N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-yloxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonic acid salt crystal form and methods of preparation

Abstract

The application belongs to the technical field of pharmaceutical chemistry, and particularly relates to A, B and C crystal forms of compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-yloxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate and a preparation method. The A, B and C crystal forms provided by the application can be prepared by various conditions, the crystallization process has good purification effect, and has the advantages of process stability and easy operation, the preparation method of the crystal form is simple, the cost is low, the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-yloxy)-3,4-dihydroquinoline-1(2H)-carboxamide methanesulfonate with different crystal forms, high purity, good solubility and good stability can be obtained.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to the A, B, and C crystal forms of N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-formamide methanesulfonate and their preparation methods. Background Technology

[0002] Malignant tumors are among the major diseases that seriously affect human health and threaten human life. The World Health Organization and health departments of governments around the world have made conquering cancer a top priority. Currently, the most commonly used anticancer drugs in clinical practice are cytotoxic drugs. Due to the inherent nature of cytotoxicity, these drugs have unavoidable drawbacks such as poor selectivity, strong toxic side effects, and easy development of drug resistance. Therefore, finding new targets with high specificity, low toxicity, and good patient tolerance has become an urgent need in anticancer drug research. In recent years, with the rapid development of life science research, many specific targets based on the mechanisms of cancer cell occurrence and development have been identified, such as vascular endothelial growth factors (VEGFR1, VEGFR2, VEGFR3) that inhibit tumor angiogenesis. Angiogenesis refers to the development of new vascular systems from existing blood vessels. Normal angiogenesis only occurs in certain short-term, specific physiological processes, such as reproduction and wound healing. Abnormal angiogenesis, however, is one of the pathological manifestations 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] VEGF receptors are important targets for anti-angiogenesis. In recent years, research on small-molecule inhibitors targeting VEGF receptors has been very active, with numerous inhibitors of diverse structures reported. However, these inhibitors still face some challenges. For example, they are all competitive inhibitors of ATP, while intracellular ATP concentrations, especially in cancer cells, can reach above 5 mmol / L. Therefore, inhibitor activity should reach at least the nanomolar level to exhibit effective inhibitory effects. Furthermore, VEGF receptors belong to the tyrosine kinase superfamily, whose members are widely involved in the transduction of biological signals in vivo. Due to sequence homology, the three-dimensional structure of their ATP-binding sites is highly conserved. Therefore, improving the selectivity of inhibitors among these family members is extremely important. Chinese invention patent CN103524409A discloses a class of quinoline tyrosine kinase inhibitors. These compounds generally exhibit good in vitro inhibitory activity against tyrosine kinases, particularly VEGFR2 and VEGFR3, but the druggability of the salt and crystal forms of specific compounds has not been further investigated.

[0004] This application describes a compound, N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-formamide methanesulfonate, which exhibits outstanding VEGFR2 and VEGFR3 inhibitory activity. Further studies show that the methanesulfonate of this product can improve the physicochemical or biological properties of the drug, achieving faster dissolution and release in vivo compared to the free base, thus facilitating absorption and efficacy, and offering greater clinical advantages.

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

[0006] To address the issues of solubility, stability, and oral bioavailability of compounds in water, the inventors, through long-term efforts, discovered that N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-formamide methanesulfonate can solve these problems.

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

[0008]

[0009] Furthermore, the A crystal form of compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-formamide methanesulfonate exhibits characteristic peaks at 2θ values ​​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° in its X-ray powder diffraction pattern. Preferably, characteristic peaks are observed at 2θ values ​​of 6.5984, 10.0740, 15.2443, 17.2032, 19.8381, and 24.3214. Preferably, characteristic peaks are present at 2θ values ​​of 6.5984, 7.6194, 10.0740, 13.3938, 15.2443, 17.2032, 18.8396, 19.8381, and 24.3214. More preferably, characteristic peaks are present at 2θ values ​​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.

[0010] The present invention also provides a method for preparing crystal form A of the above-described compound, the method comprising:

[0011] Weigh the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-formamide methanesulfonate into a bottle, add solvent to dissolve it, and allow it to slowly evaporate at room temperature.

[0012] Furthermore, the solvent used in the above steps 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.

[0013] Furthermore, the present invention provides crystal form B of the above-mentioned compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-formamide methanesulfonate, whose X-ray powder diffraction pattern shows 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°. Preferably, characteristic peaks are found 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.

[0014] Furthermore, the method for preparing the B crystal form includes:

[0015] Weigh the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-formamide methanesulfonate into a bottle, add solvent to dissolve it, filter, and place the filtrate and antisolvent separately in a sealed space and let it stand at room temperature.

[0016] Furthermore, the solvent in the above steps is selected from DMF, CHCl3, and methanol, and the antisolvent is selected from Acetone, THF, and MEK. The volume of the solvent used (ml) is 0.04-0.1 times the weight of the compound (mg), and the volume of the antisolvent used (ml) is 1-5 times the volume of the solvent (ml).

[0017] Furthermore, the present invention provides the C-crystal form of the above-mentioned compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-formamide methanesulfonate, whose X-ray powder diffraction pattern shows 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°. Preferably, characteristic peaks are found at 2θ of 4.7539, 10.4270, 15.7866, 19.8422, 22.8579, and 25.8347. Preferably, characteristic peaks are present at 2θ values ​​of 4.7539, 9.4706, 10.4270, 12.6174, 15.7866, 17.6406, 19.8422, 22.8579, and 25.8347. More preferably, characteristic peaks are present at 2θ values ​​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.

[0018] Furthermore, the method for preparing the C-type crystal includes:

[0019] Weigh the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-formamide methanesulfonate into a bottle, add solvent and slurry.

[0020] Furthermore, the solvent used 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 mixed solvents such as 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. 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 is 1.5:1 to 75:1 ml / ml, and the volume ratio of other mixed solvents is 1:4 to 4:1 ml / ml.

[0021] Furthermore, the method for preparing the C-type crystal includes:

[0022] Weigh the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-formamide methanesulfonate into a bottle, add solvent to dissolve it, filter, and place the filtrate and antisolvent separately in a sealed space and let it stand at room temperature.

[0023] Furthermore, the solvent used in the step is selected from DMF, CHCl3, and methanol, and the antisolvent is selected from Ethyl formate, IPAc, IPA, MTBE, and ACN. The volume of the solvent used (ml) is 0.04-0.1 times the weight of the compound (mg), and the volume of the antisolvent used (ml) is 1-5 times the volume of the solvent (ml).

[0024] Furthermore, the method for C-type crystals includes:

[0025] Weigh the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-formamide methanesulfonate into a bottle, add solvent to dissolve it, add antisolvent, stir until a solid precipitates out.

[0026] Furthermore, the solvent used in the step is selected from DMSO, NMP, methanol, and DCM, and the antisolvent is selected from Toluene, IPA, MEK, MTBE, Acetone, n-BuOH, and Anisole. The volume of the solvent used (ml) is 0.05-0.15 times the weight of the compound (mg), and the volume of the antisolvent used (ml) is 2-10 times the volume of the solvent (ml).

[0027] Four methanesulfonate crystal forms were identified during screening and repeated preparations: methanesulfonate crystal forms A, B, and C. Representative samples of the obtained methanesulfonate crystal forms were characterized and identified using XRPD, TGA, DSC, and high-performance liquid chromatography (HPLC). The results showed that methanesulfonate crystal forms B and C were amorphous, while methanesulfonate crystal form A was a hydrate.

[0028] The transformation relationship between the amorphous form B / C and the hydrate crystal form A of methanesulfonate was investigated through suspension competition experiments. The results showed that the amorphous form C was obtained in both the Acetone (5℃, RT, and 50℃) and IPAc (RT and 50℃) systems in the suspension competition experiments between the amorphous form B / C and the hydrate crystal form A of methanesulfonate at room temperature water activity (a w In an Acetone / water system with a concentration of 0–0.6, amorphous form C is obtained. Methanesulfonic acid crystal form A transforms into an amorphous state at 150°C, and further heating to 190°C followed by cooling to 30°C will transform it into crystal form C.

[0029] It should be understood that slightly different melting point readings may be given using different types of equipment or different test conditions. The accurate melting point value for different crystal forms will be affected by compound purity, sample weight, heating rate, particle size, and the calibration and maintenance of the test equipment. The values ​​provided should not be taken as absolute values.

[0030] It should be understood that different types of equipment or different testing conditions may yield slightly different XPRD spectra and peak values. The spectra, peak values, and relative intensities of each diffraction peak for different crystal forms will be affected by compound purity, sample pretreatment, scan speed, particle size, and calibration and maintenance of the testing equipment. The values ​​provided should not be taken as absolute values.

[0031] The "X-ray powder diffraction pattern or XPRD" described in this invention is obtained by Cu-Kα ray diffraction.

[0032] The "differential scanning calorimetry or DSC" described in this invention refers to measuring the temperature difference and heat flow difference between the sample and the reference material during the sample heating or isothermal process, in order to characterize all physical and chemical changes related to thermal effects and obtain phase transition information of the sample.

[0033] The diffraction angle 2θ described in this invention is the Bragg angle, in degrees, and the error range of 2θ is ±0.2.

[0034] 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 terms of 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, the production process is stable, repeatable and controllable, and can be adapted to industrial production. Attached Figure Description

[0035] Figure 1 XPRD pattern of crystal form A of compound;

[0036] Figure 2 TGA and DSC spectra of crystal form A of compound;

[0037] Figure 3 XPRD pattern of crystal form B of compound;

[0038] Figure 4 TGA and DSC spectra of crystal form B of compound;

[0039] Figure 5 XPRD pattern of crystal form C of the compound;

[0040] Figure 6 TGA and DSC spectra of crystal form C of the compound; Detailed Implementation

[0041] The present invention will be further described in detail below with reference to embodiments, but is not limited thereto.

[0042] Test conditions of the instruments used in the experiment:

[0043] XRPD is an X-ray powder diffraction detection method: measurements were performed using PANalytical Empyrean and X'Pert. 3 The X-ray diffractometer was used for the determination according to the General Chapter 0451 of Part IV of the 2020 edition of the Chinese Pharmacopoeia. The test conditions were: Target: Cu; 45kV, 40mA.

[0044] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC): Determination was performed using a TA Discovery 5500 thermogravimetric analyzer and a TA Discovery 2500 differential scanning calorimeter, in accordance with General Chapter 0661 of the 2020 edition of the Chinese Pharmacopoeia, Part IV. Test conditions: DSC: 30℃, 10℃ / min, 300℃; TGA: 30℃, 10℃ / min, 350℃.

[0045] Example 1: Screening of N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-formamide salts. Fourteen different acids were selected and salted in the following solvents.

[0046]

[0047]

[0048] The inventors were surprised to find that methanesulfonates exhibited outstanding performance in terms of salt formation and crystallinity.

[0049] Example 2 Preparation of N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-formamide methanesulfonate crystal form

[0050] 1. Preparation of Crystal Form A

[0051] Approximately 20 mg of each K-13 methanesulfonate (N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-formamide methanesulfonate) starting sample was weighed into 3 mL vials. 2.0–3.0 mL of solvent was added to dissolve the solid. After filtration through a filter membrane, the resulting clear filtrate was sealed with a sealing film, with a small hole punched in the film. The vials were then allowed to slowly evaporate at room temperature. The evaporated solid was collected and XRPD analysis showed it to be crystal form A. The experiment is as follows:

[0052]

[0053] XRPD results showed that no change in crystal form was observed in methanesulfonate crystal form A after drying at room temperature. TGA results showed that the sample lost 12.8% of its weight when heated from room temperature to 150℃. DSC results showed that the sample exhibited four endothermic peaks at 54.5℃, 121.7℃, 129.5℃, and 240.0℃ (peak temperature), and one exothermic peak at 182.7℃ (peak temperature).

[0054] XRPD peak finding data for methanesulfonate crystal form A

[0055]

[0056]

[0057] 2. Preparation of B-type crystal

[0058] gas-liquid diffusion

[0059] Weigh approximately 20 mg of K-13 methanesulfonate into a 3-mL vial. Dissolve the solid in 1.0–2.0 mL of solvent. Filter the solution through a membrane filter to obtain a clear solution. Take another 20-mL vial and add approximately 4 mL of antisolvent. Place the 3-mL vial containing the filtrate open over the 20-mL vial, then seal the 20-mL vial and allow it to stand at room temperature. When solid precipitation is observed, collect the solid and perform XRPD testing to obtain crystal form B. The experiment is as follows:

[0060]

[0061] XRPD results showed that no change in crystal form was observed in methanesulfonate B before and after air drying at room temperature. TGA results showed that the sample lost 3.5% of its 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 temperatures).

[0062] XRPD peak finding data for methanesulfonate crystal form B

[0063]

[0064]

[0065] 3. Preparation of C-type crystal

[0066] 3.1 Gas-solid diffusion

[0067] Multiple gas-solid diffusion experiments were conducted using different solvents. Approximately 20 mg of K-13 methanesulfonate was weighed into a 3-mL vial, and approximately 3 mL of solvent was added to a 20-mL vial. The 3-mL vial was placed open inside the 20-mL vial, which was then sealed. After standing at room temperature for approximately 20 days, the solid was collected and subjected to XRPD testing, yielding the C crystal form. The experiment is as follows:

[0068]

[0069] 3.2 Gas-liquid diffusion

[0070] Weigh approximately 20 mg of K-13 methanesulfonate into a 3-mL vial. Dissolve the solid in 1.0–2.0 mL of solvent. Filter the solution through a membrane filter to obtain a clear solution. Take another 20-mL vial and add approximately 4 mL of antisolvent. Place the 3-mL vial containing the filtrate open over the 20-mL vial, then seal the 20-mL vial and allow it to stand at room temperature. When solid precipitation is observed, collect the solid and perform XRPD testing to obtain the C crystal form. The experiment is as follows:

[0071]

[0072] *: A clear solution was obtained after 10 days of gas-liquid diffusion, and then the solution was allowed to evaporate at room temperature.

[0073] 3.3 Suspension stirring at 5℃

[0074] Approximately 20 mg of K-13 methanesulfonate was weighed into each HPLC vial, and 0.5 mL of solvent was added. The resulting suspension was magnetically stirred at 5°C for approximately one week. The solid was then separated by centrifugation and XRPD analysis was performed. The room temperature suspension stirring test yielded methanesulfonate crystal form C. The experiment is as follows:

[0075]

[0076]

[0077] 3.4 Room temperature suspension stirring

[0078] Approximately 20 mg of K-13 methanesulfonate was weighed into each HPLC vial, and 0.5 mL of solvent was added. The resulting suspension was magnetically stirred at room temperature for about one week. The solid was then separated by centrifugation and XRPD analysis was performed to obtain crystal form C. The experiment is as follows:

[0079]

[0080] 3.5 50℃ Suspension stirring

[0081] Approximately 20 mg of K-13 methanesulfonate was weighed into each HPLC vial, and 0.5 mL of solvent was added. The resulting suspension was magnetically stirred at 50°C for approximately 3 days. The solid was then separated by centrifugation and XRPD analysis was performed. Crystal form C was obtained. The experiment is as follows:

[0082]

[0083]

[0084] 3.6 Temperature cycling from 50 to 5℃

[0085] Approximately 20 mg of K-13 methanesulfonate was weighed into an HPLC vial, and 0.5 mL of solvent was added. The vial was magnetically stirred at 50 °C for 3 hours. The temperature was then lowered to 5 °C at a rate of 0.1 °C / min and stirred at 5 °C for 0.5 hours. The temperature was then increased to 50 °C at a rate of 4.5 °C / min and stirred at 50 °C for 0.5 hours. This process was repeated twice. The temperature was then lowered to 5 °C at a rate of 0.1 °C / min and maintained at 5 °C. The solid was collected for XRPD analysis to obtain crystal form C. The experiment is as follows:

[0086]

[0087] 3.7 Slow cooling

[0088] Approximately 20 mg of K-13 methanesulfonate was weighed into each HPLC vial, and 1.0 mL of solvent was added. The mixture was stirred and equilibrated at 50 °C for approximately 2 hours, then filtered (using a 0.45 μm PTFE filter). The supernatant was collected. The supernatant was placed in a biological incubator and cooled from 50 °C to 5 °C at a rate of 0.1 °C / min, then maintained at 5 °C. The precipitated solid was collected and XRPD analysis was performed to obtain crystal form C. The experiment is as follows:

[0089]

[0090] 3.8 Addition of antisolvent

[0091] Approximately 20 mg of K-13 methanesulfonate was weighed into 20 mL vials and dissolved in 1.0–3.0 mL of solvent. The antisolvent was then added dropwise while stirring until solid precipitated. The process was stopped if no solid precipitated after adding a total of 10.0 mL of solvent. The precipitated solid was separated by centrifugation and XRPD testing was performed. For systems where no solid precipitated after the addition of antisolvent, crystallization was induced at room temperature. The antisolvent addition experiment yielded methanesulfonate crystal form C. The experiment is as follows:

[0092]

[0093] *: The solution remained clear after adding the antisolvent and stirring for 3 days, and then evaporated at room temperature.

[0094] 3.9 Salt formation reaction

[0095] Weigh approximately 4.8 mg of methanesulfonic acid into an HPLC vial, dilute with 0.5 mL of solvent, then weigh an equimolar amount of free K-13 sample (approximately 20 mg) and add it to the HPLC vial. Stir magnetically at room temperature for 5 days. Collect the resulting solid and perform XRPD analysis. The methanesulfonate crystal form C was obtained in the salt formation reaction experiment. The experiment is as follows:

[0096]

[0097] XRPD results showed that no change in crystal form was observed in methanesulfonate C before and after air drying at room temperature. TGA results showed that the sample lost 2.5% of its 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).

[0098] XRPD peak finding data for mesylate crystal form C

[0099]

[0100]

[0101] 3.10 Performance Evaluation of Crystal Form C

[0102] Hygroscopic

[0103] The hygroscopicity of the non-crystalline form C of methanesulfonate was evaluated by DVS testing at 25°C within the 0%RH to 95%RH range. DVS and XRPD characterization results showed that the hygroscopic weight gain of the crystalline form C sample at 25°C / 80%RH was approximately 0.46%, indicating slight hygroscopicity (hygroscopicity classification criteria refer to the 2015 edition of the Chinese Pharmacopoeia). XRPD results showed that the crystal form of the sample remained unchanged after the DVS test. Experiments showed that the hygroscopicity of crystalline form C was superior to that of crystalline forms A and B.

[0104] Solid-state stability of C form of methanesulfonic acid:

[0105] The HPLC purity of methanesulfonate crystal form C sample did not decrease significantly after being placed in a closed environment at 60℃ for 24 hours, and in an open environment at 25℃ / 60%RH for 1 and 4 weeks. After being placed in an open environment at 40℃ / 75%RH for 4 weeks, the purity decreased from 99.22 area% to 98.80 area%, with an increase of 0.38% in impurities with an RRT of 0.81. The HPLC data of the samples before and after stability testing are summarized below. The XRPD comparison results of the samples before and after the stability test show that the crystal form of the samples did not change after the stability test. The experiment shows that the solid-state stability of crystal form C is better than that of crystal forms A and B.

[0106]

[0107] *: Samples stored at -20℃ were tested simultaneously with samples that had been stable for 4 weeks.

[0108] Methanesulfonate crystal form C is slightly hygroscopic and its crystal form did not change after DVS testing. No significant change in purity was observed after being placed in a closed environment at 60℃ for 24 hours and in an open environment at 25℃ / 60%RH for 4 weeks. After being placed in an open environment at 40℃ / 75%RH for 4 weeks, the purity decreased by 0.42 area. No crystal form change was observed in any of the samples after stability testing.

[0109] Example 3: Experiment on Influencing Factors of Crystal Forms A, B, and C

[0110]

[0111] Based on comprehensive evaluation, the amorphous C form of methanesulfonate is the dominant crystal form.

[0112] Example 4

[0113] Comparison of oral absorption of K-13 (free base) and its methanesulfonate (N-(3-fluorophenyl)-6-(6,7-dimethoxyquinoline-4-oxy)-3,4-dihydroquinoline-1(2H)-formamide methanesulfonate)

[0114]

[0115]

[0116]

[0117]

[0118] As can be seen from the table above, after the free base is prepared into mesylate, the blood drug concentration increases significantly, and the in vivo exposure C... max and AUC lastThe levels increased by 3.14 times and 2.46 times respectively, and the oral bioavailability increased significantly (from 20% to 50%), meeting the needs of the human body and helping to exert the drug's efficacy.

[0119] 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 within the protection scope of the present invention.

Claims

1. A C crystalline form of the compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-yloxy)-3,4-dihydroquinoline-l(2H)-carboxamide methanesulfonate, characterized by, The X-ray powder diffraction pattern has characteristic peaks at 2-theta values of 4.7°±0.2°, 10.4°±0.2°, 15.7°±0.2°, 19.8°±0.2°, 22.8°±0.2°, 25.8°±0.2° using Cu-Kα radiation.

2. A method for preparing the C crystal form of claim 1, comprising: (a) weighing compound N-(3-fluorophenyl)-6-(6, 7-dimethoxyquinolin-4-yloxy)-3,4- dihydroquinoline-l(2H)-carboxamide methanesulfonate into a bottle, adding solvent to slurry; 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 mixed solvents 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, the volume of the solvent or mixed solvent used is 0.025 times the weight of the compound, ml / g, the volume ratio of Acetone / H2O in the mixed solvent is 1.5:1~75:1, ml / ml, and the volume ratio of other mixed solvents is 1:4~4:1, ml / ml.

3. A method for preparing the C crystal form of claim 1, comprising: (a) weighing compound N-(3-fluorophenyl)-6-(6, 7-dimethoxyquinolin-4-yloxy)-3,4- dihydroquinoline-l(2H)-carboxamide methanesulfonate into a bottle, adding solvent to dissolve, filtering, and placing the filtrate and anti-solvent, each independently, in a closed space, and standing at room temperature; 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 of the solvent used is 0.04-0.1 times the weight of the compound, ml / mg, and the volume of the anti-solvent used is 1-5 times the volume of the solvent.

4. A method for preparing the C crystal form of claim 1, comprising: (a) Weigh compound N-(3-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-yloxy)-3,4- dihydroquinoline-l(2H)-carboxamide methanesulfonate into a bottle, add solvent to dissolve, add antisolvent, stir until solid precipitates; solvent of step (a) is selected from DMSO, NMP, methanol, DCM, the antisolvent is selected from toluene, IPA, MEK, MTBE, acetone, n-BuOH, anisole, the volume of solvent used is 0.05-0.15 times the weight of the compound, ml / mg, the volume of antisolvent used is 2-10 times the volume of solvent.

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