CN113717111A

CN113717111A - Crystal form of quinazoline compound and preparation method thereof

Info

Publication number: CN113717111A
Application number: CN202010446294.6A
Authority: CN
Inventors: 鲁霞; 樊孝天; 张晓宇
Original assignee: Crystal Pharmatech Co Ltd
Current assignee: Crystal Pharmatech Co Ltd
Priority date: 2020-05-25
Filing date: 2020-05-25
Publication date: 2021-11-30
Also published as: WO2021238835A1

Abstract

The invention relates to a crystal form C of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide, a preparation method thereof and a medicament containing the same, wherein the crystal form C is an anhydrate, and a characteristic peak exists in an X-ray powder diffraction pattern of the crystal form C at a diffraction angle 2 theta of 5.6 degrees +/-0.2 degrees, 10.5 degrees +/-0.2 degrees and 12.8 degrees +/-0.2 degrees by using Cu-Kalpha radiation. The crystal form C is an anhydrate, has obvious advantages in drug development compared with the existing solvate, and in addition, the solubility of the crystal form C is obviously improved compared with the existing solvate on the premise of keeping good stability.

Description

Crystal form of quinazoline compound and preparation method thereof

Technical Field

The invention relates to the technical field of drug crystals. In particular to a novel crystal form of a quinazoline compound (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidyl) -2-butenamide, a preparation method and application thereof.

Technical Field

The pan-ErbB kinase family consists of four receptors, including Her1(EGFR, ErbB1), Her2(Neu, ErbB2), Her3(ErbB3) and Her4(ErbB 4). In the process of cell signaling, after the ErbB kinase family protein is combined with a corresponding ligand, a cascade reaction of a downstream signaling pathway of tyrosine kinase, such as Ras-Raf-MAPK or PI3-K/AKT, is induced, and therefore the inhibition of the apoptosis process and the promotion of the cell proliferation process are caused. The receptor is also an important target in tumor intervention treatment along with the over-expression of the ubiquitin-ErbB family protein in the occurrence and development processes of various tumors.

(2E) The chemical structure of the (E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidyl) -2-butenamide is shown as the formula (I):

(2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide, a compound of formula (1), is a specific, irreversible pan ErbB family kinase inhibitor, capable of inhibiting EGFR signaling pathway transduction and inducing apoptosis in the H3255 GR cell line containing EGFR T790M. The compounds are effective on gefitinib-sensitive and drug-resistant non-small cell lung cancer (NSCLC) cell lines. In 2018, FDA approved the compound as first line drug for the treatment of non-small cell lung cancer.

Different polymorphic forms (including solvated forms) of a solid material may have different properties such as melting point, hygroscopicity, physicochemical stability, particle morphology, flowability, bulk density, compressibility, apparent solubility, and dissolution rate, among others. These properties can directly affect the ease of processing and manufacturing solid drugs, as well as the stability, dissolution and bioavailability of the drug product, which in turn affects the quality, efficacy and safety of the drug product. For example, solvates may contain organic solvents that are toxic to living organisms and use as pharmaceutical raw materials can pose a serious safety risk; the hydrate may be dehydrated under the conditions of high temperature and low humidity, and the solid form is changed, so that the challenges are brought to the process production and the storage of raw materials and medicines. New polymorphic forms of a pharmaceutically useful compound may provide an opportunity to improve the performance characteristics of a pharmaceutical product.

The patent CN 1972688B discloses a preparation method of the compound of formula (I) above, but does not mention the crystal form of the compound. Various solvates of the compound of formula (I) above are disclosed in CN107793368A, but no anhydrous crystalline form of the compound is reported. According to a great amount of experimental researches, only solvates of the compound of the formula (I) can be obtained by adopting the existing conventional crystal form preparation methods, but the solvates have control difficulty and inconvenience in the development of pharmaceutical preparations compared with anhydrous substances. Therefore, there is a great need to provide anhydrous crystalline forms of the compounds of formula (I) that meet the pharmaceutical requirements. In addition, the existing crystal form of the compound shown in the formula (I) has low solubility, and the dissolution and bioavailability of the compound are limited to a great extent, so that the drug effect is influenced. There is therefore also a need to provide new crystalline forms of the compound of formula (I) which are not only anhydrous, but also have significantly improved solubility.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide an anhydrous crystal form of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidyl) -2-butenamide, which not only meets the medicinal requirements, but also has remarkably improved solubility.

The invention also provides a preparation method of the anhydrous crystal form of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidyl) -2-butenamide, the anhydrous crystal form of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidyl) -2-butenamide can be stably and controllably obtained by the method, and the method is simple to operate.

In order to solve the technical problems, the invention adopts a technical scheme that:

crystalline form C of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide, being an anhydrous crystalline form, having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2 Θ of 5.6 ° ± 0.2 °,10.5 ° ± 0.2 °,12.8 ° ± 0.2 ° using Cu-ka radiation.

Further, the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at one or two or three of diffraction angles 2 theta of 18.8 degrees +/-0.2 degrees, 23.6 degrees +/-0.2 degrees, 25.4 degrees +/-0.2 degrees.

Furthermore, the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at one or two or three positions with diffraction angles 2 theta of 6.8 degrees +/-0.2 degrees, 16.7 degrees +/-0.2 degrees and 26.3 degrees +/-0.2 degrees.

In a preferred embodiment, form C has an X-ray powder diffraction having characteristic peaks at diffraction angles 2 θ of 5.6 ° ± 0.2 °,6.8 ° ± 0.2 °,10.5 ° ± 0.2 °,12.8 ° ± 0.2 °,16.7 ° ± 0.2 °,18.8 ° ± 0.2 °,23.6 ° ± 0.2 °,25.4 ° ± 0.2 °,26.3 ° ± 0.2 °.

In a still further preferred embodiment, said form C has an X-ray powder diffraction pattern having characteristic peaks with relative intensities greater than 10% at diffraction angles 2 Θ of 5.6 ° ± 0.2 °,6.8 ° ± 0.2 °,10.5 ° ± 0.2 °,12.8 ° ± 0.2 °,16.7 ° ± 0.2 °,18.8 ° ± 0.2 °,23.6 ° ± 0.2 °,25.4 ° ± 0.2 °,26.3 ° ± 0.2 °.

In some specific embodiments, form C has an X-ray powder diffraction pattern having relative intensities of characteristic peaks at diffraction angles 2 Θ of greater than 40%, preferably greater than 50%, more preferably greater than 60%, at diffraction angles 2 Θ of 5.6 ° ± 0.2 °,10.5 ° ± 0.2 °,12.8 ° ± 0.2 °.

In some specific embodiments, form C has an X-ray powder diffraction pattern with relative intensities of characteristic peaks at diffraction angles 2 Θ of greater than 25%, preferably greater than 30%, at 18.8 ° ± 0.2 °,23.6 ° ± 0.2 °,25.4 ° ± 0.2 °.

Form C of the present invention having a typical X-ray powder diffraction pattern substantially as shown in figure 1 or 2.

In some embodiments according to the invention, form C, when heated to about 160 ℃ when subjected to thermogravimetric analysis, has a gradient of about 1.8% mass loss with a TGA as shown in figure 3.

The invention also provides a preparation method of the crystal form C of the (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidyl) -2-butenamide, which comprises the following steps:

(1) heating a (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidyl) -2-butenamide raw material to a first temperature under the protection of inert gas to obtain an intermediate;

(2) cooling the intermediate to a second temperature to obtain a crystal form C;

wherein the first temperature is greater than 140 ℃, the second temperature is less than or equal to 140 ℃, and the difference between the first temperature and the second temperature is greater than 20 ℃.

Preferably, the difference between the first temperature and said second temperature is in the range of 30 ℃ to 200 ℃. Specifically, for example, the difference between the first temperature and the second temperature is 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃, 100 ℃, 110 ℃, 120 ℃, 130 ℃, 140 ℃, 150 ℃, 160 ℃, 170 ℃, 180 ℃, 190 ℃ or 200 ℃.

According to a preferred aspect of the present invention, the first temperature is 160-200 ℃ and the second temperature is 5-30 ℃.

In one embodiment, the first temperature is 175-185 ℃, and the second temperature is room temperature.

Further, the (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide raw material is preferably Dacrotinib monohydrate crystal form II reported by CN 107793368A. The dacomitinib monohydrate crystal form II has an X-ray powder diffraction pattern at a 2 theta (°) value of: characteristic peaks are present at 4.5 ° ± 0.2 °,12.8 ° ± 0.2 °, 15.4 ° ± 0.2 °, 18.4 ° ± 0.2 °, 21.6 ° ± 0.2 °, 22.7 ° ± 0.2 °, 24.0 ° ± 0.2 ° and 26.5 ° ± 0.2 °. In addition, other (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide starting materials may also be employed, such as other solvates of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide (which may be, for example, those reported in CN107793368A or crystalline forms prepared by other conventional crystallization methods), or may also be amorphous.

By way of example, the starting (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide may be prepared by: dissolving chemically synthesized (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidyl) -2-butenamide in an ether solvent or chloroalkane or ester solvent or a mixed solvent consisting of one or more solvents selected from alcohols, alkyl nitriles, alkanes, ketones and benzenes, adding an anti-solvent, stirring for crystallization or cooling to obtain a solid, the solid can be used as the raw material of the (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidyl) -2-butenamide. Wherein the ether solvent may be, for example, tetrahydrofuran; the chlorinated alkane may be, for example, chloroform; the ester solvent may be, for example, ethyl acetate; the alkane may be, for example, n-heptane, the hydrocarbyl nitrile may be, for example, acetonitrile, the alcohol may be, for example, methanol or ethanol, the ketone may be, for example, acetone, and the benzene series may be, for example, toluene. In some specific operations, (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidyl) -2-butenamide is dissolved in tetrahydrofuran, and is combined with methanol, N-heptane, acetonitrile, toluene and water to form a mixed system, and the temperature is reduced or stirred by adding an anti-solvent, or the (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidyl) -2-butenamide is dissolved in chloroform and is combined with isopropyl acetate, N-heptane, acetonitrile and toluene to form a mixed system, and the temperature is reduced or stirred by adding an anti-solvent, or stirring in various alcohols, ketones, esters and water to obtain a solid, and using the solid as the raw material of the present invention.

Further, in the process of the present invention, the rate of temperature increase and decrease does not have a decisive influence on the formation of form C. However, in order to integrate various considerations such as industrial implementation, it is recommended to heat at a rate of 5 to 30 ℃/min in the step (1); specifically, the heating is performed at a rate of 10 to 20 ℃/min. In the step (2), the intermediate may be naturally cooled to room temperature.

The invention also provides a medicament for treating cancer, which comprises an active ingredient, wherein the active ingredient comprises the crystal form C of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidyl) -2-butenamide.

Generally, the drug includes adjuvants in addition to the active ingredient, the selection of adjuvants, the preparation of drugs, etc. can be carried out in a manner well known in the pharmaceutical art.

The active ingredient may comprise only crystalline form C of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide, when crystalline form C of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide is present in an effective amount. Compared with the existing medicine containing (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidyl) -2-butenamide, the crystal form C has remarkably improved solubility, so that the auxiliary material can be more flexibly selected, and the dosage is expected to be reduced.

The medicine for treating cancer is particularly used for treating drug-resistant non-small cell lung cancer.

Compared with the prior art, the novel anhydrous crystal form of the (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidyl) -2-butenamide provided by the invention has the advantages of good stability, low hygroscopicity, satisfaction of medicinal requirements, and remarkable improvement of solubility and dissolution rate, so that the novel anhydrous crystal form is expected to be more ideal medicament selection, and is expected to provide better bioavailability, and is beneficial to improvement of medicament effect and reduction of dosage.

Drawings

FIG. 1 is an X-ray powder diffraction pattern of form C obtained in example 1;

FIG. 2 is an X-ray powder diffraction pattern of form C obtained in example 2;

FIG. 3 is a thermogravimetric analysis of form C obtained in example 2;

figure 4 is a differential scanning calorimetry trace of form C obtained in example 2;

FIG. 5 is an X-ray powder diffraction pattern of form C obtained in example 3;

FIG. 6 is an X-ray powder diffraction pattern of form A obtained in example 4;

FIG. 7 is an X-ray powder diffraction pattern of form C obtained in example 4;

FIG. 8 is the dissolution profile of form C obtained in example 3;

FIG. 9 is a chart of hygroscopicity test (DVS) of crystalline form C obtained in example 2;

FIG. 10 is a X-ray powder diffraction contrast chart of the crystalline form C obtained in example 2 before and after hygroscopicity test;

fig. 11 is a graph of X-ray powder diffraction contrast of form C obtained in example 2 before and after stable standing.

Detailed Description

To aid in understanding the various embodiments disclosed herein, the following description is provided:

the X-ray powder diffraction pattern is characteristic for a particular crystalline form. To determine if it is the same as the known crystal type, care should be taken with respect to the relative positions of the peaks (i.e., 2 θ) rather than their relative intensities. This is because the relative intensities of the spectra vary due to the dominant orientation effect resulting from differences in crystal conditions, particle size and other assay conditions, particularly the low intensity peak (intensity less than 20%) may not be present in some cases, the relative intensities of the diffraction peaks are not characteristic of the determination of the crystal form, in fact, the relative intensities of the diffraction peaks in the XRPD spectra are related to the preferred orientation of the crystals, and the peak intensities shown herein are illustrative and not used for absolute comparison. In addition, it is known in the art that when crystals of a compound are measured by X-ray diffraction, a certain measurement error of about ± 0.2 ° may exist in 2 θ values of the same crystal form due to the influence of a measuring instrument or measuring conditions, etc. Therefore, this error should be taken into account when determining each crystalline structure. The peak position is usually expressed in the XRD pattern by the 2 theta angle or the d value of the interplanar distance, with a simple conversion relationship between them: where d represents the interplanar spacing d, λ represents the wavelength of the incident X-rays, and θ is the diffraction angle. It should also be noted that in the identification of mixtures, a partial loss of diffraction lines may occur due to, for example, a reduction in the content. In addition, due to the influence of experimental factors such as sample height, an overall shift in peak angle is caused, and a certain shift is usually allowed. Thus, it will be understood by those skilled in the art that the X-ray diffraction patterns of the crystalline forms referred to herein need not be identical to the X-ray diffraction patterns of the examples referred to herein, that "the same XRPD patterns" as used herein does not mean absolute identity, that the same peak positions may differ by + -0.2 deg. (or more) and that the peak intensities allow for some variability. Any crystalline form having the same or similar pattern as the characteristic peaks in these maps is within the scope of the present application. One skilled in the art can compare the profiles listed in this application to a profile of an unknown crystalline form to confirm whether the two sets of profiles reflect the same or different crystalline forms.

On the basis of a specific X-ray crystal diffraction pattern, a person skilled in the art is generally allowed to select several characteristic peaks to define the crystal form, and the selection of the characteristic peaks is comprehensively considered for a certain purpose without strict limitation, for example, the person skilled in the art is more inclined to select a peak with higher relative intensity, a peak with relatively low angle and a characteristic peak with complete peak shape, and select a characteristic peak which is enough to be distinguished from other crystals, so that the characteristic peaks have the significance of being distinguished, identified and identified. Thus, it cannot be concluded that a different crystal form is constituted or that the range of crystal forms is beyond the original request merely because the combination of selected characteristic peaks changes.

It should be noted that the numerical values and numerical ranges mentioned in this application should not be construed narrowly as numerical values or numerical ranges per se, and those skilled in the art will appreciate that they can be varied in accordance with specific technical circumstances and that they can be varied widely around specific numerical values without departing from the spirit and principles of this application.

The term "room temperature" as used herein refers to the natural ambient temperature achieved without additional heating or cooling, with the corresponding specific temperature typically being between 10 ℃ and 30 ℃.

The present application is further defined by reference to the following examples describing in detail the methods of making and using the crystalline forms of the present application. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the application.

The instrument and method for data acquisition:

the X-ray powder diffraction pattern described in the present application is in the PANalytical Empyrean type X-ray powder diffractometer and PANalytical X' Pert³Collected on a model X-ray powder diffractometer.

The process parameters for the Empyrean type X-ray powder diffraction are as follows:

x-ray type: cu, K alpha

Kα1

：1.540598；Kα2

：1.544426

The K alpha 2/K alpha 1 intensity ratio: 0.50

Voltage: 45 KV (kV)

Current: 40 milliampere (mA)

Divergent slit: automatic

Scanning mode: continuous

Scanning range: from 3.0 to 40.0 degrees

Scanning time of each step: 17.780 seconds

Step length: 0.0167 degree

PANalytical X'Pert³The method parameters for type X-ray powder diffraction are as follows:

x-ray type: cu, K alpha

Kα1

：1.540598；Kα2

：1.544426

The K alpha 2/K alpha 1 intensity ratio: 0.50

Voltage: 45 KV (kV)

Current: 40 milliampere (mA)

Divergent slit: 1/16 degrees

Scanning mode: continuous

Scanning range: from 3.0 to 40.0 degrees

Scanning time of each step: 46.665 seconds

Step length: 0.0263 degree

The Differential Scanning Calorimetry (DSC) data described herein are obtained from TA Instruments Q200 and Discovery DSC 2500 differential scanning calorimetry Instruments, the instrument control software is Q Series and TRIOS, respectively, and the Analysis software is Universal Analysis. 1-10 mg of sample is usually taken and placedIn a capped (unless otherwise specified) aluminum crucible, N was dried at a temperature rise rate of 10 ℃/min at 50mL/min₂While the TA software records the thermal changes of the sample during the temperature rise. In the present application, melting point is reported in terms of starting temperature.

Thermogravimetric Analysis (TGA) data described herein were taken from TA Instruments model Q5000 and Discovery TGA5500 thermogravimetric analyzers, instrument control software Q Series and TRIOS, respectively, and analytical software Universal Analysis. Usually, 2-15 mg of sample is placed in a platinum crucible, and N is dried at a heating rate of 10 ℃/min at 50mL/min in a sectional high-resolution detection mode₂While the TA software records the weight change of the sample during the temperature increase.

The following examples were conducted at room temperature unless otherwise specified.

In the following specific examples, (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide solid as a starting material was detected as crystalline and the crystalline form was monohydrate crystalline form II reported in CN 107793368A.

Example 1

About 20 mg of a solid of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide was weighed out and placed in a DSC aluminum crucible, and the (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide was heated (at a heating rate of 10 ℃/min) to about 180 ℃ under nitrogen using DSC, and then cooled naturally to room temperature (about 25 ℃) to obtain a solid product.

The X-ray powder diffraction data of the solid obtained in this example are shown in table 1, and the XRPD pattern thereof is shown in fig. 1, which indicates that the obtained solid product is the form C described herein.

TABLE 1

Numbering	Diffraction angle	2 theta (± 0.2 °)	d value	Relative strength%
					1	5.62	15.72	100.00
2	6.76	13.09	23.66
				3	8.33	10.61	4.71
4	10.46	8.46	73.12
				5	12.85	6.89	85.63
6	13.56	6.53	3.45
				7	15.40	5.75	2.31
8	16.74	5.30	22.67
				9	17.41	5.09	4.91
10	18.04	4.92	10.20
				11	18.77	4.73	38.48
12	19.65	4.52	7.12
				13	20.45	4.34	11.02
14	21.03	4.22	11.26
				15	21.77	4.08	11.02
16	22.79	3.90	16.59
				17	23.61	3.77	38.13
18	24.88	3.58	14.26
				19	25.41	3.51	40.15
20	26.31	3.39	14.58
				21	27.31	3.27	4.84
22	27.93	3.19	6.60
				23	29.08	3.07	4.60
24	29.84	2.99	2.65

Example 2

Weighing about 20 mg of solid (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide in a DSC aluminum crucible, heating (heating rate of 10 ℃/min) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide to 180 ℃ by DSC under nitrogen protection using DSC to obtain a solid product, conducting parallel experiments for 20 times, mixing the solid products obtained in 20 times uniformly, sampling and detecting.

Upon examination, the solid product obtained exhibited X-ray powder diffraction data as shown in table 2, an XRPD pattern as shown in figure 2, a TGA pattern as shown in figure 3, and a DSC pattern as shown in figure 4, indicating that the solid product obtained was crystalline form C as described herein, the TGA data indicating that the sample of this crystalline form lost about 1.8% of weight upon heating to 160 ℃, and a single melting endotherm in DSC between 167 ℃ and 200 ℃, indicating that the crystalline form was (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide anhydride.

TABLE 2

Numbering	Diffraction angle	2 theta (± 0.2 °)	d value	Relative strength%
					1	5.64	15.40	91.75
2	6.72	12.96	27.60
				3	10.48	8.36	67.64
4	12.93	6.79	75.08
				5	16.72	5.27	27.55
6	18.04	4.89	21.18
				7	18.82	4.69	65.11
8	19.70	4.48	15.82
				9	20.49	4.31	25.71
10	21.15	4.18	21.50
				11	21.78	4.06	24.71
12	22.82	3.88	34.68
				13	23.51	3.77	100.00
14	25.37	3.50	82.47
				15	26.28	3.38	29.36
16	29.96	3.18	14.23
				17	29.07	3.06	12.28

Example 3

About 1 g of solid (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide is weighed and placed in a vacuum drying oven, and the solid product is obtained after the (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide is heated to 170 ℃ under vacuum protection and then naturally cooled to room temperature (about 25 ℃) and then sampled for detection.

The X-ray powder diffraction data of the obtained solid product is shown in table 3, the XRPD pattern of the solid product is shown in fig. 5, and the result shows that the obtained solid product is the crystal form C described in the application, and the crystal form is (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidyl) -2-butenamide anhydride.

TABLE 3

Numbering	Diffraction angle	2 theta (± 0.2 °)	d value	Relative strength%
					1	5.59	15.82	100.00
2	6.72	13.16	15.49
				3	10.44	8.47	66.65
4	12.84	6.89	89.63
				5	16.72	5.30	21.61
6	17.96	4.94	6.93
				7	18.73	4.74	31.30
8	21.04	4.22	11.77
				9	21.78	4.08	9.50
10	22.72	3.91	15.74
				11	23.66	3.76	31.90
12	24.79	3.59	9.45
				13	25.42	3.50	33.81
14	26.30	3.39	10.96
				15	27.22	3.28	4.46

Example 4

About 100 mg of a solid of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide was weighed out and dissolved in 3 ml of tetrahydrofuran, and the resulting sample was sonicated for about 2 minutes and then filtered using a 0.22 micron filter to give a clear solution. Slowly adding water dropwise into the clarified solution until solid is precipitated, stirring the obtained suspension at room temperature for 2 hours, performing solid-liquid separation, and removing the supernatant, wherein the obtained solid wet sample is solvate crystal form A, the X-ray powder diffraction data of the crystal form A is shown in Table 4, and the XRPD pattern of the crystal form A is shown in FIG. 6. And (3) placing about 10mg of the wet crystal form A in a DSC aluminum crucible, heating the sample (with the heating rate of 10 ℃/min) to 50 ℃ by using DSC under the protection of nitrogen, balancing for 10 minutes, then continuously heating the sample (with the heating rate of 10 ℃/min) to 160 ℃ by using DSC under the protection of nitrogen, naturally cooling to room temperature (about 25 ℃) to obtain a solid product, and sampling and detecting.

Upon examination, the solid product obtained exhibited X-ray powder diffraction data as shown in table 5 and an XRPD pattern as shown in fig. 7. The results indicate that the resulting solid product was crystalline form C as described herein and that this crystalline form was (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide anhydride.

TABLE 4

Numbering	Diffraction angle	2 theta (± 0.2 °)	d value	Relative strength%
					1	5.44	16.25	100.00
2	6.03	14.66	2.33
				3	9.76	9.07	1.93
4	10.73	8.25	1.76
				5	11.08	7.99	6.21
6	12.10	7.31	5.54
				7	15.27	5.80	2.95
8	16.27	5.45	2.67
				9	17.31	5.12	3.21
10	18.07	4.91	1.86
				11	19.50	4.55	0.85
12	21.11	4.21	1.61
				13	21.72	4.09	4.00
14	22.40	3.97	8.62
				15	24.30	3.66	0.71
16	27.26	3.27	0.52
				17	29.46	3.03	0.61
18	32.84	2.73	0.83

TABLE 5

Example 5: dynamic solubility contrast study

Samples of form C prepared in example 2 and form II in CN107793368A were added to a FaSSIF solution (simulated artificial intestinal fluid in the uneaten state) at ph6.5 at room temperature (about 25 ℃), and the content of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide in the solution was determined by High Performance Liquid Chromatography (HPLC) after 1 hour, 2 hours, 4 hours and 24 hours, respectively. The results of the experiment are shown in Table 6.

TABLE 6 dynamic solubility contrast study

The results show that the new form C of the present application has significantly higher solubility and dissolution rate in FaSSIF compared to form II in CN 107793368A.

Example 6: dissolution Rate comparison study

In order to further compare the dissolution difference between the crystal form C and the prior art in a simulated human body environment, 400 mg of each of the samples of the crystal form C prepared in example 3 and the crystal form II in CN107793368A was added to 900 ml of FaSSIF solution (simulated uneaten artificial intestinal fluid) with ph6.5 at 37 ℃, poured into a dissolution cup, and the dissolution rate was tested by using a dissolution instrument. The dissolution conditions are shown in Table 7, the dissolution profile is shown in FIG. 8, and the dissolution data are shown in Table 8.

TABLE 7

Dissolution instrument	CPE-010Agilent 708DS
		Method	Pulp process
Medium	pH6.5 FaSSIF solution
		Volume of medium	900mL
Rotational speed	50rpm
		Temperature of the medium	37 ℃
Sampling point




		5,10,15,20,30,45,60,120min
Supplementary medium			No

TABLE 8

The result shows that the dissolution of the crystal form C of the application is faster than that of the crystal form II in CN107793368A in the prior art, the solubility is higher than that of the crystal form II in CN107793368A from 5 minutes, and the solubility reaches 6 times of that of the crystal form II disclosed in CN107793368A in 2 hours.

Example 7: hygroscopicity assay of form C:

about 10mg of the crystalline form C prepared in example 2 was taken and tested for hygroscopicity by a dynamic moisture sorption (DVS) apparatus. The results of the experiment are shown in Table 9. The DVS profile of the hygroscopicity assay is shown in fig. 9, and the XRPD contrast profile before and after sample testing is shown in fig. 10.

TABLE 9 hygroscopicity experiment of form C

Description of hygroscopicity characteristics and definition of hygroscopicity increase (guidance of hygroscopicity test in appendix XIX J, 2010 edition of Chinese pharmacopoeia, experimental conditions: 25 ℃. + -. 1 ℃, 80% relative humidity):

deliquescence: absorb sufficient water to form liquid

Has the characteristics of moisture absorption: the moisture-drawing weight gain is not less than 15 percent

Moisture absorption: the moisture-drawing weight gain is less than 15 percent but not less than 2 percent

Slightly hygroscopic: the moisture-drawing weight gain is less than 2 percent but not less than 0.2 percent

No or almost no hygroscopicity: the moisture-attracting weight gain is less than 0.2 percent

The results show that form C of the present application gained 1.35% weight after equilibration at 80% humidity, and was slightly hygroscopic according to the defined standard of hygroscopicity weight gain. The crystal form C can be kept stable under different humidity conditions, has good hygroscopicity, can be kept stable without strict humidity control in the production and storage processes of medicines, has low requirements on preparation processes and storage conditions, and has strong application value.

Example 8: stability test of Crystal form C

Three samples of the crystal form C prepared in example 2 were taken and placed open at 25 ℃, 60% relative humidity, 40 ℃, 75% relative humidity and 80 ℃ ambient humidity, respectively, and sampled after a set time to measure XRPD and purity. The results are shown in FIG. 11 and Table 10, respectively. The results show that the crystal form of the crystal form C sample of the application is kept unchanged and the purity is not reduced after the crystal form C sample is placed under all experimental conditions, and the crystal form C of the application has excellent stability.

Table 10 stability test of form C

Conditions of standing	Time of standing	Crystal form change	Relative purity
					25 ℃ and 60% relative humidity	45 days	Is kept unchanged	101.4％
40 ℃ and 75% relative humidity	45 days	Is kept unchanged	100.8％
				80℃	24 hours	Is kept unchanged	100.2％

The above embodiments are merely illustrative of the technical concepts and features of the present application, and the purpose of the present invention is to enable those skilled in the art to understand the content of the present application and implement the present application, and not to limit the protection scope of the present application. All equivalent changes and modifications made according to the spirit of the present application should be covered in the protection scope of the present application.

Claims

1. A crystalline form C of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide characterized in that: the crystal form C is an anhydrate, and an X-ray powder diffraction pattern of the crystal form C has characteristic peaks at diffraction angles 2 theta of 5.6 degrees +/-0.2 degrees, 10.5 degrees +/-0.2 degrees and 12.8 degrees +/-0.2 degrees by using Cu-Kalpha radiation.

2. Form C according to claim 1, characterized in that: the X-ray powder diffraction pattern of the crystal form C has a characteristic peak at a diffraction angle 2 theta of 18.8 degrees +/-0.2 degrees; and/or the X-ray powder diffraction pattern of the crystal form C has a characteristic peak at a diffraction angle 2 theta of 23.6 +/-0.2 degrees; and/or the X-ray powder diffraction pattern of the crystal form C has a characteristic peak at a diffraction angle 2 theta of 25.4 +/-0.2 degrees; and/or the X-ray powder diffraction pattern of the crystal form C has a characteristic peak at a diffraction angle 2 theta of 6.8 +/-0.2 degrees; and/or the X-ray powder diffraction pattern of the crystal form C has a characteristic peak at a diffraction angle 2 theta of 16.7 +/-0.2 degrees; and/or the X-ray powder diffraction pattern of the crystal form C has a characteristic peak at a diffraction angle 2 theta of 26.3 +/-0.2 degrees.

3. Form C according to claim 1, characterized in that: the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at diffraction angles 2 theta of 18.8 degrees +/-0.2 degrees, 23.6 degrees +/-0.2 degrees and 25.4 degrees +/-0.2 degrees; and/or the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at diffraction angles 2 theta of 6.8 degrees +/-0.2 degrees, 16.7 degrees +/-0.2 degrees and 26.3 degrees +/-0.2 degrees.

4. Form C according to claim 1, characterized in that: the X-ray powder diffraction pattern of form C remains consistent with fig. 1 or fig. 2.

5. A process for the preparation of crystalline form C of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide according to any one of claims 1 to 4, characterized in that: the method comprises the following steps:

(2) cooling the intermediate to a second temperature to obtain the crystal form C;

the first temperature is higher than 140 ℃, the second temperature is less than or equal to 140 ℃, and the difference between the first temperature and the second temperature is higher than 20 ℃.

6. A process for the preparation of crystalline form C of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide according to claim 5, characterized in that: the difference between the first temperature and the second temperature is 30-200 ℃.

7. A process for the preparation of crystalline form C of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide according to claim 5, characterized in that: the first temperature is 160-200 ℃, and the second temperature is 5-30 ℃.

8. A process for the preparation of crystalline form C of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide according to claim 5, characterized in that: the (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidyl) -2-butenamide is a solvate or amorphous form of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidyl) -2-butenamide.

9. A process for the preparation of crystalline form C of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide according to claim 5, characterized in that: in the step (1), heating at a speed of 5-30 ℃/min; and (2) naturally cooling the intermediate to room temperature.

10. A medicament for the treatment of cancer comprising an active ingredient, characterized in that it comprises the crystalline form C of (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7-methoxy-6-quinazolinyl ] -4- (1-piperidinyl) -2-butenamide according to any one of claims 1 to 4.