A new crystal form of citric acid monosalt of a pyridopyrimidone compound and its preparation method and application

Abstract

The present invention belongs to the field of medicinal chemistry, and discloses a new crystal form of a citric acid salt of a pyridopyrimidone compound, and its preparation method and application. The citric acid salt crystal form Form A of the compound of the present invention uses Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at the following positions: 4.1±0.2°, 12.8±0.2°, 15.7±0.2°, 17.2±0.2°, 18.9±0.2°, 20.7±0.2°. The crystal form Form A of the present invention is a stable anhydrous crystal form with a solubility of 6.36 mg / mL in 37°C water for 24 hours, which is significantly improved compared to the free state, has good chemical stability, and is non-hygroscopic. The preparation method of the crystal form Form A of the present invention is simple to operate and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a new crystal form of a citric acid monosalt of a pyridopyrimidone compound, a preparation method and an application thereof. Background Art

[0002] Recent studies have revealed that the fibroblast growth factor receptor (FGFR) family regulates many key biological processes, including embryonic development, cell proliferation, differentiation, migration, apoptosis, angiogenesis, and metabolism. Abnormal activation of the FGFR family is associated with cancer cell survival and migration, tumor angiogenesis, and poor prognosis. Therefore, there is a need to develop effective, selective inhibitors of the FGFR family for the treatment of FGFR-dependent cancers. Chinese patent CN110809576A discloses a class of compounds that are fibroblast growth factor receptor kinase inhibitors and their use in the treatment of hyperproliferative diseases. These compounds not only demonstrate greater potency than previously known compounds as FGFR kinase inhibitors in vitro, but are also found to be irreversible inhibitors of FGFR-3, as well as FGFR-1 and FGFR-2, and are therefore useful as therapeutic agents for a variety of hyperproliferative diseases, particularly cancer. Among them is a pyridopyrimidinone compound, namely (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one, with the structural formula

[0003]

[0004] So far, there is no literature at home or abroad reporting the crystal form of the salt of the above compound, as well as the preparation method and use thereof.

[0005] Crystal form is a key factor influencing drug quality, efficacy, and formulation processing. Polymorphism refers to the phenomenon in which the same compound can form two or more molecular spatial arrangements, resulting in different solid crystals, by controlling its formation conditions. Different crystal forms of the same compound have the same chemical composition but different microscopic crystal structures, resulting in differences in appearance, morphology, physicochemical properties, and biological activity. These properties directly affect the formulation processing of drugs and affect their stability, solubility, and bioavailability, thereby affecting their quality, safety, efficacy, and application. Therefore, the research and preparation of a single, pure crystalline form of (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one is of great significance. Summary of the Invention

[0006] In view of this, the object of the present invention is to provide a crystalline form of a citrate monosalt of (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one that is suitable for industrial production, has good chemical stability, and is non-hygroscopic.

[0007] (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one monocitrate, the structural formula of which is as follows:

[0008]

[0009] Starting with the monocitrate salt of the compound, the applicant conducted polymorph screening experiments under various conditions. XRPD results of the resulting solid revealed 12 polymorphic forms: Form A, Form B / B1, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, and Form K. Form A and Form D were found to be stable crystalline forms of the monocitrate salt. Suspension competition experiments with Forms A and D, the dominant salt forms, revealed that Form A was the more thermodynamically stable anhydrous crystalline form at room temperature and 50°C.

[0010] The present invention uses the internationally recognized X-ray powder diffraction method (XRPD) to study and characterize the citrate monocrystalline form of the compound, the X-ray powder diffraction pattern of which is as follows: Figure 1 As shown, expressed in 2θ angle, its X-ray powder diffraction pattern has characteristic peaks at the following positions: 4.1±0.2°, 12.8±0.2°, 15.7±0.2°, 17.2±0.2°, 18.9±0.2°, and 20.7±0.2°.

[0011] Furthermore, the citrate monocrystalline form Form A of the compound has an X-ray powder diffraction pattern expressed in 2θ angles having characteristic peaks at the following positions: 4.1±0.2°, 9.8±0.2°, 12.8±0.2°, 13.7±0.2°, 15.0±0.2°, 15.7±0.2°, 16.4±0.2°, 17.2±0.2°, 18.9±0.2°, 19.9±0.2°, 20.7±0.2°, and 21.3±0.2°.

[0012] Furthermore, the citrate monocrystalline form Form A of the compound has an X-ray powder diffraction pattern expressed in 2θ angles having characteristic peaks at the following positions: 4.1±0.2°, 8.4±0.2°, 9.8±0.2°, 11.9±0.2°, 12.8±0.2°, 13.7±0.2°, 15.0±0.2°, 15.7±0.2°, 16.4±0.2°, 16.7±0.2°, 17.2±0.2°, 18.4±0.2°, 18.9±0.2°, 19.9±0.2°, 20.7±0.2°, 21.3±0.2°, 21.9±0.2°, 22.1±0.2°, 22.6±0.2°, and 24.1±0.2°.

[0013] The present invention also performs thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) on the citric acid salt crystal form A of the above compound. Figure 2 As shown, the sample has a weight loss of about 1.1% before 120°C; the DSC spectrum is as follows Figure 3 As shown, the melting point of the sample is about 178° C. The crystalline form A of the citrate monohydrate of the above compound is an anhydrate.

[0014] The present invention also provides a method for preparing the citrate monohydrate crystal form Form A of the compound (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one, comprising vacuum drying and crystallizing the citrate monohydrate of the compound.

[0015] In some embodiments, the vacuum drying temperature is 20 to 50°C and the time is 2 to 24 hours. In some embodiments, the vacuum drying temperature is room temperature and the time is 2 hours. In some embodiments, the vacuum drying temperature is room temperature and the time is 16 hours. In some embodiments, the vacuum drying temperature is 50°C and the time is 2 hours. In some embodiments, the vacuum drying temperature is room temperature and the time is 24 hours.

[0016] The preparation method of the citric acid monosalt of the compound comprises the following steps:

[0017] (a) adding citric acid and a solvent to the compound and mixing them to form a suspension;

[0018] (b) suspending and stirring at room temperature to separate out solid;

[0019] (c) isolating and obtaining a citric acid monosalt of the compound;

[0020] The compound is (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one.

[0021] In some embodiments, the solvent in step (a) is selected from at least one of acetonitrile, isopropanol, acetone, dichloromethane, and tetrahydrofuran.

[0022] In some embodiments, the suspension stirring time of step (b) is 10-72 hours. In some embodiments, the suspension stirring time of step (b) is 15 hours. In some embodiments, the suspension stirring time of step (b) is 72 hours.

[0023] In some embodiments, the separation in step (c) is vacuum filtration or centrifugal separation.

[0024] The present invention also provides the use of the citrate monocrystalline form Form A of the compound in the preparation of a drug for treating a hyperproliferative disease associated with the inhibition of fibroblast growth factor receptor kinase.

[0025] The hyperproliferative disease is one or more of lung cancer, breast cancer, ovarian cancer, endometrial cancer, urothelial cancer, bladder cancer, gastric cancer, head and neck cancer, prostate cancer, multiple myeloma, leukemia, brain cancer, eye cancer, liver cancer and skin cancer.

[0026] The present invention also provides a pharmaceutical composition for treating hyperproliferative diseases associated with the inhibition of fibroblast growth factor receptor kinase, which is prepared by combining the citrate monocrystalline form Form A of the compound and conventional pharmaceutical excipients.

[0027] According to conventional formulation processes, the citrate monocrystalline Form A of the compound of the present invention is mixed with at least one conventional pharmaceutical excipient to prepare any oral or injectable formulation suitable for clinical use, such as tablets, capsules, pills, powders, ointments, dispersants, granules, injections, lyophilized powder injections, etc. The pharmaceutical excipients include sodium citrate, calcium phosphate, fillers, binders, humectants, disintegrants, retardants, absorption enhancers, wetting agents, absorbents, lubricants, and mixtures thereof. Among them, fillers such as starch, lactose, sucrose, glucose, mannitol and silicic acid; binders such as carboxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic; humectants such as glycerol; disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, low-substituted hydroxypropyl cellulose; retarder solutions such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol and glyceryl monostearate; absorbents such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate.

[0028] As can be seen from the above technical solution, the present invention provides a crystalline form of the monocitrate salt of a compound, Form A, as well as its preparation method and application. Form A is a stable anhydrous crystalline form with a 24-hour solubility of 6.36 mg / mL in water at 37°C, significantly improved compared to the free form. It exhibits excellent chemical stability and is non-hygroscopic. The preparation method of Form A is simple and suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments.

[0030] Figure 1 is the X-ray powder diffraction pattern of the citric acid salt crystal form Form A of the compound;

[0031] Figure 2 is a thermogravimetric analysis diagram of the citric acid salt crystal form Form A of the compound;

[0032] Figure 3 is a differential scanning calorimetry diagram of the citric acid salt crystal form Form A of the compound;

[0033] Figure 4 The X-ray powder diffraction patterns of the stability samples before and after storage;

[0034] Figure 5 is a DVS diagram of the citric acid salt crystal form Form A of the compound;

[0035] Figure 6The figure shows the X-ray powder diffraction pattern of the citrate monocrystalline form Form A of the compound before and after DVS testing. DETAILED DESCRIPTION

[0036] The present invention provides a crystalline form of the citrate monosalt of the compound (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one, Form A, and its preparation method and application. Those skilled in the art can refer to the contents of this article and appropriately improve the process parameters to achieve it. It should be noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in the present invention. The methods and applications of the present invention have been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0037] The test materials used in the present invention are all common commercial products and can be purchased in the market.

[0038] The present invention is further described below with reference to the following examples. The X-ray powder diffraction (XRPD) instrument used was a Bruker D8Advance, with a copper target wavelength of The instrument was calibrated using the included standard (corundum) for Kα radiation at 40 kV and 40 mA, a θ-2θ goniometer, nickel filter, and SSD160-2 detector. The instrument was tested at room temperature, with the sample placed on a non-reflective plate. Detailed testing conditions are as follows: angular range: 3–40° 2θ, step size: 0.02° 2θ, and speed: 0.2 sec / step.

[0039] Thermogravimetric analysis (TGA) data were collected using a Mettler-Toledo TGA2 instrument, controlled by STAResoftware, and analyzed using STARe software. Typically, 1-10 mg of sample was placed in an alumina crucible. Using segmented high-resolution detection, the sample was heated from 30°C to 350°C at a rate of 10 kJ / min under a 50 mL / min dry nitrogen atmosphere.

[0040] Differential thermal analysis (DSC) data were collected using a Mettler-Toledo DSC3 instrument, controlled by STAResoftware, and analyzed using STARe software. Typically, 0.5-5 mg of sample was placed in a perforated aluminum crucible (covered). The temperature was raised from 30°C to 300°C at a rate of 10 kJ / min under a flow of 50 mL / min of dry nitrogen.

[0041] Example 1

[0042] Weigh 5000.73 mg of the free sample ((E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one) and 2172.27 mg of citric acid into a 50 mL single-necked vial. Add 20 mL of acetonitrile and sonicate at room temperature to dissolve the sample. Add a stirrer and stir the vial at room temperature for 3 days. Vacuum filter the suspension to obtain a white solid. The solid was placed in a vacuum oven at room temperature and dried for 24 hours to obtain a crystalline form of the citrate monosalt of compound (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one, Form A.

[0043] The obtained compound citrate monocrystalline form A was subjected to X-ray powder diffraction thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) detection. Figure 1-3 .

[0044] like Figure 1 As shown, the citrate monocrystalline form Form A of the compound has an X-ray powder diffraction pattern expressed in 2θ angles having characteristic peaks at the following positions: 4.1±0.2°, 8.4±0.2°, 9.8±0.2°, 11.9±0.2°, 12.8±0.2°, 13.7±0.2°, 15.0±0.2°, 15.7±0.2°, 16.4±0.2°, 16.7±0.2°, 17.2±0.2°, 18.4±0.2°, 18.9±0.2°, 19.9±0.2°, 20.7±0.2°, 21.3±0.2°, 21.9±0.2°, 22.1±0.2°, 22.6±0.2°, and 24.1±0.2°.

[0045] like Figure 2 As shown, the TGA spectrum shows that the citrate monocrystalline form Form A of the compound has a weight loss of about 1.1% before 120°C.

[0046] like Figure 3 As shown, the DSC spectrum shows that the melting point of the citrate monocrystalline form Form A of the compound is about 178°C.

[0047] Example 2

[0048] Approximately 200 mg of the free-state sample ((E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one) was weighed into a 20 mL glass vial. 86.91 mg of citric acid and 8 mL of acetonitrile were added, and sonication was performed to form a suspension. A stirring bar was added, and the suspension was stirred at room temperature on a magnetic stirrer. After stirring at room temperature for approximately 3 days, the resulting solid was isolated by vacuum filtration and dried under vacuum at room temperature for 2 hours to obtain the compound's citrate monocrystalline Form A. X-ray powder diffraction, thermogravimetric analysis, and differential thermal analysis were consistent with the results of Example 1.

[0049] Example 3:

[0050] Approximately 20 mg of the free-state sample ((E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one) was weighed into a 3 mL glass vial. 8 mg of citric acid and 0.5 mL of isopropanol were added, and sonication was performed to form a suspension. A stirrer was added, and the suspension was stirred on a magnetic stirrer at room temperature. After stirring at room temperature for approximately 3 days, the suspension was centrifuged, and the resulting solid was isolated and dried under vacuum at room temperature for 16 hours to obtain Form A of the compound's mono-citrate salt. X-ray powder diffraction, thermogravimetric analysis, and differential thermal analysis were consistent with the results of Example 1.

[0051] Example 4:

[0052] Weigh 5000.73 mg of the free sample ((E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one) and 2172.27 mg of citric acid into a 50 mL single-necked flask. Add 20 mL of acetonitrile and sonicate at room temperature to dissolve the sample. Add a stirrer and stir the flask at room temperature for 3 days. Vacuum filter the suspension to obtain a white solid. Dry the solid in a 50°C vacuum oven for 2 hours to obtain Form A, the monocrystalline citrate salt of the compound.

[0053] Example 5. Evaluation of the Form A Crystalline Form of the Citrate Monohydrate of the Compound

[0054] The crystalline form of the prepared compound, the monocrystalline citrate Form A, was evaluated, including equilibrium solubility in water, solid-state physicochemical stability, and hygroscopicity.

[0055] 1. Equilibrium solubility in water

[0056] The Form A crystal sample prepared in Example 1 was tested for its 24-hour equilibrium solubility in water. In the test, approximately 20 mg of the solid was mixed with 1 mL of water in a 3 mL glass vial. A stirrer was added, and the vial was mounted on a magnetic stirrer in a 37°C incubator with stirring. After 24 hours, the filtrate was separated and tested for HPLC concentration. The results, shown in Table 1, show that the 24-hour equilibrium solubility of the Form A crystal in water was 6.36 mg / mL, significantly improved compared to the hydrophobic free base (compound (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one).

[0057] Table 1 Equilibrium solubility results in water

[0058] Solid form Equilibrium solubility in water at 37°C (mg / mL) FormA 6.36 Free base 0

[0059] 2. Equilibrium solubility in gastric simulated fluid

[0060] The Form A crystal form sample prepared in Example 1 was tested for its equilibrium solubility in simulated gastric fluid over a 24-hour period. In this test, approximately 20 mg of the solid was mixed with 1 mL of water in a 3 mL glass vial. A stirrer was added, and the vial was mounted on a magnetic stirrer in a 37°C incubator with stirring. After 24 hours, the filtrate was separated and its concentration was measured by HPLC. The results, shown in Table 2, show a 24-hour equilibrium solubility of the Form A crystal form in simulated gastric fluid of 1.30 mg / mL.

[0061] Table 2 Equilibrium solubility data in gastric simulated fluid

[0062] Solid form Equilibrium solubility in water at 37°C (mg / mL) FormA 1.30

[0063] 3. One-week stability

[0064] The Form A crystal sample prepared in Example 1 was placed under 25°C / 60% RH (long-term) and 40°C / 75% RH (accelerated) conditions for one week, and then tested for HPLC purity and crystal form change. The results are shown in Table 3.

[0065] Table 3 One-week stability evaluation results

[0066]

[0067] After one week of storage under the two test conditions, the HPLC purity of Form A did not decrease significantly, the chemical stability was good, and no crystal form change was observed in the sample, indicating good crystal form stability. Figure 4 shown.

[0068] 4. Hygroscopicity assessment

[0069] To assess the stability risk of the Form A crystal sample prepared in Example 1 at 25°C with humidity changes, a DVS test was performed on Form A, and the solid sample collected after the test was subjected to XRPD testing. The results are shown in Table 4. At 90% RH, the Form A crystal form absorbed a maximum of approximately 0.047% water. The sample was not hygroscopic and the crystal form did not change. The DVS and XRPD test results are shown in Table 4. Figure 5 and Figure 6 shown.

[0070] Table 4 Hygroscopicity evaluation results

[0071] Solid form DVS maximum weight gain (%) Whether the crystal form changes before and after the test Hygroscopicity FormA 0.04657 no Non-hygroscopic

[0072] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in the present invention should be included in the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one citrate monohydrate Form A, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form Form A expressed in 2θ angles has characteristic peaks at the following positions: 4.1±0.2°, 12.8±0.2°, 15.7±0.2°, 17.2±0.2°, 18.9±0.2°, and 20.7±0.2°.

2. The (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one citrate monosalt crystalline form Form A according to claim 1, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form Form A expressed in 2θ angles has characteristic peaks at the following positions: 4.1±0.2°, 9.8±0.2°, 12.8±0.2°, 13.7±0.2°, 15.0±0.2°, 15.7±0.2°, 16.4±0.2°, 17.2±0.2°, 18.9±0.2°, 19.9±0.2°, 20.7±0.2°, and 21.3±0.2°.

3. The (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one citrate monosalt crystalline form Form A according to claim 1, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form Form A expressed in 2θ angles has characteristic peaks at the following positions: 4.1±0.2°, 8.4±0.2°, 9.8±0.2°, 11.9±0.2°, 12.8±0.2°, 13.7±0.2°, 15.0±0.2°, 15.7±0.2°, 16.4±0.2°, 16.7±0.2°, 17.2±0.2°, 18.4±0.2°, 18.9±0.2°, 19.9±0.2°, 20.7±0.2°, 21.3±0.2°, 21.9±0.2°, 22.1±0.2°, 22.6±0.2°, and 24.1±0.2°.

4. The (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one citrate monosalt crystalline form Form A according to claim 1, characterized in that: Its X-ray powder diffraction pattern is shown in Figure 1.

5. A method for preparing the (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one citrate monosalt crystalline form Form A according to any one of claims 1 to 4, characterized in that: The citric acid monosalt of (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one was vacuum dried and crystallized.

6. The method according to claim 5, characterized in that The vacuum drying temperature is 20 to 50° C., and the drying time is 2 to 24 hours.

7. The method according to claim 5 or 6, characterized in that The preparation method of the citric acid monosalt of (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one comprises the following steps: (a) (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one was added to citric acid and a solvent, and the mixture was mixed to form a suspension; (b) suspending and stirring at room temperature to separate out solid; (c) The citrate monosalt of (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one was isolated.

8. The method according to claim 7, characterized in that The solvent in step (a) is selected from at least one of acetonitrile, isopropanol, acetone, dichloromethane and tetrahydrofuran.

9. The method according to claim 7, characterized in that The suspension stirring time in step (b) is 10 to 72 hours.

10. The method according to claim 7, characterized in that The separation in step (c) is vacuum filtration or centrifugal separation.

11. Use of the citrate monocrystalline form Form A of (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one according to any one of claims 1 to 4 in the preparation of a medicament for treating hyperproliferative diseases associated with the inhibition of fibroblast growth factor receptor kinase.

12. The application according to claim 11, characterized in that: The hyperproliferative disease is one or more of lung cancer, breast cancer, ovarian cancer, endometrial cancer, urothelial cancer, bladder cancer, gastric cancer, head and neck cancer, prostate cancer, multiple myeloma, leukemia, brain cancer, eye cancer, liver cancer and skin cancer.

13. A pharmaceutical composition for treating a hyperproliferative disease associated with inhibition of fibroblast growth factor receptor kinase, characterized in that: The invention is prepared by combining the citrate monosalt crystal form Form A of (E)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one according to any one of claims 1 to 4 and conventional pharmaceutical excipients.

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