Synthesis method of furoimidazopyridine compound, crystal form of furoimidazopyridine compound, and crystal form of salt thereof

Abstract

Provided is a method for synthesizing a compound 2-[(2R,5S)-5-[2-[(R)-1-hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile as a selective Jak1 / TYK2 kinase inhibitor. The compound is prepared by nucleophilic substitution, palladium-carbon reduction, and cyclization reaction using 7-chloro-6-nitrofuro[3,2-b]pyridine as a starting material. The synthesis method has mild reaction conditions, high product yield, and high purity, and is suitable for industrial production. Further provided are a crystal form of the compound, a crystal form of a salt thereof, and respective methods of preparation. The crystal form of the compound and the crystal form of the salt thereof have good physical and chemical properties and are suitable for drug development.

Description

Synthetic methods of furanoimidazopyridine compounds, crystal forms of furanoimidazopyridine compounds and crystal forms of their salts. Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis, specifically to a method for synthesizing compound 2-[(2R,5S)-5-[2-[(R)-1-hydroxyethyl]furano[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (hereinafter referred to as Compound I), which is a selective Jak1 / TYK2 kinase inhibitor. This invention also relates to the crystal form of Compound I, the crystal form of its salts, and methods for preparing them. Furthermore, this invention relates to pharmaceutical compositions and formulations comprising the crystal form of Compound I and / or the crystal form of its salts, and the use of the crystal form of Compound I and the crystal form of its salts in the treatment of diseases and symptoms related to Jak1 / TYK2. Background Technology

[0002] Protein kinases represent a large family of proteins that play important roles in regulating a variety of 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 kinase (PDGFR); and serine / threonine kinases, such as β-RAF.

[0003] The Janus kinase family comprises four known members: Jak1, Jak2, Jak3, and tyrosine kinase 2 (TYK2). These cytoplasmic tyrosine kinases are associated with membrane cytokine receptors, such as the common γ-chain receptor and the transmembrane protein glycoprotein 130 (gp130) (Murray, J. Immunol. 178(5):2623-2629, 2007). Nearly 40 cytokine receptors signal through a combination of these four Jak family members and their seven downstream substrates: signal transduction activators of the transcription (STAT) family (Ghoreschi et al., Immunol Rev. 228(l):273-287, 2009). Cytokines that bind to their receptors initiate Jak activation via mutual and autophosphorylation. Jak family kinases, in turn, phosphorylate cytokine receptor residues, creating binding sites for proteins containing sarcoma homology 2 (SH2), such as STAT factors and other regulators, which are subsequently activated by Jak phosphorylation. Activated STAT enters the cell nucleus and begins to promote the expression of survival factors, cytokines, chemokines, and molecules transported by leukocytes (Schindler et al., J. Biol. Chem. 282(28):20059-20063, 2007). Jak activation also leads to cell proliferation via pathways mediated by phosphoinositol 3-kinase (PI3K) and protein kinase B.

[0004] Jak3 and Jak1 are components of common γ-chain cytokine receptor complexes, and blocking either one inhibits the signaling of inflammatory cytokines (interleukin (IL)-2,4,7,9,15, and 21) (Ghoreschi et al., Immunol. Rev. 228(l):273-287, 2009). In contrast, other pathologically relevant cytokines (such as IL-6) are dependent solely on Jak1. Thus, Jak1 blocking inhibits the signaling of many pro-inflammatory cytokines (Guschin et al., EMBO J. 14(7):1421-1429, 1995). The clinical efficacy of the IL-6 receptor neutralizing antibody tocilizumab in rheumatoid arthritis (RA) has been observed (Maini et al., Arthritis Rheum. 54(9):2817-2829, 2006).

[0005] International patent application WO2018067422A1 discloses a 1H-furano[3,2-b]imidazo[4,5-d]pyridine derivative as a selective Jak1 kinase inhibitor and its preparation method, including compound I and its preparation method. The synthetic route is as follows:

[0006]

[0007] Bioassay results indicate that compound I is an effective selective Jak1 inhibitor and exhibits 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 its TYK2 bioactivity, and the disclosed method for preparing compound I involves high reaction temperatures, numerous impurities, and low product yield, making it unsuitable for industrial production. Therefore, it is necessary to develop a method for preparing compound I with mild reaction conditions, high product yield, high purity, and suitability for industrial production.

[0008] Currently, there are no reports on the crystal forms of compound I and its salts in existing technologies. Comprehensive and systematic polymorphic screening in drug development to select the most suitable crystal form is an essential research aspect that cannot be ignored. Therefore, it is necessary to further screen the crystal forms of compound I and its salts to develop crystal forms with good stability, low hygroscopicity, and suitability for industrial production, providing more and better options for subsequent drug development.

[0009] Summary of the Invention

[0010] The purpose of this invention is to provide a method for preparing compound I (i.e., compound I) with mild reaction conditions, high product yield, high purity, and suitability for industrial production. The synthetic route of this method is as follows:

[0011]

[0012] The method includes the following steps:

[0013] Step 1:

[0014] Add ethanol, compound IV, compound V and DIPEA to the reaction vessel and start stirring;

[0015] Heat to 65–90°C, keep warm and stir overnight;

[0016] Stop the reaction and lower the system temperature to 15–30°C;

[0017] Add water dropwise to the system and continue stirring;

[0018] Filtering and washing the filter cake;

[0019] The filter cake was dried to obtain compound of formula III;

[0020] Step 2:

[0021] Tetrahydrofuran, the compound of formula III obtained in step 1, and palladium on carbon were added to the reaction vessel;

[0022] The system was purged with nitrogen, and then with hydrogen.

[0023] Under hydrogen pressure of 0.1 to 1.0 MPa and temperature of 20-35°C, maintain the temperature and stir for 16-120 hours;

[0024] After the reaction is complete, filter the reaction solution and wash the filter cake.

[0025] The filtrates were combined and concentrated to obtain a concentrate of compound II.

[0026] Step 3:

[0027] Add tetrahydrofuran, (R)-lactamide and Et3O-BF4 to the first reaction vessel, start stirring, and dissolve for later use;

[0028] Add the concentrate of compound II and ethanol to the second reaction vessel, and heat the material in the second reaction vessel to 40-85°C;

[0029] The material in the first reaction vessel is added dropwise to the second reaction vessel. After the addition is completed, the mixture in the second reaction vessel is kept at 40-85℃ for 0.5-6 hours.

[0030] After the reaction was completed, the pH of the system was adjusted to 1-3, extracted with an organic solvent, the organic phase was discarded, the pH of the aqueous phase was adjusted to 9-10 with an inorganic alkaline aqueous solution, filtered, and the filter cake was dried to obtain compound I.

[0031] In a preferred embodiment, in step 1 above:

[0032] The volume-to-mass ratio (mL / g) of ethanol to compound IV is 5:1 to 20:1, preferably 10:1;

[0033] The molar ratio of compound IV, compound V and DIPEA is 1:1 to 1.1:2 to 3, preferably 1:1.01:2.2;

[0034] After stirring is started, under nitrogen protection, the temperature is raised to 65-90°C, preferably 70-90°C, more preferably 70-80°C, and stirred for 5-16 hours, preferably 10-16 hours.

[0035] After stopping the reaction, lower the system temperature to 15–25°C;

[0036] The volume-to-mass ratio (mL / g) of water to compound IV added to the system is 10:1 to 20:1, preferably 15:1;

[0037] After adding water dropwise to the system, stir for 2-6 hours at 0-30°C, preferably at 5-15°C, more preferably at 5-10°C, preferably for 4 hours.

[0038] The filter cake is washed with an aqueous ethanol solution, wherein 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; and the volume-to-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.

[0039] The filter cake is dried under vacuum or by forced air at 45-55°C, preferably 50°C.

[0040] In a preferred embodiment, in step 2 above:

[0041] The volume-to-mass ratio (mL / g) of tetrahydrofuran to the compound of formula III is 10:1 to 70:1, preferably 20:1 to 70:1;

[0042] The palladium on carbon is 5% Pd / C, 50% wet palladium on carbon, and the mass ratio (g / g) of palladium on carbon to compound of formula III is 0.15:1 to 0.16:1, preferably 0.15:1;

[0043] Stirring at 25-35°C under a hydrogen pressure of 0.5-1.0 MPa for 24-96 hours;

[0044] The filter cake is washed with tetrahydrofuran, and the filtrates are combined and concentrated to obtain a tetrahydrofuran solution of compound II. The volume-to-mass ratio (mL / g) of the tetrahydrofuran used for washing to compound II is 2:1 to 4:1, preferably 2:1 to 3:1 (mass of compound II obtained in step 2 after 100% yield). Preferably, the tetrahydrofuran solution of compound II is replaced with ethanol to obtain an ethanol solution of compound II, wherein the volume-to-mass ratio (mL / g) of ethanol to compound II is 2:1 to 5:1, preferably 2:1 to 4:1, more preferably 2:1 to 3:1 (mass of compound II obtained in step 2 after 100% yield).

[0045] In a preferred embodiment, in step 3 above:

[0046] The volume-to-mass ratio (mL / g) of tetrahydrofuran to the concentrate of compound II is 6:1 to 12:1;

[0047] The molar ratio of the concentrate of compound II, (R)-lactic acid and Et3O-BF4 is 1:4-5:4-5;

[0048] The volume-to-mass ratio (mL / g) of ethanol to the concentrate of formula II is from 10:1 to 16:1, preferably 14:1;

[0049] After adding the concentrate of compound II and ethanol to the second reaction vessel, the material in the second reaction vessel is heated to 40-85°C, preferably 45-70°C, more preferably 45-50°C under nitrogen protection.

[0050] The mixture in the second reaction vessel is kept at 45-70°C, preferably 45-50°C, for 2-5 hours, preferably 3 hours.

[0051] After the reaction is complete, the pH of the system is adjusted to 1-3 with hydrochloric acid, which is 1M HCl or 12M HCl, preferably 12M HCl; the inorganic base aqueous solution is a saturated sodium carbonate aqueous solution or a saturated potassium carbonate aqueous solution, preferably a saturated potassium carbonate aqueous solution.

[0052] After the reaction was completed, the organic solvent used for extraction was dichloromethane or ethyl acetate;

[0053] The filter cake is vacuum dried or blown dry at 50–55°C.

[0054] In a preferred embodiment, the compound of formula I obtained in step 3 above is subjected to column chromatography for separation and purification, wherein the eluent is a mixed solution of ethyl acetate and ethanol (V... EA :V EtOH =100:1 to 30:1, mL / mL).

[0055] Another object of the present invention is to provide a crystal form of a compound of formula I, which is referred to herein as crystal form 1 of compound of formula I.

[0056] The X-ray powder diffraction pattern of the compound of formula I of the present invention has characteristic peaks at 2theta values ​​of 8.5°±0.2°, 14.8°±0.2°, and 16.1°±0.2°.

[0057] In a preferred embodiment, the X-ray powder diffraction pattern of the compound of formula I of the present invention has characteristic peaks at 2theta values ​​of 8.5°±0.2°, 14.8°±0.2°, 16.1°±0.2°, 17.1°±0.2°, 18.8°±0.2°, and 19.6°±0.2°.

[0058] In a further preferred embodiment, the X-ray powder diffraction pattern of the compound of formula I of the present invention has characteristic peaks at 2theta values ​​of 8.5°±0.2°, 14.8°±0.2°, 16.1°±0.2°, 17.1°±0.2°, 18.8°±0.2°, 19.6°±0.2°, 23.8°±0.2°, 25.3°±0.2°, and 26.1°±0.2°.

[0059] Without limitation, the X-ray powder diffraction data of compound crystal form 1 of Formula I of the present invention are shown in Table 1.

[0060] Table 1

[0061]

[0062] Without limitation, the X-ray powder diffraction (XRPD) pattern of the crystal form 1 of compound I of the present invention is shown in Figure 1.

[0063] Non-limitingly, the differential scanning calorimetry (DSC) spectrum of the compound of formula I, crystal form 1 of the present invention, is shown in Figure 2A. The DSC spectrum shows that the initial melting point of the compound of formula I, crystal form 1 of the present invention, is 160.76 °C, and the broad endothermic peak at 91.85 °C is the solvent peak for dehydration.

[0064] Non-limiting, the thermogravimetric analysis (TGA) spectrum of the compound of formula I, crystal form 1 of the present invention, is shown in Figure 3. The TGA spectrum shows that the compound of formula I, crystal form 1 of the present invention, exhibits a step weight loss of 5.353% when heated from 25°C to 133°C, corresponding to the weight percentage loss of one molecule of water.

[0065] Non-limitingly, the dynamic moisture adsorption (DVS) spectrum of the compound of formula I, crystal form 1 of the present invention, is shown in Figure 4. The DVS spectrum shows that the compound of formula I of the present invention absorbs moisture and gains 5.2% weight from 0% RH to 95% RH, indicating that the sample absorbs moisture, but cannot completely remove water during desorption (2% remains).

[0066] This invention provides a method for preparing crystal form 1 of compound I, as detailed below:

[0067] Method 1:

[0068] The compound of formula I was dissolved in a solvent and stirred at room temperature. Water was added to the solution of the compound of formula I, and the mixture was stirred, filtered, and dried to obtain crystal form 1 of the compound of formula I.

[0069] In a preferred embodiment, the solvent is selected from one or more of acetone, methanol, and water; the solvent is preferably acetone, or a mixture of methanol and water, or a mixture of acetone and water, wherein the volume ratio (mL / mL) of methanol to water in the mixture of methanol and water is 30:1 to 1:1, preferably 9:1, and the volume ratio (mL / mL) of acetone to water in the mixture of acetone and water is 6:1 to 1:1, preferably 4:1.

[0070] In a preferred embodiment, the volume-to-mass ratio (mL / g) of the solvent to the compound of formula I is 20:1 to 45:1, and the volume-to-mass ratio (mL / g) of the water added to the solution of the compound of formula I is 20:1 to 90:1.

[0071] In a preferred embodiment, the compound of formula I is dissolved in a solvent at 50-60°C.

[0072] In a preferred embodiment, after dissolving the compound of formula I in a solvent, the mixture is stirred at room temperature for 0.5-24 hours.

[0073] In a preferred embodiment, after adding water to the solution of the compound of formula I, the mixture is stirred at room temperature for 0.5-24 hours, and then cooled to 5-15°C and stirred for 1-4 hours.

[0074] Method 2:

[0075] A solvent was added to the compound of formula I, and the mixture was sonicated to obtain a suspension of the compound of formula I. The suspension of the compound of formula I was kept in the dark and stirred. The mixture was then centrifuged and the solid was collected to obtain crystal form 1 of the compound of formula I.

[0076] In a preferred embodiment, the solvent is selected from one or more of tetrahydrofuran, methyl tert-butyl ether, water, acetone, isopropanol, dichloromethane, and ethanol.

[0077] In a preferred embodiment, the suspension of the compound of formula I is stirred at room temperature, or at 45-55°C, preferably 50°C.

[0078] In a preferred embodiment, the suspension of the compound of formula I is protected from light and stirred for 6-10 days.

[0079] Method 3:

[0080] Add solvent to compound I and stir to dissolve it at 50-60°C to obtain a solution of compound I. Filter the solution of compound I while it is hot, cool the filtrate at -20-10°C to crystallize, centrifuge, collect the solid, and obtain crystal form 1 of compound I.

[0081] In a preferred embodiment, the solvent is selected from one or more of acetone, tetrahydrofuran, and dichloromethane.

[0082] In a preferred embodiment, after filtering the solution of the compound of formula I while it is still hot, it is slowly cooled to room temperature at a rate of 6°C / h, and then cooled to crystallize at -20 to 10°C, preferably 2 to 8°C.

[0083] Method 4:

[0084] Add the first solvent to the compound of formula I, sonicate to obtain a supersaturated solution of the compound of formula I, filter, add the second solvent to the filtrate and stir, centrifuge, collect the solid, and obtain crystal form 1 of the compound of formula I.

[0085] In a preferred embodiment, the first solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, acetone, and isopropanol, and the second solvent is selected from one or more of water, methyl tert-butyl ether, and dichloromethane.

[0086] In a preferred embodiment, the volume ratio (mL / mL) of the first solvent to the second solvent is 1:5 to 1:20, preferably 1:10.

[0087] Another object of the present invention is to provide crystal forms of salts of Formula I compounds, specifically crystal forms of hydrochloride, sulfate, hydrobromide, and phosphate of Formula I compounds, which are referred to herein as crystal form A of hydrochloride, crystal form B of sulfate, crystal form C of hydrobromide, and crystal form D of phosphate of Formula I compounds, respectively.

[0088] The X-ray powder diffraction pattern of the hydrochloride crystal form A of the compound of formula I of the present invention has characteristic peaks at 2theta values ​​of 6.4°±0.2°, 12.8°±0.2°, 14.2°±0.2°, and 19.0°±0.2°.

[0089] In a preferred embodiment, the X-ray powder diffraction pattern of the hydrochloride crystal form A of the compound of formula I of the present invention has characteristic peaks at 2theta values ​​of 6.4°±0.2°, 8.5°±0.2°, 11.6°±0.2°, 12.8°±0.2°, 14.2°±0.2°, 17.1°±0.2°, and 19.0°±0.2°.

[0090] In a further preferred embodiment, the X-ray powder diffraction pattern of the hydrochloride crystal form A of the compound of formula I of the present invention has characteristic peaks at 2theta values ​​of 6.4°±0.2°, 8.5°±0.2°, 11.6°±0.2°, 12.8°±0.2°, 14.2°±0.2°, 17.1°±0.2°, 19.0°±0.2°, 19.7°±0.2°, 21.3°±0.2°, and 24.5°±0.2°.

[0091] Without limitation, the X-ray powder diffraction data of the hydrochloride crystal form A of the compound of formula I of the present invention are shown in Table 2.

[0092] Table 2

[0093]

[0094]

[0095] Without limitation, the XRPD pattern of the hydrochloride crystal form A of the compound of formula I of the present invention is shown in Figure 5.

[0096] Non-limiting, the DSC spectrum of the hydrochloride crystal form A of the compound of formula I of the present invention is shown in Figure 6.

[0097] This invention provides a method for preparing crystal form A of the hydrochloride salt of compound I, as detailed below:

[0098] The compound of formula I is dissolved in a solvent to obtain a solution of the compound of formula I. An ethanol solution of hydrochloric acid is added to the solution of the compound of formula I while stirring. The mixture is stirred, centrifuged, the solid is collected, and dried to obtain the hydrochloride crystal form A of the compound of formula I.

[0099] In a preferred embodiment, the compound of formula I is dissolved in a solvent by ultrasonic heating.

[0100] In a preferred embodiment, the solvent is one or more of ethanol, acetone, acetonitrile, and isopropanol.

[0101] In a preferred embodiment, the concentration of the hydrochloric acid ethanol solution is 30-60 mg / mL, preferably 50 mg / mL.

[0102] In a preferred embodiment, after adding the ethanol solution of hydrochloric acid, stirring is continued at room temperature for 4-24 hours.

[0103] The X-ray powder diffraction pattern of the sulfate crystal form B of the compound of formula I of the present invention has characteristic peaks at 2theta values ​​of 12.2°±0.2°, 17.1°±0.2°, 18.4°±0.2°, and 20.1°±0.2°.

[0104] In a preferred embodiment, the X-ray powder diffraction pattern of the sulfate crystal form B of the compound of formula I of the present invention has characteristic peaks at 2theta values ​​of 12.2°±0.2°, 17.1°±0.2°, 18.4°±0.2°, 19.6°±0.2°, 20.1°±0.2°, 20.6°±0.2°, and 22.1°±0.2°.

[0105] In a further preferred embodiment, the X-ray powder diffraction pattern of the sulfate crystal form B of the compound of formula I of the present invention has characteristic peaks at 2theta values ​​of 12.2°±0.2°, 17.1°±0.2°, 18.4°±0.2°, 19.6°±0.2°, 20.1°±0.2°, 20.6°±0.2°, 22.1°±0.2°, 23.5°±0.2°, 26.8°±0.2°, and 29.3°±0.2°.

[0106] Non-limitingly, the X-ray powder diffraction data of sulfate crystal form B of the compound of formula I of the present invention are shown in Table 3.

[0107] Table 3

[0108]

[0109]

[0110] Non-limiting, the XRPD pattern of sulfate crystal form B of the compound of formula I of the present invention is shown in Figure 7.

[0111] Non-limiting, the DSC spectrum of the sulfate crystal form B of the compound of formula I of the present invention is shown in Figure 8.

[0112] Non-limiting, the TGA spectrum of the sulfate crystal form B of the compound of formula I of the present invention is shown in Figure 9.

[0113] Non-limiting, the DVS spectrum of the sulfate crystal form B of the compound of formula I of the present invention is shown in Figure 10.

[0114] This invention provides a method for preparing sulfate crystal form B of compound I, as detailed below:

[0115] The compound of formula I is dissolved in a solvent to obtain a solution of the compound of formula I. An ethanol solution of sulfuric acid is added to the solution of the compound of formula I while stirring. The mixture is stirred, centrifuged, the solid is collected, and dried to obtain the sulfate crystal form B of the compound of formula I.

[0116] In a preferred embodiment, the compound of formula I is dissolved in a solvent by ultrasonic heating.

[0117] In a preferred embodiment, the solvent is one or more of ethanol, acetone, acetonitrile, and isopropanol.

[0118] In a preferred embodiment, the concentration of the sulfuric acid ethanol solution is 30-60 mg / mL, preferably 50 mg / mL.

[0119] In a preferred embodiment, after adding the ethanol solution of sulfuric acid, stirring is continued at room temperature for 4-24 hours.

[0120] The X-ray powder diffraction pattern of the hydrobromide crystal form C of the compound of formula I of the present invention has characteristic peaks at 2theta values ​​of 6.3°±0.2°, 12.6°±0.2°, and 18.9°±0.2°.

[0121] In a preferred embodiment, the X-ray powder diffraction pattern of the hydrobromide crystal form C of the compound of formula I of the present invention has characteristic peaks at 2theta values ​​of 6.3°±0.2°, 8.5°±0.2°, 12.6°±0.2°, 18.9°±0.2°, 21.3°±0.2°, 24.4°±0.2°, and 25.2°±0.2°.

[0122] Without limitation, the X-ray powder diffraction data of the hydrobromide crystal form C of the compound of formula I of the present invention are shown in Table 4.

[0123] Table 4

[0124]

[0125]

[0126] Without limitation, the XRPD pattern of the hydrobromide crystal form C of the compound of formula I of the present invention is shown in Figure 11.

[0127] Non-limiting, the DSC spectrum of the hydrobromide crystal form C of the compound of formula I of the present invention is shown in Figure 12.

[0128] This invention provides a method for preparing the hydrobromide crystal form C of compound I, as detailed below:

[0129] The compound of formula I is dissolved in a solvent to obtain a solution of the compound of formula I. An ethanol solution of hydrobromic acid is added to the solution of the compound of formula I while stirring. The mixture is stirred, centrifuged, the solid is collected, and dried to obtain the hydrobromide crystal form C of the compound of formula I.

[0130] In a preferred embodiment, the compound of formula I is dissolved in a solvent by ultrasonic heating.

[0131] In a preferred embodiment, the solvent is one or more of ethanol, acetone, acetonitrile, and isopropanol.

[0132] In a preferred embodiment, the concentration of the hydrobromic acid ethanol solution is 30-60 mg / mL, preferably 50 mg / mL.

[0133] In a preferred embodiment, after adding the ethanol solution of hydrobromic acid, stirring is continued at room temperature for 4-24 hours.

[0134] The X-ray powder diffraction pattern of the phosphate crystal form D of the compound of formula I of the present invention has characteristic peaks at 2theta values ​​of 6.1°±0.2°, 10.9°±0.2°, and 12.2°±0.2°.

[0135] In a preferred embodiment, the X-ray powder diffraction pattern of the phosphate crystal form D of the compound of formula I of the present invention has characteristic peaks at 2theta values ​​of 6.1°±0.2°, 10.9°±0.2°, 11.7°±0.2°, and 12.2°±0.2°.

[0136] Non-limitingly, the X-ray powder diffraction data of the phosphate crystal form D of the compound of formula I of the present invention are shown in Table 5.

[0137] Table 5

[0138]

[0139] Without limitation, the XRPD pattern of phosphate crystal form D of the compound of formula I of the present invention is shown in Figure 13.

[0140] Non-limiting, the DSC spectrum of the phosphate crystal form D of the compound of formula I of the present invention is shown in Figure 14.

[0141] Non-limiting, the TGA spectrum of the phosphate crystal form D of the compound of formula I of the present invention is shown in Figure 15.

[0142] Non-limiting, the DVS spectrum of the phosphate crystal form D of the compound of formula I of the present invention is shown in Figure 16.

[0143] This invention provides a method for preparing phosphate crystal form D of compound I, as detailed below:

[0144] The compound of formula I is dissolved in a first solvent to obtain a solution of the compound of formula I. An ethanol solution of phosphoric acid is added to the solution of the compound of formula I while stirring. The stirring is continued, the mixture is centrifuged, and the solid is collected. A second solvent is added to the collected solid, the mixture is stirred, centrifuged, and the solid is collected and dried to obtain the phosphate crystal form D of the compound of formula I.

[0145] In a preferred embodiment, the compound of formula I is dissolved in a first solvent by ultrasonic heating.

[0146] In a preferred embodiment, the first solvent is one or more of ethanol, acetone, acetonitrile and isopropanol, and the second solvent is a mixed solvent of acetone and water, wherein the volume ratio (mL / mL) of acetone to water is 7:1-9:1.

[0147] In a preferred embodiment, the concentration of the ethanol solution of phosphoric acid is 30-60 mg / mL, preferably 50 mg / mL.

[0148] In a preferred embodiment, after adding the ethanol solution of phosphoric acid, stirring is continued at room temperature for 4-24 hours; after adding the second solvent, stirring is continued at room temperature overnight.

[0149] The present invention also provides a pharmaceutical composition comprising crystal form 1 of compound I, crystal form A of hydrochloride of compound I, crystal form B of sulfate of compound I, crystal form C of hydrobromide of compound I, and / or crystal form D of phosphate of compound I, and a pharmaceutical formulation comprising crystal form 1 of compound I, crystal form A of hydrochloride of compound I, crystal form B of sulfate of compound I, crystal form C of hydrobromide of compound I, and / or crystal form D of phosphate of compound I.

[0150] The present invention also provides the use of compound I crystal form 1, compound I hydrochloride crystal form A, compound I sulfate crystal form B, compound I hydrobromide crystal form C and / or compound I phosphate crystal form D in the preparation of a medicament for treating diseases or symptoms associated with Jak1 / TYK2, wherein the diseases or symptoms may be autoimmune diseases or disorders, such as rheumatoid arthritis or inflammatory diseases or disorders, and cancer or tumor proliferative diseases or disorders. Attached Figure Description

[0151] Figure 1 shows the XRPD pattern of crystal form 1 of compound I of the present invention.

[0152] Figure 2A shows the DSC spectrum of crystal form 1 of compound I of the present invention.

[0153] Figure 2B shows another DSC spectrum of the crystal form 1 of compound I of the present invention.

[0154] Figure 3 is the TGA spectrum of crystal form 1 of compound I of the present invention.

[0155] Figure 4 shows the DVS spectrum of crystal form 1 of compound I of the present invention.

[0156] Figure 5 shows the XRPD pattern of the hydrochloride crystal form A of the compound of formula I of the present invention.

[0157] Figure 6 shows the DSC spectrum of the hydrochloride crystal form A of the compound of formula I of the present invention.

[0158] Figure 7 shows the XRPD pattern of sulfate crystal form B of compound I of the present invention.

[0159] Figure 8 shows the DSC spectrum of the sulfate crystal form B of the compound of formula I of the present invention.

[0160] Figure 9 shows the TGA spectrum of the sulfate crystal form B of the compound of formula I of this invention.

[0161] Figure 10 shows the DVS spectrum of the sulfate crystal form B of the compound of formula I of the present invention.

[0162] Figure 11 shows the XRPD pattern of the hydrobromide crystal form C of the compound of formula I of the present invention.

[0163] Figure 12 shows the DSC spectrum of the hydrobromide crystal form C of the compound of formula I of the present invention.

[0164] Figure 13 shows the XRPD pattern of phosphate crystal form D of compound I of the present invention.

[0165] Figure 14 shows the DSC spectrum of phosphate crystal form D of compound I of the present invention.

[0166] Figure 15 shows the TGA spectrum of phosphate crystal form D of the compound of formula I of the present invention.

[0167] Figure 16 shows the DVS spectrum of phosphate crystal form D of compound I of the present invention.

[0168] Figure 17 is an XRPD overlay of the crystal form 1 of compound I of the present invention after being placed under high temperature and accelerated conditions for 2 weeks.

[0169] Figure 18 is an XRPD overlay of the phosphate crystal form D of the compound of formula I of the present invention after being placed under high temperature and accelerated conditions for 2 weeks.

[0170] Figure 19 is a DSC overlay image of the crystal form 1 of compound I of the present invention after being placed under high temperature and accelerated conditions for 2 weeks.

[0171] Figure 20 is a DSC overlay of the phosphate crystal form D of the compound of formula I of the present invention after being placed under high temperature and accelerated conditions for 2 weeks. Detailed Implementation

[0172] The following embodiments further illustrate the present invention; however, they do not constitute a limitation or restriction on the scope of the present invention.

[0173] The equipment information and operating conditions used in this invention are as follows:

[0174]

[0175]

[0176] The information on the raw materials and reagents used in this invention is as follows:

[0177] Material Purity / Grade Batch Number Manufacturer Formula V Compound ≥98.0% KM1009-1804001 Shanghai Ruiwa Technology Co., Ltd. Formula IV Compound ≥98.0% KM1008-1804001 Shanghai Ruiwa Technology Co., Ltd. N,N-Diisopropylethylamine (DIPEA) ARKM261A-1801002 Shanghai Qiao Chemical Technology Co., Ltd. Ethanol / 160321047B Nanjing Chemical Reagent Co., Ltd. Methanol ARP1176856 GENERAL-REAGENT Tetrahydrofuran AR Grade P1167158 GENERAL-REAGENT Dichloromethane ARP1216848 GENERAL-REAGENT Ethyl Acetate (EA) ARP1080359 GENERAL-REAGENT Acetone ARP1160778 GENERAL-REAGENT Purified Water Milli-Q Freshly Prepared Milli-Q Methyl tert-butyl ether ARP1135054 GENERAL-REAGENT Isopropanol HPLC 6553 IU 13 Anhui Shilian Special Solvents Co., Ltd. Palladium on Carbon (Pd / C) ARKM416A-1603001 Shaanxi Ruike New Materials Co., Ltd. (R)-Lactamide ARKM1012-1806001 Shanghai Zhongnai Biomedical Technology Co., Ltd. Et3O-BF4 ARKM416A-1603001 Shaanxi Ruike New Materials Co., Ltd. Hydrochloric Acid ARGM007-1809001 Suzhou Zhoushi Chemical Potassium Carbonate Industrial Grade GM009-1804001 Shanghai Weitang Industrial Co., Ltd.

[0178] Example

[0179] Preparation of Compounds of Formula III

[0180]

[0181] Example 1: Preparation of Compound III

[0182] Add ethanol (4 mL), compound IV (0.20 g, 1.0 eq), compound V (0.18 g, 1.0 eq), and DIPEA (0.39 g, 3.0 eq) to a 25 mL three-necked flask and start stirring. Under nitrogen protection, heat the system to reflux (70-80 °C) and stir overnight at reflux temperature. Cool the system to room temperature (15-20 °C), during which solids precipitate. Add water dropwise (4 mL) to the system and stir at room temperature (15-20 °C) for 2 hours. Filter the system, and wash the filter cake with an ethanol-water solution (2 mL, V / V, 1:1). Dry the filter cake under vacuum at 45-50 °C for 16 hours. A total of about 0.21 g of yellow solid was obtained, with an LC-MS purity of 96.4% (214 nm) and a yield of 69%.

[0183] MS-ESI: [M+1] + 303.1

[0184] 1 H 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).

[0185] Example 2 Preparation of Compound III

[0186] Add ethanol (120 mL, 20V), compound IV (6.0 g, 1.0 eq), compound V (5.4 g, 1.01 eq), and DIPEA (11.7 g, 3.0 eq) to a 250 mL three-necked flask and start stirring. Under nitrogen protection, heat the system to 70–80 °C (internal temperature) and stir for 8 hours. Cool the system to room temperature (15–20 °C), during which solid precipitates. Add water dropwise (120 mL, 20V) to the system and stir at room temperature (10–15 °C) for 2 hours. Filter the mixture, and wash the filter cake with an ethanol-water solution (30 mL, 1:1). Dry the filter cake under vacuum at 50 °C for 16 hours. A total of about 7.7 g of yellow solid was obtained, with an HPLC purity of 95.5% and a yield of 84.3%.

[0187] MS-ESI and 1 The H NMR data are consistent with those of Example 1.

[0188] Example 3 Preparation of Compound III

[0189] Add ethanol (5 mL, 10V), compound IV (0.50 g, 1.0 eq), compound V (0.45 g, 1.01 eq), and DIPEA (0.98 g, 3.0 eq) to a 25 mL three-necked flask and start stirring. Under nitrogen protection, heat the system to 70–80 °C and reflux for 5 hours. Cool the system to room temperature (15–20 °C), during which solid precipitates. Add water dropwise (5 mL, 10V) to the system and stir at room temperature (10–15 °C) for 2 hours. Filter the mixture, and wash the filter cake with an ethanol-water solution (1:1) (1.5 mL, 3V). Dry the filter cake under vacuum at 50 °C for 16 hours. A total of approximately 0.54 g of brown solid was obtained, with an HPLC purity of 95.4% and a yield of 71%.

[0190] MS-ESI and 1 The H NMR data are consistent with those of Example 1.

[0191] Example 4 Preparation of Compound III

[0192] Add ethanol (5 mL, 10V), compound IV (0.50 g, 1.0 eq), compound V (0.45 g, 1.01 eq), and DIPEA (0.72 g, 2.2 eq) to a 25 mL three-necked flask and start stirring. Under nitrogen protection, heat the system to 70–80 °C and reflux for 5 hours. Cool the system to room temperature (15–20 °C), during which solid precipitates. Add water dropwise (7.5 mL, 15V) to the system and stir at room temperature (10–15 °C) for 1 hour. Cool the system to 5–10 °C and continue stirring for 2 hours. Filter the mixture, and wash the filter cake with an ethanol-water solution (1:1) (1.5 mL, 3V). Dry the filter cake under vacuum at 50 °C for 16 hours. A total of approximately 0.57 g of brown solid was obtained, with an HPLC purity of 91.4% and a yield of 75%.

[0193] MS-ESI and 1 The H NMR data are consistent with those of Example 1.

[0194] Example 5 Preparation of Compound III

[0195] Add 50 mL of ethanol (10V), compound IV (5.0 g, 1.0 eq), compound V (4.5 g, 1.01 eq), and DIPEA (7.2 g, 2.2 eq) to a 250 mL three-necked flask and start stirring. Under nitrogen protection, heat the system to 70–80 °C and reflux for 5 hours. Cool the system to room temperature (15–20 °C), during which a solid precipitates. Add water dropwise (75 mL, 15V) to the system and stir at room temperature (10–15 °C) for 1 hour. Cool the system to 5–10 °C and continue stirring for 2 hours. Filter the mixture, and wash the filter cake with an ethanol-water solution (1:1, 15 mL). Dry the filter cake under vacuum at 50 °C for 16 hours. A total of approximately 6.6 g of yellow solid was obtained, with an HPLC purity of 94.2% and a yield of 86.7%.

[0196] MS-ESI and 1 The H NMR data are consistent with those of Example 1.

[0197] Example 6 Preparation of Compound III

[0198] Add ethanol (180 mL, 10V), compound IV (17.8 g, 1.0 eq), compound V (16.0 g, 1.01 eq), and DIPEA (25.7 g, 2.2 eq) to a 500 mL three-necked flask and start stirring. Under nitrogen protection, heat the system to 70–80 °C and reflux for 5 hours. Cool the system to room temperature (15–20 °C), during which solids precipitate. Add water dropwise (270 mL, 15V) to the system and stir at room temperature (10–15 °C) for 1 hour. Cool the system to 5–10 °C and continue stirring for 2 hours. Filter the mixture, and wash the filter cake with an ethanol-water solution (ethanol:water = 1:1.5, v / v, 40 mL). Dry the filter cake under vacuum at 50 °C for 16 hours. A total of approximately 23.0 g of brown solid was obtained, with an HPLC purity of 95.3% and a yield of 85.2%.

[0199] MS-ESI and 1 The H NMR data are consistent with those of Example 1.

[0200] Example 7 Preparation of Compound III

[0201] Add ethanol (1000 mL, 10V), compound IV (100 g, 1.0 eq), compound V (89.9 g, 1.01 eq), and DIPEA (143.2 g, 2.2 eq) to a 3000 mL three-necked flask and start stirring. Under nitrogen protection, heat the system to 85–90 °C (internal temperature: approximately 75 °C) and reflux with stirring for 10 hours. Cool the system to room temperature (15–20 °C), during which solids precipitate. Add water dropwise (1500 mL, 15V) to the system and stir at room temperature (10–15 °C) for 1 hour. Cool the system to 5–10 °C and continue stirring for 2 hours. Filter the mixture, and wash the filter cake with an ethanol-water solution (1:1.5, v / v, 200 mL). Dry the filter cake at 50 °C with forced air for 16 hours. A total of 130 g of reddish-brown solid was obtained, with an HPLC purity of 94.2% and a yield of 85.5%.

[0202] MS-ESI and 1 The H NMR data are consistent with those of Example 1.

[0203] Example 8 Preparation of Compound III

[0204] Add ethanol (2000 mL, 10V), compound IV (200 g, 1.0 eq), compound V (179.7 g, 1.01 eq), and DIPEA (286.4 g, 2.2 eq) to a 5000 mL three-necked flask and start stirring. Under nitrogen protection, heat the system to 70–80 °C (internal temperature: approximately 65–70 °C) and reflux with stirring for 16 hours. Cool the system to room temperature (15–20 °C). A solid precipitated; water (3000 mL, 15V) was added dropwise to the system, and the system was stirred at room temperature (10-15℃) for 1 hour; the system was cooled to 5-10℃ and stirred for another 2 hours; the mixture was filtered, and the filter cake was washed with an ethanol-water solution (1:1.5, v / v, 400 mL); the filter cake was dried in a forced-air dryer at 50℃ for 16 hours; a total of 251 g of reddish-brown solid was obtained, with an HPLC purity of 93.4%, a content of 94.7%, and a yield of 78.1%.

[0205] MS-ESI and 1 The H NMR data are consistent with those of Example 1.

[0206] Example 9 Preparation of Compound III

[0207] Add 5000 mL of ethanol (10V), compound IV (500 g, 1.0 eq), compound V (450 g, 1.01 eq), and DIPEA (723 g, 2.2 eq) to a 20000 mL three-necked flask and start stirring. Under nitrogen protection, heat the system to 80-90 °C (internal temperature: approximately 70-80 °C) and reflux with stirring for 16 hours. Cool the system to room temperature (25-30 °C), during which solids precipitate. Add the following to the system: Water (7500 mL, 15V) was added dropwise, and the system was stirred at room temperature (25-30℃) for 1 hour; the system was cooled to 10-15℃ and stirred for another 2 hours; the mixture was filtered, and the filter cake was washed with an ethanol-water solution (1:1.5, v / v, 1000 mL); the filter cake was vacuum dried in a vacuum oven at 50-55℃ for 24 hours; a total of 623 g of product was obtained, with an HPLC purity of 93.7%, an ethanol residue of 0.5%, a content of 93.1%, and a yield of 76.2%.

[0208] MS-ESI and 1 The H NMR data are consistent with those of Example 1.

[0209] Example 10 Preparation of Compound III

[0210] Add ethanol (100 mL, 10V), compound IV (10.0 g, 1.0 eq), compound V (9.0 g, 1.01 eq), and DIPEA (14.3 g, 2.2 eq) to a 500 mL three-necked flask and start stirring. Heat the system to 70–80 °C and reflux for 16 hours. Cool the system to room temperature (20–30 °C), during which solids precipitate. Add water (150 mL, 15V) to the system and stir at room temperature (20–30 °C) for 2 hours. Cool the system to 5–10 °C and continue stirring for 2 hours. Filter the mixture, and wash the filter cake with an ethanol-water solution (1:1.5, v / v, 25 mL). Dry the filter cake in a vacuum oven at 50–55 °C for 16 hours. A total of 13.7 g of product was obtained, with an HPLC purity of 93.7% and a yield of 90%.

[0211] MS-ESI and 1 The H NMR data are consistent with those of Example 1.

[0212] Example 11 Preparation of Compound III

[0213] Add ethanol (17 kg, 10 V), compound IV (2.2 kg, 1.0 eq), compound V (1.98 kg, 1.01 eq), and DIPEA (3.19 kg, 2.2 eq) to reactor R0462, and start stirring; under nitrogen protection, heat the system to 75–80 °C (internal temperature: approximately 70–80 °C) and stir for 16 hours; cool the system to room temperature (15–25 °C), during which solids precipitate; add water dropwise to the system (… 33 kg (15V) was stirred at room temperature (10-15℃) for 2 hours; the system was cooled to 5-10℃ and stirred for another 4 hours; the mixture was filtered, and the filter cake was washed with an ethanol-water solution (ethanol:water = 1:2, v / v, 6.2 kg); the filter cake was dried in a jacket at a temperature of 45-55℃ under vacuum to ≤-0.08 MPa for 16 hours; a total of 2.64 kg of brown solid was obtained, with an HPLC purity of 94.0%, a content of 93.4%, and a yield of 79.04%.

[0214] MS-ESI and 1 The H NMR data are consistent with those of Example 1.

[0215] Preparation of Compounds of Formula II

[0216]

[0217] Example 12 Preparation of Compound II

[0218] Compound III (5.0 g), THF (50 mL, 10 V), and palladium on carbon (0.75 g, 10% Pd / C, 50% wet) were added sequentially to a 100 mL stainless steel pressure vessel. The system was purged with nitrogen five times and hydrogen five times. The system was pressurized with hydrogen to 0.50 MPa and heated to 25-35 °C with stirring for 24 hours. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with tetrahydrofuran (20 mL). The filtrate was concentrated to dryness to give 4.2 g of brown solid with an HPLC purity of 94.9% and a yield of 93.3%.

[0219] MS-ESI: [M+1] + 273.1

[0220] 1H 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).

[0221] Example 13 Preparation of Compound II

[0222] Compound III (120.0 g), THF (2400 mL, 20 V), and palladium on carbon (18 g, 10% Pd / C, 50% wet) were added sequentially to a 5000 mL stainless steel pressure vessel. The system was purged with nitrogen five times and hydrogen five times. The system was pressurized with hydrogen to 0.50 MPa and heated to 25-35 °C with stirring for 24 hours. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with tetrahydrofuran (600 mL) (until TLC showed almost no fluorescence). The filtrate was concentrated to obtain 130 g of black semi-oily solid with an HPLC purity of 91.7% and a yield of 120.26%.

[0223] MS-ESI and 1 The H NMR data are consistent with those of Example 12.

[0224] Example 14 Preparation of Compound II

[0225] Compound III (100.0 g), THF (2000 ml, 20V), and palladium on carbon (15.0 g, 10% Pd / C, 50% wet) were added sequentially to a 5L stainless steel pressure vessel. The system was purged with nitrogen five times and hydrogen five times. The system was pressurized with hydrogen to 0.5-1.0 MPa, the jacket temperature was set to 30℃, and the mixture was stirred for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with THF (1000 mL). A total of 3877 g of THF solution of compound II was obtained.

[0226] Post-treatment 1: Take the above filtrate (1820g, which, based on a 100% yield, contains approximately 40g of compound II) and concentrate it to (2-3V, 80-120mL) using a rotary evaporator; replace the system with ethanol (150mL×2) to (2-3V, 80-120mL); a total of 78g of ethanol solution of compound II was obtained, with a purity of 47.25% and a yield of 92.14%.

[0227] Post-treatment 2: Take the above filtrate (450g, which contains approximately 10g of compound II at a 100% yield) and concentrate it to dryness using a rotary evaporator; a total of 10.5g of brownish-red solid was obtained.

[0228] Post-treatment 3: Take the above filtrate (450g, equivalent to about 10g of compound II) into a flask; concentrate it to about 30-40mL (3-4V) by rotation; replace the concentrate residue with ethanol (50mL×2) to about 30-40mL (3-4V); obtain a black oily concentrate residue, which is directly added to the next reaction.

[0229] MS-ESI and 1 The H NMR data are consistent with those of Example 12.

[0230] Example 15 Preparation of Compound II

[0231] Add tetrahydrofuran (240 mL, 20V), compound III (12.0 g), and palladium on carbon (1.8 g, 5% Pd / C, 50% wet) sequentially to a 500 mL three-necked flask; purge the system five times with nitrogen and five times with hydrogen; keep the system heated and stirred at room temperature (25-30 °C) under hydrogen pressure (approximately 0.1 MPa) for 48 hours; filter the reaction solution, and wash the filter cake with tetrahydrofuran (60 mL); concentrate the combined filtrate to 20-30 mL by rotary evaporation; purge to 20-30 mL with ethanol (60 mL × 2); a total of 24 g of ethanol solution of compound II is obtained, which is used directly in the next reaction step.

[0232] MS-ESI and 1 The H NMR data are consistent with those of Example 12.

[0233] Example 16 Preparation of Compound II

[0234] Tetrahydrofuran (1500 mL, 15V), compound III (100 g), and palladium on carbon (15 g, 5% Pd / C, 50% wet) were added sequentially to a 5000 mL three-necked flask. The system was purged with nitrogen five times and hydrogen five times. The system was kept at hydrogen pressure (approximately 0.1 MPa) and at room temperature (20-25 °C) with stirring for 48 hours. The reaction solution was filtered, and the filter cake was washed with tetrahydrofuran (200 mL). The combined filtrates were concentrated to 200-300 mL by rotary evaporation. A total of 185.6 g of THF solution of compound II was obtained, with an HPLC purity of 94.2% and a content of 43.2%, yielding a purity of 94.0%.

[0235] MS-ESI and 1 The H NMR data are consistent with those of Example 12.

[0236] Example 17 Preparation of Compound II

[0237] Tetrahydrofuran (12400 mL, 20V), compound III (620 g), and palladium on carbon (93 g, 5% Pd / C, 50% wet) were added sequentially to a 20000 mL three-necked flask. The system was purged with nitrogen five times and hydrogen five times. The system was kept at hydrogen pressure (approximately 0.1 MPa) and at room temperature (30-35 °C) with stirring for 48 hours. The reaction solution was filtered through diatomaceous earth (200 g), and the filter cake was washed with tetrahydrofuran (1200 mL). The combined filtrates were concentrated to 1200-1800 mL by rotary evaporation. A total of 1664 g of tetrahydrofuran solution of compound II was obtained, with an HPLC purity of 93.8%, a content of 34.57%, and a yield of 110.6%.

[0238] MS-ESI and 1 The H NMR data are consistent with those of Example 12.

[0239] Example 18 Preparation of Compound II

[0240] THF (140 mL, 70 V), compound III (2.0 g), and palladium on carbon (0.3 g, 5% Pd / C, 50% wet) were added to a 250 mL high-pressure reactor. The reactor lid was closed and the nut tightened. The reactor was purged three times with nitrogen and three times with hydrogen. The reactor was then pressurized with hydrogen to a pressure of approximately 0.50 ± 0.05 MPa, and the inlet valve was closed. The stirrer was turned on at a speed of 500 r / min. The reactor was kept at a hydrogen pressure of 0.5 ± 0.05 MPa at 25-35 °C, and the reaction was carried out with stirring for 96 h. The reaction solution was filtered through diatomaceous earth (10 g), and the filter cake was washed with tetrahydrofuran (60 mL). The combined filtrate was concentrated to dryness by rotary evaporation to obtain 1.8 g of semi-oily solid with an HPLC purity of 91.2%. The yield was 99.9%.

[0241] MS-ESI and 1 The H NMR data are consistent with those of Example 12.

[0242] Example 19 Preparation of Compound II

[0243] THF (167 kg, 70 V), compound III (2.64 kg), and palladium on carbon (0.4 kg, 5% Pd / C, 50% wet) were added to a 500 L high-pressure reactor. The reactor was purged with nitrogen five times and hydrogen five times. The reactor was then purged with hydrogen to a pressure of approximately 0.50 ± 0.05 MPa, and the inlet valve was closed. The stirring device was turned on. The reactor was kept at a hydrogen pressure of 0.5 ± 0.05 MPa at 25-35 °C, and the reaction was carried out with stirring for 120 h. The reactor was then filtered, and the filter cake was washed with tetrahydrofuran (13 kg). The combined filtrates were distilled under reduced pressure (to 2 V ~ 3 V) to obtain a tetrahydrofuran solution of compound II: 11 kg; HPLC purity 90.7%, content 18.5%; yield 91.9%.

[0244] MS-ESI and 1 The H NMR data are consistent with those of Example 12.

[0245] Example 20 Preparation of Compound II

[0246] Tetrahydrofuran (60 mL, 12V), compound III (5.0 g), and palladium on carbon (0.75 g, 5% Pd / C, 50% wet) were added sequentially to a 100 mL stainless steel pressure vessel. The system was purged with nitrogen five times and hydrogen five times. The system was pressurized with hydrogen to 0.5-1.0 MPa, the jacket temperature was set to 30 °C, and the mixture was stirred for 42 hours. 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 THF solution of compound II was obtained. The solution was concentrated to (2-3V, 10-15 mL) using a rotary evaporator. The system was then purged with ethanol (25 mL × 2) to (2-3V, 10-15 mL). The resulting ethanol solution of compound II was used directly in the next reaction step.

[0247] MS-ESI and 1 The H NMR data are consistent with those of Example 12.

[0248] Preparation of Compound I

[0249]

[0250] Example 21 Preparation of Compound I

[0251] Add THF (60 mL, 12V), (R)-lactamide (6.6 g, 4.0 eq), and Et3O-BF4 (13.9 g, 4.0 eq) to a 250 mL three-necked flask (flask #1), and start stirring. Stir the mixture in flask #1 under nitrogen protection. Add compound II (5.0 g, 1.0 eq) and ethanol (80 mL, 16V) to another 250 mL three-necked flask (flask #2). Heat the system to 70±5℃ under nitrogen protection. Add the mixture from flask #1 dropwise to flask #2 over 10-20 minutes using a syringe. Heat the system to 85±5℃ (internal temperature 72-75℃) under nitrogen protection and react for 2 hours. Cool the system to room temperature. Concentrate the reaction mixture by rotary evaporation until almost no distillate remains. Add 1M... HCl (80 mL) was added to the concentrated residue, and the pH was approximately 1 as measured by pH paper. The system was extracted four times with DCM (50 mL × 4). The aqueous phase was adjusted to pH 7-8 with saturated sodium bicarbonate solution. The mixture was stirred at room temperature for 0.5 h. After filtration, the filter cake was washed with water (60 mL) and EA (10 mL) respectively. The filter cake was vacuum dried at 50 °C for 16 h, yielding 4.3 g of a pale yellow solid with a purity of 95.0%. The solid was dissolved in methanol (30 mL). 4.1 g of silicon-based metal scavenger and active... 1.0 g of activated carbon was added, and the system was heated to 50 °C and stirred for 1 h. After cooling, the mixture was filtered and washed with methanol (30 mL). The filtrate was concentrated by rotary evaporation until almost no fraction flowed out. Methanol (10 mL) and MTBE (25 mL) were added to the residue, and the system was heated to 50 °C and stirred for 0.5 h. After cooling, the system was cooled to 10 ± 5 °C and stirred for 0.5 h. After filtration, the filter cake was washed with MTBE (25 mL). The filter cake was vacuum dried at 50 °C for 16 h to obtain 3.2 g of pale yellow solid with a purity of 97.9%.

[0252] MS-ESI: [M+1] + 327.6

[0253] 1 H NMR(400MHz, CDCl3):8.988(s,1H),7.922(d,1H),7.175(d,1H),5.200-5.265(m,1H),4.859-4.942(m,1H),4.350- 4.406(t,1H),4.020-4.108(m,2H),3.067(d,1H),2.619-2.779(m,3H),2.108-2.269(m,2H),1.790-1.895(m,3H).

[0254] Example 22 Preparation of Compound I

[0255] Add THF (650 mL, 12V), (R)-lactamide (70.6 g, 4.0 eq), and Et3O-BF4 (150.6 g, 4.0 eq) to a 1000 mL three-necked flask (1#), and start stirring; stir the mixture in flask 1# under nitrogen protection. Add compound II (54 g, 1.0 eq) and ethanol (860 mL, 16V) to another 2000 mL three-necked flask (2#); heat the system to 70±5℃ under nitrogen protection; slowly add the mixture from flask 1# to flask 2# over 1 hour; heat the system to 85±5℃ (internal temperature 72-75℃) under nitrogen protection and react for 2 hours; cool the system to room temperature; concentrate the reaction solution by rotary evaporation until almost no distillate flows out; add 1M... HCl (450 mL) was added to the concentrated residue, and the pH was approximately 1 as measured by pH paper. The system was extracted four times with DCM (270 mL × 4). The aqueous phase was adjusted to pH 7-8 with saturated sodium bicarbonate solution. The mixture was stirred at room temperature for 0.5 h. The mixture was filtered, and the filter cake was washed with water (540 mL). MTBE (270 mL) was added to the filter cake, and the mixture was stirred at room temperature for 0.5 h. The mixture was filtered, and the filter cake was washed with MTBE (108 mL). The filter cake was vacuum dried at 50 °C for 16 h, yielding 49.2 g of a pale yellow solid with an HPLC purity of 94.2%. The solid was dissolved in methanol (380 mL), and 44 g of a silicon-based metal scavenger was added. Add activated carbon (5.4 g) to the mixture, heat the system to 50 °C and stir for 1 h; cool, filter, and wash with methanol (430 mL); concentrate the filtrate by rotary evaporation to (80-110 mL, 1.5V-2V); add MTBE (540 mL) to the residue, heat the system to 50 °C and stir for 1 h; cool, and cool the system to 10±5 °C and stir for 0.5 h; filter, and wash the filter cake with MTBE (270 mL); obtain 42.4 g of filter cake with HPLC purity of 96.9%; dry the filter cake under vacuum at 50 °C for 16 h to obtain 41.0 g of pale yellow solid with HPLC purity of 96.7% and yield of 63.3%.

[0256] Purification of Formula I compounds:

[0257] Dissolve compound I (41 g) in methanol; add silica gel (50 g) to the solution, then concentrate the system to dryness and set aside; add silica gel (200 g) to the chromatography column and compact it with an air pump; load compound I mixed with silica gel into the chromatography column and use an air pump; elute with V... MeOH :V DCM Elute the chromatography column with a ratio of 1:100 to 1:30; collect the qualified components and concentrate to dryness; vacuum dry the product at 50°C for 16 hours; a total of 36g of off-white solid was obtained with an HPLC purity of 98.5%.

[0258] MS-ESI and 1The H NMR data are consistent with those of Example 21.

[0259] Example 23 Preparation of Compound I

[0260] Add THF (60 mL, 6V), (R)-lactamide (13.2 g, 4.0 eq), and Et3O-BF4 (27.9 g, 4.0 eq) to a 100 mL single-necked flask #1, and start stirring; stir the material in #1 under nitrogen protection and set aside; add compound II (10 g, 1.0 eq) and ethanol (100 mL, 10V) to another 250 mL three-necked flask #2; heat the system to 70 ± 5 °C under nitrogen protection; stir the material in three-necked flask #1 for 20 mL. The solution was slowly added dropwise to three-necked flask #2; under nitrogen protection, the system was heated to 80±5℃ (internal temperature 72-75℃) and reacted for 0.5h; the system was cooled to room temperature (20-30℃); the reaction solution was concentrated to approximately 50mL-80mL using a rotary evaporator at 30-40℃; water (100mL, 10V) was added to the system, and then the system was concentrated to almost no distillate flow using a rotary evaporator at 30-40℃; the system was cooled to 20-30℃; the system temperature was controlled at 20-30℃, and a 12M... The pH of the system was adjusted to 2-3 with HCl (5.5 g); the system was extracted with ethyl acetate (50 mL × 2, 5 V × 2); the organic phase was discarded, and the aqueous phase was transferred to a flask; the system temperature was controlled at 20-30℃, and the pH of the system was adjusted to 8-9 with saturated potassium carbonate solution (23 g); the system temperature was controlled at 20-25℃, and the system was stirred for 2 h; the system was filtered, and the filter cake was washed with water (50 mL) and MTBE (50 mL); the filter cake was dried in a blower at 50℃ for 24 h to obtain 18 g of yellowish-brown solid with an HPLC purity of 93.5%.

[0261] MS-ESI and 1 The H NMR data are consistent with those of Example 21.

[0262] Example 24 Preparation of Compound I

[0263] Add THF (120 mL, 12V), (R)-lactamide (13.2 g, 4.0 eq), and Et3O-BF4 (27.8 g, 4.0 eq) to a 250 mL three-necked flask (flask #1), and start stirring; stir the contents of flask #1 under nitrogen protection and set aside; add compound II (10 g, 1.0 eq) and ethanol (140 mL, 14V) to another 500 mL three-necked flask (flask #2); under nitrogen protection. The system was heated to 40-45℃ (internal temperature); the material in three-necked flask #1 was added dropwise to three-necked flask #2 over approximately 1 hour; under nitrogen protection, the reaction was maintained at 40-45℃ (internal temperature) for 4.5 hours; the system was cooled to room temperature, and water (20 mL, 2V) was added; the system was concentrated using a rotary evaporator at 30-40℃ until almost no distillate flowed out; the system was cooled to 20-30℃; the system temperature was controlled at 20-30℃, and 12M... The pH of the system was adjusted to 2-3 with HCl (3 mL); the system was extracted with ethyl acetate (50 mL × 2, 5V × 2); the organic phase was discarded, and the aqueous phase was transferred to a flask; the system temperature was controlled at 20-30℃, and the pH of the system was adjusted to 8-9 with 50% potassium carbonate solution (15 mL); the system temperature was controlled at 20-25℃, and the system was stirred for 2 h; the system was filtered, and the filter cake was washed with water (50 mL) and acetone (50 mL); the crude product was slurried and stirred with water (50 mL) at 20-25℃ for 1 h; the system was filtered, and the filter cake was washed with water (50 mL) and acetone (50 mL); the filter cake was dried in a blower at 50℃ for 24 h to obtain 17.8 g of yellowish-brown solid with an HPLC purity of 95.3%.

[0264] MS-ESI and 1 The H NMR data are consistent with those of Example 21.

[0265] Example 25 Preparation of Compound I

[0266] Add THF (60 mL, 12V), (R)-lactamide (6.6 g, 4.0 eq), and Et3O-BF4 (13.9 g, 4.0 eq) to a 250 mL three-necked flask #1, and start stirring; stir the mixture in #1 under nitrogen protection and set aside; add compound II (5 g, 1.0 eq) and ethanol (70 mL, 14V) to another 250 mL three-necked flask #2; heat the system to 40-45 °C (internal temperature) under nitrogen protection; stir the mixture in three-necked flask #1 for approximately 20 mL. Add the solution dropwise to three-necked flask #2; under nitrogen protection, maintain the reaction temperature at 40-45℃ (internal temperature) for 3 hours; cool the system to room temperature; filter, and rinse the filter cake with THF (10 mL); add water (10 mL, 2V) to the filtrate; concentrate the filtrate to 10-20 mL (2V-4V) by rotary evaporation; replace and concentrate the remainder to 10-20 mL (2V-4V) with ethyl acetate (25 mL × 2); add water (50 mL, 10V) to the concentrate; control the internal temperature at 20-25℃, and evaporate the system with 12M... Adjust the pH to 1-2 with HCl (4.1 g); add activated carbon (0.5 g) to the system and stir at room temperature for 2 h; filter, rinse the filter cake with water (10 mL) and 1M HCl (10 mL); extract the combined filtrates with ethyl acetate (25 mL × 2), discarding the organic phase; control the internal temperature at 20-25℃, adjust the pH to 9-10 with saturated potassium carbonate solution (15 g); control the internal temperature at 15-20℃, stir the system for 1 h; filter, rinse the filter cake with water (10 mL); slurry the filter cake with acetone aqueous solution (50 mL, V / V = 1:1) for 1 h; filter, rinse the filter cake with acetone aqueous solution (10 mL, V / V = 1:1); dry the filter cake in a blower at 50℃ for 24 h; obtain 5.0 g of light gray solid, HPLC purity 95.6%, yield 83.5%;

[0267] Purification of Formula I compounds:

[0268] Add 5.0 g of the obtained solid and 40 mL of methanol to a flask and stir at room temperature for 10 minutes until the material is basically dissolved. Add 0.5 g of activated carbon and 4.0 g of silica gel to the system. Heat the system to 50-55 °C and stir for 2 hours. Filter with 5 g of silica gel and wash the filter cake with 50 mL of methanol. Concentrate the filtrate to 5-10 mL using a rotary evaporator. Add 50 mL of MTBE to the remaining concentrate. Heat the system to reflux and reflux for 1 hour. Cool the system to 5-10 °C and stir for 1 hour. Filter and wash the filter cake with MTBE. Dry the filter cake in a vacuum drying oven at 50 °C for 16 hours. Obtain 3.0 g of off-white solid with a yield of 60% and a purity of 97.9%. Concentrate the filtrate to dryness to obtain 1.4 g of yellow solid.

[0269] MS-ESI and1 The H NMR data are consistent with those of Example 21.

[0270] Example 26 Preparation of Compound I

[0271] Add THF (55 mL, 12 V), (R)-lactamide (5.9 g, 4.0 eq), and Et3O-BF4 (12.6 g, 4.0 eq) to a 250 mL three-necked flask #1, and start stirring; stir the material in #1 under nitrogen protection and set aside; add the compound of formula II (4.5 g, calculated based on 100% yield of 5.0 g of compound of formula III in Example 20) and ethanol (70 mL, 15.5 V) to another 250 mL three-necked flask #2; heat the system to reflux under nitrogen protection; The material in flask #1 was added dropwise to flask #2; under nitrogen protection, the mixture was heated to 85±5°C (internal temperature 74-76°C) and reacted for 1 hour; the system was cooled to room temperature; the mixture was filtered, and the filter cake was washed with THF (10 mL); water (10 mL, 2V) was added to the filtrate; the filtrate was concentrated to 10-20 mL (2V-4V) by rotary evaporation; the remaining filtrate was concentrated to 10-20 mL (2V-4V) by displacing with ethyl acetate (25 mL × 2); water (50 mL, 10V) was added to the remaining concentrate; the internal temperature was controlled at 20-25°C, and the system was treated with 12M... Adjust the pH to 1-2 with HCl (3.6 g); add activated carbon (0.5 g) to the system and stir at room temperature for 2 h; filter, rinse the filter cake with water (10 mL) and 1M HCl (10 mL); extract the combined filtrates with ethyl acetate (25 mL × 2), discarding the organic phase; control the internal temperature at 20-25℃, adjust the pH to 9-10 with saturated potassium carbonate solution (15 g); control the internal temperature at 15-20℃, and stir the system for 1 h; filter, rinse the filter cake with water (10 mL); slurry the filter cake with acetone aqueous solution (50 mL, V / V = 1:1) for 1 h; filter, rinse the filter cake with acetone aqueous solution (10 mL, V / V = 1:1); dry the filter cake in a blower at 50℃ for 16 h; obtain 4.9 g of light gray solid with HPLC purity of 94.5%.

[0272] Purification of Formula I compounds:

[0273] The obtained solid (4.9 g) and ethanol (100 mL) were added to a flask and stirred at room temperature for 10 minutes until the material was basically dissolved. Silica gel (5.0 g, 1X) was added to the system. The system was concentrated to dryness by rotary evaporation and set aside. The crude product of compound I with silica gel was passed through a silica gel column (40 g, 8X) and eluted with a mixture of ethyl acetate and ethanol (V). EA :V EtOH=100:1 to 30:1); the components were detected by TLC, the components containing the product were collected and concentrated to dryness; 0.5 g of white product with a purity of 95.0% and 2.9 g of light yellow product with a purity of 98.7% were obtained; ethyl acetate (30 mL) and ethanol (3 mL) were added to the flask containing 2.9 g of product; the system was heated to reflux and refluxed for 1 h; the system was cooled to 5-10 °C and stirred for 1 h; the filter cake was filtered and washed with ethyl acetate (5 mL); the filter cake was dried in a vacuum drying oven at 50 °C for 16 h; 2.3 g of light yellow to off-white solid was obtained, with an HPLC purity of 99.6% and no impurities >0.1%. The total yield of the second and third steps was 42.7%.

[0274] MS-ESI and 1 The H NMR data are consistent with those of Example 21.

[0275] Example 27 Preparation of Compound I

[0276] Add THF (120 mL, 12V), (R)-lactamide (13.2 g, 4.0 eq), and Et3O-BF4 (27.8 g, 4.0 eq) to a 250 mL three-necked flask #1, and start stirring; stir the contents of #1 under nitrogen protection and set aside; add the concentrated residue obtained from post-treatment 3 of Example 14 (containing about 10 g of compound II) and ethanol (140 mL, 14V) to another 500 mL three-necked flask #2; heat the system to 45 ± 2 °C under nitrogen protection; stir the contents of three-necked flask #1... The material was added dropwise to a three-necked flask #2; under nitrogen protection, the mixture was heated to 45±5℃ (internal temperature 45℃) and reacted for 6 hours; the system was cooled to room temperature; the mixture was filtered, and the filter cake was washed with THF (20mL); water (20mL, 2V) was added to the filtrate; the filtrate was concentrated to 20-40mL (2V-4V) by rotary evaporation; the remainder was concentrated to 20-40mL (2V-4V) by replacing with ethyl acetate (50mL×2); water (90mL, 10V) was added to the remaining concentrate; the internal temperature was controlled at 20-25℃, and the system was treated with 12M... Adjust the pH to 1-2 with HCl (8.0 g); add activated carbon (1.0 g) to the system and stir at room temperature for 2 h; filter, rinse the filter cake with water (20 mL) and 1M HCl (20 mL); extract the combined filtrates with ethyl acetate (50 mL × 2), discarding the organic phase; adjust the pH to 9-10 with saturated potassium carbonate solution (28 g) while maintaining the internal temperature at 20-25℃; stir the system for 1 h while maintaining the internal temperature at 15-20℃; filter, rinse the filter cake with water (20 mL); slurry the filter cake with acetone aqueous solution (100 mL, V / V = 1:1) for 1 h; filter, rinse the filter cake with acetone aqueous solution (20 mL, V / V = 1:1); dry the filter cake in a blower at 50℃ for 16 h to obtain 15.0 g of light gray solid with a purity of 92.4%.

[0277] Purification of Formula I compounds:

[0278] Add the obtained solid (10 g) and ethanol (100 mL) to a flask; heat the system to 50-60 °C and stir at 50-60 °C for 30 minutes until the material is basically dissolved; add silica gel (20.0 g, 2X) to the system; concentrate the system to dryness by rotary evaporation and set aside; pass the crude compound of formula I with silica gel through a silica gel column (100 g, 10X), elute the column with ethyl acetate until there are basically no precursors (about 1.5 L), and then elute with a mixed solution of ethyl acetate and ethanol (V). EA :V EtOH =100:1 to 30:1, V EA :V EtOH =100:1:0.5L, V EA :V EtOH=30:1, 1.5L); Analyze the components using TLC and collect the components still containing the product; Concentrate the qualified components by rotary evaporation to (50mL, 5V); Replace the solvent with ethyl acetate (50mL×2) to (50mL, 5V); Cool the system to 5-10℃ and stir at 5-10℃ for 2h; Filter, and wash the filter cake with ethyl acetate (5mL); Concentrate the mother liquor to dryness to obtain 0.6g of product; Dry the filter cake in a vacuum drying oven at 50℃ for 16 hours; Obtain 4.6g of off-white solid with a purity of 98.1%, and the total yield of the second and third steps is 57.6%.

[0279] MS-ESI and 1 The H NMR data are consistent with those of Example 21.

[0280] Example 28 Preparation of Compound I

[0281] Add THF (660 mL, 12V), (R)-lactamide (72 g, 4.0 eq), and Et3O-BF4 (153.5 g, 4.0 eq) to a 1000 mL three-necked flask #1, and start stirring; stir the material in #1 under nitrogen protection and set aside; take a tetrahydrofuran solution (127.3 g, equivalent to 55 g of compound II) prepared in Example 16 into the flask, replace it with EtOH (280 mL × 2) to about 120-180 mL, transfer the remaining concentrate to a 2000 mL three-necked flask #2, and add ethanol (770 mL, 14V). Under nitrogen protection, stir the system... Heat to 45-50℃ (internal temperature); add the material from three-necked flask #1 dropwise to three-necked flask #2 over approximately 1 hour; under nitrogen protection, maintain the temperature at 45-50℃ (maintaining approximately 45℃) for 3 hours; cool the system to room temperature; filter, and rinse the filter cake with THF (60 mL); add water (110 mL, 2V) to the filtrate; concentrate the filtrate to 110-220 mL (2V-4V) by rotary evaporation; replace the remaining filtrate with ethyl acetate (280 mL × 2) and concentrate to 110-220 mL (2V-4V); add water (550 mL, 10V) to the remaining concentrate; control the internal temperature at 20-25℃, and adjust the pH of the system to 1-2 with 12M HCl (35 g); add activated carbon (5.5 g) to the system and stir the system at room temperature for 2 hours; filter, and rinse the filter cake with water (110 mL), 1M HCl... The mixture was rinsed with HCl (110 mL); the combined filtrates were extracted with ethyl acetate (280 mL × 2), and the organic phase was discarded; the internal temperature was controlled at 20-25℃, and the pH of the system was adjusted to 9-10 with 50% potassium carbonate solution (180 g); the internal temperature was controlled at 15-20℃, and the system was stirred for 2 h; the mixture was filtered, and the filter cake was rinsed with water (110 mL); the filter cake was slurried with acetone aqueous solution (550 mL, V / V = 1:1) for 2 h; the mixture was filtered, and the filter cake was rinsed with acetone aqueous solution (110 mL, V / V = 1:1); the filter cake was dried in a blower at 50℃ for 16 h; 80 g of light gray solid was obtained, with an HPLC purity of 96.4%, a content of 50.32%, and a yield of 61.1%.

[0282] Purification of Formula I compounds:

[0283] The obtained solid (80 g), silica gel (160 g, 2X), and ethanol (800 mL) were added to a flask; the system was heated to 50-60 °C and stirred at 50-60 °C for 30 minutes; the system was concentrated to dryness by rotary evaporation and set aside; the crude compound of formula I mixed with silica gel was passed through a silica gel column (800 g, 10X), and the column was eluted with ethyl acetate until there were essentially no precursors, and then eluted with a mixture of ethyl acetate and ethanol (V... EA :V EtOH=100:1 to 30:1); Analyze the components using TLC and collect the components that show essentially no impurities on TLC; Concentrate the qualified components by rotary evaporation to (~200 mL); Replace the remaining concentrate with methanol (~200 mL) twice; Replace the remaining concentrate with MTBE (~200 mL) twice; Add MTBE (~300 mL) to the remaining concentrate; Heat the system to reflux and reflux for 1 h; Cool the system to 5-10℃ and stir at 5-10℃ for 2 h; Filter, and wash the filter cake with MTBE (30 mL); Dry the filter cake in a vacuum drying oven at 50℃ for 16 h; Obtain 39 g of light yellow solid with HPLC purity of 99.7% and no impurities >0.1%.

[0284] MS-ESI and 1 The H NMR data are consistent with those of Example 21.

[0285] Example 29 Preparation of Compound I

[0286] Add THF (11 kg, 12 V), (R)-lactamide (1.64 kg, 5.0 eq), and Et3O-BF4 (3.50 kg, 5.0 eq) to a 100 L reactor #1, and start stirring. Stir the material in reactor #1 under nitrogen protection. Take a tetrahydrofuran solution (5.4 kg) of the compound of formula II prepared in Example 19, replace it twice with 4.2 kg × 2 ethanol, and transfer it to a 100 L reactor #2 with 11.2 kg, 14 V ethanol. Heat the system to 45-50 °C (internal temperature) under nitrogen protection. Add the material from reactor #1 dropwise to reactor #2 over approximately 1 hour. Maintain the system at 45-50 °C under nitrogen protection. The reaction was kept at a constant temperature for 3 hours. THF (1.0 kg, 12 V), (R)-lactamide (0.16 kg, 0.50 eq), and Et3O-BF4 (0.35 kg, 0.50 eq) were added to a 5 L beaker and stirred until dissolved. The solution was added dropwise to reactor #2 and kept at a constant temperature for 2 hours. The system was cooled to room temperature. The mixture was filtered, and the filter cake was rinsed with THF (1.0 kg). Water (2 kg, 2 V) was added to the filtrate. The filtrate was concentrated to 3 L (2 V - 4 V) by rotary evaporation. The remaining filtrate was concentrated to 3 L (2 V - 4 V) by replacing it with ethyl acetate (4 kg × 2). Water (10 kg, 10 V) was added to the remaining concentrate. The internal temperature was controlled at 20-25 °C, and the system was treated with 12 M... Adjust the pH to 1-2 with HCl; add 0.1 kg of activated carbon to the system and stir at room temperature for 2 hours; filter, and rinse the filter cake with 2 kg of water. The mixture was rinsed with HCl (2 kg); the combined filtrates were extracted with ethyl acetate (3.90 kg × 2), and the organic phase was discarded; the internal temperature was controlled at 20-25℃, and the pH of the system was adjusted to 9-10 with 50% potassium carbonate solution; the internal temperature was controlled at 15-20℃, and the system was stirred for 2 h; the mixture was filtered, and the filter cake was rinsed with water (2 kg); the filter cake was slurried with acetone aqueous solution (8.9 kg, V / V = 1:1) at 25-30℃ for 2 h; the system was cooled to 5-10℃, and slurrying was continued for 2 h; the mixture was filtered, and the filter cake was rinsed with acetone aqueous solution (1.86 kg, V / V = 1:2); the filter cake was dried under vacuum at 50-55℃ to obtain 1.3 kg of solid with a content of 39.9% and an HPLC purity of 97.1%.

[0287] Purification of Formula I compounds:

[0288] Add the above solid (1.3 kg) and ethanol (6.50 kg) to a rotary flask; heat the system to 45-55℃ and stir for 30 minutes at 45-55℃ until the material is basically dissolved; add silica gel (2.60 kg) to the rotary flask and concentrate under reduced pressure in a 50-60℃ water bath until almost no distillate flows out; replace with ethyl acetate (6.50 kg) until almost no distillate flows out, and set aside; prepare and clean the chromatography column, then add silica gel (13.00 kg, 200-300 mesh) to the silica gel column; compact the silica gel column with ethyl acetate (26.0 kg); add the prepared sample to the silica gel column and level it; elute the column with ethyl acetate (52.0 kg), then elute with a mixture of ethyl acetate and ethanol (V EA :V EtOH =100:1, 65.6Kg,) Elution column, mixed solution of ethyl acetate and ethanol (V EA :V EtOH =80:1, 64.7Kg) elution column, mixed solution of ethyl acetate and ethanol (V EA :V EtOH =50:1, 123.1Kg) elution column, mixed solution of ethyl acetate and ethanol (V EA :V EtOH Elute the column with a 30:1 ratio (64.8 kg); collect the fraction with a purity ≥99.0% as indicated by HPLC; concentrate the fraction with a purity ≥99.0% in a reaction vessel to the minimum stirring volume; add 4.0 kg of methanol to the reaction vessel and concentrate to the minimum stirring volume; add 6.50 kg × 5 MTBE to the reaction vessel and concentrate to the minimum stirring volume; add 6.50 kg of MTBE to the reaction vessel; heat the system to reflux and reflux for 1 h; cool the system to 5-10℃ and stir at 5-10℃ for 2 h; filter, and wash the filter cake with MTBE (1.3 kg); obtain 260 g of wet product; dry the filter cake in a vacuum drying oven at 50-55℃ for 16 hours; remove from the oven, and obtain a total of 0.250 kg of product with an HPLC purity of 100.0%.

[0289] MS-ESI and 1 The H NMR data are consistent with those of Example 21.

[0290] The following examples of preparing crystal form 1, hydrochloride crystal form A, sulfate crystal form B, hydrobromide crystal form C, and phosphate crystal form D of compound I all use compound I as raw material.

[0291] Preparation of crystal form 1 of compound I

[0292] Example 30

[0293] Compound I (172.6 g) and acetone (2705 g, ~3500 mL) were added to a 5000 mL three-necked flask; the mixture was heated to 50-60 °C and stirred at 50-60 °C for 2 hours; the system was cooled to room temperature (25-30 °C); the mixture was stirred at room temperature (25-30 °C) for 24 hours; the mixture was distilled under reduced pressure until the volume of the liquid in the flask was approximately 0.8-0.9 L; the temperature of the liquid was lowered to 15-25 °C, and approximately 4.3 kg of purified water was added; the mixture was stirred at room temperature for 2 hours, then cooled to 5-10 °C and stirred for another 2 hours; the mixture was filtered, and the filter cake was washed with water; the filter cake was dried in a blower at 50-55 °C for 16 hours; a total of 158.8 g of off-white solid was obtained, with a yield of 92.0%. Upon testing, the white solid was identified as compound I, crystal form 1, and its XRPD, DSC, TGA, and DVS spectra are shown in Figures 1, 2A, 3, and 4, respectively.

[0294] Example 31

[0295] 100 mg of compound I was dissolved in 2 mL of acetone at 50-55 °C, cooled to room temperature and stirred for about 16 hours, then 2 mL of water was added and stirred at room temperature for 2 hours. The mixture was then cooled to 10-15 °C and stirred for another 2 hours. The mixture was filtered and the solid was collected. Analysis showed that the solid was crystal form 1 of compound I, and its XRPD pattern was consistent with Figure 1.

[0296] Example 32

[0297] Compound I (200 mg) was substantially dissolved in 9 mL of methanol / water (9:1) at room temperature. 5 mg of crystal form 1 of compound I was added, and a solid precipitated. The mixture was stirred overnight at room temperature. Water (18 mL) was added, and the mixture was stirred at room temperature for 4 h. The temperature was then lowered to 5–10 °C and stirred for 1 h. The mixture was filtered and dried under vacuum (approximately 50 °C) to obtain 180 mg of a white solid. Analysis confirmed that this white solid was compound I, crystal form 1, and its XRPD pattern was consistent with Figure 1.

[0298] Example 33

[0299] The same crystallization method as in Example 32 was used, but the crystallization solvent was replaced with acetone / water (4:1) to prepare crystal form 1 of compound I. Its XRPD pattern is consistent with that in Figure 1.

[0300] Compound I, crystal form 1, can also be prepared by the following methods.

[0301] Room temperature pulping and crystallization

[0302] Example 34

[0303] Approximately 20 mg of compound I was weighed into a glass vial, and an appropriate amount of tetrahydrofuran was added. The vial was sonicated for five minutes to obtain a suspension. The vial was wrapped in aluminum foil to protect it from light and placed on a Labquaker rotator, which was rotated 360 degrees at room temperature. After 10 days, the suspension sample was centrifuged, and the solid residue at the bottom was collected. After evaporating the solvent, a white solid was obtained. Analysis showed that this white solid was crystal form 1 of compound I, and its XRPD pattern was consistent with Figure 1.

[0304] Examples 35-40

[0305] The same crystallization method as in Example 34 was used, with the crystallization solvents replaced by methyl tert-butyl ether, water, acetone, isopropanol, dichloromethane, and ethanol, respectively, to prepare crystal form 1 of compound I. The results are shown in Table 6 below.

[0306] Table 6

[0307] Example Number Crystallization Solvent Formula I Compound Crystal Form 35 Methyl tert-butyl ether Crystal Form 1 36 Crystal Form 1 37 Acetone Crystal Form 1 38 Isopropanol Crystal Form 1

[0308] 39 Dichloromethane crystal form 140 Ethanol crystal form 1

[0309] The XRPD patterns of the compounds of formula I, crystal form 1, obtained in Examples 35-40 are consistent with those in Figure 1.

[0310] 50℃ pulping and crystallization

[0311] Example 41

[0312] Approximately 20 mg of compound I was weighed into a glass bottle, and an appropriate amount of tetrahydrofuran was added. The mixture was sonicated for five minutes to obtain a suspension. The sample bottle was wrapped in aluminum foil to protect it from light and placed in a shaker at 50°C for further stirring. After 10 days, the suspension sample was centrifuged, and the solid residue at the bottom was collected. After evaporating the solvent, a white solid was obtained. Analysis showed that this white solid was crystal form 1 of compound I, and its XRPD pattern was consistent with Figure 1.

[0313] Examples 42-45

[0314] The same crystallization method as in Example 41 was used, but the crystallization solvents were replaced with methyl tert-butyl ether, water, acetone, and isopropanol, respectively, to prepare compound I crystal form 1. The results are shown in Table 7 below.

[0315] Table 7

[0316] Example Number Crystallization Solvent Formula I Compound Crystal Form 42 Methyl tert-butyl ether Crystal Form 1 43 Crystal Form 1 44 Acetone Crystal Form 1 45 Isopropanol Crystal Form 1

[0317] The XRPD patterns of the compounds of formula I, crystal form 1, obtained in Examples 42-45 are consistent with those in Figure 1.

[0318] Example 46

[0319] Using the same crystallization method as in Example 41, but replacing the crystallization solvent with methanol, the crystal form of Formula I was prepared. The resulting crystal XRPD was consistent with that in Figure 1, which is the crystal form of Formula I, but the DSC showed an additional peak at about 151°C, as shown in Figure 2B.

[0320] Saturated solution heating-rapid cooling crystallization

[0321] Example 47

[0322] Approximately 30 mg of compound I was weighed into a vial. An appropriate amount of acetone was added to the vial, and the vial was placed on a magnetic stirrer. The water bath temperature was controlled at 50 ± 2 °C, and the stirring speed at 200 rpm. Heating promoted sample dissolution. After dissolution, the vial was kept at this temperature for 15 min. While still hot, the supersaturated solution was filtered through a 0.45 μm filter membrane. The filtrate was transferred to a new vial, and the vial was immediately placed in a -20 °C freezer. After overnight storage, the solvent system containing the precipitated solid was centrifuged, and the solid was collected. After the solvent was allowed to evaporate naturally, a white solid was obtained. Analysis showed that the solid was compound I, crystal form 1, and its XRPD pattern was consistent with Figure 1.

[0323] Example 48

[0324] The same crystallization method as in Example 47 was used, except that the crystallization solvent was replaced with tetrahydrofuran to prepare crystal form 1 of Formula I. The XRPD pattern of the obtained crystal form 1 of Formula I is consistent with that in Figure 1.

[0325] Saturated solution heating-slow cooling crystallization

[0326] Example 49

[0327] Approximately 30 mg of compound I was weighed into a vial. An appropriate amount of acetone was added to the vial, and the vial was placed on a magnetic stirrer. The water bath temperature was controlled at 50 ± 2 °C, and the stirring speed at 200 rpm. Heating promoted sample dissolution. After dissolution, the vial was kept at this temperature for 15 min. While still hot, the supersaturated solution was filtered through a 0.45 μm filter membrane. The filtrate was transferred to a new vial, and then slowly cooled to room temperature at a rate of 6 °C / h. The next day, the vial was refrigerated for approximately 24 hours (2–8 °C). The solvent system from which the solid precipitated was centrifuged, and the solid was collected. After the solvent was allowed to evaporate naturally, a white solid was obtained. Analysis showed that this white solid was compound I, crystal form 1, and its XRPD pattern was consistent with Figure 1.

[0328] Example 50

[0329] The same crystallization method as in Example 49 was used, except that the crystallization solvent was replaced with dichloromethane to prepare crystal form 1 of Formula I. The XRPD pattern of the obtained crystal form 1 of Formula I is consistent with that in Figure 1.

[0330] Antisolvent crystallization

[0331] Examples 51-62

[0332] Approximately 30 mg of compound I was weighed into each vial, and a certain volume of good solvent was added. The sample was then sonicated at room temperature to ensure uniform dispersion. If the solution was clear, a certain amount of solid sample was added, and sonication continued to dissolve the sample, resulting in a supersaturated solution in the good solvent. The solution was filtered through a 0.45 μm filter membrane, and the initial filtrate was discarded. The subsequent filtrate was transferred to a new vial. While stirring, approximately 10 times the volume of the antisolvent was slowly added dropwise to the vial at 50 rpm. The solvent system from which the solid precipitated was centrifuged to obtain a white solid. Analysis showed that the white solids obtained in Examples 46-57 were all of compound I, crystal form 1, and their XRPD spectra were consistent with Figure 1. The results are shown in Table 8 below.

[0333] Table 8

[0334] Example No. Crystallization Solvent (Good Solvent - Antisolvent) Formula I Compound Crystal Form 51 Methanol-Water (1:10) Crystal Form 1 52 Ethanol-Water (1:10) Crystal Form 1 53 Tetrahydrofuran-Methyl tert-butyl ether (1:10) Crystal Form 1 54 Ethanol-Methyl tert-butyl ether (1:10) Crystal Form 1 55 Methanol-Methyl tert-butyl ether (1:10) Crystal Form 1 56 Acetone-Methyl tert-butyl ether (1:10) Crystal Form 1 57 Isopropanol-Methyl tert-butyl ether (1:10) Crystal Form 1 58 Tetrahydrofuran-Dichloromethane (1:10) Crystal Form 1

[0335] 59 Ethanol-Dichloromethane (1:10) Crystal Form 160 Methanol-Dichloromethane (1:10) Crystal Form 161 Acetone-Dichloromethane (1:10) Crystal Form 162 Isopropanol-Dichloromethane (1:10) Crystal Form 1

[0336] Preparation of the hydrochloride crystal form A of compound I

[0337] Example 63

[0338] Approximately 200 mg of compound I was weighed into a vial, and 4 mL of ethanol was added. The sample was ultrasonically heated until completely dissolved. The vial was then placed on a magnetic stirrer, and 1.32 mL of an ethanol solution of hydrochloric acid (concentration of 50 mg / mL) was slowly added dropwise. A white precipitate formed. The vial was capped tightly at room temperature, and stirring was continued for one day. The suspension was then centrifuged, and the collected solid was vacuum dried overnight at 40 °C to obtain the hydrochloride solid of compound I. Analysis showed that the solid was crystal form A of the hydrochloride of compound I, and its XRPD and DSC spectra are shown in Figures 5 and 6, respectively.

[0339] Example 64

[0340] Approximately 50 mg of compound I was weighed into a vial, and 1 mL of ethanol was added. The vial was ultrasonically heated until the sample was completely dissolved. The vial was then placed on a magnetic stirrer, and 0.33 mL of an ethanol solution of hydrochloric acid (concentration of 50 mg / mL) was slowly added dropwise. A white precipitate formed. The vial was capped tightly at room temperature, and stirring was continued for one day. The suspension was then centrifuged, and the collected solid was vacuum dried overnight at 40 °C to obtain the hydrochloride solid of compound I. Analysis confirmed that the solid was crystal form A of the hydrochloride of compound I, and its XRPD pattern was consistent with Figure 5.

[0341] Preparation of sulfate crystal form B of compound of formula I

[0342] Example 65

[0343] Approximately 200 mg of compound I was weighed into a vial, and 4 ml of ethanol was added. The vial was ultrasonically heated until the sample was completely dissolved. The vial was then placed on a magnetic stirrer, and 1.4 ml of an ethanol solution of sulfuric acid (50 mg / ml) was slowly added dropwise. A white precipitate formed. The vial was capped tightly at room temperature, and stirring was continued for one day. The suspension was then centrifuged, and the collected solid was vacuum dried overnight at 40°C to obtain the sulfate solid of compound I. Analysis showed that the solid was the sulfate form B of compound I, and its XRPD, DSC, TGA, and DVS spectra are shown in Figures 7-10, respectively.

[0344] Example 66

[0345] Approximately 50 mg of compound I was weighed into a vial, and 1 ml of ethanol was added. The vial was ultrasonically heated until the sample was completely dissolved. The vial was then placed on a magnetic stirrer, and 0.35 ml of an ethanol solution of sulfuric acid (concentration of 50 mg / ml) was slowly added dropwise. A white precipitate formed. The vial was capped tightly at room temperature, and stirring was continued for one day. The suspension was then centrifuged, and the collected solid was vacuum dried overnight at 40°C to obtain the sulfate solid of compound I. Analysis showed that the solid was the sulfate form B of compound I, and its XRPD spectrum was consistent with Figure 7.

[0346] Preparation of hydrobromide crystal form C of compound I

[0347] Example 67

[0348] Approximately 200 mg of compound I was weighed into a vial, and 4 ml of ethanol was added. The sample was ultrasonically heated until completely dissolved. The vial was then placed on a magnetic stirrer, and 2.4 ml of an ethanol solution of hydrobromic acid (50 mg / ml) was slowly added dropwise. A white precipitate formed. The vial was capped tightly at room temperature, and stirring continued for one day. The suspension was then centrifuged, and the collected solid was vacuum dried overnight at 40°C to obtain solid hydrobromide of compound I. Analysis confirmed that the solid was hydrobromide of compound I, crystal form C. Its XRPD and DSC spectra are shown in Figures 11 and 12, respectively.

[0349] Example 68

[0350] Approximately 50 mg of compound I was weighed into a vial, and 1 ml of ethanol was added. The sample was ultrasonically heated until completely dissolved. The vial was then placed on a magnetic stirrer, and 0.60 ml of an ethanol solution of hydrobromic acid (concentration of 50 mg / ml) was slowly added dropwise. A white precipitate formed. The vial was capped tightly at room temperature, and stirring was continued for one day. The suspension was then centrifuged, and the collected solid was vacuum dried overnight at 40 °C to obtain the hydrobromide solid of compound I. Analysis confirmed that the solid was hydrobromide crystal form C of compound I, and its XRPD spectrum was consistent with Figure 11.

[0351] Preparation of phosphate crystal form D of compound I

[0352] Example 69

[0353] Approximately 200 mg of compound I was weighed into a vial, and 4 ml of ethanol was added. The sample was ultrasonically heated until completely dissolved. The vial was then placed on a magnetic stirrer, and 1.56 ml of an ethanol solution of phosphoric acid (concentration of 50 mg / ml) was slowly added dropwise. A white precipitate formed. The vial was capped tightly at room temperature, and stirring was continued for one day. The suspension was then centrifuged, and the collected solid was transferred to another vial. 3-4 ml of a mixed solvent, acetone / water (9 / 1, v / v), was added, and the mixture was magnetically stirred overnight at room temperature. The vial was then centrifuged, and the solid was collected and vacuum dried overnight at 40°C to obtain the phosphate solid of compound I. Analysis showed that the solid was phosphate crystal form D of compound I, and its XRPD, DSC, TGA, and DVS spectra are shown in Figures 13-16, respectively.

[0354] Example 70

[0355] Weigh approximately 50 mg of compound I into a vial, add 1 ml of ethanol, and sonicate until the sample is completely dissolved. Place the vial on a magnetic stirrer, stir magnetically, and slowly add 0.39 ml of an ethanol solution of phosphoric acid (concentration of 50 mg / ml). A white precipitate forms. Tightly cap the vial at room temperature and continue stirring for one day. Then centrifuge the suspension and transfer the collected solid to another vial. Add 0.75–1 ml of a mixed solvent: acetone / water (9 / 1, v / v), and stir magnetically overnight at room temperature. Centrifuge and collect the solid. Vacuum dry overnight at 40°C to obtain the phosphate solid of compound I. Analysis shows that this solid is phosphate crystal form D of compound I, and its XRPD pattern is consistent with Figure 13.

[0356] Experimental Section

[0357] Experimental Example 1: Solid-State Characterization

[0358] DSC, TGA and DVS tests were performed on the hydrochloride crystal form A, the sulfate crystal form B, the hydrobromide crystal form C, and the phosphate crystal form D of compound I.

[0359] DSC test results show that the sulfate crystal form B (Figure 8) and phosphate crystal form D (Figure 14) of Formula I have a single and relatively high melting point, indicating that their thermal stability is relatively good. However, the thermodynamic behavior of the hydrochloride crystal form A (Figure 6) and the hydrobromide crystal form C (Figure 12) of Formula I is complex, and their crystallinity is low. Therefore, only the sulfate crystal form B and phosphate crystal form D of Formula I were further characterized by DVS and TGA.

[0360] DVS test results show that the sulfate crystal form B (Figure 10) and the phosphate crystal form D (Figure 16) of Formula I have certain hygroscopicity. The weight gain from moisture absorption from 0%RH to 95%RH is 9.4% and 4.7%, respectively. The crystal forms of the two salts did not change significantly before and after the DVS test.

[0361] TGA test results show that the phosphate crystal form D of compound I (Figure 15) lost 2.862% of its weight from 44℃ to 120℃.

[0362] Based on the characterization results of the crystal forms of the above four salts, a comparison with crystal form 1 of compound I is shown in Table 9 below.

[0363] Table 9

[0364]

[0365] "-" indicates that no detection was performed.

[0366] In summary, the hydrochloride crystal form A and the hydrobromide crystal form C of Formula I have a wide melting range and indistinct melting point; the sulfate crystal form B of Formula I has stronger hygroscopicity than the phosphate crystal form D of Formula I; the crystal forms 1 and phosphate crystal forms D of Formula I have good crystallinity, a single melting point, and relatively low hygroscopicity.

[0367] Experiment Example 2: Solubility Test

[0368] Weigh out 4 portions each of crystal form 1 of compound I and crystal form D of phosphate of compound I into 4 mL transparent glass bottles. Add 1 mL of water, simulated gastric juice (SGF), simulated fasting intestinal juice (FaSSIF), and simulated feeding intestinal juice (FeSSIF) respectively to obtain a suspension of the sample. Quickly place the suspension in a shaker (37℃, 200 rpm) and shake for 5 minutes. Observe the sample. Add an appropriate amount of sample or medium to obtain a slight suspension. Take samples at 30 min, 2 h, 4 h, and 24 h respectively, and centrifuge at 12000 rpm for 10 minutes. Take the supernatant, dilute it appropriately, and then perform high performance liquid chromatography test. The chromatographic conditions are shown in Table 10.

[0369] Table 10 High-performance liquid chromatography conditions for solubility testing

[0370]

[0371] The sample concentration was calculated using the external standard method. The test results are shown in Table 11.

[0372] Table 11

[0373]

[0374]

[0375] The results showed that there was no significant difference in the equilibrium solubility (24h) of compound I crystal form 1 and compound I phosphate crystal form D in FaSSIF and FeSSIF; in water and simulated gastric juice (SGF), the equilibrium solubility (24h) of compound I phosphate crystal form D was 1.8 mg / mL and 30.18 mg / mL, respectively, which are 10 times and 2 times the equilibrium solubility (24h) of compound I crystal form 1, respectively. The solubility of both compound I crystal form 1 and compound I phosphate crystal form D of this invention meets pharmaceutical requirements.

[0376] Experiment Example 3 Stability Test

[0377] Approximately 1 mg of each of the Formula I compound crystal form 1 and Formula I compound phosphate crystal form D samples were weighed into 40 mL transparent glass bottles. Each sample was placed in an accelerated (40℃ / 75% RH, open) and a high-temperature (60℃, sealed) stability chamber, respectively. For open samples, the caps were removed and the bottle openings were covered with perforated aluminum foil to prevent cross-contamination; for closed samples, the caps were sealed. Samples were taken at 1 week and 2 weeks, diluted with acetonitrile / water (1 / 1) (v / v), and injected into the liquid phase to test sample purity according to the chromatographic conditions in Table 12.

[0378] Table 12

[0379]

[0380]

[0381] The sample purity was calculated using the area normalization method. The test results are shown in Table 13.

[0382] Table 13

[0383]

[0384] The results showed that the appearance of the samples of Formula I, crystal form 1 and phosphate form D, remained unchanged within 2 weeks, remaining as off-white powders with no significant difference in purity and no increase in total related substances. XRPD and DSC analyses (Figures 17-20) showed no significant difference in crystal form and initial melting point between the two samples and day 0, indicating that Formula I, crystal form 1 and phosphate form D, exhibited good physical and chemical stability under high temperature (60℃) and accelerated (40℃ / 75% RH) conditions for 2 weeks.

[0385] Experiment Example 4: TYK2 Biochemical Test

[0386] Weigh an appropriate amount of compound I and perform TYK2 biochemical testing.

[0387] The assays were performed by Reaction Biology Corp, Malvern, PA (Anastassiadis et al. Nat Biotechnol. 2011; 29(11):1039-45). The procedure is briefly described below.

[0388] Reagents:

[0389] 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, 1% DMSO. Add the required cofactors to each kinase reaction separately.

[0390] Reaction steps:

[0391] 1. Prepare the specified substrate in freshly prepared basic reaction buffer;

[0392] 2. Add the required cofactors to the above matrix solution;

[0393] 3. Add the specified kinase to the substrate solution and mix gently;

[0394] 4. The compound of formula I in DMSO was delivered into the kinase reaction mixture using an acoustic technique (Echo 550; nanoliter range) and incubated at room temperature for 20 minutes;

[0395] 5. Add to the reaction mixture 33 P-ATP (specific activity 10 μCi / μl) is used to initiate the reaction;

[0396] 6. Incubate the kinase reaction at room temperature for 2 hours;

[0397] 7. The reaction was plotted on P81 ion exchange paper;

[0398] 8. Kinase activity was detected by filtration binding method.

[0399] Test results show that compound I is also a strong TYK2 inhibitor, with an IC50 value of [missing information]. 50 Less than 10 nM.

[0400] Those skilled in the art will understand that modifications or variations can be made to the present invention based on the teachings of this specification. These modifications and variations should also be within the scope defined by the claims of the present invention.

Claims

1. A method for preparing a compound of formula I, wherein the synthetic route of the method is as follows: The method includes the following steps: Step 1: Add ethanol, compound IV, compound V and DIPEA to the reaction vessel and start stirring; heat to 65-90°C and keep stirring overnight. Stop the reaction and lower the system temperature to 15–30°C; Add water dropwise to the system and continue stirring; Filtering and washing the filter cake; The filter cake was dried to obtain compound of formula III; Step 2: Tetrahydrofuran, the compound of formula III obtained in step 1, and palladium on carbon were added to the reaction vessel; The system was purged with nitrogen, and then with hydrogen. The reaction mixture was kept at a hydrogen pressure of 0.1 to 1.0 MPa and a temperature of 20-35°C for 16-120 hours with stirring. After the reaction was completed, the reaction solution was filtered and the filter cake was washed. The filtrates were combined and concentrated to obtain a concentrate of compound II. Step 3: Add tetrahydrofuran, (R)-lactamide and Et3O-BF4 to the first reaction vessel, start stirring, and dissolve for later use; Add the concentrate of compound II and ethanol to the second reaction vessel, and heat the material in the second reaction vessel to 40-85°C; The material in the first reaction vessel is added dropwise to the second reaction vessel. After the addition is completed, the mixture in the second reaction vessel is kept at 40-85°C for 0.5-6 hours for reaction. After the reaction was completed, the pH of the system was adjusted to 1-3, extracted with an organic solvent, the organic phase was discarded, the pH of the aqueous phase was adjusted to 9-10 with an inorganic alkaline aqueous solution, filtered, and the filter cake was dried to obtain compound I.

2. The method according to claim 1, wherein in step 1 above: The volume-to-mass ratio of ethanol to the compound of formula IV is 5:1 to 20:1, preferably 10:1; The molar ratio of the compound of formula IV, the compound of formula V, and DIPEA is 1:1 to 1.1:2 to 3, preferably 1:1.01:2.2; After stirring is started, under nitrogen protection, the temperature is raised to 65-90°C, preferably 70-90°C, more preferably 70-80°C, and stirred for 5-16 hours, preferably 10-16 hours. After stopping the reaction, lower the system temperature to 15–25°C; The volume-to-mass ratio of water added to the system to the compound of formula IV is 10:1 to 20:1, preferably 15:1; After adding water dropwise to the system, stir for 2-6 hours at 0-30°C, preferably at 5-15°C, more preferably at 5-10°C, preferably for 4 hours. The filter cake is washed with an aqueous ethanol solution, wherein the volume ratio of ethanol to water in the aqueous ethanol solution is 1:1 to 1:2, preferably 1:1.5 to 1:2; and the volume-to-mass ratio 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 by forced air at 45-55°C, preferably 50°C.

3. The method according to claim 1 or 2, wherein in step 2 above: The volume-to-mass ratio 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% wet palladium on carbon, and the mass ratio of palladium on carbon to the compound of formula III is 0.15:1 to 0.16:1, preferably 0.15:1; Stirring at 25-35°C under a hydrogen pressure of 0.5-1.0 MPa for 24-96 hours; The filter cake is washed with tetrahydrofuran, and the filtrates are combined and concentrated to obtain a tetrahydrofuran solution of compound II, wherein the volume-to-mass ratio of the tetrahydrofuran used for washing to the compound II is 2:1 to 4:1, preferably 2:1 to 3:1; preferably, the tetrahydrofuran solution of compound II is replaced with ethanol to obtain an ethanol solution of compound II, wherein the volume-to-mass ratio of ethanol to compound II is 2:1 to 5:1, preferably 2:1 to 4:1, more preferably 2:1 to 3:

1.

4. The method according to any one of claims 1-3, in step 3 above: The volume-to-mass ratio of tetrahydrofuran to the concentrate of compound II is 6:1 to 12:1; The molar ratio of the concentrate of Formula II compound, (R)-lactic acid and Et3O-BF4 is 1:4-5:4-5; The volume-to-mass ratio of ethanol to the concentrate of compound II is 10:1 to 16:1, preferably 14:1; After adding the concentrate of compound II and ethanol to the second reaction vessel, the material in the second reaction vessel is heated to 40-85°C, preferably 45-70°C, more preferably 45-50°C under nitrogen protection. The mixture in the second reaction vessel is kept at 45-70°C, preferably 45-50°C, for 2-5 hours, preferably 3 hours. After the reaction is complete, the pH of the system is adjusted to 1-3 with hydrochloric acid, which is 1M HCl or 12M HCl, preferably 12M HCl; the inorganic base aqueous solution is a saturated sodium carbonate aqueous solution or a saturated potassium carbonate aqueous solution, preferably a saturated potassium carbonate aqueous solution. After the reaction was completed, the organic solvent used for extraction was dichloromethane or ethyl acetate; The filter cake is vacuum dried or blown dry at 50–55°C.

5. The method according to any one of claims 1-4, wherein the compound of formula I obtained in step 3 above is subjected to column chromatography for separation and purification, wherein the eluent is a mixed solution of ethyl acetate and ethanol.

6. A compound of formula I with crystal form 1, Its X-ray powder diffraction pattern has characteristic peaks at 2theta values ​​of 8.5°±0.2°, 14.8°±0.2°, and 16.1°±0.2°.

7. The crystal form 1 of compound I according to claim 6, wherein its X-ray powder diffraction pattern has characteristic peaks at 2theta values ​​of 8.5°±0.2°, 14.8°±0.2°, 16.1°±0.2°, 17.1°±0.2°, 18.8°±0.2°, and 19.6°±0.2°.

8. The X-ray powder diffraction pattern of compound I, crystal form 1, according to claim 6 or 7, has a 2θ value of 8.5°±0.2°, 14.8°±0.2°, 16.1°±0.2°, 17.1°±0.2°, 18.8°±0.2°, Characteristic peaks are present at 19.6°±0.2°, 23.8°±0.2°, 25.3°±0.2°, and 26.1°±0.2°.

9. A method for preparing crystal form 1 of compound I as described in any one of claims 6-8, comprising: Method 1: Dissolve the compound of formula I in a solvent, stir at room temperature, add water to the solution of the compound of formula I, stir, filter, and dry to obtain crystal form 1 of the compound of formula I; or Method 2: A solvent is added to the compound of formula I, and the mixture is sonicated to obtain a suspension of the compound of formula I. The suspension of the compound of formula I is then protected from light and stirred, centrifuged, and the solid is collected to obtain crystal form 1 of the compound of formula I; or Method 3: Add solvent to compound I, stir and dissolve at 50-60°C to obtain a solution of compound I. Filter the solution of compound I while hot, cool the filtrate at -20-10°C to crystallize, centrifuge, collect the solid, and obtain crystal form 1 of compound I; or Method 4: Add the first solvent to the compound of formula I, sonicate to obtain a supersaturated solution of the compound of formula I, filter, add the second solvent to the filtrate and stir, centrifuge, collect the solid, and obtain crystal form 1 of the compound of formula I.

10. The method according to claim 9, wherein, In Method 1, The solvent is selected from one or more of acetone, methanol, and water; the solvent is preferably acetone, or a mixture of methanol and water, or a mixture of acetone and water, wherein the volume ratio of methanol to water in the mixture of methanol and water is 30:1 to 1:1, preferably 9:1, and the volume ratio of acetone to water in the mixture of acetone and water is 6:1 to 1:1, preferably 4:

1. The volume-to-mass ratio of the solvent to the compound of formula I is 20:1 to 45:1, and the volume-to-mass ratio of water added to the solution of the compound of formula I is 20:1 to 90:

1. The compound of formula I was dissolved in a solvent at 50-60°C; After dissolving the compound of formula I in a solvent, stir at room temperature for 0.5–24 hours; After adding water to the solution of the compound of formula I, stir at room temperature for 0.5-24 hours, then cool to 5-15°C and stir for 1-4 hours. In method two, The solvent is selected from one or more of tetrahydrofuran, methyl tert-butyl ether, water, acetone, isopropanol, dichloromethane, and ethanol; The suspension of the compound of formula I is stirred at room temperature, or at 45-55°C, preferably 50°C. The suspension of the compound of formula I was kept in the dark and stirred for 6-10 days; In method three, The solvent is selected from one or more of acetone, tetrahydrofuran, and dichloromethane; After filtering the solution of the compound of formula I while it is still hot, it is slowly cooled to room temperature at a rate of 6°C / h, and then cooled to crystallize at -20-10°C, preferably 2-8°C. In method four, The first solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, acetone, and isopropanol, and the second solvent is selected from one or more of water, methyl tert-butyl ether, and dichloromethane; The volume ratio of the first solvent to the second solvent is 1:5 to 1:20, preferably 1:

10.

11. A hydrochloride salt of compound formula I, crystal form A, Its X-ray powder diffraction pattern has characteristic peaks at 2theta values ​​of 6.4°±0.2°, 12.8°±0.2°, 14.2°±0.2°, and 19.0°±0.2°.

12. The hydrochloride crystal form A of the compound of formula I according to claim 11, wherein the X-ray powder diffraction pattern has characteristic peaks at 2theta values ​​of 6.4°±0.2°, 8.5°±0.2°, 11.6°±0.2°, 12.8°±0.2°, 14.2°±0.2°, 17.1°±0.2°, and 19.0°±0.2°.

13. The hydrochloride crystal form A of the compound of formula I according to claim 11 or 12, wherein the X-ray powder diffraction pattern has characteristic peaks at 2theta values ​​of 6.4°±0.2°, 8.5°±0.2°, 11.6°±0.2°, 12.8°±0.2°, 14.2°±0.2°, 17.1°±0.2°, 19.0°±0.2°, 19.7°±0.2°, 21.3°±0.2°, and 24.5°±0.2°.

14. A method for preparing crystal form A of the hydrochloride salt of compound I as described in any one of claims 11-13, comprising: The compound of formula I is dissolved in a solvent to obtain a solution of the compound of formula I. An ethanol solution of hydrochloric acid is added to the solution of the compound of formula I while stirring. The mixture is stirred, centrifuged, the solid is collected, and dried to obtain the hydrochloride crystal form A of the compound of formula I.

15. The method according to claim 14, wherein, The compound of formula I was dissolved in a solvent by ultrasonic heating; The solvent is one or more selected from ethanol, acetone, acetonitrile, and isopropanol; The concentration of the hydrochloric acid ethanol solution is 30-60 mg / mL, preferably 50 mg / mL; After adding the hydrochloric acid ethanol solution, continue stirring at room temperature for 4-24 hours.

16. A sulfate crystal form B of compound of formula I, Its X-ray powder diffraction pattern has characteristic peaks at 2theta values ​​of 12.2°±0.2°, 17.1°±0.2°, 18.4°±0.2°, and 20.1°±0.2°.

17. The sulfate crystal form B of the compound of formula I according to claim 16, wherein the X-ray powder diffraction pattern has characteristic peaks at 2theta values ​​of 12.2°±0.2°, 17.1°±0.2°, 18.4°±0.2°, 19.6°±0.2°, 20.1°±0.2°, 20.6°±0.2°, and 22.1°±0.2°.

18. The sulfate crystal form B of the compound of formula I according to claim 16 or 17, wherein the X-ray powder diffraction pattern has characteristic peaks at 2theta values ​​of 12.2°±0.2°, 17.1°±0.2°, 18.4°±0.2°, 19.6°±0.2°, 20.1°±0.2°, 20.6°±0.2°, 22.1°±0.2°, 23.5°±0.2°, 26.8°±0.2°, and 29.3°±0.2°.

19. A method for preparing sulfate crystal form B of compound I as described in any one of claims 16-18, comprising: The compound of formula I is dissolved in a solvent to obtain a solution of the compound of formula I. An ethanol solution of sulfuric acid is added to the solution of the compound of formula I while stirring. The mixture is stirred, centrifuged, the solid is collected, and dried to obtain the sulfate crystal form B of the compound of formula I.

20. The method according to claim 19, wherein, The compound of formula I was dissolved in a solvent by ultrasonic heating; The solvent is one or more selected from ethanol, acetone, acetonitrile, and isopropanol; The concentration of the sulfuric acid ethanol solution is 30-60 mg / mL, preferably 50 mg / mL; After adding the ethanol solution of sulfuric acid, continue stirring at room temperature for 4-24 hours.

21. A compound of formula I, hydrobromide crystal form C, Its X-ray powder diffraction pattern has characteristic peaks at 2theta values ​​of 6.3°±0.2°, 12.6°±0.2°, and 18.9°±0.2°.

22. The hydrobromide crystal form C of compound I according to claim 21, wherein the X-ray powder diffraction pattern has characteristic peaks at 2theta values ​​of 6.3°±0.2°, 8.5°±0.2°, 12.6°±0.2°, 18.9°±0.2°, 21.3°±0.2°, 24.4°±0.2°, and 25.2°±0.2°.

23. A method for preparing the hydrobromide crystal form C of compound I as described in claim 21 or 22, comprising: The compound of formula I is dissolved in a solvent to obtain a solution of the compound of formula I. An ethanol solution of hydrobromic acid is added to the solution of the compound of formula I while stirring. The mixture is stirred, centrifuged, the solid is collected, and dried to obtain the hydrobromide crystal form C of the compound of formula I.

24. The method according to claim 23, wherein, The compound of formula I was dissolved in a solvent by ultrasonic heating; The solvent is one or more selected from ethanol, acetone, acetonitrile, and isopropanol; The concentration of the hydrobromic acid ethanol solution is 30-60 mg / mL, preferably 50 mg / mL; After adding the ethanol solution of hydrobromic acid, continue stirring at room temperature for 4-24 hours.

25. A phosphate crystal form D of compound of formula I, Its X-ray powder diffraction pattern has characteristic peaks at 2theta values ​​of 6.1°±0.2°, 10.9°±0.2°, and 12.2°±0.2°.

26. The phosphate crystal form D of the compound of formula I according to claim 25 has characteristic peaks in its X-ray powder diffraction pattern at 2theta values ​​of 6.1°±0.2°, 10.9°±0.2°, 11.7°±0.2°, and 12.2°±0.2°.

27. A method for preparing phosphate crystal form D of compound I as described in claim 25 or 26, comprising: The compound of formula I is dissolved in a first solvent to obtain a solution of the compound of formula I. An ethanol solution of phosphoric acid is added to the solution of the compound of formula I while stirring. The stirring is continued, the mixture is centrifuged, and the solid is collected. A second solvent is added to the collected solid, the mixture is stirred, centrifuged, and the solid is collected and dried to obtain the phosphate crystal form D of the compound of formula I.

28. The method according to claim 27, wherein, The compound of formula I is dissolved in the first solvent by ultrasonic heating; The first solvent is one or more of ethanol, acetone, acetonitrile and isopropanol; the second solvent is a mixed solvent of acetone and water, wherein the volume ratio of acetone to water is 7:1-9:

1. The concentration of the phosphoric acid ethanol solution is 30-60 mg / mL, preferably 50 mg / mL; After adding the ethanol solution of phosphoric acid, continue stirring at room temperature for 4-24 hours; after adding the second solvent, stir overnight at room temperature.

29. A pharmaceutical composition comprising crystal form 1 of the Formula I compound according to any one of claims 6-8, crystal form A of the Formula I compound hydrochloride according to any one of claims 11-13, crystal form B of the Formula I compound sulfate according to any one of claims 16-18, crystal form C of the Formula I compound hydrobromide according to claim 21 or 22, and / or crystal form D of the Formula I compound phosphate according to claim 25 or 26.

30. A pharmaceutical preparation comprising crystal form 1 of the Formula I compound according to any one of claims 6-8, crystal form A of the Formula I compound hydrochloride according to any one of claims 11-13, crystal form B of the Formula I compound sulfate according to any one of claims 16-18, crystal form C of the Formula I compound hydrobromide according to claim 21 or 22, and / or crystal form D of the Formula I compound phosphate according to claim 25 or 26.

31. Use of the compound of formula I, crystal form 1, according to any one of claims 6-8; the compound of formula I, hydrochloride crystal form A, according to any one of claims 11-13; the compound of formula I, sulfate crystal form B, according to any one of claims 16-18; the compound of formula I, hydrobromide crystal form C, according to claim 21 or 22; and / or the compound of formula I, phosphate crystal form D, according to claim 25 or 26, in the preparation of a medicament for treating diseases or symptoms related to Jak1 / TYK2.

32. The use according to claim 31, wherein the disease or condition is an autoimmune disease or disorder, such as rheumatoid arthritis or an inflammatory disease or disorder, and cancer or a tumor proliferative disease or disorder.

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