Medicinal salt of tyrosine kinase inhibitor, crystal, preparation method and application thereof

Abstract

The invention relates to a medicinal salt used as a tyrosine kinase inhibitor, a crystal, a preparation method and application thereof, in particular to a medicinal salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynyl phenyl) amino)-6-quinazoline)-2-buteneamide, a crystal form and a preparation method thereof. The invention also relates to a pharmaceutical composition containing a therapeutically effective amount of the crystal form and application of the crystal form in cancer treatment.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to a pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide, a crystal form and a preparation method thereof, as well as a pharmaceutical composition containing a therapeutically effective amount of the crystal form and an application of the pharmaceutical composition in treating cancer. Background Art

[0002] Cancer seriously threatens people's lives and quality of life. Therefore, finding highly effective and low-toxic anti-tumor drugs is a very challenging and significant topic in life sciences today. Receptor tyrosine kinases are a class of transmembrane proteins involved in signal transduction. Studies have shown that more than 50% of proto-oncogenes and oncogene products have tyrosine kinase activity, and their abnormal expression will lead to tumorigenesis. Tyrosine kinase inhibitors have been on the market since 2001 and have become a new type of anticancer drug that has emerged. Epidermal growth factor receptors (Her2 and EGFR) are both members of the receptor tyrosine kinase family. The epidermal growth factor receptor pathway plays a very important role in the occurrence and development of tumors. It has become one of the most important research and development targets in the field of tumor treatment. The drugs of this type that have been marketed include erlotinib, gefitinib, lapatinib (Tykerb, GW572016), afatinib, neratinib, osimertinib, etc.

[0003] ZL201480003627.0 discloses a method for preparing the compound (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide, which has obvious pharmacokinetic and pharmacodynamic advantages. Among them, the chemical structure and preparation method of the compound AMX3009 are specifically disclosed, but its salt formation and crystal form are not studied. Since the salt form and crystal structure of the active ingredient of the medicine often affect the chemical stability of the drug, different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, and sometimes it will be accompanied by the production of other forms of crystals.

[0004] Based on this, it is of great significance to further study the effects of the salt form and crystal form of compound AMX3009 on inhibitory activity, stability, etc., so as to obtain AMX3009 salt crystals with high inhibitory activity and excellent stability to meet practical application and production needs. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides a pharmaceutically acceptable salt, crystal form and preparation method of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (AMX3009), as well as a pharmaceutical composition containing a therapeutically effective amount of the crystal form and its use in treating cancer.

[0006] The present invention provides the following technical solutions:

[0007] In a first aspect, the present invention provides a pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide, wherein the pharmaceutically acceptable salt is maleate, methanesulfonate, p-toluenesulfonate, phosphate, L-malate, succinate, sulfate, hydrochloride, tartrate, acetate, trifluoroacetate, citrate, hydrobromide or fumarate.

[0008] Further, the pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide is preferably a compound having the following general structural formula:

[0009]

[0010] Wherein, n is 1, 2 or 3;

[0011] A is maleic acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, L-malic acid, succinic acid, sulfuric acid, hydrochloric acid, tartaric acid, acetic acid, trifluoroacetic acid, citric acid, hydrobromic acid or fumaric acid.

[0012] Further, the pharmaceutically acceptable salts of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide include but are not limited to the following:

[0013]

[0014]

[0015]

[0016]

[0017] Furthermore, the pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide is more preferably a dimaleate. Compared with (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide, its dimaleate has obvious advantages in solubility, bioavailability and pharmacokinetics, and has good drugability.

[0018] Further, the pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide can be prepared according to a conventional method for preparing salts in the field, for example: (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide is stirred with an acid in the presence of a solvent to obtain the pharmaceutically acceptable salt, wherein the acid is an organic acid or an inorganic acid and can be selected from one of maleic acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, L-malic acid, succinic acid, sulfuric acid, hydrochloric acid, tartaric acid, acetic acid, trifluoroacetic acid, citric acid, hydrobromic acid and fumaric acid.

[0019] The second aspect of the present invention provides a crystalline form of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate, including anhydrous crystalline forms A, B, C, F and hydrate crystalline forms D, E, H, K, R, V.

[0020] Further, using Cu-Kα as the radiation source, the X-ray powder diffraction pattern expressed in 2θ angles, the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 4.98±0.2°, 10.41±0.2°, 15.16±0.2°, and 19.72±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 4.98±0.2°, 5.98±0.2°, 10.41±0.2°, 14.76±0.2°, 15.16±0.2°, 16.21±0.2°, 19.72±0.2°, 22.09±0.2°, 25.80±0.2°, and 34.81±0.2°.

[0021] Furthermore, the DSC spectrum of the crystal form A shows a melting endothermic peak near 144°C.

[0022] Further, using Cu-Kα as the radiation source, the X-ray powder diffraction pattern expressed in 2θ angles, the X-ray powder diffraction pattern of the crystalline form B has characteristic peaks at 4.68±0.2°, 14.41±0.2°, 16.70±0.2°, and 18.73±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form B has characteristic peaks at 4.68±0.2°, 7.75±0.2°, 9.90±0.2°, 13.40±0.2°, 14.03±0.2°, 14.41±0.2°, 16.70±0.2°, 17.64±0.2°, 18.73±0.2°, 25.52±0.2°, 26.38±0.2°, and 33.07±0.2°.

[0023] Further, using Cu-Kα as the radiation source, the X-ray powder diffraction pattern expressed in 2θ angles, the X-ray powder diffraction pattern of the crystalline form C has characteristic peaks at 4.82±0.2°, 14.41±0.2°, 15.41±0.2°, and 19.24±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form C has characteristic peaks at 4.82±0.2°, 9.56±0.2°, 14.12±0.2°, 14.41±0.2°, 15.41±0.2°, 19.24±0.2°, 19.69±0.2°, and 25.72±0.2°.

[0024] Further, using Cu-Kα as the radiation source, the X-ray powder diffraction pattern expressed in 2θ angles, the X-ray powder diffraction pattern of the crystal form D has characteristic peaks at 5.93±0.2°, 7.91±0.2°, 14.86±0.2°, 20.33±0.2°, 25.36±0.2°, and 26.05±0.2°; more preferably, the X-ray powder diffraction pattern of the crystal form D is The final diffraction pattern has characteristic peaks at 3.37±0.2°, 3.96±0.2°, 5.93±0.2°, 7.91±0.2°, 14.86±0.2°, 16.06±0.2°, 19.20±0.2°, 20.33±0.2°, 21.81±0.2°, 25.36±0.2°, 26.05±0.2°, and 27.28±0.2°.

[0025] Further, using Cu-Kα as the radiation source, the X-ray powder diffraction pattern expressed in 2θ angles, the X-ray powder diffraction pattern of the crystalline form E has characteristic peaks at 4.75±0.2°, 5.16±0.2°, 15.65±0.2°, and 23.45±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form E has characteristic peaks at 5.16±0.2°, 6.75±0.2°, 15.65±0.2°, 16.67±0.2°, 17.84±0.2°, 18.09±0.2°, 18.90±0.2°, 23.45±0.2°, 25.07±0.2°, 26.12±0.2°, 26.74±0.2°, and 27.98±0.2°.

[0026] Further, using Cu-Kα as the radiation source, the X-ray powder diffraction pattern of the crystalline form F expressed in 2θ angles has characteristic peaks at 4.57±0.2°, 12.93±0.2°, 15.5±0.2°, and 18.44±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form F has characteristic peaks at 4.57±0.2°, 7.06±0.2°, 8.51±0.2°, 12.93±0.2°, 15.5±0.2°, 18.44±0.2°, 19.33±0.2°, 20.23±0.2°, 20.94±0.2°, 25.58±0.2°, 25.85±0.2°, and 26.31±0.2°.

[0027] Further, using Cu-Kα as the radiation source, the X-ray powder diffraction pattern represented by 2θ angle, the X-ray powder diffraction pattern of the crystalline form H has characteristic peaks at 3.67±0.2°, 5.51±0.2°, 11.04±0.2°, 19.73±0.2°, 26.48±0.2°, and 27.86±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form H is The final diffraction pattern has characteristic peaks at 3.67±0.2°, 5.51±0.2°, 7.15±0.2°, 7.36±0.2°, 11.04±0.2°, 11.45±0.2°, 19.73±0.2°, 20.48±0.2°, 21.66±0.2°, 25.79±0.2°, 26.48±0.2°, and 27.86±0.2°.

[0028] Further, using Cu-Kα as the radiation source, the X-ray powder diffraction pattern expressed in 2θ angles, the X-ray powder diffraction pattern of the crystal form K has characteristic peaks at 5.16±0.2°, 6.96±0.2°, 15.54±0.2°, 23.34±0.2°, 25.43±0.2°, and 27.91±0.2°; more preferably, the X-ray powder diffraction pattern of the crystal form K The diffraction pattern has characteristic peaks at 5.16±0.2°, 6.96±0.2°, 13.86±0.2°, 15.54±0.2°, 17.67±0.2°, 19.62±0.2°, 23.34±0.2°, 23.79±0.2°, 24.34±0.2°, 25.43±0.2°, 27.50±0.2°, and 27.91±0.2°.

[0029] Further, using Cu-Kα as the radiation source, the X-ray powder diffraction pattern expressed in 2θ angles, the X-ray powder diffraction pattern of the crystal form R has characteristic peaks at 4.67±0.2°, 8.52±0.2°, 9.21±0.2°, 15.13±0.2°, 18.60±0.2°, and 19.69±0.2°; more preferably, the X-ray powder diffraction pattern of the crystal form R The final diffraction pattern has characteristic peaks at 4.67±0.2°, 4.93±0.2°, 7.53±0.2°, 8.52±0.2°, 9.21±0.2°, 12.49±0.2°, 15.13±0.2°, 16.28±0.2°, 16.98±0.2°, 18.60±0.2°, 19.69±0.2°, and 27.34±0.2°.

[0030] Further, using Cu-Kα as a radiation source, the X-ray powder diffraction pattern represented by 2θ angles, the X-ray powder diffraction pattern of the crystalline form V has characteristic peaks at 8.56±0.2°, 10.10±0.2°, 14.16±0.2°, 16.58±0.2°, 18.20±0.2°, 19.19±0.2°, 20.28±0.2°, 23.77±0.2°, and 26.03±0.2°; More preferably, the X-ray powder diffraction pattern of the crystalline form V has characteristic peaks at 8.56±0.2°, 10.10±0.2°, 13.48±0.2°, 14.16±0.2°, 16.58±0.2°, 18.20±0.2°, 18.40±0.2°, 19.19±0.2°, 20.28±0.2°, 22.28±0.2°, 23.77±0.2°, and 26.03±0.2°.

[0031] In the present invention, "crystal" or "crystal form" can be characterized by X-ray powder diffraction. Those skilled in the art will understand that the X-ray powder diffraction pattern is affected by the conditions of the instrument, the preparation of the sample and the purity of the sample. The relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also change with the change of the experimental conditions, so the diffraction peak intensity cannot be used as the only or decisive factor for determining the crystal form. In fact, the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystal, and the diffraction peak intensity shown in the present invention is illustrative rather than for absolute comparison. Therefore, those skilled in the art will understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to herein, and any crystal form having an X-ray powder diffraction pattern that is the same or similar to the characteristic peaks in these patterns belongs to the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with the X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.

[0032] The third aspect of the present invention provides a method for preparing the crystalline forms A, B, C, D, E, F, H, K, R, and V of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate described in the second aspect.

[0033] The preparation method of the crystal form A comprises:

[0034] AMX3009 and maleic acid are dissolved in a first organic solvent, stirred to precipitate crystals, separated and dried to obtain the crystalline form A; the first organic solvent is selected from one or more of isopropanol, acetonitrile, tetrahydrofuran, methyl isobutyl ketone, chloroform, acetone, ethyl acetate, 1,4-dioxane, isopropyl acetate, methyl tert-butyl ether, 2-methyltetrahydrofuran, and toluene;

[0035] Or, dissolving the dimaleate of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide in acetonitrile, volatilizing to precipitate a solid, and obtaining the crystalline form A; preferably, before the volatilization treatment, filtering the solution obtained by dissolving the dimaleate of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide in acetonitrile, and the volatilization step is performed at 50° C.;

[0036] Alternatively, dissolving the dimaleate of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide in methanol, adding an anti-solvent, stirring to precipitate a solid, and obtaining the crystalline form A; the anti-solvent is methyl tert-butyl ether, 2-methyltetrahydrofuran or toluene;

[0037] Alternatively, the dimaleate of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide is dissolved in acetone or acetonitrile, and the temperature is lowered to precipitate a solid to obtain the crystalline form A. Preferably, before the temperature is lowered, the dimaleate of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide is dissolved in acetone or acetonitrile to obtain a solution for filtration treatment, and the temperature reduction treatment is specifically: cooling from 50°C to 5°C at a cooling rate of 0.1°C / min.

[0038] The preparation method of the crystal form B comprises the following steps: dissolving AMX3009 and maleic acid in an appropriate amount of isopropanol, stirring at 35° C. for crystallization, filtering and separating the solid, and then drying to obtain the crystal form B.

[0039] The preparation method of the crystal form C comprises the following steps: dissolving AMX3009 dimaleate in an appropriate amount of ethanol, stirring at room temperature for crystallization, centrifuging and separating the solid, and then drying at room temperature to obtain the crystal form C.

[0040] The preparation method of the crystal form D comprises the following steps: dissolving AMX3009 dimaleate in an appropriate amount of dimethylacetamide, adding 2-methyltetrahydrofuran while stirring, dissolving the obtained solid in 2-methyltetrahydrofuran, stirring and crystallizing at room temperature, centrifuging and separating the solid, and drying at room temperature to obtain the crystal form D.

[0041] The preparation method of the crystal form E comprises the following steps: stirring AMX3009 dimaleate in an aqueous system, centrifuging and separating the solid and drying at room temperature to obtain the crystal form E; the stirring temperature is preferably 10-30° C., and the stirring time is 3-6 days, for example 5 days.

[0042] Furthermore, the aqueous system is a mixed system of an organic solvent and water. Preferably, the volume percentage of water in the mixed system is not less than 3%, for example, the volume ratio of the organic solvent to water in the mixed system is (85-97): (3-15); preferably, the organic solvent is 1,4-dioxane or isopropanol.

[0043] The preparation method of the crystal form F comprises the following steps: dissolving AMX3009 dimaleate in methanol / ethyl acetate (1:4, v / v), stirring at 40-60° C. for crystallization, centrifuging and separating the solid, and drying at room temperature to obtain the crystal form F.

[0044] The preparation method of the crystal form H comprises the following steps: putting AMX3009 dimaleate into a bottle, and placing the bottle open in a sealed bottle containing water, and performing gas-solid permeation to obtain the crystal form H.

[0045] The preparation method of the crystal form K comprises the following steps: heating the AMX3009 dimaleate crystal form E to 75-100° C. at a heating rate of 5-10° C. / min, and then cooling to room temperature to obtain the crystal form K.

[0046] The preparation method of the crystal form R comprises the following steps: performing a dynamic moisture adsorption test on the AMX3009 dimaleate crystal form A at a humidity of 0% RH-90% RH-0% RH to obtain the AMX3009 dimaleate crystal form R.

[0047] The preparation method of the crystal form V comprises the following steps: suspending and stirring AMX3009 dimaleate in isopropanol / water (volume ratio is 98 / 2) to obtain AMX3009 dimaleate crystal form V.

[0048] The fourth aspect of the present invention provides a pharmaceutical composition comprising the pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide described in the first aspect and / or the dimaleate crystalline forms A, B, C, D, E, F, H, K, R, V described in the second aspect and a pharmaceutically acceptable carrier.

[0049] The fifth aspect of the present invention provides a use of a pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide described in the first aspect, the dimaleate crystal form A, B, C, D, E, F, H, K, R, V described in the second aspect, or the pharmaceutical composition described in the fourth aspect in the preparation of a drug for treating a disease associated with protein kinase, wherein the protein kinase is EGFR receptor tyrosine kinase or HER-2 receptor tyrosine kinase.

[0050] Furthermore, the drug is administered alone or in combination with other therapeutic agents.

[0051] The present invention also provides a use of a pharmaceutically acceptable salt of the (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide described in the first aspect, the dimaleate crystal form A, B, C, D, E, F, H, K, R, V described in the second aspect, or the pharmaceutical composition described in the fourth aspect in the preparation of a drug for treating cancer, wherein the cancer includes but is not limited to EGFR resistant mutation lung cancer, head and neck cancer, Her2 positive gastric cancer, breast cancer, and colorectal cancer.

[0052] Furthermore, the drug is administered alone or in combination with other therapeutic agents.

[0053] By means of the above technical solution, the present invention has at least the following advantages:

[0054] The present invention provides a class of pharmaceutically acceptable salts of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide and dimaleate crystalline forms thereof. Compared with the (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide compound, the pharmaceutically acceptable salts thereof have obvious advantages in solubility, bioavailability and pharmacokinetics, and have good drugability. In particular, the dimaleate of AMX3009 exhibits high inhibitory activity in an inhibition rate test of EGFR drug-resistant mutation lung cancer cells.

[0055] In addition, the present invention provides a series of anhydrous crystalline forms and hydrate crystalline forms of AMX3009 dimaleate, among which anhydrous crystalline form A has high solubility, high exposure in animals, long half-life, high oral bioavailability, good bioavailability, and is currently being used in clinical trials; and this crystalline form exhibits good stability and is suitable for use in pharmaceutical preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 is the X-ray powder diffraction pattern of AMX3009 dimaleate type A crystal;

[0057] Figure 2 This is the DSC diagram of AMX3009 dimaleate type A crystal;

[0058] Figure 3 This is the TGA diagram of AMX3009 dimaleate type A crystal;

[0059] Figure 4 AMX3009 dimaleate type A crystalline 1 HNMR spectra;

[0060] Figure 5 The X-ray powder diffraction pattern of AMX3009 dimaleate type B crystal;

[0061] Figure 6 The X-ray powder diffraction pattern of AMX3009 dimaleate type C crystal;

[0062] Figure 7 The X-ray powder diffraction pattern of AMX3009 dimaleate F-type crystals;

[0063] Figure 8 The X-ray powder diffraction pattern of AMX3009 dimaleate D-type crystals;

[0064] Fig. 9 The X-ray powder diffraction pattern of AMX3009 dimaleate E-type crystals;

[0065] Fig.10 It is the X-ray powder diffraction pattern of AMX3009 dimaleate H-type crystal;

[0066] Fig.11 is the X-ray powder diffraction pattern of AMX3009 dimaleate K-type crystal;

[0067] Fig.12 The X-ray powder diffraction pattern of AMX3009 dimaleate R-type crystals;

[0068] Fig.13 The X-ray powder diffraction pattern of AMX3009 dimaleate V-type crystals;

[0069] Fig.14 This is a curve chart of the average tumor volume changes in animals in the AMX3009 and Afatinib efficacy experiments. DETAILED DESCRIPTION

[0070] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention belongs. The terms used herein in the specification of the present invention are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items. The term "includes" or "comprising" described in the present invention means that it may include or contain other components in addition to the components described. The term "includes" or "comprising" described in the present invention may also be replaced by the closed form "for" or "consisting of..."

[0071] The present invention is further described below in conjunction with examples so that those skilled in the art can better understand the present invention and implement it, but the examples are not intended to limit the present invention.

[0072] Example 1

[0073] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide maleate, and the specific preparation process is as follows:

[0074] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (47.4 g, 103.2 mmol, 1 eq) and isopropanol (470 mL) were added to a 10L three-necked flask, stirred, heated to 70°C, and a solution of maleic acid (12.0 g, 103.2 mmol, 1 eq) in isopropanol (235 mL) was added dropwise. The addition was completed within one hour. After the addition is complete, the temperature is controlled at 60°C-65°C, and stirring is continued for 12-15 hours. An off-white solid is generated. The temperature is slowly lowered to 20°C-25°C and stirring is continued for 1 hour. The mixture is filtered using a Buchner funnel and dried with air at 40°C-45°C for 48-50 hours to obtain 46.9 g of an off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide maleate with a yield of 78.9%.

[0075] Example 2

[0076] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate, and the specific preparation process is as follows:

[0077] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (474.1 g, 1.03 mol, 1 eq) and isopropanol (4700 mL) were added into a 10 L three-necked flask, stirred, heated to 70°C, and maleic acid (239.4 g, 2.06 mmol, 2 eq) in isopropanol (4700 mL) was added dropwise. The addition was completed within one hour. After the addition is complete, the temperature is controlled at 60°C-65°C, and stirring is continued for 12-15 hours. An off-white solid is generated. The temperature is slowly lowered to 20°C-25°C and stirring is continued for 1 hour. The mixture is filtered using a Buchner funnel and dried at 40°C-45°C for 48-50 hours to obtain 609.0 g of an off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide dimaleate, with a yield of 85.4%. Melting point: 138-142°C.

[0078] 1 H NMR (400 MHz, DMSO-d 6 )δ9.98(s,1H),9.87(s,1H),8.93(s,1H),8.60(s,1H),8.00–7.95(m,1H),7.89–7.81 (m,1H),7.41(t,J=7.9Hz,1H),7.36(s,1H),7.24(dt,J=7.6,1.4Hz,1H),6.86–6.71(m ,2H),6.14(s,4H),4.39(dd,J=5.8,3.6Hz,2H),4.22(s,1H),3.98(d,J=5.6Hz,2H),3 .84(dd,J=5.7,3.6Hz,2H),3.55(q,J=7.0Hz,2H),2.82(s,6H),1.14(t,J=7.0Hz,3H).

[0079] Example 3

[0080] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate, and the specific preparation process is as follows:

[0081] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (47.4 g, 103.2 mmol, 1 eq) and ethyl acetate (470 mL) were added to a 10L three-necked flask, stirred, heated to 70°C, and maleic acid (23.9 g, 206.4 mmol, 2 eq) in isopropanol (470 mL) was added dropwise. The addition was completed within one hour. After the addition is complete, the temperature is controlled at 60°C-65°C, and stirring is continued for 12-15 hours. An off-white solid is generated. The temperature is slowly lowered to 20°C-25°C and stirring is continued for 1 hour. The mixture is filtered using a Buchner funnel and dried at 40°C-45°C for 48-50 hours to obtain 64.3 g of an off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate with a yield of 90.2%.

[0082] Example 4

[0083] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate, and the specific preparation process is as follows:

[0084] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (47.4 g, 103.2 mmol, 1 eq) and acetonitrile (940 mL) were added into a 10 L three-necked flask, stirred, heated to 70 ° C, and maleic acid (23.9 g, 206.4 mmol, 2 eq) in acetonitrile (940 mL) was added dropwise. The addition was completed within one hour. After the addition, the temperature was controlled at 60°C-65°C, and stirring was continued for 12-15 hours. An off-white solid was generated. The temperature was slowly lowered to 20°C-25°C and stirring was continued for 1 hour. The mixture was filtered through a Buchner funnel and dried at 40°C-45°C for 48-50 hours to obtain 66.8 g of an off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate with a yield of 93.8%.

[0085] Example 5

[0086] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate, and the specific preparation process is as follows:

[0087] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (47.4 g, 103.2 mmol, 1 eq) and tetrahydrofuran (600 mL) were added into a 10L three-necked flask, stirred, heated to 70°C, and maleic acid (23.9 g, 206.4 mmol, 2 eq) in tetrahydrofuran (600 mL) was added dropwise. The addition was completed within one hour. After the addition is complete, the temperature is controlled at 60°C-65°C, and stirring is continued for 12-15 hours. An off-white solid is generated. The temperature is slowly lowered to 20°C-25°C and stirring is continued for 1 hour. The mixture is filtered using a Buchner funnel and dried with air at 40°C-45°C for 48-50 hours to obtain 62.9 g of an off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate with a yield of 88.2%.

[0088] Example 6

[0089] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate, and the specific preparation process is as follows:

[0090] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (47.4 g, 103.2 mmol, 1 eq) and methyl tert-butyl ether (1000 mL) were added to a 10L three-necked flask, stirred, heated to 70°C, and maleic acid (23.9 g, 206.4 mmol, 2 eq) in isopropanol (1000 mL) was added dropwise. The mixture was added dropwise within one hour. After completion, the temperature was controlled at 60°C-65°C, and stirring was continued for 12-15 hours. An off-white solid was generated. The temperature was slowly lowered to 20°C-25°C and stirring was continued for 1 hour. The mixture was filtered using a Buchner funnel and dried at 40°C-45°C for 48-50 hours to obtain 65.0 g of an off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate with a yield of 91.3%.

[0091] Example 7

[0092] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide methanesulfonate, and the specific preparation process is as follows:

[0093] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (10 g, 0.021 mol, 1 eq) and isopropanol (100 mL) were added to a 10 L three-necked flask, stirred, heated to 70 ° C, and methanesulfonic acid (2.0 g, 0.021 mol, 1 eq) in isopropanol (20 mL) was added dropwise. The addition was completed within one hour. After that, the temperature was controlled at 60°C-65°C, stirring was continued for 12-15 hours, an off-white solid was generated, the temperature was slowly lowered to 20°C-25°C and stirring was continued for 1 hour, filtered through a Buchner funnel, and dried at 40°C-45°C for 48-50 hours to obtain 6.1 g of off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide methanesulfonate with a yield of 50.1%.

[0094] Example 8

[0095] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide dimethanesulfonate, and the specific preparation process is as follows:

[0096] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (10 g, 0.021 mol, 1 eq) and isopropanol (100 mL) were added to a 10 L three-necked flask, stirred, heated to 70 ° C, and methanesulfonic acid (4.1 g, 0.043 mol, 2 eq) in isopropanol (30 mL) was added dropwise. The addition was completed within one hour. After that, the temperature was controlled at 60°C-65°C, stirring was continued for 12-15 hours, an off-white solid was generated, the temperature was slowly lowered to 20°C-25°C and stirring was continued for 1 hour, filtered through a Buchner funnel, and dried at 40°C-45°C for 48-50 hours to obtain an off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide dimethanesulfonate 7.8 g, with a yield of 55.2%.

[0097] Example 9

[0098] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide trimesylate, and the specific preparation process is as follows:

[0099] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (10 g, 0.021 mol, 1 eq) and isopropanol (100 mL) were added to a 10 L three-necked flask, stirred, heated to 70 ° C, and methanesulfonic acid (6.3 g, 0.065 mol, 3 eq) in isopropanol (40 mL) was added dropwise. The addition was completed within one hour. After that, the temperature was controlled at 60°C-65°C, stirring was continued for 12-15 hours, an off-white solid was generated, the temperature was slowly lowered to 20°C-25°C and stirring was continued for 1 hour, filtered through a Buchner funnel, and dried at 40°C-45°C for 48-50 hours to obtain an off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide trimesylate 9.4 g, with a yield of 58.4%.

[0100] Example 10

[0101] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide p-toluenesulfonate, and the specific preparation process is as follows:

[0102] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (10 g, 0.021 mol, 1 eq) and isopropanol (100 mL) were added to a 10 L three-necked flask, stirred, heated to 70 ° C, and p-toluenesulfonic acid (7.5 g, 0.043 mol, 2 eq) in isopropanol (20 mL) was added dropwise. The addition was completed within one hour. After that, the temperature was controlled at 60°C-65°C, stirring was continued for 12-15 hours, an off-white solid was generated, the temperature was slowly lowered to 20°C-25°C and stirring was continued for 1 hour, filtered through a Buchner funnel, and dried at 40°C-45°C for 48-50 hours to obtain an off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide p-toluenesulfonate 7.4 g, with a yield of 42.3%.

[0103] Embodiment 11

[0104] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide phosphate, and the specific preparation process is as follows:

[0105] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (10 g, 0.021 mol, 1 eq) and isopropanol (100 mL) were added into a 10 L three-necked flask, stirred, heated to 70 ° C, and phosphoric acid (2.1 g, 0.021 mol, 1 eq) was added dropwise. The mixture was stirred for 12-15 hours, and an off-white solid was generated. The mixture was slowly cooled to 20-25°C and stirred for 1 hour. The mixture was filtered through a Buchner funnel and dried at 40-45°C for 48-50 hours to obtain 5.3 g of an off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide phosphate with a yield of 46.7%.

[0106] Example 12

[0107] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide L-malate, and the specific preparation process is as follows:

[0108] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (10 g, 0.021 mol, 1 eq) and isopropanol (100 mL) were added into a 10 L three-necked flask, stirred, heated to 70 ° C, and L-malic acid (5.8 g, 0.044 mmol, 2 eq) in isopropanol (20 mL) was added dropwise. The addition was completed within one hour, and then added dropwise. After completion, the temperature was controlled at 60°C-65°C, stirring was continued for 12-15 hours, an off-white solid was generated, the temperature was slowly lowered to 20°C-25°C and stirring was continued for 1 hour, filtered through a Buchner funnel, and dried at 40°C-45°C for 48-50 hours to obtain 6.7 g of an off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide L-malate with a yield of 42.7%.

[0109] Embodiment 13

[0110] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide succinate, and the specific preparation process is as follows:

[0111] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (10 g, 0.021 mol, 1 eq) and isopropanol (100 mL) were added into a 10 L three-necked flask, stirred, heated to 70 ° C, and succinic acid (2.1 g, 0.022 mmol, 1 eq) in isopropanol (20 mL) was added dropwise. The addition was completed within one hour, and then added dropwise. After completion, the temperature was controlled at 60-65°C, and stirring was continued for 12-15 hours, and an off-white solid was generated. The temperature was slowly lowered to 20-25°C and stirring was continued for 1 hour, and the mixture was filtered with suction using a Buchner funnel, and dried at 40-45°C for 48-50 hours to obtain 9.4 g of off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide succinate, with a yield of 62.3%. Melting point: 77.5-97.5°C.

[0112] 1 H NMR (400 MHz, DMSO-d 6 )δ9.77(s,1H),9.67(s,1H),8.92(s,1H),8.54(s,1H),8.01(s,1H),7.9 2–7.85(m,1H),7.39(t,J=7.9Hz,1H),7.34(s,1H),7.24–7.17(m,1H),6 .89–6.77(m,1H),6.70–6.61(m,1H),4.40–4.33(m,2H),4.21(s,5H),3. 87–3.80(m,2H),3.59–3.40(m,4H),2.48(s,5H),1.13(t,J=7.0Hz,3H).

[0113] Embodiment 14

[0114] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide sulfate, and the specific preparation process is as follows:

[0115] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (10 g, 0.021 mol, 1 eq) and isopropanol (100 mL) were added to a 10 L three-necked flask, stirred, heated to 70 ° C, and sulfuric acid (2.1 g, 0.022 mol, 1 eq) was added dropwise. The addition was completed within one hour. After the addition was completed, the temperature was controlled to be 40 ° C. The temperature was kept at 60-65°C and stirring was continued for 12-15 hours to generate an off-white solid. The mixture was slowly cooled to 20-25°C and stirring was continued for 1 hour. The mixture was filtered through a Buchner funnel and dried with air at 40-45°C for 48-50 hours to obtain 4.3 g of an off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide sulfate. The yield was 35.6%.

[0116] Embodiment 15

[0117] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dihydrochloride, and the specific preparation process is as follows:

[0118] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (10 g, 0.021 mol, 1 eq) and isopropanol (100 mL) were added to a 10 L three-necked flask, stirred, heated to 70 ° C, and an ethanol solution of hydrogen chloride (2 M, 21 mL, 0.042 mol, 2 eq) was added dropwise. The addition was completed within one hour. After the addition was completed, , control the temperature at 60°C-65°C, continue stirring for 12-15 hours, an off-white solid is generated, slowly cool to 20°C-25°C and continue stirring for 1 hour, filter with a Buchner funnel, and air dry at 40°C-45°C for 48-50 hours to obtain an off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dihydrochloride 10.5 g, yield 100%.

[0119] Example 16

[0120] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide ditartrate, and the specific preparation process is as follows:

[0121] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (10 g, 0.021 mol, 1 eq) and isopropanol (100 mL) were added to a 10 L three-necked flask, stirred, heated to 70 ° C, and tartaric acid (3.26 g, 0.022 mol, 1 eq) in isopropanol solution was added dropwise. The addition was completed within one hour. After the addition was completed, The temperature was controlled at 60-65°C, and stirring was continued for 12-15 hours, and an off-white solid was generated. The temperature was slowly lowered to 20-25°C and stirring was continued for 1 hour. The mixture was filtered with suction using a Buchner funnel, and dried by forced air at 40-45°C for 48-50 hours to obtain 6.1 g of an off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide ditartrate, with a yield of 42.7%. Melting point: 96.0-130.5°C.

[0122] 1 H NMR (400 MHz, DMSO-d 6 )δ9.76(s,1H),9.65(s,1H),8.92(s,1H),8.54(s,1H),8.04–7.99(m,1H),7.92–7.85 (m,1H),7.39(t,J=7.9Hz,1H),7.33(s,1H),7.24–7.17(m,1H),6.88–6.77(m,1H),6.6 4(d,J=15.3Hz,1H),4.36(dd,J=5.7,3.6Hz,2H),4.20(d,J=9.6Hz,4H),3.87–3.71(m, 3H), 3.55 (q, J = 7.0Hz, 2H), 3.45 (d, J = 6.5Hz, 2H), 3.17 (s, 4H), 1.14 (t, J = 7.0Hz, 3H).

[0123] Embodiment 17

[0124] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide diacetate, and the specific preparation process is as follows:

[0125] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (10 g, 0.021 mol, 1 eq) and isopropanol (100 mL) were added to a 10 L three-necked flask, stirred, heated to 70 ° C, and acetic acid (2.6 g, 0.043 mol, 2 eq) was added dropwise. The addition was completed within one hour. After the addition was completed, the temperature was controlled to be 40 ° C. The temperature was kept at 60-65°C and stirring was continued for 12-15 hours to generate an off-white solid. The mixture was slowly cooled to 20-25°C and stirring was continued for 1 hour. The mixture was filtered through a Buchner funnel and dried with air at 40-45°C for 48-50 hours to obtain 5.6 g of an off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide diacetate in a yield of 44.8%.

[0126] Embodiment 18

[0127] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide di(trifluoroacetic acid) salt, and the specific preparation process is as follows:

[0128] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (10 g, 0.021 mol, 1 eq) and isopropanol (100 mL) were added to a 10 L three-necked flask, stirred, heated to 70 ° C, and trifluoroacetic acid (5.0 g, 0.043 mol, 2 eq) was added dropwise. The addition was completed within one hour. After the addition was completed, the temperature was controlled to The mixture was stirred at 60-65°C for 12-15 hours to generate an off-white solid. The temperature was slowly lowered to 20-25°C and the stirring was continued for 1 hour. The mixture was filtered using a Buchner funnel and dried with air at 40-45°C for 48-50 hours to obtain 5.7 g of an off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide di(trifluoroacetic acid) salt in a yield of 37.9%.

[0129] Embodiment 19

[0130] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide citrate, and the specific preparation process is as follows:

[0131] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (10 g, 0.021 mol, 1 eq) and isopropanol (100 mL) were added to a 10 L three-necked flask, stirred, heated to 70 ° C, and citric acid (8.3 g, 0.043 mol, 1 eq) was added dropwise. The addition was completed within one hour. After the addition was completed, the temperature was controlled to be 40 ° C. The temperature was kept at 60-65°C, and stirring was continued for 12-15 hours, and an off-white solid was generated. The temperature was slowly lowered to 20-25°C, and stirring was continued for 1 hour. The mixture was filtered with suction through a Buchner funnel, and dried at 40-45°C for 48-50 hours to obtain 6.4 g of off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide citrate, with a yield of 46.7%. Melting point: 59.0-69.0°C.

[0132] 1 HNMR (400 MHz, DMSO-d 6 )δ9.74(d,J=16.1Hz,2H),8.91(d,J=5.6Hz,1H),8.55(s,1H),8.00(s,1H),7.88(d,J=8.1 Hz,1H),7.39(t,J=7.9Hz,1H),7.34(s,1H),7.21(d,J=7.5Hz,1H),6.80(dt,J=13.7,6.5Hz ,1H),6.68(d,J=15.4Hz,1H),4.40–4.34(m,2H),4.19(s,1H),3.86–3.70(m,3H),3.67(d,J =6.5Hz,2H),3.55(q,J=7.0Hz,2H),2.72–2.61(m,4H),2.59(s,6H),1.13(t,J=7.0Hz,3H).

[0133] Embodiment 20

[0134] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dihydrobromide, and the specific preparation process is as follows:

[0135] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (10 g, 0.021 mol, 1 eq) and isopropanol (100 mL) were added into a 10 L three-necked flask, stirred, heated to 70 ° C, and hydrobromic acid (3.52 g, 0.043 mol, 2 eq) was added dropwise. The addition was completed within one hour. After the addition was completed, the temperature was controlled to be 40 ° C. The temperature was kept at 60-65°C and stirring was continued for 12-15 hours to generate an off-white solid. The mixture was slowly cooled to 20-25°C and stirred for 1 hour. The mixture was filtered through a Buchner funnel and dried at 40-45°C for 48-50 hours to obtain 7.0 g of an off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dihydrobromide with a yield of 52.1%.

[0136] Embodiment 21

[0137] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-buteneamide difumarate, and the specific preparation process is as follows:

[0138] Under nitrogen protection, (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (10 g, 0.021 mol, 1 eq) and isopropanol (100 mL) were added into a 10 L three-necked flask, stirred, heated to 70 ° C, and a solution of fumaric acid (5.1 g, 2.06 mmol, 2 eq) in isopropanol (100 mL) was added dropwise. The addition was completed within one hour, and then added dropwise. After completion, the temperature was controlled at 60°C-65°C, stirring was continued for 12-15 hours, an off-white solid was generated, the temperature was slowly lowered to 20°C-25°C and stirring was continued for 1 hour, filtered through a Buchner funnel, and dried at 40°C-45°C for 48-50 hours to obtain an off-white solid (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dihydrobromide 11.8 g, yield 77.9%.

[0139] Embodiment 22

[0140] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate crystal form A, and the specific preparation process is as follows:

[0141] 40g AMX3009 and 20g maleic acid were added to 400mL isopropanol, heated to 70°C, reacted for 5 hours, slowly cooled to room temperature, stirred for 2 hours, allowed to stand for 16 hours, filtered, and dried at 50°C. The X-ray powder diffraction pattern of the crystalline sample is shown in Figure 1 After correction with silicon powder, the crystal has characteristic peaks at about 4.98±0.2°, 5.98±0.2°, 10.41±0.2°, 14.76±0.2°, 15.16±0.2°, 16.21±0.2°, 19.72±0.2°, 22.09±0.2°, 25.80±0.2°, and 34.81±0.2°. The DSC spectrum is shown in Figure 2 , with a sharp melting endothermic peak at 144°C. TGA spectrum is shown in Figure 3 , the mass lost at 120℃ accounts for 0.8% of the mass before weight loss. NMR results ( 1 HNMR) Figure 4 The NMR results showed that the molar ratio of free base to maleic acid was about 1.0:1.9, and there was no residual solvent. This crystal form was defined as crystal form A.

[0142] Embodiment 23

[0143] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate crystal form A, and the specific preparation process is as follows:

[0144] 15 mg of AMX3009 dimaleate was placed in a 3 mL vial, and 1.0-3.0 mL of acetonitrile was added. After shaking and filtering, the supernatant was taken, and the vial containing the clear solution was sealed with a sealing film and 4 small holes were pierced on it, and it was placed at 50°C for slow evaporation. When the solvent was completely evaporated, the obtained solid was collected, and its X-ray powder diffraction pattern and DSC spectrum were studied and compared to determine that the product was A crystal form.

[0145] Embodiment 24

[0146] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate crystal form A, and the specific preparation process is as follows:

[0147] 30 mg of AMX3009 dimaleate was added to a 20 mL vial, dissolved with 0.2-3.4 mL of methanol, and then an antisolvent was added to the clear solution, and stirred while adding dropwise until solids precipitated. The precipitated solids were separated by centrifugation, and their X-ray powder diffraction pattern and DSC spectrum were studied and compared to determine that the product was Form A. The types of antisolvents are shown in the following table:

[0148] Good solvent Anti-solvent system Anti-solvent addition amount (mL) The obtained crystal form Methanol Methyl tert-butyl ether 3 A crystal form Methanol 2-Methyltetrahydrofuran 3.5 A crystal form Methanol Toluene 5 A crystal form

[0149] Embodiment 25

[0150] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate crystal form A, and the specific preparation process is as follows:

[0151] 20 mg of AMX3009 dimaleate was placed in a 3 mL vial, 1.0-2.5 mL of solvent (acetone or acetonitrile) was added, and the supernatant was filtered after stirring at 50°C for about 2 hours. The obtained supernatant was placed in a biochemical incubator and cooled from 50°C to 5°C at a cooling rate of 0.1°C / min. The precipitated solid was collected, and its X-ray powder diffraction pattern and DSC spectrum were studied and compared to determine that the product was A crystal form.

[0152] Embodiment 26

[0153] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate crystal form B, and the specific preparation process is as follows:

[0154] 10g AMX3009 and 5g maleic acid were added to 100mL isopropanol, heated to 38 degrees, reacted for 5 hours, quickly cooled to room temperature, stirred for 2 hours, allowed to stand for 16 hours, filtered and dried. The X-ray powder diffraction pattern of the crystalline sample is shown in Figure 5 The crystals have characteristic peaks at approximately 4.68±0.2°, 7.75±0.2°, 9.90±0.2°, 13.40±0.2°, 14.03±0.2°, 14.41±0.2°, 16.70±0.2°, 17.64±0.2°, 18.73±0.2°, 25.52±0.2°, 26.38±0.2°, and 33.07±0.2°.

[0155] Embodiment 27

[0156] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate crystal form C, and the specific preparation process is as follows:

[0157] 20 mg of AMX3009 dimaleate was placed in a 1.5 mL vial, 0.5 mL of ethanol was added, and magnetic stirring was performed at room temperature for about 5 days. The solid was separated by centrifugation and dried in a fume hood at room temperature. The X-ray powder diffraction pattern of the crystalline sample is shown in Figure 6 The crystal has characteristic peaks at about 4.82±0.2°, 9.56±0.2°, 14.12±0.2°, 14.41±0.2°, 15.41±0.2°, 19.24±0.2°, 19.69±0.2°, and 25.72±0.2°. This crystal form is defined as C crystal form.

[0158] Embodiment 28

[0159] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate Form F, and the specific preparation process is as follows:

[0160] 20 mg of AMX3009 dimaleate was placed in a 1.5 mL vial, 0.5 mL of methanol / ethyl acetate (1:4, v / v) was added, and the solution was clarified after magnetic stirring at 50°C for about 4 days. About 20 mg of the sample was added, and magnetic stirring was continued at 50°C for about 1 day. The solid was separated by centrifugation and dried in a fume hood at room temperature. The X-ray powder diffraction pattern of the crystalline sample is shown in Figure 7 The crystal has characteristic peaks at about 4.57±0.2°, 7.06±0.2°, 8.51±0.2°, 12.93±0.2°, 15.5±0.2°, 18.44±0.2°, 19.33±0.2°, 20.23±0.2°, 20.94±0.2°, 25.58±0.2°, 25.85±0.2°, and 26.31±0.2°. This crystal form is defined as F crystal form.

[0161] Embodiment 29

[0162] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate crystal form D, and the specific preparation process is as follows:

[0163] 30 mg of AMX3009 dimaleate was placed in a 20 mL glass bottle, 0.2 mL of dimethylacetamide was added to dissolve, and 8 mL of anti-solvent 2-methyltetrahydrofuran was added dropwise while stirring. The precipitated solid was separated by centrifugation and placed at room temperature to dry. 5.7 mg of the obtained solid was weighed into a 1.5 mL vial, 0.5 mL of 2-methyltetrahydrofuran was added, and magnetic stirring was performed at room temperature for 19 hours. The separated solid was dried at room temperature. The X-ray powder diffraction pattern of the crystalline sample is shown in Figure 8The crystal has characteristic peaks at about 3.37±0.2°, 3.96±0.2°, 5.93±0.2°, 7.91±0.2°, 14.86±0.2°, 16.06±0.2°, 19.20±0.2°, 20.33±0.2°, 21.81±0.2°, 25.36±0.2°, 26.05±0.2°, and 27.28±0.2°. This crystal form is defined as D crystal form.

[0164] Embodiment 30

[0165] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate crystal form E, and the specific preparation process is as follows:

[0166] Place 20 mg of AMX3009 dimaleate in a 1.5 mL vial and add 0.5 mL of solvent water / 1,4-dioxane (5:95, v / v, water activity a w ~0.4), the obtained turbid solution was placed under magnetic stirring at room temperature for about 5 days, and then the solid was collected by centrifugation and dried in a fume hood at room temperature. The X-ray powder diffraction pattern of the crystalline sample is shown in Fig. 9 The crystal has characteristic peaks at about 5.16±0.2°, 6.75±0.2°, 15.65±0.2°, 16.67±0.2°, 17.84±0.2°, 18.09±0.2°, 18.90±0.2°, 23.45±0.2°, 25.07±0.2°, 26.12±0.2°, 26.74±0.2°, and 27.98±0.2°. This crystal form is defined as E crystal form.

[0167] In addition, the water activity a w ~0.3 solvent system (water: isopropanol volume ratio is 3:97) and water activity a w The above stirring experiment was carried out in a solvent system of 400 μg / mL (water: isopropanol volume ratio of 15:85) with a concentration of 400 μg / mL and a concentration of 0.5 μg / mL. Other conditions were the same, and the X-ray powder diffraction pattern showed that the crystals were all in the E form.

[0168] Embodiment 31

[0169] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate Form H, and the specific preparation process is as follows:

[0170] 69 mg of AMX3009 dimaleate was placed in a 3 mL vial and opened in a 20 mL glass bottle (with 4 mL of water). The sample was collected after 19 days of gas-solid permeation. The X-ray powder diffraction pattern of the crystalline sample is shown in Fig.10 The crystal has characteristic peaks at about 3.67±0.2°, 5.51±0.2°, 7.15±0.2°, 7.36±0.2°, 11.04±0.2°, 11.45±0.2°, 19.73±0.2°, 20.48±0.2°, 21.66±0.2°, 25.79±0.2°, 26.48±0.2°, and 27.86±0.2°. This crystal form is defined as H crystal form.

[0171] Embodiment 32

[0172] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate crystal form K, and the specific preparation process is as follows:

[0173] AMX3009 dimaleate crystal E was heated to 75°C at a heating rate of 10°C / min, kept at this temperature for 2 minutes, cooled to 30°C at a rate of 20°C / min, and then placed under ambient conditions. The X-ray powder diffraction pattern of the crystalline sample was shown in Fig.11 The crystal has characteristic peaks at about 5.16±0.2°, 6.96±0.2°, 13.86±0.2°, 15.54±0.2°, 17.67±0.2°, 19.62±0.2°, 23.34±0.2°, 23.79±0.2°, 24.34±0.2°, 25.43±0.2°, 27.50±0.2°, and 27.91±0.2°. This crystal form is defined as K crystal form.

[0174] Embodiment 33

[0175] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate crystal form R, and the specific preparation process is as follows:

[0176] A dynamic moisture adsorption test was performed on AMX3009 dimaleate crystal form A at 25°C, with humidity ranging from 0% RH to 95% RH to 0% RH. The X-ray powder diffraction pattern of the crystalline sample is shown in Fig.12The crystal has characteristic peaks at about 4.67±0.2°, 4.93±0.2°, 7.53±0.2°, 8.52±0.2°, 9.21±0.2°, 12.49±0.2°, 15.13±0.2°, 16.28±0.2°, 16.98±0.2°, 18.60±0.2°, 19.69±0.2°, and 27.34±0.2°. This crystal form is defined as R crystal form.

[0177] Embodiment 34

[0178] This embodiment relates to the preparation of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide dimaleate crystal form V, and the specific preparation process is as follows:

[0179] AMX3009 dimaleate was stirred magnetically in isopropanol / water (volume ratio 98 / 2) at room temperature, and the solid was collected by centrifugation and dried in a fume hood at room temperature. The X-ray powder diffraction pattern of the crystalline sample is shown in Fig.13 The crystal has characteristic peaks at about 8.56±0.2°, 10.10±0.2°, 13.48±0.2°, 14.16±0.2°, 16.58±0.2°, 18.20±0.2°, 18.40±0.2°, 19.19±0.2°, 20.28±0.2°, 22.28±0.2°, 23.77±0.2°, and 26.03±0.2°. This crystal form is defined as V crystal form.

[0180] Test Example 1 In vitro cell inhibition rate test

[0181] The (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide pharmaceutically acceptable salt prepared by the present invention was tested for the inhibition rate of EGFR drug-resistant mutation lung cancer cells, and the specific operation was as follows:

[0182] Compound preparation: Use dimethyl sulfoxide to prepare the compound into a dilution solution with a final concentration of 1000 times. The final concentrations of the compound test are 1000, 250, 62.5, 15.63, 3.91, 0.98, 0.25, 0.06, and 0.02 nM. Then dilute the compound with culture medium to prepare a compound with a final concentration of 20 times.

[0183] Cell Culture: Spin down the suspended cells, resuspend in growth medium, and count using a cell counter. Dilute the cell suspension to the desired density in growth medium. Add 95 μL of cells to each well, followed by 5 μL of 20x final concentration of compound, 5% CO 2, incubate at 37°C for 72 hours. Detection: Equilibrate the cell plate to room temperature. Add 50 μL CellTiter- Reagent, mix and shake for 2 minutes, incubate at room temperature for 10 minutes. Detect with SpectraMax Paradigm.

[0184] Data analysis: IC50 was calculated using GraphPad Prism 8.0.

[0185] %Inh=100-(RLU compound-RLU blank) / (RLU control-RLU blank)×100%RLUcontrol: only cells and DMSO were added, no drugs were added.

[0186] RLU blank: only culture medium and DMSO, no cells.

[0187] The test results are shown in Table 1 below:

[0188] Table 1

[0189]

[0190] From the in vitro cell inhibition rate test results in Table 1, it can be seen that AMX3009 dimaleate has better inhibitory activity against the above two EGFR mutation lung cancer cells compared with drugs such as osimertinib and afatinib.

[0191] Test Example 2: Animal in vivo pharmacodynamics test

[0192] The in vivo efficacy of the test drug AMX3009 dimaleate in its A-type crystalline form on Ba / F3-FL-EGFR-S768I cell subcutaneous homograft tumors in a BALB / c nude mouse model was studied.

[0193] Experimental drug: AMX3009 dimaleate in crystalline form A

[0194] Experimental animals: 40 female mice, 6-8 weeks old, weighing 18-22 g.

[0195] Drug preparation: Weigh appropriate amounts of experimental drugs, prepare type A crystals into 1, 0.5, and 0.25 mg / mL pure aqueous solutions, respectively, and prepare the oral control drug afatinib into a 1 mg / mL solution.

[0196] Drug administration: free drinking water and free food intake, oral administration, the dose is 10μL / g (different concentrations in different groups).

[0197] operate:

[0198] Ba / F3-FL-EGFR-S768I cell line was cultured, collected, prepared and diluted into a cell suspension with a viable cell concentration of 1×10^7 cells / mL, and inoculated into mice under the right armpit. The average tumor volume reached about 124.44mm 3 The mice were randomly divided into 5 groups according to the tumor volume. The drug was administered according to the weight of the mice: 10μL / g. If the weight loss exceeded 15%, the drug administration plan was adjusted accordingly. The health status and death of the animals were checked every day. Routine examinations included the tumor growth, activity, diet, weight, eyes, hair and other abnormal behaviors of the animals. The body weight was measured every day, and the tumor volume was measured three times a week (Monday, Wednesday and Friday). The tumor volume was measured by vernier caliper, and the formula was TV = 0.5a × b 2 , where a is the long diameter of the tumor and b is the short diameter of the tumor.

[0199] The results of the anti-tumor efficacy evaluation of AMX3009 and Afatinib on the Ba / F3-FL-EGFR-S768I cell homologous transplant tumor model (calculated based on the tumor volume on the 13th day after administration) are shown in the table below:

[0200]

[0201]

[0202] The curve of the change of average tumor volume of animals in the AMX3009 and afatinib efficacy experiments with treatment time is shown in Fig.14 As shown in the figure, it can be seen that AMX3009 maleic acid also exhibits strong pharmacodynamic effects in animals.

[0203] Test Example 3 Results of single pharmacokinetic test in SD rats

[0204] The results of a single pharmacokinetic test of the test drug AMX3009 dimaleate in SD rats were studied.

[0205] Experimental drug: AMX3009 dimaleate in crystalline form A

[0206] Experimental animals: Each group contained 4 female and 4 male SD rats aged 6 weeks, for a total of 16 rats.

[0207] Drug preparation: Accurately weigh appropriate amounts of the test sample AMX3009 maleate salt and dissolve it in normal saline to obtain a colorless clear liquid (pH ~ 6) with a concentration of 1 mg / mL for intravenous injection and oral administration.

[0208] Administration: The oral group fasted for about 13 to 14 hours before administration and resumed feeding about 4 hours after administration.

[0209] Sample collection and processing: Intravenous injection group, before administration, and 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h and 24h after administration.

[0210] The blood sampling time points of the oral PO group were: before administration, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 12h and 24h after administration. The results of the single pharmacokinetic test in SD rats are shown in the table below:

[0211] Intravenous injection group, dose 5 mg / kg (n=8)

[0212]

[0213] Oral group (PO), dose 10 mg / kg (n=8)

[0214]

[0215]

[0216] AUC(0-t)—t is 48h; MRT(0-t)—t is 48h

[0217] The results of a single pharmacokinetic test in SD rats showed that AMX3009 dimaleate had a high in vivo exposure and high bioavailability.

[0218] Test Example 4 Solubility and stability test

[0219] The crystalline form of the dimaleate of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide prepared by the present invention and (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide (AMX3009 free base) were tested for solubility and stability, and the specific results are as follows:

[0220] (1) Solubility test

[0221] In water, 0.1 mol hydrochloric acid, and simulated intestinal fluid FaSSIF, AMX3009 free base and AMX3009 dimaleate type A crystals were prepared into supersaturated solutions, oscillated to dissolve, and after 24 hours, the supernatant was centrifuged and the solubility was determined by high performance liquid chromatography according to the external standard method. The results are as follows:

[0222]

[0223] As can be seen from the above table, the solubility of AMX3009 free base in water and FaSSIF (simulated intestinal fluid) is low, and the solubility of AMX3009 dimaleic acid form A is significantly improved.

[0224] (2) Stability test

[0225] Short-term stability study of Form A:

[0226] Weigh an appropriate amount of AMX3009 dimaleate type A crystals into a glass vial, seal the vial with a sealing film, poke about 10 to 20 small pinholes, place it at 25°C / 60% RH for 1 week, and place it at 80°C for 1 day with the lid closed. Test the purity and XRPD to evaluate its physical and chemical stability. The results are as follows:

[0227]

[0228] The results of the stability test show that the purity and crystal form of Type A crystals remain essentially unchanged when placed at 25°C / 60% RH for 1 week, 80°C for 1 day, and 25°C / 60% RH for 1 week.

[0229] Long-term stability study of Form A:

[0230] AMX3009 dimaleate type A crystals were placed in PE bags, covered with aluminum foil bags, and placed under 25°C / 60%RH and 40°C / 75%RH conditions for 6 months, and 5°C conditions for 36 months, and tested by X-ray powder diffraction to evaluate its stability. The test results are shown in the following table:

[0231] Crystal form 25℃ / 60%RH6 months 40℃ / 75%RH6 months 5℃36 months Type A crystal Type A crystal Type A crystal Type A crystal

[0232] It can be seen from the above table that Form A has good long-term stability under simulated market packaging conditions and different temperature and humidity conditions.

[0233] Short-term stability study of Form E:

[0234] Weigh an appropriate amount of AMX3009 dimaleate E-type crystals into a glass vial, seal the vial with a sealing film, poke about 10 to 20 small pinholes, and place it under 25℃ / 60%RH and 40℃ / 75%RH conditions for 1 week to test purity and XRPD to evaluate its physical and chemical stability. The results are as follows:

[0235]

[0236] The results show that the purity and crystal form of type E crystals remain basically unchanged when placed under 25°C / 60% RH and 40°C / 75% RH conditions for one week, indicating that the crystals have good stability.

[0237] In summary, AMX3009 dimaleate form A has high solubility in water, 0.1 mol hydrochloric acid, and simulated intestinal fluid, and has good stability, and is suitable for application in pharmaceutical preparations.

[0238] The above-described embodiments are only preferred embodiments for fully illustrating the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or changes made by those skilled in the art based on the present invention are within the protection scope of the present invention. The protection scope of the present invention shall be subject to the claims.

Claims

1. A pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide, characterized in that The pharmaceutically acceptable salt is maleate, methanesulfonate, p-toluenesulfonate, phosphate, L-malate, succinate, sulfate, hydrochloride, tartrate, acetate, trifluoroacetate, citrate, hydrobromide or fumarate.

2. The pharmaceutically acceptable salt according to claim 1, characterized in that The pharmaceutically acceptable salt has the following general structural formula: Wherein, n is 1, 2 or 3; A is maleic acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, L-malic acid, succinic acid, sulfuric acid, hydrochloric acid, tartaric acid, acetic acid, trifluoroacetic acid, citric acid, hydrobromic acid or fumaric acid.

3. The pharmaceutically acceptable salt according to claim 2, characterized in that n is 2, and A is maleic acid.

4. A dimaleate crystalline form A of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide, characterized in that: Using Cu-Kα as the radiation source, the X-ray powder diffraction pattern represented by 2θ angles, the X-ray powder diffraction pattern of the crystal form A has characteristic peaks at 4.98±0.2°, 10.41±0.2°, 15.16±0.2°, and 19.72±0.2°.

5. The dimaleate crystalline form A according to claim 4, characterized in that: The X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 4.98±0.2°, 5.98±0.2°, 10.41±0.2°, 14.76±0.2°, 15.16±0.2°, 16.21±0.2°, 19.72±0.2°, 22.09±0.2°, 25.80±0.2°, and 34.81±0.2°.

6. A method for preparing the dimaleate crystal form A according to claim 4 or 5, characterized in that: The preparation method comprises: Dissolving (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide and maleic acid in a first organic solvent, stirring to precipitate crystals, and separating to obtain the crystalline form A; the first organic solvent is selected from one or more of isopropanol, acetonitrile, tetrahydrofuran, methyl isobutyl ketone, chloroform, acetone, ethyl acetate, 1,4-dioxane, isopropyl acetate, methyl tert-butyl ether, 2-methyltetrahydrofuran, and toluene; Alternatively, dissolving the dimaleate of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide in acetonitrile, volatilizing to precipitate a solid, and obtaining the crystalline form A; Alternatively, dissolving the dimaleate of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide in methanol, adding an anti-solvent, stirring to precipitate a solid, and obtaining the crystalline form A; the anti-solvent is methyl tert-butyl ether, 2-methyltetrahydrofuran or toluene; Alternatively, the dimaleate of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide is dissolved in acetone or acetonitrile, and the temperature is lowered to precipitate a solid to obtain the crystalline form A.

7. A dimaleate crystalline form B of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide, characterized in that: Using Cu-Kα as the radiation source, the X-ray powder diffraction pattern expressed in 2θ angles, the X-ray powder diffraction pattern of the crystalline form B has characteristic peaks at 4.68±0.2°, 7.75±0.2°, 9.90±0.2°, 13.40±0.2°, 14.03±0.2°, 14.41±0.2°, 16.70±0.2°, 17.64±0.2°, 18.73±0.2°, 25.52±0.2°, 26.38±0.2°, and 33.07±0.2°.

8. A dimaleate crystalline form C of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide, characterized in that: Using Cu-Kα as the radiation source, the X-ray powder diffraction pattern expressed in 2θ angles, the X-ray powder diffraction pattern of the crystalline form C has characteristic peaks at 4.82±0.2°, 9.56±0.2°, 14.12±0.2°, 14.41±0.2°, 15.41±0.2°, 19.24±0.2°, 19.69±0.2°, and 25.72±0.2°.

9. A dimaleate crystalline form D of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide, characterized in that: Using Cu-Kα as the radiation source, the X-ray powder diffraction pattern expressed in 2θ angles, the X-ray powder diffraction pattern of the crystalline form D has characteristic peaks at 3.37±0.2°, 3.96±0.2°, 5.93±0.2°, 7.91±0.2°, 14.86±0.2°, 16.06±0.2°, 19.20±0.2°, 20.33±0.2°, 21.81±0.2°, 25.36±0.2°, 26.05±0.2°, and 27.28±0.2°.

10. A dimaleate crystalline form E of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide, characterized in that: Using Cu-Kα as the radiation source, the X-ray powder diffraction pattern expressed in 2θ angles, the X-ray powder diffraction pattern of the crystalline form E has characteristic peaks at 5.16±0.2°, 6.75±0.2°, 15.65±0.2°, 16.67±0.2°, 17.84±0.2°, 18.09±0.2°, 18.90±0.2°, 23.45±0.2°, 25.07±0.2°, 26.12±0.2°, 26.74±0.2°, and 27.98±0.2°.

11. The dimaleate crystalline form E according to claim 10, characterized in that: The preparation method of the dimaleate crystal form E comprises the following steps: The dimaleate of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide is stirred in an aqueous system, and the solid is separated by centrifugation to obtain the crystalline form E; the aqueous system is a mixed system of water and an organic solvent, the organic solvent is isopropanol or 1,4-dioxygen, and the volume proportion of water in the aqueous system is not less than 3%.

12. A dimaleate crystalline form F of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide, characterized in that: Using Cu-Kα as the radiation source, the X-ray powder diffraction pattern expressed in 2θ angles, the X-ray powder diffraction pattern of the crystalline form F has characteristic peaks at 4.57±0.2°, 7.06±0.2°, 8.51±0.2°, 12.93±0.2°, 15.5±0.2°, 18.44±0.2°, 19.33±0.2°, 20.23±0.2°, 20.94±0.2°, 25.58±0.2°, 25.85±0.2°, and 26.31±0.2°.

13. A dimaleate crystalline form H of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide, characterized in that: Using Cu-Kα as the radiation source, the X-ray powder diffraction pattern expressed in 2θ angles, the X-ray powder diffraction pattern of the crystalline form H has characteristic peaks at 3.67±0.2°, 5.51±0.2°, 7.15±0.2°, 7.36±0.2°, 11.04±0.2°, 11.45±0.2°, 19.73±0.2°, 20.48±0.2°, 21.66±0.2°, 25.79±0.2°, 26.48±0.2°, and 27.86±0.2°.

14. A dimaleate crystal form K of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide, characterized in that: Using Cu-Kα as the radiation source, the X-ray powder diffraction pattern expressed in 2θ angles, the X-ray powder diffraction pattern of the crystal form K has characteristic peaks at 5.16±0.2°, 6.96±0.2°, 13.86±0.2°, 15.54±0.2°, 17.67±0.2°, 19.62±0.2°, 23.34±0.2°, 23.79±0.2°, 24.34±0.2°, 25.43±0.2°, 27.50±0.2°, and 27.91±0.2°.

15. A dimaleate crystalline form R of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide, characterized in that: Using Cu-Kα as the radiation source, the X-ray powder diffraction pattern represented by 2θ angles and interplanar spacing (d value), the X-ray powder diffraction pattern of the crystalline form R has characteristic peaks at 4.67±0.2°, 4.93±0.2°, 7.53±0.2°, 8.52±0.2°, 9.21±0.2°, 12.49±0.2°, 15.13±0.2°, 16.28±0.2°, 16.98±0.2°, 18.60±0.2°, 19.69±0.2°, and 27.34±0.2°.

16. A dimaleate crystalline form V of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide, characterized in that: Using Cu-Kα as the radiation source, the X-ray powder diffraction pattern represented by 2θ angles and interplanar spacing (d value), the X-ray powder diffraction pattern of the crystalline form V has characteristic peaks at 8.56±0.2°, 10.10±0.2°, 13.48±0.2°, 14.16±0.2°, 16.58±0.2°, 18.20±0.2°, 18.40±0.2°, 19.19±0.2°, 20.28±0.2°, 22.28±0.2°, 23.77±0.2°, and 26.03±0.2°.

17. A pharmaceutical composition, characterized in that A pharmaceutically acceptable salt comprising the (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxy ether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide of any one of claims 1 to 3, and / or the dimaleate crystalline form of any one of claims 4 to 16, and a pharmaceutically acceptable carrier.

18. Use of a pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide according to any one of claims 1 to 3, a dimaleate crystalline form according to any one of claims 4 to 16, or a pharmaceutical composition according to claim 17 in the preparation of a medicament for treating a disease associated with a protein kinase, wherein the protein kinase is an EGFR receptor tyrosine kinase or a HER-2 receptor tyrosine kinase.

19. Use of a pharmaceutically acceptable salt of (E)-4-(dimethylamino)-N-(7-(2-ethoxyethoxyether)-4-((3-ethynylphenyl)amino)-6-quinazoline)-2-butenamide as claimed in any one of claims 1 to 3, a dimaleate crystalline form as claimed in any one of claims 4 to 16, or a pharmaceutical composition as claimed in claim 17 in the preparation of a drug for treating cancer, wherein the cancer includes EGFR resistant mutation lung cancer, head and neck cancer, Her2 positive gastric cancer, breast cancer or colorectal cancer.

20. The use according to claim 18 or 19, characterized in that The drug is administered alone or in combination with other therapeutic agents.

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