Method for synthesizing polymorphic substances of furomidazopyridine compounds and polymorphic substances of salts

Abstract

A method for synthesizing the compound 2-[(2R,5S)-5-[2-methylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile as a selective JAK1 / TYK2 kinase inhibitor. This compound is prepared by nucleophilic substitution, palladium carbide reduction, and cyclization using 7-chloro-6-nitrofuro[3,2-b]pyridine as the starting material. This synthesis method has mild reaction conditions, high product yield, and high purity, making it suitable for industrial production. The crystalline form of the compound, its salt crystalline form, and a method for its preparation are also described. The crystalline form of the compound and its salt crystalline form have favorable physical and chemical properties, making them suitable for drug development.

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to the field of drug synthesis, in particular to a method for the synthesis of the compound 2-[(2R,5S)-5-[2-methylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (hereinafter referred to as Compound I or compound of formula I) as a selective JAK1 / TYK2 kinase inhibitor. The present invention also relates to crystalline forms of Compound I and its salts, as well as methods for their preparation. Furthermore, the present invention also relates to pharmaceutical compositions and pharmaceutical formulations comprising crystalline forms of Compound I and / or crystalline forms of its salts, as well as the use of 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 play an important role in regulating multiple cellular processes and 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 b-RAF.

[0003] The Janus kinase family includes four known family members: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). These cytoplasmic tyrosine kinases associate with membrane cytokine receptors, such as the common gamma chain receptor and glycoprotein 130 (gp130) transmembrane protein (Murray, J. Immunol. 178 (5): 2623 - 2629, 2007). Approximately 40 cytokine receptors signal through a combination of these four JAK family members and their seven downstream substrates: signal transducer and activator of transcription (STAT) family members (Ghoreschi et al., Immunol Rev. 228 (l): 273 - 287, 2009). Cytokines that bind to their receptors activate JAKs by transphosphorylation and / or autophosphorylation. Activated JAK family kinases then phosphorylate cytokine receptors, generating binding sites for Src homology 2 (SH2)-containing proteins (such as STAT factors and other regulatory factors), which then activate them through JAK phosphorylation. Activated STATs enter the cell nucleus and begin to promote the expression of survival factors, cytokines, chemokines, and molecules trafficking in leukocytes (Schindler et al., J. Biol. Chem. 282(28):20059-20063, 2007). JAK activation also leads to cell proliferation through pathways mediated by phosphoinositide-3-kinase (PI3K) and protein kinase B.

[0004] JAK3 and JAK1 are components of a common gamma chain cytokine receptor complex, and blocking either one of the two 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 only dependent on JAK1. Thus, JAK1 blocking inhibits the signaling of many proinflammatory cytokines (Guschin et al, EMBO J. 14 (7): 1421 - 1429, 1995). 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-furo[3,2-b]imidazo[4,5-d]pyridine derivatives as selective JAK1 kinase inhibitors, including compound I and its preparation method, and their preparation method. The synthetic route is as follows:

[0006] [ka]

[0007] Biological testing shows that compound I is a potent and selective JAK1 inhibitor, exhibiting selective inhibition of IL-6-induced STAT3 phosphorylation, but not selective inhibition of thrombopoietin-induced STAT3 phosphorylation. However, international patent application WO2018067422A1 does not disclose the biological activity of TYK2. In addition, the disclosed preparation method of compound I involves high temperature, produces too many impurities, and has a low yield, making it unsuitable for large-scale production. Therefore, it is necessary to develop a preparation method of compound I that has milder reaction conditions, higher product yield, higher purity, and is suitable for large-scale / industrial production.

[0008] At present, there is no report on the crystalline form of compound I and its salts. Comprehensive and systematic polymorph screening and selection of the most suitable crystalline form for development are essential and important research contents. Therefore, it is necessary to further screen the crystalline forms of compound I and its salts, and develop crystalline forms with good stability and low hygroscopicity, which are suitable for large-scale production, and provide 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 preparing a compound of formula I (i.e., compound I) under mild reaction conditions, with high product yield and high purity, suitable for industrial production. The synthetic route of this method is as follows:

[0010] [ka]

[0011] The method includes the following steps: Step 1: Add ethanol, compound of formula IV, compound of formula V and DIPEA to a reaction vessel and begin stirring; Heat to 65-90°C, maintain temperature, and stir overnight; Stop the reaction and reduce the temperature of the system to 15-30°C; Add water dropwise to the system and continue stirring; Filter and wash the filter cake; The filter 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 on carbon to a reaction vessel; The system is purged with nitrogen and then with hydrogen; Maintain the temperature at 20-35°C and stir under hydrogen pressure of 0.1-1.0 MPa for 16-120 hours; After the reaction is completed, the reaction liquid is filtered and the filter cake is washed; The filtrates are combined and concentrated to obtain a concentrate of the compound of formula II; Step 3: The concentrate of the compound of formula II obtained in step 2 or the compound of formula II, as well as trimethyl orthoacetate and tetrahydrofuran are added to a reaction vessel; the material system in the reaction vessel is heated to the reflux of tetrahydrofuran; pyridine hydrochloride is added to the reaction vessel, and the resulting material system is reacted at a temperature of 50-90°C for 4-20 hours, and then separated and purified to obtain the compound of formula I.

[0012] In some embodiments of step 1 above: The volumetric 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 1:1-1.1:2-3, preferably 1:1.01:2.2; After starting stirring, heat under nitrogen protection to increase the temperature to 65 to 90°C, preferably 70 to 90°C, more preferably 70 to 80°C, maintain the temperature, and stir for 5 to 16 hours, preferably 10 to 16 hours; After the reaction is stopped, the temperature of the system is reduced to 15-25°C; The volumetric mass ratio (mL / g) of water to the compound of formula IV added to the system is 10:1-20:1, preferably 15:1; After adding water to the system, the mixture is stirred 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 filter cake is washed with an aqueous ethanol solution, in which the volume ratio (mL / mL) of ethanol to water in the aqueous ethanol solution is 1:1 to 1:2, preferably 1:1.5 to 1:2; the volume mass ratio (mL / g) of the aqueous ethanol solution to the compound of formula IV is 2:1 to 10:1, preferably 2:1 to 5:1, more preferably 2:1 to 3:1; The filter cake is dried under vacuum or with a blower at a temperature of 45-55°C, preferably 50°C.

[0013] In some embodiments of step 2 above: The volumetric 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 on carbon is 5% Pd / C, 50% water wet, and the mass ratio (g / g) of palladium on 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 under hydrogen pressure of 0.5-1.0 MPa for 24-96 hours; The concentrate of the compound of formula II obtained by combining and concentrating the filtrate is a tetrahydrofuran solution of the compound of formula II, and the volumetric 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 100% yield of 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 volumetric 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 100% yield of step 2).

[0014] In some of the embodiments of step 3 above, the volumetric 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 of the embodiments of step 3 above, the volumetric 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 replaced with toluene, tetrahydrofuran, or methyl tertiary butyl ether for the next step; in some embodiments, the volumetric mass ratio (mL:mg) of toluene, tetrahydrofuran, or methyl tertiary butyl ether used for the replacement to the concentrate of the compound of formula II is 2.0:1 to 4.0:1; In some of the 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 of the 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 of the embodiments of the above step 3, 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 of the embodiments of the above step 3, 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, adding the concentrate of the compound of formula II or the compound of formula II, trimethyl orthoacetate and a solvent to a reaction vessel under nitrogen protection, and then heating the material system in the reaction vessel until the solvent refluxes; After pyridine hydrochloride is added 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 of the embodiments of step 3 above, after the reaction is completed, 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 resulting compound of formula I is separated and purified by column chromatography, and the eluent is a mixture 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 above, the resulting compound of formula I is dried at 50-55° C. under vacuum or with a blower.

[0017] Another object of the present invention is to provide a crystalline form of the compound of formula I, hereinafter designated as crystalline form 1 of the compound of formula I.

[0018] [ka]

[0019] Crystalline Form 1 of the compound of formula I has an X-ray powder diffraction pattern exhibiting 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 pattern of crystalline Form 1 of the compound of Formula I exhibits 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 pattern of crystalline Form 1 of the compound of Formula I exhibits 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-limiting X-ray powder diffraction data of crystalline Form 1 of the compound of formula I of the present invention is shown in Table 1.

[0023] [Table 1]

[0024] A non-limiting X-ray powder diffraction (XRPD) pattern of crystalline Form 1 of the compound of formula I of the present invention is shown in FIG.

[0025] A non-limiting differential scanning calorimetry (DSC) thermogram of crystalline form 1 of the compound of formula I of the present invention is shown in Figure 2. 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] A non-limiting thermogravimetric analysis (TGA) thermogram of crystalline form 1 of compound of formula I of the present invention is shown in Figure 3. The TGA thermogram shows that crystalline form 1 of compound of formula I of the present invention has only a 0.42% weight loss between 25°C and 162°C. Crystalline form 1 of compound of formula I does not contain water of crystallization or solvent.

[0027] A non-limiting dynamic vapor sorption (DVS) isotherm plot of crystalline form 1 of compound of formula I of the present invention is shown in Figure 4. The DVS isotherm plot shows a 13.86% weight gain of crystalline form 1 of compound of formula I of the present invention upon moisture absorption from 0% RH to 95% RH, indicating that the sample is hygroscopic. The moisture absorption curve during desorption shows hysteresis, which, 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), indicates that the crystalline form of compound of formula I changes after moisture absorption.

[0028] The present invention provides a method for preparing crystalline form 1 of 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, and the filter 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, followed by stirring at 50° C. for 1 hour, cooling to 10° C., stirring for 0.5 hours, filtering, washing the filter cake with MTBE, and drying the filter cake 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 the silicon-based metal removing agent and activated carbon are added to the system.

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

[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 exhibiting 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 pattern of crystalline form A of the hydrochloride salt of the compound of formula I exhibits 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 pattern of crystalline form A of the hydrochloride salt of the compound of formula I exhibits 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-limiting X-ray powder diffraction data for crystalline form A of the hydrochloride salt of the compound of formula I of the present invention is shown in Table 2.

[0036] [Table 2]

[0037] A non-limiting XRPD pattern of crystalline form A of the hydrochloride salt of the compound of formula I of the present invention is shown in FIG.

[0038] A non-limiting DSC thermogram of crystalline form A of the hydrochloride salt of the compound of formula I of the present invention is shown in FIG.

[0039] The present invention provides a method for preparing crystalline form A of the hydrochloride salt of 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, and the acetone solution of hydrochloric acid is added to the acetone solution of the compound of formula I with stirring, and the stirring is continued, and 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 compound of formula I in acetone is 10-50 mg / mL, preferably 20 mg / mL; In some embodiments, the concentration of the hydrochloric acid in acetone is 15-35 mg / mL, preferably 25 mg / mL; In some embodiments, after the addition of the acetone solution of hydrochloric acid, stirring is continued at room temperature for 4 to 48 hours, preferably 24 hours; In some embodiments, the solids are collected by centrifugation and dried under vacuum at 30-60° C. overnight.

[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 exhibiting 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 pattern of crystalline form B of the hydrochloride salt of the compound of Formula I exhibits 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 pattern of crystalline form B of the hydrochloride salt of the compound of Formula I exhibits 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-limiting X-ray powder diffraction data for crystalline form B of the hydrochloride salt of compound of formula I of the present invention is shown in Table 3:

[0045] [Table 3]

[0046] A non-limiting XRPD pattern of crystalline form B of the hydrochloride salt of the compound of formula I of the present invention is shown in FIG.

[0047] As a non-limiting example, a DSC thermogram of crystalline form B of the hydrochloride salt of the compound of formula I of the present invention is shown in FIG.

[0048] The present invention provides a method for preparing crystalline form B of the hydrochloride salt of compound of formula I, specifically, the method is described as follows: The compound of formula I is dissolved in ethyl acetate to obtain a solution of the compound of formula I in ethyl acetate, the solution of hydrochloric acid in ethyl acetate is added to the solution of the compound of formula I in ethyl acetate with stirring, the stirring is continued, and the solid is collected and 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 compound of formula I in ethyl acetate is 10-30 mg / mL, preferably 20 mg / mL; In some embodiments, the concentration of the hydrochloric acid in ethyl acetate solution is 15-35 mg / mL, preferably 25 mg / mL; In some embodiments, after adding the solution of hydrochloric acid in ethyl acetate, stirring is continued at room temperature for 4 to 48 hours, preferably 24 hours; In some embodiments, the solids are collected by centrifugation and dried under vacuum at 30-60° C. overnight.

[0050] Crystalline form C of the hydrochloride salt of the compound of formula I of the present invention has an X-ray powder diffraction pattern exhibiting 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 pattern of crystalline form C of the hydrochloride salt of the compound of Formula I exhibits 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-limiting X-ray powder diffraction data for crystalline form C of the hydrochloride salt of the compound of formula I of the present invention is shown in Table 4:

[0053] [Table 4]

[0054] A non-limiting XRPD pattern of crystalline form C of the hydrochloride salt of the compound of formula I of the present invention is shown in FIG.

[0055] As a non-limiting example, a DSC thermogram of crystalline form C of the hydrochloride salt of the compound of formula I of the present invention is shown in FIG.

[0056] Recrystallization or crystal conversion of crystalline form A of the hydrochloride salt of the compound of formula I with a solvent is performed to obtain crystalline form C of the hydrochloride salt of the compound of formula I, wherein 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, stirred at room temperature, and the solid is collected 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 vessel containing crystalline form A of the hydrochloride salt of the compound of formula I to prepare a suspension, which is stirred at room temperature and 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 the stirring is 4 to 48 hours, preferably 24 hours.

[0060] In some embodiments, the solids are collected by centrifugation and dried under vacuum at 30-60° C. overnight.

[0061] Crystalline form D of the sulfate salt of the compound of formula I of the present invention has an X-ray powder diffraction pattern exhibiting 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 pattern of crystalline form D of the sulfate salt of the compound of Formula I exhibits 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-limiting X-ray powder diffraction data for crystalline form D of the sulfate salt of the compound of formula I of the present invention is shown in Table 5:

[0064] [Table 5]

[0065] A non-limiting XRPD pattern of crystalline form D of the sulfate salt of the compound of formula I of the present invention is shown in FIG.

[0066] As a non-limiting example, a DSC thermogram of crystalline form D of the sulfate salt of the compound of formula I of the present invention is shown in FIG.

[0067] The present invention provides a method for preparing crystalline form D of the sulfate salt of 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, the acetone solution of sulfuric acid is added to the acetone solution of the compound of formula I with stirring, the stirring is continued, and the solid is collected and dried to obtain crystalline form D of the sulfate salt 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 compound of formula I in acetone is 10-30 mg / mL, preferably 20 mg / mL.

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

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

[0072] In some embodiments, the solids are collected by centrifugation and dried under vacuum at 30-60° C. overnight.

[0073] Crystalline form E of the phosphate salt of the compound of formula I of the present invention has an X-ray diffraction pattern exhibiting 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-limiting X-ray powder diffraction data for crystalline form E of the phosphate salt of the compound of formula I of the present invention is shown in Table 6:

[0075] [Table 6]

[0076] A non-limiting XRPD pattern of crystalline form E of the phosphate salt of the compound of formula I of the present invention is shown in FIG.

[0077] As a non-limiting example, a DSC thermogram of crystalline form E of the phosphate salt of the compound of formula I of the present invention is shown in FIG.

[0078] The present invention provides a method for preparing crystalline form E of the phosphate salt of 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, the acetone solution of phosphoric acid is added to the acetone solution of the compound of formula I with stirring, the stirring is continued, and the solid is collected and 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 from 1:1.0 to 1:1.5.

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

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

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

[0084] In some embodiments, the solids are collected by centrifugation and dried under vacuum at 30-60° C. overnight.

[0085] In some embodiments, the recrystallization or crystalline conversion of crystalline form E of the phosphate salt of the compound of formula I is performed using a solvent, and the product is still crystalline form E of the phosphate salt 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 crystalline Form E of the phosphate salt of the compound of Formula I and stirring at room temperature, and the solid is collected and dried.

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

[0088] Crystalline form F of the phosphate salt of the compound of formula I of the present invention has an X-ray powder diffraction pattern exhibiting 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 pattern of crystalline form F of the phosphate salt of the compound of Formula I exhibits 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 pattern of crystalline form F of the phosphate salt of the compound of Formula I exhibits 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-limiting X-ray powder diffraction data for crystalline form F of the phosphate salt of the compound of formula I of the present invention is shown in Table 7:

[0092] [Table 7]

[0093] A non-limiting XRPD pattern of crystalline form F of the phosphate salt of the compound of formula I of the present invention is shown in FIG.

[0094] A non-limiting DSC thermogram of crystalline form F of the phosphate salt 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 salt of the compound of formula I of the present invention is 198.78°C.

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

[0096] The present invention provides a method for preparing crystalline form F of the phosphate salt of compound of formula I, specifically, the method is described as follows: dissolving crystalline form E of the phosphate salt of the compound of formula I in a first solvent to obtain a solution of crystalline form E of the phosphate salt of the compound of formula I in a first solvent, adding an anti-solvent, stirring, collecting the solid, and drying to obtain crystalline form F of the phosphate salt of the compound of formula I; or In some embodiments, the first solvent is a solvent capable of dissolving crystalline form E of the phosphate salt of the compound of formula I, preferably methanol; the anti-solvent is a solvent in which it is difficult to dissolve crystalline form E of the phosphate salt of the compound of formula I, preferably isopropyl acetate.

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

[0098] In some embodiments, an anti-solvent is used to dilute the first solvent solution of crystalline Form E of the phosphate salt of the compound of Formula I by 5-15 times, preferably 10 times.

[0099] In some embodiments, after dissolving crystalline form E of the phosphate salt of the compound of formula I in a first solvent, a small amount of seed crystals of crystalline form F of the phosphate salt of the compound of formula I is added until the system becomes slightly turbid, and then an anti-solvent is added.

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

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

[0102] Crystalline form G of the mesylate salt of the compound of formula I of the present invention has an X-ray powder diffraction pattern exhibiting 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 pattern of crystalline form G of the mesylate salt of the compound of formula I exhibits 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-limiting X-ray powder diffraction data for crystalline form G of the mesylate salt of the compound of formula I of the present invention is shown in Table 8.

[0105] [Table 8]

[0106] A non-limiting XRPD pattern of crystalline form G of the mesylate salt of compound of formula I of the present invention is shown in FIG.

[0107] A non-limiting DSC thermogram of crystalline form G of the mesylate salt of the compound of formula I of the present invention is shown in Figure 21. The DSC thermogram shows that the initial melting point of crystalline form G of the mesylate salt of the compound of formula I of the present invention is 218.78°C.

[0108] A non-limiting DVS isotherm plot of crystalline form G of the mesylate salt of the compound of formula I of the present invention is shown in FIG.

[0109] The present invention provides a method for preparing crystalline form G of the mesylate salt of 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, and the acetone solution of methanesulfonic acid is added to the acetone solution of the compound of formula I with stirring, and the stirring is continued, and the solid is collected and dried to obtain 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 compound of formula I in acetone is 10-30 mg / mL, preferably 20 mg / mL.

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

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

[0114] In some embodiments, the solids are collected by centrifugation and dried under vacuum at 30-60° C. overnight.

[0115] Crystalline form H of the hydrobromide salt of the compound of formula I of the present invention has an X-ray powder diffraction pattern exhibiting 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 pattern of crystalline form H of the hydrobromide salt of the compound of Formula I exhibits 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 pattern of crystalline form H of the hydrobromide salt of the compound of Formula I exhibits 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-limiting X-ray powder diffraction data for crystalline form H of the hydrobromide salt of the compound of formula I of the present invention is shown in Table 9.

[0119] [Table 9]

[0120] A non-limiting XRPD pattern of crystalline form H of the hydrobromide salt of the compound of formula I of the present invention is shown in FIG.

[0121] As a non-limiting example, a DSC thermogram of crystalline form H of the hydrobromide salt of the compound of formula I of the present invention is shown in FIG.

[0122] The present invention provides a method for preparing crystalline form H of the hydrobromide salt of 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, the acetone solution of hydrobromic acid is added to the acetone solution of the compound of formula I with stirring, the stirring is continued, the solid is collected and dried to obtain crystalline form H of the hydrobromic acid 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 compound of formula I in acetone is 10-30 mg / mL, preferably 20 mg / mL.

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

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

[0127] In some embodiments, the solids are collected by centrifugation and dried under vacuum at 30-60° C. overnight.

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

[0129] In some embodiments, the recrystallization or crystal conversion comprises the steps of: preparing a suspension by mixing crystalline form H of the hydrobromide salt of the compound of formula I with one or both of acetonitrile and methyl ethyl ketone, stirring at room temperature, centrifuging, collecting the solid and drying; Preferably, one or both of acetonitrile and methyl ethyl ketone are added to a vessel containing crystalline form H of the hydrobromide salt of the compound of formula I to prepare a suspension, which is stirred at room temperature, centrifuged, and the solid is collected and dried.

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

[0131] Non-limiting X-ray powder diffraction data for crystalline Form J of the hydrobromide salt of the compound of formula I of the present invention is shown in Table 10.

[0132] [Table 10]

[0133] A non-limiting XRPD pattern of crystalline form J of the hydrobromide salt of the compound of formula I of the present invention is shown in FIG.

[0134] The present invention provides a method for preparing crystalline form J of the hydrobromide salt of compound of formula I, specifically, the method is described as follows: The compound of formula I is dissolved in ethyl acetate to obtain a solution of the compound of formula I in ethyl acetate, the solution of hydrobromic acid in ethyl acetate is added to the solution of the compound of formula I in ethyl acetate with stirring, the stirring is continued, and the solid is collected and dried to obtain 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 compound of formula I in ethyl acetate is 10-30 mg / mL, preferably 20 mg / mL.

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

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

[0139] Crystalline form K of the hydrobromide salt of the compound of formula I of the present invention has an X-ray powder diffraction pattern exhibiting 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 pattern of crystalline form K of the hydrobromide salt of the compound of formula I exhibits 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 pattern of crystalline form K of the hydrobromide salt of the compound of formula I exhibits 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-limiting X-ray powder diffraction data for crystalline form K of the hydrobromide salt of the compound of formula I of the present invention is shown in Table 11:

[0143] [Table 11]

[0144] A non-limiting XRPD pattern of crystalline form K of the hydrobromide salt of the compound of formula I of the present invention is shown in FIG.

[0145] As a non-limiting example, a DSC thermogram of crystalline form K of the hydrobromide salt of the compound of formula I of the present invention is shown in FIG.

[0146] A non-limiting DVS isotherm plot of crystalline form K of the hydrobromide salt of compound of formula I of the present invention is shown in Figure 28. The DVS isotherm plot shows a weight gain of 11.84% of crystalline form K of the hydrobromide salt of compound of formula I of the present invention upon moisture absorption from 0% RH to 95% RH, indicating that the sample is hygroscopic. The moisture absorption curve during desorption shows hysteresis, which, combined with the XRPD patterns of the sample before and after the DVS test (see Figure 29 for the XRPD pattern after the test), indicates that the crystalline form of crystalline form K of the hydrobromide salt of compound of formula I of the present invention changed after moisture absorption.

[0147] The present invention provides a method for preparing crystalline form K of the hydrobromide salt of compound of formula I, specifically, the method is described as follows: Recrystallization or crystal transformation of crystalline form H of the hydrobromide salt of the compound of formula I using n-heptane gives crystalline form K of the hydrobromide salt of the compound of formula I.

[0148] In some embodiments, a suspension is prepared by mixing n-heptane with crystalline form H of the hydrobromide salt of the compound of formula I, stirring at room temperature, and collecting the solid and drying to obtain crystalline form K of the hydrobromide salt of the compound of formula I.

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

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

[0151] Crystalline form L of the fumarate salt of the compound of formula I of the present invention has an X-ray powder diffraction pattern exhibiting 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 salt of the compound of formula I exhibits 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 salt of the compound of formula I exhibits 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-limiting X-ray powder diffraction data for crystalline form L of the fumarate salt of the compound of formula I of the present invention is shown in Table 12.

[0155] [Table 12]

[0156] A non-limiting XRPD pattern of crystalline form L of the fumarate salt of the compound of formula I of the present invention is shown in FIG.

[0157] As a non-limiting example, a DSC thermogram of crystalline form L of the fumarate salt of the compound of formula I of the present invention is shown in FIG.

[0158] The present invention provides a method for preparing crystalline form L of the fumarate salt of 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, and the ethanolic solution of fumaric acid is added to the solution of the compound of formula I with stirring, and the stirring is continued, and the solid is collected and dried to obtain crystalline form L of the fumarate salt 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, where the solvent is 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 10-30 mg / mL, preferably 20 mg / mL.

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

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

[0163] In some embodiments, the solids are collected by centrifugation and dried under vacuum at 30-60° C. overnight.

[0164] Crystalline form M of the benzenesulfonate salt of the compound of formula I of the present invention has an X-ray powder diffraction pattern exhibiting 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 salt of the compound of formula I exhibits 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 salt of the compound of formula I exhibits 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-limiting X-ray powder diffraction data for crystalline form M of the benzenesulfonate salt of the compound of formula I of the present invention is shown in Table 13.

[0168] [Table 13]

[0169] As a non-limiting example, the XRPD pattern of crystalline form M of the benzenesulfonate salt of the compound of formula I of the present invention is shown in FIG.

[0170] As a non-limiting example, the DSC thermogram of crystalline form M of the benzenesulfonate salt of the compound of formula I of the present invention is shown in Figure 33. It shows that the initial melting point of crystalline form M of the benzenesulfonate salt of the compound of formula I of the present invention is 198.73°C.

[0171] Non-limiting DVS isotherm plots of crystalline form M of the benzenesulfonate salt of compound of formula I of the present invention are shown in Figure 34. The DVS isotherm plots show a 4.6% weight gain of crystalline form M of the benzenesulfonate salt of compound of formula I of the present invention upon moisture absorption from 0% RH to 95% RH. At a humidity of 85% RH, crystalline form M of the benzenesulfonate salt of compound of formula I of the present invention reaches a 0.54% weight gain, and at 70% RH, crystalline form M of the benzenesulfonate salt of compound of formula I of the present invention reaches a 0.97% weight gain. After moisture absorption, the crystalline form of crystalline form M of the benzenesulfonate salt of compound of formula I of the present invention 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 the benzenesulfonate salt of 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, the acetone solution of benzenesulfonic acid is added to the acetone solution of the compound of formula I with stirring, the stirring is continued, and the solid is collected and dried to obtain 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 compound of formula I in acetone is 10-30 mg / mL, preferably 20 mg / mL; In some embodiments, the concentration of the benzenesulfonic acid in the acetone solution is 15-35 mg / mL, preferably 25 mg / mL; In some embodiments, after adding the acetone solution of benzenesulfonic acid, stirring is continued at room temperature for 4 to 48 hours, preferably 24 hours; In some embodiments, the solids are collected by centrifugation and dried under vacuum at 30-60° C. overnight.

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

[0176] Non-limiting X-ray powder diffraction data for crystalline form N of the citrate salt of the compound of formula I of the present invention is shown in Table 14.

[0177] [Table 14]

[0178] A non-limiting XRPD pattern of crystalline form N of the citrate salt of the compound of formula I of the present invention is shown in FIG.

[0179] As a non-limiting example, a DSC thermogram of crystalline form N of the citrate salt of the compound of formula I of the present invention is shown in FIG.

[0180] The present invention provides a method for preparing crystalline form N of the citrate 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 a solution of the compound of formula I in ethyl acetate, the solution of citric acid in ethyl acetate is added to the solution of the compound of formula I in ethyl acetate with stirring, the stirring is continued, and the solid is collected and dried to obtain 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 compound of formula I in ethyl acetate is 10-30 mg / mL, preferably 20 mg / mL; In some embodiments, the concentration of the citric acid in ethyl acetate solution is 15-35 mg / mL, preferably 25 mg / mL; In some embodiments, after adding the citric acid in ethyl acetate solution, stirring is continued at room temperature for 4 to 48 hours, preferably 24 hours; In some embodiments, the solids are collected by centrifugation and dried under vacuum at 30-60° C. overnight.

[0182] Crystalline form O of the tartrate salt of the compound of formula I of the present invention has an X-ray powder diffraction pattern exhibiting 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 pattern of crystalline form O of the tartrate salt of the compound of Formula I exhibits 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 pattern of crystalline form O of the tartrate salt of the compound of Formula I exhibits 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-limiting X-ray powder diffraction data for crystalline form O of the tartrate salt of compound of formula I of the present invention is shown in Table 15:

[0186] [Table 15]

[0187] A non-limiting XRPD pattern of crystalline form O of the tartrate salt of compound of formula I of the present invention is shown in FIG.

[0188] As a non-limiting example, a DSC thermogram of crystalline form O of the tartrate salt of the compound of formula I of the present invention is shown in Figure 39. 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] Without limitation, a TGA thermogram of crystalline form O of the tartrate salt of compound of formula I of the present invention is shown in Figure 40. The TGA thermogram shows that crystalline form O of the tartrate salt of compound of formula I of the present invention has only a 0.05% weight loss between 26°C and 120°C, indicating that crystalline form O of the tartrate salt of compound of formula I does not contain water of crystallization or solvent.

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

[0191] The present invention provides a method for preparing crystalline form O of the tartrate salt of compound of formula I, specifically, the method is described as follows: Mixing a compound of formula I with a first solvent and dissolving the compound until the solution is clear to obtain a solution of the compound of formula I in the first solvent; mixing tartaric acid with a second solvent and dissolving the compound until the solution is clear to obtain a solution of tartaric acid in the second solvent; adding the second solvent solution of tartaric acid to the solution of the compound of formula I in the first solvent with stirring, performing rate controlled cooling with stirring, collecting and drying the solid to obtain crystalline form O of the tartrate salt of the compound of formula I.

[0192] In some embodiments, the first solvent and the second solvent 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), 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 compound of formula I in acetone is 15-70 mg / mL, preferably 40-60 mg / mL, and more preferably 50 mg / mL.

[0196] In some embodiments, the concentration of the tartaric acid in 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, the acetone solution of tartaric acid is added to the acetone solution of the compound of Formula I at 40-60°C, preferably 45-55°C.

[0200] In some embodiments, rate controlled cooling is achieved by the following steps: 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; 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 to 15° C., for example 5 to 10° C., and the temperature is maintained while stirring for 0.5 to 3 hours, preferably 1 to 2 hours.

[0201] In the present invention, rate controlled cooling allows the system to be gradually cooled in stages and maintained within a given temperature range for a given duration.

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

[0203] In some embodiments, during rate controlled cooling, the system continues to be 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 to 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 with a blower for 5-48 hours, preferably 16-28 hours.

[0206] The present invention also provides pharmaceutical compositions 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 pharmaceutical formulations 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 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 in the preparation of a medicament for treating a JAK1 / TYK2-related disease or condition, wherein the disease or condition may be an autoimmune disease or disorder, such as rheumatoid arthritis or an inflammatory disease or disorder, and a cancer or a tumor proliferative disease or disorder.

[0209] In the present invention, unless otherwise specified, the temperatures included refer to the internal temperatures of the reaction system.

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

[0211] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an XRPD pattern of crystalline form 1 of the compound of formula I of the present invention.

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

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

[0214] FIG. 4 is a DVS isotherm plot of crystalline Form 1 of the compound of formula I of the present invention.

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

[0216] FIG. 6 is an XRPD pattern of crystalline form A of the hydrochloride salt of the compound of formula I of the present invention.

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

[0218] FIG. 8 is an XRPD pattern of crystalline form B of the hydrochloride salt of the compound of formula I of the present invention.

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

[0220] FIG. 10 is an XRPD pattern of crystalline form C of the hydrochloride salt of the compound of formula I of the present invention.

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

[0222] FIG. 12 is an XRPD pattern of crystalline form D of the sulfate salt of the compound of formula I of the present invention.

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

[0224] FIG. 14 is an XRPD pattern of crystalline form E of the phosphate salt of the compound of formula I of the present invention.

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

[0226] FIG. 16 is an XRPD pattern of crystalline form F of the phosphate salt of the compound of formula I of the present invention.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0242] FIG. 32 is an XRPD pattern of crystalline form M of the benzenesulfonate salt of the compound of formula I of the present invention.

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

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

[0245] FIG. 35 is an XRPD overlay pattern of crystalline form M of the benzenesulfonate salt of the compound of formula I of the present invention before and after DVS testing.

[0246] FIG. 36 is an XRPD pattern of crystalline form N of the citrate salt of the compound of formula I of the present invention.

[0247] FIG. 37 is a DSC thermogram of crystalline form N of the citrate salt of the compound of Formula I of the present invention.

[0248] FIG. 38 is an XRPD pattern of crystalline form O of the tartrate salt of the compound of formula I of the present invention.

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

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

[0251] FIG. 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] FIG. 42 is an XRPD overlay pattern of crystalline form O of the tartrate salt of compound of formula I of the present invention before and after DVS testing.

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

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

[0255] FIG. 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 two weeks of exposure to elevated temperature and accelerated conditions.

[0256] FIG. 46 is an XRPD overlay pattern of crystalline form O of the tartrate salt of compound of Formula I of the present invention after two weeks of exposure to elevated temperature and accelerated conditions.

[0257] FIG. 47 is a DSC overlay thermogram of crystalline form F of the phosphate salt of the compound of Formula I of the invention after two weeks of exposure to elevated temperature and accelerated conditions.

[0258] FIG. 48 is a DSC overlay thermogram of crystalline form O of the tartrate salt of the compound of Formula I of the invention after two weeks of exposure to elevated temperature and accelerated conditions.

[0259] FIG. 49 is an XRPD overlay pattern of crystalline Form 1 of compound of formula I of the present invention after two weeks of exposure to elevated temperature and accelerated conditions.

[0260] FIG. 50 is a DSC overlay thermogram of crystalline Form 1 of compound of formula I of the present invention after two weeks of exposure to elevated temperature and accelerated conditions.

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

[0262] [Table 16] JPEG0007628967000020.jpg169169

[0263] The information regarding the raw materials and reagents used in the present invention is as follows:

[0264] [Table 17] JPEG0007628967000022.jpg111169

[0265] [Example] Preparation of Compounds of Formula III

[0266] [ka]

[0267] Example 1 Preparation of Compound of Formula III Ethanol (4 mL), compound of formula IV (0.20 g, 1.0 equiv.), compound of formula V (0.18 g, 1.0 equiv.), and DIPEA (0.39 g, 3.0 equiv.) were added to a 25 mL three-neck flask and stirred; under nitrogen protection, the system was heated to reflux (70-80 °C) and stirred at reflux temperature overnight; the system was cooled to room temperature (15-20 °C) and the solid was precipitated 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; 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; about 0.21 g of yellow solid was obtained, the LC-MS purity was 96.4% (214 nm), and the yield was 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 Compound of Formula III Ethanol (120mL, 20V), compound of formula IV (6.0g, 1.0eq), compound of formula V (5.4g, 1.01eq), and DIPEA (11.7g, 3.0eq) were added to a 250mL three-neck flask and stirred; under nitrogen protection, the system was heated to 70-80℃ (internal temperature) and stirred while maintaining the temperature for 8 hours; the system was cooled to room temperature (15-20℃) and the solid was precipitated during cooling; water (120mL, 20V) was added dropwise to the system and the system was stirred at room temperature (10-15℃) for 2 hours; filtered, the filter cake was washed with aqueous ethanol (30mL, 1:1), and the filter cake was dried under vacuum at 50℃ for 16 hours; in total, about 7.7g of yellow solid was obtained, the HPLC purity was 95.5%, and the yield was 84.3%.

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

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

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

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

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

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

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

[0277] Example 6 Preparation of Compound of Formula III Ethanol (180 mL, 10 V), compound of formula IV (17.8 g, 1.0 equiv.), compound of formula V (16.0 g, 1.01 equiv.), and DIPEA (25.7 g, 2.2 equiv.) were added to a 500 mL three-neck flask and stirred; under nitrogen protection, the system was heated to reflux at 70-80°C and stirred for 5 hours; the system was cooled to room temperature (15-20°C) and the solid was precipitated during cooling; water (270 The system was cooled to 5-10°C and stirred for 2 hours; filtered, and the filter cake was washed with an aqueous ethanol solution (ethanol:water=1:1.5, V / V, 40 mL); the filter cake was dried under vacuum at 50°C for 16 hours; in total, about 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 1 H NMR data is consistent with Example 1.

[0279] Example 7 Preparation of Compound of Formula III Ethanol (1000 mL, 10V), the compound of formula IV (100 g, 1.0 equiv.), the compound of formula V (89.9 g, 1.01 equiv.), and DIPEA (143.2 g, 2.2 equiv.) were added to a 3000 mL three-neck flask and stirred; under nitrogen protection, the system was heated to 85-90°C (internal temperature: about 75°C) and refluxed, and stirred for 10 hours; the system was cooled to room temperature (15-20°C), and the solid was precipitated during cooling. Water (1500mL, 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, the filter cake was washed with aqueous ethanol (1:1.5, V / V, 200mL), and the filter cake was dried under vacuum at 50°C for 16 hours; about 130g of reddish brown solid was obtained in total, with an HPLC purity of 94.2% and a yield of 85.5%.

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

[0281] Example 8 Preparation of Compound of Formula III Ethanol (2000 mL, 10V), compound of formula IV (200 g, 1.0 equiv.), compound of formula V (179.7 g, 1.01 equiv.), and DIPEA (286.4 g, 2.2 equiv.) were added to a 5000 mL three-neck flask and stirred; under nitrogen protection, the system was heated to 70-80°C (internal temperature: about 65-70°C) to reflux and stirred for 16 hours; the system was cooled to room temperature (15-20°C) and solids were precipitated during cooling; water ( 3000mL, 15V) was dropped into 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, the filter cake was washed with aqueous ethanol solution (1:1.5, V / V, 400mL), and the filter cake was dried at 50°C for 16 hours using a blower; a total of about 251g 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 1 H NMR data is consistent with Example 1.

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

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

[0285] Example 10 Preparation of Compound of Formula III Ethanol (100 mL, 10V), compound of formula IV (10.0 g, 1.0 equiv.), compound of formula V (9.0 g, 1.01 equiv.), and DIPEA (14.3 g, 2.2 equiv.) were added to a 500 mL three-neck flask and stirred; the system was heated to 70-80°C to reflux and stirred for 16 hours; the system was cooled to room temperature (20-30°C) and the solid was allowed to precipitate during cooling; water (150 mL , 15V) was added to the system, and the system was 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 filter cake was washed with aqueous ethanol (1:1.5, V / V, 25mL), and the filter cake was dried in an oven under vacuum at 50-55°C for 16 hours; about 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 1 H NMR data is consistent with Example 1.

[0287] Example 11 Preparation of Compound of Formula III Ethanol (17 Kg, 10 V), compound of formula IV (2.2 Kg, 1.0 eq.), compound of formula V (1.98 Kg, 1.01 eq.), and DIPEA (3.19 Kg, 2.2 eq.) were added to an 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) and solids were allowed to precipitate during cooling; water (33 Kg, 15 V) was added dropwise to the system, and the system was cooled to room temperature. The mixture was stirred at room temperature (10-15°C) for 2 hours; the system was cooled to 5-10°C and stirred for 4 hours; filtered, the filter cake was washed with aqueous ethanol solution (ethanol:water=1:2, V / V, 6.2Kg), and the filter cake was dried under vacuum (≦-0.08MPa) at a jacket temperature of 45-55°C for 16 hours; a total of about 2.64g 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 1 H NMR data is consistent with Example 1.

[0289] Preparation of Compounds of Formula II

[0290] [ka]

[0291] Example 12 Preparation of Compound of Formula II The compound of formula III (5.0 g), THF (50 mL, 10 V) and palladium on carbon (0.75 g, 10% Pd / C, 50% wet) were added successively to a 100 mL stainless steel autoclave; the system was purged with nitrogen five times, then with hydrogen five times; 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 solution 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 a brown solid, with an HPLC purity of 94.9% and a yield of 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 of Formula II The compound of formula III (120.0 g), THF (2400 mL, 20 V) and palladium on carbon (18 g, 10% Pd / C, 50% wet) were added successively to a 5000 mL stainless steel autoclave; the system was purged with nitrogen five times, then with hydrogen five times; the pressure of the system was increased to 0.50 MPa with hydrogen, then the system was heated to 25-35 °C and stirred for 24 hours while maintaining the temperature; the reaction solution was filtered through diatomaceous earth, the filter cake was washed with THF (600 mL) (until TLC showed almost no fluorescence), and the filtrate was concentrated to obtain 130 g of a black semi-oily solid, with an HPLC purity of 91.7% and a yield of 120.26%.

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

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

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

[0297] Work-up 2: The above filtrate (450 g, about 10 g of compound of formula II calculated according to 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, calculated to be about 10 g of the compound of formula II) was added to a flask and concentrated to about 30-40 mL (3-4 V) using a rotary evaporator; the concentrated residue was replaced with ethanol (50 mL x 2) to about 30-40 mL (3-4 V) to obtain a black oily concentrated residue, which was directly supplied to the next reaction step.

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

[0300] Example 15: Preparation of compounds of formula II THF (240 mL, 20 V), the compound of formula III (12.0 g), and palladium on carbon (1.8 g, 5% Pd / C, 50% wet) were added successively to a 5000 mL three-neck flask; the system was purged with nitrogen five times, then with hydrogen five times; the system was stirred under hydrogen pressure (about 0.1 MPa) for 48 hours 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 ethanol (60 mL × 2) to 20-30 mL; an ethanol solution of 24 g of the compound of formula II was obtained, which was used directly in the next reaction step.

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

[0302] Example 16 Preparation of Compound of Formula II THF (1500 mL, 15V), compound of formula III (100 g), and palladium on carbon (15 g, 5% Pd / C, 50% wet) were added successively to a 5000 mL three-neck flask; the system was purged with nitrogen five times, then purged with hydrogen five times; the system was stirred under hydrogen pressure (about 0.1 MPa) while maintaining the temperature at room temperature (20-25 °C) for 48 hours; 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 compound of formula II in THF, with an HPLC purity of 94.2%, a content of 43.2%, and a content yield of 94.0%.

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

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

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

[0306] Example 18 Preparation of Compound of Formula II THF (140 mL, 70 V), the compound of formula III (2.0 g), and palladium on carbon (0.3 g, 5% Pd / C, 50% wet) were added to a 250 mL autoclave; the autoclave was covered with a cap and the nut was tightened; the system was purged with nitrogen three times, then with hydrogen three times; the autoclave was filled with hydrogen to a pressure of about 0.50 ± 0.05 MPa, and the inlet valve was closed; the stirring device was started with a rotation speed of 500 r / min; the hydrogen pressure of the autoclave was maintained at 0.5 ± 0.05 MPa at 25-35 °C, and the system was stirred for 96 h to react, and the reaction liquid 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 a semi-oily solid, with an HPLC purity of 91.2% and a yield of 99.9%.

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

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

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

[0310] Example 20: Preparation of compound of formula II THF (60 mL, 12 V), the compound of formula III (5.0 g), and palladium on carbon (0.75 g, 5% Pd / C, 50% wet) were added to a 100 mL stainless steel autoclave; the system was purged with nitrogen five times, then with hydrogen five times; the system pressure 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 completed, the reaction solution was filtered through diatomaceous earth, and the filter cake was washed with THF (100 mL); a total of 197.8 g of the compound of formula II in THF solution was obtained; the solution was concentrated to (2-3 V, 10-15 mL) using a rotary evaporator; the system was replaced with ethanol (25 mL × 2) to (2-3 V, 10-15 mL); an ethanol solution of the compound of formula II was obtained, which was directly used in the next reaction step.

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

[0312] Preparation of Compounds of Formula I

[0313] [ka]

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

[0315] The system was cooled to room temperature, and the reaction solution in the system was concentrated using a rotary evaporator until no fractions were essentially eluted; Water (50 mL) was added to the system, and the pH value of the system was adjusted to 9-10 using 4M sodium hydroxide solution; The system was extracted with ethyl acetate (50 mL), filtered, and the filter cake was washed with ethyl acetate (10 mL) to obtain 3.5 g of the filter cake wet product of the compound of formula I. LC-MS test showed that the purity of the compound of formula I was 99.22%; The filtrate obtained by filtration and washing was separated, and the aqueous phase was extracted with ethyl acetate (50 mL), and the organic phases were combined and concentrated to dryness to obtain 2.8 g of the crude product of the compound of formula I. LC-MS test 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 Compound of Formula I The compound of formula II (54 g, 1.0 eq.), trimethyl orthoacetate (71.5 g, 3.0 eq.) and THF (1.35 L) were added to a 3 L three-neck flask; under nitrogen protection, the system was heated to reflux; pyridine hydrochloride (2.27 g, 0.1 eq.) was added to the three-neck flask; under nitrogen protection, the system was heated to 75 ± 5 ° C (internal temperature 60-63 ° C) and reacted for 8 hours. HPLC monitoring showed that 1.5% of the compound of formula II remained in the system; the system was cooled to room temperature and trimethyl orthoacetate (11.9 g, 0.5 eq.) and pyridine hydrochloride (1.14 g, 0.05 eq.) were added to the system; under nitrogen protection, the system was heated to 75 ± 5 ° C (internal temperature 60-63 ° C) 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 in 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 there was essentially no effluent; water (540 mL, 10 V) was added to the system, and the pH of the system was adjusted to 9-10 using 4 M sodium hydroxide solution; the system was filtered, and the filter cake was washed with water (270 mL), then with MTBE (270 mL), and the obtained filter cake was dried under vacuum at 50°C for 16 hours to obtain 56 g of a crude product of the compound of formula II, with an HPLC purity of 96.32%; the obtained crude product was dissolved in 600 mL of methanol until the solution became transparent, and a silicon-based metal removal agent (43 g) and activated carbon (5.4 g) were added to the system. The mixture was heated to reflux and the temperature was maintained for 1 hour (internal temperature 50°C); the system was cooled to room temperature, filtered through diatomaceous earth, and washed with methanol (15 mL) until the filtrate no longer emitted fluorescence; the methanol solution was concentrated to dryness and the drop rate of the distillate was slowed down; MTBE (540 mL) was added to the obtained solid, the system was heated to reflux at 50°C 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 filter cake was washed with chilled MTBE (100 mL); the obtained filter 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 about 23 g of a pale yellow solid; MTBE (230 mL) was added and the temperature was raised to 50°C and the system was refluxed for 10 minutes; Methanol was added to the system in portions until the total amount added was about 30 mL and the material was essentially dissolved and the solution was clear; The system was cooled to 10-15°C and stirred for 1 hour; Filtered and the filter cake was washed with chilled MTBE (50 mL); The filter cake was dried under vacuum at 50°C for 16 hours to obtain 8.7 g of the compound of formula I as an off-white solid, with a purity of 97.8% by HPLC.

[0320] Further refinement: 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 a reaction flask, the system was ground at room temperature for 4 hours, filtered, the filter cake was washed with MTBE (20 mL), and the filter 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 1 H NMR data is consistent with Example 21.

[0322] Example 23 Preparation of Compound of Formula I A solution of the compound of formula II prepared in Example 14 in THF (45 g, containing about 1 g of the compound of formula II, 1 equivalent) that was not subjected to work-up was added to the flask, and the solution was concentrated to 3 mL by rotary evaporation. Toluene (5 mL) was added to the flask, and then rotary evaporated to 3 mL, and this process was repeated twice to obtain a black oily concentrated residue.

[0323] 1.0 g of black oily concentrated residue obtained in the previous step, trimethyl orthoacetate (1.32 g, 3.0 eq.) and THF (25 mL) were added to a 100 mL three-neck flask; under nitrogen protection, the system was heated to reflux; pyridine hydrochloride (0.08 g, 0.2 eq.) was added to the three-neck flask; under nitrogen protection, the system was heated to 65-70°C (internal temperature) and reacted for 5 hours; sampled 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, sampled 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 of Formula I A solution of the compound of formula II prepared in Example 14 in THF (450 g, containing about 10.0 g of the compound of formula II, 1 equivalent) without workup was added to the flask, and the solution was concentrated to 20-30 mL by rotary evaporation. Toluene (50 mL) was added to the flask, and the system was rotary evaporated to 20-30 mL, and this process was repeated twice to obtain a black oily concentrated residue, which was dissolved in THF (20 mL, 2 V)I until the solution became clear.

[0325] The THF solution obtained in the previous step, trimethyl orthoacetate (13.2 g, 3.0 eq.) and THF (230 mL) were added to a 500 mL three-neck flask; under nitrogen protection, the system was heated to reflux; pyridine hydrochloride (0.8 g, 0.2 eq.) was added to the three-neck flask; under nitrogen protection, the system was heated to 65-70°C (internal temperature) and reacted for 10 hours; a sample was 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 by rotary evaporator until there was essentially no effluent; the system was supplemented with water (100 mL, 10 V); the pH value of the system was adjusted to 9 using saturated potassium carbonate solution; the system was filtered, and the filter cake was washed successively 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 earthy yellow crude product of compound of formula I, with an HPLC purity of 89.7% and a crude yield of 84.5%.

[0327] Purification of the compound of formula I: The crude product of the compound 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 materials were essentially dissolved and the solution was clear; silica gel (5.0 g, 1X) was added to the system, and the system was concentrated to dryness by rotary evaporator for later use; the solid crude product obtained by rotary evaporation was passed through a silica gel column (40 g, 8X), and the column was eluted with a mixed solution of ethyl acetate and petroleum ether (V EA :V PE =2:1); fractions containing the compound of formula I by TLC test were collected and concentrated to dryness to give 0.5 g of the compound of formula I with a purity of 96.5% and 3.2 g of a 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 the system was stirred for 1 hour while maintaining the temperature; 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 as a pale yellow to off-white solid, free of impurities, with 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 Compound of Formula I The THF solution of the compound of formula II prepared in Example 14 (130 g, containing about 56 g of the compound of formula II, 1 equivalent) that was not subjected to post-treatment was added to the 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, THF (500 mL) was added until the solid dissolved and the solution became clear, the resulting solution was transferred to a 2 L three-neck flask, 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; a sample was 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 reaction solution was cooled to room temperature, and a portion of the reaction solution (corresponding to the amount containing 55 g of the compound of formula II before the reaction) was taken and water (110 mL, 2 V) was added; the mixture 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, and then water (440 mL, 8 V) was added and stirred at room temperature (25-30°C) for 30 minutes; 50% carbonate was added. The pH of the system was adjusted to 8-9 using sodium solution (1.5 g (total solution mass)); 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, and the filter cake was dried at 50 ° C for 24 hours to obtain 55 g of compound of formula I with an earthy yellow color, the purity was 96.6%, the content was 87.53%, and the content yield of the crude product was 80.4%.

[0331] Purification of the compound of formula I: The crude product (55 g) of the compound of formula I with 96.6% HPLC purity obtained in the previous step, 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 by a rotary evaporator until there was essentially no fraction flowing out, and then replaced with n-heptane (200 mL) to dryness, the system was mixed with silica gel, 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 = 1:1 to pure EA); TLC test revealed that the compound component A of formula I and cross component B were recovered.

[0332] Component A was concentrated to about 100 mL by rotary evaporator, and the concentrated residue was replaced with about 200 mL of methanol twice, then replaced with MTBE (about 200 mL) twice, and then about 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 (1 hour); the system was cooled to 5-10 ° C, stirred at 5-10 ° C for 2 hours, filtered, and the filter cake was washed with MTBE (30 mL); the filter 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 with a content of >0.1%.

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

[0334] The above compound of formula I (4.8 g) (purity 99.35%), MTBE (50 mL) and ethanol (5 mL) were added to a flask, the system was heated to 55-60 ° C, the system was refluxed for 0.5 hours, 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, stirred at 5-10 ° C for 2 hours, filtered, and the filter cake was washed with MTBE (10 mL); the washed filter cake was dried under vacuum at 50-55 ° C for 16 hours to obtain 4.0 g of the compound of formula I, the purity was 99.75%, and the content of impurities was not more than 0.1%.

[0335] Example 26 Preparation of Compound of Formula I The THF solution of the compound of formula II prepared in Example 14 (14.5 g, containing about 5.0 g of the compound of formula II, 1 equivalent) without post-treatment was added to the flask, the solution was replaced with toluene (25 mL x 2), concentrated to about 10-15 mL, then replaced with THF (25 mL), concentrated to about 10-15 mL, then added THF (115 mL) until the solid dissolved and the solution became clear, and the resulting solution was transferred to a 500 L three-neck flask; trimethyl orthoacetate (6.6 g, 3.0 equivalents) was added to the system; under nitrogen protection, the system was heated to reflux; pyridine hydrochloride (0.42 g, 0.2 equivalents) was added to the three-neck flask; under nitrogen protection, the system was heated to 70-75 ° C (internal temperature) and reacted for 15 hours; sampled and tested. HPLC showed that 4.0% of the compound of formula II remained in the reaction solution; trimethyl orthoacetate (0.5 g) and pyridine hydrochloride (0.1 g) were added to the system, and the system was refluxed at 70-75°C (internal temperature) for 5 hours; a sample was taken and tested. HPLC showed that 0.05% of the compound of formula II remained in the reaction solution, and the purity of the compound of formula I was 92.80%.

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

[0337] The reaction liquid obtained in the previous step was cooled to room temperature, 570 g of water was added, and the system was concentrated to 600-900 mL (2-3 V) by a rotary evaporator, the concentrated residue was transferred to a 10 L flask, 2000 g of water (about 7 V) was slowly added, the system was stirred at room temperature for 1 hour, then 2300 g of water (about 8 V) was added, the system was stirred at room temperature (25-30 ° C) for 1 hour, and the pH of the system was adjusted to 8-9 using 50% potassium carbonate solution (8.5 g); 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 filter cake was washed with water (500 g); the washed filter cake was dried at 50 ° C for 72 hours, sampled, and the water content was tested. The water content tested by the Karl Fischer method was 3.2%. The crude product of the compound of formula I was obtained in an amount of 252 g with an earthy yellow color, with an HPLC purity of 97.5%, a content of 89.8%, and a crude content yield of 72.3%.

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

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

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

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

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

[0343] The reaction liquid of the previous step was cooled to 25 ℃, and 2.0 kg of water was added; Distillation was carried out under reduced pressure at 45 ± 5 ℃ to a volume of about 2L, and 2L of water was added to the rotary evaporation flask, and the material liquid in the flask was transferred to the reactor, and 5 kg of water was slowly added, and stirred at 25 ℃ for 1 hour; 5 kg of water was added to the reactor, and stirred at 25 ℃ 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 ℃ for 1 hour; The material liquid in the reactor was cooled to 10-15 ℃, and stirred for 2 hours; The system was filtered, and the filter cake was washed with 2 kg of water, and then dried under vacuum at 45-55 ℃ for 48 hours to obtain 0.91 kg of the compound of formula I, the water content tested by KF method was 0.2%, the HPLC purity was 95.71%, the water content was 85.39%, and the content yield was 71.4%.

[0344] Purification of the compound of formula I: The compound of formula I (0.91 kg) with 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 materials, and the solution was essentially transparent; silica gel (1.82 kg) was added to the rotary evaporation flask, and the system was concentrated to a dry powder under reduced pressure at 50-60°C; n-heptane (1.82 kg) was added to the rotary evaporation flask; The mixture was added to a rotary evaporation flask, and the system was concentrated and replaced at 40-50 °C to make a dry 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 and dried in the previous step was added to the column, and the column was eluted with n-heptane (18 kg), a mixture of n-heptane / ethyl acetate (1:1 V / V, 72 kg; 1:2 V / V, 158 kg; 1:5 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) in sequence, 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 50L reactor and the system was concentrated under vacuum at 40-50°C to a minimum stirring volume (about 6L); MTBE (5.0kg x 5) was added to the reactor and the system was concentrated and replaced 5 times; MTBE (1.2kg) was added to the reactor and the system was heated to reflux (50-60°C) and 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; Filtered and the filter cake was washed with MTBE (0.25kg); 0.62kg of the compound of formula I was obtained, and the HPLC purity was 100.0%; The filter cake was dried at 50°C for 16 hours to obtain 0.55kg of the compound of formula I, and the moisture content tested by KF method was 0.04% and the Pd residue was <2ppm.

[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 a minimum stirring volume (about 1 L); MTBE (1.5 kg × 2) was added to the reaction flask, and the system was heated in a water bath at 45-50 ° C, distilled under vacuum to a minimum stirring volume, and replaced twice; MTBE (1.5 kg) and absolute ethanol (0.14 kg) were added to the reaction flask, and the system was heated to 50-60 ° C and stirred for 1 hour; The material liquid in the reaction flask was cooled to 20-25 ° C, and the system was stirred for 1 hour while maintaining the temperature; Cooled, the temperature of the material liquid in the reaction flask was reduced to 6-10 ° C, and the system was stirred for 2 hours while maintaining the temperature; Filtered, and the filter cake was washed with MTBE (0.24 kg); Filter cake, MTBE (1.5 kg) / absolute ethanol (0.14 kg) was 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 liquid in the reaction flask was reduced to 20-25°C, and the system was stirred for 1 hour while maintaining the temperature;Cooled, the temperature of the material liquid in the reaction flask was reduced to 6-10°C, and the system was stirred for 2 hours while maintaining the temperature;Filtered, and the filter cake was washed with MTBE (0.24 kg);115 g of wet product was obtained, the HPLC purity was 99.8%, and the maximum individual impurity content was 0.09%;The wet product was dried at 45-55°C under a vacuum of ≦-0.080 MPa for 16 hours;0.10 kg of the compound of formula I was obtained, and the moisture content tested by KF method was 0.08%, the HPLC purity was 99.8%, the maximum individual impurity content was 0.09%, and the Pd residue was less than 2 ppm.

[0347] Unless otherwise stated, the compound of formula I, as finally purified and prepared in Example 27, is the starting material in the following examples.

[0348] Preparation of Crystalline Form 1 of Compound of Formula I [Example 30] The wet product and the crude product of the filter cake of the compound of formula I obtained in Example 21 were combined and dissolved in methanol (40 mL); silicon-based metal removing agent (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. Filtered and washed the filter cake with MTBE (15 mL); the filter 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%. When tested, the solid was crystalline form 1 of the compound of formula I. Please refer to Figures 1-4 for the XRPD pattern, DSC thermogram, TGA thermogram and DVS isotherm plot.

[0349] Preparation of Crystalline Form A of the Hydrochloride Salt of Compound of Formula I [Example 31] Approximately 50 mg of the compound of formula I was weighed and placed in a small bottle, 2.5 mL of acetone was added, and the system was subjected to ultrasonic treatment and heating until the compound was completely dissolved, to prepare a 20 mg / mL solution of the compound of formula I in acetone. The sample bottle was placed on a magnetic stirring plate, magnetic stirring was performed, and 0.73 mL of a solution of hydrochloric acid in acetone (the concentration of the solution of hydrochloric acid in acetone was 25 mg / mL) was slowly dripped in to produce a white precipitate, the cap of the bottle was tightly covered at room temperature, and the system was stirred for one day, and then the suspension was centrifuged and the collected solid was dried overnight at 40° C. under vacuum to obtain a hydrochloride salt solid of the compound of formula I. When tested, the solid was crystalline form A of the hydrochloride salt of the compound of formula I. See Figures 6 and 7 for the XRPD pattern and DSC thermogram.

[0350] Preparation of Crystalline Form B of the Hydrochloride of Compound of Formula I [Example 32] Approximately 50 mg of the compound of formula I was weighed and placed in a small bottle, 2.5 mL of ethyl acetate was added, and the system was subjected to ultrasonication and heating until the compound was completely dissolved, to prepare a 20 mg / mL solution of the compound of formula I in ethyl acetate. The sample bottle was placed on a magnetic stirring plate, magnetic stirring was performed, and 0.73 mL of a solution of hydrochloric acid in ethyl acetate (the concentration of the solution of hydrochloric acid in ethyl acetate was 25 mg / mL) was slowly dripped in to produce a white precipitate, the bottle cap was tightly covered at room temperature, and the system was stirred for one day, and then the suspension was centrifuged and the collected solid was dried overnight at 40° C. under vacuum to obtain a hydrochloride salt solid of the compound of formula I. When tested, the solid was crystalline form B of the hydrochloride salt of the compound of formula 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 of Formula I [Example 33] 5 mg of crystalline form A of the hydrochloride salt of the compound of formula I prepared in Example 31 was weighed and placed in a small bottle, an appropriate amount of methanol was added, the resulting sample suspension was magnetically stirred at room temperature overnight, the system was centrifuged to separate the solid from the liquid, the solid was collected and dried under vacuum at 40° C. overnight to obtain a solid of the hydrochloride salt of the compound of formula I. When tested, the solid was crystalline form C of the hydrochloride salt of the compound of formula I. Please refer to Figures 10 and 11 for the XRPD pattern and DSC thermogram.

[0352] [Examples 34 to 36] The same crystallization method as in Example 33 was adopted. The solvent was changed to acetonitrile, n-heptane and methyl ethyl ketone to prepare the crystalline form C of the hydrochloride salt of the compound of formula I. 34~36 The XRPD pattern of the solid compound prepared in was consistent with FIG.

[0353] <Preparation of Crystalline Form D of the Sulfate Salt of the Compound of Formula I> [Example 37] Approximately 50 mg of the compound of formula I was weighed and placed in a small bottle, 2.5 mL of acetone was added, and the system was subjected to ultrasonic treatment and heating until the compound was completely dissolved, to prepare a 20 mg / mL solution of the compound of formula I in acetone. The sample bottle was placed on a magnetic stirring plate and magnetically stirred, and 0.77 mL of a solution of sulfuric acid in acetone (the concentration of the solution of sulfuric acid in acetone was 25 mg / mL) was added, producing a white precipitate, the bottle cap was tightly covered at room temperature, and the system was stirred for one day, and then the suspension was centrifuged and the collected solid was dried overnight at 40° C. under vacuum to obtain a sulfate salt solid of the compound of formula I. When tested, the solid was crystalline form D of the sulfate salt of the compound of formula I. See Figures 12 and 13 for the XRPD pattern and DSC thermogram.

[0354] <Preparation of Crystal Form E of the Phosphate of the Compound of Formula I> [Example 38] Approximately 50 mg of the compound of formula I was weighed and placed in a small bottle, 2.5 mL of acetone was added, and the system was subjected to ultrasonic treatment and heating until the compound was completely dissolved, to prepare a 20 mg / mL solution of the compound of formula I in acetone. The sample bottle was placed on a magnetic stirring plate, magnetic stirring was performed, and 0.86 mL of a solution of phosphoric acid in acetone (the concentration of the solution of phosphoric acid in acetone was 25 mg / mL) was slowly dripped in to produce a white precipitate, the bottle cap was tightly covered at room temperature, and the system was stirred for one day, and then the suspension was centrifuged and the collected solid was dried overnight at 40° C. under vacuum to obtain a phosphate solid of the compound of formula I. When tested, the solid was the crystalline form E of the phosphate salt of the compound of formula I. See Figures 14 and 15 for the XRPD pattern and DSC thermogram.

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

[0356] Ion chromatography tests were carried out on the sample solutions and standard solutions (see Table 16 for the test method). A standard curve was plotted with the peak area of ​​the counter ion on the ion chromatogram corresponding to the concentration of the counter ion in the standard sample solution, and the concentration of the counter ion in each sample was calculated using the external standard method. The content of the counter ion in the crystal form E of the phosphate salt of the compound of formula I was calculated to determine the salt formation rate of the compound of formula I and the corresponding counter ion in the crystal form E of the phosphate salt of the compound of formula I.

[0357] [Table 18]

[0358] Please refer to Table 17 for the counter ion content in the crystal form E of the phosphate salt of the compound of formula I. The compound of formula I and phosphoric acid were fed in a molar ratio of 1:1.1 to 0.5 g of the crystal form E of the phosphate salt of the compound of formula I, and reacted. The actual content of phosphate anion in the obtained phosphate salt was 25.6%, which was basically consistent with the theoretical content of 24.9%. The molar ratio of salt formation was 1:1.04 (compound of formula I:phosphoric acid).

[0359] [Table 19]

[0360] [Example 39] 5 mg of the phosphate form E of the compound of formula I prepared in Example 38 was weighed and placed in a small bottle, an appropriate amount of methanol was added, the sample suspension was magnetically stirred at room temperature overnight, the system was centrifuged to separate the solid from the liquid, the solid was collected and dried under vacuum at 40° C. overnight to obtain a phosphate solid of the compound of formula I. When tested, the solid was found to be the phosphate form E of the compound of formula I. Its XRPD pattern is consistent with FIG. 14.

[0361] [Examples 40 to 42] The same method as in Example 39 was employed. The solvent was changed to acetonitrile, n-heptane and methyl ethyl ketone to prepare crystalline form E of the phosphate salt of compound of formula I. When tested, the XRPD patterns of the solid compounds prepared in Examples 40-42 were consistent with FIG.

[0362] <Preparation of Crystalline Form F of the Phosphate of the Compound of Formula I> [Example 43] Approximately 500 mg of the compound of formula I was weighed and placed in a small bottle, 20 mL of acetone was added, and the system was subjected to ultrasonic treatment and heating until the sample was completely dissolved, resulting in a 25 mg / mL solution of the compound of formula I in acetone. The sample bottle was placed on a magnetic stirring plate, magnetic stirring was performed, and 8.57 mL of a solution of phosphoric acid in acetone (the concentration of the solution of phosphoric acid in acetone was 25 mg / mL) was slowly added dropwise overnight. The suspension was suction filtered, 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, magnetic stirring was performed at room temperature, and the solution was then diluted 10 times with the anti-solvent isopropyl acetate. The system was stirred overnight, the suspension was filtered, the solid was dried under vacuum at 50°C, and the solid was collected to obtain a phosphate solid of the compound of formula I. When tested, the solid was crystalline form F of the phosphate salt of the compound of formula I. See Figures 16-19 for the XRPD patterns, DSC thermograms and DVS isotherm plots as well as the XRPD patterns after DVS testing.

[0363] Preparation of Crystalline Form G of the Mesylate Salt of the Compound of Formula I [Example 44] Approximately 50 mg of the compound of formula I was weighed out and placed in a small bottle, 2.5 mL of acetone was added, and the system was subjected to ultrasonication and heating until the compound was completely dissolved, to prepare a 20 mg / mL solution of the compound of formula I in acetone. The sample bottle was placed on a magnetic stirring plate, magnetic stirring was performed, 0.73 mL of a solution of methanesulfonic acid in acetone (the concentration of the solution of methanesulfonic acid in acetone was 25 mg / mL) was slowly added dropwise to produce a white precipitate, the cap of the bottle was tightly covered at room temperature, the system was stirred for 1 day, the suspension was centrifuged, and the collected solid was dried overnight at 40° C. under vacuum to obtain a mesylate salt solid of the compound of formula I. When tested, the solid was crystalline form G of the mesylate salt of the compound of formula I. See Figures 20, 21 and 22 for the XRPD pattern, DSC thermogram and DVS isotherm plot.

[0364] Preparation of Crystal Form H of the Hydrobromide Salt of the Compound of Formula I [Example 45] Approximately 50 mg of the compound of formula I was weighed out and placed in a small bottle, 2.5 mL of acetone was added, and the system was subjected to ultrasonic treatment and heating until the compound was completely dissolved, to prepare a 20 mg / mL solution of the compound of formula I in acetone. The sample bottle was placed on a magnetic stirring plate, magnetic stirring was performed, and 1.32 mL of a solution of hydrobromic acid in acetone (the concentration of the solution of hydrobromic acid in acetone was 25 mg / mL) was slowly added dropwise to produce a white precipitate, the cap of the bottle was tightly covered at room temperature, the system was stirred for one day, the suspension was centrifuged, and the collected solid was dried overnight at 40° C. under vacuum to obtain a hydrobromide salt solid of the compound of formula I. When tested, the solid was crystalline form H of the hydrobromide salt of the compound of formula I. See Figures 23 and 24 for the XRPD pattern and DSC isotherm plot.

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

[0366] [Example 47] The same method as in Example 46 was used. The solvent was changed to methyl ethyl ketone to prepare the crystalline form H of the hydrobromide salt of the compound of formula I. 47 The XRPD pattern of the solid compound prepared in is consistent with FIG.

[0367] Preparation of Crystal Form J of the Hydrobromide Salt of the Compound of Formula I [Example 48] Approximately 50 mg of the compound of formula I was weighed out and placed in a small bottle, 2.5 mL of ethyl acetate was added, and the system was subjected to ultrasonication and heating until the compound was completely dissolved, to prepare a 20 mg / mL solution of the compound of formula I in ethyl acetate. The sample bottle was placed on a magnetic stirring plate, magnetic stirring was performed, and 1.32 mL of a solution of hydrobromic acid in ethyl acetate (the concentration of the solution of hydrobromic acid in ethyl acetate was 25 mg / mL) was slowly dripped in to produce a white precipitate, the bottle cap was tightly covered at room temperature, the system was stirred for 1 day, the suspension was centrifuged, and the collected solid was dried overnight at 40° C. under vacuum to obtain a hydrobromide salt solid of the compound of formula I. When tested, the solid was crystalline form J of the hydrobromide salt of the compound of formula I. See FIG. 25 for the XRPD pattern.

[0368] Preparation of Crystal Form K of the Hydrobromide Salt of the Compound of Formula I [Example 49] 5 mg of the hydrobromide salt of compound of formula I prepared in Example 46 was weighed and placed in a small bottle, an appropriate amount of n-heptane was added, the sample suspension was magnetically stirred at room temperature overnight, the system was centrifuged to separate the solid from the liquid, the solid was collected and dried under vacuum at 40° C. overnight to obtain a hydrobromide salt solid of compound of formula I. When tested, the solid was the hydrobromide salt of compound of formula I in crystal form K. Please refer to Figures 26-29 for the XRPD pattern, DSC thermogram, and DVS isotherm plot as well as the XRPD pattern after DVS test.

[0369] Preparation of Crystalline Form L of the Fumarate Salt of the Compound of Formula I [Example 50] Approximately 50 mg of the compound of formula I was weighed out and placed in a small bottle, 2.5 mL of ethyl acetate was added, and the system was subjected to ultrasonication and heating until the compound was completely dissolved, to prepare a 20 mg / mL solution of the compound of formula I in ethyl acetate. The sample bottle was placed on a magnetic stirring plate, magnetic stirring was performed, 0.87 mL of a solution of fumaric acid in ethanol (the concentration of the fumaric acid in ethanol solution was 25 mg / mL) was slowly added dropwise to produce a white precipitate, the bottle cap was tightly covered at room temperature, the system was stirred for 1 day, the suspension was centrifuged, and the collected solid was dried overnight at 40° C. under vacuum to obtain a solid fumarate salt of the compound of formula I. When tested, the solid was crystalline form L of the fumarate salt of the compound of formula 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 salt. When tested, the XRPD pattern of the solid compound prepared in Example 51 is consistent with FIG.

[0371] Preparation of Crystalline Form M of the Benzenesulfonate Salt of the Compound of Formula I [Example 52] Approximately 50 mg of the compound of formula I was weighed and placed in a small bottle, 2.5 mL of acetone was added, and the system was subjected to ultrasonic treatment and heating until the compound was completely dissolved, to prepare a 20 mg / mL acetone solution of the compound of formula I. The sample bottle was placed on a magnetic stirring plate, magnetic stirring was performed, and 1.34 mL of an acetone solution of benzenesulfonic acid (the concentration of the acetone solution of benzenesulfonic acid was 25 mg / mL) was slowly dripped in to generate a white precipitate, the bottle cap was tightly covered at room temperature, the system was stirred for 1 day, the suspension was centrifuged, and the collected solid was dried overnight at 40° C. under vacuum to obtain a benzenesulfonate salt solid of the compound of formula I. When tested, the solid was crystalline form M of the benzenesulfonate salt of the compound of formula I. See Figures 32-35 for the XRPD pattern, DSC thermogram, and DVS isotherm plot as well as the XRPD pattern after DVS testing.

[0372] Preparation of Crystal Form N of the Citrate Salt of the Compound of Formula I [Example 53] Approximately 50 mg of the compound of formula I was weighed out and placed in a small bottle, 2.5 mL of ethyl acetate was added, and the system was subjected to ultrasonication and heating until the compound was completely dissolved, to prepare a 20 mg / mL solution of the compound of formula I in ethyl acetate. The sample bottle was placed on a magnetic stirring plate, magnetic stirring was performed, and 1.58 mL of a solution of citric acid in ethyl acetate (the concentration of the solution of citric acid in ethyl acetate was 25 mg / mL) was slowly added dropwise to produce a white precipitate, the bottle cap was tightly covered at room temperature, the system was stirred for 1 day, the suspension was centrifuged, and the collected solid was dried overnight at 40° C. under vacuum to obtain a citrate salt solid of the compound of formula I. When tested, the solid was crystalline form N of the citrate salt of the compound of formula 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 the compound of formula I was weighed and placed in a small bottle, 2.5 mL of ethyl acetate was added, and the system was subjected to ultrasonication and heating until the compound was completely dissolved, preparing a 20 mg / mL solution of the compound of formula I in ethyl acetate. The sample bottle was placed on a magnetic stirring plate, magnetic stirring was performed, and 1.12 mL of a solution of L-(+)-tartaric acid in ethyl acetate (the concentration of the solution of L-(+)-tartaric acid in ethyl acetate was 25 mg / mL) was slowly added dropwise to produce a white precipitate, the cap of the bottle was tightly covered at room temperature, the system was stirred for one day, the suspension was centrifuged, and the collected solid was dried overnight at 40°C under vacuum to obtain a solid of the L-(+)-tartrate salt of the compound of formula I. When tested, the solid was crystalline form O of the tartrate salt of the compound of formula I. See Figures 38-42 for the XRPD pattern, DSC thermogram, TGA thermogram, and DVS isotherm plot as well as the XRPD pattern after DVS testing.

[0374] The salt formation rate test of the crystalline form O of the tartrate salt of the compound of formula I was carried out as follows: 1 H NMR was performed using: Approximately 5 mg of the compound of formula I and the crystalline form O of the tartrate salt of the compound of formula I were weighed out and placed in a magnetic tube, respectively. The samples were dissolved in 0.6 mL of DMSO d6 until each solution became transparent. Each sample solution was scanned in a conventional manner using a Bruker AVANCE 400 MHz nuclear magnetic resonance spectrometer to determine the sample 1 H-NMR data was collected.

[0375] NMR spectroscopy shows that the crystalline form O of the tartrate salt of the compound of formula I 1 H NMR showed that it contains one more hydrogen than the compound of formula I because tartaric acid is a diacid. It can be seen that the salt formation molar ratio between the free base and tartaric acid is 2:1. For specific information, please refer to Figure 43 and Figure 44.

[0376] The salt formation rate test of crystalline form O of the tartrate salt of the compound of formula I was carried out using chemical titration: A non-aqueous titration apparatus was used to titrate the samples using methanolic potassium hydroxide VS. The content of tartaric acid in the samples was calculated using a formula based on the titrant concentration and titrant consumption.

[0377] [Table 20]

[0378] [Table 21]

[0379] 80mL of methanol solution was taken and placed in a titration cup, and titration was performed in triplicate according to the blank titration conditions. 160mg of acid potassium phthalate standard dried at 105℃ to constant weight was precisely weighed, 50mL of methanol solution was added, the system was subjected to ultrasonic treatment to dissolve, and then transferred to a titration cup, and titration was performed in triplicate according to the sample titration conditions. 100mg of crystal form O of the tartrate salt of compound of formula I was precisely weighed, 80mL of methanol solution was added, the system was subjected to ultrasonic treatment to dissolve, and then transferred to a titration cup, and titration was performed in triplicate according to the sample titration conditions.

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

[0381]

number

[0382] W: Weight of potassium hydrogen phthalate standard (g) V: Amount of methanolic potassium hydroxide VS consumed in the titration of the acid potassium phthalate standard solution (mL) V0: Amount of methanolic potassium hydroxide VS consumed in titrating the blank solution (mL) M: Molecular weight of potassium hydrogen phthalate standard The tartaric acid content in the samples was calculated according to the following formula:

[0383]

number

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

[0385] [Example 55] Approximately 500 mg of the compound of formula I was weighed out and placed in a small bottle, 20 mL of acetone was added, and the system was subjected to ultrasonic treatment and heating until the compound was completely dissolved, to prepare a 25 mg / mL acetone solution of the compound of formula I. The sample bottle was placed on a magnetic stirring plate, magnetic stirring was performed, and 11.2 mL of an 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 a solid L-(+)-tartrate salt of the compound of formula I. When tested, the solid was the crystalline form O of the tartrate salt of the compound of formula I. Its XRPD pattern is consistent with FIG. 38.

[0386] [Example 56] 2.0g of the compound of formula I (HPLC purity 99.9%) prepared by purification of component A in Example 27, and 40mL of acetone (20V) were added to flask 1#, and the system was stirred and dissolved until the solution became clear; 0.61g of L-(+)-tartaric acid and 40mL of acetone (20V) were added to flask 2#, and the system was stirred and dissolved until the solution became clear; 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; Concentrated to about 40mL; The system was stirred at room temperature of 25-30°C for 1 hour; The system was cooled to 5-10°C and stirred at 5-10°C for 1 hour; Filtered, and the filter cake was dried at 50-55°C with a blower for 16 hours to obtain 2.4g of product, with an HPLC purity of 99.6% and a yield of 95.6%. Upon testing, the solid was crystalline form O of the tartrate salt of the compound of Formula I. Its XRPD pattern is consistent with FIG.

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

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

[0389] [Example 59] 189.6 g (HPLC purity 99.9%) of the compound of formula I prepared by purification of component A in Example 28 and 3792 mL of acetone (20 V) were added to flask 1#, the temperature was raised to 50-55°C, and the system was stirred and dissolved until the solution became transparent; 57.6 g of L-(+)-tartaric acid and 3792 mL of acetone (20 V) were added to flask 2#, the temperature was raised to 50-55°C, and the system was stirred and dissolved until the solution became transparent. 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; concentrated under vacuum to about 3800mL (about 20V); cooled to 17-21°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 at 50-55°C with a blower for 28 hours to obtain 223.2g of product with HPLC purity of 99.98% and yield of 94.0%. When tested, the solid was crystalline form O of the tartrate salt of compound of formula I. Its XRPD pattern is consistent with Figure 38.

[0390] [Example 60] 0.65 kg (HPLC purity 100.0%) of the compound of formula I prepared by 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 to 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, and then transferred to PT1 and compressed to the reactor through a pipeline filter; the amount of reaction liquid 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 to PT2 (reactor 1) using nitrogen through a pipeline filter. 2); 2.6 kg of acetone was added to the rotary flask, the flask was washed, and the system was transferred to PT1 and compressed to PT2 with nitrogen through a pipeline filter; The temperature of the material liquid 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 at 40-50°C, and the system was stirred and reacted for 4 hours; The system was cooled and the temperature in the reactor was reduced to 25-35°C; Distilled under vacuum, the vacuum was controlled below 0.080MPa, and the material liquid in the reactor was distilled under vacuum to a calibrated volume of 13.0L;The temperature of the material liquid 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 filter cake was washed with acetone (2.5 kg);A sample was taken and analyzed. The HPLC purity of the tartrate salt of the compound of formula I in the filter cake was 99.98%;The maximum individual impurity content: 0.02%;The filter cake was dried under vacuum (below -0.080MPa) at 45-55°C for 24 hours;A sample was taken and analyzed, and the acetone residue was below 5000 ppm;The oven was cooled to 15-25°C;Dried, 0.74 kg of product was obtained, and a sample was taken and analyzed. HPLC purity of the tartrate salt of the compound of formula I: 99.95%; maximum individual impurity content: 0.03%; residual solvent meets the requirements.Upon further testing, the product was crystalline form O of the tartrate salt of the compound of Formula I. Its XRPD pattern is consistent with FIG.

[0391] [Experimental Section] <Experimental Example 1: Solubility test> Crystalline form 1 of the compound of formula I, crystalline form F of the phosphate salt of the compound of formula I and crystalline form O of the tartrate salt of the compound of formula I were each divided into 4 appropriate portions and weighed, respectively placed in 4mL transparent glass bottles, and 1mL of water, simulated gastric fluid (SGF), fasting simulated intestinal fluid (FaSSIF) and fed simulated intestinal fluid (FeSSIF) were added, respectively, to obtain sample suspensions, and the suspensions were quickly transferred to a shaker (37°C, 200 rpm) and shaken. After 5 minutes, the samples were observed, and a certain amount of sample or medium was added to obtain a gentle suspension, and sampling was performed at 30 minutes, 2 hours, 4 hours and 24 hours, respectively. The samples were centrifuged at 12000 rpm for 10 minutes to obtain the supernatant, which was appropriately diluted and subjected to high performance liquid chromatography. Please refer to Table 20 for the chromatography conditions.

[0392] [Table 22]

[0393] The 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 crystalline form F of the phosphate salt of the compound of formula I and crystalline form O of the tartrate salt of the compound of formula I could significantly improve the solubility of the compound in water, SGF and FaSSIF. The solubility of crystalline form F of the phosphate salt of the compound of formula I in water, SGF, FaSSIF and FeSSIF at 24 hours was 27-fold, 10-fold, 60-fold and 1-fold that of the compound of formula I, respectively, and the solubility of crystalline form O of the tartrate salt of the compound of formula I in water, SGF, FaSSIF and FeSSIF at 24 hours was 9-fold, 2-fold, 7-fold and 1-fold that of the compound of formula I, respectively.

[0396] <Experimental Example 2: Stability Test 1> Approximately 1 mg of crystalline form 1 of the compound of formula I, crystalline form F of the phosphate salt of the compound of formula I, and crystalline form O of the tartrate salt of the compound of formula I were weighed and placed in a 20 mL transparent glass bottle, respectively, and each sample was placed in a stability chamber at accelerated conditions (40°C / 75%RH, open) and elevated temperatures (60°C, closed). For open samples, the caps of the bottles were removed and the necks of the bottles were covered with aluminum foil paper pierced with a pinhole to avoid cross-contamination; for closed samples, the bottles were covered and tightly sealed. Samples were taken at the first and second week, respectively, and the samples were diluted with 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] The purity of the samples 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 of formula I, crystalline form F of phosphate of compound of formula I and crystalline form O of tartrate of compound of formula I did not change within 2 weeks and were off-white powders. There was no significant difference in purity and no obvious increase in impurities, indicating good chemical stability within 2 weeks. XRPD and DSC tests (Figures 45-50) showed that there was no significant difference in the crystal form and initial melting point of crystalline form F of phosphate of compound of formula I and crystalline form O of tartrate of compound of formula I compared with those on day 0, indicating good physical stability of phosphate and tartrate of compound of formula I within 2 weeks at high temperature (60°C) and accelerated conditions (40°C / 75%RH). The crystal form of crystalline form 1 of compound of formula I changed at high temperature (60°C) and accelerated conditions (40°C / 75%RH). The results of characterization of the free base before and after DVS tests show that the stability of the crystalline form of the free base is poor.

[0401] <Experimental Example 3: Stability Test 2> Crystalline form O of the tartrate salt of compound of formula I was tested using suspension equilibrium, heat-quench / slow cool crystallization, antisolvent, and solution evaporation and crystallization techniques to determine whether crystal transformation occurred in different solvents and test conditions and to further verify its thermodynamic stability.

[0402] [1. Slow Solution Evaporation (EVA)] The crystal form O of the tartrate salt of the compound of formula I prepared in Example 55 was divided into 5 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, and the contents in the bottle were sonicated to dissolve the sample, and the resulting solution was filtered into a new sample bottle with a 0.45 μm nylon membrane, and the sample bottle was opened and placed in a draft chamber, and the solvent was allowed to evaporate naturally at room temperature (about 20 to 25 ° C.), and the precipitated solid was collected. When tested, the solid obtained in the five tests was the crystal form O of the tartrate salt of the compound of formula I, and their XRPD patterns were consistent with FIG. 38.

[0403] [Table 26]

[0404] [2 Suspension equilibrium method (slurry)] Eighteen appropriate portions of the sample of the tartrate salt of the compound of formula I were weighed, and then a certain 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, respectively, to obtain two suspension samples in each solvent system, and the samples were stored at room temperature and at high temperature (50°C) and slurried. The room temperature sample bottle (wrapped in tin foil to protect from light) was placed on a Labquaker rotator for 360° rotation, and the high temperature sample was placed in a 50°C constant temperature shaking incubator and slurried, and a portion of the suspension sample was taken on the 3rd, 7th, and 14th days, respectively, centrifuged, and the solid residue was collected, and the solvent was evaporated to dryness at room temperature (20-25°C), and the solid was collected. When tested, the obtained solid was the tartrate salt of the compound of formula I, and their XRPD patterns were consistent with FIG. 38.

[0405] [Table 27]

[0406] [3. Anti-solvent method] A sample of the crystalline form O of the tartrate salt of the compound of formula I was divided into 21 portions and weighed, and a certain volume of the good solvent in Table 26 was added sequentially, and the system was subjected to ultrasonic treatment to dissolve, and the resulting solution was filtered into a new sample bottle with a 0.45 μm nylon membrane, and different poor solvents were slowly dropped into each sample bottle under magnetic stirring, and the solvent system in which the solid precipitated was centrifuged, the solid was collected, and the solvent was evaporated at room temperature (20-25 ° C) to dryness; the solvent system in which the solid did not precipitate was stirred for 48 hours. If the solid did not precipitate, the bottle was opened and the system was stirred until the solid precipitated. When tested, the obtained solid was the crystalline form O of the tartrate salt of the compound of formula I, and their XRPD pattern is consistent with Figure 38.

[0407] [Table 28]

[0408] [5. Solution heating-quenching method (HFC)] Five portions (approximately 20 mg / portion) of a sample of the crystalline form O of the tartrate salt of the compound of formula I were weighed and placed in a sample bottle, and appropriate amounts of tetrahydrofuran, acetone, ethanol, isopropanol and methanol (see Table 27 for specific amounts) were added, respectively, and 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 temperature was maintained for 15 minutes, and the solution was filtered hot through a 0.45 μm membrane and transferred to a new sample bottle, which was immediately transferred to a refrigerator at -20°C overnight. The solvent systems in which solids precipitated were centrifuged, the solids were collected, and the solvent was evaporated at room temperature (20-25°C) to dryness; the solvent systems in which solids did not precipitate were placed in a refrigerator at -20°C until a large amount of solids precipitated. In the tetrahydrofuran and acetone systems, solids did not always precipitate. When tested, the solids obtained from the ethanol, isopropanol and methanol systems were crystalline form O of the tartrate salt of the compound of formula I, and their XRPD spectra were consistent with FIG.

[0409] [Table 29]

[0410] [6. Solution heating-slow cooling method (HSC)] Five portions (approximately 20 mg / portion) of a sample of the crystalline form O of the tartrate salt of the compound of formula I were weighed and placed in a sample bottle, and appropriate amounts of tetrahydrofuran, acetone, ethanol, isopropanol and methanol (see Table 28 for specific amounts) were added, respectively, and 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 temperature was maintained for 15 minutes, and the solution was filtered hot through a 0.45 μm membrane, transferred to a new sample bottle, slowly cooled to room temperature at 6°C / h overnight, the sample bottle was placed in a refrigerator (2-8°C), and the solvent systems in which solids precipitated were centrifuged, the solids were collected, and the solvent was evaporated at room temperature (20-25°C) to dryness; the solvent systems in which solids did not precipitate were placed in a refrigerator at -20°C until a large amount of solids precipitated. In the tetrahydrofuran, acetone and methanol systems, solids did not precipitate at all times. When tested, the solids obtained from the ethanol and isopropanol systems were crystalline form O of the tartrate salt of the compound of Formula I, and their XRPD patterns were consistent with FIG.

[0411] [Table 30]

[0412] The above test results showed that after treating crystalline form O of the tartrate salt of compound of formula I with different methods, including suspension equilibrium method, heat-quench / slow-cool crystallization method, anti-solvent method, and solution evaporation and crystallization method, the product was still a single crystalline form O. Crystalline form O of the tartrate salt of compound of formula I is a thermally stable and predominant crystalline form.

[0413] <Test 4: TYK2 biochemistry test> An appropriate amount of a compound of formula I was weighed out for the TYK2 biochemical assay.

[0414] This test was performed by Reaction Biology Corp, Malvern, PA (Anastassiadis et al. Nat Biotechnol. 2011; 29(11):1039-45). The steps 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. Required cofactors were added to each kinase reaction.

[0416] Reaction steps: 1. Prepare the indicated substrate in freshly prepared base reaction buffer; 2. Transfer the necessary cofactors into the matrix solution above; 3. Transfer the designated kinase to the substrate solution and mix thoroughly and gently; 4. Transfer the compound of formula I in DMSO to the kinase reaction mixture using Acoustic technology (Echo550; nanoliter range) and incubate at room temperature for 20 minutes; 5. 33 P-ATP (specific activity: 10 μCi / μl) was introduced into the reaction mixture and allowed to react; 6. Incubate at room temperature and allow the kinase reaction to proceed for 2 hours; 7.P81 Plot reactions on ion exchange paper; 8. Test for kinase activity in a filter binding assay.

[0417] The results show that the compound of formula I is also a potent TYK2 inhibitor, with an IC 50 was shown to be less than 10 nM.

[0418] Those skilled in the art can understand the present invention under the guidance of this specification and make some modifications or changes to it, which should be within the scope of the present invention as defined in the claims. Furthermore, the present invention includes the following aspects. [Aspect 1] A method for preparing a compound of formula I, the synthetic route of which is as follows: [ka] The method includes the steps of: Step 1: Add ethanol, compound of formula IV, compound of formula V and DIPEA to a reaction vessel and begin stirring; Heat to 65-90°C, maintain temperature, and stir overnight; Stop the reaction and reduce the temperature of the system to 15-30°C; Add water dropwise to the system and continue stirring; Filter and wash the filter cake; The filter 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 on carbon to a reaction vessel; The system is purged with nitrogen and then with hydrogen; Maintain the temperature at 20-35°C and stir under hydrogen pressure of 0.1-1.0 MPa for 16-120 hours; After the reaction is completed, the reaction liquid is filtered and the filter cake is washed; The filtrates are combined and concentrated to obtain a concentrate of the compound of formula II; Step 3: The concentrate of the compound of formula II obtained in step 2 or the compound of formula II, as well as trimethyl orthoacetate and tetrahydrofuran are added to a reaction vessel; the material system in the reaction vessel is heated to the reflux of tetrahydrofuran; pyridine hydrochloride is added to the reaction vessel, and the resulting material system is reacted at a temperature of 50-90°C for 4-20 hours, and then separated and purified to obtain the compound of formula I. [Aspect 2] In step 1 above: The volumetric 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 1:1-1.1:2-3, preferably 1:1.01:2.2; After starting stirring, heat under nitrogen protection to increase the temperature to 65 to 90°C, preferably 70 to 90°C, more preferably 70 to 80°C, maintain the temperature, and stir for 5 to 16 hours, preferably 10 to 16 hours; After the reaction is stopped, the temperature of the system is reduced to 15-25°C; The volumetric mass ratio (mL / g) of water to the compound of formula IV added to the system is 10:1-20:1, preferably 15:1; After adding water to the system, the mixture is stirred 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 filter cake is washed with an aqueous ethanol solution, in which the volume ratio (mL / mL) of ethanol to water in the aqueous ethanol solution is 1:1 to 1:2, preferably 1:1.5 to 1:2; the volume mass ratio (mL / g) of the aqueous ethanol solution to the compound of formula IV is 2:1 to 10:1, preferably 2:1 to 5:1, more preferably 2:1 to 3:1; 2. The method of embodiment 1, wherein the filter cake is dried under vacuum or with a blower at a temperature of 45-55° C., preferably 50° C. [Aspect 3] In step 2 above: The volumetric 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 on carbon is 5% Pd / C, 50% water wet, and the weight ratio of palladium on 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 under hydrogen pressure of 0.5-1.0 MPa for 24-96 hours; The method according to embodiment 1 or 2, wherein the concentrate of the compound of formula II obtained by combining and concentrating the filtrate is a tetrahydrofuran solution of the compound of formula II, and the volumetric mass ratio of tetrahydrofuran to the compound of formula II is 2:1 to 4:1, preferably 2:1 to 3:1; 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 volumetric 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 volumetric 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 the volumetric 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 replaced with toluene, tetrahydrofuran or methyl tertiary butyl ether for the next step; preferably, the volumetric mass ratio (mL:mg) of the toluene, tetrahydrofuran or methyl tertiary butyl ether used for replacement to the concentrate of the compound of formula II 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, the concentrate of the compound of formula II or the compound of formula II, trimethyl orthoacetate and a solvent are added to a reaction vessel under nitrogen protection, and then the material system in the reaction vessel is heated until the solvent refluxes; After pyridine hydrochloride is added 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 completed, 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 compound of formula I obtained is separated and purified by column chromatography, the eluent being a mixture of ethyl acetate and n-heptane (V EA :V n-ヘプタン = 1:1 to 1:0, mL / mL); The method according to any one of aspects 1 to 3, wherein the compound of formula I obtained is preferably dried at 50-55° C. under vacuum or with a blower. [Aspect 5] Crystalline Form 1 of the compound of formula I,

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

Claims

1. A method for preparing a compound of formula I, the synthetic route of which is as follows: 【Chemistry 1】 The method includes the steps of: Step 1: Add ethanol, compound of formula IV, compound of formula V and N,N-diisopropylethylamine (DIPEA) to a reaction vessel and begin stirring; Apply heat to raise temperature to 65-90°C and maintain temperature and stir overnight; Stop the reaction and lower the temperature of the system to 15-30°C; Add water dropwise to the system and continue stirring; Filter and wash the filter cake; Drying the filter cake gives the compound of formula III; Step 2: Add tetrahydrofuran, the compound of formula III obtained in step 1, and palladium on carbon to a reaction vessel; The system is purged with nitrogen and then with hydrogen; Maintain the temperature at 20-35° C. and stir under hydrogen pressure of 0.1-1.0 MPa for 16-120 hours; After the reaction is completed, the reaction liquid is filtered and the filter cake is washed; The filtrates are combined and concentrated to obtain a concentrate of the compound of formula II; Step 3: The concentrate of the compound of formula II obtained in step 2 or the compound of formula II, trimethyl orthoacetate and tetrahydrofuran are added to a reaction vessel; the composition in the reaction vessel is heated to the reflux of tetrahydrofuran; pyridine hydrochloride is added to the reaction vessel, and the resulting composition is reacted at a temperature of 50-90° C. for 4-20 hours, and then separated and purified to obtain the compound of formula I.

2. In the step 1: The volumetric mass ratio (mL / g) of ethanol to the compound of formula IV is 5:1 to 20:1; The molar ratio of the compound of formula IV, the compound of formula V and N,N-diisopropylethylamine (DIPEA) is 1:1-1.1:2-3; After starting stirring, under nitrogen protection, heat to increase the temperature to 65-90°C, maintain the temperature and stir for 5-16 hours; After the reaction is stopped, the temperature of the system is lowered to 15-25°C; The volumetric mass ratio (mL / g) of water to the compound of formula IV added to the system is 10:1 to 20:1; After adding water to the system, stir for 2-6 hours at a temperature of 0-30°C; The filter cake is washed with an aqueous ethanol solution, in which the volume ratio (mL / mL) of ethanol to water in the aqueous ethanol solution is 1:1 to 1:2; the volume mass ratio (mL / g) of the aqueous ethanol solution to the compound of formula IV is 2:1 to 10:1; The process of claim 1, wherein the filter cake is dried under vacuum or with a blower at a temperature of 45-55°C.

3. In step 2: The volumetric mass ratio (mL / g) of tetrahydrofuran to the compound of formula III is 10:1 to 70:1; The palladium on carbon is 5% Pd / C, 50% water wet, and the weight ratio of palladium on carbon to the compound of formula III is 0.15:1 to 0.16:1; Maintain the temperature at 25-35° C. and stir under 0.5-1.0 MPa hydrogen pressure for 24-96 hours; The method according to claim 1 or 2, wherein the concentrate of the compound of formula II obtained by combining and concentrating the filtrate is a tetrahydrofuran solution of the compound of formula II, and the volumetric mass ratio of tetrahydrofuran to the compound of formula II is 2:1 to 4:

1.

4. The method of claim 3, wherein step 2 further comprises replacing the tetrahydrofuran solution of the compound of formula II with ethanol to obtain an ethanol solution of the compound of formula II, wherein the volumetric mass ratio of ethanol to the compound of formula II is 2:1 to 5:

1.

5. In step 3: the volumetric 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 the volumetric mass ratio (mL:mg) of tetrahydrofuran to the compound of formula II is 1.5:1 to 5.0:1; The process according to any one of claims 1 to 4, wherein after pyridine hydrochloride is added to the reactor under nitrogen protection, the composition is reacted at a temperature of 50 to 90°C for a period of 4 to 20 hours.

6. The method of any one of claims 1 to 5, wherein step 3 further comprises displacing the concentrate of the compound of formula II with toluene, tetrahydrofuran or methyl tertiary butyl ether for the next step, wherein the volumetric mass ratio (mL:mg) of toluene, tetrahydrofuran or methyl tertiary butyl ether used for the substitution to the concentrate of the compound of formula II is 2.0:1 to 4.0:

1.

7. The method of claim 1, wherein the molar ratio of the compound of formula II to trimethyl orthoacetate in the concentrate of the compound of formula II is from 3.0:1 to 3.5:1, or the molar ratio of the compound of formula II to trimethyl orthoacetate is from 3.0:1 to 3.5:

1.

8. The method of claim 1, wherein 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.

9. The method of claim 1, wherein step 3 further comprises adding the concentrate of the compound of formula II or the compound of formula II, as well as trimethyl orthoacetate and a solvent to a reaction vessel under nitrogen protection, and then heating the composition in the reaction vessel until the solvent refluxes.

10. The method of claim 1, wherein step 3 further comprises purifying the product after the reaction is completed with a solvent selected from the group consisting of water, methanol, ethanol, methyl tertiary butyl ether, and any combination thereof.

11. The method according to any one of claims 1 to 5, wherein the compound of formula I obtained is dried at 50-55°C under vacuum or with a blower.

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