Crystal form of aromatic ring derivative and preparation method and application thereof

Abstract

This invention discloses a crystal form of an aromatic ring derivative, its preparation method and application. Specifically, it discloses the salt form, crystal form, pharmaceutical composition and use of the compound shown in formula (I).

Description

Technical Field

[0001] This invention relates to the crystal form, salt form, pharmaceutical composition of the compound represented by formula (I), and its use as an S1P1 agonist.

[0002] This application claims the following priority: CN 202111555458.X, application date December 17, 2021. Prior Technology

[0003] Sphingosine-1-phosphate (S1P) is an amphipathic biological signaling molecule belonging to the lysophospholipid (LP) family. S1P can activate complex downstream signaling by acting on five G protein-coupled receptor subtypes—sphingosine-1-phosphate receptors (S1PR1-5)—thereby regulating important physiological and biochemical functions. S1P binding to different S1P receptors can regulate different physiological functions, playing a crucial role in maintaining health and in the development of disease.

[0004] S1P1 receptor agonists interfere with lymphocyte trafficking, sequestering them in lymph nodes and other secondary lymphoid tissues. This leads to a reduction in peripheral circulating lymphocytes, and the clinical value of lymphocyte sequestration lies in removing them from the view of inflammation and / or autoimmune responses in surrounding tissues. This sequestration of lymphocytes (e.g., in lymph nodes) is thought to result from the simultaneous action of agonist-driven functional antagonism of S1P1 receptors on T cells (thus reducing the ability of S1P1 to mobilize T cells to flow out of lymph nodes) and sustained agonism of S1P1 receptors on lymph node endothelium (thus enhancing the barrier function against lymphocyte migration). Therefore, S1P1 receptor agonists reduce the body's autoimmune capacity by blocking lymphocyte transport and can thus be used as immunosuppressants to treat various autoimmune diseases.

[0005] The S1P1 agonist fingolimod (FTY720) has been approved by the FDA for the treatment of relapsing-remitting multiple sclerosis (MS), opening up a new therapeutic area for immune diseases. Although FTY720 has clinical efficacy, it is a non-selective S1P receptor agonist. Its binding to S1P3 in vivo often leads to a series of significant side effects, such as bradycardia, greatly limiting its application in the treatment of immune diseases. Therefore, the discovery of second-generation, highly selective S1P1 agonists, making them more effective, with fewer side effects, and with a wider range of applications for the treatment of immune diseases, has become a hot topic in drug research.

[0006] Application number PCT / CN2019 / 123485 (application date December 6, 2019) discloses an S1P1 agonist with the following structure: (I). Summary of the Invention

[0007] This invention provides a calcium salt of the compound shown in formula (Ⅰ). .

[0008] In some embodiments of the present invention, the above-mentioned calcium salt is... .

[0009] The present invention also provides a crystal form G of the calcium salt of the compound shown in formula (II), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.98±0.2°, 10.12±0.2°, 13.56±0.2°, 14.66±0.2°, 15.22±0.2°, and 18.48±0.2°.

[0010] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form G has characteristic diffraction peaks at the following 2θ angles: 8.98±0.2°, 10.12±0.2°, 13.56±0.2°, 14.66±0.2°, 15.22±0.2°, 16.34±0.2°, 16.92±0.2°, 18.48±0.2°, 22.67±0.2°, and 23.06±0.2°.

[0011] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form G described above has an X-ray powder diffraction pattern substantially as shown in FIG7.

[0012] In some embodiments of the present invention, the analytical data of the X-ray powder diffraction pattern of the above-mentioned crystal form G are shown in Table 7. Table 7 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 8.98 1219.24 0.12 9.84 100.00 10.12 903.05 0.14 8.74 74.07 13.56 187.67 0.14 6.53 15.39 14.66 63.10 0.12 6.04 5.18 15.22 265.12 0.10 5.82 21.74 16.34 70.68 0.16 5.42 5.80 16.92 70.96 0.14 5.24 5.82 18.48 144.72 0.14 4.80 11.87 19.13 47.76 0.24 4.64 3.92 20.44 75.91 0.16 4.34 6.23 21.18 28.48 0.39 4.19 2.34 22.67 89.34 0.18 3.92 7.33 23.06 68.88 0.14 3.86 5.65 24.90 99.38 0.16 3.58 8.15 26.32 37.92 0.16 3.39 3.11 27.24 56.07 0.16 3.27 4.60 30.88 27.23 0.24 2.90 2.23

[0013] In some embodiments of the present invention, the aforementioned crystal form G is characterized in that it further comprises water and a solvent; in, The solvent is selected from ethanol and isopropanol; The solvent content is 0.1%-6.0%; The water content is 0.1-4.0%.

[0014] In some embodiments of the present invention, the content of the solvent is 1.0% to 5.5%, and the content of water is 3.0% to 4.5%.

[0015] In some embodiments of the present invention, the solvent is ethanol, the content of which is 1.0% to 5.5%, and the content of which is water is 3.0% to 4.5%.

[0016] In some embodiments of the present invention, the content of the solvent is 1.64% to 4.77%, and the content of water is 3.09% to 4.37%.

[0017] In some embodiments of the present invention, the solvent is ethanol, the content of which is 1.64% to 4.77%, and the content of which is water is 3.09% to 4.37%.

[0018] In some embodiments of the present invention, the solvent is ethanol, wherein the ethanol content is 4.77% and the water content is 3.09%.

[0019] In some embodiments of the present invention, the solvent is ethanol, wherein the ethanol content is 3.05% and the water content is 3.89%.

[0020] In some embodiments of the present invention, the solvent is ethanol, wherein the content of ethanol is 1.97% and the content of water is 4.37%.

[0021] In some embodiments of the present invention, the solvent is ethanol, wherein the content of ethanol is 1.64% and the content of water is 3.75%.

[0022] The characteristic diffraction peaks used in this specification are selected from the observed diffraction patterns. When distinguishing multiple crystalline solids, peaks that are visible in the crystalline solid but invisible in other crystalline solids are preferred characteristic peaks for identifying the crystalline solid, rather than peak size. If such characteristic peaks are used, even one or two peaks can characterize the crystalline solid. In particular, crystal form G can be distinguished from other crystalline forms (such as anhydrous forms) disclosed in this specification by the presence of characteristic diffraction peaks. Furthermore, by comparing the measured spectra, if their characteristic peaks are consistent, the powder X-ray diffraction spectra are substantially identical. Crystal form G can change its solvent hydration state due to variations in solvent and water content. Crystal forms G with different solvent hydration contents share common characteristic peaks, as shown in Figures 1 and 18-21.

[0023] In some embodiments of the present invention, the common characteristic peaks are at least three peaks selected from the diffraction angles (2θ): 8.98±0.2°, 10.12±0.2°, 13.56±0.2°, 14.66±0.2°, 15.22±0.2°, and 18.48±0.2°.

[0024] In some embodiments of the present invention, the common characteristic peaks are at least three peaks selected from diffraction angles (2θ): 8.98±0.2°, 10.12±0.2°, 13.56±0.2°, 14.66±0.2°, 15.22±0.2°, 16.34±0.2°, 16.92±0.2°, 18.48±0.2°, 22.67±0.2°, and 23.06±0.2°. It should be noted that in this invention, the content (%) represents the mass ratio, and the unit is g / g.

[0025] In another aspect, the present invention also provides a method for preparing crystalline form G. According to an embodiment of the present invention, the method comprises: dissolving the compound shown in formula (I) in a sodium ethoxide solution, followed by stirring, filtering, and vacuum drying in the presence of calcium chloride to obtain crystalline form G. This method differs from the conventional methods for forming calcium salt crystal forms in the prior art. The method of the present invention uses the presence of calcium chloride instead of calcium hydroxide, and the crystalline form G needs to be obtained after drying.

[0026] In some embodiments of the present invention, the above method includes: heating the compound shown in formula (I) and anhydrous ethanol to 35-45°C, stirring for 5-30 minutes, adding sodium ethoxide solution, stirring for 2-3 hours, adding calcium chloride solution dropwise, stirring for 1-3 hours, cooling to 20-30°C, stirring for 4-6 hours, filtering, rinsing the filter cake with purified water, rinsing with ethanol, and drying the filter cake under reduced pressure at 25-35°C to obtain crystal form G.

[0027] In some embodiments of the present invention, the mass ratio of sodium ethoxide to anhydrous ethanol in the above-mentioned sodium ethoxide solution is (0.01-0.05):(0.40-0.80).

[0028] In some embodiments of the present invention, the mass ratio of sodium ethoxide to anhydrous ethanol in the above-mentioned sodium ethoxide solution is 0.035:0.631.

[0029] In some embodiments of the present invention, the mass ratio of calcium chloride to pure water in the above-mentioned calcium chloride solution is (0.01-0.08):(0.20-1.00).

[0030] In some embodiments of the present invention, the mass ratio of calcium chloride to pure water in the above-mentioned calcium chloride solution is 0.040:0.847.

[0031] The present invention also provides crystal form A of the compound shown in formula (Ⅰ), Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.25±0.2°, 6.28±0.2°, 10.5±0.2°, 12.69±0.2°, 15.45±0.2°, and 16.02±0.2°.

[0032] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.25±0.2°, 6.28±0.2°, 10.5±0.2°, 12.69±0.2°, 15.45±0.2°, 16.02±0.2°, 16.60±0.2°, 20.66±0.2°, 21.39±0.2°, and 22.28±0.2°.

[0033] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form A described above has an X-ray powder diffraction pattern substantially as shown in FIG1.

[0034] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the above-mentioned crystal form A are shown in Table 1 below. Table 1 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 5.25 957 0.26 16.82 54.9 6.28 647 0.24 14.07 37.1 8.31 391 0.25 10.63 22.4 9.71 403 0.18 9.10 23.1 10.50 789 0.39 8.42 45.3 11.96 394 0.12 7.39 22.6 12.69 1033 0.38 6.97 59.3 13.03 533 0.44 6.79 30.6 13.40 375 0.15 6.60 21.5 15.45 1743 0.34 5.73 100 16.02 987 0.37 5.53 56.6 16.60 825 0.30 5.34 47.3 17.50 532 0.16 5.06 30.5 19.12 1052 0.34 4.64 60.4 20.66 1196 0.65 4.30 68.6 21.39 1317 0.71 4.15 75.6 22.28 1422 0.50 3.99 81.6 22.75 931 0.45 3.90 53.4 24.13 589 0.27 3.68 33.8 24.93 740 0.19 3.57 42.5 25.26 633 1.16 3.52 36.3 25.95 613 0.54 3.43 35.2 27.13 540 0.33 3.28 31

[0035] The present invention also provides a compound of crystal form B shown in formula (Ⅰ), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.96±0.2°, 11.71±0.2°, 15.55±0.2°, 17.35±0.2°, 20.62±0.2°, and 21.16±0.2°.

[0036] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2θ angles: 6.96±0.2°, 10.80±0.2°, 11.71±0.2°, 13.39±0.2°, 15.55±0.2°, 17.35±0.2°, 18.45±0.2°, 20.62±0.2°, 21.16±0.2°, and 21.81±0.2°.

[0037] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form B described above has an X-ray powder diffraction pattern substantially as shown in FIG2.

[0038] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the above-mentioned crystal form B are shown in Table 2. Table 2 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 5.90 56.28 0.31 14.97 10.12 6.96 133.17 0.31 12.69 23.94 8.43 62.90 0.31 10.49 11.31 10.80 110.78 0.24 8.19 19.92 11.71 202.82 0.39 7.56 36.47 13.39 125.43 0.39 6.61 22.55 15.55 256.69 0.20 5.70 46.15 17.35 323.49 0.87 5.11 58.16 18.45 131.46 0.24 4.81 23.64 20.62 556.17 0.28 4.31 100.00 21.16 530.27 0.35 4.20 95.34 21.81 266.83 0.39 4.08 47.98 23.15 130.52 0.47 3.84 23.47 24.49 250.34 0.24 3.64 45.01 25.49 250.04 0.39 3.49 44.96 33.11 11.62 0.94 2.71 2.09

[0039] The present invention also provides the crystal form C of the compound shown in formula (Ⅰ), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 12.69±0.2°, 14.38±0.2°, 16.23±0.2°, 17.40±0.2°, 18.61±0.2°, and 19.74±0.2°.

[0040] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form C has characteristic diffraction peaks at the following 2θ angles: 12.69±0.2°, 14.38±0.2°, 16.23±0.2°, 17.40±0.2°, 18.61±0.2°, 19.74±0.2°, 20.46±0.2°, 20.94±0.2°, 21.75±0.2°, and 25.44±0.2°.

[0041] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form C has an X-ray powder diffraction pattern substantially as shown in FIG3.

[0042] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the above-mentioned crystal form C are shown in Table 3. Table 3 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 10.34 20.18 0.47 8.56 4.56 12.69 142.83 0.14 6.97 32.30 14.38 266.87 0.12 6.16 60.35 16.23 249.54 0.10 5.46 56.44 17.40 166.61 0.14 5.10 37.68 17.86 138.54 0.12 4.97 31.33 18.61 158.32 0.12 4.77 35.80 19.74 442.17 0.14 4.50 100.00 20.46 146.85 0.20 4.34 33.21 20.94 158.72 0.12 4.24 35.90 21.29 131.16 0.12 4.17 29.66 21.75 336.65 0.12 4.09 76.14 23.09 80.23 0.16 3.85 18.15 23.80 91.72 0.12 3.74 20.74 25.44 144.65 0.28 3.50 32.71 26.41 81.60 0.12 3.37 18.45 27.74 26.82 0.39 3.22 6.07

[0043] The present invention also provides the crystal form D of the compound shown in formula (Ⅰ), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.33±0.2°, 13.94±0.2°, 18.82±0.2°, 22.76±0.2°, 24.24±0.2°, and 27.90±0.2°.

[0044] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form D described above has an X-ray powder diffraction pattern substantially as shown in FIG4.

[0045] In some embodiments of the present invention, the analytical data of the X-ray powder diffraction pattern of the crystal form D are shown in Table 4. Table 4 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 4.65 8.44 0.94 19.01 4.53 9.33 61.21 0.12 9.48 32.85 13.94 45.87 0.16 6.35 24.61 17.19 6.60 0.79 5.16 3.54 18.82 186.36 0.12 4.71 100.00 22.76 49.61 0.16 3.91 26.62 24.24 13.02 0.94 3.67 6.98 27.90 14.03 0.47 3.20 7.53

[0046] The present invention also provides the crystal form E of the compound shown in formula (Ⅰ), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.84±0.2°, 10.65±0.2°, 11.53±0.2°, 15.41±0.2°, 17.29±0.2°, and 20.65±0.2°.

[0047] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2θ angles: 6.84±0.2°, 10.65±0.2°, 11.53±0.2°, 13.78±0.2°, 15.41±0.2°, 17.29±0.2°, 20.22±0.2°, 20.65±0.2°, 23.90±0.2°, and 25.26±0.2°.

[0048] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form E described above has an X-ray powder diffraction pattern substantially as shown in FIG5.

[0049] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the above-mentioned crystal form E are shown in Table 5. Table 5 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 6.84 213.57 0.12 12.93 24.96 8.34 46.17 0.24 10.60 5.40 10.65 131.82 0.12 8.31 15.41 11.53 275.98 0.08 7.67 32.26 13.78 130.09 0.55 6.42 15.21 15.41 568.65 0.18 5.75 66.47 17.29 317.03 0.16 5.13 37.06 18.12 193.21 0.12 4.90 22.58 20.22 441.18 0.12 4.39 51.57 20.65 855.52 0.08 4.30 100.00 21.85 173.38 0.24 4.07 20.27 22.64 159.84 0.24 3.93 18.68 23.90 347.11 0.14 3.72 40.57 25.26 309.61 0.24 3.53 36.19 27.65 44.83 0.24 3.23 5.24

[0050] The present invention also provides a diethylamine salt of the compound shown in formula (I).

[0051] The present invention also provides crystal form F of the diethylamine salt of the compound shown in formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 10.36±0.2°, 10.96±0.2°, 12.01±0.2°, 13.05±0.2°, 16.66±0.2°, and 18.99±0.2°.

[0052] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form F has characteristic diffraction peaks at the following 2θ angles: 10.36±0.2°, 10.96±0.2°, 12.01±0.2°, 13.05±0.2°, 16.66±0.2°, 18.99±0.2°, 20.42±0.2°, 20.98±0.2°, 22.11±0.2°, and 23.93±0.2°.

[0053] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form F described above has an X-ray powder diffraction pattern substantially as shown in FIG6.

[0054] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the above-mentioned crystal form F are shown in Table 6. Table 6 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 10.36 119.43 0.10 8.54 22.45 10.96 200.05 0.10 8.07 37.60 12.01 532.05 0.10 7.37 100.00 13.05 168.95 0.12 6.79 31.75 16.66 514.45 0.10 5.32 96.69 17.86 57.46 0.14 4.97 10.80 18.99 161.92 0.12 4.67 30.43 19.27 74.44 0.12 4.61 13.99 19.96 80.73 0.12 4.45 15.17 20.42 85.76 0.14 4.35 16.12 20.98 140.17 0.12 4.23 26.35 21.43 61.04 0.12 4.15 11.47 22.11 122.11 0.14 4.02 22.95 23.93 446.60 0.14 3.72 83.94 24.88 82.80 0.16 3.58 15.56 26.38 27.06 0.24 3.38 5.09 27.20 96.56 0.16 3.28 18.15 27.73 74.63 0.14 3.22 14.03 30.64 45.36 0.16 2.92 8.53 35.71 12.05 0.47 2.51 2.26 39.02 6.96 0.31 2.31 1.31

[0055] The present invention also provides a crystal form H of the calcium salt of the compound shown in formula (Ⅰ), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.32±0.2°, 9.57±0.2°, 11.83±0.2°, 12.76±0.2°, 13.48±0.2°, and 14.83±0.2°.

[0056] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form H has characteristic diffraction peaks at the following 2θ angles: 7.32±0.2°, 9.57±0.2°, 11.83±0.2°, 12.76±0.2°, 13.48±0.2°, 14.83±0.2°, 16.64±0.2°, 17.69±0.2°, 18.91±0.2°, and 21.33±0.2°.

[0057] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form H has an X-ray powder diffraction pattern substantially as shown in FIG8.

[0058] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the above-mentioned crystal form H are shown in Table 8. Table 8 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 7.32 31.92 0.47 12.07 27.57 9.57 72.38 0.12 9.24 62.52 11.83 42.53 0.24 7.48 36.73 12.76 115.78 0.28 6.94 100.00 13.48 104.78 0.10 6.57 90.51 14.83 56.68 0.31 5.97 48.96 16.64 42.14 0.31 5.33 36.40 17.69 40.85 0.47 5.01 35.28 18.91 71.48 0.16 4.69 61.74 21.33 92.62 0.16 4.17 80.00 23.78 67.60 0.12 3.74 58.39

[0059] The present invention also provides crystal form I of the calcium salt of the compound shown in formula (Ⅰ), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.27±0.2°, 8.93±0.2°, 11.23±0.2°, 12.34±0.2°, 13.66±0.2°, and 16.06±0.2°.

[0060] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form I described above has characteristic diffraction peaks at the following 2θ angles: 7.27±0.2°, 8.93±0.2°, 11.23±0.2°, 12.34±0.2°, 13.66±0.2°, 16.06±0.2°, 17.97±0.2°, 20.82±0.2°, 23.42±0.2°, and 24.38±0.2°. In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form I described above has an X-ray powder diffraction pattern substantially as shown in FIG9.

[0061] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the above-mentioned crystal form I are shown in Table 9. Table 9 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 7.27 21.18 0.24 12.16 23.93 8.93 67.89 0.12 9.90 76.70 11.23 80.80 0.16 7.88 91.29 12.34 37.44 0.20 7.17 42.30 13.66 88.51 0.12 6.48 100.00 16.06 37.63 0.16 5.52 42.52 17.97 42.64 0.20 4.94 48.17 20.82 9.74 0.94 4.27 11.00 23.42 36.68 0.12 3.80 41.44 24.38 23.10 0.24 3.65 26.10

[0062] The present invention also provides crystal form J of the calcium salt of the compound shown in formula (Ⅰ), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.73±0.2°, 9.49±0.2°, 11.99±0.2°, 12.89±0.2°, 15.16±0.2°, and 19.58±0.2°.

[0063] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form J has characteristic diffraction peaks at the following 2θ angles: 4.52±0.2°, 8.73±0.2°, 9.49±0.2°, 11.99±0.2°, 12.89±0.2°, 15.16±0.2°, 19.58±0.2°, 21.96±0.2°, 24.84±0.2°, and 26.66±0.2°.

[0064] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form J described above has an X-ray powder diffraction pattern substantially as shown in FIG10.

[0065] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the above-mentioned crystal form J are shown in Table 10. Table 10 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 4.52 6.35 0.94 19.54 1.85 8.73 230.64 0.14 10.13 67.36 9.49 342.39 0.18 9.32 100.00 11.99 52.90 0.63 7.38 15.45 12.89 39.80 0.24 6.87 11.63 15.16 51.84 0.47 5.85 15.14 19.58 33.83 0.47 4.53 9.88 21.96 30.00 0.94 4.05 8.76 24.84 26.40 0.63 3.58 7.71 26.66 11.47 0.94 3.34 3.35

[0066] The present invention also provides a crystal form K of the calcium salt of the compound shown in formula (Ⅰ), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.57±0.2°, 9.32±0.2°, 11.06±0.2°, 12.65±0.2°, 14.08±0.2°, and 14.71±0.2°.

[0067] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form K has characteristic diffraction peaks at the following 2θ angles: 7.66±0.2°, 8.57±0.2°, 9.32±0.2°, 11.06±0.2°, 12.65±0.2°, 14.08±0.2°, 14.71±0.2°, 15.08±0.2°, 15.79±0.2°, and 19.29±0.2°.

[0068] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form K described above has an X-ray powder diffraction pattern substantially as shown in FIG11.

[0069] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the above-mentioned crystal form K are shown in Table 11 below. Table 11 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 6.82 53.61 0.16 12.96 5.97 7.66 67.14 0.24 11.54 7.48 8.57 897.97 0.16 10.31 100.00 9.32 472.14 0.16 9.49 52.58 11.06 129.01 0.35 8.00 14.37 12.65 138.66 0.55 7.00 15.44 14.08 119.10 0.24 6.29 13.26 14.71 176.56 0.16 6.02 19.66 15.08 232.49 0.12 5.87 25.89 15.79 112.77 0.12 5.61 12.56 17.85 38.97 0.47 4.97 4.34 19.29 107.59 0.31 4.60 11.98 21.31 83.59 0.24 4.17 9.31 24.67 107.77 0.16 3.61 12.00

[0070] The present invention also provides a crystal form L of the calcium salt of the compound shown in formula (Ⅰ), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.69±0.2°, 9.78±0.2°, 13.46±0.2°, 14.72±0.2°, 15.40±0.2°, and 15.98±0.2°.

[0071] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form L described above has an X-ray powder diffraction pattern substantially as shown in FIG12.

[0072] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the above-mentioned crystal form L are shown in Table 12. Table 12 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 8.69 352.70 0.12 10.17 100.00 9.78 232.10 0.12 9.04 65.80 13.46 39.74 0.28 6.58 11.27 14.72 50.20 0.16 6.02 14.23 15.40 42.16 0.24 5.75 11.95 15.98 36.71 0.24 5.55 10.41 17.47 21.47 0.24 5.08 6.09 18.68 20.43 0.24 4.75 5.79 21.91 39.27 0.24 4.06 11.13

[0073] The present invention also provides a crystal form M of the calcium salt of the compound shown in formula (Ⅰ), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.09±0.2°, 10.87±0.2°, 13.62±0.2°, 14.55±0.2°, 15.77±0.2°, and 16.39±0.2°.

[0074] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form M described above has an X-ray powder diffraction pattern substantially as shown in FIG13.

[0075] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the above-mentioned crystal form M are shown in Table 13. Table 13 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 8.09 62.44 0.12 10.93 35.92 10.87 41.97 0.24 8.14 24.14 13.62 173.83 0.14 6.50 100.00 14.55 63.24 0.16 6.09 36.38 15.77 31.49 0.16 5.62 18.12 16.39 55.45 0.16 5.41 31.90 18.44 39.68 0.16 4.81 22.83 19.19 52.13 0.24 4.63 29.99 30.42 11.82 0.63 2.94 6.80

[0076] The present invention also provides crystal form N of the calcium salt of the compound shown in formula (Ⅰ), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.79±0.2°, 12.44±0.2°, 14.94±0.2°, 16.11±0.2°, 17.50±0.2°, and 20.98±0.2°.

[0077] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form N has an X-ray powder diffraction pattern substantially as shown in FIG14.

[0078] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the above-mentioned crystal form N are shown in Table 14. Table 14 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 7.79 45.29 0.47 11.34 24.17 12.44 187.41 0.14 7.12 100.00 14.48 14.97 0.94 6.12 7.99 14.94 40.33 0.16 5.93 21.52 16.11 73.38 0.16 5.50 39.15 16.58 62.66 0.31 5.35 33.43 17.50 34.62 0.20 5.07 18.47 20.98 30.52 0.24 4.23 16.29

[0079] The present invention also provides a crystal form O of the calcium salt of the compound shown in formula (Ⅰ), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.40±0.2°, 8.52±0.2°, 12.01±0.2°, 12.24±0.2°, 14.67±0.2°, and 16.86±0.2°.

[0080] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form O has characteristic diffraction peaks at the following 2θ angles: 7.40±0.2°, 8.52±0.2°, 12.01±0.2°, 12.24±0.2°, 14.67±0.2°, 15.35±0.2°, 16.86±0.2°, 18.05±0.2°, 19.77±0.2°, and 22.02±0.2°.

[0081] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form O has an X-ray powder diffraction pattern substantially as shown in FIG15.

[0082] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the above-mentioned crystal form O are shown in Table 15. Table 15 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 7.40 215.39 0.16 11.94 25.21 8.52 219.73 0.16 10.38 25.72 12.01 740.02 0.08 7.37 86.62 12.24 854.29 0.16 7.23 100.00 14.67 240.13 0.14 6.04 28.11 15.35 132.30 0.39 5.77 15.49 16.86 270.37 0.20 5.26 31.65 18.05 121.69 0.24 4.91 14.25 19.77 169.85 0.31 4.49 19.88 22.02 184.58 0.18 4.04 21.61 23.52 105.48 0.79 3.78 12.35 25.72 48.75 0.39 3.46 5.71 31.80 68.93 0.24 2.81 8.07

[0083] The present invention also provides a crystal form P of the calcium salt of the compound shown in formula (Ⅰ), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.49±0.2°, 13.38±0.2°, 14.04±0.2°, 16.28±0.2°, 16.78±0.2°, 20.22±0.2°, and 20.86±0.2°.

[0084] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2θ angles: 11.49±0.2°, 13.38±0.2°, 14.04±0.2°, 16.28±0.2°, 16.78±0.2°, 18.81±0.2°, 20.22±0.2°, 20.86±0.2°, 23.16±0.2°, 24.66±0.2°, and 25.87±0.2°.

[0085] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form P has an X-ray powder diffraction pattern substantially as shown in FIG16.

[0086] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the above-mentioned crystal form P are shown in Table 16. Table 16 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 9.98 36.08 0.24 8.86 13.70 11.49 124.53 0.10 7.70 47.30 13.38 81.27 0.12 6.62 30.87 14.04 263.29 0.10 6.31 100.00 16.28 99.48 0.14 5.45 37.78 16.78 248.41 0.12 5.28 94.35 18.81 70.34 0.12 4.72 26.72 20.22 113.07 0.10 4.39 42.95 20.86 139.00 0.12 4.26 52.79 23.16 109.05 0.16 3.84 41.42 24.66 77.38 0.14 3.61 29.39 25.87 31.41 0.24 3.44 11.93 27.06 29.62 0.35 3.29 11.25 29.72 21.75 0.24 3.01 8.26 34.38 13.56 0.47 2.61 5.15

[0087] The present invention also provides strontium salts of the compounds shown in formula (Ⅰ).

[0088] In some embodiments of the present invention, the crystal form Q of the strontium salt of the compound shown in formula (I) is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.01±0.2°, 8.96±0.2°, 10.08±0.2°, 13.54±0.2°, 14.84±0.2°, and 24.67±0.2°.

[0089] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form Q has characteristic diffraction peaks at the following 2θ angles: 5.01±0.2°, 8.96±0.2°, 10.08±0.2°, 13.54±0.2°, 14.84±0.2°, 18.43±0.2°, 21.10±0.2°, 22.10±0.2°, 23.80±0.2°, and 24.67±0.2°.

[0090] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form Q described above has an X-ray powder diffraction pattern substantially as shown in FIG17.

[0091] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the above-mentioned crystal form Q are shown in Table 17. Table 17 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 5.01 2170 0.27 17.62 63.6 5.41 370 0.25 16.33 5.6 8.96 4088 0.23 9.86 100 10.08 1837 0.23 8.77 42.6 11.55 317 0.20 7.66 2.4 13.05 329 0.44 6.78 5.9 13.54 894 0.25 6.54 19.6 14.84 900 0.46 5.96 35.7 15.20 696 0.70 5.83 37 16.46 577 0.33 5.38 12.5 16.95 435 0.31 5.23 6.6 18.43 782 0.27 4.81 15.8 18.89 401 0.60 4.69 9.9 20.35 454 0.19 4.36 3.1 21.10 575 0.40 4.21 12.8 22.10 411 0.40 4.02 4.2 22.52 612 0.54 3.95 18.3 23.15 450 0.78 3.84 7.5 23.70 435 0.13 3.75 1.3 24.67 958 0.27 3.61 19.9 25.81 403 0.36 3.45 4.7 26.19 454 0.38 3.40 7.4 27.15 438 0.39 3.28 7.7 29.25 293 0.29 3.05 1.8 30.51 267 0.47 2.93 2.9 34.40 253 0.60 2.61 3.6

[0092] The present invention also proposes a pharmaceutical composition comprising the aforementioned crystal forms A, B, C, D, E, diethylamine salt, F, calcium salt, G, H, I, J, K, L, M, N, O, P, strontium salt, or Q.

[0093] In some embodiments of the present invention, the aforementioned drug composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, coenzyme, mediator, or combination thereof.

[0094] The present invention also proposes the use of the aforementioned crystal forms A, B, C, D, E, diethylamine salt, F, calcium salt, G, H, I, J, K, L, M, N, O, P, strontium salt, Q, or pharmaceutical compositions in the preparation of medicaments for use in diseases related to S1P1 receptors.

[0095] In some embodiments of the present invention, the aforementioned S1P1 receptor-related diseases are selected from ulcerative colitis, Crohn's disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, primary cholecystitis, allergic dermatitis, cerebral hemorrhage, graft-versus-host disease, psoriasis, type I diabetes, acne, microbial infections or diseases, and viral infections and diseases.

[0096] Definitions and Explanations

[0097] Unless otherwise stated, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications related to this invention are incorporated herein by reference in their entirety. Although any methods and substances similar to or identical to those described herein may be used in the practice or testing of this invention, preferred methods, apparatus, and substances are described herein.

[0098] "Crystal form" or "crystalline shape" refers to a solid having a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and / or polymorphs of compounds, solvates, hydrates, inclusion compounds, eutectics, salts, solvates of salts, and hydrates of salts. The crystalline form of a substance can be obtained by many methods known in the art. These methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, such as in nanopores or capillaries, crystallization on a surface or template, such as on a polymer, crystallization in the presence of additives such as co-crystallized antimolecules, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding, etc.

[0099] "Amorphous" or "amorphous form" refers to matter formed when its particles (molecules, atoms, ions) are arranged non-periodically in three-dimensional space. It is characterized by a diffuse X-ray powder diffraction pattern without sharp peaks. Amorphous is a special physical form of solid matter; its locally ordered structural features suggest a close connection to crystalline substances. The amorphous form of matter can be obtained through many methods known in the art. These methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques, etc.

[0100] "Solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents used in the implementation of this invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tributanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, etc.

[0101] "Antisolvent" refers to a fluid that promotes the precipitation of a product (or product precursor) from a solvent. Antisolvents can include cold gases, fluids that promote precipitation through chemical reactions, or fluids that reduce the solubility of a product in a solvent; they can be the same liquid as the solvent but at a different temperature, or they can be a different liquid from the solvent.

[0102] "Solvate" refers to a crystal having a solvent on its surface, in its lattice, or both on its surface and in its lattice. The solvent can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, terbutanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methylpyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof, etc. A specific example of a solvate is a hydrate, wherein the solvent on its surface, in its lattice, or both on its surface and in its lattice is water. A hydrate may or may not have other solvents besides water on its surface, in its lattice, or both on its surface and in its lattice.

[0103] Crystalline or amorphous forms can be identified using a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0104] X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions in an XRPD spectrum primarily depend on the crystal structure and are relatively insensitive to experimental details, while the relative peak heights depend on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD spectrum with certain peak positions, which is essentially as shown in the XRPD spectrum provided in the accompanying drawings. Furthermore, the measurement of 2θ in the XRPD spectrum can have experimental errors; the measurement of 2θ in the XRPD spectrum may differ slightly between different instruments and different samples, therefore the value of 2θ cannot be considered absolute. Based on the instrument conditions used in the experiments according to the present invention, the diffraction peaks have an error tolerance of ±0.2°.

[0105] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly α-Al₂O₃) as a function of temperature by continuously heating or cooling under programmed control. The melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystal form described in this invention is characterized by a DSC chart with characteristic peak positions, which is essentially as shown in the DSC chart provided in the accompanying drawings. However, DSC spectra can have experimental errors; the peak positions and peak values ​​of DSC spectra may vary slightly between different instruments and different samples. Therefore, the peak position or peak value of the DSC endothermic peak cannot be considered absolute. Based on the instrument conditions used in the experiments according to this invention, the melting peak has an error tolerance of ±3 °C.

[0106] Solids with the same chemical composition often form isomers, or polymorphs, with different crystal structures under different thermodynamic conditions. This phenomenon is called polymorphism or polyphase polymorphism. When temperature and pressure conditions change, these polymorphs can transform into each other; this phenomenon is called crystal form transformation. Due to crystal form transformation, the mechanical, electrical, and magnetic properties of the crystal undergo significant changes. When the temperature of the crystal form transformation is within a measurable range, this transformation process can be observed on a differential scanning calorimeter (DSC) chart. The DSC chart is characterized by having an exothermic peak reflecting this transformation process, and simultaneously possessing two or more endothermic peaks, which are characteristic endothermic peaks of the different crystal forms before and after the transformation. The crystal form or amorphous form of the compounds of this invention can undergo crystal form transformation under appropriate conditions.

[0107] Thermogravimetric analysis (TGA) is a technique used under programmed control to determine the mass change of a substance with temperature. It is suitable for examining the loss of solvent in crystals or the sublimation and decomposition of samples, and can infer the presence of water of crystallization or crystallization solvent in the crystal. The mass change shown by the TGA curve depends on many factors, including sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples. In some embodiments, the calcium salt crystal form A described in this invention loses approximately 5.1% of its weight at around 150 °C. Based on the instrumentation used in the experiments according to this invention, there is an error tolerance of ±0.3% for the mass change.

[0108] In the context of this invention, the 2θ values ​​in X-ray powder diffraction patterns are all in degrees (°).

[0109] The term "basically as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in an X-ray powder diffraction pattern, DSC pattern, or TGA result are shown in its figure.

[0110] When referring to a spectrum or / and the data appearing in the graph, a "peak" refers to a feature that is recognizable by a person skilled in the art and is not attributable to background noise.

[0111] In the context of this invention, when the terms "about" or "approximately" are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, for those skilled in the art to which this invention pertains, the term "about" or "approximately" means within an acceptable standard error of the average value. Whenever a number with a value of N is disclosed, any number having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is explicitly disclosed, where "+ / -" means addition or subtraction.

[0112] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0113] The salt form, crystal form, or pharmaceutical composition of the present invention can be used to prepare a medicament for S1P1 receptor-related diseases. S1P1 receptor-related diseases are selected from ulcerative colitis, Crohn's disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, primary biliary cholangitis, atopic dermatitis, intracerebral hemorrhage, graft-versus-host disease, psoriasis, type I diabetes, acne, microbial infections or diseases, and viral infections or diseases. Simple Explanation of the Diagram

[0114] Figure 1 shows the X-ray powder diffraction (XRPD) image of crystal form A. Figure 2 shows the X-ray powder diffraction (XRPD) image of crystal form B. Figure 3 shows the X-ray powder diffraction (XRPD) image of crystal form C. Figure 4 shows the X-ray powder diffraction (XRPD) image of crystal form D. Figure 5 shows the X-ray powder diffraction (XRPD) image of crystal form E. Figure 6 shows the X-ray powder diffraction (XRPD) image of crystal form F. Figure 7 shows the X-ray powder diffraction (XRPD) image of crystal form G. Figure 8 shows the X-ray powder diffraction (XRPD) image of crystal form H. Figure 9 shows the X-ray powder diffraction (XRPD) image of crystal form I. Figure 10 shows the X-ray powder diffraction (XRPD) image of crystal form J. Figure 11 shows the X-ray powder diffraction (XRPD) diagram of crystal form K. Figure 12 shows the X-ray powder diffraction (XRPD) image of crystal form L. Figure 13 shows the X-ray powder diffraction (XRPD) diagram of crystal form M. Figure 14 shows the X-ray powder diffraction (XRPD) diagram of crystalline N. Figure 15 shows the X-ray powder diffraction (XRPD) diagram of crystal form O. Figure 16 shows the X-ray powder diffraction (XRPD) image of crystal form P. Figure 17 shows the X-ray powder diffraction (XRPD) diagram of crystal form Q. Figure 18 shows the X-ray powder diffraction (XRPD) image of crystal form G. Figure 19 shows the X-ray powder diffraction (XRPD) diagram of crystal form G. Figure 20 shows the X-ray powder diffraction (XRPD) image of crystal form G. Figure 21 shows the X-ray powder diffraction (XRPD) diagram of crystal form G. Implementation

[0115] The present application is described in detail below with reference to embodiments, but this does not imply any adverse limitations on the present application. The present application has been described in detail herein, and specific embodiments thereof have also been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope thereof.

[0116] The X-ray powder diffraction analysis method used in this invention is as follows: X-ray powder diffraction tests were performed at room temperature using a Bruker D2 PHASER diffractometer (300W low-power X-ray emitter). The sample powder was placed on a silicon sheet, and an X-ray Cu(Kα) tube was used, with an intensity ratio of Kα2 / Kα1 of 0.50 (1.54439 Å / 1.5406 Å). The instrument was set to 30 kV and 10 mA, with a step size of 0.02º (2θ), a scan time of 0.15 s per step, and a total of 1837 steps.

[0117] The differential scanning calorimetry (DSC) analysis method used in this invention is as follows: Differential scanning calorimetry data are collected using TA Discovery DSC. Specifically, several milligrams of sample are weighed into a Tzero aluminum disk and sealed with a corresponding Tzero aluminum disk cover. Under nitrogen atmosphere, the sealed sample is heated from room temperature to 300 ºC at a heating rate of 10 ºC / min.

[0118] The thermogravimetric analysis (TGA) method used in this invention is as follows: TA Discovery TGA is used to collect thermogravimetric analysis data. Specifically, under a nitrogen atmosphere, several milligrams of sample are heated from room temperature to 350 ºC at a heating rate of 10 ºC / min.

[0119] The polarizing microscope (PLM) analysis method used in this invention is as follows: at room temperature, the sample morphology is analyzed using an Olympus BX53M polarizing microscope.

[0120] The high-performance liquid chromatography (HPLC) analysis method used in this invention is as follows: the purity and stability of the sample are tested using an Agilent 1260, and the conditions are shown in Table 18 below. Table 18: HPLC Purity Methods instrument Agilent 1260 HPLC chromatographic column Poroshell 120 EC-C18 2.7 microns, 4.6 x 150 mm, P / N: 693975-902 (T) mobile phase A: 0.1% phosphoric acid aqueous solution; B: ACN Washing process Time (minutes) A (%) B (%) 0.0 90 10 2.0 90 10 8.0 20 80 18.0 10 90 25.0 10 90 25.1 90 10 30.0 90 10 Runtime 30 minutes Flow rate 1.0 ml / min detector UV 230 nanometers Injection volume 5.0 microliters Sample chamber temperature room temperature Column temperature 30 ºC Needle washing solvent ACN

[0121] The hygroscopicity analysis method used in this invention is as follows: the hygroscopicity of the sample is evaluated using SMS ADVENTURE DVS under nitrogen atmosphere at 25 °C. Approximately 30 mg of sample is used in the test, and the test method is as follows: Method 1 (for crystal-free type): From 0%RH to 95%RH, each stage increases by 10%RH (from 90%RH to 95%RH, an increase of 5%RH). From 95%RH to 0%RH, each stage decreases by 10%RH (from 95%RH to 90%RH, decreases by 5%RH). Method 2 (for aqueous cosolvents): The ambient humidity is increased to 95%RH, with each subsequent stage increasing by 10%RH (from 90% to 95%RH, the increase is 5%RH). From 95%RH to 0%RH, decrease by 10%RH in each stage (from 95%RH to 90%RH, decrease by 5%RH); From 0%RH to 95%RH, each stage increases by 10%RH (from 90%RH to 95%RH, each stage increases by 5%RH).

[0122] The analytical method for determining the moisture content of the present invention is as follows: Moisture content data of the sample is collected using a Karl Fischer (KF) moisture titrator (Metrohm 870 / 803, Switzerland). The measurement is performed using a volumetric method, with HYDRANAL Composite-2 (Sigma-Aldrich, P / N: 34806) as the titrant and anhydrous methanol as the solvent. The stirring time is 30 s. Specifically, ~50 mg of sample (accurate to 0.001 g) is weighed, and the moisture content of the sample is tested using the aforementioned KF moisture titrator. The measurement is performed twice in parallel, and the average value is taken.

[0123] This invention utilizes liquid nuclear magnetic resonance (1H NMR): sample analysis was performed using a Bruker 400M NMR spectrometer with DMSO-d6 as the solvent.

[0124] This invention utilizes solid-state nuclear magnetic resonance (ssNMR): a Bruker 500 MHz wide-cavity solid-state NMR spectrometer with a 4 mm dual-resonance magic-angle rotating probe for data collection. A cross-polarization / magic-angle rotation (CP / MAS) method was employed, and to avoid the influence of rotating sidebands, a sideband suppression technique (TOSS) was incorporated to collect the 13C fingerprint spectrum of the samples. The cross-polarization matching conditions were optimized using adamantane, and the chemical shift was corrected using an adamantane high-field signal (29.5 ppm). The magic angle rotation speed was 8 kHz, the 1H 90-degree pulse was 3.45 μs, and the decoupling method was TPPM. Specific experimental conditions are as follows: Test #2: Pulse delay 8 s, contact time 2 ms, accumulated 1500 times. Test #3: Pulse delay 2 s, contact time 2 ms, accumulated 1500 times. Test #4: Pulse delay 2 s, contact time 0.2 ms, accumulated 3100 times.

[0125] The Chinese meanings of solvent abbreviations or English terms used in this invention are shown in Table 19 below: Table 19 Solvents (English and Chinese) English Chinese English Chinese MeOH methanol EtOH ethanol IPA Isopropanol 2-Butanol 2-Butanol Acetone acetone MEK Butanone MIBK 4-Methyl-2-pentanone EtOAc Ethyl acetate IPAc Isopropyl acetate MTBE Methyl tributyl ether CPME Cyclopentyl methyl ether THF Tetrahydrofuran 1,4-Dioxane 1,4-Dioxane DMSO dimethyl monoxide DMF dimethylformamide DCM dichloromethane CHCl3 chloroform n-Heptane n-Heptane 2-MeTHF 2-Methyltetrahydrofuran Toluene Toluene H 2O water ACN Acetonitrile Butyl acetate n-Butyl acetate Methyl acetate Methyl acetate Cumene Cumene Anisole aniline Hexane hexane -- --

[0126] To enable those skilled in the art to better understand this invention, specific embodiments of the invention will be described below.

[0127] Example 1: Preparation of crystal form A At room temperature, the compound shown in formula (I) was stirred in anisole / n-heptane (4:3, v / v) to precipitate a solid, which was then filtered and dried under vacuum at 45°C for 36 h to obtain crystal form A.

[0128] Example 2: Preparation of crystal form B The compound shown in formula (I) (2.0 g) was dissolved in IPAC (10 mL), heated to 60 °C, and Heptane (40 mL) was added dropwise. The mixture was cooled to 40 °C, and a large amount of solid began to precipitate. Heptane (10 mL) was added, and the mixture was stirred for 2 h. The mixture was filtered and dried under vacuum at 45 °C for 36 h to obtain crystal form B.

[0129] Example 3: Preparation of crystal form D At room temperature, the compound shown in formula (I) was stirred in MeOH / H2O (9:2, v / v) to precipitate a solid, which was then filtered and dried under vacuum at 45°C for 36 h to obtain crystal form D.

[0130] Example 4: Preparation of Crystal Form C Crystal form D is heated to 137℃ to obtain crystal form C.

[0131] Example 5: Preparation of crystal form E At room temperature, the compound shown in formula (I) was stirred in CPME / Heptane (2:3, v / v) to precipitate a solid, which was then filtered and dried under vacuum at 45°C for 36 h to obtain crystal form E.

[0132] Example 6: Preparation of crystal form F (including the salt formation step) The compound shown in formula (I) (0.4 g) was dissolved in EtOH (3.0 mL) at room temperature. After stirring to dissolve, an ethanol solution of diethylamine (69.4 mg diethylamine; 0.8 mL ethanol) was slowly added. After stirring at room temperature for 19 h, a solid precipitated. The solid was filtered and dried under vacuum at 30 °C for 3 h to obtain crystal form F.

[0133] Example 7: Crystal form G Method 1: Add the compound of formula (I) (0.2651 kg, 0.595 mol) and anhydrous ethanol (0.9488 kg) to a reaction vessel, heat to 35-45℃, and stir for 5-30 minutes. Add sodium ethoxide solution (sodium ethoxide: 0.035 kg, 0.514 mol; anhydrous ethanol: 0.6310 kg), stir for 2-3 hours, add calcium chloride solution dropwise (calcium chloride: 0.040 kg, 0.357 mol; purified water: 0.847 kg), stir for 1-3 hours, cool to 20-30℃, stir for 4-6 hours, filter, rinse the filter cake with purified water, and rinse with ethanol. Dry the filter cake under reduced pressure at 25-35℃ to obtain 0.2185 kg of the compound of formula (II) with crystal form G, yield: 79.1%. Method 2: Weigh 10.72 g of the compound shown in formula (I) into a single-necked flask, add EtOH (105 mL) and stir magnetically for ~0.5 h. Add C2H5Ona (1.64 g) and stir at room temperature for 1.5 h. Dissolve anhydrous CaCl2 (1.5 g) in EtOH / H2O (2:1, v / v, 45 mL) and add 1% seed crystal (crystal form G) calcium chloride solution. Add calcium chloride solution dropwise and stir for 16 h. Take the suspension and determine the XRPD of the sample, which shows crystal form D. Filter, wash the filter cake twice each with H2O and EtOH, and test the XRPD of the wet sample, which shows crystal form J. Dry under reduced pressure at 50 ºC for 4 hours and determine the XRPD, which shows crystal form G. Method 3: Add Ca(OH)₂ (2mg) to the compound (21mg) shown in formula (I), add 0.2mL EtOH / H₂O (9:1, v / v), stir magnetically at room temperature for 3 days, filter, and vacuum dry at 50℃ for 2h to obtain crystal form G. Method 4: Add Ca(OH)₂ (2mg) to the compound shown in formula (I) (21mg), add 0.2mL IPA / H₂O (9:1, v / v), stir magnetically at room temperature for 4 days, filter, and vacuum dry at 50℃ for 2h to obtain crystal form G.

[0134] For the product obtained by filtration in Method 3, the content of water and solvent was tested and its XRPD was detected by using different drying times, temperatures or vacuum levels. The results are shown in Table 20 below. Table 20 Solvent (ethanol) content Water content parsing table picture 4.77% 3.09% Table 21 Figure 18 3.05% 3.89% Table 22 Figure 19 1.97% 4.37% Table 23 Figure 20 1.64% 3.75% Table 24 Figure 21 Analysis Table 21 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 9.02 5227 0.17 9.80 100.00 10.17 3060 0.18 8.69 58.50 13.62 949 0.22 6.49 18.20 14.83 374 0.23 5.97 7.20 15.18 1478 0.23 5.83 28.30 16.48 440 0.19 5.38 8.40 17.01 449 0.19 5.21 8.60 18.51 1032 0.17 4.79 19.70 19.10 307 0.26 4.64 5.90 20.46 272 0.25 4.34 5.20 21.27 251 0.28 4.17 4.80 22.63 319 0.26 3.93 6.10 23.26 221 0.16 3.82 4.20 24.95 913 0.18 3.57 17.50 26.41 223 0.21 3.37 4.30 27.35 333 0.17 3.26 6.40 30.82 64.2 0.36 2.90 1.20 Analysis Table 22 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 9.04 5672 0.18 9.78 100.00 10.17 2803 0.20 8.69 49.40 13.60 872 0.29 6.50 15.40 14.83 425 0.16 5.97 7.50 15.19 1551 0.24 5.83 27.30 16.50 517 0.18 5.37 9.10 17.03 503 0.21 5.20 8.90 18.52 1135 0.19 4.79 20.00 19.13 320 0.22 4.64 5.60 20.47 260 0.27 4.34 4.60 21.24 276 0.29 4.18 4.90 22.60 369 0.28 3.93 6.50 23.23 222 0.43 3.83 3.90 24.96 1106 0.19 3.56 19.50 26.41 294 0.19 3.37 5.20 27.35 363 0.18 3.26 6.40 30.80 67.1 0.39 2.90 1.20 Analysis Table 23 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 9.00 4460 0.22 9.82 100.00 10.11 1992 0.23 8.74 44.70 13.57 732 0.25 6.52 16.40 14.76 462 0.16 6.00 10.40 15.15 1576 0.25 5.84 35.30 16.43 522 0.22 5.39 11.70 16.97 512 0.26 5.22 11.50 18.47 1244 0.22 4.80 27.90 19.03 364 0.28 4.66 8.20 20.38 293 0.26 4.35 6.60 21.18 307 0.27 4.19 6.90 22.58 573 0.25 3.93 12.80 23.21 313 0.47 3.83 7.00 24.92 1092 0.25 3.57 24.50 26.33 368 0.18 3.38 8.30 27.28 436 0.23 3.27 9.80 30.76 128 0.26 2.90 2.90 Analysis Table 24 Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [Å] Rel. Int. [%] 9.01 5007 0.19 9.80 100.00 10.11 2643 0.19 8.74 52.80 13.59 884 0.21 6.51 17.70 14.79 427 0.20 5.98 8.50 15.18 1628 0.23 5.83 32.50 16.45 512 0.18 5.38 10.20 17.01 525 0.20 5.21 10.50 18.50 1178 0.19 4.79 23.50 19.07 368 0.23 4.65 7.30 20.41 289 0.24 4.35 5.80 21.25 325 0.26 4.18 6.50 22.61 471 0.24 3.93 9.40 23.25 260 0.48 3.82 5.20 24.95 925 0.21 3.57 18.50 26.37 302 0.18 3.38 6.00 27.34 373 0.18 3.26 7.50 30.79 116 0.25 2.90 2.30

[0135] Stability verification of crystal form G in different solvents: Method 1: Add 0.5 mL of the appropriate solvent (the appropriate solvent can be EtOH, H2O, EtOH / H2O=970 / 30, 927 / 73, 855 / 145, 704 / 296, v / v) to crystal form G (50 mg). Stir magnetically at room temperature for 4 days, filter, and vacuum dry at 50℃ for 2 hours to obtain crystal form G. Method 2: Add 15 mg of crystal form G to a 4 mL glass bottle and place it into a 20 mL glass bottle containing 3 mL of volatile solvent (MeOH or EtOH). Seal the 20 mL glass bottle tightly and let it stand at room temperature for about a week. Filter and dry under vacuum at 50°C for 2 hours to obtain crystal form G.

[0136] Example 8: Preparation of crystal form H Add 50 mg of crystal form G to 0.5 mL of MeOH, stir magnetically at room temperature for 4 days, filter, and obtain crystal form H.

[0137] Example 9: Preparation of Crystal Form I Add crystal form G (50 mg) and MeOH (0.5 mL) to an HPLC vial, and stir magnetically for 7 days at 50 ºC to obtain a suspension. Filter to obtain crystal form I.

[0138] Example 10: Preparation of crystal form J Method 1: Add 0.5 mL of solvent (2-Butanol or Toluene) to crystal form G (50 mg) and stir magnetically at room temperature for 4 days. Filter to obtain crystal form J. Method 2: Add crystal form G (50 mg) and IPA (0.5 mL) to an HPLC vial, and stir magnetically for 7 days at 50 ºC to obtain a suspension. Filter to obtain crystal form J. Method 3: Add crystal form G (50 mg) to an HPLC vial, add EtOAc / n-Heptane = 1 / 2, v / v (0.5 mL), and magnetically stir for 7 days at 50 ºC to obtain a suspension. Filter to obtain crystal form J. Method 4: Weigh ~21 mg of the compound shown in formula (I) of Example 1 (purity 93 area%) and ~2 mg of Ca(OH)2 into an HPLC vial; add 0.2 mL of EtOH / H2O (9:1, v / v), and stir magnetically at room temperature; after stirring for 3 days, centrifuge to separate the samples, and test the XRPD of the wet sample, which is crystal form J.

[0139] Example 11: Preparation of crystal form K Add crystal form G (50 mg) to an HPLC vial, add 2-MeTHF / n-Heptane = 1 / 2, v / v (0.5 mL), and magnetically stir at 50 ºC for 7 days to obtain a suspension. Filter to obtain crystal form K.

[0140] Example 12: Preparation of crystal form L Under nitrogen protection, crystal form K was heated to 80ºC and cooled to room temperature to obtain crystal form L.

[0141] Example 13: Preparation of crystal form M Add 15 mg of crystalline form G to a 20 mL glass bottle, add DMF, and stir to dissolve at room temperature. Gradually add H₂O to the glass bottle until a solid appears, filter, and obtain crystalline form M.

[0142] Example 14: Preparation of crystalline N Add 15 mg of crystalline form G to a 4 mL glass bottle, then add DMF to dissolve it completely. If it cannot be dissolved completely, perform membrane filtration (nylon membrane, 0.22 μm pore size) on the suspension, and then place the solution into separate 20 mL glass bottles containing 4 mL of H₂O. Seal the 20 mL glass bottles tightly and leave them at room temperature until solid precipitates. Filter to obtain crystalline form N.

[0143] Example 15: Preparation of Crystal Form O The sample of crystal form G was dissolved in Acetone, and after standing for about 10 minutes, a solid precipitated out. After filtration, crystal form O was obtained.

[0144] Example 16: Preparation of crystal form P Add 15 mg of crystalline form G to a 20 mL glass bottle, then add Acetone and stir to dissolve at room temperature. Gradually add MTBE to the glass bottle until a solid appears, filter, and obtain crystalline form P.

[0145] Example 17: Preparation of crystal form Q The compound shown in formula (I) (110 mg) was added to a 20 mL single-necked flask, EtOH (1 mL) was added, and the mixture was magnetically stirred until clear. Sodium ethoxide (16 mg) was added, and the mixture was magnetically stirred at 40 °C for 1 hour. Strontium chloride aqueous solution (300 mg / mL) was added dropwise, and the mixture was stirred at 28 °C for 12 hours. The mixture was filtered and dried to obtain crystal form Q.

[0146] Example 18 Among the crystal forms A to Q disclosed above, some crystal forms have poor reproducibility in preparation and some cannot be purified. Therefore, the inventors selected four crystal forms with good reproducibility and easy purification: crystal form A, crystal form B, crystal form G, and crystal form Q. Under the same conditions, they conducted experiments under high temperature, high humidity, and light conditions to examine their stability. The experimental scheme and results are shown in Table 25, and the shape changes are shown in Table 26. Table 25 condition Crystal form A Crystal form B Crystal form G Crystal form Q initial purity 99.28% 99.44% 99.60% 96.52% After being placed at a high temperature of 60℃ for 30 days 94.57% 97.21% 99.12% 95.32% At a temperature of 25℃ and a relative humidity of 90%±5%, after being placed for 30 days... 98.49% 98.50% 98.78% 95.26% After being placed under a light intensity of 4500 Lx ± 500 Lx for 30 days 94.45% 94.55% 96.02% 93.15% Table 26 condition Crystal form A Crystal form B Crystal form G Crystal form Q initial state off-white solid off-white solid off-white solid off-white solid High temperature 60℃ 5 days off-white solid off-white solid off-white solid off-white solid 10 days pale yellow solid off-white solid off-white solid off-white solid 30 days Yellow solid off-white solid off-white solid off-white solid The temperature is 25℃, and the relative humidity is 90%±5%. 5 days off-white solid off-white solid off-white solid off-white solid 10 days off-white solid off-white solid off-white solid off-white solid 30 days off-white solid off-white solid off-white solid off-white solid The light intensity is 4500 Lx ± 500 Lx 5 days off-white solid off-white solid off-white solid off-white solid 10 days pale yellow solid pale yellow solid pale yellow solid pale yellow solid 30 days Yellow solid Yellow solid Yellow solid Yellow solid As shown in Tables 25 and 26 above, crystal form G has higher stability than other crystal forms under high temperature, high humidity and light conditions.

[0147] Example 19 The purity of crystal forms A, B, G, and Q, with the same mass and packaging, was examined under storage conditions of 25°C and 40°C, as shown in Table 27. Table 27 Days Crystal form A Crystal form B Crystal form G Crystal form Q 25℃ 40℃ 25℃ 40℃ 25℃ 40℃ 25℃ 40℃ 0 days 99.03% 99.03% 99.14% 99.14% 99.48% 99.48% 96.21% 96.21% 15 days 98.91% 98.73% 99.05% 98.88% 99.42% 99.28% 96.24% 96.07% 30 days 98.93% 98.42% 99.00% 98.73% 99.43% 99.27% 96.31% 95.99% 45 days 98.87% 98.30% 98.93% 98.68% 99.43% 99.24% 96.29% 95.90% 60 days 98.85% 98.15% 98.94% 98.66% 99.41% 99.16% 96.25% 95.76% 90 days 98.73% 97.69% 98.86% 98.40% 99.36% 99.01% 96.18% 95.61% As shown in Table 27 above, crystal form G exhibits higher stability after 90 days of storage at 25℃ and 40℃.

[0148] without

Claims

1. A compound with crystal form G as shown in formula (II), wherein, The X-ray powder diffraction pattern of crystal form G has characteristic diffraction peaks at the following 2θ angles: 8.98±0.2°, 10.12±0.2°, 13.56±0.2°, 14.66±0.2°, 15.22±0.2°, and 18.48±0.2°.

2. Crystal form G as described in claim 1, wherein, The X-ray powder diffraction pattern of crystal form G has characteristic diffraction peaks at the following 2θ angles: 8.98±0.2°, 10.12±0.2°, 13.56±0.2°, 14.66±0.2°, 15.22±0.2°, 16.34±0.2°, 16.92±0.2°, 18.48±0.2°, 22.67±0.2°, and 23.06±0.2°.

3. Crystal form G as described in claim 1 or 2, wherein, The X-ray powder diffraction pattern of crystal form G is shown in Figure 7.

4. Crystal form G as described in claim 1 or 2, wherein, The crystal form G further comprises water and a solvent; wherein the solvent is selected from ethanol and isopropanol; the content of the solvent is 0.1% to 6.0%; and the content of water is 0.1% to 4.0%.

5. A method for preparing crystal form G as described in any one of claims 1-4, wherein, include: The compound shown in formula (I) was dissolved in sodium ethoxide solution, and then stirred, filtered, and dried under reduced pressure in the presence of calcium chloride to obtain crystal form G; 6. A pharmaceutical composition, wherein, It includes crystal form G as described in any one of claims 1-4.

7. Use of a crystal form G as described in any one of claims 1-4 or a pharmaceutical composition as described in claim 6 in the preparation of a medicament for use in S1P1 receptor-related diseases.

8. The use as described in claim 7, wherein the S1P1 receptor-related diseases are selected from ulcerative colitis, Crohn's disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, primary cholecystitis, allergic dermatitis, cerebral hemorrhage, graft-versus-host disease, psoriasis, type I diabetes, acne, microbial infections or diseases, and viral infections and diseases.

Images