Methods for the synthesis of froimidazopyridine compounds, polymorphs, and polymorphs of salts

Abstract

To provide a method for synthesizing a compound as a selective JAK1 / TYK2 kinase inhibitor: 2-[(2R,5S)-5-[2-methylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile.SOLUTION: The present invention provides a method for preparing a compound of formula I. As the starting material, 7-chloro-6-nitrofuro[3,2-b]pyridine is employed. The compound is prepared by nucleophilic substitution, palladium carbon reduction and cyclization reactions.SELECTED DRAWING: Figure 1

Description

Detailed description of the invention

[0001] [Technical Field] The present invention relates to the field of drug synthesis, and more particularly to a method for synthesizing the compound 2-[(2R,5S)-5-[2-methylfluoro[3,2-b]imidazo[4,5-d]pyridine-1-yl]tetrahydropyran-2-yl]acetonitrile (hereinafter referred to as Compound I or the compound of Formula I) as a selective JAK1 / TYK2 kinase inhibitor. The present invention also relates to the crystalline forms of Compound I and its salts, and to methods for preparing them. Furthermore, the present invention relates to pharmaceutical compositions and pharmaceutical formulations comprising the crystalline form of Compound I and / or its salts, and to the use of the crystalline forms of Compound I and its salts in the treatment of JAK1 / TYK2-related diseases and conditions.

[0002] [Background technology] Protein kinases are a family of proteins that regulate multiple cellular processes and play a crucial role in maintaining cellular function. These kinases include at least: non-receptor tyrosine kinases such as the Janus kinase family (JAK1, JAK2, JAK3, and TYK2); receptor tyrosine kinases such as platelet-derived growth factor receptor (PDGFR); and serine / threonine kinases such as β-RAF.

[0003] The Janus kinase family includes four known family members: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). These cytoplasmic tyrosine kinases are associated with membrane cytokine receptors (such as common gamma chain receptors and glycoprotein 130 (gp130) transmembrane protein) (Murray, J. Immunol. 178 (5): 2623 - 2629, 2007). Approximately 40 cytokine receptors transmit signals through combinations of these four JAK family members and their seven downstream substrates: signaling and activator of transcription (STAT) family members (Ghoreschi et al., Immunol Rev. 228 (l): 273 - 287, 2009). Cytokines that bind to their receptors activate JAK by phosphate transfer and / or autophosphorylation. Next, activated JAK family kinases phosphorylate cytokine receptors, generating binding sites for proteins containing Src homology 2 (SH2) (such as STAT factors and other regulators), from which JAK phosphorylation activates them. Activated STAT enters the cell nucleus and begins to promote the expression of survival factors, cytokines, chemokines, and molecules for leukocyte transport (Schindler et al., J. Biol. Chem. 282(28):20059-20063, 2007). JAK activation also triggers cell proliferation via pathways mediated by phosphoinositide-3-kinase (PI3K) and protein kinase B.

[0004] JAK3 and JAK1 are components of common gamma-chain cytokine receptor compounds, and blocking either one of them can inhibit the signaling of inflammatory cytokines (interleukin (IL)-2, 4, 7, 9, 15, and 21) (Ghoreschi et al., Immunol. Rev. 228 (l): 273 - 287, 2009). In contrast, other pathologically relevant cytokines (such as IL-6) are dependent only on JAK1. Therefore, JAK1 blocking inhibits the signaling of many pro-inflammatory cytokines (Guschin et al., EMBO J. 14 (7): 1421 - 1429, 1995). The clinical efficacy of the IL-6 receptor neutralizing antibody tocilizumab for rheumatoid arthritis (RA) has been recognized (Maini et al, Arthritis Rheum. 54(9):2817-2829, 2006).

[0005] International patent application WO2018067422A1 discloses 1H-flu[3,2-b]imidazo[4,5-d]pyridine derivatives as selective JAK1 kinase inhibitors, including compound I and a method for preparing the same. The synthetic route is as follows:

[0006] [ka]

[0007] Biological studies have shown that compound I is a potent and selective JAK1 inhibitor, exhibiting selective inhibition of IL-6-induced STAT3 phosphorylation and not selective inhibition of thrombopoietin-induced STAT3 phosphorylation. However, international patent application WO2018067422A1 does not disclose the biological activity of TYK2. Furthermore, the disclosed method for preparing compound I involves high temperatures, generates too many impurities, and results in low yields, making it unsuitable for large-scale production. Therefore, it is necessary to develop a method for preparing compound I that has milder reaction conditions, higher product yields, higher purity, and is suitable for large-scale / industrial production.

[0008] Currently, there is no report on the crystalline forms of Compound I and its salts. The selection of the optimal crystalline form for comprehensive and systematic polymorph screening and development is one of the essential and important research contents. Therefore, it is necessary to further screen the crystalline forms of Compound I and its salts and develop a crystalline form with good stability and low hygroscopicity, which is suitable for large-scale production and provides more and better options for the subsequent development of the drug.

[0009] 〔Summary of the Invention〕 The object of the present invention is to provide a method for producing a compound of formula I (i.e., Compound I) suitable for industrial production with high product yield and high purity under mild reaction conditions. The synthetic route of this method is as follows:

[0010]

Chemical formula

[0011] The above method includes the following steps: Step 1: Add ethanol, a compound of formula IV, a compound of formula V, and DIPEA to a reaction vessel and start stirring; Heat to raise the temperature to 65 - 90 °C, maintain the temperature, and stir overnight; Stop the reaction and lower the temperature of the system to 15 - 30 °C; Dropwise add water to the system and continue stirring; Filter and wash the filter cake; Dry the filter cake to obtain a compound of formula III; Step 2: Add tetrahydrofuran, the compound of formula III obtained in Step 1, and palladium carbon to a reaction vessel; Purge the system with nitrogen and then with hydrogen; Maintain the temperature at 20 - 35 °C and stir for 16 - 120 hours under a hydrogen pressure of 0.1 - 1.0 MPa; After the reaction is completed, filter the reaction solution and wash the filter cake; The filtrates are combined and concentrated to obtain a concentrate of the compound of formula II; Step 3: Add the concentrate of the compound of formula II obtained in step 2, or the compound of formula II, along with trimethyl orthoacetate and tetrahydrofuran, to the reaction vessel; heat the material system in the reaction vessel to reflux of tetrahydrofuran; add pyridine hydrochloride to the reaction vessel and react the resulting material system at a temperature of 50-90°C for 4-20 hours, then separate and purify to obtain the compound of formula I.

[0012] In the embodiment of step 1 described above: The volume mass ratio (mL / g) of ethanol to the compound of formula IV is 5:1 to 20:1, preferably 10:1; The molar ratio of the compound of formula IV, the compound of formula V, and DIPEA is 1:1 to 1.1:2 to 3, preferably 1:1.01:2.2; After starting the stirring, under nitrogen protection, heat to raise the temperature to 65-90°C, preferably 70-90°C, more preferably 70-80°C, maintain the temperature, and stir for 5-16 hours, preferably 10-16 hours; After stopping the reaction, reduce the system temperature to 15-25°C; The volume mass ratio (mL / g) of water added to the system to the compound of formula IV is 10:1 to 20:1, preferably 15:1; After adding water to the system, stir for 2 to 6 hours, preferably 4 hours, at a temperature of 0 to 30°C, preferably 5 to 15°C, more preferably 5 to 10°C; The filtered cake is washed with an aqueous ethanol solution, the volume ratio of ethanol to water in the aqueous ethanol solution (mL / mL) being 1:1 to 1:2, preferably 1:1.5 to 1:2; the volume mass ratio of the aqueous ethanol solution to the compound of formula IV (mL / g) being 2:1 to 10:1, preferably 2:1 to 5:1, more preferably 2:1 to 3:1; The filtered cake is dried under vacuum or using a blower at a temperature of 45-55°C, preferably 50°C.

[0013] In some embodiments of step 2 described above: The volume mass ratio (mL / g) of tetrahydrofuran to the compound of formula III is 10:1 to 70:1, preferably 20:1 to 70:1; The palladium-carbon is 5% Pd / C, 50% water-moistened, and the mass ratio (g / g) of palladium-carbon to the compound of formula III is 0.15:1 to 0.16:1, preferably 0.15:1; Maintain the temperature at 25-35°C and stir for 24-96 hours under a hydrogen pressure of 0.5-1.0 MPa; The concentrate of the compound of formula II obtained by combining and concentrating the filtrates is a tetrahydrofuran solution of the compound of formula II, and the volume mass ratio (mL / g) of tetrahydrofuran to the compound of formula II for washing is 2:1 to 4:1, preferably 2:1 to 3:1 (the mass of the compound of formula II is calculated according to the 100% yield in step 2); preferably, the tetrahydrofuran solution of the compound of formula II is replaced with ethanol to obtain an ethanol solution of the compound of formula II, and the volume mass ratio (mL / g) of ethanol to the compound of formula II is 2:1 to 5:1, preferably 2:1 to 4:1, more preferably 2:1 to 3:1 (the mass of the compound of formula II is calculated according to the 100% yield in step 2).

[0014] In some embodiments of step 3 above, the volume mass ratio (mL:mg) of tetrahydrofuran to the compound of formula II in the concentrate of the compound of formula II is 1.5:1 to 5.0:1; or in some embodiments of step 3 above, the volume mass ratio (mL:mg) of tetrahydrofuran to the compound of formula II is 1.5:1 to 5.0:1.

[0015] In some embodiments of step 3 above, the concentrate of the compound of formula II is substituted with toluene, tetrahydrofuran, or methyl tertiary butyl ether for the next step; in some embodiments, the volume mass ratio (mL:mg) of the concentrate of the compound of formula II to the toluene, tetrahydrofuran, or methyl tertiary butyl ether used for substitution is 2.0:1 to 4.0:1; In some embodiments of step 3 above, the molar ratio of the compound of formula II to trimethyl orthoacetate in the concentrate of the compound of formula II is 3.0:1 to 3.5:1; or in some embodiments of step 3 above, the molar ratio of the compound of formula II to trimethyl orthoacetate is 3.0:1 to 3.5:1; In some embodiments of step 3 above, the molar ratio of the compound of formula II to pyridine hydrochloride in the concentrate of the compound of formula II is 0.2:1 to 0.3:1; or in some embodiments of step 3 above, the molar ratio of the compound of formula II to pyridine hydrochloride is 0.2:1 to 0.3:1; In some embodiments of step 3 above, a concentrate of the compound of formula II or the compound of formula II, along with trimethyl orthoacetate and the solvent, are added to the reaction vessel under nitrogen protection, and the material system in the reaction vessel is heated until the solvent refluxes; After adding pyridine hydrochloride to the reactor under nitrogen protection, the material system is reacted at a temperature of 50-90°C, preferably 65-75°C, for 4-20 hours, preferably 5-15 hours. In some embodiments of step 3 described above, after the reaction is complete, the product is purified with a solvent selected from the group consisting of water, methanol, ethanol, methyl tertiary butyl ether, and any combination thereof.

[0016] In some embodiments of step 3 above, the obtained compound of formula I is separated and purified by column chromatography, and the eluent is a mixed solution of ethyl acetate and n-heptane (V EA :V n-ヘプタン = 1:1 to 1:0 (mL / mL); In some embodiments of step 3 described above, the obtained compound of formula I is dried at 50-55°C under vacuum or using a blower.

[0017] Another object of the present invention is to provide a crystalline form of the compound of formula I, which will hereafter be named crystalline form 1 of the compound of formula I.

[0018] [ka]

[0019] Crystal form 1 of the compound of formula I has an X-ray powder diffraction pattern showing characteristic peaks at 2theta(2θ) angles of 13.4°±0.2°, 17.6°±0.2°, and 21.9°±0.2°.

[0020] In some embodiments, the X-ray powder diffraction patterns of crystalline form 1 of the compound of formula I show characteristic peaks at 2theta angles of 9.0°±0.2°, 13.4°±0.2°, 17.6°±0.2°, 18.1°±0.2°, 21.9°±0.2°, and 27.3°±0.2°.

[0021] In some embodiments, the X-ray powder diffraction patterns of crystalline form 1 of the compound of formula I show characteristic peaks at 2theta angles of 9.0°±0.2°, 10.4°±0.2°, 13.4°±0.2°, 17.6°±0.2°, 18.1°±0.2°, 18.7°±0.2°, 21.9°±0.2°, 24.1°±0.2°, and 27.3°±0.2°.

[0022] Non-limitingly, Table 1 shows the X-ray powder diffraction data for crystalline form 1 of the compound of formula I of the present invention.

[0023] [Table 1]

[0024] Non-limitingly, Figure 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline form 1 of the compound of formula I of the present invention.

[0025] Non-limitingly, Figure 2 shows a differential scanning calorimetry (DSC) thermogram of crystalline form 1 of the compound of formula I of the present invention. The DSC thermogram shows that the initial melting point of crystalline form 1 of the compound of formula I of the present invention is 173.38°C.

[0026] Non-limitingly, Figure 3 shows a thermogravimetric analysis (TGA) thermogram of crystalline form 1 of the compound of formula I of the present invention. The TGA thermogram shows that there is only a 0.42% weight loss of crystalline form 1 of the compound of formula I of the present invention at temperatures from 25°C to 162°C. Crystalline form 1 of the compound of formula I does not contain crystal water or solvent.

[0027] Non-limitingly, Figure 4 shows the dynamic vapor sorption (DVS) isotherm plot of crystalline form 1 of the compound of formula I of the present invention. The DVS isotherm plot shows a 13.86% weight increase of crystalline form 1 of the compound of formula I of the present invention due to moisture absorption from 0%RH to 95%RH, indicating that the sample is hygroscopic. The moisture absorption curve during desorption shows hysteresis, and when combined with the XRPD patterns of the sample before and after the DVS isotherm test (see Figure 5 for the XRPD pattern after the test), it is shown that the crystalline form of crystalline form 1 of the compound of formula I changes after moisture absorption.

[0028] The present invention provides a method for preparing crystalline form 1 of a compound of formula I, specifically, the method is described as follows: The crude product of the compound of formula I is dissolved in methanol, stirred at 40-60°C for 0.5-2 hours, cooled to 5-15°C, stirred for 15 minutes to 1 hour, filtered, the filtered cake is washed with MTBE and dried to obtain crystalline form 1 of the compound of formula I.

[0029] In some embodiments, the crude product of the compound of formula I is dissolved in methanol, stirred at 50°C for 1 hour, cooled to 10°C, stirred for 0.5 hours, filtered, the filtered cake is washed with MTBE, and the filtered cake is dried under vacuum at 50°C for 16 hours to obtain crystalline form 1 of the compound of formula I.

[0030] In some embodiments, the volume ratio of methanol to MTBE is 3:1 to 2:1, preferably 8:3; In some embodiments, the crude product of the compound of formula I is dissolved in methanol, and then a silicon-based metal remover and activated carbon are added to the system.

[0031] Another object of the present invention is to provide crystalline forms of the compounds of formula I, specifically the crystalline forms of hydrochloride, sulfate, phosphate, mesylate, hydrobromide, fumarate, benzenesulfonate, citrate, and L-(+)-tartrate of the compounds of formula I (abbreviated as tartrate in this application). These will be named below as crystalline form A of hydrochloride, crystalline form B of hydrochloride, crystalline form C of hydrochloride, crystalline form D of sulfate, crystalline form E of phosphate, crystalline form F of phosphate, crystalline form G of mesylate, crystalline form H of hydrobromide, crystalline form J of hydrobromide, crystalline form K of hydrobromide, crystalline form L of fumarate, crystalline form M of benzenesulfonate, crystalline form N of citrate, and crystalline form O of tartrate.

[0032] Crystalline form A of the hydrochloride salt of the compound of formula I of the present invention has an X-ray powder diffraction pattern showing characteristic peaks at 2theta angles of 7.3°±0.2°, 12.1°±0.2°, and 20.9°±0.2°.

[0033] In some embodiments, the X-ray powder diffraction patterns of crystalline form A of the hydrochloride salt of the compound of formula I show characteristic peaks at 2theta angles of 7.3°±0.2°, 12.1°±0.2°, 18.7°±0.2°, 20.9°±0.2°, 23.5°±0.2°, and 24.0°±0.2°.

[0034] In some embodiments, the X-ray powder diffraction patterns of crystalline form A of the hydrochloride salt of the compound of formula I show characteristic peaks at 2theta angles of 7.3°±0.2°, 10.6°±0.2°, 12.1°±0.2°, 12.8°±0.2°, 14.0°±0.2°, 18.7°±0.2°, 20.9°±0.2°, 23.5°±0.2°, and 24.0°±0.2°.

[0035] Non-limitingly, Table 2 shows the X-ray powder diffraction data for crystalline form A of the hydrochloride salt of the compound of formula I of the present invention.

[0036] [Table 2]

[0037] Non-limitingly, Figure 6 shows the XRPD pattern of crystalline form A of the hydrochloride salt of the compound of formula I of the present invention.

[0038] Non-limitingly, Figure 7 shows the DSC thermogram of crystalline form A of the hydrochloride salt of the compound of formula I of the present invention.

[0039] The present invention provides a method for preparing crystalline form A of the hydrochloride salt of a compound of formula I, specifically, the method is described as follows: The compound of formula I is dissolved in acetone to obtain an acetone solution of the compound of formula I. An acetone solution of hydrochloric acid is added to the acetone solution of the compound of formula I while stirring, stirring is continued, the solid is collected, and dried to obtain crystalline form A of the hydrochloride salt of the compound of formula I.

[0040] In some embodiments, the compound of formula I is subjected to sonication, heating, and then dissolved in acetone; In some embodiments, the concentration of the acetone solution of the compound of formula I is 10 to 50 mg / mL, preferably 20 mg / mL; In some embodiments, the concentration of the hydrochloric acid solution in acetone is 15-35 mg / mL, preferably 25 mg / mL; In some embodiments, after adding the acetone solution of hydrochloric acid, stirring is continued at room temperature for 4 to 48 hours, preferably 24 hours; In some embodiments, the solid is recovered by centrifugation and dried overnight under vacuum at 30-60°C.

[0041] Crystalline form B of the hydrochloride salt of the compound of formula I of the present invention has an X-ray powder diffraction pattern showing characteristic peaks at 2theta angles of 7.2°±0.2°, 20.0°±0.2°, and 22.6°±0.2°.

[0042] In some embodiments, the X-ray powder diffraction patterns of crystalline form B of the hydrochloride salt of the compound of formula I show characteristic peaks at 2theta angles of 7.2°±0.2°, 10.2°±0.2°, 11.5°±0.2°, 18.0°±0.2°, 20.0°±0.2°, 22.6°±0.2°, and 25.9°±0.2°.

[0043] In some embodiments, the X-ray powder diffraction patterns of crystalline form B of the hydrochloride salt of the compound of formula I show characteristic peaks at 2theta angles of 7.2°±0.2°, 10.2°±0.2°, 11.5°±0.2°, 14.1°±0.2°, 14.5°±0.2°, 18.0°±0.2°, 20.0°±0.2°, 22.6°±0.2°, and 25.9°±0.2°.

[0044] Non-limitingly, Table 3 shows the X-ray powder diffraction data for crystalline form B of the hydrochloride salt of the compound of formula I of the present invention:

[0045] [Table 3]

[0046] Non-limitingly, Figure 8 shows the XRPD pattern of crystalline form B of the hydrochloride salt of the compound of formula I of the present invention.

[0047] Non-limitingly, Figure 9 shows the DSC thermogram of crystalline form B of the hydrochloride salt of the compound of formula I of the present invention.

[0048] The present invention provides a method for preparing crystalline form B of the hydrochloride salt of a compound of formula I, specifically, the method is described as follows: The compound of formula I is dissolved in ethyl acetate to obtain an ethyl acetate solution of the compound of formula I. An ethyl acetate solution of hydrochloric acid is added to the ethyl acetate solution of the compound of formula I while stirring, stirring is continued, the solid is recovered, and it is dried to obtain crystalline form B of the hydrochloride salt of the compound of formula I.

[0049] In some embodiments, the compound of formula I is subjected to sonication, heating, and then dissolved in ethyl acetate; In some embodiments, the concentration of the ethyl acetate solution of the compound of formula I is 10 to 30 mg / mL, preferably 20 mg / mL; In some embodiments, the concentration of the ethyl acetate solution of hydrochloric acid is 15 to 35 mg / mL, preferably 25 mg / mL; In some embodiments, after adding an ethyl acetate solution of hydrochloric acid, stirring is continued at room temperature for 4 to 48 hours, preferably 24 hours; In some embodiments, the solid is recovered by centrifugation and dried overnight under vacuum at 30-60°C.

[0050] The crystalline form C of the hydrochloride salt of the compound of formula I of the present invention has an X-ray powder diffraction pattern showing characteristic peaks at 2theta angles of 10.7°±0.2°, 21.5°±0.2°, and 24.3°±0.2°.

[0051] In some embodiments, the X-ray powder diffraction patterns of crystalline form C of the hydrochloride salt of the compound of formula I show characteristic peaks at 2theta angles of 5.3°±0.2°, 10.7°±0.2°, 21.5°±0.2°, 24.3°±0.2°, and 30.4°±0.2°.

[0052] Non-limitingly, Table 4 shows the X-ray powder diffraction data for crystalline form C of the hydrochloride salt of the compound of formula I of the present invention:

[0053] [Table 4]

[0054] Non-limitingly, Figure 10 shows the XRPD pattern of crystalline form C of the hydrochloride salt of the compound of formula I of the present invention.

[0055] Non-limitingly, Figure 11 shows the DSC thermogram of crystalline form C of the hydrochloride salt of the compound of formula I of the present invention.

[0056] Crystalline form A of the hydrochloride salt of compound I is recrystallized or transformed using a solvent to obtain crystalline form C of the hydrochloride salt of compound I, where the solvent is selected from the group consisting of methanol, acetonitrile, n-heptane, methyl ethyl ketone, and any combination thereof.

[0057] In some embodiments, a solvent is mixed with crystalline form A of the hydrochloride salt of the compound of formula I to prepare a suspension, which is stirred at room temperature, the solid is recovered, and dried to obtain crystalline form C of the hydrochloride salt of the compound of formula I.

[0058] In some embodiments, a solvent is added to a container containing crystalline form A of the hydrochloride salt of the compound of formula I to prepare a suspension, which is stirred at room temperature, the solid is collected, and dried to obtain crystalline form C of the hydrochloride salt of the compound of formula I.

[0059] In some embodiments, the duration of stirring is 4 to 48 hours, preferably 24 hours.

[0060] In some embodiments, the solid is recovered by centrifugation and dried overnight under vacuum at 30-60°C.

[0061] The crystalline form D of the sulfate of the compound of formula I of the present invention has an X-ray powder diffraction pattern showing characteristic peaks at 2theta angles of 6.0°±0.2°, 22.8°±0.2°, and 25.2°±0.2°.

[0062] In some embodiments, the X-ray powder diffraction patterns of crystalline form D of the sulfate of the compound of formula I show characteristic peaks at 2theta angles of 6.0°±0.2°, 12.3°±0.2°, 17.5°±0.2°, 22.8°±0.2°, and 25.2°±0.2°.

[0063] Non-limitingly, Table 5 shows the X-ray powder diffraction data for crystalline form D of the sulfate of the compound of formula I of the present invention:

[0064] [Table 5]

[0065] Non-limitingly, Figure 12 shows the XRPD patterns of crystalline form D of the sulfate of the compound of formula I of the present invention.

[0066] Non-limitingly, Figure 13 shows the DSC thermogram of crystalline form D of the sulfate of the compound of formula I of the present invention.

[0067] The present invention provides a method for preparing crystalline form D of the sulfate of the compound of formula I, specifically, the method is described as follows: The compound of formula I is dissolved in acetone to obtain an acetone solution of the compound of formula I. An acetone solution of sulfuric acid is added to the acetone solution of the compound of formula I while stirring, stirring is continued, the solid is collected, and it is dried to obtain the crystalline form D of the sulfate of the compound of formula I.

[0068] In some embodiments, the compound of formula I is subjected to sonication, heating, and then dissolved in acetone.

[0069] In some embodiments, the concentration of the acetone solution of the compound of formula I is 10 to 30 mg / mL, preferably 20 mg / mL.

[0070] In some embodiments, the concentration of the sulfuric acid-acetone solution is 15 to 35 mg / mL, preferably 25 mg / mL.

[0071] In some embodiments, after adding a sulfuric acid solution in acetone, stirring is continued at room temperature for 4 to 48 hours, preferably 24 hours.

[0072] In some embodiments, the solid is recovered by centrifugation and dried overnight under vacuum at 30-60°C.

[0073] The crystalline form E of the phosphate of the compound of formula I of the present invention has an X-ray diffraction pattern showing characteristic peaks at 2theta angles of 6.2°±0.2°, 15.5°±0.2°, 17.4°±0.2°, and 24.6°±0.2°.

[0074] Non-limitingly, Table 6 shows the X-ray powder diffraction data for crystalline form E of the phosphate of the compound of formula I of the present invention:

[0075] [Table 6]

[0076] Non-limitingly, Figure 14 shows the XRPD pattern of crystalline form E of the phosphate of the compound of formula I of the present invention.

[0077] Non-limitingly, Figure 15 shows the DSC thermogram of crystalline form E of the phosphate of the compound of formula I of the present invention.

[0078] The present invention provides a method for preparing crystalline form E of the phosphate of a compound of formula I, specifically, the method is described as follows: The compound of formula I is dissolved in acetone to obtain an acetone solution of the compound of formula I. An acetone solution of phosphoric acid is added to the acetone solution of the compound of formula I while stirring, stirring is continued, the solid is collected, and it is dried to obtain crystalline form E of the phosphate salt of the compound of formula I.

[0079] In some embodiments, the compound of formula I is subjected to sonication, heating, and then dissolved in acetone.

[0080] In some embodiments, the molar ratio of the compound of formula I to phosphoric acid is 1:1.0 to 1:1.5.

[0081] In some embodiments, the concentration of the acetone solution of the compound of formula I is 10 to 30 mg / mL, preferably 20 mg / mL.

[0082] In some embodiments, the concentration of the phosphoric acid solution in acetone is 15 to 35 mg / mL, preferably 25 mg / mL.

[0083] In some embodiments, after adding a phosphoric acid solution in acetone, stirring is continued at room temperature for 4 to 48 hours, preferably 24 hours.

[0084] In some embodiments, the solid is recovered by centrifugation and dried overnight under vacuum at 30-60°C.

[0085] In some embodiments, recrystallization or crystallization of the phosphate form E of the compound of formula I is performed using a solvent, the product still being the phosphate form E of the compound of formula I, and the solvent is selected from the group consisting of methanol, acetonitrile, n-heptane, methyl ethyl ketone, and any combination thereof.

[0086] In some embodiments, during recrystallization or crystal transformation, a suspension is prepared by mixing a solvent with the crystalline form E of the phosphate of the compound of formula I, stirring at room temperature, recovering the solid, and drying it.

[0087] In some embodiments, the duration of stirring during recrystallization or crystallization is 4 to 48 hours, preferably overnight; In some embodiments, the solid is recovered by centrifugation during recrystallization or crystal transformation and dried overnight under vacuum at 30-60°C.

[0088] The crystalline form F of the phosphate of the compound of formula I of the present invention has an X-ray powder diffraction pattern showing characteristic peaks at 2theta angles of 16.6°±0.2°, 17.2°±0.2°, and 22.6°±0.2°.

[0089] In some embodiments, the X-ray powder diffraction patterns of crystalline form F of the phosphate of the compound of formula I show characteristic peaks at 2theta angles of 11.6°±0.2°, 14.8°±0.2°, 16.6°±0.2°, 17.2°±0.2°, 22.6°±0.2°, and 26.6°±0.2°.

[0090] In some embodiments, the X-ray powder diffraction patterns of crystalline form F of the phosphate of the compound of formula I show characteristic peaks at 2theta angles of 11.1°±0.2°, 11.6°±0.2°, 14.8°±0.2°, 16.6°±0.2°, 17.2°±0.2°, 21.2°±0.2°, 22.6°±0.2°, and 26.6°±0.2°.

[0091] Non-limitingly, Table 7 shows the X-ray powder diffraction data for crystalline form F of the phosphate of the compound of formula I of the present invention:

[0092] [Table 7]

[0093] Non-limitingly, Figure 16 shows the XRPD pattern of crystalline form F of the phosphate of the compound of formula I of the present invention.

[0094] Non-limitingly, the DSC thermogram of crystalline form F of the phosphate of the compound of formula I of the present invention is shown in Figure 17. The DSC thermogram shows that the initial melting point of crystalline form F of the phosphate of the compound of formula I of the present invention is 198.78°C.

[0095] Non-limitingly, Figure 18 shows the DVS isotherm plot of the crystalline form F of the phosphate of the compound of formula I of the present invention. The DVS isotherm plot shows a 6.5% weight increase in the crystalline form F of the phosphate of the compound of formula I of the present invention due to moisture absorption from 0%RH to 95%RH. At a humidity of 85%RH, the crystalline form F of the phosphate of the compound of formula I reaches a weight increase of 0.72%, and at 70%RH, the crystalline form F of the phosphate of the compound of formula I reaches a weight increase of 1.95%. After moisture absorption, the crystalline form F of the phosphate of the compound of formula I does not change (see Figure 19 for the XRPD pattern after moisture absorption).

[0096] This invention provides a method for preparing crystalline form F of the phosphate of a compound of formula I, specifically, the method is described as follows: The crystalline form E of the phosphate of compound I is dissolved in a first solvent to obtain a first solvent solution of the crystalline form E of the phosphate of compound I, a poor solvent is added, the mixture is stirred, the solid is recovered, and the mixture is dried to obtain the crystalline form F of the phosphate of compound I; or, In some embodiments, the first solvent is a solvent capable of dissolving crystalline form E of the phosphate of the compound of formula I, preferably methanol; the poor solvent is a solvent that does not readily dissolve crystalline form E of the phosphate of the compound of formula I, preferably isopropyl acetate.

[0097] In some embodiments, the first solvent is added in an amount that can completely dissolve the crystalline form E of the phosphate of the compound of formula I.

[0098] In some embodiments, a poor solvent is used to dilute a first solvent solution of crystalline form E of the phosphate of compound I by 5 to 15 times, preferably 10 times.

[0099] In some embodiments, the crystalline form E of the phosphate of the compound of formula I is dissolved in a first solvent, then a small amount of seed crystals of the crystalline form F of the phosphate of the compound of formula I is added until the system becomes slightly cloudy, and then a poor solvent is added.

[0100] In some embodiments, after adding the poor solvent, stirring is continued at room temperature for 4 to 48 hours, preferably 24 hours.

[0101] In some embodiments, the solid is recovered by centrifugation and dried under vacuum at 30-60°C, preferably 50°C.

[0102] The crystalline form G of the mesylate salt of the compound of formula I of the present invention has an X-ray powder diffraction pattern showing characteristic peaks at 2theta angles of 8.6°±0.2°, 19.9°±0.2°, and 24.9°±0.2°.

[0103] In some embodiments, the X-ray powder diffraction patterns of crystalline form G of the mesylate of the compound of formula I show characteristic peaks at 2theta angles of 8.6°±0.2°, 18.1°±0.2°, 18.6°±0.2°, 19.9°±0.2°, 24.0°±0.2°, and 24.9°±0.2°.

[0104] Non-limitingly, Table 8 shows the X-ray powder diffraction data for crystalline form G of the mesylate salt of the compound of formula I of the present invention.

[0105] [Table 8]

[0106] Non-limitingly, Figure 20 shows the XRPD pattern of crystalline form G of the mesylate of the compound of formula I of the present invention.

[0107] Non-limitingly, Figure 21 shows the DSC thermogram of crystalline form G of the mesylate of the compound of formula I of the present invention. The DSC thermogram shows that the initial melting point of crystalline form G of the mesylate of the compound of formula I of the present invention is 218.78°C.

[0108] Non-limitingly, Figure 22 shows the DVS isotherm plots of crystalline form G of the mesylate salt of the compound of formula I of the present invention.

[0109] The present invention provides a method for preparing crystalline form G of the mesylate of a compound of formula I, specifically, the method is described as follows: The compound of formula I is dissolved in acetone to obtain an acetone solution of the compound of formula I. An acetone solution of methanesulfonic acid is added to the acetone solution of the compound of formula I while stirring, stirring is continued, the solid is collected, and it is dried to obtain the crystalline form G of the mesylate salt of the compound of formula I.

[0110] In some embodiments, the compound of formula I is subjected to sonication, heating, and then dissolved in acetone.

[0111] In some embodiments, the concentration of the acetone solution of the compound of formula I is 10 to 30 mg / mL, preferably 20 mg / mL.

[0112] In some embodiments, the concentration of the acetone solution of methanesulfonic acid is 15 to 35 mg / mL, preferably 25 mg / mL.

[0113] In some embodiments, after adding an acetone solution of methanesulfonic acid, stirring is continued at room temperature for 4 to 48 hours, preferably 24 hours.

[0114] In some embodiments, the solid is recovered by centrifugation and dried overnight under vacuum at 30-60°C.

[0115] The crystalline form H of the hydrobromide salt of the compound of formula I of the present invention has an X-ray powder diffraction pattern showing characteristic peaks at 2theta angles of 7.2°±0.2°, 20.7°±0.2°, and 24.0°±0.2°.

[0116] In some embodiments, the X-ray powder diffraction patterns of crystalline form H of the hydrobromide salt of the compound of formula I show characteristic peaks at 2theta angles of 7.2°±0.2°, 17.9°±0.2°, 18.8°±0.2°, 20.7°±0.2°, and 24.0°±0.2°.

[0117] In some embodiments, the X-ray powder diffraction patterns of crystalline form H of the hydrobromide salt of the compound of formula I show characteristic peaks at 2theta angles of 7.2°±0.2°, 11.9°±0.2°, 17.0°±0.2°, 17.9°±0.2°, 18.8°±0.2°, 20.7°±0.2°, 24.0°±0.2°, and 27.5°±0.2°.

[0118] Non-limitingly, Table 9 shows the X-ray powder diffraction data for crystalline form H of the hydrobromide salt of the compound of formula I of the present invention.

[0119] [Table 9]

[0120] Non-limitingly, Figure 23 shows the XRPD pattern of the crystalline form H of the hydrobromide salt of the compound of formula I of the present invention.

[0121] Non-limitingly, Figure 24 shows the DSC thermogram of the crystalline form H of the hydrobromide salt of the compound of formula I of the present invention.

[0122] This invention provides a method for preparing crystalline form H of the hydrobromide salt of the compound of formula I, specifically, the method is described as follows: The compound of formula I is dissolved in acetone to obtain an acetone solution of the compound of formula I. An acetone solution of hydrobromide is added to the acetone solution of the compound of formula I while stirring, stirring is continued, the solid is collected, and it is dried to obtain the crystalline form H of hydrobromide of the compound of formula I.

[0123] In some embodiments, the compound of formula I is subjected to sonication, heating, and then dissolved in acetone.

[0124] In some embodiments, the concentration of the acetone solution of the compound of formula I is 10 to 30 mg / mL, preferably 20 mg / mL.

[0125] In some embodiments, the concentration of the hydrobromic acid solution in acetone is 15 to 35 mg / mL, preferably 25 mg / mL.

[0126] In some embodiments, after adding an acetone solution of hydrobromic acid, stirring is continued at room temperature for 4 to 48 hours, preferably 24 hours.

[0127] In some embodiments, the solid is recovered by centrifugation and dried overnight under vacuum at 30-60°C.

[0128] In some embodiments, recrystallization or crystallization of the hydrobromide salt of the compound of formula I is performed using a solvent, the product is still the hydrobromide salt crystalline form H, and the solvent is selected from the group consisting of acetonitrile, methyl ethyl ketone and any combination thereof.

[0129] In some embodiments, recrystallization or crystallization includes the following steps: Prepare a suspension by mixing one or both of acetonitrile and / or methyl ethyl ketone with the crystalline form H of the hydrobromide salt of the compound of formula I, stir at room temperature, centrifuge, collect the solid, and dry it; Preferably, acetonitrile and / or methyl ethyl ketone are added to a container containing the crystalline form H of the hydrobromide salt of the compound of formula I to prepare a suspension, which is stirred at room temperature, centrifuged, the solid is collected, and dried.

[0130] The crystalline form J of the hydrobromide salt of the compound of formula I of the present invention has an X-ray powder diffraction pattern showing characteristic peaks at 2theta angles of 6.2°±0.2° and 15.0°±0.2°.

[0131] Non-limitingly, Table 10 shows the X-ray powder diffraction data for the crystalline form J of the hydrobromide salt of the compound of formula I of the present invention.

[0132] [Table 10]

[0133] Non-limitingly, Figure 25 shows the XRPD pattern of the hydrobromide salt of the compound of formula I of the present invention in crystalline form J.

[0134] The present invention provides a method for preparing crystalline form J of the hydrobromide salt of the compound of formula I, specifically, the method is described as follows: The compound of formula I is dissolved in ethyl acetate to obtain an ethyl acetate solution of the compound of formula I. An ethyl acetate solution of hydrobromide is added to the ethyl acetate solution of the compound of formula I while stirring, stirring is continued, the solid is recovered, and it is dried to obtain the crystalline form J of the hydrobromide salt of the compound of formula I.

[0135] In some embodiments, the compound of formula I is subjected to sonication, heating, and then dissolved in ethyl acetate.

[0136] In some embodiments, the concentration of the ethyl acetate solution of the compound of formula I is 10 to 30 mg / mL, preferably 20 mg / mL.

[0137] In some embodiments, the concentration of the ethyl acetate solution of hydrobromic acid is 15 to 35 mg / mL, preferably 25 mg / mL.

[0138] In some embodiments, after adding an ethyl acetate solution of hydrobromic acid, stirring is continued at room temperature for 4 to 48 hours, preferably 24 hours; In some embodiments, the solid is recovered by centrifugation and dried overnight under vacuum at 30-60°C.

[0139] The crystalline form K of the hydrobromide salt of the compound of formula I of the present invention has an X-ray powder diffraction pattern showing characteristic peaks at 2theta angles of 17.1°±0.2°, 22.0°±0.2°, and 24.2°±0.2°.

[0140] The X-ray powder diffraction patterns of the hydrobromide salt of the compound of formula I in crystalline form K show characteristic peaks at 2theta angles of 17.1°±0.2°, 20.1°±0.2°, 22.0°±0.2°, 22.6°±0.2°, 24.2°±0.2°, and 28.8°±0.2°.

[0141] The X-ray powder diffraction patterns of the hydrobromide salt of the compound of formula I in crystalline form K show characteristic peaks at 2theta angles of 9.5°±0.2°, 17.1°±0.2°, 20.1°±0.2°, 22.0°±0.2°, 22.6°±0.2°, 24.2°±0.2°, 27.7°±0.2°, and 28.8°±0.2°.

[0142] Non-limitingly, Table 11 shows the X-ray powder diffraction data for the hydrobromide salt of the compound of formula I of the present invention in crystalline form K:

[0143] [Table 11]

[0144] Non-limitingly, Figure 26 shows the XRPD pattern of the hydrobromide salt of the compound of formula I of the present invention in crystalline form K.

[0145] Non-limitingly, Figure 27 shows the DSC thermogram of the hydrobromide salt of the compound of formula I of the present invention in crystalline form K.

[0146] Non-limitingly, Figure 28 shows the DVS isotherm plot of crystalline form K of the hydrobromide salt of the compound of formula I of the present invention. The DVS isotherm plot shows an 11.84% weight increase of crystalline form K of the hydrobromide salt of the compound of formula I of the present invention due to hygroscopic absorption from 0%RH to 95%RH, indicating that the sample is hygroscopic. The hygroscopic absorption curve during desorption shows hysteresis, and when combined with the XRPD patterns of the sample before and after the DVS test (see Figure 29 for the XRPD pattern after the test), it shows that the crystalline form of crystalline form K of the hydrobromide salt of the compound of formula I changed after hygroscopic absorption.

[0147] This invention provides a method for preparing the crystalline form K of the hydrobromide salt of the compound of formula I, specifically, the method is described as follows: Using n-heptane, the hydrobromide salt of the compound of formula I is recrystallized or transformed into its crystalline form H to obtain the hydrobromide salt of the compound of formula I, crystalline form K.

[0148] In some embodiments, n-heptane is mixed with hydrobromide salt crystalline form H of the compound of formula I to prepare a suspension, which is stirred at room temperature, the solid is recovered, and dried to obtain hydrobromide salt crystalline form K of the compound of formula I.

[0149] In some embodiments, n-heptane is added to a container containing the hydrobromide salt crystalline form H of the compound of formula I to prepare a suspension, which is stirred at room temperature, the solid is collected, and dried to obtain the hydrobromide salt crystalline form K of the compound of formula I.

[0150] In some embodiments, the duration of stirring is 4 to 48 hours, preferably 24 hours; In some embodiments, the solid is recovered by centrifugation and dried overnight under vacuum at 30-60°C.

[0151] The crystalline form L of the fumarate of the compound of formula I of the present invention has an X-ray powder diffraction pattern that exhibits characteristic peaks at 2theta angles of 6.1°±0.2°, 16.3°±0.2°, and 26.4°±0.2°.

[0152] The X-ray powder diffraction pattern of crystalline form L of the fumarate of compound I shows characteristic peaks at 2theta angles of 6.1°±0.2°, 13.4°±0.2°, 15.7°±0.2°, 16.3°±0.2°, and 26.4°±0.2°.

[0153] The X-ray powder diffraction pattern of crystalline form L of the fumarate of compound I shows characteristic peaks at 2theta angles of 6.1°±0.2°, 13.4°±0.2°, 15.7°±0.2°, 16.3°±0.2°, 22.6°±0.2°, 23.2°±0.2°, 23.8°±0.2°, and 26.4°±0.2°.

[0154] Non-limitingly, Table 12 shows the X-ray powder diffraction data for crystalline form L of the fumarate of the compound of formula I of the present invention.

[0155] [Table 12]

[0156] Non-limitingly, Figure 30 shows the XRPD pattern of the crystalline form L of the fumarate of the compound of formula I of the present invention.

[0157] Non-limitingly, Figure 31 shows the DSC thermogram of crystalline form L of the fumarate of the compound of formula I of the present invention.

[0158] The present invention provides a method for preparing crystalline form L of the fumarate of the compound of formula I, specifically, the method is described as follows: The compound of formula I is dissolved in a solvent to obtain a solution of the compound of formula I. An ethanol solution of fumaric acid is added to the solution of the compound of formula I while stirring, stirring is continued, the solid is collected, and dried to obtain the crystalline form L of the fumarate of the compound of formula I.

[0159] In some embodiments, the compound of formula I is subjected to sonication, heating, and then dissolved in a solvent, the solvent being selected from the group consisting of ethyl acetate, acetone, and any combination thereof.

[0160] In some embodiments, the concentration of the solution of the compound of formula I is 10 to 30 mg / mL, preferably 20 mg / mL.

[0161] In some embodiments, the concentration of the fumaric acid ethanol solution is 15 to 35 mg / mL, preferably 25 mg / mL.

[0162] In some embodiments, after adding an ethanol solution of fumaric acid, stirring is continued at room temperature for 4 to 48 hours, preferably 24 hours.

[0163] In some embodiments, the solid is recovered by centrifugation and dried overnight under vacuum at 30-60°C.

[0164] The crystalline form M of the benzenesulfonate of the compound of formula I of the present invention has an X-ray powder diffraction pattern showing characteristic peaks at 2theta angles of 7.5°±0.2°, 18.5°±0.2°, 25.2°±0.2°, and 29.8°±0.2°.

[0165] The X-ray powder diffraction pattern of crystalline form M of the benzenesulfonate of the compound of formula I shows characteristic peaks at 2theta angles of 7.5°±0.2°, 14.1°±0.2°, 15.2°±0.2°, 18.5°±0.2°, 22.4°±0.2°, 23.0°±0.2°, 25.2°±0.2°, and 29.8°±0.2°.

[0166] The X-ray powder diffraction pattern of crystalline form M of the benzenesulfonate of the compound of formula I shows characteristic peaks at 2theta angles of 7.5°±0.2°, 12.5°±0.2°, 14.1°±0.2°, 15.2°±0.2°, 18.5°±0.2°, 22.4°±0.2°, 23.0°±0.2°, 24.6°±0.2°, 25.2°±0.2°, and 29.8°±0.2°.

[0167] Non-limitingly, Table 13 shows the X-ray powder diffraction data for crystalline form M of the benzenesulfonate of the compound of formula I of the present invention.

[0168] [Table 13]

[0169] Non-limitingly, Figure 32 shows the XRPD pattern of crystalline form M of the benzenesulfonate of the compound of formula I of the present invention.

[0170] Non-limitingly, Figure 33 shows the DSC thermogram of crystalline form M of the benzenesulfonate of the compound of formula I of the present invention. This indicates that the initial melting point of crystalline form M of the benzenesulfonate of the compound of formula I of the present invention is 198.73°C.

[0171] Non-limitingly, Figure 34 shows the DVS isotherm plot of crystalline form M of the benzenesulfonate of the compound of formula I of the present invention. The DVS isotherm plot shows a 4.6% weight increase of crystalline form M of the benzenesulfonate of the compound of formula I of the present invention due to moisture absorption from 0%RH to 95%RH. At a humidity of 85%RH, the crystalline form M of the benzenesulfonate of the compound of formula I reaches a weight increase of 0.54%, and at 70%RH, the crystalline form M of the benzenesulfonate of the compound of formula I reaches a weight increase of 0.97%. After moisture absorption, the crystalline form of crystalline form M of the benzenesulfonate of the compound of formula I does not change (see Figure 35 for the XRPD pattern after moisture absorption).

[0172] The present invention provides a method for preparing crystalline form M of a benzenesulfonate of a compound of formula I, specifically, the method is described as follows: The compound of formula I is dissolved in acetone to obtain an acetone solution of the compound of formula I. An acetone solution of benzenesulfonic acid is added to the acetone solution of the compound of formula I while stirring, stirring is continued, the solid is collected, and it is dried to obtain the crystalline form M of the benzenesulfonate salt of the compound of formula I.

[0173] In some embodiments, the compound of formula I is subjected to sonication, heating, and then dissolved in acetone.

[0174] In some embodiments, the concentration of the acetone solution of the compound of formula I is 10 to 30 mg / mL, preferably 20 mg / mL; In some embodiments, the concentration of the acetone solution of benzenesulfonic acid is 15 to 35 mg / mL, preferably 25 mg / mL; In some embodiments, after adding an acetone solution of benzenesulfonic acid, stirring is continued at room temperature for 4 to 48 hours, preferably 24 hours; In some embodiments, the solid is recovered by centrifugation and dried overnight under vacuum at 30-60°C.

[0175] The crystalline form N of the citrate of the compound of formula I of the present invention has an X-ray powder diffraction pattern showing characteristic peaks at 2theta angles of 15.8°±0.2°, 17.0°±0.2°, and 21.1°±0.2°.

[0176] Non-limitingly, Table 14 shows the X-ray powder diffraction data for crystalline form N of the citrate of the compound of formula I of the present invention.

[0177] [Table 14]

[0178] Non-limitingly, Figure 36 shows the XRPD pattern of crystalline form N of the citrate of the compound of formula I of the present invention.

[0179] Non-limitingly, Figure 37 shows the DSC thermogram of crystalline form N of the citrate of the compound of formula I of the present invention.

[0180] This invention provides a method for preparing crystalline form N of the citrate of the compound of formula I, specifically, the method is described as follows: The compound of formula I is dissolved in ethyl acetate to obtain an ethyl acetate solution of the compound of formula I. An ethyl acetate solution of citrate is added to the ethyl acetate solution of the compound of formula I while stirring, stirring is continued, the solid is collected, and dried to obtain the crystalline form N of the citrate salt of the compound of formula I.

[0181] In some embodiments, the compound of formula I is subjected to sonication, heating, and then dissolved in ethyl acetate; In some embodiments, the concentration of the ethyl acetate solution of the compound of formula I is 10 to 30 mg / mL, preferably 20 mg / mL; In some embodiments, the concentration of the ethyl acetate solution of citrate is 15 to 35 mg / mL, preferably 25 mg / mL; In some embodiments, after adding an ethyl acetate solution of citrate, stirring is continued at room temperature for 4 to 48 hours, preferably 24 hours; In some embodiments, the solid is recovered by centrifugation and dried overnight under vacuum at 30-60°C.

[0182] The crystalline form O of the tartrate salt of the compound of formula I of the present invention has an X-ray powder diffraction pattern showing characteristic peaks at 2theta angles of 6.3°±0.2°, 26.1°±0.2°, and 26.9°±0.2°.

[0183] In some embodiments, the X-ray powder diffraction patterns of crystalline form O of the tartrate of the compound of formula I show characteristic peaks at 2theta angles of 6.3°±0.2°, 12.5°±0.2°, 15.1°±0.2°, 26.1°±0.2°, 26.9°±0.2°, and 27.5°±0.2°.

[0184] In some embodiments, the X-ray powder diffraction patterns of crystalline form O of the tartrate salt of the compound of formula I show characteristic peaks at 2theta angles of 6.3°±0.2°, 11.4°±0.2°, 12.5°±0.2°, 14.1°±0.2°, 14.4°±0.2°, 15.1°±0.2°, 26.1°±0.2°, 26.9°±0.2°, and 27.5°±0.2°.

[0185] Non-limitingly, Table 15 shows the X-ray powder diffraction data for crystalline form O of the tartrate salt of the compound of formula I of the present invention:

[0186] [Table 15]

[0187] Non-limitingly, Figure 38 shows the XRPD pattern of crystalline form O of the tartrate salt of the compound of formula I of the present invention.

[0188] Non-limitingly, Figure 39 shows the DSC thermogram of crystalline form O of the tartrate salt of the compound of formula I of the present invention. The DSC thermogram shows that the initial melting point of crystalline form O of the tartrate salt of the compound of formula I of the present invention is 218.80°C.

[0189] Non-limitingly, Figure 40 shows the TGA thermogram of crystalline form O of the tartrate salt of the compound of formula I of the present invention. The TGA thermogram shows that crystalline form O of the tartrate salt of the compound of formula I of the present invention has only a 0.05% weight loss at 26°C to 120°C, indicating that crystalline form O of the tartrate salt of the compound of formula I does not contain crystal water or solvent.

[0190] Non-limitingly, Figure 41 shows the DVS isotherm plot of crystalline form O of the tartrate of the compound of formula I of the present invention. The DVS isotherm plot shows a 6.85% weight increase of crystalline form O of the tartrate of the compound of formula I of the present invention due to moisture absorption from 0% RH to 95% RH. At a humidity of 80% RH, the weight increase of crystalline form O of the tartrate of the compound of formula I reaches 1.80%. After moisture absorption, the crystalline form of crystalline form O of the tartrate of the compound of formula I does not change (see Figure 42 for the XRPD pattern after moisture absorption).

[0191] The present invention provides a method for preparing crystalline form O of the tartrate salt of the compound of formula I, specifically, the method is described as follows: The compound of formula I is mixed with a first solvent, and the compound is dissolved until the solution becomes clear to obtain a first solvent solution of the compound of formula I; tartaric acid is mixed with a second solvent, and the compound is dissolved until the solution becomes clear to obtain a second solvent solution of tartaric acid; the second solvent solution of tartaric acid is added to the first solvent solution of the compound of formula I while stirring, and controlled cooling is performed while stirring, the solid is recovered and dried to obtain crystalline form O of the tartrate salt of the compound of formula I.

[0192] In some embodiments, the first and second solvents are selected from the group consisting of acetone, ethyl acetate, and any combination thereof.

[0193] In some embodiments, the molar ratio of the compound of formula I to tartaric acid is 1:(0.5~1.5), preferably 1:(0.5~0.7), and more preferably 1:(0.55~0.6).

[0194] In some embodiments, in crystalline form O of the tartrate salt of the compound of formula I, the molar ratio of the compound of formula I to tartaric acid is 2:1.

[0195] In some embodiments, the concentration of the acetone solution of the compound of formula I is 15 to 70 mg / mL, preferably 40 to 60 mg / mL, and more preferably 50 mg / mL.

[0196] In some embodiments, the concentration of the tartaric acid acetone solution is 5 to 35 mg / mL, preferably 10 to 25 mg / mL, and more preferably 15 mg / mL.

[0197] In some embodiments, the compound of formula I is mixed with acetone, and the temperature is raised to 40-60°C, preferably 50-55°C, to dissolve the compound of formula I until the solution becomes clear.

[0198] In some embodiments, tartaric acid is mixed with acetone, and the temperature is raised to 40-60°C, preferably 50-55°C, to dissolve the tartaric acid until the solution becomes clear.

[0199] In some embodiments, a tartaric acid acetone solution is added to an acetone solution of the compound of formula I at 40-60°C, preferably 45-55°C.

[0200] In some embodiments, speed-controlled cooling is achieved by the following steps: Stir the system for 0.5 to 3 hours, preferably 1 to 2 hours, at room temperature of 35 to 60°C, preferably 40 to 60°C; Continue cooling the system to 15-35°C, maintain the temperature, and stir for 0.5-3 hours, preferably 1-2 hours; The system is continuously cooled to 5-15°C, for example, 5-10°C, and the temperature is maintained while stirring for 0.5-3 hours, preferably 1-2 hours.

[0201] In the present invention, rate-controlled cooling can gradually cool the system in stages and maintain a predetermined temperature range for a certain duration.

[0202] In some embodiments, during rate-controlled cooling, the system is stirred for 0.5 to 3 hours, preferably 1 to 2 hours, at room temperature of 35 to 60°C, preferably 40 to 60°C, and then concentrated to one-third to two-thirds of its original volume, preferably half of its original volume.

[0203] In some embodiments, during rate-controlled cooling, the system is kept cooled to 15-35°C, the temperature is maintained, and after stirring for 0.5-3 hours, preferably 1-2 hours, the system is concentrated to one-third to two-thirds of its original volume, preferably half of its original volume.

[0204] In some embodiments, the purity of the compound of formula I is greater than 90%, preferably greater than 95%, and more preferably greater than 99%.

[0205] In some embodiments, the recovered solid is dried at 40-60°C under reduced pressure or using a blower for 5-48 hours, preferably 16-28 hours.

[0206] The present invention also provides a pharmaceutical composition comprising crystalline form 1 of the compound of formula I, crystalline form A of the hydrochloride salt of the compound of formula I, crystalline form B of the hydrochloride salt of the compound of formula I, crystalline form C of the hydrochloride salt of the compound of formula I, crystalline form D of the sulfate salt of the compound of formula I, crystalline form E of the phosphate salt of the compound of formula I, crystalline form F of the phosphate salt of the compound of formula I, crystalline form G of the mesylate salt of the compound of formula I, crystalline form H of the hydrobromide salt of the compound of formula I, crystalline form J of the hydrobromide salt of the compound of formula I, crystalline form K of the hydrobromide salt of the compound of formula I, crystalline form L of the fumarate salt of the compound of formula I, crystalline form M of the benzenesulfonate salt of the compound of formula I, crystalline form N of the citrate salt of the compound of formula I, and / or crystalline form O of the tartrate salt of the compound of formula I.

[0207] The present invention also provides a pharmaceutical formulation comprising crystalline form 1 of the compound of formula I, crystalline form A of the hydrochloride salt of the compound of formula I, crystalline form B of the hydrochloride salt of the compound of formula I, crystalline form C of the hydrochloride salt of the compound of formula I, crystalline form D of the sulfate salt of the compound of formula I, crystalline form E of the phosphate salt of the compound of formula I, crystalline form F of the phosphate salt of the compound of formula I, crystalline form G of the mesylate salt of the compound of formula I, crystalline form H of the hydrobromide salt of the compound of formula I, crystalline form J of the hydrobromide salt of the compound of formula I, crystalline form K of the hydrobromide salt of the compound of formula I, crystalline form L of the fumarate salt of the compound of formula I, crystalline form M of the benzenesulfonate salt of the compound of formula I, crystalline form N of the citrate salt of the compound of formula I, and / or crystalline form O of the tartrate salt of the compound of formula I.

[0208] Use of crystalline form 1 of compound of formula I, crystalline form A of hydrochloride of compound of formula I, crystalline form B of hydrochloride of compound of formula I, crystalline form C of hydrochloride of compound of formula I, crystalline form D of sulfate of compound of formula I, crystalline form E of phosphate of compound of formula I, crystalline form F of phosphate of compound of formula I, crystalline form G of mesylate of compound of compound of formula I, crystalline form H of hydrobromide of compound of compound of formula I, crystalline form J of hydrobromide of compound of formula I, crystalline form K of hydrobromide of compound of formula I, crystalline form L of fumarate of compound of compound of formula I, crystalline form M of benzenesulfonate of compound of compound of formula I, crystalline form N of citrate of compound of compound of formula I and / or crystalline form O of tartrate of compound of formula I in the preparation of agents for the treatment of JAK1 / TYK2-related diseases or conditions, wherein the disease or condition may be an autoimmune disease or disorder, such as rheumatoid arthritis or an inflammatory disease or disorder, and cancer or a tumor-proliferative disease or disorder.

[0209] Unless otherwise specified in this invention, the temperatures included refer to the internal temperature of the reaction system.

[0210] Regarding the melting point, in DSC testing, the actual measured initial melting point will vary within a certain range due to the influence of the measuring instrument, heating rate, crystal shape, etc., and those skilled in the art will understand that this variation is generally within ±5°C.

[0211] [Brief explanation of the drawing] Figure 1 shows the XRPD pattern of crystalline form 1 of the compound of formula I of the present invention.

[0212] Figure 2 is a DSC thermogram of crystalline form 1 of the compound of formula I of the present invention.

[0213] Figure 3 is a TGA thermogram of crystalline form 1 of the compound of formula I of the present invention.

[0214] Figure 4 shows the DVS isotherm plot of crystalline form 1 of the compound of formula I of the present invention.

[0215] Figure 5 shows the XRPD overlay pattern of crystalline form 1 of the compound of formula I of the present invention before and after DVS testing.

[0216] Figure 6 shows the XRPD pattern of crystalline form A of the hydrochloride salt of the compound of formula I of the present invention.

[0217] Figure 7 is a DSC thermogram of crystalline form A of the hydrochloride salt of the compound of formula I of the present invention.

[0218] Figure 8 shows the XRPD pattern of crystalline form B of the hydrochloride salt of the compound of formula I of the present invention.

[0219] Figure 9 is a DSC thermogram of crystalline form B of the hydrochloride salt of the compound of formula I of the present invention.

[0220] Figure 10 shows the XRPD pattern of crystalline form C of the hydrochloride salt of the compound of formula I of the present invention.

[0221] Figure 11 is a DSC thermogram of crystalline form C of the hydrochloride salt of the compound of formula I of the present invention.

[0222] Figure 12 shows the XRPD pattern of crystalline form D of the sulfate of the compound of formula I of the present invention.

[0223] Figure 13 is a DSC thermogram of crystalline form D of the sulfate of the compound of formula I of the present invention.

[0224] Figure 14 shows the XRPD pattern of crystalline form E of the phosphate of the compound of formula I of the present invention.

[0225] Figure 15 is a DSC thermogram of crystalline form E of the phosphate of the compound of formula I of the present invention.

[0226] Figure 16 shows the XRPD pattern of crystalline form F of the phosphate of the compound of formula I of the present invention.

[0227] Figure 17 is a DSC thermogram of crystalline form F of the phosphate of the compound of formula I of the present invention.

[0228] Figure 18 is a DVS isotherm plot of crystalline form F of the phosphate of the compound of formula I of the present invention.

[0229] Figure 19 is an XRPD overlay pattern of crystalline form F of the phosphate of the compound of formula I of the present invention before and after the DVS test.

[0230] Figure 20 is an XRPD pattern of crystalline form G of the mesylate of the compound of formula I of the present invention.

[0231] Figure 21 is a DSC thermogram of crystalline form G of the mesylate of the compound of formula I of the present invention.

[0232] Figure 22 is a DVS isotherm plot of crystalline form G of the mesylate of the compound of formula I of the present invention.

[0233] Figure 23 is an XRPD pattern of crystalline form H of the hydrobromide of the compound of formula I of the present invention.

[0234] Figure 24 is a DSC thermogram of crystalline form H of the hydrobromide of the compound of formula I of the present invention.

[0235] Figure 25 is an XRPD pattern of crystalline form J of the hydrobromide of the compound of formula I of the present invention.

[0236] Figure 26 is an XRPD pattern of crystalline form K of the hydrobromide of the compound of formula I of the present invention.

[0237] Figure 27 is a DSC thermogram of crystalline form K of the hydrobromide of the compound of formula I of the present invention.

[0238] Figure 28 is a DVS isotherm plot of crystalline form K of the hydrobromide of the compound of formula I of the present invention.

[0239] Figure 29 is an XRPD overlay pattern of crystalline form K of the hydrobromide of the compound of formula I of the present invention before and after the DVS test.

[0240] Figure 30 is an XRPD pattern of crystalline form L of the fumarate of the compound of formula I of the present invention.

[0241] Figure 31 is a DSC thermogram of crystalline form L of the fumarate of the compound of formula I of the present invention.

[0242] Figure 32 shows the XRPD pattern of crystalline form M of the benzenesulfonate of the compound of formula I in the present invention.

[0243] Figure 33 is a DSC thermogram of crystalline form M of the benzenesulfonate of the compound of formula I in the present invention.

[0244] Figure 34 is a DVS isotherm plot of crystalline form M of the benzenesulfonate of the compound of formula I of the present invention.

[0245] Figure 35 shows the XRPD overlay patterns of crystalline form M of the benzenesulfonate of the compound of formula I of the present invention before and after DVS testing.

[0246] Figure 36 shows the XRPD pattern of crystalline form N of the citrate of the compound of formula I of the present invention.

[0247] Figure 37 is a DSC thermogram of crystalline form N of the citrate of the compound of formula I of the present invention.

[0248] Figure 38 shows the XRPD pattern of crystalline form O of the tartrate salt of the compound of formula I of the present invention.

[0249] Figure 39 is a DSC thermogram of crystalline form O of the tartrate salt of the compound of formula I of the present invention.

[0250] Figure 40 is a TGA thermogram of crystalline form O of the tartrate salt of the compound of formula I of the present invention.

[0251] Figure 41 is a DVS isotherm plot of crystalline form O of the tartrate salt of the compound of formula I of the present invention.

[0252] Figure 42 shows the XRPD overlay patterns of crystalline form O of the tartrate of the compound of formula I of the present invention before and after DVS testing.

[0253] Figure 43 shows the 1 1 1H NMR spectrum of crystalline form 1 of the compound of formula I of the present invention.

[0254] Figure 44 shows the 1 1 1H NMR spectrum of crystalline form O of the tartrate salt of the compound of formula I of the present invention.

[0255] Figure 45 is an XRPD overlay pattern of crystalline form F of the phosphate salt of the compound of formula I of the present invention after being placed under high temperature and accelerated conditions for 2 weeks.

[0256] Figure 46 is an XRPD overlay pattern of crystalline form O of the tartrate salt of the compound of formula I of the present invention after being placed under high temperature and accelerated conditions for 2 weeks.

[0257] Figure 47 is a DSC overlay thermogram of crystalline form F of the phosphate salt of the compound of formula I of the present invention after being placed under high temperature and accelerated conditions for 2 weeks.

[0258] Figure 48 is a DSC overlay thermogram of crystalline form O of the tartrate salt of the compound of formula I of the present invention after being placed under high temperature and accelerated conditions for 2 weeks.

[0259] Figure 49 is an XRPD overlay pattern of crystalline form 1 of the compound of formula I of the present invention after being placed under high temperature and accelerated conditions for 2 weeks.

[0260] Figure 50 is a DSC overlay thermogram of crystalline form 1 of the compound of formula I of the present invention after being placed under high temperature and accelerated conditions for 2 weeks.

[0261] 〔Embodiment〕 The following embodiments further illustrate the present invention, but do not constitute a limitation or restriction on the scope of the present invention.

[0262]

Table 16

[0263] Information regarding the raw materials and reagents used in this invention is as follows:

[0264] [Table 17] JPEG0007855657000022.jpg108159

[0265] [Examples] <Preparation of the compound of formula III>

[0266] [ka]

[0267] [Example 1: Preparation of the compound of Formula III] Ethanol (4 mL), compound of formula IV (0.20 g, 1.0 equivalent), compound of formula V (0.18 g, 1.0 equivalent), and DIPEA (0.39 g, 3.0 equivalents) were added to a 25 mL three-necked flask and stirred; under nitrogen protection, the system was heated to reflux (70-80°C) and stirred overnight at reflux temperature; the system was cooled to room temperature (15-20°C), allowing the solid to precipitate during cooling; water (4 mL) was added dropwise to the system and the system was stirred at room temperature (15-20°C) for 2 hours; the system was filtered, the filter cake was washed with aqueous ethanol solution (2 mL, V / V, 1:1), and the filter cake was dried under vacuum at 45-50°C for 16 hours; approximately 0.21 g of yellow solid was obtained, with an LC-MS purity of 96.4% (214 nm) and a yield of 69%.

[0268] MS-ESI:[M+1] + :303.1 1H NMR (400MHz, CDCl3): 9.238(s, 1H), 8.400(d, 1H), 7.968(d, 1H), 6.987(d, 1H), 4.537~4.613(m, 1H), 4.305~4.350(m, 1H), 3.6 61~3.722(m, 1H), 3.313~3.366(m, 1H), 2.590~2.699(m, 2H), 2.407~2.454(m, 1H), 1.815~2.035(m, 1H), 1.688~1.806(m, 2H).

[0269] [Example 2: Preparation of the compound of Formula III] Ethanol (120 mL, 20V), compound of formula IV (6.0 g, 1.0 equivalent), compound of formula V (5.4 g, 1.01 equivalent), and DIPEA (11.7 g, 3.0 equivalent) were added to a 250 mL three-necked flask and stirred; under nitrogen protection, the system was heated to 70-80°C (internal temperature) and stirred while maintaining the temperature for 8 hours; the system was cooled to room temperature (15-20°C), and the solid was precipitated during cooling; water (120 mL, 20V) was added dropwise to the system and the system was stirred at room temperature (10-15°C) for 2 hours; the system was filtered, the filtered cake was washed with aqueous ethanol solution (30 mL, 1:1), and the filtered cake was dried under vacuum at 50°C for 16 hours; a total of approximately 7.7 g of yellow solid was obtained, with an HPLC purity of 95.5% and a yield of 84.3%.

[0270] MS-ESI and 1 The 1H NMR data is consistent with that of Example 1.

[0271] [Example 3: Preparation of compound III] Ethanol (5 mL, 10 V), the compound of formula IV (0.50 g, 1.0 equivalent), the compound of formula V (0.45 g, 1.01 equivalents), and DIPEA (0.98 g, 3.0 equivalents) were added to a 25 mL three-necked flask and stirred; under nitrogen protection, the system was heated to 70 - 80 °C and refluxed, and stirred for 5 hours; the system was cooled to room temperature (15 - 20 °C), and a solid precipitated during cooling; water (5 mL, 10 V) was added dropwise to the system, and the system was stirred at room temperature (10 - 15 °C) for 2 hours; filtered, the filter cake was washed with an ethanol aqueous solution (1:1) (1.5 mL, 3 V), and the filter cake was dried under vacuum at 50 °C for 16 hours, and about 0.54 g of a brown solid was obtained in total, the HPLC purity was 95.4%, and the yield was 71%.

[0272] MS-ESI and 1 The H NMR data is consistent with that of Example 1.

[0273] [Example 4 Preparation of the Compound of Formula III] Ethanol (5 mL, 10 V), the compound of formula IV (0.50 g, 1.0 equivalent), the compound of formula V (0.45 g, 1.01 equivalents), and DIPEA (0.72 g, 2.2 equivalents) were added to a 25 mL three-necked flask and stirred; under nitrogen protection, the system was heated to 70 - 80 °C and refluxed, and stirred for 5 hours; the system was cooled to room temperature (15 - 20 °C), and a solid precipitated during cooling; water (7.5 mL, 15 V) was added dropwise to the system, and the system was stirred at room temperature (set10 - set15 °C) for 1 hour; the system was cooled to 5 - 10 °C and stirred for 2 hours; filtered, the filter cake was washed with an ethanol aqueous solution (1:1) (1.5 mL, 3 V), and the filter cake was dried under vacuum at 50 °C for 16 hours; about 0.57 g of a brown solid was obtained in total, the HPLC purity was 91.4%, and the yield was 75%.

[0274] MS-ESI and 1 The H NMR data is consistent with that of Example 1.

[0275] [Example 5 Preparation of the Compound of Formula III] Ethanol (50 mL, 10V), compound of formula IV (5.0 g, 1.0 equivalent), compound of formula V (4.5 g, 1.01 equivalent), and DIPEA (7.2 g, 2.2 equivalents) were added to a 250 mL three-necked flask and stirred; under nitrogen protection, the system was heated to 70-80°C under reflux and stirred for 5 hours; the system was cooled to room temperature (15-20°C), and the solid was precipitated during cooling; water (75 mL, 15V) was added dropwise to the system and the system was stirred at room temperature (10-15°C) for 1 hour; the system was cooled to 5-10°C and stirred for 2 hours; the system was filtered, the filter cake was washed with aqueous ethanol solution (1:1, 15 mL), and the filter cake was dried under vacuum at 50°C for 16 hours; a total of approximately 6.6 g of yellow solid was obtained, with an HPLC purity of 94.2% and a yield of 86.7%.

[0276] MS-ESI and 1 The 1H NMR data is consistent with that of Example 1.

[0277] [Example 6: Preparation of compound III] Ethanol (180 mL, 10V), compound of formula IV (17.8 g, 1.0 equivalent), compound of formula V (16.0 g, 1.01 equivalent), and DIPEA (25.7 g, 2.2 equivalents) were added to a 500 mL three-necked flask and stirred; under nitrogen protection, the system was heated to 70-80°C under reflux and stirred for 5 hours; the system was cooled to room temperature (15-20°C), and the solid was precipitated during cooling; water (270 (mL, 15V) was added dropwise to the system and the system was stirred at room temperature (10-15°C) for 1 hour; the system was cooled to 5-10°C and stirred for 2 hours; filtered and the filtered cake was washed with an aqueous ethanol solution (ethanol:water = 1:1.5, V / V, 40 mL); the filtered cake was dried under vacuum at 50°C for 16 hours; a total of approximately 23.0 g of brown solid was obtained, with an HPLC purity of 95.3% and a yield of 85.2%.

[0278] MS-ESI and 1 The 1H NMR data is consistent with that of Example 1.

[0279] [Example 7: Preparation of the compound of formula III] Ethanol (1000 mL, 10V), compound of formula IV (100 g, 1.0 equivalent), compound of formula V (89.9 g, 1.01 equivalent), and DIPEA (143.2 g, 2.2 equivalents) were added to a 3000 mL three-necked flask and stirred; under nitrogen protection, the system was heated to 85-90°C (internal temperature: approximately 75°C) under reflux and stirred for 10 hours; the system was cooled to room temperature (15-20°C), and the solid was allowed to precipitate during cooling. The system was then stirred dropwise with water (1500 mL, 15V) and the system was stirred at room temperature (10-15°C) for 1 hour. The system was then cooled to 5-10°C and stirred for 2 hours. The system was filtered, the filter cake was washed with aqueous ethanol solution (1:1.5, V / V, 200 mL), and the filter cake was dried under vacuum at 50°C for 16 hours. A total of approximately 130 g of reddish-brown solid was obtained, with an HPLC purity of 94.2% and a yield of 85.5%.

[0280] MS-ESI and 1 The 1H NMR data is consistent with that of Example 1.

[0281] [Example 8: Preparation of compound III] Ethanol (2000 mL, 10V), compound of formula IV (200 g, 1.0 equivalent), compound of formula V (179.7 g, 1.01 equivalent), and DIPEA (286.4 g, 2.2 equivalents) were added to a 5000 mL three-necked flask and stirred; under nitrogen protection, the system was heated to 70-80°C (internal temperature: approximately 65-70°C) under reflux and stirred for 16 hours; the system was cooled to room temperature (15-20°C), and the solid was precipitated during cooling; water ( 3000 mL (15V) was added dropwise to the system, and the system was stirred at room temperature (10-15°C) for 1 hour; the system was cooled to 5-10°C and stirred for 2 hours; the system was filtered, the filter cake was washed with an aqueous ethanol solution (1:1.5, V / V, 400 mL), and the filter cake was dried at 50°C for 16 hours using a blower; a total of approximately 251 g of reddish-brown solid was obtained, with an HPLC purity of 93.4%, a content of 94.7%, and a content yield of 78.1%.

[0282] MS-ESI and 1 The 1H NMR data is consistent with that of Example 1.

[0283] [Example 9: Preparation of Compound III] Ethanol (5000 mL, 10V), compound of formula IV (500 g, 1.0 equivalent), compound of formula V (450 g, 1.01 equivalent), and DIPEA (723 g, 2.2 equivalents) were added to a 20000 mL three-necked flask and stirred; under nitrogen protection, the system was heated to 80-90°C (internal temperature: approximately 70-80°C) under reflux and stirred for 16 hours; the system was cooled to room temperature (25-30°C), and the solid was precipitated during cooling; water (7500 mL, 15V) was added to the system. The solution was added dropwise, and the system was stirred at room temperature (25-30°C) for 1 hour; the system was cooled to 10-15°C and stirred for 2 hours; the system was filtered, the filtered cake was washed with an aqueous ethanol solution (1:1.5, V / V, 1000 mL), and the filtered cake was dried in an oven at 50-55°C under vacuum for 24 hours; a total of approximately 623 g of product was obtained, with an HPLC purity of 93.7%, an ethanol residue content of 0.5%, a content content of 93.1%, and a content yield of 76.2%.

[0284] MS-ESI and 1 The 1H NMR data is consistent with that of Example 1.

[0285] [Example 10: Preparation of the compound of Formula III] Ethanol (100 mL, 10V), compound of formula IV (10.0 g, 1.0 equivalent), compound of formula V (9.0 g, 1.01 equivalent), and DIPEA (14.3 g, 2.2 equivalents) were added to a 500 mL three-necked flask and stirred; the system was heated to 70-80°C under reflux and stirred for 16 hours; the system was cooled to room temperature (20-30°C), and the solid was precipitated during cooling; water (150 mL) The system was mixed with 15V (1:1.5V) and stirred at room temperature (20-30°C) for 2 hours; the system was cooled to 5-10°C and stirred for 2 hours; filtered, the filtered cake was washed with aqueous ethanol solution (1:1.5V / V, 25mL), and the filtered cake was dried in an oven at 50-55°C under vacuum for 16 hours; approximately 13.7g of product was obtained in total, with an HPLC purity of 93.7% and a yield of 90%.

[0286] MS-ESI and 1 The 1H NMR data is consistent with that of Example 1.

[0287] [Example 11: Preparation of Compound III] Ethanol (17 kg, 10V), compound of formula IV (2.2 kg, 1.0 equivalent), compound of formula V (1.98 kg, 1.01 equivalent), and DIPEA (3.19 kg, 2.2 equivalents) were added to the R0462 reactor and stirred; under nitrogen protection, the system was heated to 75-80°C (internal temperature, approximately 70-80°C) and stirred for 16 hours; the system was cooled to room temperature (15-25°C), allowing the solid to precipitate during cooling; water (33 kg, 15V) was added dropwise to the system, and the system was cooled to room temperature. The mixture was stirred at warm temperature (10-15°C) for 2 hours; the system was cooled to 5-10°C and stirred for 4 hours; filtered, the filtered cake was washed with an aqueous ethanol solution (ethanol:water = 1:2, V / V, 6.2 kg), and the filtered cake was dried under vacuum (≤-0.08 MPa) at a jacket temperature of 45-55°C for 16 hours; a total of approximately 2.64 g of brown solid was obtained, with an HPLC purity of 94.0%, a content of 93.4%, and a content yield of 79.04%.

[0288] MS-ESI and 1 The 1H NMR data is consistent with that of Example 1.

[0289] <Preparation of the compound of formula II>

[0290] [ka]

[0291] [Example 12: Preparation of the compound of formula II] Compound III (5.0 g), THF (50 mL, 10V), and palladium-carbon (0.75 g, 10% Pd / C, 50% wet) were successively added to a 100 mL stainless steel autoclave; the system was purged 5 times with nitrogen, then 5 times with hydrogen; the pressure of the system was increased to 0.50 MPa with hydrogen, and then the system was heated to 25-35°C and stirred for 24 hours while maintaining the temperature; the reaction mixture was filtered through diatomaceous earth, the filter cake was washed with THF (20 mL), and the filtrate was concentrated to dryness to obtain 4.2 g of brown solid. The HPLC purity was 94.9% and the yield was 93.3%.

[0292] MS-ESI:[M+1] + :273.1 1 H NMR (400MHz, CDCl3): 7.988(s, 1H), 7.688(d, 1H), 6.805(d, 1H), 4.190~4.338(m, 3H), 3.584~3.648(m, 1H), 3.147~3.2 06(t, 1H), 2.594~2.651(d, 2H), 2.318~2.364(m, 1H), 1.917~1.974(m, 1H), 1.633~1.738(m, 1H), 1.456~1.525(m, 1H).

[0293] [Example 13: Preparation of compound II] Compound III (120.0 g), THF (2400 mL, 20V), and palladium-carbon (18 g, 10% Pd / C, 50% wet) were successively added to a 5000 mL stainless steel autoclave; the system was purged 5 times with nitrogen, then 5 times with hydrogen; the pressure of the system was increased to 0.50 MPa with hydrogen, and then the system was heated to 25-35°C and stirred for 24 hours while maintaining the temperature; the reaction mixture was filtered through diatomaceous earth, the filter cake was washed with THF (600 mL) (until the TLC showed almost no fluorescence), and the filtrate was concentrated to obtain 130 g of a black semi-oily solid. The HPLC purity was 91.7% and the yield was 120.26%.

[0294] MS-ESI and 1 The 1H NMR data is consistent with that of Example 12.

[0295] [Example 14: Preparation of the compound of formula II] 100.0 g of the compound of formula III, 2000 mL of THF (20V), and 15.0 g of palladium-carbon (10% Pd / C, 50% wet) were continuously added to a 5 L stainless steel autoclave; the system was purged 5 times with nitrogen, then 5 times with hydrogen; the pressure of the system was increased to 0.5-1.0 MPa with hydrogen, the jacket temperature was set to 30°C, and the system was stirred for 16 hours while maintaining the temperature; the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with THF (1000 mL) to obtain a total of 3877 g of the compound of formula II in THF solution.

[0296] Post-treatment 1: The above filtrate (1820 g, approximately 40 g of the compound of formula II calculated according to a 100% yield) was concentrated to (2-3 V, 80-120 mL) using a rotary evaporator, and the system was replaced with ethanol (150 mL x 2) to obtain an ethanol solution of 78 g of the compound of formula II, with a content of 47.25% and a content yield of 92.14%.

[0297] Post-treatment 2: The above filtrate (450 g, approximately 10 g of the compound of formula II calculated according to a 100% yield) was concentrated to dryness using a rotary evaporator; 10.5 g of a brownish-red solid was obtained.

[0298] Post-treatment 3: The above filtrate (450 g, approximately 10 g of the compound of formula II after calculation) was added to a flask and concentrated to approximately 30-40 mL (3-4 V) using a rotary evaporator; the concentrated residue was replaced with approximately 30-40 mL (3-4 V) of ethanol (50 mL x 2) to obtain a black oily concentrated residue, which was then supplied directly to the next reaction step.

[0299] MS-ESI and 1 The 1H NMR data is consistent with that of Example 12.

[0300] [Example 15] Preparation of the compound of formula II THF (240 mL, 20V), compound III (12.0 g), and palladium-carbon (1.8 g, 5% Pd / C, 50% wet) were continuously added to a 5000 mL three-necked flask; the system was purged five times with nitrogen, then five times with hydrogen; the system was stirred for 48 hours under hydrogen pressure (approximately 0.1 MPa) while maintaining the temperature at room temperature (25-30°C); the filtrate was filtered, and the filter cake was washed with THF (60 mL); the combined filtrate was concentrated to 20-30 mL using a rotary evaporator, and the system was replaced with 20-30 mL of ethanol (60 mL x 2); an ethanol solution of 24 g of compound II was obtained and used directly in the next reaction step.

[0301] MS-ESI and 1 The 1H NMR data is consistent with that of Example 12.

[0302] [Example 16: Preparation of the compound of formula II] THF (1500 mL, 15V), compound III (100 g), and palladium-carbon (15 g, 5% Pd / C, 50% wet) were continuously added to a 5000 mL three-necked flask; the system was purged 5 times with nitrogen, then 5 times with hydrogen; the system was stirred for 48 hours under hydrogen pressure (approximately 0.1 MPa) while maintaining the temperature at room temperature (20-25°C); the filtrate was filtered, and the filter cake was washed with THF (200 mL); the combined filtrate was concentrated to 200-300 mL using a rotary evaporator to obtain 185.6 g of THF of compound II, with an HPLC purity of 94.2%, a content of 43.2%, and a content yield of 94.0%.

[0303] MS-ESI and 1 The 1H NMR data is consistent with that of Example 12.

[0304] [Example 17: Preparation of the compound of formula II] THF (12400 mL, 20V), compound III (620 g), and palladium-carbon (93 g, 5% Pd / C, 50% wet) were continuously added to a 20000 mL three-necked flask; the system was purged five times with nitrogen, then five times with hydrogen; the system was stirred for 48 hours under hydrogen pressure (approximately 0.1 MPa) while maintaining the temperature at room temperature (30-35°C); the filtrate was filtered through diatomaceous earth (200 g); the filter cake was washed with THF (1200 mL); the combined filtrate was concentrated to 1200-1800 mL using a rotary evaporator to obtain a THF solution of 1664 g of compound II. The HPLC purity was 93.8%, the content was 34.57%, and the content yield was 110.6%.

[0305] MS-ESI and 1 The 1H NMR data is consistent with that of Example 12.

[0306] [Example 18: Preparation of the compound of formula II] THF (140 mL, 70V), compound III (2.0 g), and palladium-carbon (0.3 g, 5% Pd / C, 50% wet) were added to a 250 mL autoclave; the autoclave was capped and the nut was tightened; the system was purged three times with nitrogen, then three times with hydrogen; the autoclave was filled with hydrogen to a pressure of approximately 0.50 ± 0.05 MPa and the inlet valve was closed; the stirrer was started at a rotational speed of 500 r / min; the hydrogen pressure in the autoclave was maintained at 0.5 ± 0.05 MPa at 25-35°C and the system was stirred for 96 hours to allow the reaction to proceed; the reaction mixture was filtered through diatomaceous earth (10 g) and the filter cake was washed with THF (60 mL); the combined filtrate was concentrated and dried using a rotary evaporator to obtain 1.8 g of semi-oily solid, with an HPLC purity of 91.2% and a yield of 99.9%.

[0307] MS-ESI and 1 The 1H NMR data is consistent with that of Example 12.

[0308] [Example 19: Preparation of the compound of formula II] THF (167 kg, 70V), compound III (2.64 g), and palladium carbon (0.4 kg, 5% Pd / C, 50% wet) were added to a 500 L autoclave; the system was purged five times with nitrogen, then five times with hydrogen; the autoclave was filled with hydrogen to a pressure of approximately 0.50 ± 0.05 MPa, and the inlet valve was closed; the stirring device was started; the hydrogen pressure in the autoclave was maintained at 0.5 ± 0.05 MPa at 25-35°C, and the system was stirred for 120 hours to allow it to react; the system was filtered under pressure, and the filtered cake was washed with THF (13 kg); the combined filtrate was distilled under reduced pressure (up to 2V-3V) to obtain 11 kg of THF solution of compound II, with an HPLC purity of 90.7%, a content of 18.5%, and a content yield of 91.9%.

[0309] MS-ESI and 1 The 1H NMR data is consistent with that of Example 12.

[0310] [Example 20: Preparation of the compound of formula II] THF (60 mL, 12V), compound III (5.0 g), and palladium-carbon (0.75 g, 5% Pd / C, 50% wet) were added to a 100 mL stainless steel autoclave; the system was purged five times with nitrogen, then five times with hydrogen; the pressure of the system was increased to 0.5-1.0 MPa with hydrogen, the jacket temperature was set to 30°C, and the system was stirred for 42 hours while maintaining the temperature; after the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with THF (100 mL); a total of 197.8 g of compound II in THF solution was obtained; the solution was concentrated to (2-3V, 10-15 mL) using a rotary evaporator; the system was replaced with ethanol (25 mL x 2) to (2-3V, 10-15 mL); an ethanol solution of compound II was obtained and used directly in the next reaction step.

[0311] MS-ESI and 1 The 1H NMR data is consistent with that of Example 12.

[0312] <Preparation of the compound of formula I>

[0313] [ka]

[0314] Preparation of the compound of formula I [Example 21: Preparation of the compound of formula I] Compound II (5 g, 1.0 equivalent), trimethyl orthoacetate (6.6 g, 3.0 equivalents), and THF (125 mL) were added to a 250 mL three-necked flask; the system was heated to reflux under nitrogen protection; pyridine hydrochloride (210 mg, 0.1 equivalent) was added to the three-necked flask; the system was heated to 75 ± 5 °C (internal temperature 60-63 °C) under nitrogen protection and reacted for 8 hours. HPLC monitoring showed that compound II was completely converted. The purity of compound I in the residual reaction solution was 93.1%.

[0315] The system was cooled to room temperature, and the reaction solution in the system was concentrated using a rotary evaporator until virtually no fractions leached out. Water (50 mL) was added to the system, and the pH of the system was adjusted to 9-10 using a 4 M sodium hydroxide solution. The system was extracted with ethyl acetate (50 mL), filtered, and the filtration cake was washed with ethyl acetate (10 mL) to obtain 3.5 g of the wet filtration cake product of the compound of formula I. LC-MS testing showed that the purity of the compound of formula I was 99.22%. The filtrate obtained by filtration and washing was separated, the aqueous phase was extracted with ethyl acetate (50 mL), the organic phase was combined, and the mixture was concentrated to dryness to obtain 2.8 g of the crude product of the compound of formula I. LC-MS testing showed that the purity of the compound of formula I was 95.08%.

[0316] MS-ESI:[M+1] + :297.0 1H NMR (400MHz, DMSO): 8.78 (s, 1H), 8.32 (d, 1H), 7.25 (d, 1H), 4.60 (m, 1H), 4.10~4.13 (t, 2H), 3.91 (m, 1H), 2.93~2. 98(m, 1H), 2.80~2.86(m, 1H), 2.84(s, 3H), 2.50(m, 1H), 2.16~2.19(m, 1H), 1.99~2.02(m, 1H), 1.69~1.77(m, 1H).

[0317] [Example 22: Preparation of the compound of formula I] Compound II (54 g, 1.0 equivalent), trimethyl orthoacetate (71.5 g, 3.0 equivalents), and THF (1.35 L) were added to a 3 L three-necked flask; the system was heated to reflux under nitrogen protection; pyridine hydrochloride (2.27 g, 0.1 equivalent) was added to the three-necked flask; the system was heated to 75 ± 5 °C (internal temperature 60-63 °C) under nitrogen protection and reacted for 8 hours. HPLC monitoring showed that 1.5% of compound II remained in the system; the system was cooled to room temperature and replenished with trimethyl orthoacetate (11.9 g, 0.5 equivalents) and pyridine hydrochloride (1.14 g, 0.05 equivalents); the system was heated to 75 ± 5 °C (internal temperature 60-63 °C) under nitrogen protection and reacted for 4 hours. HPLC monitoring showed that 0.4% of the compound of formula II remained in the system, and the purity of the compound of formula II in the reaction solution of the system was 91.6%.

[0318] The system was cooled to room temperature, and the reaction solution in the system was concentrated using a rotary evaporator until essentially no effluent fraction remained; water (540 mL, 10V) was added to the system, and the pH of the system was adjusted to 9-10 with 4M sodium hydroxide solution; the system was filtered, the filter cake was washed with water (270 mL), then with MTBE (270 mL), and the resulting filter cake was dried under vacuum at 50°C for 16 hours to obtain 56 g of the crude product of compound II, with an HPLC purity of 96.32%; the obtained crude product was dissolved in 600 mL of methanol until the solution was clear, and silicon-based metal remover (43 g) and activated carbon (5.4 g) were added to the system. The mixture was heated to reflux and maintained at a temperature of 50°C for 1 hour; the system was cooled to room temperature, filtered through diatomaceous earth, and washed with methanol (15 mL) until the filtrate no longer fluoresced; the methanol solution was concentrated to dryness to reduce the dropping rate of the distillate; MTBE (540 mL) was added to the obtained solid, the system was heated to 50°C and refluxed, and stirred for 1 hour until the solid was completely dissolved; the system was cooled to 10-15°C, stirred for 1 hour, filtered, and the filtered cake was washed with chilled MTBE (100 mL); the obtained filtered cake was dried under vacuum at 50°C for 16 hours to obtain 28.0 g of the compound of formula I, with an HPLC purity of 98.8%.

[0319] The compound of formula I was collected from the mother liquor; The filtrate obtained in the previous step was concentrated to dryness to obtain approximately 23 g of pale yellow solid; MTBE (230 mL) was added, the temperature was raised to 50°C, and the system was refluxed for 10 minutes; methanol was added in portions to the system until the total amount added was approximately 30 mL, the material was basically dissolved, and the solution became clear; the system was cooled to 10-15°C and stirred for 1 hour; the system was filtered, and the filtration cake was washed with chilled MTBE (50 mL); the filtration cake was dried under vacuum at 50°C for 16 hours to obtain 8.7 g of off-white solid compound I, and HPLC showed a purity of 97.8%.

[0320] Further purification: The compound of formula I (11.7 g) with a purity of 97.8% obtained in the previous step and MTBE (60 mL) were added to the reaction flask, the system was pulverized at room temperature for 4 hours, filtered, the filtered cake was washed with MTBE (20 mL), and the filtered cake was dried under vacuum at 50°C for 16 hours to obtain 10.8 g of off-white compound of formula I, with an HPLC purity of 98.1%.

[0321] MS-ESI of the product of the compound of formula I above and 1 The 1H NMR data is consistent with that of Example 21.

[0322] [Example 23: Preparation of the compound of formula I] Without being subjected to post-treatment, a THF solution of the compound of formula II prepared in Example 14 (45 g, containing approximately 1 g of the compound of formula II, 1 equivalent) was added to a flask, and the solution was concentrated to 3 mL using a rotary evaporator. Toluene (5 mL) was added to the flask, and then subjected to rotary evaporation to 3 mL. This process was repeated twice to obtain a black oily concentrated residue.

[0323] 1.0 g of the black oily concentrate obtained in the previous step, trimethyl orthoacetate (1.32 g, 3.0 equivalents), and THF (25 mL) were added to a 100 mL three-necked flask; under nitrogen protection, the system was heated to reflux; pyridine hydrochloride (0.08 g, 0.2 equivalents) was added to the three-necked flask; under nitrogen protection, the system was heated to 65-70°C (internal temperature) and reacted for 5 hours; a sample was taken and tested. HPLC monitoring showed that 0.48% of the compound of formula II remained in the reaction solution, and the purity of the compound of formula I was 90.10%; the system was refluxed and reacted for 5 hours, a sample was taken and tested. HPLC showed that the compound of formula II in the reaction solution was completely converted, and the purity of the compound of formula I was 91.79%.

[0324] [Example 24: Preparation of Compound I] Without being subjected to post-treatment, a THF solution of the compound of formula II prepared in Example 14 (450 g, containing approximately 10.0 g of the compound of formula II, 1 equivalent) was added to a flask, and the solution was concentrated to 20-30 mL using a rotary evaporator. Toluene (50 mL) was added to the flask, and the system was subjected to rotary evaporation to 20-30 mL. This process was repeated twice to obtain a black oily concentrated residue, which was then dissolved in THF (20 mL, 2V)I until the solution became clear.

[0325] The THF solution obtained in the previous step, trimethyl orthoacetate (13.2 g, 3.0 equivalents), and THF (230 mL) were added to a 500 mL three-necked flask; the system was heated to reflux under nitrogen protection; pyridine hydrochloride (0.8 g, 0.2 equivalents) was added to the three-necked flask; the system was heated to 65-70°C (internal temperature) under nitrogen protection and reacted for 10 hours; samples were taken and tested. HPLC monitoring showed that 0.7% of the compound of formula II remained in the reaction solution, and the purity of the compound of formula I was 90.1%.

[0326] The system was cooled to room temperature and water (20 mL, 2 V) was added; the system was concentrated using a rotary evaporator until essentially no fraction was leaching out; water (100 mL, 10 V) was added to the system; the pH of the system was adjusted to 9 using saturated potassium carbonate solution; the system was filtered and the filter cake was sequentially washed with water (50 mL, 5 V) and MTBE (50 mL, 5 V); the washed filter cake was dried under vacuum at 50°C for 16 hours to obtain 9.2 g of crude product of the compound of formula I, which was soil-yellow in color. The HPLC purity was 89.7% and the crude product yield was 84.5%.

[0327] Purification of the compound of formula I: The crude product of compound I of formula I with a purity of 89.7% obtained in the previous step (5.0 g) and ethanol (50 mL) were added to a flask, and the system was stirred at room temperature for 20 minutes until the material was basically dissolved and the solution was clear; silica gel (5.0 g, 1X) was added to the system, and the system was concentrated to dryness for later use by rotary evaporator; the solid crude product obtained by rotary evaporation was passed through a silica gel column (40 g, 8X), and the column was passed through a mixed solution of ethyl acetate and petroleum ether (V EA :V PE Elution was performed in a 2:1 ratio; the fraction containing the compound of formula I was recovered by TLC testing, concentrated to dryness, and yielded 0.5 g of the compound of formula I with a purity of 96.5% and 3.2 g of the pale yellow compound of formula I with an HPLC purity of 99.3%.

[0328] The compound of formula I with HPLC purity of 99.3% and MTBE (30 mL) were added to a flask, the system was heated to reflux, and the system was refluxed for 1 hour; the system was cooled to 5-10°C and stirred for 1 hour while maintaining the temperature; the system was filtered, the filter cake was washed with MTBE (5 mL), and the filter cake was dried under vacuum at 50°C for 16 hours to obtain 2.8 g of the compound of formula I, which was free of impurities, had an HPLC purity of 99.8%, and a content of >0.1%. The total yield of the second and third steps was 47.3%.

[0329] [Example 25: Preparation of the compound of formula I] Without being subjected to post-treatment, a THF solution of the compound of formula II prepared in Example 14 (130 g, containing approximately 56 g of the compound of formula II, 1 equivalent) was added to a flask, the solution was replaced with toluene (280 mL x 2), concentrated to 120-130 mL, then replaced with THF (280 mL), concentrated to 120-180 mL, and THF (500 mL) was added until the solid dissolved and the solution became clear. The resulting solution was transferred to a 2 L three-necked flask, and THF (700 mL) and trimethyl orthoacetate (74.0 g, 3.0 equivalents) were added to the system; under nitrogen protection, the system was heated to 70-75°C (internal temperature) and reacted for 10 hours; samples were taken and tested. HPLC monitoring showed that 0.1% of the compound of formula II remained in the reaction solution, and the purity of the compound of formula I was 93.2%.

[0330] The above reaction solution was cooled to room temperature, and a portion of the reaction solution (corresponding to the amount containing 55 g of compound II before the reaction) was taken and water (110 mL, 2 V) was added; it was concentrated to 110-160 mL (2-3 V) using a rotary evaporator; water (400 mL, 7 V) was slowly added to the concentrated residue; the system was stirred at room temperature for 30 minutes, then water (440 mL, 8 V) was added and stirred at room temperature (25-30°C) for 30 minutes; 50% carbonate The pH of the system was adjusted to 8-9 using a solution of lium (1.5 g (mass of total solution)); the system was stirred at room temperature (25-30°C) for 30 minutes; the temperature of the system was cooled to 10-15°C, the system was stirred at 10-15°C for 2 hours, and subjected to suction filtration. The filtration cake was dried at 50°C for 24 hours to obtain 55 g of the soil-yellow compound of formula I. The purity was 96.6%, the content was 87.53%, and the yield of the crude product was 80.4%.

[0331] Purification of the compound of formula I: Crude product of compound I of formula I with HPLC purity of 96.6% obtained in the previous step (55 g), silica gel (110 g, 2X), and ethanol (500 mL) were added to a flask; the system was heated to 50°C and stirred at 50°C for 30 minutes; the system was concentrated using a rotary evaporator until essentially no eluting fraction remained, then replaced with n-heptane (200 mL) and allowed to dry, the system and silica gel were mixed, and the system was eluted using a column packed with silica gel (550 g, 10X); the eluent was a mixed solution of ethyl acetate and n-heptane (V EA :V n-ヘプタン The ratio was set to 1:1 (pure EA); compound component A and cross-component B of formula I were recovered by TLC testing.

[0332] Component A was concentrated to approximately 100 mL using a rotary evaporator, the concentrated residue was replaced twice with approximately 200 mL of methanol, then replaced twice with MTBE (approximately 200 mL), and then approximately 300 mL of MTBE was added; the system was heated to reflux and refluxed for 1 hour, then the system was cooled to room temperature (25-30°C) and stirred at room temperature for 1 hour; the system was cooled to 5-10°C and stirred at 5-10°C for 2 hours, filtered, and the filtered cake was washed with MTBE (30 mL); the filtered cake was dried under vacuum at 50°C for 16 hours to obtain 37.6 g of a pale yellow solid of the compound of formula I, with an HPLC purity of 99.85% and no impurities of a content >0.1%.

[0333] Component B was concentrated to dryness using a rotary evaporator, ground with MTBE (50 mL) for 1 hour, cooled the system to 5-10°C, stirred at 5-10°C for 2 hours, filtered, and washed the filtered cake with MTBE (10 mL); the washed filtered cake was dried under vacuum at 50°C for 16 hours to obtain 6 g of a pale yellow solid of compound I, with an HPLC purity of 99.35% and containing two impurities with a content of >0.1%.

[0334] 4.8 g of the compound of formula I (99.35% purity), 50 mL of MTBE, and 5 mL of ethanol were added to a flask. The system was heated to 55-60°C and refluxed for 0.5 hours. The system was then cooled to room temperature (25-30°C) and stirred for 1 hour. The system was then cooled to 5-10°C, stirred for 2 hours, filtered, and the filtered cake was washed with 10 mL of MTBE. The washed filtered cake was dried under vacuum at 50-55°C for 16 hours to obtain 4.0 g of the compound of formula I, with a purity of 99.75% and no impurities exceeding 0.1%.

[0335] [Example 26: Preparation of the compound of formula I] The THF solution of the compound of formula II prepared in Example 14 (14.5 g, containing approximately 5.0 g of the compound of formula II, 1 equivalent), which was not subjected to post-treatment, was added to a flask. The solution was replaced with toluene (25 mL x 2), concentrated to approximately 10-15 mL, then replaced with THF (25 mL), concentrated to approximately 10-15 mL, and then THF (115 mL) was added until the solid dissolved and the solution became clear. The resulting solution was transferred to a 500 L three-necked flask; trimethyl orthoacetate (6.6 g, 3.0 equivalents) was added to the system; the system was heated under nitrogen protection until reflux was achieved; pyridine hydrochloride (0.42 g, 0.2 equivalents) was added to the three-necked flask; the system was heated to 70-75°C (internal temperature) under nitrogen protection and reacted for 15 hours; samples were taken and tested. HPLC showed that 4.0% of the compound of formula II remained in the reaction mixture; the system was supplemented with trimethyl orthoacetate (0.5 g) and pyridine hydrochloride (0.1 g), and refluxed at 70-75°C (internal temperature) for 5 hours; samples were taken and tested. HPLC showed that 0.05% of the compound of formula II remained in the reaction mixture, and the purity of the compound of formula I was 92.80%.

[0336] [Example 27: Preparation of Compound I] Without post-treatment, a THF solution of the compound of formula II prepared in Example 14 (817 g, containing approximately 282.6 g of the compound of formula II, 1 equivalent) was added to a flask, the solution was replaced with toluene (approximately 1400 mL x 2) and concentrated to approximately 550-850 mL, then replaced with THF (approximately 1400 mL x 2) and concentrated to approximately 550-850 mL, and THF (approximately 6500 mL) was added until the solid dissolved and the solution became clear, and the solution was transferred to a 10 L three-necked flask; trimethyl orthoacetate (374.0 g, 3.0 equivalents) was added to the system; the system was heated to reflux under nitrogen protection; pyridine hydrochloride (24.0 g, 0.2 equivalents) was added to the three-necked flask; the system was heated to 70-75°C (internal temperature) under nitrogen protection and reacted for 12 hours; samples were taken and tested. HPLC showed that 4.1% of compound II remained in the reaction solution; the purity of compound I was 85.5%; trimethyl orthoacetate (22 g) and pyridine hydrochloride (1.4 g) were added to the reaction system; under nitrogen protection, the system was heated to 70-75°C (internal temperature) and reacted for 5 hours; samples were taken and tested. HPLC showed that 0.7% of compound II remained in the reaction solution, and the purity of compound I was 91.4%.

[0337] The reaction mixture obtained in the previous step was cooled to room temperature, 570g of water was added, and the system was concentrated to 600-900mL (2-3V) using a rotary evaporator. The concentrated residue was transferred to a 10L flask, 2000g of water (approximately 7V) was slowly added, and the system was stirred at room temperature for 1 hour. Then, 2300g of water (approximately 8V) was added, and the system was stirred at room temperature (25-30°C) for 1 hour. The pH of the system was adjusted to 8-9 using 50% potassium carbonate solution (8.5g). The system was stirred at room temperature (25-30°C) for 1 hour, the system was cooled to 10-15°C, stirred at 10-15°C for 2 hours, filtered, and the filtered cake was washed with water (500g). The washed filtered cake was dried at 50°C for 72 hours, a sample was taken, and the water content was tested. The water content tested by the Karl Fischer method was 3.2%. A crude product of the soil-yellow compound of formula I was obtained, with an HPLC purity of 97.5%, a content of 89.8%, and a crude product yield of 72.3%.

[0338] Purification of the compound of formula I: 252 g of the crude product of compound I obtained in the previous step and ethanol (1004 g, approximately 1000 mL) were added to a flask; the system was heated to 50-60°C and stirred for 30 minutes at 50-60°C until the material was basically dissolved and the solution was clear; the system was divided into two equal parts, silica gel (252 g) was added to each part, and each part was concentrated using a rotary evaporator until there was basically no leaching fraction left; for later use, each part was replaced with n-heptane (272 g, approximately 400 mL) until there was basically no leaching fraction left; A silica gel column was compressed and packed with silica gel (3000 g, 200-300 mesh) and n-heptane (5.4 kg, approximately 8 L). The crude product obtained in the previous step was separated by column chromatography and eluted with a mixture of n-heptane and ethyl acetate (1:1 V / V, 15.5 kg, approximately 20 L; 1:2 V / V, 28.5 kg, approximately 35 L; 1:5 V / V, 25.5 kg, approximately 25 L) and pure ethyl acetate (62 kg, 70 L). Component A and cross-component B of the compound of formula I were recovered by TLC testing.

[0339] Component A was concentrated using a rotary evaporator until no more fractions leached out; the concentrated residue was transferred to a 2000 mL flask and replaced with MTBE (370 g, approximately 500 mL) until no more fractions leached out; MTBE (1330 g, approximately 1800 mL) was added to the concentrated residue; the system was heated to reflux and refluxed for 1 hour; the system was cooled to room temperature (25-30°C) and stirred at room temperature (1 hour); cooled to 5-10°C and stirred at 5-10°C for 2 hours; filtered, and the filtered cake was washed with MTBE (75 g, approximately 100 mL); the HPLC purity of the washed filtered cake was 99.9%; the filtered cake was dried under vacuum at 50°C for 16 hours to obtain 190 g of compound I, which had an HPLC purity of 99.9% and a water content of 0.07% according to the KF test.

[0340] Component B was concentrated to dryness using a rotary evaporator; the resulting solid was transferred to a 500 mL necked flask; the mixture was replaced with MTBE (85 g, approximately 120 mL) until the fraction essentially stopped flowing out; MTBE (200 g, approximately 300 mL) and methanol (23 g, approximately 30 mL) were added to the concentrated residue; the system was heated to reflux and refluxed for 1 hour; the system was cooled to room temperature (25-30°C) and stirred at room temperature (1 hour); cooled to 5-10°C and stirred at 5-10°C for 1 hour; filtered, and the filtered cake was washed with MTBE (22 g, approximately 30 mL); the washed filtered cake was tested under vacuum at 50°C for 16 hours to obtain 20 g of a pale yellow solid of compound I, with an HPLC purity of 99.6%.

[0341] [Example 28: Preparation of the compound of formula I] A THF solution of the compound of formula II prepared in Example 19 (27.0 g, containing approximately 5.0 g of the compound of formula II, 1 equivalent) was added to a flask, the solution was replaced with toluene (25 mL x 2) and concentrated to approximately 10-15 mL; then replaced with THF (25 mL) and concentrated to approximately 10-15 mL; THF (115 mL) was added until the solid dissolved and the solution became clear, and the solution was transferred to a 500 mL three-necked flask; trimethyl orthoacetate (6.6 g, 3.0 equivalents) was added to the system; the system was heated to reflux under nitrogen protection; pyridine hydrochloride (0.42 g, 0.2 equivalents) was added to the three-necked flask; the system was heated to 70-75°C (internal temperature) under nitrogen protection and reacted for 12 hours; samples were taken and tested. HPLC showed that 0.19% of compound II remained in the reaction solution, and the purity of compound I was 93.3%.

[0342] [Example 29: Preparation of Compound I] A THF solution of the compound of formula II prepared in Example 19 (5.40 g, containing approximately 1.0 g of the compound of formula II, 1 equivalent) was transferred to a flask, the solution was replaced with toluene (4.3 kg x 2) and concentrated to approximately 2 L, then replaced with THF (4.3 kg) and concentrated to approximately 2 L, THF (19 kg) was added, and the system was transferred to a 50 L reactor; trimethyl orthoacetate (1.32 kg, 3.0 equivalents) was added to the system; the system was heated to reflux under nitrogen protection; pyridine hydrochloride (85.0 g, 0.2 equivalents) was added to a three-necked flask; the system was heated to 70-75°C (internal temperature) under nitrogen protection and reacted for 12 hours; samples were taken and tested. HPLC showed that 4.22% of compound II remained in the reaction solution; the purity of compound I was 80.30%. Trimethyl orthoacetate (80g) and pyridine hydrochloride (5g) were added to the reaction system, and under nitrogen protection, the system was heated to 70-75°C (internal temperature) and reacted for 5 hours. Samples were taken and tested. HPLC showed that 0.56% of compound II remained in the reaction solution, and the purity of compound I was 92.48%.

[0343] The reaction mixture from the previous step was cooled to 25°C and 2.0 kg of water was added; distillation was carried out under reduced pressure at 45±5°C to a volume of approximately 2 L, and 2 L of water was added to a rotary evaporation flask. The material solution in the flask was transferred to the reactor, 5 kg of water was slowly added, and the mixture was stirred at 25°C for 1 hour; 5 kg of water was added to the reactor and the mixture was stirred at 25°C for 1 hour; 32 g of 50% potassium carbonate solution was added dropwise to the reactor to adjust the pH of the system to 8-9, and the system was stirred at 25°C for 1 hour; the material solution in the reactor was cooled to 10-15°C and stirred for 2 hours; the system was filtered, the filtered cake was washed with 2 kg of water, and then dried under vacuum at 45-55°C for 48 hours to obtain 0.91 kg of compound I. The water content tested by the KF method was 0.2%, the HPLC purity was 95.71%, the water content was 85.39%, and the yield was 71.4%.

[0344] Purification of the compound of formula I: The compound of formula I (0.91 kg) with an HPLC purity of 95.71% obtained in the previous step and ethanol (3.6 kg) were added to a 20 L rotary evaporation flask; the system was heated to 50-60°C and stirred at 50-60°C for 30 minutes to dissolve the material, and the solution was basically clear; silica gel (1.82 kg) was added to the rotary evaporation flask, and the system was concentrated under reduced pressure at 50-60°C to obtain a dry powder; n-heptane (1.82 kg) was added to the above The compound was added to a rotary evaporation flask, the system was concentrated and replaced at 40-50°C, and dried into a powder; an appropriate washing column was prepared, silica gel (11 kg, 200-300 mesh) was added to the column, and the column was compressed with nitrogen; n-heptane (27 kg) was added to the column, and the column was compressed with nitrogen; the silica gel-like compound of formula I concentrated to dryness in the previous step was added to the column, and the column was compressed with n-heptane (18 kg), n-heptane / ethyl acetate mixture (1:1 V / V, 72 kg; 1:2 V / V, 158 kg; 1:5 The compound was sequentially eluted with V / V (142 kg), a mixture of n-heptane / ethyl acetate (1:5 V / V, 70 kg), a mixture of n-heptane / ethyl acetate (1:5 V / V, 175 kg), and ethyl acetate (205 kg), and a TLC test was performed to recover component A and cross-component B of the compound of formula I.

[0345] Component A was added to a 50 L reactor, and the system was concentrated under vacuum at 40-50°C to a minimum stirring volume (approximately 6 L); MTBE (5.0 kg × 5) was added to the reactor, the system was concentrated, and the system was substituted 5 times; MTBE (1.2 kg) was added to the reactor, the system was heated to reflux (50-60°C), and the system was refluxed for 1 hour while maintaining the temperature; the system was cooled to 20-30°C and stirred while maintaining the temperature (1 hour); the system was cooled to 5-10°C and stirred at 5-10°C for 2 hours; the system was filtered, and the filtered cake was washed with MTBE (0.25 kg); 0.62 kg of compound I was obtained, and the HPLC purity was 100.0%; the filtered cake was dried at 50°C for 16 hours to obtain 0.55 kg of compound I, and the water content tested by the KF method was 0.04%, and the Pd residue was <2 ppm.

[0346] Component B was added to the reaction flask, and the system was concentrated under vacuum in a water bath at 45-50°C to the minimum stirring volume (approximately 1 L); MTBE (1.5 kg x 2) was added to the reaction flask, the system was heated in a water bath at 45-50°C, distilled under vacuum to the minimum stirring volume, and substituted twice; MTBE (1.5 kg) and anhydrous ethanol (0.14 kg) were added to the reaction flask, the system was heated to 50-60°C, and stirred for 1 hour; the material solution in the reaction flask was cooled to 20-25°C, and the system was stirred for 1 hour while maintaining the temperature; the system was cooled, the temperature of the material solution in the reaction flask was lowered to 6-10°C, and the system was stirred for 2 hours while maintaining the temperature; the system was filtered, and the filtered cake was washed with MTBE (0.24 kg); the filtered cake and MTBE (1.5 kg) / anhydrous ethanol (0.14 kg) were added to the reaction flask; The system was stirred and heated to 50-60°C, and stirred for 1 hour while maintaining the temperature; cooled, the temperature of the material solution in the reaction flask was lowered to 20-25°C, and the system was stirred for 1 hour while maintaining the temperature; cooled, the temperature of the material solution in the reaction flask was lowered to 6-10°C, and the system was stirred for 2 hours while maintaining the temperature; filtered, and the filtered cake was washed with MTBE (0.24 kg); 115 g of wet product was obtained, with an HPLC purity of 99.8% and a maximum individual impurity content of 0.09%; the wet product was dried at 45-55°C for 16 hours under a vacuum of ≤-0.080 MPa; 0.10 kg of compound I was obtained, with a water content of 0.08% as tested by the KF method, an HPLC purity of 99.8%, a maximum individual impurity content of 0.09%, and a Pd residue of 2 ppm or less.

[0347] Unless otherwise specified, the compound of formula I that has been ultimately purified and prepared in Example 27 will be used as the starting material in the following examples.

[0348] <Preparation of crystalline form 1 of compound I> [Example 30] The wet and crude products of the filtration cake of the compound of formula I obtained in Example 21 were combined and dissolved in methanol (40 mL); silicon-based metal remover (4.0 g) and activated carbon (1.0 g) were added to the methanol solution, and the system was heated to 50°C and stirred for 1 hour; the system was cooled to 10 ± 5°C and stirred at that temperature for 0.5 hours. The mixture was filtered, and the filtration cake was washed with MTBE (15 mL); the filtration cake was dried under vacuum at 50°C for 16 hours to obtain 2.5 g of an off-white solid of the compound of formula I, with an HPLC purity of 98.4%. Testing revealed that the solid was crystalline form 1 of the compound of formula I. See Figures 1-4 for XRPD patterns, DSC thermograms, TGA thermograms, and DVS isotherm plots.

[0349] <Preparation of crystalline form A of the hydrochloride salt of compound I> [Example 31] Approximately 50 mg of compound I was weighed and placed in a small bottle. 2.5 mL of acetone was added, and the system was subjected to sonication and heating until the compound was completely dissolved, preparing a 20 mg / mL acetone solution of compound I. The sample bottle was placed on a magnetic stirring plate and magnetic stirring was performed. 0.73 mL of acetone solution of hydrochloric acid (the concentration of the acetone solution of hydrochloric acid was 25 mg / mL) was slowly added dropwise to form a white precipitate. The bottle cap was tightly covered at room temperature, and the system was stirred for 1 day. The suspension was then centrifuged, and the recovered solid was dried overnight under vacuum at 40°C to obtain the hydrochloride solid of compound I. Testing revealed that the solid was crystalline form A of the hydrochloride salt of compound I. See Figures 6 and 7 for the XRPD pattern and DSC thermogram.

[0350] <Preparation of crystalline form B of the hydrochloride salt of compound I> [Example 32] Approximately 50 mg of compound I was weighed and placed in a small bottle. 2.5 mL of ethyl acetate was added, and the system was subjected to sonication and heating until the compound was completely dissolved, preparing an ethyl acetate solution of compound I at a concentration of 20 mg / mL in ethyl acetate. The sample bottle was placed on a magnetic stirring plate and magnetically stirred. 0.73 mL of ethyl acetate solution of hydrochloric acid (the concentration of the ethyl acetate solution of hydrochloric acid was 25 mg / mL) was slowly added dropwise to form a white precipitate. The bottle cap was tightly covered at room temperature, and the system was stirred for 1 day. The suspension was then centrifuged, and the recovered solid was dried overnight under vacuum at 40°C to obtain the hydrochloride solid of compound I. Testing revealed that the solid was crystalline form B of the hydrochloride salt of compound I. See Figures 8 and 9 for the XRPD pattern and DSC thermogram.

[0351] <Preparation of crystalline form C of the hydrochloride salt of compound I> [Example 33] 5 mg of crystalline form A of the hydrochloride salt of compound I prepared in Example 31 was weighed, placed in a small bottle, an appropriate amount of methanol was added, and the resulting sample suspension was magnetically stirred overnight at room temperature. The system was then centrifuged to separate the solid from the liquid, and the solid was collected. It was dried overnight under vacuum at 40°C to obtain the hydrochloride salt solid of compound I. Testing revealed that the solid was crystalline form C of the hydrochloride salt of compound I. See Figures 10 and 11 for the XRPD pattern and DSC thermogram.

[0352] [Examples 34-36] The same crystallization method as in Example 33 was employed. The solvents were changed to acetonitrile, n-heptane, and methyl ethyl ketone, and crystalline form C of the hydrochloride salt of the compound of formula I was prepared. When tested, it was found to be the same as in Example 33. 34~36 The XRPD patterns of the solid compounds prepared using this method were consistent with those shown in Figure 10.

[0353] <Preparation of crystalline form D of the sulfate of compound I> [Example 37] Approximately 50 mg of compound I was weighed and placed in a small bottle. 2.5 mL of acetone was added, and the system was subjected to sonication and heating until the compound was completely dissolved, preparing a 20 mg / mL acetone solution of compound I. The sample bottle was placed on a magnetic stirring plate and magnetically stirred with 0.77 mL of sulfuric acid-acetone solution (the concentration of the sulfuric acid-acetone solution was 25 mg / mL). A white precipitate was formed, the bottle cap was tightly covered at room temperature, and the system was stirred for 1 day. The suspension was then centrifuged, and the recovered solid was dried overnight under vacuum at 40°C to obtain the sulfate solid of compound I. Testing revealed that the solid was crystalline form D of the sulfate of compound I. See Figures 12 and 13 for the XRPD pattern and DSC thermogram.

[0354] <Preparation of crystalline form E of the phosphate of the compound of formula I> [Example 38] Approximately 50 mg of compound I was weighed and placed in a small bottle. 2.5 mL of acetone was added, and the system was subjected to sonication and heating until the compound was completely dissolved, preparing a 20 mg / mL acetone solution of compound I. The sample bottle was placed on a magnetic stirring plate and magnetically stirred. 0.86 mL of acetone solution of phosphoric acid (the concentration of the acetone solution of phosphoric acid was 25 mg / mL) was slowly added dropwise to form a white precipitate. The bottle cap was tightly covered at room temperature, and the system was stirred for 1 day. The suspension was then centrifuged, and the recovered solid was dried overnight under vacuum at 40°C to obtain the phosphate solid of compound I. Testing revealed that the solid was crystalline form E of the phosphate of compound I. See Figures 14 and 15 for the XRPD pattern and DSC thermogram.

[0355] The salt formation ratio of crystalline form E of the phosphate of compound I was tested using ion chromatography: Approximately 0.5 g of crystalline form E of the phosphate of compound I was weighed, placed in a small liquid-phase bottle, completely dissolved in 1 mL of water, and then used as the sample solution. Bulk phosphoric acid standard solution (1000 ppm) was diluted 10-fold and 20-fold with water to obtain 100 ppm and 50 ppm standard sample solutions, respectively.

[0356] Ion chromatography tests were performed on both the sample solution and the standard solution (see Table 16 for the test methods). The standard curve was plotted using the peak area of ​​the counterion on the ion chromatogram corresponding to the concentration of the counterion in the standard sample solution. The concentration of the counterion in each sample was calculated using the external standard method, and the counterion content in the crystalline form E of the phosphate of the compound of formula I was calculated to determine the salt formation ratio of the compound of formula I and the corresponding counterion in the crystalline form E of the phosphate of the compound of formula I.

[0357] [Table 18]

[0358] For the counterion content of the phosphate of compound I in crystalline form E, please refer to Table 17. 0.5 g of crystalline form E of the phosphate of compound I was reacted with compound I and phosphoric acid in a molar ratio of 1:1.1. The measured content of phosphate anions in the resulting phosphate was 25.6%, which was in essentially agreement with the theoretical content of 24.9%. The salt-forming molar ratio was 1:1.04 (compound I:phosphoric acid).

[0359] [Table 19]

[0360] [Example 39] 5 mg of crystalline form E of the phosphate of compound I, prepared in Example 38, was weighed and placed in a small bottle. An appropriate amount of methanol was added, and the sample suspension was magnetically stirred overnight at room temperature. The system was then centrifuged to separate the solid from the liquid, and the solid was collected. It was dried overnight under vacuum at 40°C to obtain the phosphate solid of compound I. Testing confirmed that the solid was crystalline form E of the phosphate of compound I. Its XRPD pattern matched that of Figure 14.

[0361] [Examples 40-42] The same method as in Example 39 was employed. The solvents were changed to acetonitrile, n-heptane, and methyl ethyl ketone to prepare crystalline form E of the phosphate of the compound of formula I. Tests revealed that the XRPD patterns of the solid compounds prepared in Examples 40-42 were consistent with those in Figure 14.

[0362] <Preparation of crystalline form F of the compound phosphate of formula I> [Example 43] Approximately 500 mg of compound I was weighed and placed in a small bottle. 20 mL of acetone was added, and the system was subjected to sonication and heating until the sample was completely dissolved, yielding a 25 mg / mL acetone solution of compound I. The sample bottle was placed on a magnetic stirring plate, and magnetic stirring was performed. 8.57 mL of acetone solution of phosphoric acid (the concentration of the acetone solution of phosphoric acid was 25 mg / mL) was slowly added dropwise over the night. The suspension was filtered by suction, and the solid was dried under vacuum at 50°C. The solid was collected and placed in a 100 mL glass bottle. Methanol was slowly added dropwise until the solution became clear, and magnetic stirring was performed at room temperature. The solution was then diluted 10-fold with the poor solvent isopropyl acetate. The system was stirred overnight, the suspension was filtered, and the solid was dried under vacuum at 50°C. The solid was collected to obtain the phosphate solid of compound I. Testing revealed that the solid was crystalline form F of the phosphate of compound I. For XRPD patterns, DSC thermograms, DVS isotherm plots, and XRPD patterns after DVS testing, please refer to Figures 16-19.

[0363] <Preparation of crystalline form G of the mesylate salt of compound I> [Example 44] Approximately 50 mg of compound I was weighed and placed in a small bottle. 2.5 mL of acetone was added, and the system was subjected to sonication and heating until the compound was completely dissolved, preparing a 20 mg / mL acetone solution of compound I. The sample bottle was placed on a magnetic stirring plate and magnetically stirred. 0.73 mL of acetone solution of methanesulfonic acid (the concentration of the acetone solution of methanesulfonic acid was 25 mg / mL) was slowly added dropwise to form a white precipitate. The bottle cap was tightly covered at room temperature, and the system was stirred for 1 day. The suspension was centrifuged, and the recovered solid was dried overnight under vacuum at 40°C to obtain the mesylate solid of compound I. Testing revealed that the solid was crystalline form G of the mesylate of compound I. See Figures 20, 21, and 22 for XRPD patterns, DSC thermograms, and DVS isotherm plots.

[0364] <Preparation of crystalline form H of the hydrobromide compound of formula I> [Example 45] Approximately 50 mg of compound I was weighed and placed in a small bottle. 2.5 mL of acetone was added, and the system was subjected to sonication and heating until the compound was completely dissolved, preparing a 20 mg / mL acetone solution of compound I. The sample bottle was placed on a magnetic stirring plate and magnetically stirred. 1.32 mL of acetone solution of hydrobromide (the concentration of the acetone solution of hydrobromide was 25 mg / mL) was slowly added dropwise to form a white precipitate. The bottle cap was tightly covered at room temperature, and the system was stirred for 1 day. The suspension was centrifuged, and the recovered solid was dried overnight under vacuum at 40°C to obtain the hydrobromide salt solid of compound I. Testing confirmed that the solid was the crystalline form H of hydrobromide salt of compound I. See Figures 23 and 24 for the XRPD pattern and DSC isotherm plot.

[0365] [Example 46] 5 mg of the hydrobromide crystalline form H of the compound of formula I, prepared in Example 46, was weighed and placed in a small bottle. An appropriate amount of acetonitrile was added, and the sample suspension was magnetically stirred overnight at room temperature. The system was then centrifuged to separate the solid from the liquid, and the solid was collected. It was dried overnight under vacuum at 40°C to obtain the hydrobromide solid of the compound of formula I. Testing confirmed that the solid was still the hydrobromide crystalline form H of the compound of formula I. Its XRPD pattern was consistent with that shown in Figure 23.

[0366] [Example 47] The same method as in Example 46 was employed. The solvent was changed to methyl ethyl ketone to prepare crystalline form H of the hydrobromide salt of the compound of formula I. When tested, Example 47 The XRPD patterns of the solid compounds prepared using this method are consistent with those shown in Figure 23.

[0367] <Preparation of crystalline form J of the hydrobromide salt of compound I> [Example 48] Approximately 50 mg of compound I was weighed and placed in a small bottle. 2.5 mL of ethyl acetate was added, and the system was subjected to sonication and heating until the compound was completely dissolved, preparing a 20 mg / mL ethyl acetate solution of compound I. The sample bottle was placed on a magnetic stirring plate and magnetic stirring was performed. 1.32 mL of ethyl acetate solution of hydrobromide (the concentration of the ethyl acetate solution of hydrobromide was 25 mg / mL) was slowly added dropwise to form a white precipitate. The bottle cap was tightly covered at room temperature, and the system was stirred for 1 day. The suspension was centrifuged, and the recovered solid was dried overnight under vacuum at 40°C to obtain the hydrobromide salt solid of compound I. Testing revealed that the solid was crystalline form J of the hydrobromide salt of compound I. See Figure 25 for the XRPD pattern.

[0368] <Preparation of the crystalline form K of the hydrobromide salt of the compound of formula I> [Example 49] 5 mg of crystalline form H of the hydrobromide salt of compound I of formula I, prepared in Example 46, was weighed and placed in a small bottle. An appropriate amount of n-heptane was added, and the sample suspension was magnetically stirred overnight at room temperature. The system was then centrifuged to separate the solid from the liquid, and the solid was collected. It was dried overnight under vacuum at 40°C to obtain the hydrobromide salt solid of compound I of formula I. Testing revealed that the solid was crystalline form K of the hydrobromide salt of compound I of formula I. See Figures 26-29 for the XRPD pattern, DSC thermogram, DVS isotherm plot, and XRPD pattern after DVS testing.

[0369] <Preparation of crystalline form L of the fumarate of the compound of formula I> [Example 50] Approximately 50 mg of compound I was weighed and placed in a small bottle. 2.5 mL of ethyl acetate was added, and the system was subjected to sonication and heating until the compound was completely dissolved, preparing a 20 mg / mL ethyl acetate solution of compound I. The sample bottle was placed on a magnetic stirring plate and magnetically stirred. 0.87 mL of ethanol solution of fumaric acid (concentration of ethanol solution of fumaric acid was 25 mg / mL) was slowly added dropwise to form a white precipitate. The bottle cap was tightly covered at room temperature, and the system was stirred for 1 day. The suspension was centrifuged, and the recovered solid was dried overnight under vacuum at 40°C to obtain the fumarate solid of compound I. Testing confirmed that the solid was crystalline form L of the fumarate of compound I. See Figures 30 and 31 for the XRPD pattern and DSC thermogram.

[0370] [Example 51] The same crystallization method as in Example 50 was employed. Ethyl acetate was replaced with acetone to prepare crystalline form L of the fumarate. Tests showed that the XRPD pattern of the solid compound prepared in Example 51 matched that of Figure 30.

[0371] <Preparation of crystalline form M of benzenesulfonate of compound I> [Example 52] Approximately 50 mg of compound I was weighed and placed in a small bottle. 2.5 mL of acetone was added, and the system was subjected to sonication and heating until the compound was completely dissolved, preparing a 20 mg / mL acetone solution of compound I. The sample bottle was placed on a magnetic stirring plate and magnetically stirred. 1.34 mL of acetone solution of benzenesulfonic acid (the concentration of the acetone solution of benzenesulfonic acid was 25 mg / mL) was slowly added dropwise to form a white precipitate. The bottle cap was tightly covered at room temperature, and the system was stirred for 1 day. The suspension was centrifuged, and the recovered solid was dried overnight under vacuum at 40°C to obtain the benzenesulfonate solid of compound I. Testing revealed that the solid was crystalline form M of the benzenesulfonate of compound I. See Figures 32-35 for the XRPD pattern, DSC thermogram, DVS isotherm plot, and XRPD pattern after DVS testing.

[0372] <Preparation of crystalline form N of the citrate of compound I> [Example 53] Approximately 50 mg of compound I was weighed and placed in a small bottle. 2.5 mL of ethyl acetate was added, and the system was subjected to sonication and heating until the compound was completely dissolved, preparing a 20 mg / mL ethyl acetate solution of compound I. The sample bottle was placed on a magnetic stirring plate and magnetic stirring was performed. 1.58 mL of ethyl acetate solution of citrate (the concentration of the ethyl acetate solution of citrate was 25 mg / mL) was slowly added dropwise to form a white precipitate. The bottle cap was tightly covered at room temperature, and the system was stirred for 1 day. The suspension was centrifuged, and the recovered solid was dried overnight under vacuum at 40°C to obtain the citrate solid of compound I. Testing revealed that the solid was crystalline form N of the citrate of compound I. See Figures 36 and 37 for the XRPD pattern and DSC thermogram.

[0373] <Preparation of crystalline form O of the tartrate salt of the compound of formula I> [Example 54] Approximately 50 mg of compound I was weighed and placed in a small bottle. 2.5 mL of ethyl acetate was added, and the system was subjected to sonication and heating until the compound was completely dissolved, preparing a 20 mg / mL ethyl acetate solution of compound I. The sample bottle was placed on a magnetic stirring plate and magnetically stirred. 1.12 mL of ethyl acetate solution of L-(+)-tartaric acid (the concentration of the ethyl acetate solution of L-(+)-tartaric acid was 25 mg / mL) was slowly added dropwise to form a white precipitate. The bottle cap was tightly covered at room temperature, and the system was stirred for 1 day. The suspension was centrifuged, and the recovered solid was dried overnight under vacuum at 40°C to obtain the L-(+)-tartrate solid of compound I. Testing revealed that the solid was crystalline form O of the tartrate salt of compound I. See Figures 38-42 for XRPD patterns, DSC thermograms, TGA thermograms, DVS isotherm plots, and XRPD patterns after DVS testing.

[0374] The salt formation ratio test for crystalline form O of the tartrate salt of compound I was performed. 1 This was performed using 1H NMR spectroscopy: Approximately 5 mg of compound I and crystalline form O of the tartrate salt of compound I were weighed and placed in magnetic tubes. Each sample was dissolved in 0.6 mL of DMSO d6 until the solution became clear. Each sample solution was then scanned using a Bruker AVANCE 400 MHz nuclear magnetic resonance spectrometer in a standard manner. 1 H-NMR data was collected.

[0375] The NMR spectrum is of the crystalline form O of the compound tartrate of formula I. 1 The 1H NMR spectrum showed that the compound in formula I contains one more hydrogen atom than the compound in formula I. This is because tartaric acid is a diacid. The molar ratio of the free base to tartaric acid for salt formation can be understood to be 2:1. For specific information, please refer to Figures 43 and 44.

[0376] The salt formation ratio of crystalline form O of the tartrate salt of the compound of formula I was tested using chemical titration: A non-aqueous titrator was used, and the sample was titrated with methanolic potassium hydroxide (VS). The tartaric acid content in the sample was calculated using a formula based on the titrant concentration and the amount of titrant consumed.

[0377] [Table 20]

[0378] [Table 21]

[0379] 80 mL of methanol solution was taken, placed in a titration cup, and titrated in 3 replicates according to the blank titration conditions. 160 mg of potassium acid phthalate standard, dried to a constant weight at 105°C, was accurately weighed, 50 mL of methanol solution was added, the system was sonicated to dissolve, and then transferred to a titration cup. Titration was performed in 3 replicates according to the sample titration conditions. 100 mg of crystalline form O of the tartrate of compound I was accurately weighed, 80 mL of methanol solution was added, the system was sonicated to dissolve, and then transferred to a titration cup. Titration was performed in 3 replicates according to the sample titration conditions.

[0380] The titer (T) of the titrant was calculated according to the following formula:

[0381]

number

[0382] W: Weighing amount of potassium bituminate standard (g) V: Amount of methanolic potassium hydroxide (VS) consumed in the titration of the acidic potassium phthalate standard solution (mL) V0: Amount of methanolic potassium hydroxide (VS) consumed (mL) used in titrating the blank solution. M: Molecular weight of potassium bitarate standard The tartaric acid content in the sample was calculated according to the following formula:

[0383]

number

[0384] T: Titer (mol / L) of calibrated methanolic potassium hydroxide VS V: Amount of methanolic potassium hydroxide (VS) consumed for titration of the sample solution (mL) V0: Amount of methanolic potassium hydroxide (VS) consumed (mL) used in titrating the blank solution. M: Molecular weight of tartaric acid W: Sample weight (g) The final titration results showed that the tartaric acid content in crystalline form O of the tartrate salts of the compound of formula I was 19.2 w / w% and 21.1 w / w%, respectively, which is consistent with the theoretical value of 20.2 w / w% when the molar ratio of free base to tartaric acid is 2:1.

[0385] [Example 55] Approximately 500 mg of the compound of formula I was weighed, placed in a small bottle, and 20 mL of acetone was added. The system was subjected to sonication and heating until the compound was completely dissolved, and a 25 mg / mL acetone solution of the compound of formula I was prepared. The sample bottle was placed on a magnetic stirring plate and magnetic stirring was performed. 11.2 mL of acetone solution of L-(+)-tartaric acid (the concentration of the acetone solution of L-(+)-tartaric acid was 25 mg / mL) was slowly added dropwise, the system was stirred overnight, filtered, and the solid was dried under vacuum at 50°C to obtain the L-(+)-tartrate solid of the compound of formula I. Testing revealed that the solid was crystalline form O of the tartrate of the compound of formula I. Its XRPD pattern matches that shown in Figure 38.

[0386] [Example 56] 2.0 g of compound I (HPLC purity 99.9%), prepared by the purification of component A in Example 27, and 40 mL of acetone (20V) were added to flask 1, and the system was stirred until the solution became clear to dissolve the compounds; 0.61 g of L-(+)-tartaric acid and 40 mL of acetone (20V) were added to flask 2, and the system was stirred until the solution became clear to dissolve the compounds; the solution in flask 2 was added to flask 1 within 2-3 minutes; the temperature of the system was raised to 50-60°C and the system was stirred for 2 hours; the system was cooled to room temperature; the system was concentrated to approximately 40 mL; the system was stirred at room temperature (25-30°C) for 1 hour; the system was cooled to 5-10°C and stirred for 1 hour at 5-10°C; the system was filtered, and the filter cake was dried using a blower at 50-55°C for 16 hours to obtain 2.4 g of product, with an HPLC purity of 99.6% and a yield of 95.6%. Tests revealed that the solid was crystalline form O of the tartrate salt of the compound of formula I. Its XRPD pattern matches that shown in Figure 38.

[0387] [Example 57] 2.0 g of compound I (HPLC purity 99.9%), prepared by the purification of component A in Example 27, and 40 mL of acetone (20V) were added to flask #1, and the temperature was raised to 50-55°C. The system was stirred until the solution became clear to dissolve the compound; 0.61 g of L-(+)-tartaric acid and 40 mL of acetone (20V) were added to flask #2, and the temperature was raised to 50-55°C. The system was stirred until the solution became clear; The solution in flask #2 was added to flask #1 within 2-3 minutes; the system was stirred at 45-50°C for 2 hours; the system was concentrated to approximately 40 mL under vacuum at 45-50°C; cooled to 20-25°C and stirred for 1 hour; cooled to 5-10°C and stirred at 5-10°C for 1 hour; filtered, and the filter cake was dried using a blower at 50-55°C for 16 hours to obtain 2.4 g of product, with an HPLC purity of 99.8% and a yield of 95.62%. Testing revealed that the solid was crystalline form O of the tartrate salt of compound I. Its XRPD pattern matches that shown in Figure 38.

[0388] [Example 58] 36.0 g of compound I (HPLC purity 99.85%), prepared by the purification of component A in Example 26, and 720 mL of acetone (20V) were added to flask #1, and the temperature was raised to 50-55°C. The system was stirred until the solution became clear and dissolved. 11.0 g of L-(+)-tartaric acid and 720 mL of acetone (20V) were added to flask #2, and the temperature was raised to 50-55°C until the solution became clear. The system was stirred until dissolved; the solution in flask #2 was added to flask #1 at 45-55°C within 2-3 minutes; the system was stirred at 45-50°C for 2 hours; concentrated to approximately 720 mL under vacuum; cooled to 5-10°C and stirred at 5-10°C for 1 hour; filtered, and the filter cake was dried using a blower at 50-55°C for 16 hours to obtain 43.6 g of product, with an HPLC purity of 99.96% and a yield of 96.6%. Testing revealed that the solid was crystalline form O of the tartrate salt of the compound of formula I. Its XRPD pattern matches that shown in Figure 38.

[0389] [Example 59] 189.6 g of compound I (HPLC purity 99.9%), prepared by the purification of component A in Example 28, and 3792 mL of acetone (20V) were added to flask #1, and the temperature was raised to 50-55°C. The system was stirred until the solution became clear to dissolve the compounds. 57.6 g of L-(+)-tartaric acid and 3792 mL of acetone (20V) were added to flask #2, and the temperature was raised to 50-55°C. The system was stirred until the solution became clear to dissolve the compounds. The mixture was dissolved; the solution in flask #2 was added to flask #1 at 45-55°C; the system was stirred at 45-50°C for 2 hours; the mixture was concentrated to approximately 3800 mL (approximately 20V) under vacuum; it was cooled to 17-21°C and stirred for 1 hour; it was cooled to 5-10°C and stirred at 5-10°C for 1 hour; the mixture was filtered, and the filter cake was dried using a blower at 50-55°C for 28 hours to obtain 223.2 g of product. The HPLC purity was 99.98%, and the yield was 94.0%. Testing revealed that the solid was crystalline form O of the tartrate salt of the compound of formula I. Its XRPD pattern matches that shown in Figure 38.

[0390] [Example 60] 0.65 kg (HPLC purity 100.0%) of compound I prepared by the purification of component A in Example 30, and 7.7 kg of acetone were added to a rotary flask, and the flask was rotated in a water bath at 40-50°C for 1 hour to make the solution clear; the clear solution was transferred to PT1 (reactor 1) and compressed into the reactor in the purification area using nitrogen through a pipeline filter; 2.6 kg of acetone was added to the rotary flask, the flask was washed, then transferred to PT1 and compressed into the reactor through a pipeline filter; the amount of reaction solution in the reactor in the purification room was calibrated to 13.0 L; 7.7 kg of acetone and 0.198 kg of L-tartaric acid were added to the rotary flask, and the rotary flask was rotated in a water bath at 40-50°C for 1 hour to make the solution clear; the clear solution was transferred to PT1 and compressed into PT2 (reactor 1) using nitrogen through a pipeline filter 2) Compressed to PT1; 2.6 kg of acetone was added to a rotary flask, the flask was washed, the system was transferred to PT1, and compressed to PT2 using nitrogen through a pipeline filter; the temperature of the material solution in the reactor was heated to 40-50°C, and the material in PT2 was added to the reactor within 1 hour; the temperature of the material in the reactor was controlled to 40-50°C, and the system was stirred and reacted for 4 hours; it was cooled, and the temperature in the reactor was lowered to 25-35°C; the system Distillation was performed under vacuum, with the vacuum controlled to 0.080 MPa or less, and the material solution in the reactor was distilled under vacuum to a calibration volume of 13.0 L; the temperature of the material solution in the reactor was cooled to 15-25°C and the system was stirred at this temperature for 1 hour; the temperature in the reactor was cooled to 0-10°C; the temperature in the reactor was controlled to 0-10°C and the system was stirred at 10°C for 1 hour; the system was subjected to suction filtration and the filtration cake was washed with acetone (2.5 kg); a sample was taken and analyzed. The HPLC purity of the tartrate of compound I in the filtration cake was 99.98%; maximum individual impurity content: 0.02%; the filtration cake was dried under vacuum (-0.080 MPa or less) at 45-55°C for 24 hours; a sample was taken and analyzed, and the acetone residue was 5000 ppm or less; the oven was cooled to 15-25°C; dried to obtain 0.74 kg of product, a sample was taken and analyzed. HPLC purity of the tartrate of compound I: 99.95%; maximum individual impurity content: 0.03%; residual solvent meets requirements.Further testing revealed that the product was crystalline form O of the tartrate salt of the compound of formula I. Its XRPD pattern matched that shown in Figure 38.

[0391] [Experimental Section] <Experimental Example 1: Solubility Test> Crystal form 1 of compound I, crystal form F of the phosphate of compound I, and crystal form O of the tartrate of compound I were each divided into four appropriate amounts and weighed. Each was placed in a 4 mL clear glass bottle, and 1 mL of water, simulated gastric juice (SGF), simulated fasting intestinal fluid (FaSSIF), and simulated feeding intestinal fluid (FeSSIF) were added to each to obtain a sample suspension. The suspension was quickly transferred to a shaker (37°C, 200 rpm) and shaken. After 5 minutes, the sample was observed, and a certain amount of sample or medium was added to obtain a gentle suspension. Sampling was performed at 30 minutes, 2 hours, 4 hours, and 24 hours. The sample was centrifuged at 12000 rpm for 10 minutes to obtain the supernatant, which was diluted as appropriate and subjected to high-performance liquid chromatography. Refer to Table 20 for chromatography conditions.

[0392] [Table 22]

[0393] Sample concentrations were calculated using the external standard method. The test results are shown in Table 21.

[0394] [Table 23]

[0395] The results showed that the crystalline form F of the phosphate of compound I and the crystalline form O of the tartrate of compound I can significantly improve the solubility of the compound in water, SGF, and FaSSIF. At 24 hours, the solubility of crystalline form F of the phosphate of compound I in water, SGF, FaSSIF, and FeSSIF was 27 times, 10 times, 60 times, and 1 time, respectively, compared to that of compound I. At 24 hours, the solubility of crystalline form O of the tartrate of compound I in water, SGF, FaSSIF, and FeSSIF was 9 times, 2 times, 7 times, and 1 time, respectively, compared to that of compound I.

[0396] <Experimental Example 2: Stability Test 1> Approximately 1 mg each of crystalline form 1 of compound I, crystalline form F of the phosphate of compound I, and crystalline form O of the tartrate of compound I was weighed and placed in 20 mL clear glass bottles. Each sample was then placed in a stabilization chamber under accelerated conditions (40°C / 75%RH, open) and high temperature conditions (60°C, sealed). For the open samples, the bottle caps were removed and the necks of the bottles were covered with aluminum foil punctured with pinholes to prevent cross-contamination; for the sealed samples, the bottles were covered and tightly sealed. Samples were taken in the first and second weeks, diluted with a diluent (methanol / water (1 / 1) (v / v)), and the liquid phase was injected according to the chromatographic conditions in Table 22 to measure the sample purity.

[0397] [Table 24]

[0398] Sample purity was calculated using the area percentage method. The test results are shown in Table 23.

[0399] [Table 25]

[0400] The results showed that the appearance of crystalline form 1 of compound I, crystalline form F of the phosphate of compound I, and crystalline form O of the tartrate of compound I remained unchanged within two weeks, indicating they were off-white powders. There was no significant difference in purity, no apparent increase in impurities, and good chemical stability within two weeks was demonstrated. XRPD and DSC tests (Figures 45-50) showed no significant difference in crystal form or initial melting point of crystalline form F of the phosphate of compound I and crystalline form O of the tartrate of compound I compared to day 0, demonstrating good physical stability of the phosphate and tartrate of compound I within two weeks under high temperature (60°C) and accelerated conditions (40°C / 75%RH). The crystal form of crystalline form 1 of compound I changed under high temperature (60°C) and accelerated conditions (40°C / 75%RH). Characterization of the free base before and after the DVS test showed that the crystal form of the free base had poor stability.

[0401] <Experimental Example 3: Stability Test 2> The crystalline form O of the tartrate salt of the compound of formula I was tested using the suspension equilibrium method, heating-quenching / slow cooling crystallization method, poor solvent method, and solution volatilization and crystallization method to investigate whether crystallization occurred under different solvents and test conditions, and to further verify its thermodynamic stability.

[0402] [1. Slow solution evaporation method (EVA)] The crystalline form O of the tartrate of the compound of formula I, prepared in Example 55, was divided into five portions (10 mg / portion) and weighed. Each portion was placed in a sample bottle, and appropriate amounts of tetrahydrofuran, ethanol, methanol, acetone, and isopropanol (see Table 24 for specific amounts) were added to each bottle. The bottles were then sonicated to dissolve the samples. The resulting solutions were filtered into new sample bottles with a 0.45 μm nylon membrane. The sample bottles were opened, placed in a fume hood, and the solvent was allowed to evaporate naturally at room temperature (approximately 20-25°C) to collect the precipitated solids. Tests revealed that the solids obtained in the five tests were crystalline form O of the tartrate of the compound of formula I, and their XRPD patterns matched those in Figure 38.

[0403] [Table 26]

[0404] [2. Suspension equilibrium method (slurry)] Samples of crystalline form O of the tartrate salt of the compound of formula I were divided into 18 appropriate amounts and weighed. Then, a fixed amount of tetrahydrofuran, ethanol, ethyl acetate, n-heptane, toluene, methyl tertiary butyl ether, isopropanol, methanol, and acetone (see Table 25 for specific amounts) were added to each solvent system to obtain two suspension samples. The samples were stored at room temperature and at high temperature (50°C) and then slurried. The room temperature sample bottle (wrapped in tin foil to protect from light) was placed on a Labquaker rotator to rotate 360°, and the high-temperature sample was placed in a 50°C constant temperature shaking incubator and slurried. A portion of the suspension sample was taken on the 3rd, 7th, and 14th days, respectively, centrifuged, and the solid residue was recovered. The solvent was evaporated at room temperature (20-25°C) and dried, and the solid was recovered. When tested, the obtained solids were crystalline form O of the tartrate salt of the compound of formula I, and their XRPD patterns matched those in Figure 38.

[0405] [Table 27]

[0406] [3. Anti-solvent method] A sample of crystalline form O of the tartrate salt of the compound of formula I was divided into 21 portions and weighed. A constant volume of good solvent from Table 26 was added sequentially, and the system was subjected to sonication to dissolve. The resulting solution was filtered through a 0.45 μm nylon membrane into a new sample bottle. Different poor solvents were slowly added dropwise to each sample bottle under magnetic stirring. Solvent systems in which solids precipitated were centrifuged, the solids were recovered, and the solvents were evaporated and dried at room temperature (20-25°C). Solvent systems in which no solids precipitated were stirred for 48 hours. If no solids precipitated, the bottle was opened and the system was stirred until solids precipitated. The tests showed that the obtained solids were crystalline form O of the tartrate salt of the compound of formula I, and their XRPD patterns matched those in Figure 38.

[0407] [Table 28]

[0408] [5. Solution heating-rapid cooling method (HFC)] A sample of crystalline form O of the tartrate salt of compound I was divided into five portions (approximately 20 mg / portion), weighed, and placed in a sample bottle. Appropriate amounts of tetrahydrofuran, acetone, ethanol, isopropanol, and methanol (see Table 27 for specific amounts) were added to each portion. The sample bottle was placed on a magnetic heating stirrer and heated at 200 rpm in a water bath at approximately 50°C to dissolve the compounds. The temperature was maintained for 15 minutes, and the solution was filtered while still hot through a 0.45 μm film. The solution was transferred to a new sample bottle, and the bottle was immediately placed in a refrigerator at -20°C overnight. Solvent systems in which solid precipitated were centrifuged, the solid was recovered, and the solvent was evaporated and dried at room temperature (20-25°C). Solvent systems in which solid did not precipitate were placed in a refrigerator at -20°C until a large amount of solid precipitated. In the tetrahydrofuran and acetone systems, solids did not always precipitate. Tests revealed that the solids obtained from ethanol, isopropanol, and methanol systems were crystalline form O of the tartrate salt of compound I, and their XRPD spectra were consistent with Figure 38.

[0409] [Table 29]

[0410] [6. Solution heating-slow cooling method (HSC)] A sample of crystalline form O of the tartrate salt of compound I was divided into five portions (approximately 20 mg / portion), weighed, and placed in a sample bottle. Appropriate amounts of tetrahydrofuran, acetone, ethanol, isopropanol, and methanol (see Table 28 for specific amounts) were added to each portion. The sample bottle was placed on a magnetic heating stirrer and heated at 200 rpm in a water bath at approximately 50°C to dissolve the compounds. The temperature was maintained for 15 minutes, and the solution was filtered while still hot through a 0.45 μm film. The solution was transferred to a new sample bottle and slowly cooled to room temperature overnight at 6°C / h. The sample bottle was then placed in a refrigerator (2-8°C), and the solvent systems in which solid precipitated were centrifuged to recover the solid. The solvent was then evaporated and dried at room temperature (20-25°C). Solvent systems in which solid did not precipitate were placed in a refrigerator at -20°C until a large amount of solid precipitated. In the tetrahydrofuran, acetone, and methanol systems, solid precipitation did not always occur. Tests revealed that the solids obtained from ethanol and isopropanol systems were crystalline form O of the tartrate salt of the compound of formula I, and their XRPD patterns matched those shown in Figure 38.

[0411] [Table 30]

[0412] The above test results showed that after treating crystalline form O of the tartrate salt of compound I using different methods, including the suspension equilibrium method, the heating-quenching / slow cooling crystallization method, the poor solvent method, and the solution volatilization and crystallization method, the product remained a single crystalline form O. Crystallographic form O of the tartrate salt of compound I is a thermally stable and dominant crystalline form.

[0413] <Test 4: TYK2 Biochemistry Test> An appropriate amount of compound I was weighed for the TYK2 biochemical test.

[0414] This study was conducted by Reaction Biology Corp, Malvern, PA (Anastassiadis et al. Nat Biotechnol. 2011; 29(11):1039-45). The steps involved are briefly described below.

[0415] reagent: Basic reaction buffer: 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / ml BSA, 0.1 mM Na3VO4, 2 mM DTT, and 1% DMSO. The necessary cofactors were added to each kinase reaction.

[0416] Reaction steps: 1. Prepare the specified substrate in a newly prepared basic reaction buffer; 2. Transfer the necessary cofactors to the matrix solution described above; 3. Transfer the specified kinase to the substrate solution and mix thoroughly and gently; 4. Using acoustic technology (Echo550; nanoliter range), transfer the compound of formula I in DMSO to the kinase reaction mixture and incubate at room temperature for 20 minutes; 5. 33 P-ATP (specific activity: 10 μCi / μl) is introduced into the reaction mixture and the reaction is carried out; 6. Culture at room temperature and perform the kinase reaction for 2 hours; 7. Plot the reaction onto P81 ion exchange paper; 8. Test kinase activity using a filter-binding assay.

[0417] The test results showed that the compound of formula I is also a potent TYK2 inhibitor, and its IC 50 This indicated that the concentration was less than 10 nM.

[0418] Those skilled in the art can understand the present invention under the direction of this specification and make several modifications or changes. These modifications and changes should be within the scope specified in the claims of the present invention. Furthermore, the present invention includes the following embodiments. [Aspect 1] A method for preparing the compound of formula I, wherein the synthetic route of the method is as follows: [ka] The above method includes the following steps: Step 1: Add ethanol, compound IV, compound V, and DIPEA to the reaction vessel and begin stirring; Heat to raise the temperature to 65-90°C, maintain the temperature, and stir overnight; Stop the reaction and lower the system temperature to 15-30°C; Add water dropwise to the system and continue stirring; Filter and wash the filtered cake; The filtered cake is dried to obtain the compound of formula III; Step 2: Add tetrahydrofuran, the compound of formula III obtained in step 1, and palladium carbon to the reaction vessel; Purge the system with nitrogen, then with hydrogen; Maintain the temperature at 20-35°C and stir for 16-120 hours under a hydrogen pressure of 0.1-1.0 MPa; After the reaction is complete, filter the reaction solution and wash the filter cake; The filtrates are combined and concentrated to obtain a concentrate of the compound of formula II; Step 3: Add the concentrate of the compound of formula II obtained in step 2, or the compound of formula II, along with trimethyl orthoacetate and tetrahydrofuran, to the reaction vessel; heat the material system in the reaction vessel to reflux of tetrahydrofuran; add pyridine hydrochloride to the reaction vessel and react the resulting material system at a temperature of 50-90°C for 4-20 hours, then separate and purify to obtain the compound of formula I. [Aspect 2] In step 1 above: The volume mass ratio (mL / g) of ethanol to the compound of formula IV is 5:1 to 20:1, preferably 10:1; The molar ratio of the compound of formula IV, the compound of formula V, and DIPEA is 1:1 to 1.1:2 to 3, preferably 1:1.01:2.2; After starting the stirring, under nitrogen protection, heat to raise the temperature to 65-90°C, preferably 70-90°C, more preferably 70-80°C, maintain the temperature, and stir for 5-16 hours, preferably 10-16 hours; After stopping the reaction, reduce the system temperature to 15-25°C; The volume mass ratio (mL / g) of water added to the system to the compound of formula IV is 10:1 to 20:1, preferably 15:1; After adding water to the system, stir for 2 to 6 hours, preferably 4 hours, at a temperature of 0 to 30°C, preferably 5 to 15°C, more preferably 5 to 10°C; The filtered cake is washed with an aqueous ethanol solution, the volume ratio of ethanol to water in the aqueous ethanol solution (mL / mL) being 1:1 to 1:2, preferably 1:1.5 to 1:2; the volume mass ratio of the aqueous ethanol solution to the compound of formula IV (mL / g) being 2:1 to 10:1, preferably 2:1 to 5:1, more preferably 2:1 to 3:1; The method according to embodiment 1, wherein the filtered cake is dried at a temperature of 45 to 55°C, preferably 50°C, using a vacuum or a blower. [Aspect 3] In step 2 above: The volume mass ratio (mL / g) of tetrahydrofuran to the compound of formula III is 10:1 to 70:1, preferably 20:1 to 70:1; The palladium-carbon is 5% Pd / C, 50% water-wet, and the mass ratio of palladium-carbon to the compound of formula III is 0.15:1 to 0.16:1, preferably 0.15:1; Maintain the temperature at 25-35°C and stir for 24-96 hours under a hydrogen pressure of 0.5-1.0 MPa; The concentrate of the compound of formula II obtained by combining and concentrating the filtrates is a tetrahydrofuran solution of the compound of formula II, and the volume mass ratio of tetrahydrofuran to the compound of formula II is 2:1 to 4:1, preferably 2:1 to 3:1; preferably the method according to embodiment 1 or 2, wherein the tetrahydrofuran solution of the compound of formula II is replaced with ethanol to obtain an ethanol solution of the compound of formula II, and the volume mass ratio of ethanol to the compound of formula II is 2:1 to 5:1, preferably 2:1 to 4:1, more preferably 2:1 to 3:1. [Aspect 4] In step 3 above: The volume-to-mass ratio (mL:mg) of tetrahydrofuran to the compound of formula II in the concentrate is 1.5:1 to 5.0:1; or the volume-to-mass ratio (mL:mg) of tetrahydrofuran to the compound of formula II is 1.5:1 to 5.0:1. Preferably, the concentrate of the compound of formula II is substituted with toluene, tetrahydrofuran, or methyl tertiary butyl ether for the next step; preferably, the volume mass ratio (mL:mg) of the concentrate of the compound of formula II to the toluene, tetrahydrofuran, or methyl tertiary butyl ether used for substitution is 2.0:1 to 4.0:1; Preferably, the molar ratio of the compound of formula II to trimethyl orthoacetate in the concentrate of the compound of formula II is 3.0:1 to 3.5:1; or the molar ratio of the compound of formula II to trimethyl orthoacetate is 3.0:1 to 3.5:1; Preferably, the molar ratio of the compound of formula II to pyridine hydrochloride in the concentrate of the compound of formula II is 0.2:1 to 0.3:1; or the molar ratio of the compound of formula II to pyridine hydrochloride is 0.2:1 to 0.3:1; Preferably, a concentrate of the compound of formula II or the compound of formula II, along with trimethyl orthoacetate and a solvent, are added to the reaction vessel under nitrogen protection, and then the material system in the reaction vessel is heated until the solvent refluxes; After adding pyridine hydrochloride to the reactor under nitrogen protection, the material system is reacted at a temperature of 50-90°C, preferably 65-75°C, for 4-20 hours, preferably 5-15 hours. Preferably, after the reaction is complete, the product is purified with a solvent selected from the group consisting of water, methanol, ethanol, methyl tertiary butyl ether, and any combination thereof; Preferably, the resulting compound of formula I is separated and purified by column chromatography, and the eluent is a mixed solution of ethyl acetate and n-heptane (V EA :V n-ヘプタン = 1:1 to 1:0 (mL / mL); Preferably, the method according to any one of embodiments 1 to 3, wherein the obtained compound of formula I is dried at 50 to 55°C under vacuum or using a blower. [Aspect 5] Crystal form 1 of the compound of formula I,

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[0419] [Figure 1] This is the XRPD pattern of crystalline form 1 of the compound of formula I of the present invention. [Figure 2] This is a DSC thermogram of crystalline form 1 of the compound of formula I of the present invention. [Figure 3] This is a TGA thermogram of crystalline form 1 of the compound of formula I of the present invention. [Figure 4] This is a DVS isotherm plot of crystalline form 1 of the compound of formula I of the present invention. [Figure 5] This is the XRPD overlay pattern of crystalline form 1 of the compound of formula I of the present invention before and after DVS testing. [Figure 6] This is the XRPD pattern of crystalline form A of the hydrochloride salt of the compound of formula I of the present invention. [Figure 7] This is a DSC thermogram of crystalline form A of the hydrochloride salt of the compound of formula I of the present invention. [Figure 8] This is the XRPD pattern of crystalline form B of the hydrochloride salt of the compound of formula I of the present invention. [Figure 9] This is a DSC thermogram of crystalline form B of the hydrochloride salt of the compound of formula I of the present invention. [Figure 10] This is the XRPD pattern of the crystalline form C of the hydrochloride salt of the compound of formula I of the present invention. [Figure 11] This is a DSC thermogram of crystalline form C of the hydrochloride salt of the compound of formula I of the present invention. [Figure 12] This is the XRPD pattern of the crystalline form D of the sulfate of the compound of formula I of the present invention. [Figure 13] This is a DSC thermogram of crystalline form D of the sulfate of the compound of formula I of the present invention. [Figure 14] This is the XRPD pattern of the crystalline form E of the phosphate of the compound of formula I of the present invention. [Figure 15] This is a DSC thermogram of the crystalline form E of the phosphate of the compound of formula I of the present invention. [Figure 16] This is the XRPD pattern of the crystalline form F of the compound phosphate of formula I of the present invention. [Figure 17] This is a DSC thermogram of the crystalline form F of the phosphate of the compound of formula I of the present invention. [Figure 18] This is a DVS isotherm plot of the crystalline form F of the phosphate of the compound of formula I of the present invention. [Figure 19] This shows the XRPD overlay patterns of the crystalline form F of the compound phosphate of formula I of the present invention before and after DVS testing. [Figure 20] This is the XRPD pattern of crystalline form G of the mesylate salt of the compound of formula I of the present invention. [Figure 21] This is a DSC thermogram of crystalline form G of the mesylate salt of the compound of formula I of the present invention. [Figure 22] This is a DVS isotherm plot of the crystalline form G of the mesylate of the compound of formula I of the present invention. [Figure 23] This is the XRPD pattern of the crystalline form H of the hydrobromide salt of compound I of the present invention. [Figure 24]This is a DSC thermogram of the crystalline form H of the hydrobromide salt of the compound of formula I of the present invention. [Figure 25] This is the XRPD pattern of the crystalline form J of the hydrobromide salt of the compound of formula I of the present invention. [Figure 26] This is the XRPD pattern of the crystalline form K of the hydrobromide salt of the compound of formula I of the present invention. [Figure 27] This is a DSC thermogram of the crystalline form K of the hydrobromide salt of the compound of formula I of the present invention. [Figure 28] This is a DVS isotherm plot of the crystalline form K of the hydrobromide salt of the compound of formula I of the present invention. [Figure 29] This shows the XRPD overlay patterns of the hydrobromide salt of the compound of formula I of the present invention, crystalline form K, before and after DVS testing. [Figure 30] This is the XRPD pattern of the crystalline form L of the fumarate of the compound of formula I of the present invention. [Figure 31] This is a DSC thermogram of the crystalline form L of the fumarate of the compound of formula I of the present invention. [Figure 32] This is the XRPD pattern of the crystalline form M of the benzenesulfonate of the compound of formula I of the present invention. [Figure 33] This is a DSC thermogram of the crystalline form M of the benzenesulfonate salt of the compound of formula I of the present invention. [Figure 34] This is a DVS isotherm plot of the crystalline form M of the benzenesulfonate of the compound of formula I of the present invention. [Figure 35] This shows the XRPD overlay patterns of crystalline form M of the benzenesulfonate of the compound of formula I of the present invention before and after DVS testing. [Figure 36] This is the XRPD pattern of crystalline form N of the citrate of compound I of the present invention. [Figure 37] This is a DSC thermogram of crystalline form N of the citrate of the compound of formula I of the present invention. [Figure 38] This is the XRPD pattern of crystalline form O of the tartrate salt of the compound of formula I of the present invention. [Figure 39] This is a DSC thermogram of crystalline form O of the tartrate salt of the compound of formula I of the present invention. [Figure 40] This is a TGA thermogram of crystalline form O of the tartrate salt of the compound of formula I of the present invention. [Figure 41] This is a DVS isotherm plot of crystalline form O of the tartrate salt of the compound of formula I of the present invention. [Figure 42] This shows the XRPD overlay patterns of crystalline form O of the tartrate salt of the compound of formula I of the present invention before and after DVS testing. [Figure 43] This is the 1H NMR spectrum of crystalline form 1 of the compound of formula I of the present invention. [Figure 44] This is the 1H NMR spectrum of the crystalline form O of the tartrate salt of the compound of formula I of the present invention. [Figure 45] This is an XRPD overlay pattern of crystalline form F of the phosphate of compound I of the present invention after being subjected to high temperature and accelerated conditions for two weeks. [Figure 46] This is an XRPD overlay pattern of crystalline form O of the tartrate of compound I of the present invention after being subjected to high temperature and accelerated conditions for two weeks. [Figure 47] This is a DSC overlay thermogram of crystalline form F of the phosphate of compound I of the present invention after being subjected to high temperature and accelerated conditions for two weeks. [Figure 48] This is a DSC overlay thermogram of crystalline form O of the tartrate salt of compound I of the present invention after being subjected to high temperature and accelerated conditions for two weeks. [Figure 49] This is an XRPD overlay pattern of crystalline form 1 of the compound of formula I of the present invention after being subjected to high temperature and accelerated conditions for two weeks. [Figure 50] This is a DSC overlay thermogram of crystalline form 1 of the compound of formula I of the present invention after being subjected to high temperature and accelerated conditions for two weeks.

Claims

1. A crystal O of the compound tartrate of formula I, 【Chemistry 1】 Crystal O, whose X-ray powder diffraction pattern shows characteristic peaks at 2 theta angles of 6.3°±0.2°, 26.1°±0.2°, and 26.9°±0.2°.

2. Crystal O of the tartrate salt of the compound of formula I according to claim 1, wherein the X-ray powder diffraction pattern of the crystal shows characteristic peaks at 2 theta angles of 6.3°±0.2°, 12.5°±0.2°, 15.1°±0.2°, 26.1°±0.2°, 26.9°±0.2°, and 27.5°±0.2°.

3. Crystal O of the tartrate salt of the compound of formula I according to claim 1 or 2, wherein the X-ray powder diffraction pattern of the crystal shows characteristic peaks at 2 theta angles of 6.3°±0.2°, 11.4°±0.2°, 12.5°±0.2°, 14.1°±0.2°, 14.4°±0.2°, 15.1°±0.2°, 26.1°±0.2°, 26.9°±0.2°, and 27.5°±0.2°.

4. A method for preparing crystal O of a tartrate salt of a compound of formula I according to any one of claims 1 to 3, comprising: The compound of formula I is mixed with a first solvent, and the compound is dissolved until the solution becomes clear to obtain a first solvent solution of the compound of formula I; tartaric acid is mixed with a second solvent, and the compound is dissolved until the solution becomes clear to obtain a second solvent solution of tartaric acid; the second solvent solution of tartaric acid is added to the first solvent solution of the compound of formula I while stirring, and controlled cooling is performed while stirring, the solid is recovered and dried to obtain crystals O of the tartrate salt of the compound of formula I; A preparation method in which the first solvent and the second solvent are selected from the group consisting of acetone, ethyl acetate, and any combination thereof.

5. The preparation method according to claim 4, wherein the molar ratio of the compound of formula I to tartaric acid is 1:(0.5 to 1.5).

6. The preparation method according to claim 4, wherein in the tartrate crystal O of the compound of formula I, the molar ratio of the compound of formula I to tartaric acid is 2:

1.

7. The preparation method according to claim 4, wherein the concentration of the acetone solution of the compound of formula I is 15 to 70 mg / mL.

8. The preparation method according to claim 4, wherein the concentration of the acetone solution of tartaric acid is 5 to 35 mg / m.

9. The preparation method according to claim 4, comprising mixing the compound of formula I with acetone and raising the temperature to 40 to 60°C until the compound of formula I is dissolved.

10. The preparation method according to claim 4, comprising mixing tartaric acid with acetone and raising the temperature to 40-60°C to dissolve the tartaric acid until the solution becomes clear.

11. The preparation method according to claim 4, comprising adding an acetone solution of tartaric acid to an acetone solution of the compound of formula I at 40 to 60°C.

12. The preparation method according to claim 4, further comprising drying the recovered solid at 40 to 60°C under reduced pressure or using a blower for 5 to 48 hours.

13. The speed-controlled cooling described above is achieved by the following steps in the preparation method according to any one of claims 4 to 12: 1) Stir the system for 0.5 to 3 hours at room temperature of 35 to 60°C; 2) Continue cooling the system to 15-35°C, maintain the temperature, and stir for 0.5-3 hours; 3) Continue cooling the system to 5-15°C, maintain the temperature, and stir for 0.5-3 hours.

14. The preparation method according to claim 13, wherein in step 1), the system is stirred at room temperature of 35 to 60°C for 0.5 to 3 hours, and then the system is concentrated to one-third to two-thirds of its original volume.

15. The preparation method according to claim 13, wherein in step 2), the system is continuously cooled to 15 to 35°C, the temperature is maintained, and after stirring for 0.5 to 3 hours, the system is concentrated to one-third to two-thirds of its original volume.

16. The preparation method according to any one of claims 4 to 15, wherein the purity of the compound of formula I is greater than 90%.

17. A pharmaceutical composition comprising crystals O of a compound tartrate of formula I as described in any one of claims 1 to 3.

18. A pharmaceutical preparation comprising crystals O of a compound tartrate of formula I as described in any one of claims 1 to 3.

19. A pharmaceutical composition for treating JAK1 / TYK2-related diseases or conditions, comprising crystal O of a tartrate salt of a compound of formula I according to any one of claims 1 to 3.

20. The pharmaceutical composition according to claim 19, wherein the disease or condition is an autoimmune disease or disorder.

21. The pharmaceutical composition according to claim 19 or 20, wherein the disease or condition is rheumatoid arthritis or an inflammatory disease or disorder.

22. The pharmaceutical composition according to claim 19 or 20, wherein the disease or condition is cancer or a tumor-proliferative disease or disorder.

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