Crystal forms of n-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate and preparation method thereof

Abstract

The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to crystal forms A, B and C of compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate and a preparation method therefor. The three crystal forms A, B and C provided in the present invention can be prepared under multiple different conditions, and the crystallization process therefor has a good purification effect, and has the advantageous characteristics of a stable process, easy operation, etc. The method for preparing the crystal forms is simple and low in cost, and can obtain different crystal forms of compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate with a high purity, a good solubility, and good stability.

Description

[Corrected 03.01.2025 according to Rule 26] Crystalline form of N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate and its preparation method Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to A, B, and C crystal forms of N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxyl)-3,4-dihydroquinoline-1(2H)-formamide methanesulfonate and a preparation method. Background Art

[0002] Malignant tumors are among the major diseases that seriously impact human health and threaten human life. The World Health Organization and national health departments have made conquering cancer a top priority. Currently, the most commonly used anticancer drugs in clinical practice are primarily cytotoxic agents. Due to their inherent cytotoxicity, these drugs inevitably suffer from poor selectivity, strong side effects, and the development of drug resistance. Therefore, identifying new targets with high specificity, low toxicity, and good patient tolerance is a pressing need in anticancer drug research. In recent years, with the rapid advancement of life science research, numerous specific targets based on the mechanisms of cancer cell development and progression have been identified, such as vascular endothelial growth factors (VEGFR1, VEGFR2, and VEGFR3) that inhibit tumor angiogenesis. Angiogenesis is the development of new vascular systems from pre-existing blood vessels. Normal angiogenesis occurs only in certain short-term, specific physiological processes, such as reproduction and wound healing. Abnormal angiogenesis, however, is a pathological manifestation of malignant diseases such as tumors, rheumatoid arthritis, and diabetic retinopathy. Since Folkman proposed the hypothesis that angiogenesis is closely related to the occurrence and development of tumors, a large number of clinical practices and experimental studies have confirmed that inhibiting tumor-mediated angiogenesis can effectively inhibit tumor growth and metastasis.

[0003] The VEGF receptor is an important target for anti-angiogenesis. In recent years, research on small-molecule inhibitors targeting the VEGF receptor has been very active, with a large number of inhibitors with diverse structures reported. However, these inhibitors currently present several challenges. For example, they are all competitive inhibitors of ATP, and intracellular ATP concentrations, particularly within cancer cells, can reach over 5 mmol / L. Therefore, inhibitor activity must reach at least nanomolar levels to demonstrate effective inhibitory effects. Furthermore, the VEGF receptor belongs to the tyrosine kinase superfamily, whose members are widely involved in the transmission of biological signals in the body. Due to sequence homology, the three-dimensional structure of their ATP binding sites is highly conserved. Therefore, improving the selectivity of inhibitors within these family members is extremely important. Chinese invention patent publication number CN103524409A discloses a class of quinoline tyrosine kinase inhibitors. These compounds generally exhibit good in vitro inhibition of tyrosine kinase activity, particularly against VEGFR2 and VEGFR3. However, further investigation into the drugability of the salt and crystalline forms of the specific compounds has not been conducted.

[0004] This application describes a compound, N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate, which exhibits significant VEGFR2 and VEGFR3 inhibitory activity. Further studies have shown that the methanesulfonate salt of this compound can improve the drug's physicochemical and biological properties and achieve faster dissolution and release in the body than the free base, facilitating absorption and efficacy, and offering clinical advantages.

[0005] Given the importance of solid drug crystal forms and their stability in clinical treatment, in-depth research on the polymorphic forms of the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate is of great significance for the development of drugs suitable for industrial production and with good biological activity. Summary of the Invention

[0006] In response to the problems of compound solubility, stability and oral bioavailability in water, the inventors have made long-term efforts and discovered that N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate can solve this problem.

[0007] The present invention further provides a compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-formamide methanesulfonate, whose structural formula is as follows:

[0008] Furthermore, the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate Form A has an X-ray powder diffraction pattern with characteristic peaks at 2θ of 6.5°±0.2°, 10.0°±0.2°, 15.2°±0.2°, 17.2°±0.2°, 19.8°±0.2°, and 24.3°±0.2°. Preferably, characteristic peaks are present at 2θ of 6.5984, 10.0740, 15.2443, 17.2032, 19.8381, and 24.3214. Preferably, characteristic peaks are present at 2θ of 6.5984, 7.6194, 10.0740, 13.3938, 15.2443, 17.2032, 18.8396, 19.8381, and 24.3214. Preferably, characteristic peaks are present at 2θ of 6.5984, 7.6194, 10.0740, 13.1889, 13.3938, 15.2443, 17.2032, 18.8396, 19.8381, 24.3214, 25.8243, and 27.6430.

[0009] The present invention also provides a method for preparing the crystalline form A of the above-mentioned compound, the method comprising:

[0010] Weigh the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate into a bottle, add solvent to dissolve it, and slowly evaporate it at room temperature.

[0011] Furthermore, the solvent in the above step is Acetone / H2O, EtOH / H2O, methanol / water, THF / H2O or ACN / H2O, with a volume ratio of 3-4:1, and the volume (ml) of the solvent used is 0.1-0.5 times the weight (mg) of the compound.

[0012] Furthermore, the present invention provides a crystalline form B of the above-mentioned compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate, which has characteristic peaks at 2θ of 5.3°±0.2°, 9.6°±0.2°, 14.5°±0.2°, 21.5°±0.2°, 24.1°±0.2°, and 27.0°±0.2° in its X-ray powder diffraction pattern. Preferably, characteristic peaks are at 2θ of 5.3766, 9.6473, 14.5320, 21.5785, 24.1021, and 27.0263. Preferably, characteristic peaks are present at 2θ values ​​of 5.3766, 8.4489, 9.6473, 11.3723, 14.5320, 17.0842, 21.5785, 24.1021, and 27.0263. Preferably, characteristic peaks are present at 2θ values ​​of 5.3766, 8.4489, 9.6473, 10.7522, 11.3723, 14.5320, 15.6624, 17.0842, 21.5785, 24.1021, 27.0263, and 29.8914.

[0013] Furthermore, the method for preparing the B crystal form comprises:

[0014] Weigh the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate into a bottle, add a solvent to dissolve it, filter it, and place the filtrate and the anti-solvent in a closed space separately and let it stand at room temperature.

[0015] Furthermore, the solvent in the above steps is selected from DMF, CHCl3, and methanol, and the anti-solvent is selected from Acetone, THF, and MEK. The volume (ml) of the solvent used is 0.04-0.1 times the weight (mg) of the compound, and the volume (ml) of the anti-solvent used is 1-5 times the volume (ml) of the solvent.

[0016] Furthermore, the present invention provides a crystalline form C of the above-mentioned compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate, which has characteristic peaks at 2θ of 4.7°±0.2°, 10.4°±0.2°, 15.7°±0.2°, 19.8°±0.2°, 22.8°±0.2°, and 25.8°±0.2° in its X-ray powder diffraction pattern. Preferably, characteristic peaks are at 2θ of 4.7539, 10.4270, 15.7866, 19.8422, 22.8579, and 25.8347. Preferably, characteristic peaks are present at 2θ of 4.7539, 9.4706, 10.4270, 12.6174, 15.7866, 17.6406, 19.8422, 22.8579, and 25.8347. Preferably, characteristic peaks are present at 2θ of 4.7539, 9.4706, 10.4270, 11.0858, 12.6174, 14.0934, 15.7866, 17.6406, 19.8422, 22.8579, 25.8347, and 27.6134.

[0017] Furthermore, the method for preparing the C crystal form comprises:

[0018] The compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate was weighed into a bottle, and a solvent was added to slurry.

[0019] Furthermore, the solvent in the step is selected from IPA, MEK, IPAc, 1-PrOH, ethanol, methanol, Acetone, 2-MeTHF, EtOAc, MTBE, ACN, 1,4-Dioxane, THF, DCM, MIBK, Anisole, n-BuOH, or a mixed solvent NMP / Anisole, DMAc / n-Hexane, DMSO / MEK, Acetone / H2O, Acetone / EtOH, DMF / Toluene, CHCl3 / n-Heptane, EtOH / H2O, NMP / EtOAc, DMSO / Toluene, DMF / MIBK, CHCl3 / THF, MeOH / CPME, and the volume (ml) of the solvent or mixed solvent used is 0.025 times the weight (g) of the compound, the volume ratio of Acetone / H2O in the mixed solvent ml / ml is 1.5:1 to 75:1, and the volume ratio of other mixed solvents ml / ml is 1:4 to 4:1.

[0020] Furthermore, the method for preparing the C crystal form comprises:

[0021] Weigh the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate into a bottle, add a solvent to dissolve it, filter it, and place the filtrate and the anti-solvent in a closed space separately and let it stand at room temperature.

[0022] Furthermore, the solvent in the step is selected from DMF, CHCl3, and methanol, and the anti-solvent is selected from Ethyl formate, IPAc, IPA, MTBE, and ACN. The volume (ml) of the solvent used is 0.04-0.1 times the weight (mg) of the compound, and the volume (ml) of the anti-solvent used is 1-5 times the volume (ml) of the solvent.

[0023] Furthermore, the method for producing the C crystal form comprises:

[0024] Weigh the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate into a bottle, add solvent to dissolve it, add anti-solvent, and stir until solid precipitates.

[0025] Furthermore, the solvent in the step is selected from DMSO, NMP, methanol, and DCM, and the anti-solvent is selected from Toluene, IPA, MEK, MTBE, Acetone, n-BuOH, and Anisole. The volume (ml) of the solvent used is 0.05-0.15 times the weight (mg) of the compound, and the volume (ml) of the anti-solvent used is 2-10 times the volume (ml) of the solvent.

[0026] Four mesylate crystalline forms, Forms A, B, and C, were discovered during screening and repeated preparations. Representative samples of the resulting mesylate crystalline forms were characterized and identified using XRPD, TGA, DSC, and high-performance liquid chromatography (HPLC). The results showed that Forms B and C were anhydrous, while Form A was a hydrate.

[0027] The transformation relationship between anhydrous mesylate crystals B / C and hydrate crystals A was studied by suspension competition experiments. The results showed that the anhydrous mesylate crystals B / C and C in the Acetone (5℃, RT and 50℃) and IPAc (RT and 50℃) systems gave anhydrous mesylate crystals C; the suspension competition experiments between anhydrous mesylate crystals B / C and hydrate crystals A at room temperature (a w ) is 0-0.6 in an Acetone / water system to obtain anhydrous Form C. Methanesulfonic acid Form A is converted to an amorphous state at 150°C, and further heating to 190°C and cooling to 30°C will convert to Form C.

[0028] It should be understood that using different types of equipment or using different test conditions may give slightly different melting point readings. The exact value of the melting point of different crystalline forms will be affected by compound purity, sample weight, heating rate, particle size, and calibration and maintenance of the test equipment. The values ​​provided should not be regarded as absolute values.

[0029] It should be understood that using different equipment or testing conditions may produce slightly different XPRD patterns and peak values. The patterns, peak values, and relative intensities of diffraction peaks for different crystalline forms will be affected by compound purity, sample preparation, scanning speed, particle size, and calibration and maintenance of the testing equipment. The values ​​provided should not be considered absolute.

[0030] The "X-ray powder diffraction pattern or XPRD" mentioned in the present invention is obtained by Cu-Kα ray diffraction.

[0031] The "differential scanning calorimetry or DSC" mentioned in the present invention refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining the sample at a constant temperature, so as to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.

[0032] The diffraction angle 2θ described in the present invention is the Bragg angle, with the unit being degree, and the error range of the 2θ is ±0.2.

[0033] The beneficial effects of the present invention are as follows: the A, B, and C crystal forms of the compound of formula (1) provided by the present invention have advantages in stability, solubility, and formulation dissolution, are more suitable for drug development, meet the requirements of oral bioavailability and efficacy, can meet the pharmaceutical requirements of production, transportation, and storage, and the production process is stable, repeatable, and controllable, and can be adapted to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 XPRD spectrum of Form A of the compound;

[0035] Figure 2 TGA and DSC spectra of Form A of the compound;

[0036] Figure 3 XPRD pattern of Form B of the compound;

[0037] Figure 4 TGA and DSC spectra of Form B of the compound;

[0038] Figure 5 XPRD spectrum of Form C of the compound;

[0039] Figure 6 TGA and DSC spectra of Form C of the compound; DETAILED DESCRIPTION

[0040] The present invention will be further described in detail below with reference to the examples, but is not limited thereto.

[0041] Test conditions of the instruments used in the experiment:

[0042] XRPD is X-ray powder diffraction detection: measured using PANalytical Empyrean and X'Pert 3 The results were carried out using an X-ray diffractometer according to the 0451 General Rules of Part IV of the 2020 edition of the Chinese Pharmacopoeia. The test conditions were: Target: Cu; 45kV, 40mA.

[0043] TGA thermogravimetric analysis and DSC differential scanning calorimetry: The measurements were performed using a TA Discovery 5500 thermogravimetric analyzer and a TA Discovery 2500 differential scanning calorimeter in accordance with the 2020 edition of the Chinese Pharmacopoeia, Part IV, General Chapter 0661. The test conditions were: DSC: 30°C, 10°C / min, 300°C; TGA: 30°C, 10°C / min, 350°C.

[0044] Example 1: Screening of salt forms of N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide. Fourteen different acids were selected and salts were formed in the following solvents:

[0045] The inventors surprisingly found that the methanesulfonate has outstanding performance in terms of salt formation and crystallinity.

[0046] Example 2 Preparation of Crystalline N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-formamide Methanesulfonate

[0047] 1. Preparation of Form A

[0048] Weigh approximately 20 mg of each starting sample of K-13 methanesulfonate (N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate) into a 3 mL vial. Add 2.0-3.0 mL of solvent to dissolve the solid. After filtering through a membrane, seal the resulting clear filtrate with a small hole punched through a sealing film and allow it to evaporate slowly at room temperature. The evaporated solid was collected and analyzed by XRPD, revealing Form A. The experiment is as follows:

[0049] XRPD results showed that the mesylate salt Form A did not change in crystalline form upon drying at room temperature. TGA results showed that the sample lost 12.8% weight upon heating from room temperature to 150°C. DSC results showed that the sample exhibited four endothermic peaks at 54.5°C, 121.7°C, 129.5°C, and 240.0°C (peak temperature), and one exothermic peak at 182.7°C (peak temperature).

[0050] XRPD peak search data of mesylate salt form A

[0051] 2. Preparation of Form B

[0052] Gas-liquid diffusion

[0053] Approximately 20 mg of each K-13 mesylate salt was weighed into a 3-mL vial. 1.0-2.0 mL of solvent was used to dissolve the solid. Filter the solution through a membrane to obtain a clear solution. Approximately 4 mL of antisolvent was added to another 20-mL vial. The 3-mL vial containing the filtrate was placed open inside the 20-mL vial. The 20-mL vial was then sealed and allowed to stand at room temperature. When solid precipitation was observed, the solid was collected and analyzed by XRPD, yielding Form B. The experiment was as follows:

[0054] XRPD results showed that the mesylate salt Form B did not change in crystalline form before and after drying at room temperature. TGA results showed that the sample lost 3.5% weight when heated from room temperature to 150°C. DSC results showed that overlapping endothermic peaks were observed at 222.1°C and 230.3°C (peak temperature).

[0055] XRPD peak search data of mesylate salt form B

[0056] 3. Preparation of Form C

[0057] 3.1 Gas-solid diffusion

[0058] Several gas-solid diffusion experiments were conducted using different solvents. Approximately 20 mg of K-13 mesylate salt was weighed into a 3-mL vial. Approximately 3 mL of solvent was added to a 20-mL vial. The 3-mL vial was then placed open inside the 20-mL vial, which was then sealed. After standing at room temperature for ~20 days, the solid was collected and analyzed by XRPD, yielding Form C. The experiment was as follows:

[0059] 3.2 Gas-liquid diffusion

[0060] Approximately 20 mg of each K-13 mesylate salt was weighed into a 3-mL vial. 1.0-2.0 mL of solvent was used to dissolve the solid. Filter the solution through a membrane to obtain a clear solution. Approximately 4 mL of antisolvent was added to another 20-mL vial. The 3-mL vial containing the filtrate was placed open inside the 20-mL vial. The 20-mL vial was then sealed and allowed to stand at room temperature. When solid precipitation was observed, the solid was collected and analyzed by XRPD, yielding Form C. The experiment was as follows:

[0061] *: A clear solution was obtained after 10 days of gas-liquid diffusion, which was then evaporated at room temperature.

[0062] 3.3 Suspension stirring at 5℃

[0063] Approximately 20 mg of each K-13 mesylate salt was weighed into an HPLC vial. 0.5 mL of solvent was added to each vial. The resulting suspension was magnetically stirred at 5°C for approximately one week. The solid was separated by centrifugation and analyzed by XRPD. A room temperature suspension stirring experiment yielded Form C of the mesylate salt. The experiment was as follows:

[0064] 3.4 Suspension stirring at room temperature

[0065] About 20 mg of each K-13 mesylate salt was weighed into an HPLC vial, and 0.5 mL of solvent was added to each vial. The resulting suspension was placed under magnetic stirring at room temperature for about 1 week. The solid was separated by centrifugation and subjected to XRPD analysis to obtain Form C. The experiment is as follows:

[0066] 3.5 50℃ suspension stirring

[0067] Approximately 20 mg of each K-13 mesylate salt was weighed into an HPLC vial. 0.5 mL of solvent was added to each vial. The resulting suspension was magnetically stirred at 50°C for approximately 3 days. The solid was separated by centrifugation and analyzed by XRPD. Form C was obtained. The experiment was as follows:

[0068] 3.6 50~5℃ Temperature Cycle

[0069] Weigh approximately 20 mg of each K-13 mesylate salt into an HPLC vial, add 0.5 mL of solvent, and magnetically stir at 50°C for 3 hours. Cool to 5°C at a rate of 0.1°C / min and stir at 5°C for 0.5 hour; then heat to 50°C at a rate of 4.5°C / min and stir at 50°C for 0.5 hour. Repeat this step twice, then cool to 5°C at a rate of 0.1°C / min and maintain at 5°C. Collect the solid for XRPD analysis, and obtain Form C. The experiment is as follows:

[0070] 3.7 Slow cooling

[0071] Approximately 20 mg of each K-13 mesylate salt was weighed into an HPLC vial. 1.0 mL of solvent was added to each vial. The mixture was stirred and equilibrated at 50°C for approximately 2 hours, then filtered (using a 0.45 μm PTFE filter) to obtain the supernatant. The resulting supernatant was placed in an incubator and cooled from 50°C to 5°C at a rate of 0.1°C / min and maintained at 5°C. The precipitated solid was collected and analyzed by XRPD to obtain Form C. The experiment was as follows:

[0072] 3.8 Antisolvent Addition

[0073] Approximately 20 mg of each K-13 mesylate salt was weighed into a 20-mL vial and dissolved in 1.0-3.0 mL of solvent. The antisolvent was then added dropwise to the clear solution with stirring until solid precipitated. If no solid precipitated after adding a total of 10.0 mL of solvent, the solution was discontinued. The precipitated solid was separated by centrifugation and analyzed by XRPD. Systems that showed no solid precipitation after the addition of antisolvent were allowed to evaporate at room temperature to induce crystallization. Form C of the mesylate salt was obtained in the antisolvent addition experiment. The experiment was as follows:

[0074] *: After adding the antisolvent and stirring for 3 days, the solution remained clear and then evaporated at room temperature.

[0075] 3.9 Salt-forming reaction

[0076] Weigh ~4.8 mg of methanesulfonic acid into an HPLC vial and dilute with 0.5 mL of solvent. Then, weigh an equimolar amount of free K-13 sample (~20 mg) and add it to the HPLC vial. Stir magnetically at room temperature for 5 days. The resulting solid was collected and analyzed by XRPD. The salt formation reaction yielded Form C of the methanesulfonate salt. The experiment is as follows:

[0077] XRPD results showed that the mesylate salt Form C did not change in crystalline form before and after drying at room temperature. TGA results showed that the sample lost 2.5% weight when heated from room temperature to 150°C. DSC results showed that overlapping endothermic peaks were observed at 234.6°C and 241.9°C (peak temperatures).

[0078] XRPD peak search data of mesylate salt form C

[0079] 3.10 Performance evaluation of Form C

[0080] Hygroscopicity

[0081] The hygroscopicity of Form C, anhydrous mesylate, was evaluated by DVS testing at 25°C and 0% to 95% relative humidity. DVS and XRPD characterization results indicated that Form C, anhydrous mesylate, exhibited a moisture absorption weight gain of approximately 0.46% at 25°C / 80% relative humidity, indicating slight hygroscopicity (hygroscopicity classification criteria refer to the 2015 edition of the Chinese Pharmacopoeia). XRPD results revealed that the crystal form remained unchanged after DVS testing. This experiment demonstrates that Form C exhibits superior hygroscopicity to Forms A and B.

[0082] Solid-state stability of methanesulfonic acid form C:

[0083] The HPLC purity of the mesylate Form C sample did not decrease significantly after being stored at 60°C closed for 24 hours and at 25°C / 60% RH open for 1 and 4 weeks. After being stored open for 4 weeks at 40°C / 75% RH, the purity decreased from 99.22 area% to 98.80 area%, with an increase of 0.38% in the impurity with RRT 0.81. The HPLC data for the samples before and after stability testing are summarized below. XRPD comparison of the samples before and after the stability test showed that the crystal form of the samples did not change after the stability test. The experiment shows that Form C has better solid-state stability than Forms A and B.

[0084] *: Samples were stored at -20°C and tested simultaneously with the 4-week stability samples.

[0085] The mesylate salt form C is slightly hygroscopic and its crystal form does not change after DVS testing. No significant change in purity is observed after being placed under closed conditions at 60°C for 24 hours and exposed at 25°C / 60% RH for 4 weeks. The purity decreases by 0.42 area% after being exposed at 40°C / 75% RH for 4 weeks. No crystal form change occurs in any of the samples after stability testing.

[0086] Example 3 Test on factors affecting crystal forms A, B, and C

[0087] Comprehensive evaluation shows that anhydrous form C of mesylate is the dominant form.

[0088] Example 4

[0089] Comparative study on oral absorption of K-13 (free base) and its methanesulfonate (N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate)

[0090] As can be seen from the table above, after the free base is prepared into the mesylate, the blood concentration increases significantly, and the in vivo exposure Cmax and AUC last The increase was 3.14 times and 2.46 times respectively, and the oral bioavailability was significantly increased (from 20% to 50%), which met the needs of the human body and helped to exert the efficacy of the drug.

[0091] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate, whose structural formula is as follows:

2. A crystalline form A of the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ of 6.5°±0.2°, 10.0°±0.2°, 15.2°±0.2°, 17.2°±0.2°, 19.8°±0.2°, and 24.3°±0.2°.

3. A method for preparing the crystal form A according to claim 2, comprising: (a) Weigh the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate into a bottle, add a solvent to dissolve it, and evaporate it slowly at room temperature.

4. The method according to claim 3, characterized in that The solvent of step (a) is Acetone / H2O, EtOH / H2O, methanol / water, THF / H2O or ACN / H2O, and the volume ratio is 3-4:

1. The volume (ml) of the solvent is 0.1-0.5 times the weight (mg) of the compound.

5. Form B of the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ of 5.3°±0.2°, 9.6°±0.2°, 14.5°±0.2°, 21.5°±0.2°, 24.1°±0.2°, and 27.0°±0.2°.

6. A method for preparing the B crystal form according to claim 5, comprising: (a) Weigh the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate into a bottle, add a solvent to dissolve it, filter it, and place the filtrate and the anti-solvent in a closed space separately and stand at room temperature.

7. The method according to claim 6, characterized in that The solvent of step (a) is selected from DMF, CHCl3, methanol, and the anti-solvent is selected from Acetone, THF, MEK, the volume (ml) of the solvent used is 0.04-0.1 times the weight (mg) of the compound, and the volume (ml) of the anti-solvent used is 1-5 times the volume (ml) of the solvent.

8. Crystal form C of the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ of 4.7°±0.2°, 10.4°±0.2°, 15.7°±0.2°, 19.8°±0.2°, 22.8°±0.2°, and 25.8°±0.2°.

9. A method for preparing the crystal form C according to claim 8, comprising: (a) Weigh the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate into a bottle, and add a solvent to slurry.

10. The method according to claim 9, characterized in that The solvent of step (a) is selected from IPA, MEK, IPAc, 1-PrOH, ethanol, methanol, Acetone, 2-MeTHF, EtOAc, MTBE, ACN, 1,4-Dioxane, THF, DCM, MIBK, Anisole, n-BuOH, or a mixed solvent NMP / Anisole, DMAc / n-Hexane, DMSO / MEK, Acetone / H2O, Acetone / EtOH, DMF / Toluene, CHCl3 / n-Heptane, EtOH / H2O, NMP / EtOAc, DMSO / Toluene, DMF / MIBK, CHCl3 / THF, MeOH / CPME, and the volume (ml) of the solvent or mixed solvent is 0.025 times the weight (g) of the compound, the volume ratio of Acetone / H2O in the mixed solvent is ml / ml of 1.5:1 to 75:1, and the volume ratio of other mixed solvents is ml / ml of 1:4 to 4:

1.

11. A method for preparing the crystal form C according to claim 8, comprising: (a) Weigh the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate into a bottle, add a solvent to dissolve it, filter it, and place the filtrate and the anti-solvent in a closed space separately and stand at room temperature.

12. The method according to claim 11, characterized in that The solvent of step (a) is selected from DMF, CHCl3, methanol, and the anti-solvent is selected from Ethyl formate, IPAc, IPA, MTBE, ACN. The volume (ml) of the solvent used is 0.04-0.1 times the weight (mg) of the compound, and the volume (ml) of the anti-solvent used is 1-5 times the volume (ml) of the solvent.

13. A method for preparing the crystal form C according to claim 8, comprising: (a) Weigh the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate into a bottle, add a solvent to dissolve it, add an anti-solvent, and stir until a solid precipitates.

14. The method according to claim 13, characterized in that The solvent of step (a) is selected from DMSO, NMP, methanol, and DCM, and the anti-solvent is selected from Toluene, IPA, MEK, MTBE, Acetone, n-BuOH, and Anisole. The volume (ml) of the solvent used is 0.05-0.15 times the weight (mg) of the compound, and the volume (ml) of the anti-solvent used is 2-10 times the volume (ml) of the solvent.

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