelength laser as the excitation light. RFU 665 nm and RFU 620 nm were measured, and the final data was analyzed as RFU 665 nm / RFU 620 nm × 10000.

[0207]

[0208] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and the scope of protection of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A crystal form C of compound 1, characterized in that: The crystal form C, when subjected to Cu-Kα radiation, exhibits X-ray powder diffraction peaks at the following positions, as represented by 2θ: 5.32±0.2°, 8.42±0.2°, 10.62±0.2°, 11.48±0.2°, 13.46±0.2°, 16.14±0.2°, 16.57±0.2°, 16.96±0.2°, 17.26±0.2°, and 18.11±0.2°. 。 2. The crystal form C as described in claim 1, characterized in that: The crystal form C satisfies one or more of the following conditions: (1) The X-ray powder diffraction pattern of the crystal form C, expressed in terms of 2θ angle, further has diffraction peaks at one or more of the following positions: 19.42±0.2°, 21.26±0.2°, 22.11±0.2°, 22.73±0.2°, 23.05±0.2°, 23.45±0.2°, 25.98±0.2°, 26.71±0.2°, 26.89±0.2°; (2) The differential scanning calorimetry of the crystal form C has an endothermic peak at 213.3℃; (3) The thermogravimetric analysis of the crystal form C shows that it loses 2.1% of its weight when heated to 200°C; and loses 1.5% of its weight when heated to 230°C.

3. The crystal form C as described in claim 2, characterized in that: The X-ray powder diffraction pattern of crystal form C, expressed at an angle of 2θ, also shows diffraction peaks at one or more of the following locations: 12.23±0.2°, 13.00±0.2°, 14.76±0.2°, 20.33±0.2°, 24.89±0.2°, 28.50±0.2°, 31.74±0.2°, 34.46±0.2°, 35.94±0.2°, and 37.67±0.2°.

4. The crystal form C as described in claim 3, characterized in that: The crystal form C satisfies one or more of the following conditions: (1) The X-ray powder diffraction pattern of the crystal form C, expressed in terms of 2θ angle, has the diffraction peaks shown in the table below: ； (2) The differential scanning calorimetry of the crystal form C has an endothermic peak at 213.3℃ and a heat of fusion of 95.16 J / g; (3) The thermogravimetric analysis diagram of the crystal form C is basically shown in Figure 6.

5. The crystal form C as described in claim 4, characterized in that: The crystal form C satisfies one or two of the following conditions: (1) The X-ray powder diffraction pattern of the crystal form C, expressed in terms of 2θ angle, is basically shown in Figure 5; (2) The differential scanning calorimetry of the crystal form C is basically as shown in Figure 6.

6. A method for preparing crystal form C as described in any one of claims 1 to 5, characterized in that: It is either Option 1 or Option 2; among them, Option 1 includes the following steps: converting the suspension of compound 1 with a solvent into crystal form C to obtain the crystal form C of compound 1; ， Compound 1 is selected from crystal forms B, A, G, H, I, M, and E; crystal form B is characterized by diffraction peaks at the following positions in its X-ray powder diffraction pattern (denoted by 2θ) using Cu-Kα radiation: 7.53±0.2°, 8.83±0.2°, 12.72±0.2°, 13.98±0.2°, 14.20±0.2°, 15.05±0.2°, 15.44±0.2°, 17.68±0.2°, 18.13±0.2°, 18.38±0.2°, 18.86±0.2°, 21.24±0.2°, 22.44±0.2°, and 24.54±0.2°; crystal form A is characterized by diffraction peaks at the following positions in its X-ray powder diffraction pattern (denoted by 2θ) using Cu-Kα radiation. The X-ray powder diffraction pattern of the crystal form G, using Cu-Kα radiation, exhibits diffraction peaks at the following positions: 5.97±0.2°, 12.27±0.2°, 13.30±0.2°, 14.31±0.2°, 16.08±0.2°, 16.60±0.2°, 17.93±0.2°, and 20.24±0.2°. The X-ray powder diffraction pattern of the crystal form G, expressed as 2θ, using Cu-Kα radiation, exhibits diffraction peaks at the following positions: 6.41±0.2°, 6.88±0.2°, 8.75±0.2°, 12.82±0.2°, 13.38±0.2°, 13.73±0.2°, 16.74±0.2°, 17.64±0.2°, 19.24±0.2°, and 21.68±0.2°. 0.2°, 22.77±0.2°, 26.14±0.2° and 26.49±0.2°; the crystal form H, using Cu-Kα radiation, has diffraction peaks at the following positions in its 2θ X-ray powder diffraction pattern: 5.41±0.2°, 6.13±0.2°, 7.92±0.2°, 11.19±0.2°, 12.26±0.2° and 21.91±0.2°; the crystal form I, using Cu-Kα radiation, has diffraction peaks at the following positions in its 2θ X-ray powder diffraction pattern: 6.80±0.2°, 7.22±0.2°, 8.03±0.2°, 8.35±0.2°, 9.70±0.2°, 10.28±0.2° and 19.84±0.2°. 0.2°; the crystal form M, using Cu-Kα radiation, has X-ray powder diffraction peaks at the following positions in its 2θ X-ray powder diffraction pattern: 5.52±0.2°, 7.96±0.2°, 9.41±0.2°, 13.36±0.2°, 14.68±0.2°, 17.93±0.2°, 18.70±0.2°, 25.75±0.2°, 26.11±0.2°, and 26.50±0.2°; the crystal form E, using Cu-Kα radiation, has X-ray powder diffraction peaks at the following positions in its 2θ X-ray powder diffraction pattern: 6.07±0.2°, 8.97±0.2°, 9.32±0.2°, 9.87±0.2°, 13.05±0.2°, and 13.27±0.2°.2°、14.09±0.2°、15.78±0.2°、16.98±0.2°、18.27±0.2°、18.47±0.2°、21.26±0.2°、22.41±0.2°；. When compound 1 is selected from crystal form A, crystal form G, crystal form H, crystal form I, crystal form M and crystal form E, the solvent is acetone or acetone / water; when the solvent is acetone / water, the volume ratio of acetone to water is 986:14 – 950:50; the crystallization temperature is 20-30℃. When compound 1 is in crystal form B, the solvent is acetonitrile or ethanol; the crystallization temperature is 20-50℃. Option 2 includes the following steps: crystallizing compound 1 in a solvent to obtain crystal form C of compound 1; the solvent is ethanol or isopropanol; the mass-to-volume ratio of compound 1 to the solvent is 100mg:2mL; the crystallization temperature is 50-60℃.

7. The method for preparing crystal form C as described in claim 6, characterized in that: In the first scheme, when compound 1 is crystal form B, the crystal transformation temperature is 20-30℃.

8. The method for preparing crystal form C as described in claim 6, characterized in that: In Scheme 2, the preparation method satisfies one or more of the following conditions: (1) The crystallization temperature is 55℃; (2) The crystallization time is 24h.

9. A pharmaceutical composition comprising crystal form C as described in any one of claims 1 to 5 and a pharmaceutical excipient.

10. The use of crystal form C as described in any one of claims 1 to 5 in the preparation of a medicament for treating cancer and / or diseases treated by inhibiting EGFR and / or ErbB2 receptor tyrosine kinases.

11. The use of crystal form C as described in claim 10 in the preparation of a medicament, wherein the medicament is a medicament for treating a disease by selectively inhibiting ErbB2 receptor tyrosine kinase.

12. The use of crystal form C as described in claim 10 in the preparation of a medicament, wherein the cancer and the disease are breast cancer, gastric cancer, ovarian cancer, or lung cancer.

13. The use of crystal form C as described in claim 10 in the preparation of a drug, wherein the crystal form C is a therapeutically effective amount.

14. The use of crystal form C as described in any one of claims 1 to 5 in the preparation of EGFR and / or ErbB2 receptor tyrosine kinase inhibitors.

15. The application as described in claim 14, wherein the EGFR and / or ErbB2 receptor tyrosine kinase inhibitor is a selective ErbB2 receptor tyrosine kinase inhibitor.

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