CN113045587A - Crystal form of macrocyclic compound and preparation method thereof - Google Patents
Crystal form of macrocyclic compound and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a crystal form of a macrocyclic compound and a preparation method thereof, the preparation method is simple, 10 different crystal forms can be obtained, wherein the crystal form I has excellent stability, the problem that the compound A is easy to decompose in an amorphous form under the condition of illumination can be well solved, the macrocyclic compound is more suitable for preparing clinical drugs, and the safety and the effectiveness of the drugs can be better ensured.
Description
Technical Field
The invention relates to the field of medicines, in particular to a crystal form of a macrocyclic compound and a preparation method thereof.
Background
The NTRK genes comprise NTRK1, NTRK2, and NTRK3, which are responsible for the synthesis of the family proteins, TRKA, TRKB, and TRKC, encoding Tropomyosin Receptor Kinase (TRK), respectively. Binding of neurotrophic factors to TRK proteins induces receptor dimerization, phosphorylation and activation of downstream signaling cascades of PI3K, RAS/MAPK/ERK and PLC-gamma.
Alterations in TRK signaling pathways, including gene fusion, protein overexpression, or single nucleotide alterations, have been found to be causative factors in many tumors, particularly fusion of NTRK genes, among the most well-defined ones, and the discovery that NTRK fusion proteins function as oncogenic drivers, promoting cancer cell growth and survival has led to the emergence of NTRK gene fusion as a new target for cancer therapy.
In 11 months in 2018, a first-generation drug LOXO-101 which can effectively treat 17 tumors and aims at patients with NTRK1/NTRK2/NTRK3 fusion is newly marketed in the United states, however, a part of cancer patients can generate drug resistance to the first-generation drug, and the drug resistance mutation of TRK kinase is one of the main reasons for generating the drug resistance, so that more effective drugs capable of overcoming the drug resistance of the first-generation drug need to be developed.
The compound A in the application is reported to be used for treating tumor diseases related to NTRK gene fusion, has the function of inhibiting protein kinase, and is expected to become a new second-generation medicament capable of overcoming the drug resistance of the first-generation medicament and applied to clinical treatment. The stability of the compound is particularly important in the case of preparing a medicament, which is a guarantee for the safety and effectiveness of the medicament, and therefore, the development of a more stable crystal form of the compound is very necessary.
Disclosure of Invention
The invention mainly solves the technical problem of providing a crystal form of a macrocyclic compound, which can improve the stability of the compound.
In order to solve the technical problems, the invention adopts a technical scheme that:
providing a crystal form I of a compound shown as a formula A, and obtaining an X-ray powder diffraction pattern by using Cu-Kalpha radiation, wherein the X-ray powder diffraction pattern at least comprises characteristic peaks at 8.8 +/-0.2, 9.9 +/-0.2, 13.1 +/-0.2, 14.9 +/-0.2, 17.7 +/-0.2, 19.8 +/-0.2, 21.6 +/-0.2 and 23.3 +/-0.2 degrees 2 theta:
further, the X-ray powder diffraction pattern also comprises characteristic peaks at 12.3 +/-0.2, 15.7 +/-0.2, 17.1 +/-0.2, 19.3 +/-0.2, 20.3 +/-0.2, 24.5 +/-0.2, 24.9 +/-0.2, 26.4 +/-0.2, 27.7 +/-0.2 and 31.6 +/-0.2 degrees 2 theta.
Further form I as described above, characterized in that said X-ray powder diffraction pattern is as shown in figure 3.
Further, the peak intensities of the characteristic peaks at 8.8 ± 0.2, 9.9 ± 0.2, 13.1 ± 0.2, 14.9 ± 0.2, 17.7 ± 0.2, 19.8 ± 0.2, 21.6 ± 0.2, 23.3 ± 0.2 degrees 2 θ are in order of about: 16.8%, 14.9%, 77.4%, 35.9%, 13.1%, 77.4%, 100%, 75.9%.
Further, the peak intensities of the characteristic peaks at 12.3 ± 0.2, 15.7 ± 0.2, 17.1 ± 0.2, 19.3 ± 0.2, 20.3 ± 0.2, 24.5 ± 0.2, 24.9 ± 0.2, 26.4 ± 0.2, 27.7 ± 0.2, 31.6 ± 0.2 degrees 2 θ are in order of about: 17.2%, 34.5%, 12.2%, 73.6%, 21.9%, 14.2%, 18.5%, 12.9%, 30.5%, 14.2%
Further, in the differential scanning calorimetry analysis of the crystal form I, a melting endothermic peak is at 322 +/-2 ℃.
The invention also provides a preparation method of the crystal form I, which comprises the following steps:
mixing an amorphous compound A with an organic solvent a, and placing the mixture under a sealing condition for 68-80 hours; the amorphous compound A: the feed-liquid ratio of the organic solvent a is 6-10 mg/mL; the organic solvent a is one or more selected from tetrahydrofuran, acetonitrile, toluene, isopropyl acetate, isopropyl ether, ethanol and ethylene glycol dimethyl ether.
Further, the mixture is placed under a sealing condition for 72 hours; the amorphous compound A: the feed-to-liquid ratio of the organic solvent was 8 mg/mL.
The invention also provides another preparation method of the crystal form I, which comprises the following steps:
mixing the amorphous compound A with an organic solvent b, and stirring for 40-55 h; the amorphous compound A: the material-liquid ratio of the organic solvent b is 50-70 mg/mL; the organic solvent b is selected from one of tert-butyl alcohol, diethyl ether, isopropyl ether, ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, dimethyl carbonate, cyclohexane, n-heptane, acetonitrile and ethylene glycol dimethyl ether.
Further, the stirring time was 48h, and the amorphous compound a: the feed-to-liquid ratio of the organic solvent b was 60 mg/mL.
Furthermore, the above preparation methods are all carried out under the condition of keeping out light.
Since amorphous compound a is unstable and easily decomposed under light, it is required to be kept as stable as possible under light-shielding conditions during the preparation of crystals from amorphous compound a, and in the specific examples of the present invention, the solution is placed in a brown bottle.
The invention also provides application of the crystal form I in preparation of TRK inhibitors and/or protein kinase inhibitors.
The compound A can be used as a TRK inhibitor and can be used for treating tumor diseases caused by NTRK gene fusion, and the compound A also has the effect of inhibiting the activity of protein kinase, can be used as a protein kinase inhibitor and can be used for treating TRK and related diseases mediated by protein kinase, so that the crystal form I of the compound A can also be used for preparing medicines for treating TRK and related diseases mediated by protein kinase, the stability of the crystal form I is well improved, and the compound A is more suitable for being applied to medicines.
The invention also provides a pharmaceutical composition, which comprises the crystal form I.
The invention also provides a crystal form II of the compound shown as the formula A, and an X-ray powder diffraction pattern obtained by using Cu-k alpha radiation at least comprises characteristic peaks at 2 theta positions of 9.3 +/-0.2, 12.7 +/-0.2, 14.7 +/-0.2, 16.5 +/-0.2, 19.4 +/-0.2, 19.8 +/-0.2, 21.8 +/-0.2 and 24.2 +/-0.2 degrees.
Further, the X-ray powder diffraction pattern also comprises characteristic peaks positioned at 12.4 +/-0.2, 18.9 +/-0.2, 23.2 +/-0.2, 25.5 +/-0.2, 26.0 +/-0.2, 28.6 +/-0.2, 30.3 +/-0.2 and 32.8 +/-0.2 degrees 2 theta;
further, in the differential scanning calorimetry analysis of the crystal form II, a melting endothermic peak exists at 100 +/-2 ℃ and 319 +/-2 ℃.
The invention also provides a crystal form III of the compound shown as the formula A, and an X-ray powder diffraction pattern obtained by using Cu-Kalpha radiation at least comprises characteristic peaks at 2 theta positions of 8.7 +/-0.2, 9.0 +/-0.2, 13.2 +/-0.2, 15.9 +/-0.2, 17.6 +/-0.2, 19.4 +/-0.2, 20.0 +/-0.2, 21.8 +/-0.2 and 23.3 +/-0.2 degrees.
Further, the X-ray powder diffraction pattern also comprises characteristic peaks at 10.0 +/-0.2, 12.4 +/-0.2, 15.1 +/-0.2, 17.3 +/-0.2, 17.8 +/-0.2, 19.6 +/-0.2, 19.7 +/-0.2, 24.5 +/-0.2, 25.1 +/-0.2, 26.6 +/-0.2, 27.9 +/-0.2, 31.7 +/-0.2 and 32.7 +/-0.2 degrees 2 theta;
further, in the differential scanning calorimetry analysis of the crystal form III, a melting endothermic peak exists at 316 +/-2 ℃.
The invention also provides a crystal form IV of the compound shown as the formula A, and an X-ray powder diffraction pattern obtained by using Cu-k alpha radiation at least comprises characteristic peaks at the 2 theta positions of 8.7 +/-0.2, 9.0 +/-0.2, 13.2 +/-0.2, 15.9 +/-0.2, 17.6 +/-0.2, 19.4 +/-0.2, 20.0 +/-0.2, 21.8 +/-0.2 and 23.3 +/-0.2 degrees.
Further, the X-ray powder diffraction pattern also comprises characteristic peaks at 10.0 +/-0.2, 12.4 +/-0.2, 15.1 +/-0.2, 17.3 +/-0.2, 17.8 +/-0.2, 19.6 +/-0.2, 19.7 +/-0.2, 24.5 +/-0.2, 25.1 +/-0.2, 26.6 +/-0.2, 27.9 +/-0.2, 31.7 +/-0.2 and 32.7 +/-0.2 degrees 2 theta;
further, in the differential scanning calorimetry analysis of the crystal form IV, a melting endothermic peak exists at 104 +/-2 ℃ and 322 +/-2 ℃;
further, in thermogravimetric analysis of the crystal form IV, the weight loss is continuously carried out at 50-115 +/-2 ℃, and the weight loss exists at 104 +/-2 ℃.
The invention also provides a crystal form V of the compound shown as the formula A, and the X-ray powder diffraction pattern obtained by using Cu-k alpha radiation at least comprises characteristic peaks at the 2 theta positions of 12.9 +/-0.2, 14.8 +/-0.2, 15.5 +/-0.2, 19.5 +/-0.2, 21.6 +/-0.2 and 23.2 +/-0.2 degrees.
Further, the X-ray powder diffraction pattern also comprises characteristic peaks positioned at 8.6 +/-0.2, 9.8 +/-0.2, 14.5 +/-0.2, 15.0 +/-0.2, 19.0 +/-0.2, 20.0 +/-0.2, 21.9 +/-0.2, 24.4 +/-0.2, 26.5 +/-0.2, 27.5 +/-0.2 and 32.1 +/-0.2 degrees 2 theta;
further, in the differential scanning calorimetry analysis of the crystal form V, a melting endothermic peak exists at 322 +/-2 ℃.
The invention also provides a crystal form VI of the compound shown as the formula A, and the X-ray powder diffraction pattern obtained by using Cu-k alpha radiation at least comprises characteristic peaks at the 2 theta positions of 7.4 +/-0.2, 9.4 +/-0.2, 9.9 +/-0.2, 13.0 +/-0.2, 15.4 +/-0.2, 18.1 +/-0.2 and 23.7 +/-0.2 degrees.
Further, the X-ray powder diffraction pattern also comprises characteristic peaks positioned at 11.8 +/-0.2, 17.1 +/-0.2, 18.9 +/-0.2, 19.7 +/-0.2, 21.4 +/-0.2, 22.0 +/-0.2, 25.7 +/-0.2, 27.9 +/-0.2 and 30.6 +/-0.2 degrees 2 theta;
further, in the differential scanning calorimetry analysis of the crystal form VI, melting endothermic peaks exist at 131 +/-2 ℃ and 322 +/-2 ℃;
further, in thermogravimetric analysis of the crystal form VI, the weight loss is continuously carried out at 50-160 +/-2 ℃, and the weight loss exists at 131 +/-2 ℃.
The invention also provides a crystal form VII of the compound shown as the formula A, and an X-ray powder diffraction pattern obtained by using Cu-Kalpha radiation at least comprises characteristic peaks at 2 theta positions of 5.6 +/-0.2, 6.7 +/-0.2, 7.3 +/-0.2, 11.2 +/-0.2, 13.4 +/-0.2, 15.6 +/-0.2, 19.0 +/-0.2, 20.7 +/-0.2 and 25.2 +/-0.2 degrees.
Further, the X-ray powder diffraction pattern also comprises characteristic peaks at 14.1 +/-0.2, 14.6 +/-0.2, 16.1 +/-0.2, 16.4 +/-0.2, 18.0 +/-0.2, 19.9 +/-0.2, 24.2 +/-0.2, 26.8 +/-0.2, 27.5 +/-0.2, 29.2 +/-0.2, 30.0 +/-0.2 and 32.5 +/-0.2 degrees 2 theta;
further, in the differential scanning calorimetry analysis of the crystal form VII, a melting endothermic peak is existed at 323 +/-2 ℃.
The invention also provides a crystal form VIII of the compound shown as the formula A, and a Cu-Kalpha radiation is used to obtain an X-ray powder diffraction pattern, wherein the X-ray powder diffraction pattern at least comprises characteristic peaks positioned at 8.8 +/-0.2, 9.7 +/-0.2, 10.3 +/-0.2, 17.1 +/-0.2, 18.4 +/-0.2, 7 +/-0.2, 21.7 +/-0.2 and 27.5 +/-0.2 degrees 2 theta.
Further, the X-ray powder diffraction pattern also comprises characteristic peaks at 7.0 +/-0.2, 10.7 +/-0.2, 13.6 +/-0.2, 14.6 +/-0.2, 15.3 +/-0.2, 15.8 +/-0.2, 16.2 +/-0.2, 17.7 +/-0.2, 19.5 +/-0.2, 21.0 +/-0.2, 23.0 +/-0.2, 23.7 +/-0.2, 24.9 +/-0.2 and 28.9 +/-0.2 degrees 2 theta;
further, in the differential scanning calorimetry analysis of the crystal form VIII, melting endothermic peaks exist at 103 +/-2 ℃ and 323 +/-2 ℃;
further, in the thermogravimetric analysis of the crystalline form VIII, there is a weight loss at 103 ± 2 ℃.
The invention also provides a crystal form IX of the compound shown as the formula A, and a Cu-Kalpha radiation is used to obtain an X-ray powder diffraction pattern, wherein the X-ray powder diffraction pattern at least comprises characteristic peaks positioned at 6.9 +/-0.2, 7.7 +/-0.2, 8.3 +/-0.2, 10.9 +/-0.2, 17.1 +/-0.2, 18.8 +/-0.2, 21.8 +/-0.2 and 24.3 +/-0.2 degrees 2 theta.
Further, the X-ray powder diffraction pattern also comprises characteristic peaks at 2 theta of 8.9 +/-0.2, 11.6 +/-0.2, 12.7 +/-0.2, 13.2 +/-0.2, 14.7 +/-0.2, 18.1 +/-0.2, 19.5 +/-0.2, 20.8 +/-0.2, 21.3 +/-0.2, 22.3 +/-0.2, 24.8 +/-0.2, 25.4 +/-0.2, 26.5 +/-0.2, 27.3 +/-0.2, 28.3 +/-0.2, 29.1 +/-0.2, 30.1 +/-0.2 and 31.3 +/-0.2 degrees;
further, in the differential scanning calorimetry analysis of the crystal form IX, melting endothermic peaks are provided at 52 +/-2 ℃ and 322 +/-2 ℃;
further, in the thermogravimetric analysis of form IX, there was a weight loss at 51.7 ± 2 ℃.
The invention also provides a crystal form X of the compound shown as the formula A, and the crystal form X at least comprises characteristic peaks at 2 theta degrees of 9.1 +/-0.2, 11.5 +/-0.2, 14.5 +/-0.2, 18.8 +/-0.2, 22.1 +/-0.2 and 23.8 +/-0.2 in an X-ray powder diffraction pattern obtained by using Cu-Kalpha radiation.
Further, the X-ray powder diffraction pattern also comprises characteristic peaks positioned at 10.7 +/-0.2, 18.3 +/-0.2, 19.7 +/-0.2, 21.7 +/-0.2, 22.7 +/-0.2, 24.7 +/-0.2, 28.1 +/-0.2, 29.1 +/-0.2 and 30.3 +/-0.2 degrees 2 theta;
further, in the differential scanning calorimetry analysis of the crystal form X, melting endothermic peaks exist at 53 +/-2 ℃, 119 +/-2 ℃ and 322 +/-2 ℃;
further, in the thermogravimetric analysis of the form X, there was a weight loss at 119 ± 2 ℃.
The invention has the beneficial effects that:
the invention provides multiple crystal forms of a compound A, and the preparation method is simple and easy to implement, wherein the crystal form I has better stability than the amorphous form, can well solve the problem that the amorphous form of the compound A is easy to decompose under the condition of illumination, is more suitable for preparing clinical medicines, and can better ensure the safety and the effectiveness of the medicines.
Drawings
Figure 1 is an amorphous XRPD detection pattern of compound a of the present invention;
FIG. 2 is a DSC/TGA chromatogram of an amorphous form of Compound A of the present invention;
figure 3 is an XRPD detection pattern of form I of the invention;
figure 4 is a DSC/TGA detection profile of form I of the present invention;
figure 5 is an XRPD detection pattern of form II of the invention;
FIG. 6 is a DSC/TGA detection chart of form II of the present invention;
figure 7 is an XRPD detection pattern of form III of the invention;
FIG. 8 is a DSC/TGA survey of form III of the present invention;
figure 9 is an XRPD detection pattern of form IV of the present invention;
figure 10 is a DSC/TGA detection profile of form IV of the present invention;
FIG. 11 is an XRPD detection pattern for form V of the present invention;
FIG. 12 is a DSC/TGA survey of form V of the present invention;
figure 13 is an XRPD detection pattern of form VI of the invention;
FIG. 14 is a DSC/TGA survey of form VI of the present invention;
figure 15 is an XRPD detection pattern of form VII of the present invention;
figure 16 is a DSC/TGA detection profile of form VII of the present invention;
FIG. 17 is an XRPD assay of form VIII of the present invention;
FIG. 18 is a DSC/TGA detection graph of form VIII of the present invention;
figure 19 is an XRPD detection pattern of form IX of the invention;
figure 20 is a DSC/TGA detection graph of form IX of the present invention;
FIG. 21 is an XRPD detection pattern for form X of the present invention;
figure 22 is a DSC/TGA detection graph of form X of the present invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the accompanying drawings, and it should be understood that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In the invention, X-ray powder diffraction (XRPD) analysis adopts Dx-2700BH, Cu target irradiation. The synchronous thermal analyzer (TGA/DSC) of the invention is a Mettler-Toledo TGA/DSC analyzer3+. The rate of temperature rise of the apparatus was 10K/min.
EXAMPLE 1 preparation of amorphous form
After 5g of compound a was dissolved in 50ml to 80ml of a mixed solvent of DCM and MeOH (V: V ═ 4: 6 to 6: 4), the mixture was concentrated under reduced pressure in a water bath at 45 ℃. A translucent solid was obtained. The XRPD assay result (fig. 1) obtained was amorphous. DSC/TGA measurement (FIG. 2) showed that an exothermic peak was observed at about 170. + -. 2 ℃ and an endothermic peak was observed at 322. + -. 2 ℃.
Example 2 preparation of form I
20mg of amorphous compound A was taken and placed in a small brown glass bottle, and the small brown bottle was placed in a larger colorless glass bottle, and 2.5ml of organic solvent a was added to the colorless glass bottle, sealed and allowed to stand for 72 hours. A powdery solid was obtained. The XRPD measurements are shown in fig. 3 and table 1. The DSC/TGA profile shows (fig. 4) that form I shows an endothermic peak at 322 ± 2 ℃ (onset) and the sample starts to melt.
In this embodiment, the organic solvent a adopts one or more of tetrahydrofuran, acetonitrile, toluene, isopropyl acetate, isopropyl ether, ethanol, and ethylene glycol dimethyl ether, and all of them obtain the same crystal form, which is defined as crystal form I.
TABLE 1
Example 3 preparation of form I
Taking 30mg of amorphous compound A, placing the amorphous compound A in a brown glass bottle, adding 0.5ml of single organic solvent b into the glass bottle, dispersing the amorphous compound A, and stirring the mixture at room temperature for 48 hours under sealed conditions to obtain powdery solid. XRPD assay showed form I as in example 2.
In this embodiment, the organic solvent b is selected from any one of tert-butyl alcohol, diethyl ether, isopropyl ether, ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, dimethyl carbonate, cyclohexane, n-heptane, acetonitrile, and ethylene glycol dimethyl ether, and can obtain the crystal form I of the compound a.
Example 4 preparation of crystalline form II
Taking 20mg of the compound A, placing the compound A in a brown glass bottle, adding a proper amount of dichloromethane into the glass bottle to dissolve and clarify, opening the mouth, standing the mixture, and slowly volatilizing the mixture to obtain a crystalline solid. The XRPD assay results are shown in fig. 5 and table 2, and are defined as form II. DSC/TGA profile shows (fig. 6) that form II shows endothermic peaks at 100 ± 2 ℃ (onset) and 319 ± 2 ℃ (onset), with a weight loss of about 11.8% at the first endothermic peak stage, calculated as hemisolvate.
TABLE 2
Characteristic peak: 9.3 +/-0.2 degrees; 12.7 +/-0.2 degrees; 14.7 +/-0.2 degrees; 16.5 +/-0.2 degrees; 19.4 +/-0.2 degrees; 19.8 +/-0.2 degrees; 21.8 +/-0.2 degrees; 24.2 +/-0.2 degrees;
preferred characteristic peaks further include: 12.4 +/-0.2 degrees; 18.9 +/-0.2 degrees; 23.2 +/-0.2 degrees; 25.5 +/-0.2 degrees; 26.0 +/-0.2 degrees; 28.6 +/-0.2 degrees; 30.3 +/-0.2 degrees; 32.8 +/-0.2 degrees;
example 5 preparation of form III
Taking 20mg of the compound A, placing the compound A in a brown glass bottle, adding a proper amount of chloroform into the glass bottle to dissolve and clarify the compound A, opening the glass bottle, standing the glass bottle, and slowly volatilizing the compound A to obtain a crystalline solid. The XRPD assay results are shown in fig. 7 and table 3, and are defined as form III. A DSC/TGA profile (figure 8) shows that form III exhibits an endothermic peak at 316 ± 2 ℃ (onset); no obvious weight loss before 100 ℃.
TABLE 3
Characteristic peak: 8.7 +/-0.2 degrees; 9.0 +/-0.2 degrees; 13.2 +/-0.2 degrees; 15.9 +/-0.2 degrees; 17.6 +/-0.2 degrees; 19.4 +/-0.2 degrees; 20.0 +/-0.2 degrees; 21.8 +/-0.2 degrees; 23.3 +/-0.2 degrees;
preferred characteristic peaks further include: 10.0 plus or minus 0.2 degrees; 12.4 +/-0.2 degrees; 15.1 +/-0.2 degrees; 17.3 +/-0.2 degrees; 17.8 +/-0.2 degrees; 19.6 +/-0.2 degrees; 19.7 +/-0.2 degrees; 24.5 +/-0.2 degrees; 25.1 +/-0.2 degrees; 26.6 +/-0.2 degrees; 27.9 +/-0.2 degrees; 31.7 +/-0.2 degrees; 32.7 +/-0.2 degrees.
Example 6 preparation of form IV
Taking 20mg of compound A, placing the compound A in a brown glass bottle, adding 1.0ml of tetrahydrofuran into the glass bottle to dissolve and clarify, opening the mouth, standing and slowly volatilizing to obtain a crystalline solid. The XRPD assay results are shown in fig. 9 and table 4, and are defined as form IV. A DSC/TGA profile (figure 10) shows that form IV exhibits endothermic peaks at 104 ± 2 ℃ (onset) and 322 ± 2 ℃ (onset); and (3) continuous weight loss occurs at 50-115 +/-2 ℃, wherein obvious weight loss exists at 104 +/-2 ℃, the weight loss is about 8%, and the crystal form IV is a semi-solvate through calculation.
TABLE 4
Characteristic peak: 5.0 +/-0.2 degrees; 6.1 +/-0.2 degrees; 9.9 +/-0.2 degrees; 10.9 +/-0.2 degrees; 13.6 +/-0.2 degrees; 15.6 +/-0.2 degrees; 19.7 +/-0.2 degrees; 21.8 +/-0.2 degrees;
preferred characteristic peaks further include: 7.9 +/-0.2 degrees; 9.6 +/-0.2 degrees; 11.5 +/-0.2 degrees; 14.4 +/-0.2 degrees; 15.0 +/-0.2 degrees; 17.4 +/-0.2 degrees; 18.5 +/-0.2 degrees; 21.0 +/-0.2 degrees; 23.1 +/-0.2 degrees; 23.4 +/-0.2 degrees; 25.2 +/-0.2 degrees; 27.6 +/-0.2 degrees; 28.3 +/-0.2 degrees; 29.2 +/-0.2 deg.
Example 7 preparation of form V
Taking 20mg of compound A, placing the compound A in a brown glass bottle, adding 0.5ml of methanol into the glass bottle, dissolving and clarifying, opening the mouth, standing, and slowly volatilizing to obtain a crystalline solid. The XRPD pattern is shown in fig. 11 and table 5, and is defined as form V. DSC/TGA profile (figure 12) shows that form V shows an endothermic peak at 322 ± 2 ℃ (onset) and the sample begins to melt.
TABLE 5
Characteristic peak: 12.9 +/-0.2 degrees; 14.8 +/-0.2 degrees; 15.5 +/-0.2 degrees; 19.5 +/-0.2 degrees; 21.6 +/-0.2 degrees; 23.2 +/-0.2 degrees;
preferred characteristic peaks further include: 8.6 +/-0.2 degrees; 9.8 +/-0.2 degrees; 14.5 +/-0.2 degrees; 15.0 +/-0.2 degrees; 19.0 +/-0.2 degrees; 20.0 +/-0.2 degrees; 21.9 +/-0.2 degrees; 24.4 +/-0.2 degrees; 26.5 +/-0.2 degrees; 27.5 +/-0.2 degrees; 32.1 +/-0.2 degrees.
Example 8 preparation of form VI
Taking 20mg of compound A, placing the compound A in a brown glass bottle, adding 0.7ml of acetone into the glass bottle, dissolving and clarifying, opening the mouth, standing, and slowly volatilizing to obtain a crystalline solid. XRPD assay results are shown in fig. 13 and table 6, defined as form VI. A DSC/TGA profile (fig. 14.) shows that form VI exhibits endothermic peaks at 131 ± 2 ℃ (onset) and 322 ± 2 ℃ (onset), and an exothermic peak at 171 ℃; the continuous weight loss occurs at 50-160 +/-2 ℃, wherein the obvious weight loss occurs at 131 +/-2 ℃.
TABLE 6
Characteristic peak: 7.4 +/-0.2 degrees; 9.4 +/-0.2 degrees; 9.9 +/-0.2 degrees; 13.0 plus or minus 0.2 degrees; 15.4 +/-0.2 degrees; 18.1 +/-0.2 degrees; 23.7 +/-0.2 degrees;
preferred characteristic peaks further include: 11.8 +/-0.2 degrees; 17.1 +/-0.2 degrees; 18.9 +/-0.2 degrees; 19.7 +/-0.2 degrees; 21.4 +/-0.2 degrees; 22.0 +/-0.2 degrees; 25.7 +/-0.2 degrees; 27.9 +/-0.2 degrees; 30.6 +/-0.2 degrees.
Example 9 preparation of form VI
Placing 40mg of amorphous compound A (or crystal form I) in a brown glass bottle, adding 0.5ml of acetone into the glass bottle, dispersing and amorphous, and stirring at room temperature for 48 hours under sealed condition to obtain powdery solid. XRPD assay showed the same as example 8, as form VI.
Example 10 preparation of crystalline form VII
Taking 20mg of the compound A, placing the compound A in a brown glass bottle, adding 2.5ml of butanone into the glass bottle, dissolving and clarifying, opening the mouth, standing, and slowly volatilizing to obtain a crystalline solid. XRPD measurements are shown in fig. 15 and table 7 and are defined as form VII. DSC/TGA profile (fig. 16) shows that form VII shows an endothermic peak at 323 ± 2 ℃ (onset) and the sample begins to melt; the sample did not lose significant weight until 100 ℃.
TABLE 7
Characteristic peak: 5.6 +/-0.2 degrees; 6.7 +/-0.2 degrees; 7.3 +/-0.2 degrees; 11.2 +/-0.2 degrees; 13.4 +/-0.2 degrees; 15.6 +/-0.2 degrees; 19.0 +/-0.2 degrees; 20.7 +/-0.2 degrees; 25.2 +/-0.2 degrees;
preferred characteristic peaks further include: 14.1 +/-0.2 degrees; 14.6 +/-0.2 degrees; 16.1 +/-0.2 degrees; 16.4 +/-0.2 degrees; 18.0 +/-0.2 degrees; 19.9 +/-0.2 degrees; 24.2 +/-0.2 degrees; 26.8 +/-0.2 degrees; 27.5 +/-0.2 degrees; 29.2 ± 0.2 °; 30.0 +/-0.2 degrees; 32.5 +/-0.2 degrees.
Example 11 preparation of crystalline form VII
Taking 30mg of amorphous compound A (or crystal form I), placing the amorphous compound A (or crystal form I) in a brown glass bottle, adding 0.5ml of butanone into the glass bottle, dispersing the amorphous compound, and stirring the amorphous compound at room temperature for 48 hours under sealed conditions to obtain powdery solid. XRPD assay showed the same as example 10 as form VI.
Example 12 preparation of crystalline form VIII
30mg of amorphous Compound A was placed in a brown glass bottle, and 0.5ml of methyl tert-ether was added to the bottle to disperse the amorphous compound, followed by stirring at room temperature under a sealed condition for 48 hours to obtain a powdery solid. The XRPD assay results are shown in fig. 17 and table 8, and are defined as form VIII. A DSC/TGA profile (fig. 18) shows that form VIII shows endothermic peaks at 103 ± 2 ℃ (onset), 323 ± 2 ℃ (onset), respectively; almost no weight loss before 100 ℃, and the weight loss is about 9 percent at 103 +/-2 ℃.
TABLE 8
Characteristic peak: 8.8 +/-0.2 degrees; 9.7 +/-0.2 degrees; 10.3 +/-0.2 degrees; 17.1 +/-0.2 degrees; 18.4 +/-0.2 degrees; 7 +/-0.2 degrees; 21.7 +/-0.2 degrees; 27.5 +/-0.2 degrees;
preferred characteristic peaks further include: 7.0 +/-0.2 degrees; 10.7 +/-0.2 degrees; 13.6 +/-0.2 degrees; 14.6 +/-0.2 degrees; 15.3 +/-0.2 degrees; 15.8 +/-0.2 degrees; 16.2 +/-0.2 degrees; 17.7 +/-0.2 degrees; 19.5 +/-0.2 degrees; 21.0 +/-0.2 degrees; 23.0 +/-0.2 degrees; 23.7 +/-0.2 degrees; 24.9 +/-0.2 degrees; 28.9 +/-0.2 degrees.
Example 13 preparation of crystalline form IX
30mg of amorphous Compound A was placed in a brown glass bottle, and 0.5ml of water was added to the bottle to disperse the amorphous compound, followed by stirring at room temperature for 72 hours under a sealed condition to obtain a powdery solid. The XRPD pattern is shown in fig. 19 and table 9 and is defined as form IX. DSC/TGA characterization (fig. 20) shows: form IX presents two endothermic peaks at 52 ± 2 ℃ (onset) and 322 ± 2 ℃ (onset), beginning to lose weight of about 4.2% (about 1eq) around 51.7 ℃; while two consecutive exothermic peaks follow the first endothermic peak.
TABLE 9
Characteristic peak: 6.9 +/-0.2 degrees; 7.7 +/-0.2 degrees; 8.3 +/-0.2 degrees; 10.9 +/-0.2 degrees; 17.1 +/-0.2 degrees; 18.8 +/-0.2 degrees; 21.8 +/-0.2 degrees; 24.3 +/-0.2 degrees;
preferred characteristic peaks further include: 8.9 +/-0.2 degrees; 11.6 +/-0.2 degrees; 12.7 +/-0.2 degrees; 13.2 +/-0.2 degrees; 14.7 +/-0.2 degrees; 18.1 +/-0.2 degrees; 19.5 +/-0.2 degrees; 20.8 +/-0.2 degrees; 21.3 +/-0.2 degrees; 22.3 +/-0.2 degrees; 24.8 +/-0.2 degrees; 25.4 +/-0.2 degrees; 26.5 +/-0.2 degrees; 27.3 +/-0.2 degrees; 28.3 +/-0.2 degrees; 29.1 +/-0.2 degrees; 30.1 +/-0.2 degrees; 31.3 +/-0.2 degrees.
Example 14 preparation of form X
Taking 35mg of amorphous compound A, placing the amorphous compound A in a brown glass bottle, adding 0.4ml of dioxane into the glass bottle, dispersing the amorphous compound, and stirring the mixture at room temperature for 72 hours under sealed conditions to obtain powdery solid. The XRPD pattern is shown in fig. 21 and table 10, and is defined as form X. A DSC/TGA profile (fig. 22.) shows form X with endothermic peaks at 53 ± 2 ℃ (onset), 119 ± 2 ℃ (onset), 322 ± 2 ℃ (onset); the crystal form X has obvious weight loss at 119 +/-2 ℃.
Characteristic peak: 9.1 +/-0.2 degrees; 11.5 +/-0.2 degrees; 14.5 +/-0.2 degrees; 18.8 +/-0.2 degrees; 22.1 +/-0.2 degrees; 23.8 +/-0.2 degrees;
preferred characteristic peaks further include: 10.7 +/-0.2 degrees; 18.3 +/-0.2 degrees; 19.7 +/-0.2 degrees; 21.7 +/-0.2 degrees; 22.7 +/-0.2 degrees; 24.7 +/-0.2 degrees; 28.1 +/-0.2 degrees; 29.1 +/-0.2 degrees; 30.3 +/-0.2 degrees.
Example 15
Stability of the crystalline form of the invention compared to the amorphous form:
TABLE 11 amorphous stability Effect data
Table 12 crystal form I stability effect data
As can be seen from the comparison of the data in tables 11 and 12, the stability of the crystal form I of the present invention is superior to that of the amorphous form under all conditions, the amorphous form is significantly degraded under light, and the crystal form I of the present invention can be kept stable under light, high temperature or high humidity.
TABLE 13 variation of major impurities for Compound A
The data in table 13 demonstrate that compound a has significantly increased amorphous impurity levels under light conditions, while the impurity levels of form I remain substantially stable, further demonstrating the better stability of form I of the present invention.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (18)
1. A crystalline form I of a compound of formula a, wherein an X-ray powder diffraction pattern obtained using Cu-k α radiation includes at least characteristic peaks at 8.8 ± 0.2, 9.9 ± 0.2, 13.1 ± 0.2, 14.9 ± 0.2, 17.7 ± 0.2, 19.8 ± 0.2, 21.6 ± 0.2, 23.3 ± 0.2 degrees 2 Θ:
2. form I according to claim 1, further comprising characteristic peaks in the X-ray powder diffraction pattern at 12.3 ± 0.2, 15.7 ± 0.2, 17.1 ± 0.2, 19.3 ± 0.2, 20.3 ± 0.2, 24.5 ± 0.2, 24.9 ± 0.2, 26.4 ± 0.2, 27.7 ± 0.2, 31.6 ± 0.2 degrees 2 Θ.
3. Form I according to claim 1 or 2, characterized in that the X-ray powder diffraction pattern is as shown in figure 3.
4. Form I according to any one of claims 1 to 3, characterized by a melting endotherm at 322 ℃ ± 2 ℃ in differential scanning calorimetry.
5. A process for preparing form I according to any one of claims 1 to 4, comprising:
mixing an amorphous compound A with an organic solvent a, and placing the mixture under a sealing condition for 68-80 hours; the amorphous compound A: the feed-liquid ratio of the organic solvent a is 6-10 mg/mL; the organic solvent a is one or more selected from tetrahydrofuran, acetonitrile, toluene, isopropyl acetate, isopropyl ether, ethanol and ethylene glycol dimethyl ether.
Further, the mixture is placed under a sealing condition for 72 hours; the amorphous compound A: the feed-to-liquid ratio of the organic solvent was 8 mg/mL.
6. A process for preparing form I according to any one of claims 1 to 4, comprising: mixing the amorphous compound A with an organic solvent b, and stirring for 40-55 h; the amorphous compound A: the material-liquid ratio of the organic solvent b is 50-70 mg/mL; the organic solvent b is selected from one of tert-butyl alcohol, diethyl ether, isopropyl ether, ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, dimethyl carbonate, cyclohexane, n-heptane, acetonitrile and ethylene glycol dimethyl ether.
Further, the stirring time was 48h, and the amorphous compound a: the feed-to-liquid ratio of the organic solvent b was 60 mg/mL.
7. The method according to any one of claims 5 to 6, wherein the method is carried out under a condition of shielding from light.
8. Use of the crystalline form I according to any one of claims 1 to 4 for the preparation of a TRK inhibitor and/or a protein kinase inhibitor.
9. A pharmaceutical composition comprising the crystalline form I according to any one of claims 1 to 4.
10. A crystalline form II of a compound of formula a, wherein an X-ray powder diffraction pattern obtained using Cu-k α radiation includes at least characteristic peaks at 9.3 ± 0.2, 12.7 ± 0.2, 14.7 ± 0.2, 16.5 ± 0.2, 19.4 ± 0.2, 19.8 ± 0.2, 21.8 ± 0.2, 24.2 ± 0.2 degrees 2 Θ:
further, the X-ray powder diffraction pattern also comprises characteristic peaks positioned at 12.4 +/-0.2, 18.9 +/-0.2, 23.2 +/-0.2, 25.5 +/-0.2, 26.0 +/-0.2, 28.6 +/-0.2, 30.3 +/-0.2 and 32.8 +/-0.2 degrees 2 theta;
further, in the differential scanning calorimetry analysis of the crystal form II, a melting endothermic peak exists at 100 +/-2 ℃ and 319 +/-2 ℃.
11. A crystalline form III of a compound of formula a, wherein an X-ray powder diffraction pattern obtained using Cu-k α radiation includes at least characteristic peaks at 8.7 ± 0.2, 9.0 ± 0.2, 13.2 ± 0.2, 15.9 ± 0.2, 17.6 ± 0.2, 19.4 ± 0.2, 20.0 ± 0.2, 21.8 ± 0.2, 23.3 ± 0.2 degrees 2 Θ:
further, the X-ray powder diffraction pattern also comprises characteristic peaks at 10.0 +/-0.2, 12.4 +/-0.2, 15.1 +/-0.2, 17.3 +/-0.2, 17.8 +/-0.2, 19.6 +/-0.2, 19.7 +/-0.2, 24.5 +/-0.2, 25.1 +/-0.2, 26.6 +/-0.2, 27.9 +/-0.2, 31.7 +/-0.2 and 32.7 +/-0.2 degrees 2 theta;
further, in the differential scanning calorimetry analysis of the crystal form III, a melting endothermic peak exists at 316 +/-2 ℃.
12. A crystalline form IV of a compound of formula a, characterized by an X-ray powder diffraction pattern using Cu-ka radiation that includes at least characteristic peaks at 8.7 ± 0.2, 9.0 ± 0.2, 13.2 ± 0.2, 15.9 ± 0.2, 17.6 ± 0.2, 19.4 ± 0.2, 20.0 ± 0.2, 21.8 ± 0.2, 23.3 ± 0.2 degrees 2 Θ:
further, the X-ray powder diffraction pattern also comprises characteristic peaks at 10.0 +/-0.2, 12.4 +/-0.2, 15.1 +/-0.2, 17.3 +/-0.2, 17.8 +/-0.2, 19.6 +/-0.2, 19.7 +/-0.2, 24.5 +/-0.2, 25.1 +/-0.2, 26.6 +/-0.2, 27.9 +/-0.2, 31.7 +/-0.2 and 32.7 +/-0.2 degrees 2 theta;
further, in the differential scanning calorimetry analysis of the crystal form IV, a melting endothermic peak exists at 104 +/-2 ℃ and 322 +/-2 ℃;
further, in thermogravimetric analysis of the crystal form IV, the weight loss is continuously carried out at 50-115 +/-2 ℃, and the weight loss exists at 104 +/-2 ℃.
13. A crystalline form V of a compound of formula a, characterized by an X-ray powder diffraction pattern using Cu-k α radiation comprising at least characteristic peaks at 12.9 ± 0.2, 14.8 ± 0.2, 15.5 ± 0.2, 19.5 ± 0.2, 21.6 ± 0.2, 23.2 ± 0.2 degrees 2 Θ:
further, the X-ray powder diffraction pattern also comprises characteristic peaks positioned at 8.6 +/-0.2, 9.8 +/-0.2, 14.5 +/-0.2, 15.0 +/-0.2, 19.0 +/-0.2, 20.0 +/-0.2, 21.9 +/-0.2, 24.4 +/-0.2, 26.5 +/-0.2, 27.5 +/-0.2 and 32.1 +/-0.2 degrees 2 theta;
further, in the differential scanning calorimetry analysis of the crystal form V, a melting endothermic peak exists at 322 +/-2 ℃.
14. A crystalline form VI of a compound of formula a, wherein the X-ray powder diffraction pattern obtained using Cu-k α radiation includes at least characteristic peaks at 7.4 ± 0.2, 9.4 ± 0.2, 9.9 ± 0.2, 13.0 ± 0.2, 15.4 ± 0.2, 18.1 ± 0.2, 23.7 ± 0.2 degrees 2 Θ:
further, the X-ray powder diffraction pattern also comprises characteristic peaks positioned at 11.8 +/-0.2, 17.1 +/-0.2, 18.9 +/-0.2, 19.7 +/-0.2, 21.4 +/-0.2, 22.0 +/-0.2, 25.7 +/-0.2, 27.9 +/-0.2 and 30.6 +/-0.2 degrees 2 theta;
further, in the differential scanning calorimetry analysis of the crystal form VI, melting endothermic peaks exist at 131 +/-2 ℃ and 322 +/-2 ℃;
further, in thermogravimetric analysis of the crystal form VI, the weight loss is continuously carried out at 50-160 +/-2 ℃, and the weight loss exists at 131 +/-2 ℃.
15. A crystalline form VII of a compound of formula a, characterized by an X-ray powder diffraction pattern using Cu-ka radiation that includes at least characteristic peaks at 5.6 ± 0.2, 6.7 ± 0.2, 7.3 ± 0.2, 11.2 ± 0.2, 13.4 ± 0.2, 15.6 ± 0.2, 19.0 ± 0.2, 20.7 ± 0.2, 25.2 ± 0.2 degrees 2 Θ:
further, the X-ray powder diffraction pattern also comprises characteristic peaks at 14.1 +/-0.2, 14.6 +/-0.2, 16.1 +/-0.2, 16.4 +/-0.2, 18.0 +/-0.2, 19.9 +/-0.2, 24.2 +/-0.2, 26.8 +/-0.2, 27.5 +/-0.2, 29.2 +/-0.2, 30.0 +/-0.2 and 32.5 +/-0.2 degrees 2 theta;
further, in the differential scanning calorimetry analysis of the crystal form VII, a melting endothermic peak is existed at 323 +/-2 ℃.
16. A crystalline form VIII of a compound of formula a, characterized by an X-ray powder diffraction pattern using Cu-ka radiation comprising at least characteristic peaks at 8.8 ± 0.2, 9.7 ± 0.2, 10.3 ± 0.2, 17.1 ± 0.2, 18.4 ± 0.2, 7 ± 0.2, 21.7 ± 0.2, 27.5 ± 0.2 degrees 2 Θ:
further, the X-ray powder diffraction pattern also comprises characteristic peaks at 7.0 +/-0.2, 10.7 +/-0.2, 13.6 +/-0.2, 14.6 +/-0.2, 15.3 +/-0.2, 15.8 +/-0.2, 16.2 +/-0.2, 17.7 +/-0.2, 19.5 +/-0.2, 21.0 +/-0.2, 23.0 +/-0.2, 23.7 +/-0.2, 24.9 +/-0.2 and 28.9 +/-0.2 degrees 2 theta;
further, in the differential scanning calorimetry analysis of the crystal form VIII, melting endothermic peaks exist at 103 +/-2 ℃ and 323 +/-2 ℃;
further, in the thermogravimetric analysis of the crystalline form VIII, there is a weight loss at 103 ± 2 ℃.
17. A crystalline form IX of a compound of formula a, comprising at least characteristic peaks at 6.9 ± 0.2, 7.7 ± 0.2, 8.3 ± 0.2, 10.9 ± 0.2, 17.1 ± 0.2, 18.8 ± 0.2, 21.8 ± 0.2, 24.3 ± 0.2 degrees 2 Θ in an X-ray powder diffraction pattern obtained using Cu-ka radiation:
further, the X-ray powder diffraction pattern also comprises characteristic peaks at 2 theta of 8.9 +/-0.2, 11.6 +/-0.2, 12.7 +/-0.2, 13.2 +/-0.2, 14.7 +/-0.2, 18.1 +/-0.2, 19.5 +/-0.2, 20.8 +/-0.2, 21.3 +/-0.2, 22.3 +/-0.2, 24.8 +/-0.2, 25.4 +/-0.2, 26.5 +/-0.2, 27.3 +/-0.2, 28.3 +/-0.2, 29.1 +/-0.2, 30.1 +/-0.2 and 31.3 +/-0.2 degrees;
further, in the differential scanning calorimetry analysis of the crystal form IX, melting endothermic peaks are provided at 52 +/-2 ℃ and 322 +/-2 ℃;
further, in the thermogravimetric analysis of form IX, there was a weight loss at 51.7 ± 2 ℃.
18. A crystalline form X of a compound of formula a, characterized by an X-ray powder diffraction pattern obtained using Cu-k α radiation comprising at least characteristic peaks at 9.1 ± 0.2, 11.5 ± 0.2, 14.5 ± 0.2, 18.8 ± 0.2, 22.1 ± 0.2, 23.8 ± 0.2 degrees 2 Θ:
further, the X-ray powder diffraction pattern also comprises characteristic peaks positioned at 10.7 +/-0.2, 18.3 +/-0.2, 19.7 +/-0.2, 21.7 +/-0.2, 22.7 +/-0.2, 24.7 +/-0.2, 28.1 +/-0.2, 29.1 +/-0.2 and 30.3 +/-0.2 degrees 2 theta;
further, in the differential scanning calorimetry analysis of the crystal form X, melting endothermic peaks exist at 53 +/-2 ℃, 119 +/-2 ℃ and 322 +/-2 ℃;
further, in the thermogravimetric analysis of the form X, there was a weight loss at 119 ± 2 ℃.
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