CN110790748B - Crystal form of p-toluenesulfonate of cyclin dependent kinase inhibitor and preparation method and application thereof - Google Patents

Crystal form of p-toluenesulfonate of cyclin dependent kinase inhibitor and preparation method and application thereof Download PDF

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CN110790748B
CN110790748B CN201910701098.6A CN201910701098A CN110790748B CN 110790748 B CN110790748 B CN 110790748B CN 201910701098 A CN201910701098 A CN 201910701098A CN 110790748 B CN110790748 B CN 110790748B
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isopropyl
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cyclopropylamino
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单文俊
吕梦远
周红卫
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
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Abstract

The invention relates to a p-toluenesulfonate crystal form of a cyclin-dependent kinase inhibitor, and a preparation method and application thereof. The invention relates to a crystal form of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone p-toluenesulfonate and a preparation method thereof, as well as a pharmaceutical composition containing a therapeutically effective amount of the crystal form and application thereof in treating and/or preventing cancer or tumor-related diseases mediated by CDK 4/6.

Description

Crystal form of p-toluenesulfonate of cyclin dependent kinase inhibitor and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicine crystal forms, and particularly relates to a (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridine-3-yl) methanone p-toluenesulfonate crystal form and a preparation method and application thereof.
Background
Cyclin-dependent kinases (CDKs) are a class of serine (Ser)/threonine (Thr) kinase systems that are involved in cell cycle progression, and the CDKs act in each cycle of the cell to promote orderly proliferation of the cell. CDK4/6 is a key regulator of the cell cycle, specifically forms a complex with Cyclin D1, leads to inactivation of the cancer suppressor Rb, initiates downstream gene expression, and has an INK4A-Cyclin D-CDK4/6 pathway abnormality in about 80% of human tumors. CDK4/6 overexpression, CyclinD amplification or p16 deletion all result in abnormal CDK4/6 signaling pathway activity, leading to uncontrolled cell proliferation.
The number of new breast cancer cases in China reaches 27.24 thousands, and the incidence rate of malignant tumors of women is the first. Among them 83% are HR +/HER 2-breast cancer patients. The newly diagnosed breast cancer cases account for 12.2 percent of the world every year in China, and the new disease rate is increased by 2 times of the average level in the world. CDK4/6 is downstream of the ER/PR signaling pathway, with abnormalities in the CDK 4/6-associated signaling pathway in approximately 80% of breast cancers. Currently, CDK4/6 inhibitors which are marketed include palbociclib, ribociclib and abemacciclib, and are used for treating HR +/HER 2-breast cancer patients in combination with endocrine therapy, and the curative effect is remarkable. In 2015, the FDA approved the world's first CDK4/6 inhibitor Ibrand (Palbociclib) for marketing, and in combination with letrozole for estrogen receptor positive (ER +), human epidermal growth factor receptor 2 negative (HER2-) women with advanced breast cancer, the world sales of this breed exceeded $ 21.35 billion in 2016, and the cumulative sales of $ 15.32 billion in the first half of 2017.
Disclosure of Invention
The invention aims to provide a crystal form of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone p-toluenesulfonate.
In a preferred embodiment of the present invention, the crystalline form of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone p-toluenesulfonate has the following structure as shown in formula (I):
Figure BDA0002150850600000021
wherein: x is 0-4 and y is 0-3.
In a preferred embodiment of the invention, x is 0, 1, 2, 3 or 4, preferably 1.
In a preferred embodiment of the invention, y is 0, 1, 2 or 3, preferably 1.
In a preferred embodiment of the present invention, the crystalline form is (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone p-toluenesulfonate monohydrate, having the structural formula shown in formula (II):
Figure BDA0002150850600000022
in a preferred embodiment of the present invention, the (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone p-toluenesulfonate monohydrate is form IV.
Wherein the X-ray powder diffraction pattern of the crystal form IV has characteristic peaks at 2 theta values of 4.2 +/-0.2 degrees, 5.6 +/-0.2 degrees, 6.3 +/-0.2 degrees, 7.3 +/-0.2 degrees, 8.0 +/-0.2 degrees, 9.6 +/-0.2 degrees, 12.6 +/-0.2 degrees, 13.3 +/-0.2 degrees, 13.6 +/-0.2 degrees, 16.6 +/-0.2 degrees, 17.1 +/-0.2 degrees, 21.9 +/-0.2 degrees, 22.7 +/-0.2 degrees or 25.4 +/-0.2 degrees.
Further, the X-ray powder diffraction pattern data of said form IV is as shown in table 1.
According to Karl Fischer water content detection, 0.2g of sample is weighed, dissolved in 40Ml of methanol and injected into a Karl Fischer water content tester, and the result shows that the crystal form IV is monohydrate.
TABLE 1
Serial number 2θ(°) d value Peak intensity (I%)
1 4.176 21.1425 36.2
2 5.551 15.9075 30.9
3 6.281 14.0609 83.4
4 7.337 12.0391 100.0
5 7.955 11.10465 71.0
6 8.765 10.0801 27.6
7 9.602 9.2040 41.0
8 10.119 7.7346 15.4
9 11.342 7.7955 23.8
10 12.131 7.2899 27.2
11 12.578 7.0136 31.7
12 13.277 6.6630 42.5
13 13.559 6.5253 35.0
14 14.465 6.1185 30.4
15 14.723 6.0119 36.2
16 16.555 5.3506 39.9
17 17.108 5.1786 42.5
18 17.553 5.0484 30.4
19 18.971 4.6742 34.1
20 19.518 4.5443 35.5
21 19.912 4.4553 28.7
22 21.082 4.2106 22.5
23 21.927 4.0502 37.5
24 22.672 3.9189 72.3
25 24.572 3.6199 19.8
26 25.370 3.5079 59.7
27 26.497 3.3611 23.3
28 27.395 3.2530 28.7
29 28.475 3.1320 25.1
30 31.865 2.8061 16.6
Further, the form IV has an X-ray powder diffraction pattern as shown in figure 1.
In a preferred embodiment of the present invention, the (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone p-toluenesulfonate monohydrate is in form V.
Wherein the X-ray powder diffraction pattern of the crystal form V has characteristic peaks at 2 theta values of 4.1 +/-0.2 degrees, 4.9 +/-0.2 degrees, 6.6 +/-0.2 degrees, 7.1 +/-0.2 degrees, 10.2 +/-0.2 degrees, 12.1 +/-0.2 degrees, 12.6 +/-0.2 degrees, 14.5 +/-0.2 degrees, 17.1 +/-0.2 degrees, 24.0 +/-0.2 degrees, 25.4 +/-0.2 degrees or 26.6 +/-0.2 degrees.
Further, the X-ray powder diffraction pattern data of said form IV is as shown in table 2.
According to Karl Fischer water content detection, the crystal form V is a monohydrate crystal form.
TABLE 2
Serial number 2θ(°) d value Peak intensity (I%)
1 4.129 21.3836 83.5
2 4.878 18.1001 100.0
3 6.609 13.3639 52.3
4 7.090 12.4571 48.8
5 8.556 10.3259 28.5
6 10.166 8.6944 52.5
7 11.244 7.8626 36.1
8 11.624 7.6069 43.5
9 12.063 7.3308 49.1
10 12.577 7.0324 52.8
11 14.496 6.1055 47.0
12 15.207 5.8214 33.5
13 16.003 5.5339 33.6
14 17.114 5.1769 52.6
15 18.218 4.8655 36.6
16 20.858 4.2554 43.9
17 21.472 4.1351 42.9
18 23.950 3.7125 49.3
19 25.366 3.5084 57.0
20 26.617 3.3462 49.1
Further, the X-ray powder diffraction pattern of form V is shown in fig. 2.
The invention also aims to provide a preparation method of the crystal form of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone p-toluenesulfonate, which comprises the following steps:
(1) dissolving (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone in a benign solvent to form a solution;
(2) dissolving p-toluenesulfonic acid or hydrate thereof in a ketone, ether or alcohol solvent to form a solution;
(3) dropwise adding the solution obtained in the step (2) into the solution obtained in the step (1), optionally adding a poor solvent, and stirring for crystallization;
(4) filtering and drying;
wherein, the benign solvent in the step (1) is an alcohol solvent, preferably an alcohol solvent containing 1-4 carbon atoms, and more preferably methanol or ethanol.
The mass to volume ratio (g/ml) of the (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone to benign solvent in step (1) is 1: 5-50, preferably 1:10 to 30, preferably 1:10 to 20.
The paratoluenesulfonic acid hydrate in the step (2) is paratoluenesulfonic acid monohydrate.
The ketone solvent in the step (2) is a ketone solvent containing 3-5 carbon atoms, and acetone or butanone is preferred; the alcohol solvent is an alcohol solvent containing 1-4 carbon atoms, and preferably methanol or ethanol; the ether solvent is methyl tert-butyl ether or isopropyl ether.
The mass-to-volume ratio (g/ml) of the p-toluenesulfonic acid or the hydrate thereof to the solvent in the step (2) is 1: 5-50, preferably 1: 6-40.
In the step (3), when the poor solvent is selected to be added, the poor solvent is an alkane solvent, an ester solvent or an ether solvent; the preferred ether solvent is methyl tert-butyl ether or isopropyl ether; preferably, the ester solvent is isopropyl acetate; further, the amount (ml) of the poor solvent to be added is 10 to 40 times, preferably 14 to 34 times, the mass (g) of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone.
In the step (3), no special requirement is imposed on the stirring time, and the stirring time for preparing the crystal form IV is generally 0.5-48 hours, preferably 12-36 hours, and more preferably 12-24 hours; the stirring time for preparing the crystal form V is 0.5-48 hours, preferably 1-12 hours, and more preferably 1-5 hours.
The drying in the step (4) is carried out under the conditions of forced air heating or vacuum heating, and the drying temperature is 30-50 ℃, preferably 30-40 ℃.
It is also an object of the present invention to provide a pharmaceutical composition comprising an effective amount of the crystalline form of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone p-toluenesulfonate described above and one or more pharmaceutically acceptable excipients, preferably form IV or form V.
It is also an object of the present invention to provide a method of using a crystalline form of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone p-toluenesulfonate or a pharmaceutical composition thereof for the treatment and/or prevention of a cancer or a tumor-related disease mediated by CDK4/6, wherein the cancer or tumor-related disease comprises a brain tumor, a lung cancer, a liver cancer, a stomach cancer, an oral cancer, a head and neck cancer, an intestinal or rectal cancer, a colon cancer, a kidney cancer, an esophageal adenocarcinoma, an esophageal squamous cell cancer, a thyroid cancer, a prostate cancer, a method of the invention, Bone cancer, skin cancer, non-small cell lung cancer, carcinoma in situ, lymphoma, neurofibroma, neuroblastoma, mast cell tumor, multiple myeloma, melanoma, glioma, sarcoma or liposarcoma, glioblastoma, bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer, cancer of the female reproductive tract, testicular cancer, gastrointestinal stromal tumor, or prostate tumor; preferably selected from bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer, cancer of the female reproductive tract, testicular cancer, gastrointestinal stromal tumors, or prostate tumor.
The (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone tosylate crystal form, particularly the crystal form IV and the crystal form V, have good stability, high solubility, small hygroscopicity and good fluidity, are suitable for development of pharmaceutical preparations, and are particularly suitable for development of oral pharmaceutical preparations; has high bioavailability.
Drawings
Figure 1 is an X-ray powder diffraction pattern of form iv.
Figure 2 is an X-ray powder diffraction pattern of form v.
Detailed Description
The following detailed description of embodiments of the present invention is provided in connection with the accompanying drawings and examples. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
EXAMPLE 1 preparation of crystalline form IV
Weighing 0.5g of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone, adding 10mL of methanol, and stirring to dissolve the mixture at room temperature; 0.175g of p-toluenesulfonic acid monohydrate is weighed and dissolved in 1.0mL of ethanol, dropwise added, stirred for 30 minutes after the addition, dropwise added with 17mL of methyl tert-butyl ether, stirred overnight, filtered, and vacuum-dried at 40 ℃ for 5 hours to obtain the crystal form IV.
EXAMPLE 2 preparation of form IV
0.5g of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone was weighed, 5mL of methanol was added, the mixture was stirred and dissolved at room temperature, 0.175g of p-toluenesulfonic acid monohydrate was weighed and dissolved in 1.0mL of ethanol, and dropwise added, followed by stirring for 30 minutes, 7mL of methyl tert-butyl ether, stirring overnight, filtration, and vacuum drying at 40 ℃ for 5 hours to give crystalline form IV.
EXAMPLE 3 preparation of form V
Weighing 1.0g of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone, adding 20mL of methanol, stirring to dissolve at room temperature, weighing 0.35g of p-toluenesulfonic acid monohydrate, dissolving in 2.0mL of ethanol, dropwise adding 30mL of methyl tert-butyl ether after dropwise addition, stirring for 1.5 hours, filtering, and vacuum drying at 40 ℃ for 5 hours to obtain the crystal form V.
EXAMPLE 4 preparation of form V
Weighing 1.0g of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone, adding 10mL of methanol, stirring to dissolve at room temperature, weighing 0.35g of p-toluenesulfonic acid monohydrate, dissolving in 14mL of isopropyl ether, stirring at room temperature for 30 minutes after dropwise addition, filtering, and vacuum drying at 40 ℃ for 5 hours to obtain the crystal form V.
Test example-flowability examination
The flowability of the new crystal forms prepared in the first, second and third embodiments of the invention is examined, and the results show that the flowability of the crystal forms IV and V is good.
Table 1 flowability examination
Example 1 Example 2 Example 3 Example 4
Angle of repose 32.4° 32.8° 36.2° 35.7°
Test example two stability test
Samples of the crystalline forms prepared according to examples 1 and 3, after six months of storage under long-term stability (temperature 30 ℃, humidity 65%), were each subjected to X-ray powder diffraction, the X-ray powder diffraction patterns were analyzed and compared with the starting data, and the data are shown in table 2.
Table 2: comparative X-ray powder diffraction data of long-term stability of samples of example 1 and example 3
Figure BDA0002150850600000081
Figure BDA0002150850600000091
And (4) conclusion: comparing the XRD spectrogram, the d value and the 2 theta angle of the diffraction peak are not obviously changed. After the sample is placed under the condition of long-term stability (temperature is 30 ℃, humidity is 65%) for six months, the crystal form is not changed.
Test example three related substance examination
The samples of example 1 and example 2 were sealed in a 40 ℃ oven and a light box (5000 lx. + -. 500lx), exposed to 50 ℃ and RH 75% (saturated aqueous NaCl solution) for 10 days, and the salt content was measured by HPLC and external standard method, and the change of the salt-related substance was calculated by the chromatographic peak area normalization method. The 10 day salt samples were also examined and their XRPD determined and compared to the 0 day XRPD and the results are shown in table 3. Compared with free alkali, the crystal form of the invention can obviously improve the stability and quality of the compound, and is more suitable for preparation production.
TABLE 3 results of investigation of related substances
Figure BDA0002150850600000092
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.

Claims (18)

1. A crystal form of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone p-toluenesulfonate represented by formula (I) is characterized in that it is a crystal form IV whose X-ray powder diffraction pattern has characteristic peaks at 2 theta values of 4.2 + -0.2 °, 5.6 + -0.2 °, 6.3 + -0.2 °, 7.3 + -0.2 °, 8.0 + -0.2 °, 9.6 + -0.2 °, 12.6 + -0.2 °, 13.3 + -0.2 °, 13.6 + -0.2 °, 16.6 + -0.2 °, 17.1 + -0.2 °, 21.9 + -0.2 °, 22.7 + -0.2 ° or 25.4 + -0.2 °,
Figure FDA0003492683770000011
wherein: x is 1 and y is 1.
2. A crystalline form according to claim 1, characterized by an X-ray powder diffraction pattern substantially as shown in figure 1.
3. A crystalline form of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone p-toluenesulfonate represented by formula (I), characterized in that it is crystalline form v which has an X-ray powder diffraction pattern having characteristic peaks at 2 Θ values of 4.1 ± 0.2 °, 4.9 ± 0.2 °, 6.6 ± 0.2 °, 7.1 ± 0.2 °, 10.2 ± 0.2 °, 12.1 ± 0.2 °, 12.6 ± 0.2 °, 14.5 ± 0.2 °, 17.1 ± 0.2 °, 24.0 ± 0.2 °, 25.4 ± 0.2 ° or 26.6 ± 0.2 °
Figure FDA0003492683770000012
Wherein: x is 1 and y is 1.
4. A crystalline form according to claim 3 characterised by an X-ray powder diffraction pattern substantially as shown in figure 2.
5. A process for preparing a crystalline form of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone p-toluenesulfonate according to any one of claims 1 to 4, comprising the steps of:
1) dissolving (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone in a benign solvent to form a solution;
2) dissolving p-toluenesulfonic acid or hydrate thereof in a ketone, ether or alcohol solvent to form a solution;
3) dropwise adding the solution obtained in the step 2) into the solution obtained in the step 1), optionally adding a poor solvent, and stirring for crystallization;
4) filtering and drying;
wherein:
the benign solvent in the step 1) is selected from alcohol solvents;
the poor solvent in the step 3) is an alkane solvent, an ether solvent or an ester solvent.
6. The method according to claim 5, wherein the benign solvent in step 1) is selected from alcohol solvents having 1 to 4 carbon atoms.
7. The method according to claim 5, wherein the benign solvent in step 1) is selected from methanol and ethanol.
8. The method according to claim 5, wherein the ketone solvent in step 2) is a ketone solvent having 3 to 5 carbon atoms; the alcohol solvent is an alcohol solvent containing 1-4 carbon atoms, and the ether solvent is methyl tert-butyl ether or isopropyl ether.
9. The method according to claim 5, wherein the ketone solvent in step 2) is acetone or butanone; the alcohol solvent is methanol or ethanol.
10. The method according to claim 5, wherein the ethereal solvent in step 3) is methyl t-butyl ether or isopropyl ether, and the estereal solvent is isopropyl acetate.
11. The process according to claim 5, wherein the molar ratio of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone to p-toluenesulfonic acid is 1: 0.95 to 1.05.
12. The process according to claim 5, wherein the molar ratio of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone to p-toluenesulfonic acid is 1: 1.0.
13. the method according to claim 5, wherein the stirring time in the step 3) is 0.5 to 48 hours.
14. The method according to claim 5, wherein the stirring time in the step 3) is 12 to 24 hours.
15. A pharmaceutical composition comprising an effective amount of the crystalline form of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone p-toluenesulfonate according to any one of claims 1 to 4 and one or more pharmaceutically acceptable excipients.
16. Use of the crystalline form of (4- (cyclopropylamino) piperidin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) methanone tosylate according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 15 for the preparation of a medicament for the treatment and/or prevention of a cancer or a tumor-related disease mediated by CDK 4/6.
17. The use according to claim 16, wherein the cancer or tumor-related disease is brain, lung, liver, stomach, oral cavity, head and neck, intestinal or rectal, colon, kidney, esophageal adenocarcinoma, esophageal squamous cell, thyroid, bone, skin, non-small cell lung, carcinoma in situ, lymphoma, neurofibroma, neuroblastoma, mast cell, multiple myeloma, melanoma, glioma, sarcoma or liposarcoma, glioblastoma, bladder, ovarian, peritoneal, pancreatic, breast, uterine, cervical, endometrial, prostate, female genital tract, testicular, gastrointestinal stromal, or prostate tumor.
18. The use according to claim 16, wherein the cancer or tumor-related disease is selected from bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer, cancer of the female reproductive tract, testicular cancer, gastrointestinal stromal tumors, or prostate tumors.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106065016A (en) * 2015-04-22 2016-11-02 江苏恒瑞医药股份有限公司 A kind of crystal form of cyclin dependent kinase inhibitor and preparation method thereof
CN106661025A (en) * 2015-02-03 2017-05-10 江苏恒瑞医药股份有限公司 Hydroxyethyl sulfonate of cyclin-dependent protein kinase inhibitor, crystalline form thereof and preparation method therefor
WO2018045956A1 (en) * 2016-09-07 2018-03-15 江苏豪森药业集团有限公司 Benzimidazole compound kinase inhibitor, preparation method therefor and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106661025A (en) * 2015-02-03 2017-05-10 江苏恒瑞医药股份有限公司 Hydroxyethyl sulfonate of cyclin-dependent protein kinase inhibitor, crystalline form thereof and preparation method therefor
CN106065016A (en) * 2015-04-22 2016-11-02 江苏恒瑞医药股份有限公司 A kind of crystal form of cyclin dependent kinase inhibitor and preparation method thereof
WO2018045956A1 (en) * 2016-09-07 2018-03-15 江苏豪森药业集团有限公司 Benzimidazole compound kinase inhibitor, preparation method therefor and application thereof

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