EA044931B1 - METHOD FOR SYNTHESIS OF FUROIMIDAZOPYRIDINE COMPOUND, POLYMORPHIC SUBSTANCE AND POLYMORPH OF SALT - Google Patents

Description

Field of technology

The present invention relates to the field of synthesis of medicinal substances, namely to a method for the synthesis of the following compound 2-[(2R,5S)-5-[2-methylfuro[3,2-b]imidazo[4,5-d]pyridin-1yl] tetrahydropyran-2-yl]acetonitrile (hereinafter referred to as compound I or compound of formula I) as a selective inhibitor of JAK1/TYK2 kinase. The present invention also relates to crystalline forms of compound I and its salts, as well as methods for their preparation. In addition, the present invention also relates to a pharmaceutical composition and a pharmaceutical composition containing a crystalline form of Compound I and/or a crystalline form of its salts, as well as the use of crystalline forms of Compound I and crystalline forms of its salts for the treatment of diseases and conditions associated with JAK1/ TYK2.

State of the art

Protein kinases are a family of proteins that play important roles in modulating a variety of cellular processes and maintaining cellular functions. These kinases at least include non-receptor tyrosine kinase such as the Janus kinase family (JAK1, JAK2, JAK3 and TYK2); a receptor tyrosine kinase such as platelet-derived growth factor receptor (PDGFR); and serine/threonine kinase such as b-RAF.

The Janus kinase family includes 4 known members: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). These cytoplasmic tyrosine kinases are cytokine membrane receptors (eg, common γ-chain receptors and transmembrane glycoprotein 130 (gp130)) (Murray, J. Immunol. 178 (5): 2623-2629, 2007). Nearly 40 cytokine receptors signal through a combination of these four Janus kinases and their 7 downstream substrates: members of the signal transducers and activators of transcription (STAT) family (Ghoreschi et al., Immunol Rev. 228(I): 273-287, 2009). A cytokine that binds to its receptor activates Janus kinases by trans- and/or autophosphorylation. In turn, the activated cytokine receptor of the Janus kinase family phosphorylates the cytokine receptor, generates binding sites for proteins (such as STAT factor and other regulator) containing Src homology 2 (SH2), and phosphorylated JAK kinases then activate them. Activated STAT enters the cell nucleus and begins to stimulate the expression of survival factors, cytokines, chemokines and leukocyte transport molecules (Schindler et al., J. Biol. Chem. 282 (28): 20059-20063, 2007). Activation of JAK kinases also induces cell proliferation through phosphoinositide 3-kinase (PI3K) and protein kinase B-mediated pathways.

JAK3 and JAK1 are components of the common γ-chain cytokine receptor, and blocking either of them can inhibit inflammatory cytokine signaling (interleukin (IL)-2, 4, 7, 9, 15, and 21) (Ghoreschi et al., Immunol Rev 228(1):273-287, 2009). However, other pathology-associated cytokines (such as IL-6) depend only on JAK1. Consequently, blocking JAK1 inhibits the signaling of many proinflammatory cytokines (Guschin et al., EMBO J. 14 (7): 1421-1429, 1995). The clinical efficacy of the IL-6 receptor neutralizing antibody tocilizumab has been studied in rheumatoid arthritis (PA) (Maini et al, Arthritis Rheum. 54 (9): 2817-2829, 2006).

International application WO2018067422A1 describes 1H-furo[3,2-b]imidazo[4,54]pyridine derivatives as selective JAK1 kinase inhibitors and a method for their preparation, including a method for preparing compound I. The synthesis scheme is as follows:

Compound I

Biological studies show that Compound I is a potent and selective inhibitor of JAK1, demonstrates selective inhibition of IL-6-induced STAT3 phosphorylation, and does not demonstrate selective inhibition of thrombopoietin-induced STAT3 phosphorylation. However, WO2018067422A1 does not disclose the biological activity of TYK2. In addition, the disclosed method for producing Compound I uses high temperature, which generates too many impurities, and the method produces low yield, making it unsuitable for large-scale production. Therefore, it is necessary to develop a process for the preparation of compound I with milder reaction conditions, higher yield, higher purity, and suitable for large scale/industrial production.

To date, no crystalline form of compound I and its salts has been reported. Comprehensive and systematic screening of polymorphs and selection of the crystalline form most suitable for development is one of the indispensable and important components of research. Accordingly, it is necessary to further screen the crystalline forms of compound I and its salts, develop a crystalline form with good stability and low hygroscopicity, suitable for large-scale production and providing wider and improved opportunities for subsequent drug development.

The essence of the invention

It is an object of the present invention to provide a process for the preparation of a compound of formula I (ie compound I) with mild reaction conditions, high yield and high purity, suitable for industrial production. The synthesis scheme for this method is as follows:

this method includes the following stages.

Stage 1:

adding ethanol, a compound of formula IV, a compound of formula V, and diisopropylethylamine (DIPEA) to the reaction vessel and stirring;

heating to a temperature of 65-90°C, maintaining this temperature and stirring overnight;

cessation of the reaction and reduction of the temperature in the system to 15-30°C; adding water to the system drop by drop, continuing stirring; filtering and washing the filter cake; drying the filter cake to obtain the compound of formula III.

Stage 2:

adding tetrahydrofuran, the compound of formula III obtained in step 1, and palladium on carbon to the reaction vessel;

purging the system with nitrogen and then hydrogen;

maintaining the temperature in the range of 20-35°C and stirring for 16-120 hours at a hydrogen pressure of 0.1-1.0 MPa;

after completion of the reaction, filtering the reaction liquid and washing the filter cake;

combining the filtrate and concentrating to obtain a concentrate of the compound of formula II.

Stage 3:

adding the concentrate of the compound of formula II or the compound of formula II obtained in step 2, trimethyl-ortho-acetate and tetrahydrofuran to the reaction vessel; heating the reaction system in the reaction vessel to the boiling point of tetrahydrofuran; adding pyridine hydrochloride to the reaction vessel, reacting the resulting reaction system for 4-20 hours at a temperature of 50 to 90°C, separating and purifying to obtain the compound of formula I.

In some embodiments, the following conditions are used in the above step 1:

the volume-mass ratio (ml/g) of ethanol and the compound of formula IV is from 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 1:11.1:2-3, preferably 1:1.01:2.2;

after the start of stirring in a nitrogen atmosphere, the reaction mixture is heated to 65-90°C, preferably to 70-90°C, more preferably to 70-80°C, maintaining the specified temperature and stirring for 5-16 hours, preferably for 10- 16 hours;

- 2 044931 after the reaction stops, reduce the system temperature to 15-25°C;

the volume-mass ratio (ml/g) of water added to the system and the compound of formula IV is from 10:1 to 20:1, preferably 15:1;

after adding water to the system, stirring is carried out for 2-6 hours, preferably for 4 hours, at a temperature of 0-30°C, preferably at 5-15°C, more preferably at 5-10°C;

the filter cake is washed with an aqueous ethanol solution, wherein the volume ratio (ml/ml) of ethanol and water in the aqueous ethanol solution is from 1:1 to 1:2, preferably from 1:1.5 to 1:2; the volume-mass ratio (ml/g) of the aqueous solution of ethanol and the compound of formula IV is from 2:1 to 10:1, preferably from 2:1 to 5:1, more preferably from 2:1 to 3:1;

Drying of the filter cake is carried out in a vacuum or using a blower at a temperature of 45-55°C, preferably at 50°C.

In some embodiments, the following conditions are used in the above step 2:

the volume-mass ratio (ml/g) of tetrahydrofuran and the compound of formula III is from 10:1 to 70:1, preferably from 20:1 to 70:1;

palladium on carbon is 5% Pd/C with a moisture content of 50%, the weight ratio of palladium on carbon to the compound of formula III is from 0.15:1 to 0.16:1, preferably 0.15:1;

the temperature is maintained at 25-35°C and stirred for 24-96 hours at a hydrogen pressure of 0.5-1.0 MPa;

the concentrate of the compound of formula II, obtained by combining the filtrate and concentrating, is a solution of the compound of formula II in tetrahydrofuran, where the volume-weight ratio of tetrahydrofuran and compound of formula II is from 2:1 to 4:1, preferably from 2:1 to 3:1 ( the mass of the compound of formula II is calculated in accordance with 100% yield in step 2); Preferably, the tetrahydrofuran in which the compound of formula II is dissolved is replaced by ethanol to obtain a solution of the compound of formula II in ethanol, wherein the volume/weight ratio of ethanol to the compound of formula II is from 2:1 to 5:1, preferably from 2:1 to 4 :1, more preferably from 2:1 to 3:1 (weight of compound of formula II calculated according to 100% yield in step 2).

In some embodiments, in the above Step 3, the volume-to-mass ratio (ml/mg) of tetrahydrofuran to the compound of Formula II in the concentrate is from 1.5:1 to 5.0:1; or in some embodiments, in the above Step 3, the volume-to-mass ratio (ml/mg) of tetrahydrofuran to the compound of Formula II is from 1.5:1 to 5.0:1.

In some embodiments, the above step 3 replaces the solvent in the Formula II compound concentrate with toluene, tetrahydrofuran, or methyl tert-butyl ether for subsequent steps; in some embodiments, the volume/weight ratio (mL/mg) of toluene, tetrahydrofuran, or methyl tert-butyl ether used to replace the solvent in the Formula II compound concentrate is from 2.0:1 to 4.0:1.

In some embodiments, in the above step 3, the molar ratio of the compound of formula II in the concentrate of the compound of formula II and trimethyl ortho-acetate is from 3.0:1 to 3.5:1; or in some embodiments, in step 3 above, the molar ratio of the compound of Formula II to trimethyl ortho-acetate is from 3.0:1 to 3.5:1.

In some embodiments, in the above step 3, the molar ratio of the compound of formula II in concentrate or the compound of formula II and pyridine hydrochloride is from 0.2:1 to 0.3:1; or in some embodiments, in step 3 above, the molar ratio of the compound of formula II to pyridine hydrochloride is from 0.2:1 to 0.3:1.

In some embodiments, in the above step 3, after adding the concentrate of the compound of formula II or the compound of formula II and trimethyl ortho-acetate and the solvent to the reaction vessel, under the protection of a nitrogen atmosphere, the reaction mixture is heated in the reaction vessel to the boiling point of the solvent.

After adding pyridine hydrochloride to the reactor, under a nitrogen atmosphere, the reaction system is reacted for 4-20 hours, preferably 5-15 hours at a temperature of 50-90°C, preferably at 65-75°C.

In some embodiments, in step 3 above, after completion of the reaction, the product is purified with a solvent selected from the group consisting of water, methanol, ethanol, methyl t-butyl ether, and any combinations thereof.

In some embodiments, in the above step 3, the resulting compound of formula I is separated and purified using column chromatography, where the eluent is a mixed solution of ethyl acetate and n-heptane (Ve _A :V _H - _GE π _TAN =1:1-1: 0, ml/ml).

In some embodiments, in the above-mentioned step 3, the resulting compound of formula I is dried in a vacuum or by blower at a temperature of from 50 to 55°C.

Another object of the present invention is to provide a crystalline form of the compound of formula I, which is hereinafter referred to as crystalline form 1 of the compound of formula I.

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Crystalline Form 1 of the compound of formula I is characterized by an X-ray powder diffraction pattern containing characteristic peaks at angles 2 theta (2θ) of 13.4°±0.2°, 17.6°±0.2° and 21.9°±0 ,2°.

In some embodiments, the X-ray powder diffraction pattern of crystalline form 1 of the compound of formula I contains characteristic peaks at 2θ angles of 9.0°±0.2°, 13.4°±0.2°, 17.6°±0.2 °, 18.1°±0.2°, 21.9°±0.2° and 27.3°±0.2°.

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

Without being limited to anything, X-ray powder diffraction data of crystalline form 1 of the compound of formula I according to the invention are shown in table. 1.

Without being limited to anything, an X-ray powder diffraction (XRPD) diffraction pattern of crystalline Form 1 of the compound of Formula I of the invention is shown in FIG. 1.

Without being limited to anything, a differential scanning calorimetry (DSC) thermogram of crystalline Form 1 of the compound of Formula I of the invention is shown in FIG. 2. DSC thermograms show that the initial melting point of crystalline form 1 of the compound of formula I according to the invention is 173.38°C.

Without being limited to anything, a thermogravimetric analysis (TGA) thermogram of crystalline Form 1 of the compound of Formula I of the invention is shown in FIG. 3. The TGA thermogram shows that the weight loss of crystalline form 1 of the compound of formula I according to the invention is only 0.42% in the range from 25 to 162°C. Crystalline Form 1 of the compound of formula I does not contain water of crystallization or solvent.

Without being limited to anything, a graph of the dynamic vapor sorption (DVA) isotherm of crystalline Form 1 of the compound of Formula I of the invention is shown in FIG. 4. The DSP isotherm plot shows that the increase in the mass of crystalline form 1 of the compound of formula I of the invention is 13.86% due to moisture absorption at a relative humidity of 0 to 95%, indicating that the sample is hygroscopic. The moisture absorption curve during desorption exhibits hysteresis in combination with the XPRD diffraction pattern of the sample before and after the EAF examination (the XPRD after examination is shown in FIG. 5), indicating that moisture absorption by crystalline form 1 of the compound of formula I occurs. change in crystalline form.

The present invention provides a method for obtaining crystalline form 1 of a compound of formula I, in particular, the method is described as follows: dissolve the crude product based on a compound of formula I in methanol, stir at 40-60°C for 0.5-2 hours, cool to 5 - 4 044931

15°C, stir for 15 minutes to 1 hour, filter, wash the filter cake with MTBE and dry to obtain crystalline form 1 of the compound of formula I.

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

In some embodiments, the volume ratio of methanol to MTBE is from 3:1 to 2:1, preferably 8:3.

In some embodiments, after dissolving the crude compound of Formula I product in methanol, a silicon-based metal remover and activated carbon are added to the system.

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

The X-ray powder diffraction pattern of crystalline form A of the hydrochloride of the compound of formula I according to the present invention contains characteristic peaks at 2θ angles of 7.3°±0.2°, 12.1°±0.2° and 20.9°±0.2 °.

In some embodiments, the X-ray powder diffraction pattern of crystalline Form A hydrochloride of a compound of formula I contains characteristic peaks at 2θ angles of 7.3°±0.2°, 12.1°±0.2°, 18.7°±0, 2°, 20.9°±0.2°, 23.5°±0.2° and 24.0°±0.2°.

In some embodiments, the X-ray powder diffraction pattern of crystalline Form A hydrochloride of a compound of formula I contains characteristic peaks at 2θ angles of 7.3°±0.2°, 10.6°±0.2°, 12.1°±0, 2°, 12.8°±0.2°, 14.0°±0.2°, 18.7°±0.2°, 20.9°±0.2°, 23.5°±0, 2° and 24.0°±0.2°.

Without being limited to anything, X-ray powder diffraction data of crystalline Form A hydrochloride of the compound of formula I according to the present invention are shown in table. 2.

Without being limited to anything, an XPRD diffraction pattern of crystalline Form A hydrochloride of the compound of Formula I of the invention is shown in FIG. 6.

Without being limited to anything, a DSC thermogram of crystalline Form A hydrochloride of the compound of Formula I of the invention is shown in FIG. 7.

The present invention provides a method for preparing crystalline Form A hydrochloride of a compound of formula I, in particular, the method is described as follows: dissolve the compound of formula I in acetone to obtain a solution of the compound of formula I in acetone and add hydrochloric acid in acetone to the compound of formula I in acetone with stirring, continue stirring, collect the solid and dry to obtain crystalline Form A hydrochloride of the compound of formula I.

In some embodiments, a compound of Formula I is sonicated, heated, and then dissolved in acetone.

In some embodiments, the concentration of the compound of Formula I in acetone is 10-50 mg/ml, preferably 20 mg/ml.

In some embodiments, the concentration of hydrochloric acid in acetone is 15-35 mg/ml, preferably 25 mg/ml.

In some embodiments, after adding hydrochloric acid in acetone, continue stirring at room temperature for 4-48 hours, preferably for 24 hours.

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

The X-ray powder diffraction pattern of crystalline Form B hydrochloride of the compound of formula I according to the present invention contains characteristic peaks at 2θ angles of 7.2°±0.2°, 20.0°±0.2° and 22.6°±0.2 °.

In some embodiments, the X-ray powder diffraction pattern of crystalline form B hydrochloride of the compound of formula I contains characteristic peaks at 2θ angles of 7.2°±0.2°, 10.2°±0.2°, 11.5°±0, 2°, 18.0°±0.2°, 20.0°±0.2°, 22.6°±0.2° and 25.9°±0.2°.

In some embodiments, the X-ray powder diffraction pattern of crystalline form B hydrochloride of the compound of formula I contains characteristic peaks at 2θ angles of 7.2°±0.2°, 10.2°±0.2°, 11.5°±0, 2°, 14.1°±0.2°, 14.5°±0.2°, 18.0°±0.2°, 20.0°±0.2°, 22.6°±0, 2° and 25.9°±0.2°.

Without being limited to anything, X-ray powder diffraction data of the hydrochloride crystalline Form B of the compound of formula I according to the present invention are shown in table. 3.

Without being limited to anything, the DPR diagram of the hydrochloride crystal Form B of the compound of formula I of the invention is shown in FIG. 8.

Without being limited to anything, a DSC thermogram of the hydrochloride crystal Form B of the compound of formula I of the invention is shown in FIG. 9.

The present invention provides a method for preparing the hydrochloride crystalline Form B of a compound of formula I, in particular, the method is described as follows: dissolve the compound of formula I in ethyl acetate to obtain a solution of the compound of formula I in ethyl acetate, and add hydrochloric acid in ethyl acetate to the compound of formula I in ethyl acetate with stirring, Continue stirring, collect the solid and dry it to obtain the hydrochloride crystalline Form B of the compound of formula I.

In some embodiments, a compound of Formula I is sonicated, heated, and then dissolved in ethyl acetate.

In some embodiments, the concentration of the compound of Formula I in ethyl acetate is 10-30 mg/ml, preferably 20 mg/ml.

In some embodiments, the concentration of hydrochloric acid in the ethyl acetate is 15-35 mg/ml, preferably 25 mg/ml.

In some embodiments, after adding the hydrochloric acid to the ethyl acetate, continue stirring at room temperature for 4-48 hours, preferably for 24 hours.

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

The X-ray powder diffraction pattern of crystalline form C hydrochloride of the compound of formula I according to the present invention contains characteristic peaks at the angles

2θ, being 10.7°±0.2°, 21.5°±0.2° and 24.3°±0.2°.

In some embodiments, the X-ray powder diffraction pattern of crystalline Form C hydrochloride of a compound of formula I contains characteristic peaks at 2θ angles of 5.3°±0.2°, 10.7°±0.2°, 21.5°±0, 2°, 24.3°±0.2° and 30.4°±0.2°.

Without being limited to anything, X-ray powder diffraction data of crystalline form C hydrochloride of the compound of formula I according to the present invention are shown in table. 4.

Table 4

Diffraction angle 2Θ (°) d(A) Relative diffraction intensity I, % (based on peak height) 5.3 16.5427 10.1 10.7 8.2756 100.0 21.5 4.1379 52.3 24.3 3.6532 20.1 30.4 2.9351 15.8

Without being limited to anything, an XPRD diffraction pattern of crystalline Form C hydrochloride of the compound of Formula I of the invention is shown in FIG. 10.

Without being limited to anything, a DSC thermogram of crystalline Form C hydrochloride of the compound of Formula I of the invention is shown in FIG. eleven.

Recrystallization or crystalline transformation of the hydrochloride crystalline form A of the compound of formula I is carried out in a solvent to obtain the hydrochloride crystalline form C of the compound of formula I, the solvent being selected from the group consisting of methanol, acetonitrile, n-heptane, methyl ethyl ketone, and any combinations thereof.

In some embodiments, the solvent is mixed with the hydrochloride crystalline Form A of the compound of Formula I to form a suspension, stirred at room temperature, the solid collected and dried to obtain the hydrochloride crystalline Form C of the compound of Formula I.

In some embodiments, a solvent is added to a vessel containing a hydrochloride crystalline Form A of a compound of Formula I to form a suspension, stirred at room temperature, the solid collected, and dried to produce a hydrochloride crystalline Form C of a compound of Formula I.

In some embodiments, the mixing duration is 4-48 hours, preferably 24 hours.

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

The X-ray powder diffraction pattern of the crystalline form D sulfate of the compound of formula I according to the present invention contains characteristic peaks at 2θ angles of 6.0°±0.2°, 22.8°±0.2° and 25.2°±0.2 °.

In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal Form D of the compound of formula I contains characteristic peaks at 2θ angles of 6.0°±0.2°, 12.3°±0.2°, 17.5°±0, 2°, 22.8°±0.2° and 25.2°±0.2°.

Without being limited to anything, X-ray powder diffraction data of crystalline Form D sulfate of the compound of formula I according to the present invention is shown in table. 5.

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Table 5

Diffraction angle 2Θ (°) d(A) Relative diffraction intensity I, % (based on peak height) 6.0 14.59 100.0 12.3 7.19 12.0 17.5 5.06 9.0 22.8 3.90 36.3 25.0 3.53 17.1

Without being limited to anything, an XPRD diffraction pattern of the sulfate crystal Form D of the compound of formula I of the invention is shown in FIG. 12.

Without being limited to anything, a DSC thermogram of crystalline form D sulfate of the compound of formula I according to the invention is shown in FIG. 13.

The present invention provides a method for preparing crystalline Form D sulfate of a compound of formula I, in particular the method is described as follows:

dissolve the compound of formula I in acetone to obtain a solution of the compound of formula I in acetone and add sulfuric acid in acetone to the compound of formula I in acetone with stirring, continue stirring, collect the solid and dry to obtain crystalline Form D sulfate of the compound of formula I.

In some embodiments, a compound of Formula I is sonicated, heated, and then dissolved in acetone.

In some embodiments, the concentration of the compound of Formula I in acetone is 10-30 mg/ml, preferably 20 mg/ml.

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

In some embodiments, after adding the sulfuric acid in acetone, continue stirring at room temperature for 4-48 hours, preferably for 24 hours.

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

The X-ray powder diffraction pattern of crystalline form E of phosphate of the compound of formula I according to the present invention contains characteristic peaks at 2θ angles of 6.2°±0.2°, 15.5°±0.2°, 17.4°±0.2 ° and 24.6°±0.2°.

Without being limited to anything, X-ray powder diffraction data of crystalline phosphate form E of the compound of formula I according to the invention are shown in table. 6.

Table 6

Diffraction angle 2Θ (°) d(A) Relative diffraction intensity I, % (based on peak height) 6.2 14.24 100.0 15.5 5.70 22.4 17.4 5.09 16.9 24.6 3.62 16.1

Without being limited to anything, an XPRD diffraction pattern of the crystalline phosphate form E of the compound of formula I of the invention is shown in FIG. 14.

Without being limited to anything, a DSC thermogram of the crystalline phosphate form E of the compound of formula I of the invention is shown in FIG. 15.

The present invention provides a method for preparing crystalline phosphate form E of a compound of formula I, in particular the method is described as follows:

dissolve the compound of formula I in acetone to obtain a solution of the compound of formula I in acetone and add phosphoric acid in acetone to the compound of formula I in acetone with stirring, continue stirring, collect the solid and dry to obtain the phosphate crystalline Form E of the compound of formula I.

In some embodiments, a compound of Formula I is sonicated, heated, and then dissolved in acetone.

In some embodiments, the molar ratio of the compound of Formula I to phosphoric acid is from 1:1.0 to 1:1.5.

In some embodiments, the concentration of the compound of Formula I in acetone is 10-30 mg/ml, preferably 20 mg/ml.

In some embodiments, the concentration of phosphoric acid in acetone is 15-35 mg/ml, preferably 25 mg/ml.

In some embodiments, after adding the phosphoric acid in acetone, continue stirring at room temperature for 4-48 hours, preferably for 24 hours.

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

In some embodiments, the phosphate crystalline form E of the compound of formula I is recrystallized or crystallized in a solvent, and the product is still the phosphate crystalline form E of the compound of formula I, wherein said solvent is selected from the group consisting of methanol, acetonitrile, n-heptane , methyl ethyl ketone and any combinations thereof.

In some embodiments, during recrystallization or crystalline transformation, a solvent is mixed with the phosphate crystalline Form E of a compound of Formula I to form a suspension, which is stirred at room temperature, the solid is collected, and dried.

In some embodiments, the duration of stirring during recrystallization or crystalline transformation is from 4 to 48 hours, preferably stirring overnight.

In some embodiments, during recrystallization or crystalline transformation, the solid is collected by centrifugation and dried overnight under vacuum at 30-60°C.

The X-ray powder diffraction pattern of crystalline form F of phosphate of the compound of formula I according to the present invention contains characteristic peaks at 2θ angles of 16.6°±0.2°, 17.2°±0.2° and 22.6°±0.2 °.

In some embodiments, the X-ray powder diffraction pattern of crystalline phosphate form F of the compound of formula I contains characteristic peaks at 2θ angles of 11.6°±0.2°, 14.8°±0.2°, 16.6°±0, 2°, 17.2°±0.2°, 22.6°±0.2° and 26.6°±0.2°.

In some embodiments, the X-ray powder diffraction pattern of crystalline phosphate form F of the compound of formula I contains characteristic peaks at 2θ angles of 11.1°±0.2°, 11.6°±0.2°, 14.8°±0, 2°, 16.6°±0.2°, 17.2°±0.2°, 21.2°±0.2°, 22.6°±0.2° and 26.6°±0, 2°.

Without being limited to anything, X-ray powder diffraction data of the crystalline phosphate form F of the compound of formula I according to the present invention is shown in table. 7.

Without being limited to anything, the DPR diagram of the crystalline phosphate form F of the compound of formula I according to the invention is shown in FIG. 16.

Without being limited to anything, a DSC thermogram of the crystalline phosphate form F of the compound of formula I of the invention is shown in FIG. 17. The DSC thermogram shows that the initial melting point of the phosphate crystalline form F of the compound of formula I according to the invention is 198.78°C.

Without being limited to anything, a graph of the ADI isotherm of crystalline phosphate form F of the compound of formula I according to the present invention is shown in FIG. 18. The DSP isotherm plot shows that the increase in the mass of the crystalline form F phosphate of the compound of formula I according to the invention is 6.5% due to moisture absorption at a relative humidity of 0 to 95%. At 85% relative humidity, the weight gain of the phosphate crystalline form F of the compound of formula I is

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0.72%; at 70% relative humidity, the increase in weight of the phosphate crystalline form F of the compound of formula I is 1.95%. After absorption of moisture, the crystalline form F of the phosphate of the compound of formula I does not change (see Fig. 19 for XPRD diffraction pattern after absorption of moisture).

The present invention provides a method for preparing the crystalline phosphate form F of a compound of formula I, in particular the method is described as follows:

dissolving the phosphate crystalline form E of the compound of formula I in a first solvent to obtain the phosphate crystalline form E of the compound of formula I in the first solvent, adding an antisolvent, mixing, collecting the solid and drying to obtain the phosphate crystalline form F of the compound of formula I; or in some embodiments, the first solvent is a solvent that can dissolve the phosphate crystalline Form E of the compound of formula I, preferably methanol; An antisolvent is a solvent that has little solubility in the crystalline phosphate form E of a compound of formula I, preferably isopropyl acetate.

In some embodiments, the first solvent is added in an amount that can completely dissolve the phosphate crystalline Form E of the compound of Formula I.

In some embodiments, the antisolvent is used to dilute a solution of the phosphate crystal Form E of the compound of formula I in the first solvent by 5-15 times, preferably 10 times.

In some embodiments, after dissolving the phosphate crystalline Form E of the compound of Formula I in the first solvent, a small amount of the phosphate crystalline Form F of the compound of Formula I is added until the system becomes slightly cloudy, and then the antisolvent is added.

In some embodiments, after adding the antisolvent, stirring is continued at room temperature for 4-48 hours, preferably for 24 hours.

In some embodiments, the solid is collected by centrifugation and dried under vacuum at a temperature of from 30 to 60°C, preferably at 50°C.

The X-ray powder diffraction pattern of crystalline form G of the mesylate of the compound of formula I according to the present invention contains characteristic peaks at 2θ angles of 8.6°±0.2°, 19.9°±0.2° and 24.9°±0.2 °.

In some embodiments, the X-ray powder diffraction pattern of the mesylate crystal form G of the compound of formula I contains characteristic peaks at 2θ angles of 8.6°±0.2°, 18.1°±0.2°, 18.6°±0, 2°, 19.9°±0.2°, 24.0°±0.2° and 24.9°±0.2°.

Without being limited to anything, X-ray powder diffraction data of the mesylate crystal Form G of the compound of formula I according to the present invention are shown in table. 8.

Table 8

Diffraction angle 2Θ (°) d(A) Relative diffraction intensity I, % (based on peak height) 8.6 10.32 100.0 18.1 4.88 56.9 18.6 4.76 62.7 19.9 4.456 87.1 24.0 3.71 23.0 25.0 3.57 76.1

Without being limited to anything, the DPR diagram of the mesylate crystal Form G of the compound of formula I of the invention is shown in FIG. 20.

Without being limited to anything, a DSC thermogram of the mesylate crystal Form G of the compound of formula I of the invention is shown in FIG. 21. The DSC thermogram shows that the initial melting point of the mesylate crystal form G of the compound of formula I according to the invention is 218.78°C.

Without being limited to anything, the DSP isotherm plot of the mesylate crystal Form G of the compound of formula I of the invention is shown in FIG. 22.

The present invention provides a method for preparing crystalline form G mesylate of a compound of formula I, in particular the method is described as follows:

dissolve the compound of formula I in acetone to obtain a solution of the compound of formula I in acetone and add methanesulfonic acid in acetone to the compound of formula I in acetone with stirring, continue stirring, collect the solid and dry to obtain the mesylate crystalline form G of the compound of formula I .

In some embodiments, a compound of Formula I is sonicated, heated, and then dissolved in acetone.

In some embodiments, the concentration of the compound of Formula I in acetone is 10-30 mg/ml, preferably 20 mg/ml.

In some embodiments, the concentration of methanesulfonic acid in acetone is 15-35 mg/ml, preferably 25 mg/ml.

In some embodiments, after adding methanesulfonic acid in acetone, continue stirring at room temperature for 4-48 hours, preferably for 24 hours.

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

The X-ray powder diffraction pattern of the hydrobromide crystal Form H of the compound of formula I according to the present invention contains characteristic peaks at 2θ angles of 7.2°±0.2°, 20.7°±0.2° and 24.0°±0.2 °.

In some embodiments, the X-ray powder diffraction pattern of the hydrobromide crystal Form H of the compound of Formula I contains characteristic peaks at 2θ angles of 7.2°±0.2°, 17.9°±0.2°, 18.8°±0, 2°, 20.7°±0.2° and 24.0°±0.2°.

In some embodiments, the X-ray powder diffraction pattern of the hydrobromide crystal Form H of the compound of formula I contains characteristic peaks at 2θ angles of 7.2°±0.2°, 11.9°±0.2°, 17.0°±0, 2°, 17.9°±0.2°, 18.8°±0.2°, 20.7°±0.2°, 24.0°±0.2° and 27.5°±0, 2°.

Without being limited to anything, X-ray powder diffraction data of the hydrobromide crystal Form H of the compound of formula I according to the invention are shown in table. 9.

Without being limited to anything, the DPR diagram of the hydrobromide crystal Form H of the compound of Formula I of the invention is shown in FIG. 23.

Without being limited to anything, a DSC thermogram of the hydrobromide crystal Form H of the compound of formula I of the invention is shown in FIG. 24.

The present invention provides a method for preparing the hydrobromide crystalline form H of a compound of formula I, in particular, the method is described as follows: dissolve the compound of formula I in acetone to obtain a solution of the compound of formula I in acetone, and add hydrobromic acid in acetone to the compound of formula I in acetone with stirring, Continue stirring, collect the solid and dry to obtain the hydrobromide crystalline Form H of the compound of formula I.

In some embodiments, a compound of Formula I is sonicated, heated, and then dissolved in acetone.

In some embodiments, the concentration of the compound of Formula I in acetone is 10-30 mg/ml, preferably 20 mg/ml.

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

In some embodiments, after adding hydrobromic acid in acetone, continue stirring at room temperature for 4-48 hours, preferably for 24 hours.

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

- 11 044931

In some embodiments, the hydrobromide crystalline form H is recrystallized or converted crystalline from a compound of formula I in a solvent and the product is still the hydrobromide crystalline form H, wherein said solvent is selected from the group consisting of acetonitrile, methyl ethyl ketone, and any combination thereof.

In some embodiments, the recrystallization or crystal transformation includes the following steps:

mixing one or both of acetonitrile and methyl ethyl ketone with the hydrobromide crystalline form H of the compound of formula I to form a suspension, stirring at room temperature, centrifuging, collecting the solid and drying;

preferably adding one or both of acetonitrile and methyl ethyl ketone to a vessel containing the hydrobromide crystalline form H of the compound of formula I to form a suspension, stirring at room temperature, centrifuging, collecting the solid and drying.

The X-ray powder diffraction pattern of the hydrobromide crystal Form J of the compound of formula I according to the present invention contains characteristic peaks at 2θ angles of 6.2°±0.2° and 15.0°±0.2°.

Without being limited to anything, X-ray powder diffraction data of the hydrobromide crystal Form J of the compound of formula I according to the invention are shown in table. 10.

Table 10

Diffraction angle 20 (°) d(A) Relative diffraction intensity I, % (based on peak height) 6.2 14.23 51.2 15.0 5.88 43.0

Without being limited to anything, the DPR diagram of the hydrobromide crystal Form J of the compound of Formula I of the invention is shown in FIG. 25.

The present invention provides a method for preparing the hydrobromide crystalline Form J of a compound of formula I, in particular the method is described as follows:

dissolve the compound of formula I in ethyl acetate to obtain a solution of the compound of formula I in ethyl acetate and add hydrobromic acid in ethyl acetate to the compound of formula I in ethyl acetate with stirring, continue stirring, collect the solid to obtain the hydrobromide crystalline form J of the compound of formula I.

In some embodiments, a compound of Formula I is sonicated, heated, and then dissolved in ethyl acetate.

In some embodiments, the concentration of the compound of Formula I in ethyl acetate is 10-30 mg/ml, preferably 20 mg/ml.

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

In some embodiments, after adding hydrobromic acid in ethyl acetate, continue stirring at room temperature for 4-48 hours, preferably for 24 hours.

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

The X-ray powder diffraction pattern of crystalline form K of hydrobromide of the compound of formula I according to the present invention contains characteristic peaks at 2θ angles of 17.1°±0.2°, 22.0°±0.2° and 24.2°±0.2 °.

The X-ray powder diffraction pattern of crystalline form K of hydrobromide of the compound of formula I contains characteristic peaks at 2θ angles of 17.1°±0.2°, 20.1°±0.2°, 22.0°±0.2°, 22 .6°±0.2°, 24.2°±0.2° and 28.8°±0.2°.

The X-ray powder diffraction pattern of crystalline form K of hydrobromide of the compound of formula I contains characteristic peaks at 2θ angles of 9.5°±0.2°, 17.1°±0.2°, 20.1°±0.2°, 22 ,0°±0.2°, 22.6°±0.2°, 24.2°±0.2°, 27.7°±0.2° and 28.8°±0.2°.

Without being limited to anything, X-ray powder diffraction data of the hydrobromide crystal Form K of the compound of Formula I according to the present invention are shown in Table. eleven.

- 12 044931

Table 11

Diffraction angle 2Θ (°) d(A) Relative diffraction intensity I, % (based on peak height) 9.5 9.26 23.3 17.1 5.19 55.6 20.1 4.40 33.9 22.0 4.04 100.0 22.6 3.94 31.1 23.6 3.76 30.6 24.2 3.67 36.7 27.7 3.21 19.3 28.8 3.10 32.9

Without being limited to anything, the DPR diagram of the hydrobromide crystal Form K of the compound of Formula I of the invention is shown in FIG. 26.

Without being limited to anything, a DSC thermogram of the hydrobromide crystal Form K of the compound of Formula I of the invention is shown in FIG. 27.

Without being limited to anything, a graph of the ADI isotherm of the hydrobromide crystalline Form K of the compound of Formula I according to the present invention is shown in FIG. 28. The DSP isotherm plot shows that the increase in the mass of the hydrobromide crystalline form K of the compound of formula I of the invention is 11.84% due to moisture absorption at a relative humidity of 0 to 95%, indicating the hygroscopicity of the sample. The moisture absorption curve during desorption exhibits hysteresis in combination with the XPRD pattern of the sample before and after DSP testing (the DPR pattern after testing is shown in FIG. 29), indicating that the K hydrobromide crystalline form of the compound of formula I changed after moisture absorption.

The present invention provides a method for preparing the hydrobromide crystalline form K of a compound of formula I, in particular the method is described as follows:

carry out recrystallization or crystalline transformation of the hydrobromide crystalline form H of the compound of formula I in n-heptane to obtain the hydrobromide crystalline form K of the compound of formula I.

In some embodiments, n-heptane is mixed with the hydrobromide crystalline Form H of the compound of Formula I to form a suspension, stirred at room temperature, the solid collected, and dried to form the hydrobromide crystalline Form K of the compound of Formula I.

In some embodiments, n-heptane is added to a vessel containing the hydrobromide crystalline Form H of the compound of Formula I to form a slurry, stirred at room temperature, the solid collected, and dried to form the hydrobromide crystalline Form K of the compound of Formula I.

In some embodiments, the mixing duration is 4-48 hours, preferably 24 hours.

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

The X-ray powder diffraction pattern of crystalline form L fumarate of the compound of formula I according to the present invention contains characteristic peaks at 2θ angles of 6.1°±0.2°, 16.3°±0.2° and 26.4°±0.2 °.

The X-ray powder diffraction pattern of crystalline form L fumarate of the compound of formula I contains characteristic peaks at 2θ angles of 6.1°±0.2°, 13.4°±0.2°, 15.7°±0.2°, 16 .3°±0.2° and 26.4°±0.2°.

The X-ray powder diffraction pattern of crystalline form L fumarate of the compound of formula I contains characteristic peaks at 2θ angles of 6.1°±0.2°, 13.4°±0.2°, 15.7°±0.2°, 16 ,3°±0.2°, 22.6°±0.2°, 23.2°±0.2°, 23.8°±0.2° and 26.4°±0.2°.

Without being limited to anything, X-ray powder diffraction data of the crystalline form L fumarate of the compound of formula I according to the present invention are shown in table. 12.

- 13 044931

Without being limited to anything, the DPR diagram of the crystalline form L fumarate of the compound of formula I according to the invention is shown in FIG. thirty.

Without being limited to anything, a DSC thermogram of the fumarate crystal Form L of the compound of formula I of the invention is shown in FIG. 31.

The present invention provides a method for preparing crystalline form L fumarate of a compound of formula I, in particular the method is described as follows:

dissolve the compound of formula I in the solvent to obtain a solution of the compound of formula I in the solvent and add fumaric acid in ethanol to the compound of formula I in the solvent with stirring, continue stirring, collect the solid and dry to obtain the fumarate crystalline form L of the compound of formula I.

In some embodiments, a compound of Formula I is sonicated, heated, and then dissolved in a solvent, the solvent being selected from the group consisting of ethyl acetate, acetone, and any combination thereof.

In some embodiments, the concentration of the compound of Formula I in the solvent is 10-30 mg/ml, preferably 20 mg/ml.

In some embodiments, the concentration of fumaric acid in ethanol is 15-35 mg/ml, preferably 25 mg/ml.

In some embodiments, after adding the fumaric acid to the ethanol, stirring is continued at room temperature for 4-48 hours, preferably for 24 hours.

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

The X-ray powder diffraction pattern of the benzenesulfonate crystal form M of the compound of formula I according to the present invention contains characteristic peaks at 2θ angles of 7.5°±0.2°, 18.5°±0.2°, 25.2°±0.2 ° and 29.8°±0.2°.

The X-ray powder diffraction pattern of the benzene sulfonate crystal form M of the compound of formula I contains characteristic peaks at 2θ angles of 7.5°±0.2°, 14.1°±0.2°, 15.2°±0.2°, 18 .5°±. 0.2°, 22.4°±0.2°, 23.0°±0.2°, 25.2°±0.2° and 29.8°±0.2°.

The X-ray powder diffraction pattern of the benzene sulfonate crystal form M of the compound of formula I contains characteristic peaks at 2θ angles of 7.5°±0.2°, 12.5°±0.2°, 14.1°±0.2°, 15 ,2°±0.2°, 18.5°±0.2°, 22.4°±0.2°, 23.0°±0.2°, 24.6°±0.2°, 25 .2°±0.2° and 29.8°±0.2°.

Without being limited to anything, X-ray powder diffraction data of the benzenesulfonate crystalline form M of the compound of formula I according to the present invention are shown in table. 13.

- 14 044931

Without being limited to anything, the DPR diagram of the benzenesulfonate crystal form M of the compound of formula I of the invention is shown in FIG. 32.

Without being limited to anything, a DSC thermogram of the benzenesulfonate crystal Form M of the compound of formula I of the invention is shown in FIG. 33. The DSC thermogram shows that the initial melting point of the benzenesulfonate crystal form M of the compound of formula I according to the invention is 198.73°C.

Without being limited to anything, the DSP isotherm plot of the benzenesulfonate crystalline form M of the compound of formula I according to the present invention is shown in FIG. 34. The DSP isotherm plot shows that the increase in mass of the benzenesulfonate crystalline form M of the compound of formula I according to the invention due to moisture absorption is 4.6% at a relative humidity of 0 to 95%. At 85% relative humidity, the increase in weight of the benzenesulfonate crystalline form M of the compound of formula I is 0.54%; at 70% relative humidity, the increase in weight of the benzenesulfonate crystal form M of the compound of formula I is 0.97%. After moisture absorption, the benzene sulfonate crystalline form M of the compound of formula I does not change (XPRD diffraction pattern after moisture absorption is shown in FIG. 35).

The present invention provides a method for preparing the benzenesulfonate crystalline form M of a compound of formula I, in particular the method is described as follows:

dissolve the compound of formula I in acetone to obtain a solution of the compound of formula I in acetone and add benzenesulfonic acid in acetone to the compound of formula I in acetone with stirring, continue stirring, collect the solid and dry to obtain the benzenesulfonate crystalline form M of the compound of formula I.

In some embodiments, a compound of Formula I is sonicated, heated, and then dissolved in acetone.

In some embodiments, the concentration of the compound of Formula I in acetone is 10-30 mg/ml, preferably 20 mg/ml.

In some embodiments, the concentration of benzenesulfonic acid in acetone is 15-35 mg/ml, preferably 25 mg/ml.

In some embodiments, after adding benzenesulfonic acid in acetone, continue stirring at room temperature for 4-48 hours, preferably for 24 hours.

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

The X-ray powder diffraction pattern of the crystalline form N citrate of the compound of formula I according to the present invention contains characteristic peaks at 2θ angles of 15.8°±0.2°, 17.0°±0.2° and 21.1°±0.2 °.

Without being limited to anything, X-ray powder diffraction data of the crystalline form N citrate of the compound of formula I according to the invention are shown in table. 14.

- 15 044931

Table 14

Diffraction angle 2Θ (°) d(A) Relative diffraction intensity I, % (based on peak height) 4.8 18.35 4.3 15.8 5.62 81.4 17.0 5.21 17.7 21.1 4.21 15.5

Without being limited to anything, the DPR diagram of the N citrate crystalline form of the compound of formula I of the invention is shown in FIG. 36.

Without being limited to anything, a DSC thermogram of the N citrate crystalline form of the compound of Formula I according to the present invention is shown in FIG. 37.

The present invention provides a method for preparing the N citrate crystalline form of a compound of formula I, in particular the method is described as follows:

dissolve the compound of formula I in ethyl acetate to obtain a solution of the compound of formula I in ethyl acetate and add citric acid in ethyl acetate to the compound of formula I in ethyl acetate with stirring, continue stirring, collect the solid and dry to obtain the N citrate crystalline form of the compound of formula I.

In some embodiments, a compound of Formula I is sonicated, heated, and then dissolved in ethyl acetate.

In some embodiments, the concentration of the compound of Formula I in ethyl acetate is 10-30 mg/ml, preferably 20 mg/ml.

In some embodiments, the concentration of citric acid in ethyl acetate is 1535 mg/ml, preferably 25 mg/ml.

In some embodiments, after the citric acid is added to the ethyl acetate, stirring is continued at room temperature for 4-48 hours, preferably for 24 hours.

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

The X-ray powder diffraction pattern of crystalline form O tartrate of the compound of formula I according to the present invention contains characteristic peaks at 2θ angles of 6.3°±0.2°, 26.1°±0.2° and 26.9°±0.2 °.

In some embodiments, the X-ray powder diffraction pattern of crystalline form O tartrate of the compound of formula I contains characteristic peaks at 2θ angles of 6.3°±0.2°, 12.5°±0.2°, 15.1°±0, 2°, 26.1°±0.2°, 26.9°±0.2° and 27.5°±0.2°.

In some embodiments, the X-ray powder diffraction pattern of crystalline form O tartrate of the compound of formula I contains characteristic peaks at 2θ angles of 6.3°±0.2°, 11.4°±0.2°, 12.5°±0, 2°, 14.1°±0.2°, 14.4°±0.2°, 15.1°±0.2°, 26.1°±0.2°, 26.9°±0, 2° and 27.5°±0.2°.

Without being limited to anything, X-ray powder diffraction data of the O tartrate crystalline form of the compound of formula I according to the present invention is shown in table. 15.

Without being limited to anything, the DPR diagram of the O tartrate crystalline form of the compound of formula I according to the invention is shown in FIG. 38.

Without being limited to anything, a DSC thermogram of the O tartrate crystalline form of the compound of Formula I according to the present invention is shown in FIG. 39. The DSC thermogram shows that the initial melting point of the O tartrate crystalline form of the compound of formula I according to the invention is 218.80°C.

Without being limited to anything, a TGA thermogram of crystalline Form O tartrate of the compound of Formula I of the invention is shown in FIG. 40. The TGA thermogram shows that the weight loss of the O tartrate crystalline form of the compound of formula I of the invention is only 0.05% in the range from 26 to 120° C., which indicates that the O tartrate crystalline form of the compound of formula I does not contain water of crystallization or solvent.

Without being limited to anything, the DSP isotherm plot of crystalline Form O tartrate of the compound of formula I according to the present invention is shown in FIG. 41. The EAF isotherm diagram shows a 6.85% increase in the mass of the O tartrate crystalline form of the compound of formula I of the invention due to moisture absorption at a relative humidity of 0% to 95%. At 80% relative humidity, the weight gain of the crystalline form O tartrate of the compound of formula I is 1.80%.

After moisture absorption, the O tartrate crystalline form of the compound of formula I does not change (XPRD diffraction pattern after moisture absorption is shown in FIG. 42).

The present invention relates to a process for preparing the O tartrate crystalline form of a compound of formula I, in particular the process is described as follows:

mixing the compound of formula I with the first solvent, dissolving the compound until the solution becomes clear, and thus obtaining a solution of the compound of formula I in the first solvent; mix tartaric acid with the second solvent, dissolve it until the solution becomes clear, and thus obtain a solution of tartaric acid in the second solvent; add a solution of tartaric acid in a second solvent to a solution of a compound of formula I in a first solvent with stirring, cool at a controlled rate with stirring, collect the solid, and dry it to obtain the O tartrate crystalline form of the compound of formula I.

In some embodiments, the first solvent and the second solvent are selected from the group consisting of acetone, ethyl acetate, and any combinations thereof.

In some embodiments, the molar ratio of the compound of Formula I to tartaric acid is 1:(0.5-1.5), preferably 1:(0.5-0.7), more preferably 1:(0.55-0.6 ).

In some embodiments, the O tartrate crystalline form of the compound of Formula I has a molar ratio of the compound of Formula I to tartaric acid of 2:1.

In some embodiments, the concentration of the compound of Formula I in acetone is 15-70 mg/ml, preferably 40-60 mg/ml, more preferably 50 mg/ml.

In some embodiments, the concentration of tartaric acid in acetone is 5-35 mg/ml, preferably 10-25 mg/ml, more preferably 15 mg/ml.

In some embodiments, the compound of Formula I is mixed with acetone and the temperature is raised to 40-60°C, preferably 50-55°C, to dissolve the compound of Formula I to form a clear solution.

In some embodiments, tartaric acid is mixed with acetone and the temperature is raised to 40-60°C, preferably 50-55°C, to dissolve the tartaric acid to form a clear solution.

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

In some embodiments, controlled rate cooling is implemented using the following steps:

stir the system for 0.5-3 hours, preferably for 1-2 hours, at a temperature of 3560°C, preferably at 40-60°C;

cool the system, maintaining the temperature at 15-35°C, and stir for 0.5-3 hours, preferably for 1-2 hours;

cool the system, maintaining the temperature at 5-15°C, for example, at 5-10°C, and stir for 0.5-3 hours, preferably for 1-2 hours.

In the present invention, cooling at a controlled rate can be performed gradually in steps and maintained at a certain temperature range for a certain time.

In some embodiments, while cooling at a controlled rate, after stirring the system for 0.5-3 hours, preferably 1-2 hours, at a temperature of 35-60°C, preferably at 40-60°C, the solvent is concentrated up to one third or two thirds of the original volume, preferably up to half of the original volume.

In some embodiments, during controlled rate cooling, after maintaining the system temperature at 15-35°C and stirring for 0.5-3 hours, preferably 1-2 hours, the solvent is concentrated to one-third or two-thirds of the original

- 17 044931 volume, preferably up to half the original volume.

In some embodiments, the purity of the compound of Formula I is greater than 90%, preferably greater than 95%, more preferably greater than 99%.

In some embodiments, drying of the collected solid is carried out at a temperature of 40-60°C under reduced pressure or by blower for 5-48 hours, preferably for 16-28 hours.

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

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

Use of Compound of Formula I Hydrochloride Crystal Form 1, Hydrochloride Crystal Form A of Formula I Compound, Hydrochloride Crystal Form B of Formula I Hydrochloride Crystal Form C, Hydrochloride Crystal Form C of Formula I, Sulfate Crystal Form D of Formula I, Phosphate Crystal Form E of Formula I, Crystal Form Phosphate crystal form F of a compound of formula I, mesylate crystal form G of a compound of formula I, hydrobromide crystal form H of a compound of formula I, hydrobromide crystal form J of a compound of formula I, hydrobromide crystal form K of a compound of formula I, fumarate crystal form L of a compound of formula I, benzenesulfonate crystal form M a compound of formula I, the N citrate crystalline form of a compound of formula I, and/or the O tartrate crystalline form of a compound of formula I, in the preparation of medicaments for the treatment of diseases or conditions associated with JAK1/TYK2, which diseases or conditions may be autoimmune diseases or disorders, such as rheumatoid arthritis or inflammatory diseases or disorders, as well as cancerous or neoplastic proliferative diseases or disorders.

In the present invention, unless otherwise indicated, temperatures used refer to the internal temperatures of the reaction system.

Regarding the melting point, one skilled in the art can understand that in DSC analysis, there is a certain range of deviation for the actually measured initial melting point due to the influence of the measuring instrument, heating rate, crystal shape, etc.; As a rule, these deviations are within ±5°С.

Brief description of drawings

In fig. 1 shows an XPRD diffraction pattern of crystalline Form 1 of the compound of formula I according to the present invention.

In fig. 2 shows a DSC thermogram of crystalline Form 1 of the compound of formula I according to the present invention.

In fig. 3 shows a TGA thermogram of crystalline Form 1 of the compound of formula I according to the present invention.

In fig. 4 shows a graph of the ADI isotherm of crystalline Form 1 of the compound of formula I according to the present invention.

In fig. 5 shows an overlay of X-ray diffraction patterns of crystalline form 1 of the compound of formula I according to the present invention before and after the EAF test.

In fig. 6 shows an XPRD diffraction pattern of crystalline form A of the hydrochloride of the compound of formula I according to the present invention.

In fig. 7 shows a DSC thermogram of crystalline form A of the hydrochloride of the compound of formula I according to the present invention.

- 18 044931

In fig. 8 shows an XPRD diffraction pattern of crystalline Form B hydrochloride of the compound of formula I according to the present invention.

In fig. 9 shows a DSC thermogram of crystalline form B hydrochloride of the compound of formula I according to the present invention.

In fig. 10 shows an XPRD diffraction pattern of crystalline Form C hydrochloride of a compound of formula I according to the present invention.

In fig. 11 shows a DSC thermogram of crystalline form C hydrochloride of the compound of formula I according to the present invention.

In fig. 12 shows an XPRD diffraction pattern of crystalline form D sulfate of the compound of formula I according to the present invention.

In fig. 13 shows a DSC thermogram of crystalline form D sulfate of the compound of formula I according to the present invention.

In fig. 14 shows an XPRD diffraction pattern of crystalline phosphate form E of the compound of formula I according to the present invention.

In fig. 15 shows a DSC thermogram of crystalline phosphate form E of the compound of formula I according to the present invention.

In fig. 16 shows an XPRD diffraction pattern of crystalline phosphate form F of the compound of formula I according to the present invention.

In fig. 17 shows a DSC thermogram of the crystalline phosphate form F of the compound of formula I according to the present invention.

In fig. 18 is a graph of the ADI isotherm of crystalline phosphate form F of the compound of formula I according to the present invention.

In fig. 19 shows an overlay of X-ray diffraction patterns of crystalline form F of the phosphate of the compound of formula I according to the present invention before and after the EAF test.

In fig. 20 shows an XPRD diffraction pattern of the mesylate crystal Form G of the compound of formula I according to the present invention.

In fig. 21 shows a DSC thermogram of the mesylate crystal Form G of the compound of formula I according to the present invention.

In fig. 22 is a graph of the ADI isotherm of the mesylate crystal Form G of the compound of formula I according to the present invention.

In fig. 23 shows an XPRD diffraction pattern of the hydrobromide crystal Form H of the compound of formula I according to the present invention.

In fig. 24 shows a DSC thermogram of the hydrobromide crystal Form H of the compound of formula I according to the present invention.

In fig. 25 shows an XPRD diffraction pattern of the hydrobromide crystal Form J of the compound of formula I according to the present invention.

In fig. 26 shows an XPRD diffraction pattern of the hydrobromide crystal Form K of the compound of formula I according to the present invention.

In fig. 27 shows a DSC thermogram of the hydrobromide crystal Form K of the compound of formula I according to the present invention.

In fig. 28 is a graph of the ADI isotherm of the hydrobromide crystal Form K of the compound of formula I according to the present invention.

In fig. 29 shows an overlay of X-ray diffraction patterns of the hydrobromide crystal Form K of the compound of formula I according to the present invention before and after the EAF test.

In fig. 30 shows an XPRD diffraction pattern of the fumarate crystal Form L of the compound of formula I according to the present invention.

In fig. 31 shows a DSC thermogram of the fumarate form L crystalline of the compound of formula I according to the present invention.

In fig. 32 shows an XPRD diffraction pattern of the benzenesulfonate crystal form M of the compound of formula I according to the present invention.

In fig. 33 shows a DSC thermogram of the benzenesulfonate crystal form M of the compound of formula I according to the present invention.

In fig. 34 is a graph of the DSP isotherm of the benzenesulfonate crystalline form M of the compound of formula I according to the present invention.

In fig. 35 shows an overlay of X-ray diffraction patterns of the benzenesulfonate crystal form M of the compound of formula I according to the present invention before and after the EAF test.

In fig. 36 shows an XPRD diffraction pattern of the N citrate crystalline form of the compound of formula I according to the present invention.

In fig. 37 shows a DSC thermogram of the N citrate crystalline form of the compound of formula I according to the present invention.

In fig. 38 shows an XPRD diffraction pattern of crystalline form O tartrate of the compound of formula I according to the present invention.

- 19 044931

In fig. 39 shows a DSC thermogram of crystalline form O tartrate of the compound of formula I according to the present invention.

In fig. 40 shows a TGA thermogram of crystalline form O tartrate of a compound of formula I according to the present invention.

In fig. 41 is a graph of the DSP isotherm of crystalline form O tartrate of the compound of formula I according to the present invention.

In fig. 42 shows an overlay of X-ray diffraction patterns of crystalline form O tartrate of the compound of formula I according to the present invention before and after the EAF test.

In fig. 43 shows the 1H NMR spectrum of crystalline form 1 of the compound of formula I according to the present invention.

In fig. 44 shows the 1H NMR spectrum of the O tartrate crystalline form of the compound of formula I according to the present invention.

In fig. 45 shows an overlay of X-ray diffraction patterns of crystalline form F of the phosphate of the compound of formula I of the invention after exposure at high temperature and under accelerated degradation conditions for 2 weeks.

In fig. 46 shows an overlay of X-ray diffraction patterns of crystalline form O tartrate of a compound of formula I according to the invention after exposure at high temperature and under accelerated degradation conditions for 2 weeks.

In fig. 47 shows an overlay of DSC thermograms of crystalline phosphate form F of a compound of formula I according to the present invention after exposure at high temperature and under accelerated degradation conditions for 2 weeks.

In fig. 48 shows an overlay of DSC thermograms of the O tartaric acid crystalline form of a compound of formula I according to the present invention after exposure at high temperature and under accelerated degradation conditions for 2 weeks.

In fig. 49 shows an overlay of X-ray diffraction patterns of crystalline form 1 of a compound of formula I according to the invention after exposure at high temperature and under accelerated degradation conditions for 2 weeks.

In fig. 50 shows an overlay of DSC thermograms of crystalline form 1 of the compound of formula I of the invention after exposure at high temperature and under accelerated degradation conditions for 2 weeks.

Implementation options

The following embodiments further explain the invention, but do not limit the scope of the invention.

No. Device Model Manufacturer Method of analysis 1 High performance liquid chromatograph (UPLC) Agilent 1200, DAD Agilent Instrument: Agilent 1200 DAD, HPLC system or equivalent configuration Chromatography column: Waters XBridge Shield RP18 4.6x150 mm, 3.5 µm Mobile phase: A: 0.05% aqueous solution of phosphoric acid; B: acetonitrile 2 Liquid chromatography mass spectrometry (LC-MS) Agilent 1200 HPLC/610 0 SQ System Agilent Instrument: Agilent 1200 HPLC/6100 SQ System Chromatographic column: Agilent XDB-C18, 4.6 mmx50 mm, 1.8 µm Mobile phase: A: 0.05% TFA in water; B: 0.05% TFA in acetonitrile

- 20 044931

3 Nuclear magnetic resonance spectroscopy ^1H NMR AVANCE III 400MHz BRUKER Ultrashield-Plus Digital NMR Spectroscopy Experiment: N PROTON ¹ H experiment (default parameters) 4 Powder X-ray diffractometer (XRD) D8 Advance BRUKER C&C light source. X-ray intensity 40 kV/40 mA. Theta-theta scanning mode. Scanning angle range from 4 to 40°. Step length 0.05°. Scanning speed 0.5 sec/step. 5 Differential scanning calorimeter (DSC) Q1000 T.A. Weigh 2-4 mg of sample and place it in a non-sealed aluminum container, allowing the sample to reach equilibrium under a stream of nitrogen (50 mL/min) at 25 °C, and increase the temperature from 25 °C to 300 °C at a rate of 10 °C/min. 6 Thermogravimetric analyzer (TGA) Q500 T.A. Weigh 10-20 mg of sample and place it in a platinum sample container, hold the sample in a nitrogen stream (60 ml/min), then allow the sample to reach equilibrium in a nitrogen stream (40 ml/min) at 25 °C, and increase the temperature from 25 °C to 300 °C at a rate of 10 °C/min. 7 Dynamic Vapor Sorption (DVA) Analyzer Advantage 1 Surface Measurement System Weigh approximately 10 mg of sample and set temperature at 25 °C, dry for 60 minutes at 0% humidity and determine the moisture absorption characteristics of the sample when changing relative humidity from 0% to 95%, and the drying characteristics of the sample when the relative humidity changes from 95% to 0%. Relative change step humidity is 5%. When the rate of mass change dm/dt becomes less than 0.002%, the mass balance is calculated

- 21 044931

achieved. The balance criterion in the test is the rate of mass change less than 0.01%/min for 5 minutes, and the maximum time to reach equilibrium is 2 hours. 8 Ion chromatography ICS-2000 + AS40 Automated sampler DIONEX Chromatographic column: lonPac® AS11-NS 4x250 mm; Column temperature: 30 °C; Eluent: aqueous solution of 10 mM KOH; Flow rate: 1.00 ml/min; Suppressor: Dionex AERS 5004 mm; Suppressor electric current: 25mA; Duration: 15 min

Raw materials and reagents used in the present invention.

Material Purity/grade Batch number Manufacturer Compound of formula V >98.0% KM 1009-1804001 ZINNOVA Compound of formula IV >98.0% KM 1008-1804001 ZINNOVA N.Ndiisopropylethylamine (DIPEA) ChDA KM261A-1801002 Shanghai Qiao Chemical Science Co., Ltd. Ethanol / 160321047В Nanjing Chemical Reagent Co., Ltd. Methanol ChDA Р1176856 GENERAL-REAGENT Tetrahydrofuran (THF) ChDA Р1167158 GENERAL-REAGENT Dichloromethane (DCM) ChDA Р1216848 GENERAL-REAGENT Ethyl acetate (EA) ChDA Р1080359 GENERAL-REAGENT Acetone ChDA Р1160778 GENERAL-REAGENT Acetonitrile HPLC 6308IX20 Anhui Fulltime Specialized Solvent & Reagent Co., Ltd. n-hexane ChDA Р1196621 GENERAL-REAGENT Purified water Milli-Q Received same day Milli-Q Methyl tert-butyl ether (MTBE) ChDA Р1135054 GENERAL-REAGENT Isopropanol HPLC 6553IU13 Anhui Fulltime Specialized Solvent & Reagent Co., Ltd. Palladium on carbon (Pd/C) ChDA KM416A-1603001 Shaanxi Rock New Materials Co., Ltd. T rimethyl ortho-acetate 98%+ KM1013-1805001 Shanghai Titan Scientific Co., Ltd. Pyridine hydrochloride 98%+ KM616-1703001 Jiangsu Heng An Chemical Industry Co., Ltd. Hydrobromic acid 45% Р1337848 Adamas-beta Tartaric acid (L) 99%+ Р1311486 Adamas-beta Benzenesulfonic acid monohydrate 98%+ Р1257168 Adamas-beta Hydrochloric acid 36-38% Р1246465 GENERAL-REAGENT Sulfuric acid 95-98% 20140301 Wuxi Jiani Chemistry Co., Ltd. Methanesulfonic acid >98.0% Р1133997 GENERAL-REAGENT Fumaric acid 99% LU80M51 J&KCHEMICAL

- 22 044931

Lemon acid Pharmacologically pure 160105001С Nanjing Chemical Reagent Co., Ltd. p-toluenesulfonic acid >99.5% 20101208 Shanghai Lingfeng Chemical Reagent Co., Ltd. Phosphoric acid 85% H2160 Honeywell Metal catcher on silicon based (Thiol silica gel) Sulfur content > 3.2% — Shanghai Chiral Chemistry Co., Ltd. Potassium hydroxide in methanol (solution) ChDA 0.1 mol/l — Potassium hydrophthalate ChDA >99.5% —

Examples

Preparation of the compound of formula III.

IV III

Example 1. Preparation of the compound of formula III.

Ethanol (4 ml), compound of formula IV (0.20 g, 1.0 eq.), compound of formula V (0.18 g, 1.0 eq.) and DIPEA (0.39 g, 3.0 eq. ) added to a 25 ml three-neck flask and stirred; in a nitrogen atmosphere, the system was heated to boiling temperature (70-80°C) and stirred overnight at reflux temperature; the system was cooled to room temperature (15-20°C), with solids precipitating during cooling; Water (4 ml) was added dropwise to the system, the system was stirred for 2 hours at room temperature (15-20°C); filtered, the filter cake was washed with an aqueous solution of ethanol (2 ml, 1:1 v/v), the filter cake was dried in vacuum at 45-50°C for 16 hours; approximately 0.21 g of a yellow solid was obtained with a purity determined by LC-MS of 96.4% (214 nm) and a yield of 69%.

MS-ESI: [M+1] ⁺ : 303.1.

1H NMR (400 MHz, CDCi ₃ ): 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), 3.661-3.722 (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).

Example 2 Preparation of a compound of formula III.

Ethanol (120 ml, 20 volumes), compound of formula IV (6.0 g, 1.0 eq.), compound of formula V (5.4 g, 1.01 eq.) and DIPEA (11.7 g, 3.0 eq.) 0 eq.) added to a 250 ml three-neck flask and stirred; under a nitrogen atmosphere, the system was heated to 70-80°C (internal temperature) and stirred while maintaining the specified temperature for 8 hours; the system was cooled to room temperature (15-20°C), with solids precipitating during cooling; Water (120 ml, 20 volumes) was added dropwise to the system, the system was stirred for 2 hours at room temperature (10-15°C); filtered, the filter cake was washed with aqueous ethanol (30 ml, 1:1), the filter cake was dried in vacuum at 50°C for 16 hours. A total of approximately 7.7 g of a yellow solid was obtained with a purity determined by HPLC, 95.5% and yield 84.3%.

MS-ESI and 1H NMR data correspond to example 1.

Example 3 Preparation of a compound of formula III.

Ethanol (5 ml, 10 volumes), compound of formula IV (0.50 g, 1.0 eq.), compound of formula V (0.45 g, 1.01 eq.) and DIPEA (0.98 g, 3.0 eq.) 0 eq.) added to a 25 ml three-neck flask and stirred; in a nitrogen atmosphere, the system was heated to 70-80°C, refluxed and stirred for 5 hours; the system was cooled to room temperature (15-20°C), while solids precipitated; water (5 ml, 10 volumes) was added dropwise to the system, the system was stirred for 2 hours at room temperature (10-15°C); filtered, the filter cake was washed with an aqueous solution of ethanol (1:1) (1.5 ml, 3 volumes), the filter cake was dried in vacuum at 50°C for 16 hours; a total of approximately 0.54 g of a brown solid was obtained with an HPLC purity of 95.4% and a yield of 71%.

MS-ESI and 1H NMR data correspond to example 1.

Example 4 Preparation of a compound of formula III.

Ethanol (5 ml, 10 volumes), compound of formula IV (0.50 g, 1.0 eq.), compound of formula V (0.45 g, 1.01 eq.) and DIPEA (0.72 g, 2.0 eq. 2 eq.) added to a 25 ml three-neck flask and stirred; in a nitrogen atmosphere, the system was heated to 70-80°C, refluxed and stirred for 5 hours; the system was cooled to room temperature (15-20°C), and the solids precipitated into

- 23 044931 sediment; Water (7.5 ml, 15 volumes) was added dropwise to the system, the system was stirred for 1 hour at room temperature (10-15°C); the system was cooled to 5-10°C and stirred for 2 hours; filtered, the filter cake was washed with an aqueous solution of ethanol (1:1) (1.5 ml, 3 volumes), the filter cake was dried in vacuum at 50°C for 16 hours; a total of approximately 0.57 g of a brown solid was obtained with an HPLC purity of 91.4% and a yield of 75%.

MS-ESI and 1H NMR data correspond to example 1.

Example 5 Preparation of a compound of formula III.

Ethanol (50 ml, 10 volumes), compound of formula IV (5.0 g, 1.0 eq.), compound of formula V (4.5 g, 1.01 eq.) and DIPEA (7.2 g, 2.0 eq. 2 eq.) added to a 250 ml three-neck flask and stirred; in a nitrogen atmosphere, the system was heated to 70-80°C, refluxed and stirred for 5 hours; the system was cooled to room temperature (15-20°C), while solids precipitated; water (75 ml, 15 volumes) was added dropwise to the system, the system was stirred for 1 hour at room temperature (10-15°C); the system was cooled to 5-10°C and stirred for 2 hours; filtered, the filter cake was washed with an aqueous solution of ethanol (1:1, 15 ml), the filter cake was dried in vacuum at 50°C for 16 hours; a total of approximately 6.6 g of a yellow solid was obtained with an HPLC purity of 94.2% and a yield of 86.7%.

MS-ESI and 1H NMR data correspond to example 1.

Example 6 Preparation of a compound of formula III.

Ethanol (180 ml, 10 volumes), compound of formula IV (17.8 g, 1.0 eq.), compound of formula V (16.0 g, 1.01 eq.) and DIPEA (25.7 g, 2.0 eq.) 2 eq.) added to a 500 ml three-neck flask and stirred; in a nitrogen atmosphere, the system was heated to 70-80°C, refluxed and stirred for 5 hours; the system was cooled to room temperature (15-20°C), while solids precipitated; Water (270 ml, 15 volumes) was added dropwise to the system, the system was stirred for 1 hour at room temperature (10-15°C); the system was cooled to 5-10°C and stirred for 2 hours; filtered, the filter cake was washed with an aqueous solution of ethanol (1:1.5, 40 ml), the filter cake was dried in vacuum at 50°C for 16 hours; a total of approximately 23.0 g of a brown solid was obtained with an HPLC purity of 95.3% and a yield of 85.2%.

MS-ESI and 1H NMR data correspond to example 1.

Example 7 Preparation of a compound of formula III.

Ethanol (1000 ml, 10 volumes), compound of formula IV (100 g, 1.0 eq.), compound of formula V (89.9 g, 1.01 eq.) and DIPEA (143.2 g, 2.2 eq. .) added to a 3000 ml three-neck flask and stirred; under a nitrogen atmosphere, the system was heated to 85-90°C (internal temperature approximately 75°C), refluxed and stirred for 10 hours; the system was cooled to room temperature (15-20°C), while solids precipitated; Water (1500 ml, 15 volumes) was added dropwise to the system, the system was stirred for 1 hour at room temperature (10-15°C); the system was cooled to 5-10°C and stirred for 2 hours; filtered, the filter cake was washed with an aqueous solution of ethanol (1:1.5, v/v, 200 ml), the filter cake was dried in vacuum at 50°C for 16 hours; a total of approximately 130 g of a reddish-brown solid was obtained with an HPLC purity of 94.2% and a yield of 85.5%.

MS-ESI and 1H NMR data correspond to example 1.

Example 8 Preparation of the compound of formula III.

Ethanol (2000 ml, 10 volumes), compound of formula IV (200 g, 1.0 eq.), compound of formula V (179.7 g, 1.01 eq.) and DIPEA (286.4 g, 2.2 eq. .) added to a 5000 ml three-neck flask and stirred; under a nitrogen atmosphere, the system was heated to 70-80°C (internal temperature: approximately 65-70°C), refluxed and stirred for 16 hours; the system was cooled to room temperature (15-20°C), while solids precipitated; Water (3000 ml, 15 volumes) was added dropwise to the system, the system was stirred for 1 hour at room temperature (10-15°C); the system was cooled to 5-10°C and stirred for 2 hours; filtered, the filter cake was washed with an aqueous solution of ethanol (1:1.5, by volume, 400 ml), the filter cake was dried using an air blower at 50°C for 16 hours; a total of approximately 251 g of a reddish brown solid was obtained with an HPLC purity of 93.4%, content of 94.7%, and yield of 78.1%.

MS-ESI and 1H NMR data correspond to example 1.

Example 9. Preparation of the compound of formula III.

Ethanol (5000 ml, 10 volumes), compound of formula IV (500 g, 1.0 eq.), compound of formula V (450 g, 1.01 eq.) and DIPEA (723 g, 2.2 eq.) were added to three-neck flask with a volume of 20,000 ml and stirred; under a nitrogen atmosphere, the system was heated to 80-90°C (internal temperature: approximately 70-80°C), refluxed and stirred for 16 hours; the system was cooled to room temperature (25-30°C), while solids precipitated; Water (7500 ml, 15 volumes) was added dropwise to the system, the system was stirred for 1 hour at room temperature (25-30°C); the system was cooled to 10-15°C and stirred for 2 hours; filtered, the filter cake was washed with an aqueous solution of ethanol (1:1.5, by volume, 1000 ml), the filter cake was dried in an oven

- 24 044931 in vacuum at 50-55°C for 24 hours; a total of approximately 623 g of product was obtained with an HPLC purity of 93.7%, residual ethanol of 0.5%, content of 93.1% and yield of 76.2%.

MS-ESI and ¹ H NMR data correspond to example 1.

Example 10 Preparation of the compound of formula III.

Ethanol (100 ml, 10 volumes), compound of formula IV (10.0 g, 1.0 eq.), compound of formula V (9.0 g, 1.01 eq.) AND DIPEA (14.3 g, 2.0 eq.) 2 eq.) added to a 500 ml three-neck flask and stirred; the system was heated to 70-80°C, refluxed and stirred for 16 hours; the system was cooled to room temperature (20-30°C), while solids precipitated; water (150 ml, 15 volumes) was added to the system, the system was stirred for 2 hours at room temperature (20-30°C); the system was cooled to 5-10°C and stirred for 2 hours; filtered, the filter cake was washed with an aqueous solution of ethanol (1:1.5, by volume, 25 ml), the filter cake was dried in an oven in a vacuum at 50-55°C for 16 hours; a total of approximately 13.7 g of product was obtained with an HPLC purity of 93.7% and a yield of 90%.

MS-ESI and ¹ H NMR data correspond to example 1.

Example 11 Preparation of the compound of formula III.

Ethanol (17 kg, 10 volumes), compound of formula IV (2.2 kg, 1.0 eq.), compound of formula V (1.98 kg, 1.01 eq.) AND DIPEA (3.19 kg, 2.0 eq.) 2 eq.) added to reactor R0462 and stirred; under a nitrogen atmosphere, the system was heated to 75-80°C (internal temperature approximately 70-80°C) and stirred for 16 hours; the system was cooled to room temperature (15-25°C), while solids precipitated; Water (33 kg, 15 volumes) was added dropwise to the system, the system was stirred for 2 hours at room temperature (10-15°C); the system was cooled to 5-10°C and stirred for 4 hours; filtered, the filter cake was washed with an aqueous solution of ethanol (ethanol: water = 1:2, by volume, 6.2 kg), the filter cake was dried at a jacket temperature of 45-55 ° C in vacuum at a pressure < -0.08 MPa for 16 h; a total of approximately 2.64 kg of a brown solid was obtained with an HPLC purity of 94.0%, content of 93.4%, and yield of 79.04%.

MS-ESI and ¹ H NMR data correspond to example 1.

Preparation of the compound of formula II.

Ill II

Example 12 Preparation of a compound of formula II.

To a 100 ml stainless steel autoclave, compound of formula III (5.0 g), THF (50 ml, 10 volumes) and palladium on carbon (0.75 g, 10% Pd/C with 50% humidity) were sequentially added; the system was purged with nitrogen 5 times, then with hydrogen 5 times; the pressure in the system was increased to 0.50 MPa using hydrogen, then the system was heated to 25-35°C and stirred at this temperature for 24 hours; the reaction liquid was filtered through diatomaceous earth, the filter cake was washed with THF (20 ml) and the filtrate was concentrated to dryness to give 4.2 g of a brown solid with an HPLC purity of 94.9% and a yield of 93.3%.

MS-ESI: [M+1]+: 273.1 ^1H NMR (400 MHz, CDCl ₃ ): 7.988 (s, 1H), 7.688 (d, 1H), 6.805 (d, 1H), 4.190-4.338 ( m, 3H), 3.584-3.648 (m, 1H), 3.147-3.206 (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).

Example 13 Preparation of a compound of formula II.

To a 5000 ml stainless steel autoclave, compound of formula III (120.0 g), THF (2400 ml, 20 volumes) and palladium on carbon (18 g, 10% Pd/C with 50% humidity) were sequentially added; the system was purged with nitrogen 5 times, then with hydrogen 5 times; the pressure in the system was increased to 0.50 MPa using hydrogen, then the system was heated to 25-35°C and stirred at this temperature for 24 hours; the reaction liquid was filtered through diatomaceous earth, the filter cake was washed with THF (600 ml) (until almost no fluorescent spot was detected on TLC), and the filtrate was concentrated to give 130 g of a black semi-solid of HPLC purity 91. 7% and yield 120.26%.

MS-ESI and ¹ H NMR data correspond to example 12.

Example 14 Preparation of a compound of formula II.

In a 5 L stainless steel autoclave, compound of formula III (100.0 g), THF (2000 ml, 20 volumes) and palladium on carbon (15.0 g, 10% Pd/C with 50% humidity) were sequentially added; the system was purged with nitrogen 5 times, then with hydrogen 5 times; the pressure in the system was increased to 0.5-1.0 MPa using

- 25 044931 hydrogen, the jacket temperature was set to 30°C, the system was stirred at this temperature for 16 hours; the reaction liquid was filtered through diatomaceous earth, the filter cake was washed

THF (1000 ml), a total of 3877 g of a solution of the compound of formula II in THF was obtained.

Post-workup 1: The above filtrate (1820 g, containing approximately 40 g of compound of formula II, calculated according to a yield of 100%) was concentrated to (2-3 volumes, 80120 ml) using a rotary evaporator, then the solvent was replaced with ethanol (2x150 ml ), concentrating to (2-3 volumes, 80-120 ml); 78 g of a solution of the compound of formula II in ethanol was obtained with a content of 47.25% and a yield of 92.14%.

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

Post-processing 3: the above filtrate (450 g containing approximately 10 g of compound of formula II, calculated according to 100% yield) was added to the flask, concentrated to approximately 30-40 ml (3-4 volumes) using a rotary evaporator; the solvent was then replaced with ethanol (2x50 ml), concentrating to approximately 30-40 ml (3-4 volumes); a black oily concentrated residue was obtained which was directly used in the next step.

MS-ESI and 1H NMR data correspond to example 12.

Example 15 Preparation of a compound of formula II.

To a 5000 ml three-neck flask, THF (240 ml, 20 volumes), compound of formula III (12.0 g) and palladium on carbon (1.8 g, 5% Pd/C with 50% humidity) were added sequentially; the system was purged with nitrogen 5 times, then with hydrogen 5 times; the system was stirred for 48 hours, maintaining the temperature at room temperature (25-30°C) and under hydrogen pressure (approximately 0.1 MPa); the reaction liquid was filtered, the filter cake was washed with THF (60 ml); the combined filtrate was concentrated using a rotary evaporator to 20-30 ml, the solvent was replaced with ethanol (2x60 ml), concentrated to 20-30 ml; 24 g of a solution of the compound of formula II in ethanol was obtained, which was directly used in the next step.

MS-ESI and 1H NMR data correspond to Example 12.

Example 16 Preparation of a compound of formula II.

To a 5000 ml three-neck flask, THF (1500 ml, 15 volumes), compound of formula III (100 g) and palladium on carbon (15 g, 5% Pd/C with 50% humidity) were added sequentially; the system was purged with nitrogen 5 times, then with hydrogen 5 times; the system was stirred for 48 hours, maintaining the temperature at room temperature (20-25°C) and under hydrogen pressure (approximately 0.1 MPa); the reaction liquid was filtered, the filter cake was washed with THF (200 ml); the combined filtrate was concentrated using a rotary evaporator to 200-300 ml; 185.6 g of a solution of the compound of formula II in THF was obtained with an HPLC purity of 94.2%, a content of 43.2% and a yield of 94.0%.

MS-ESI and 1H NMR data correspond to example 12.

Example 17 Preparation of a compound of formula II.

To a 20,000 ml three-neck flask, THF (12,400 ml, 20 volumes), compound of formula III (620 g) and palladium on carbon (93 g, 5% Pd/C with 50% humidity) were added sequentially; the system was purged with nitrogen 5 times, then with hydrogen 5 times; the system was stirred for 48 hours at room temperature (30-35°C) and under hydrogen pressure (approximately 0.1 MPa); the reaction liquid was filtered through diatomite (200 g), the filter cake was washed with THF (1200 ml), the combined filtrate was concentrated using a rotary evaporator to 1200-1800 ml; 1664 g of a solution of the compound of formula II in THF was obtained with a HPLC purity of 93.8%, a content of 34.57% and a yield of 110.6%.

MS-ESI and 1H NMR data correspond to Example 12.

Example 18 Preparation of a compound of formula II.

To a 250 ml autoclave, THF (140 ml, 70 volumes), compound of formula III (2.0 g) and palladium on carbon (0.3 g, 5% Pd/C with 50% humidity) were sequentially added; cover the autoclave and tighten the nut; the system was purged with nitrogen 3 times, then with hydrogen 3 times; Hydrogen was pumped into the autoclave to approximately a pressure of 0.50±0.05 MPa, the inlet valve was closed; turned on the mixing device, setting the rotation speed to 500 rpm; the hydrogen pressure in the autoclave was maintained at 0.5±0.05 MPa and at a temperature of 25-35°C, the system was stirred to allow the reaction to proceed for 96 hours, the reaction liquid was filtered through diatomaceous earth (10 g), the filter cake was washed with THF (60 ml), the combined filtrate was concentrated on a rotary evaporator to dryness to obtain 1.8 g of a semi-solid with an HPLC purity of 91.2% and a yield of 99.9%.

MS-ESI and 1H NMR data correspond to example 12.

Example 19 Preparation of a compound of formula II.

To a 500 L autoclave, THF (167 kg, 70 volumes), compound of formula III (2.64 kg) and palladium on carbon (0.4 kg, 5% Pd/C with 50% humidity) were added sequentially; the system was purged with nitrogen 5 times,

- 26 044931 then with hydrogen 5 times; Hydrogen was pumped into the autoclave to approximately a pressure of 0.50±0.05 MPa, the inlet valve was closed; the mixing device was turned on; the hydrogen pressure in the autoclave was maintained at 0.5±0.05 MPa and at a temperature of 25-35°C the system was stirred to allow the reaction to proceed for 120 hours, the system was filtered under pressure, the filter cake was washed with THF (13 kg); the combined filtrate was distilled under reduced pressure (to 2-3 volumes) to obtain 11 kg of a solution of compound of formula II in THF with HPLC purity of 90.7%, content of 18.5% and yield of 91.9%.

MS-ESI and 'll NMR data correspond to example 12.

Example 20 Preparation of a compound of formula II.

To a 100 ml stainless steel autoclave, THF (60 ml, 12 volumes), compound of formula III (5.0 g) and palladium on carbon (0.75 g, 5% Pd/C with 50% humidity) were added sequentially; the system was purged with nitrogen 5 times, then with hydrogen 5 times; the pressure in the system was increased to 0.5-1.0 MPa using hydrogen, the jacket temperature was set to 30°C, the system was stirred for 42 hours while maintaining the specified temperature; after completion of the reaction, the reaction liquid was filtered through diatomite, the filter cake was washed with THF (100 ml); a total of 197.8 g of a solution of the compound of formula II in THF was obtained; the solution was concentrated using a rotary evaporator to (2-3 volumes, 10-15 ml); the solvent was replaced with ethanol (2x25 ml), concentrated to (2-3 volumes, 10-15 ml); the resulting compound of formula II in ethanol was directly used in the next step.

MS-ESI and 1H NMR data correspond to Example 12.

Preparation of a compound of formula I.

Example 21 Preparation of a compound of formula I.

To a 250 mL three-neck flask was added the compound of formula II (5 g, 1.0 eq.), trimethyl ortho-acetate (6.6 g, 3.0 eq.) and THF (125 mL); in a nitrogen atmosphere, the system was heated to boiling under reflux; Pyridine hydrochloride (210 mg, 0.1 eq.) was added to the same three-neck flask; under a nitrogen atmosphere, the system was heated to 75±5°C (internal temperature 60-63°C) and the reaction was carried out for 8 hours. Monitoring by HPLC showed that the compound of formula II was completely transformed. The purity of the compound of formula I in the resulting reaction liquid was 93.1%.

The system was cooled to room temperature, the reaction liquid was concentrated using a rotary evaporator until the liquid reflux no longer condensed; water (50 ml) was added to the system, the pH value of the system was adjusted to 9-10 using a 4M sodium hydroxide solution; the system was extracted with ethyl acetate (50 ml), filtered, the filter cake washed with ethyl acetate (10 ml) to obtain 3.5 g of compound of formula I as a wet product. Control by LC-MS showed that the purity of the compound of formula I was 99.22%; the resulting filtrate was separated, the aqueous phase was extracted with ethyl acetate (50 ml), the organic phases were combined and concentrated to dryness to obtain 2.8 g of the compound of formula I as crude product. Monitoring by LC-MS showed that the purity of the compound of formula I was 95.08%.

MS-ESI: [M+1]+: 297.0.

1H NMR (400 MHz, DMSO- _d6 ): 8.78 (s, 1H), 8.32 (d, 1H), 7.25 (d, 1H), 4.60 (m, 1H), 4. 10-4.13 (t, 2H), 3.91 (m, 1H), 2.93-2.98 (m, 1H), 2.80-2.86 (m, 1H), 2.84 ( s, 3H), 2.50 (m, 1H), 2.16-2.19 (m, 1H), 1.99-2.02 (m, 1H)), 1.69-1.77 (m , 1H).

Example 22 Preparation of a compound of formula I.

To a 3 L three neck flask was added the compound of formula II (54 g, 1.0 eq), trimethyl orthoacetate (71.5 g, 3.0 eq) and THF (1.35 L); in a nitrogen atmosphere, the system was heated to boiling under reflux; Pyridine hydrochloride (2.27 g, 0.1 eq.) was added to the same three-neck flask; under a nitrogen atmosphere, the system was heated to 75 ± 5° C. (internal temperature 60-63° C.) and the reaction was carried out for 8 hours. HPLC analysis showed that 1.5% of the compound of formula II remained in the system; the system was cooled to room temperature, trimethyl ortho-acetate (11.9 g, 0.5 eq.) and pyridine hydrochloride (1.14 g, 0.05 eq.) were added; under a nitrogen atmosphere, the system was heated to 75±5°C (internal temperature 6063°C) and the reaction was carried out for 4 hours. HPLC analysis showed that 0.4% of the compound of formula II remained in the system, the purity of the compound of formula I in the reaction liquid was 91.6%.

The system was cooled to room temperature, the reaction liquid was concentrated using a rotary evaporator until the liquid reflux ceased to condense; water was added to the system (540 ml, 10 volumes), the pH value of the system was adjusted to 9-10 using a 4 M hyd solution

- 27 044931 sodium oxide; filtered, the filter cake was washed with water (270 ml) and then with MTBE (270 ml), the resulting filter cake was dried in vacuum at 50°C for 16 hours to obtain 56 g of the crude compound of formula I with a purity determined by HPLC, 96 .32%; the resulting crude product was dissolved in 600 ml of methanol to obtain a clear solution, to which silicon-based metal remover (43 g) and activated carbon (5.4 g) were added, the mixture was heated to reflux and maintained at this temperature for 1 hour (internal temperature 50°C); the system was cooled to room temperature, filtered through diatomaceous earth, washed with methanol (15 ml) until the filtrate no longer showed fluorescence; The methanol solution was concentrated to dryness, the rate of distillation of the distillate became slower, MTBE (540 ml) was added to the resulting solid, the system was heated to 50°C and refluxed, and then stirred for 1 hour until the solid did not dissolve completely; the system was cooled to 10-15°C and stirred for 1 hour, filtered, the filter cake was washed with cold MTBE (100 ml); the resulting filter cake was dried in vacuo at 50°C for 16 hours to obtain 28.0 g of the compound of formula I with a purity determined by HPLC of 98.8%.

The compound of formula I was isolated from the filtrate.

The filtrate from the previous step was concentrated to dryness to give approximately 23 g of a light yellow solid; MTBE (230 ml) was added to it, the temperature was raised to 50°C and refluxed for 10 minutes; added methanol to the system in separate portions until the total amount of methanol added was approximately 30 ml, the material was almost dissolved, and the solution became clear; the system was cooled to 10-15°C and stirred for 1 hour; filtered, the filter cake was washed with cold MTBE (50 ml); the filter cake was dried in vacuo at 50° C. for 16 hours to obtain 8.7 g of an almost colorless solid (compound of formula I) with a purity determined by HPLC of 97.8%.

Further cleaning.

The compound of formula I (11.7 g) with a purity of 97.8%, obtained in the previous operation, and MTBE (60 ml) were added to the reaction flask, the system was triturated at room temperature for 4 hours, filtered, the filter cake was washed with MTBE (20 ml), and the said filter cake was dried in vacuo at 50°C for 16 hours to obtain 10.8 g of an almost colorless compound of formula I with a purity determined by HPLC of 98.1%.

MS-ESI and 1H NMR data for the above compound of formula I correspond to Example 21. Example 23. Preparation of the compound of formula I.

The compound of formula II in THF (45 g solution containing approximately 1 g of the compound of formula II, 1 eq.), which was not further processed and obtained in Example 14, was added to the flask and the solution was concentrated by rotary evaporation to 3 ml. Toluene (5 ml) was added to the flask, then concentrated by rotary evaporation to 3 ml, this step was repeated twice, leaving a black oily concentrated residue.

To a 100 mL three-neck flask, add 1.0 g of the black oily concentrated residue from the previous step, trimethyl ortho-acetate (1.32 g, 3.0 eq.) and THF (25 mL); in a nitrogen atmosphere, the system was heated to boiling under reflux; Pyridine hydrochloride (0.08 g, 0.2 eq.) was added to the same three-neck flask; in a nitrogen atmosphere, the system was heated to 65-70°C (internal temperature) and the reaction was carried out for 5 hours; took a sample and tested it. HPLC analysis showed that 0.48% of the compound of formula II remained in the reaction liquid, and the purity of the compound of formula I was 90.10%; The system was refluxed for another 5 hours, a sample was taken and tested. HPLC analysis showed that the compound of formula II in the reaction liquid was completely transformed, and the purity of the compound of formula I was 91.79%.

Example 24 Preparation of a compound of formula I.

The untreated compound of formula II in THF (450 g solution containing approximately 10.0 g of the compound of formula II, 1 eq.) obtained in Example 14 was added to the flask and the solution was concentrated by rotary evaporation to 20-30 ml. Toluene (50 ml) was added to the flask, then concentrated by rotary evaporation to 20-30 ml, this step was repeated twice to obtain a black oily concentrated residue, which was dissolved in THF (20 ml, 2 volumes) to form a clear solution.

To a 500 mL three-neck flask was added the solution of THF obtained in the previous operation, trimethyl ortho-acetate (13.2 g, 3.0 eq.) and THF (230 mL); in a nitrogen atmosphere, the system was heated to boiling under reflux; Pyridine hydrochloride (0.8 g, 0.2 eq.) was added to the same three-neck flask; in a nitrogen atmosphere, the system was heated to 65-70°C (internal temperature) and the reaction was carried out for 10 hours; took a sample and tested it. HPLC analysis indicated that 0.7% of the compound of formula II remained in the reaction liquid and the purity of the compound of formula I was 90.1%.

The system was cooled to room temperature, water was added (20 ml, 2 volumes); the system was concentrated using a rotary evaporator until no more reflux condensed; V

- 28 044931 water was added to the system (100 ml, 10 volumes); the pH value of the system was adjusted to 9 using a saturated solution of potassium carbonate; the system was filtered, the filter cake was washed successively with water (50 ml, 5 volumes) and MTBE (50 ml, 5 volumes); the washed filter cake was dried in vacuo at 50°C for 16 hours to obtain 9.2 g of crude earthy yellow product (compound of formula I) with HPLC purity of 89.7% and yield of 84.5%.

Purification of a compound of formula I.

The crude product (compound of formula I) (5.0 g) with a purity of 89.7% obtained in the previous operation and ethanol (50 ml) were added to the flask, the system was stirred at room temperature for 20 minutes until the material almost did not dissolve and the solution did not become transparent; Silica gel (5.0 g, 1X) was added to the system and the system was concentrated to dryness using a rotary evaporator for further use; the crude solid obtained after concentration by rotary evaporator was placed on a silica gel column (40 g, 8X), and the column was eluted with a mixed solution of ethyl acetate and petroleum ether (EA:PE=2:1); fractions containing the compound of formula I (control by TLC) were collected and concentrated to dryness to obtain 0.5 g of the compound of formula I with a purity of 96.5% and 3.2 g of a light yellow compound of formula I with a purity of 99.3%, determined by HPLC.

The compound of formula I, 99.3% pure by HPLC, and MTBE (30 ml) were added to the flask, the system was heated to reflux and refluxed for 1 hour; the system was cooled to 5-10°C and, maintaining the specified temperature, the system was stirred for 1 hour, filtered, the filter cake was washed with MTBE (5 ml) and the filter cake was dried in vacuum at 50°C for 16 hours to obtain a light yellow , an almost colorless solid (compound of formula I) in an amount of 2.8 g with a purity of 99.8% determined by HPLC, with an impurity content of >0.1%. The total yield at the second and third stages was 47.3%.

Example 25 Preparation of a compound of formula I.

To the flask was added the compound of formula II in THF (130 g solution containing approximately 56 g of the compound of formula 11.1 eq.), not subjected to further processing and obtained in example 14, the solvent was replaced with toluene (2x280 ml), concentrating to 120-130 ml , then replaced with THF (280 ml) and concentrated to 120-180 ml, adding THF (500 ml) until the solid dissolved and the solution became clear; the resulting solution was transferred to a 2 L three-neck flask, THF (700 ml) and trimethyl ortho-acetate (74.0 g, 3.0 eq.) were added to the system; under a nitrogen atmosphere, the system was heated to 70-75°C (internal temperature) and the reaction was carried out for 10 hours; took a sample and tested it. HPLC analysis indicated that 0.1% of the compound of formula II remained in the reaction liquid and the purity of the compound of formula I was 93.2%.

The above reaction liquid was cooled to room temperature, a portion of the reaction liquid was withdrawn (corresponding to the amount that contained 55 g of the compound of formula II before the reaction), water (110 ml, 2 volumes) was added; the system was concentrated using a rotary evaporator to 110-160 ml (2-3 volumes); water (400 ml, 7 volumes) was slowly added to the concentrated residue; the system was stirred for 30 minutes at room temperature, then water (440 ml, 8 volumes) was added, the system was stirred for 30 minutes at room temperature (25-30°C); The pH of the system was adjusted to 8-9 using a 50% potassium carbonate solution (1.5 g (weight of the total solution)); the system was stirred for 30 minutes at room temperature (25-30°C); the system was cooled to 10-15°C and stirred for 2 hours at 10-15°C, then filtered in vacuum; the filter cake was dried at 50°C for 24 hours to obtain 55 g of the earthy yellow compound of formula I with a purity of 96.6%, a content of 87.53% and a crude yield of 80.4%.

Purification of a compound of formula I.

To the flask was added the crude product (compound of formula I) (55 g) with a purity of 96.6% determined by HPLC obtained in the previous step, silica gel (110 g, 2X) and ethanol (500 ml); the system was heated to 50°C and stirred for 30 minutes at 50°C; the system was concentrated using a rotary evaporator until reflux ceased, then the solvent was replaced with n-heptane (200 ml), evaporated to dryness; added silica gel to the system and eluted on a column filled with silica gel (550 g, 10X); the eluent was a mixed solution of ethyl acetate and n-heptane with a gradual increase in the amount of ethyl acetate up to pure ethyl acetate (EA: n-heptane = 1:1); Fractions with the compound of formula I (component A) and fractions with cross-component B (control by TLC) were collected.

The component A fraction was concentrated using a rotary evaporator to approximately 100 ml, the solvent in the concentrated residue was changed twice to approximately 200 ml of methanol, then replaced twice with MTBE (about 200 ml), then approximately 300 ml of MTBE was added to the resulting residue; the system was refluxed and boiled for 1 hour, then the system was cooled to room temperature (25-30°C) and stirred at room temperature (1 hour); the system was cooled to 5-10°C, stirred at 5-10°C for 2 hours, filtered, the filter cake was washed with MTBE (30 ml); the specified filter cake was dried in vacuum at 50°C for 16 hours

- 29 044931 to obtain 37.6 g of a light yellow solid (compound of formula I) with a purity of 99.85%, determined by HPLC, with an impurity content of >0.1%.

The fraction with component B was concentrated to dryness using a rotary evaporator, triturated with MTBE (50 ml) for 1 hour, the system was cooled to 5-10°C, stirred at 5-10°C for 2 hours, filtered, the filter cake was washed with MTBE (10 ml); the washed filter cake was dried in vacuo at 50°C for 16 hours to obtain 6 g of a light yellow solid (compound of formula I) with a purity of 99.35% determined by HPLC and with two impurities of >0.1 %.

The above compound of formula I (4.8 g) with a purity of 99.35%, MTBE (50 ml) and ethanol (5 ml) were added to the flask, the system was heated to 55-60 ° C, and then refluxed for 0 .5 h; the system was cooled to room temperature (25-30°C), stirred at room temperature for 1 hour; the system was cooled to 5-10°C, stirred at 5-10°C for 2 hours, filtered, the filter cake was washed with MTBE (10 ml); the washed filter cake was dried in vacuum at 50-55°C for 16 hours to obtain 4.0 g of the compound of formula I with a purity of 99.75% and impurities containing >0.1%.

Example 26 Preparation of a compound of formula I.

The compound of formula II in THF (14.5 g solution containing approximately 5.0 g of the compound of formula II, 1 eq.), untreated and obtained in Example 14, was added to the flask, the solvent was replaced with toluene (2x25 ml) and concentrated ca. to 10-15 ml, then replaced with THF (25 ml) and concentrated to about 10-15 ml, then THF (115 ml) was added until the solid dissolved and a clear solution formed; the resulting solution was transferred into a 500 ml three-neck flask; trimethyl ortho-acetate (6.6 g, 3.0 eq.) was added to the system; in a nitrogen atmosphere, the system was heated to boiling under reflux; Pyridine hydrochloride (0.42 g, 0.2 eq.) was added to the same three-neck flask; under a nitrogen atmosphere, the system was heated to 70-75°C (internal temperature) and the reaction was carried out for 15 hours; took a sample and tested it. HPLC analysis indicated that 4.0% of the compound of formula II remained in the reaction liquid; trimethyl ortho-acetate (0.5 g) and pyridine hydrochloride (0.1 g) were added to the system and refluxed at 7075°C (internal temperature) for 5 hours; took a sample and tested it. HPLC analysis showed that 0.05% of the compound of formula II remained in the reaction liquid and the purity of the compound of formula I was 92.80%.

Example 27 Preparation of a compound of formula I.

The compound of formula II in THF (817 g solution containing approximately 282.6 g of the compound of formula II, 1 eq.) as prepared in Example 14 was added to the flask, the solvent was replaced with toluene (approximately 2 x 1400 ml) and concentrated to approximately 550-850 ml, then replaced with THF (about 2x1400 ml) and concentrated to about 550-850 ml, THF (about 6500 ml) was added until the solid dissolved and the solution became clear; the solution was transferred into a 10 L three-neck flask; trimethyl ortho-acetate (374.0 g, 3.0 eq.) was added to the system; in a nitrogen atmosphere, the system was heated to boiling under reflux; Pyridine hydrochloride (24.0 g, 0.2 eq.) was added to the same three-neck flask; under a nitrogen atmosphere, the system was heated to 70-75°C (internal temperature) and the reaction was carried out for 12 hours; took a sample and tested it. HPLC analysis indicated that 4.1% of the compound of formula II remained in the reaction liquid; the purity of the compound of formula I was 85.5%; trimethyl ortho-acetate (22 g) and pyridine hydrochloride (1.4 g) were added to the reaction system; under a nitrogen atmosphere, the system was heated to 70-75°C (internal temperature) and the reaction was carried out for 5 hours; took a sample and tested it. HPLC analysis indicated that 0.7% of the compound of formula II remained in the reaction liquid and the purity of the compound of formula I was 91.4%.

The reaction liquid obtained in the previous operation was cooled to room temperature, 570 g of water was added to it, the system was concentrated using a rotary evaporator to 600900 ml (2-3 volumes), the concentrated residue was transferred to a 10 l flask, 2000 g of water (about 7 volumes), the system was stirred at room temperature for 1 hour, then 2300 g of water (about 8 volumes) was added, the system was stirred at room temperature (25-30°C) for 1 hour, the pH value of the system was adjusted up to 8-9 using a 50% solution of potassium carbonate (8.5 g); the system was stirred at room temperature (25-30°C) for 1 hour, cooled to 1015°C and stirred at 10-15°C for 2 hours, filtered, the filter cake was washed with water (500 g); The washed filter cake was dried at 50°C for 72 hours, taking samples and checking the water content. The water content determined by the Karl Fischer method was 3.2%. 252 g of an earthy yellow crude product (compound of formula I) was obtained with a purity of 97.5% by HPLC, a content of 89.8% and a crude yield of 72.3%.

Purification of a compound of formula I.

252 g of the crude product (compound of formula I) obtained in the previous operation and ethanol (1004 g, ~1000 ml) were added to the flask; the system was heated to 50-60°C, stirred at 50-60°C in

- 30 044931 for 30 minutes, until the material has almost dissolved and the solution has become transparent; the system was divided into two equal parts, silica gel (252 g) was added to each part, each part was concentrated using a rotary evaporator until the reflux practically ceased to condense; the solvent in each part was replaced with n-heptane (272 g, ~400 ml) until the reflux practically ceased to condense; The silica gel column was packed and filled with silica gel (3000 g, 200-300 mesh) and n-heptane (5.4 kg, ~8 L), the crude product obtained from the previous operation was separated by column chromatography, eluting with a mixture of n-heptane and ethyl acetate (1:1 v/v, 15.5 kg, ~20 l; 1:2 v/v, 28.5 kg, ~35 l; 1:5 v/v, 25.5 kg, ~25 l) and pure ethyl acetate (62 kg, 70 l); Fractions containing the compound of formula I (component A) and cross-component B (control by TLC) were collected.

The fraction containing component A was concentrated using a rotary evaporator until no more reflux condensed; the concentrated residue was transferred to a 2000 ml flask, the solvent was replaced with MTBE (370 g, ~500 ml) until the reflux stopped condensing; MTBE (1330 g, ~1800 ml) was added to the concentrated residue; the system was heated to boiling under reflux and boiled for 1 hour; the system was cooled to room temperature (25-30°C), stirred at room temperature (1 hour); cooled to 5-10°C, stirred at 5-10°C for 2 hours; filtered, the filter cake was washed with MTBE (75 g, ~100 ml); the purity of the washed filter cake, determined by HPLC, was 99.9%; the filter cake was dried under vacuum at 50° C. for 16 hours to obtain 190 g of the compound of formula I with an HPLC purity of 99.9% and a water content of 0.07% by the Karl Fischer method.

The fraction containing component B was concentrated to dryness on a rotary evaporator; the resulting solid was transferred to a 500 ml one-neck flask; the solvent was replaced with MTBE (85 g, ~120 ml) until the reflux stopped condensing; MTBE (200 g, ~300 ml) and methanol (23 g, ~30 ml) were added to the concentrated residue; the system was heated to boiling under reflux and boiled for 1 hour; the system was cooled to room temperature (25-30°C), stirred at room temperature (1 hour); cooled to 5-10°C, stirred at 5-10°C for 1 hour; filtered, the filter cake was washed with MTBE (22 g, ~30 ml); the washed filter cake was dried in vacuo at 50°C for 16 hours to obtain 20 g of a light yellow solid (compound of formula I) with a purity of 99.6%, determined by HPLC.

Example 28 Preparation of a compound of formula I.

The compound of formula II in THF (27.0 g solution containing approximately 5.0 g of the compound of formula II, 1 eq.) prepared in Example 19 was added to the flask, the solvent was replaced with toluene (2x25 ml) and concentrated to approximately 10-15 ml ; the solvent was then changed to THF (25 ml) and concentrated to approximately 10-15 ml; add THF (115 ml) until the solid dissolves and the solution becomes clear; the solution was transferred into a 500 ml three-neck flask; trimethyl ortho-acetate (6.6 g, 3.0 eq.) was added to the system; in a nitrogen atmosphere, the system was heated to boiling under reflux; Pyridine hydrochloride (0.42 g, 0.2 eq.) was added to the same three-neck flask; under a nitrogen atmosphere, the system was heated to 70-75°C (internal temperature) and the reaction was carried out for 12 hours; took a sample and tested it. HPLC showed that 0.19% of the compound of formula II remained in the reaction liquid, and the purity of the compound of formula I was 93.3%.

Example 29 Preparation of a compound of formula I.

The compound of formula II in THF (5.40 kg solution containing approximately 1.0 kg of compound of formula II, 1 eq.) prepared in Example 19 was transferred to the flask, the solvent was replaced with toluene (2 x 4.3 kg) and concentrated to approximately 2 L , then the solvent was changed to THF (4.3 kg) and concentrated to approximately 2 L, after which THF (19 kg) was added, the system was transferred to a 50 L reactor; trimethyl ortho-acetate (1.32 kg, 3.0 eq) was added to the system; in a nitrogen atmosphere, the system was heated to boiling under reflux; added pyridine hydrochloride (85.0 g, 0.2 eq.); under a nitrogen atmosphere, the system was heated to 70-75°C (internal temperature) and the reaction was carried out for 12 hours; took a sample and tested it. HPLC showed that 4.22% of the compound of formula II remained in the reaction liquid; the purity of the compound of formula I was 80.30%; Trimethyl orthoacetate (80 g) and pyridine hydrochloride (5 g) were added to the reaction system, the system was heated to 70-75° C. (internal temperature) under a nitrogen atmosphere, and the reaction was carried out for 5 hours; took a sample and tested it. HPLC showed that 0.56% of the compound of formula II remained in the reaction liquid, and the purity of the compound of formula I was 92.48%.

The reaction liquid from the previous operation was cooled to 25°C, 2.0 kg of water was added; distillation under reduced pressure was carried out at 45±5°C to a volume of 2 l, 2 l of water was added to the rotary evaporating flask, the liquid material from the flask was transferred to the reactor, 5 kg of water was slowly added, stirred at 25°C for 1 hour; 5 kg of water was added to the reactor and stirred at 25°C for 1 hour; 32 g of a 50% potassium carbonate solution was added dropwise to the reactor, the pH of the system was adjusted to 8-9, the system was stirred at 25°C for 1 hour; the liquid material in the reactor was cooled to 10-15°C and stirred for 2 hours; the system was filtered, the filter cake was washed with 2 kg of water and then dried in

- 31 044931 vacuum at 45-55°C for 48 hours to obtain 0.91 kg of the compound of formula I containing water

0.2% (Karl Fischer method), with a purity of 95.71% determined by HPLC, content

85.39% and a yield of 71.4%.

Purification of a compound of formula I.

To a 20 L rotary evaporation flask was added the compound of formula I (0.91 kg) of 95.71% HPLC purity obtained in the previous operation and ethanol (3.6 kg); the system was heated to 50-60°C, stirred at 50-60°C for 30 minutes until the material dissolved and the solution became almost transparent; silica gel (1.82 kg) was added to the above rotary evaporation flask, the system was concentrated under reduced pressure at 50-60°C to form a dry powder; n-heptane (1.82 kg) was added to the above rotary evaporation flask, the system was concentrated and the solvent was replaced at 40-50°C until a dry powder was formed; prepared a suitable cleaned column to which silica gel (11 kg, 200-300 mesh) was added and the column was packed with nitrogen; n-heptane (27 kg) was added to the column and it was packed with nitrogen; a compound of formula I mixed with silica gel, concentrated to dryness in the previous operation, was added to the column; the column was eluted with n-heptane (18 kg), n-heptane/ethyl acetate (1:1 v/v, 72 kg; 1:2 v/v, 158 kg; 1:5 v/v, 142 kg), n -heptane/ethyl acetate (1:5 v/v, 70 kg), n-heptane/ethyl acetate (1:5 v/v, 175 kg) and ethyl acetate (205 kg) successively, collecting fractions containing the compound formula I (component A) and cross component B (control by TLC).

The fraction containing component A was added to a 50 L reactor, the system was concentrated in vacuum at 40-50°C to the minimum volume required for mixing (~6 L); MTBE (5x5.0 kg) was added to the reactor, the system was concentrated by changing the solvent 5 times; MTBE (1.2 kg) was added to the reactor, the system was heated to reflux (50-60°C) and boiled for 1 hour while maintaining the specified temperature; the system was cooled to 20-30°C and stirred (1 hour) while maintaining the specified temperature; the system was cooled to 5-10°C, stirred at 5-10°C for 2 hours; filtered, the filter cake was washed with MTBE (0.25 kg); 0.62 kg of the compound of formula I was obtained with a purity of 100.0% determined by HPLC; the filter cake was dried at 50°C for 16 hours to obtain 0.55 kg of the compound of formula I containing 0.04% water (Karl Fischer method) and a residual amount of Pd <2 ppm.

The fraction containing component B was added to the reaction flask, the system was concentrated in vacuo in a water bath at 45-50°C to the minimum volume required for mixing (approximately 1 l); MTBE (2x1.5 kg) was added to the reaction flask, the system was heated in a water bath at 4550°C, concentrated in vacuum to the minimum volume required for mixing, replacing the solvent twice; MTBE (1.5 kg) and absolute ethanol (0.14 kg) were added to the reaction flask, the system was heated to 50-60°C, stirred for 1 hour; the liquid material in the reaction flask was cooled to 20-25°C, the system was stirred for 1 hour while maintaining the specified temperature; cooled, the temperature of the liquid material in the reaction flask was lowered to 6-10°C, this temperature was maintained and the system was stirred for 2 hours; filtered, the filter cake was washed with MTBE (0.24 kg); added filter cake, MTBE (1.5 kg)/absolute ethanol (0.14 kg) to the reaction flask; the system was mixed, heated to 50-60°C, stirred for 1 hour while maintaining the specified temperature; cooled, the temperature of the liquid material in the reaction flask was reduced to 20-25°C, the specified temperature was maintained and the system was stirred for 1 hour; cooled, the temperature of the liquid material in the reaction flask was reduced to 6-10°C, the specified temperature was maintained and the system was stirred for 2 hours; filtered, the filter cake was washed with MTBE (0.24 kg). 115 g of wet product were obtained with an HPLC purity of 99.8% and a maximum individual impurity content of 0.09%; the wet product was dried in vacuum at a temperature of 45-55°C and at a pressure of <-0.080 MPa for 16 hours; 0.10 kg of the compound of formula I containing 0.08% water (determined by the Karl Fischer method) was obtained, with a purity of 99.8% determined by HPLC, with a maximum individual impurity content of 0.09% and a residual amount of Pd< 2 ppm

Unless otherwise indicated, the compound of formula I, finally purified and obtained in example 27, is used as starting material in the following examples.

Preparation of crystalline form 1 of the compound of formula I.

Example 30.

The wet and crude filter cake product (compound of formula I) obtained in Example 21 was combined, dissolved in methanol (40 ml); Silicon-based metal remover (4.0 g) and activated carbon (1.0 g) were added to the methanol solution, the system was heated to 50°C and stirred for 1 hour; the system was cooled to 10±5°C and stirred at this temperature for 0.5 hours; filtered, the filter cake was washed with MTBE (15 ml); the filter cake was dried in vacuo at 50°C for 16 hours to obtain 2.5 g of an almost colorless solid (compound of formula I) with a purity of 98.4%, determined by HPLC. When tested, the solid was crystalline Form 1 of the compound of formula I. In FIG. 1-4

- 32 044931 shows XPRD diffractogram, DSC thermogram, TGA thermogram and DSP isotherm graph.

Preparation of crystalline Form A hydrochloride of the compound of formula I.

Example 31.

Approximately 50 mg of the compound of formula I was weighed and placed in a small bottle, 2.5 ml of acetone was added, the system was sonicated and heated until the compound was completely dissolved to obtain a solution of the compound of formula I in acetone at a concentration of 20 mg/ml. The bottle with the sample was placed on a magnetic stirrer plate, stirred on a magnetic stirrer and 0.73 ml of hydrochloric acid in acetone was slowly added dropwise (the concentration of hydrochloric acid in acetone was 25 mg/ml), a white precipitate formed, the bottle cap was tightly closed and stirring the system at room temperature for 1 day, then the suspension was centrifuged and the collected solid was dried in vacuum at 40°C overnight to obtain the solid hydrochloride of the compound of formula I. When tested, the solid was crystalline Form A hydrochloride of the compound of formula I. The XPRD diffraction pattern and the DSC thermogram are shown in Fig. 6 and 7.

Preparation of the hydrochloride crystalline form B of the compound of formula I.

Example 32.

Approximately 50 mg of the compound of formula I was weighed and placed in a small bottle, 2.5 ml of ethyl acetate was added, the system was sonicated and heated until the compound was completely dissolved to obtain a solution of the compound of formula I in acetone at a concentration of 20 mg/ml. The bottle with the sample was placed on a magnetic stirrer plate, stirred on a magnetic stirrer and 0.73 ml of hydrochloric acid in ethyl acetate was slowly added dropwise (the concentration of hydrochloric acid in ethyl acetate was 25 mg/ml), a white precipitate formed, the bottle cap was tightly closed and stirring the system at room temperature for 1 day, then the suspension was centrifuged and the collected solid was dried in vacuum at 40°C overnight to obtain the solid hydrochloride of the compound of formula I. When tested, the solid was crystalline form B of the hydrochloride of the compound of formula I. The XPRD diffraction pattern and the DSC thermogram are shown in Fig. 8 and 9.

Preparation of crystalline Form C hydrochloride of the compound of formula I.

Example 33.

mg of the hydrochloride crystal Form A of the compound of formula I obtained in Example 31 was weighed and placed in a small bottle, a suitable amount of methanol was added, the resulting sample suspension was stirred at room temperature overnight, the system was centrifuged to separate the solid and liquid, the solid was collected and dried in vacuo overnight at 40° C. to obtain the solid hydrochloride of the compound of formula I. When tested, the solid was crystalline form C of the hydrochloride of the compound of formula I. The XPRD diffraction pattern and the DSC thermogram are shown in FIG. 10 and 11.

Examples 34-36.

The same crystallization method was used as in Example 33. The solvent was replaced with acetonitrile, n-heptane and methyl ethyl ketone to obtain the hydrochloride crystalline Form C of the compound of formula I. After testing, the XPRD diffraction patterns of the solid compounds obtained in Examples 34-36 were consistent with the diffraction patterns in fig. 10.

Preparation of crystalline form D sulfate of the compound of formula I.

Example 37.

Approximately 50 mg of the compound of formula I was weighed and placed in a small bottle, 2.5 ml of acetone was added, the system was sonicated and heated until the compound was completely dissolved to obtain a solution of the compound of formula I in acetone at a concentration of 20 mg/ml. The bottle with the sample was placed on a magnetic stirrer plate, stirred on a magnetic stirrer and 0.77 ml of a solution of sulfuric acid in acetone was added (the concentration of sulfuric acid in acetone was 25 mg/ml), a white precipitate formed, the bottle cap was tightly closed and stirred system at room temperature for 1 day, then the suspension was centrifuged and the collected solid was dried in vacuum at 40°C overnight to obtain the solid sulfate of the compound of formula I. When tested, the solid was crystalline form D sulfate of the compound of formula I. XPRD X-ray diffraction pattern and DSC thermogram are shown in Fig. 12 and 13.

Preparation of crystalline form E phosphate of the compound of formula I.

Example 38.

Approximately 50 mg of the compound of formula I was weighed and placed in a small bottle, 2.5 ml of ethyl acetate was added, the system was sonicated and heated until the compound was completely dissolved to obtain a solution of the compound of formula I in acetone at a concentration of 20 mg/ml. The bottle with the sample was placed on a magnetic stirrer plate, stirred on a magnetic stirrer and 0.86 ml of a solution of phosphoric acid in acetone was slowly added dropwise (the concentration of phosphoric acid in acetone was 25 mg/ml), a white precipitate formed, the bottle cap was tightly closed The system was capped and stirred at room temperature for 1 day, then the centen suspension was trifuged and the collected solid was dried in vacuo at 40° C. overnight to obtain the solid phosphate of the compound of formula I. When tested, the solid was crystalline form E phosphate of a compound of formula I. In FIG. 14 and 15 show the diffraction pattern

XPRD and DSC thermogram.

A test for the percentage of salt formation of the crystalline phosphate form E of the compound of formula I was carried out using ion chromatography.

Approximately 0.5 g of the phosphate crystal form E of the compound of formula I was weighed and placed in a small liquid phase bottle, completely dissolved in 1 ml of water, and then used as the test solution. The stock (1000 ppm) phosphoric acid standard solution was diluted 10 and 20 times with water to obtain 100 ppm and 50 ppm standard solutions, respectively.

Ion chromatography testing was carried out for the test solution and standard solution, respectively, see table. 16, which describes the test method. A standard curve was constructed in which the peak area of the counterion in the ion chromatogram corresponds to the concentration of the counterion in the standard solution, the concentration of the counterion in each sample was calculated using the external standard method, then the counterion content in the crystalline form E phosphate of the compound of formula I was calculated to determine the percentage of salt formation of the compound of formula I with the corresponding counterion, namely phosphate, in crystalline phosphate form E of the compound of formula I.

Table 16

Determination method using ion chromatography

Device model ICS-2000 + AS40 with auto sampler Chromatographic column lonPac®AS11-NS 4x250 mm Column temperature 30°C Eluent 10 mM KOH solution Flow rate 1.00 ml/min Suppressor Dionex AERS 5004 mm Electric current suppressor 25 mA Duration 15 minutes

In table 17 shows the counterion content of the phosphate crystalline form E of the compound of formula I. To obtain 0.5 g of the phosphate crystalline form E of the compound of formula I, the compound of formula I and phosphoric acid were taken in a molar ratio of 1:1.1 and reacted. The actual measured phosphate anion content of the resulting phosphate was 25.6%, which was basically consistent with the theoretical content of 24.9%. The molar ratio in the resulting salt during salt formation was 1:1.04 (compound of formula I: phosphoric acid).

Table 17

Results of determining the content of counterions in the crystalline form E of phosphate of the compound of formula I

Sample name Counterion at different percentages of salt formation Theoretical content, % Measured counterion content, % Phosphate crystalline form E of the compound of formula I Free base: phosphoric acid = 1:1 when making salt 24.9% 25.6%

Example 39.

mg of the phosphate crystal form E of the compound of formula I obtained in Example 38 was weighed and placed in a small bottle, an appropriate amount of methanol was added, the sample suspension was magnetically stirred at room temperature overnight, the system was centrifuged and the solid was separated from the liquid, solid collected and dried in vacuo overnight at 40° C. to obtain a solid phosphate of the compound of formula I. After testing, the solid was still the crystalline phosphate form E of the compound of formula I. Its XPRO diffraction pattern corresponds to the diffraction pattern in FIG. 14.

Examples 40-42.

The same method was used as in Example 39. The solvent was replaced with acetonitrile, nheptane and methyl ethyl ketone to obtain the phosphate crystalline Form E of the compound of formula I. After testing, the XPRD diffraction patterns of the solid compounds obtained in Examples 40-42 were consistent with the diffraction patterns in FIG. 14.

Preparation of the phosphate crystalline form F of the compound of formula I.

Example 43.

Approximately 500 mg of a compound of formula I was weighed into a small bottle and 20

- 34 044931 ml of acetone, the system was subjected to ultrasonic treatment and heating until the sample was completely dissolved to obtain a solution of the compound of formula I in acetone with a concentration of 25 mg/ml. The sample bottle was placed on a heated magnetic stirrer, and while stirring, 8.57 ml of a solution of phosphoric acid in acetone was added slowly dropwise overnight (the concentration of phosphoric acid in acetone was 25 mg/ml). The suspension was filtered with suction. After filtration, the solid was dried under vacuum at 50°C, collected and placed in a 100 ml glass bottle. Methanol was slowly added dropwise, stirred magnetically at room temperature until the solution became clear, and then the solution was diluted 10-fold with the antisolvent isopropyl acetate. The system was stirred overnight and the suspension was filtered, the solid was dried in vacuo at 50°C to obtain solid phosphate of the compound of formula I. When tested, the solid was the crystalline form F phosphate of the compound of formula I. XPRD diffraction pattern, DSC thermogram, DSP isotherm diagram and The XPRD diffraction pattern after the EAF test is shown in Fig. 16-19.

Preparation of the mesylate crystal form G of the compound of formula I.

Example 44.

Approximately 50 mg of the compound of formula I was weighed and placed in a small bottle, 2.5 ml of acetone was added, the system was sonicated and heated until the compound was completely dissolved to obtain a solution of the compound of formula I in acetone at a concentration of 20 mg/ml. The bottle with the sample was placed on a magnetic stirrer plate, stirred on a magnetic stirrer, and 0.73 ml of a solution of methanesulfonic acid in acetone was slowly added dropwise (the concentration of methanesulfonic acid in acetone was 25 mg/ml), a white precipitate formed, the bottle cap was tightly closed cap and stir the system at room temperature for 1 day, then the suspension was centrifuged and the collected solid was dried in vacuo at 40° C. overnight to obtain the solid mesylate of the compound of formula I. When tested, the solid was crystalline form G mesylate of the compound of formula I The XPRD diffraction pattern, DSC thermogram and DSP isotherm diagram are shown in Fig. 20, 21 and 22.

Preparation of crystalline form H of the hydrobromide of the compound of formula I.

Example 45.

Approximately 50 mg of the compound of formula I was weighed and placed in a small bottle, 2.5 ml of acetone was added, the system was sonicated and heated until the compound was completely dissolved to obtain a solution of the compound of formula I in acetone at a concentration of 20 mg/ml. The bottle with the sample was placed on a magnetic stirrer plate, stirred on a magnetic stirrer, and 1.32 ml of a solution of hydrobromic acid in acetone was slowly added dropwise (the concentration of hydrobromic acid in acetone was 25 mg/ml), a white precipitate formed, the bottle cap was tightly closed cap and stir the system at room temperature for 1 day, then the suspension was centrifuged and the collected solid was dried in vacuum at 40°C overnight to obtain the solid hydrobromide of the compound of formula I. When tested, the solid was the hydrobromide crystalline form H of the compound of formula I The XPRD diffraction pattern and DSC isotherm diagram are shown in Fig. 23 and 24.

Example 46.

mg of the hydrobromide crystal form H of the compound of formula I obtained in Example 46 was weighed and placed in a small bottle, a suitable amount of acetonitrile was added, the sample suspension was stirred magnetically at room temperature overnight, the system was centrifuged and the solid was separated from the liquid, solid collected and dried in vacuo overnight at 40° C. to obtain the solid hydrobromide of the compound of formula I. When tested, the solid was still the hydrobromide crystalline form H of the compound of formula I. The XPRD diffraction pattern corresponds to the diffraction pattern in FIG. 23.

Example 47.

The same method as in Example 46 was used. The solvent was changed to methyl ethyl ketone to obtain the hydrobromide crystalline form H of the compound of formula I. When tested, the XPRD diffraction pattern of the solid compound obtained in Example 47 corresponded to the diffraction pattern in FIG. 23.

Preparation of the hydrobromide crystalline form J of the compound of formula I.

Example 48.

Approximately 50 mg of the compound of formula I was weighed and placed in a small bottle, 2.5 ml of ethyl acetate was added, the system was sonicated and heated until the compound was completely dissolved to obtain a solution of the compound of formula I in ethyl acetate at a concentration of 20 mg/ml. The bottle with the sample was placed on a magnetic stirrer plate, stirred on a magnetic stirrer and 1.32 ml of a solution of hydrobromic acid in ethyl acetate was slowly added dropwise (the concentration of hydrobromic acid in ethyl acetate was 25 mg/ml), a white precipitate formed, the bottle cap was tightly closed The system was closed and stirred at room temperature for 1 day, then the suspension was centrifuged and the collected solid was dried in vacuum at

- 35 044931

40° C. overnight to obtain the solid hydrobromide of the compound of formula I. When tested, the solid was the hydrobromide crystalline form J of the compound of formula I. The XPRD diffraction pattern is shown in FIG. 25.

Preparation of the hydrobromide crystalline form K of the compound of formula I.

Example 49.

mg of the hydrobromide crystalline form H of the compound of formula I obtained in Example 46 was weighed and placed in a small bottle, a suitable amount of n-heptane was added, the sample suspension was stirred on a magnetic stirrer at room temperature overnight, the system was centrifuged, the solid was separated from the liquid, collected and dried overnight under vacuum at 40° C. to obtain the solid hydrobromide of the compound of formula I. When tested, the solid was the hydrobromide crystalline form K of the compound of formula I. An XPRD diffraction pattern, a DSC thermogram, and an EAF isotherm diagram are shown in FIG. 26-29.

Preparation of crystalline form L fumarate of the compound of formula I.

Example 50.

Approximately 50 mg of the compound of formula I was weighed and placed in a small bottle, 2.5 ml of ethyl acetate was added, the system was sonicated and heated until the compound was completely dissolved to obtain a solution of the compound of formula I in ethyl acetate at a concentration of 20 mg/ml. The bottle with the sample was placed on a magnetic stirrer plate, stirred on a magnetic stirrer, and 0.87 ml of a solution of fumaric acid in ethanol was slowly added dropwise (the concentration of fumaric acid in ethanol was 25 mg/ml), a white precipitate formed, the bottle cap was tightly closed Cap and stir the system at room temperature for 1 day, then the suspension was centrifuged and the collected solid was dried in vacuo at 40° C. overnight to obtain solid fumarate of the compound of formula I. When tested, the solid was crystalline form L fumarate of the compound of formula I The XPRD diffraction pattern and DSC thermogram are shown in Fig. 30 and 31.

Example 51.

The same crystallization method was used as in Example 50. Ethyl acetate was replaced by acetone to obtain the L fumarate crystalline form of the compound of formula I. When tested, the XPRD diffraction pattern of the solid compound obtained in Example 51 corresponded to the diffraction pattern in FIG. thirty.

Preparation of benzenesulfonate crystalline form M of the compound of formula I.

Example 52.

Approximately 50 mg of the compound of formula I was weighed and placed in a small bottle, 2.5 ml of acetone was added, the system was sonicated and heated until the compound was completely dissolved to obtain a solution of the compound of formula I in acetone at a concentration of 20 mg/ml. The bottle with the sample was placed on a magnetic stirrer plate, stirred on a magnetic stirrer, and 1.34 ml of a solution of benzenesulfonic acid in acetone was slowly added dropwise (the concentration of benzenesulfonic acid in acetone was 25 mg/ml), a white precipitate formed, the bottle cap was tightly closed The system was capped and stirred at room temperature for 1 day, then the suspension was centrifuged and the collected solid was dried in vacuo at 40° C. overnight to obtain the benzene sulfonate solid of the compound of formula I. When tested, the solid was the benzene sulfonate crystalline form of the compound of formula I The XPRD diffraction pattern, DSC thermogram and DSP isotherm diagram are shown in Fig. 32-35.

Preparation of the N citrate crystalline form of the compound of formula I.

Example 53.

Approximately 50 mg of the compound of formula I was weighed and placed in a small bottle, 2.5 ml of ethyl acetate was added, the system was sonicated and heated until the compound was completely dissolved to obtain a solution of the compound of formula I in ethyl acetate at a concentration of 20 mg/ml. The bottle with the sample was placed on a magnetic stirrer plate, stirred on a magnetic stirrer and 1.58 ml of a solution of citric acid in ethyl acetate was slowly added dropwise (the concentration of citric acid in ethyl acetate was 25 mg/ml), a white precipitate formed, the bottle cap was tightly closed cap and stir the system at room temperature for 1 day, then the suspension was centrifuged and the collected solid was dried in vacuum at 40°C overnight to obtain solid citrate of the compound of formula I. When tested, the solid was the N citrate crystalline form of the compound of formula I The XPRD diffraction pattern and DSC thermogram are shown in Fig. 36 and 37.

Preparation of the O tartrate crystalline form of the compound of formula I.

Example 54.

Approximately 50 mg of the compound of formula I was weighed and placed in a small bottle, 2.5 ml of ethyl acetate was added, the system was sonicated and heated until the compound was completely dissolved to obtain a solution of the compound of formula I in ethyl acetate at a concentration of 20 mg/ml. The bottle with the sample was placed on a magnetic stirrer plate, stirred on a magnetic stirrer, and 1.12 ml of a solution of L-(+)-tartaric acid in ethyl acetate was slowly added dropwise (concentration of E-(+)-tartaric acid in ethyl acetate was 25 mg/ml), a white precipitate formed, the bottle cap was tightly closed and the system was stirred at room temperature for 1 day, then the suspension was centrifuged and the collected solid was dried in vacuum at 40°C overnight to obtain solid b- (+)-tartrate of the compound of formula I. When tested, the solid was the O tartrate crystalline form of the compound of formula I. An XPRD diffraction pattern, a DSC thermogram, a TGA thermogram, an EAF isotherm plot, and an XPRD diffraction pattern after the EAF test are shown in FIG. 38-42.

A test for the percentage of salt formation of the O tartrate crystalline form of the compound of formula I was carried out by the 1HNMR method.

Approximately 5 mg of the compound of formula I and the O tartrate crystalline form of the compound of formula I were weighed and placed in an NMR vial, respectively. The samples were dissolved in 0.6 ml DMSO d6 to form a clear solution, and each sample solution was scanned using a Bruker AVANCE 400 MHz nuclear magnetic resonance spectrometer using a general acquisition method for ¹ NMR analysis.

H ¹ NMR spectra showed that the O tartrate crystalline form of the compound of formula I contains one more hydrogen atom than the compound of formula I. Because tartaric acid is a dibasic acid. It can be seen that the molar ratio of free base and tartaric acid in the salt is 2:1. See fig. 43 and 44 for more details.

A test for the percentage of salt formation of the O tartrate crystalline form of the compound of formula I was carried out by chemical titration.

To titrate the sample, a non-aqueous titration apparatus was used, as well as a methanol solution of potassium hydroxide. The content of tartaric acid in the sample was calculated using a formula in accordance with the titrant concentration and the volume of titrant consumed.

Table 18

Blank titration conditions

System Tiamo 2.2 light Electrode pH electrode with 1 M LiCI/EtOH, Metrohm, no. 6.0299.010 T itrator Metrohm 809 Titrando T itrant 0.1 M solution of potassium hydroxide in methanol Titrant volume 1 ml

Table 19

Sample titration conditions

System Tiamo 2.2 light Electrode pH electrode with 1 M LiCI/EtOH, Metrohm, no. 6.0299.010 T itrator Metrohm 809 Titrando T itrant 0.1 M solution of potassium hydroxide in methanol Titrant volume 1 ml Sample concentration 1.25 mg/ml

80 ml of methanol solution was taken and placed in a titration dish, titration was carried out in accordance with the titration conditions for the blank experiment in triplicate. Accurately weighed 160 mg of standard potassium acid phthalate, dried to constant weight at 105°C, added 50 ml of methanol solution, sonicated the system to dissolve, and then transferred to a titration dish and titration was carried out according to the sample titration conditions, in three repetitions. 100 mg of the O tartrate crystalline form of the compound of formula I was accurately weighed, 80 ml of methanol solution was added, the system was sonicated to dissolve and then transferred to a titration dish, and the titration was carried out according to the sample titration conditions in triplicate.

The titrant (T) of the titrant was calculated using the following formula:

IW

W: mass of standard potassium hydrogen phthalate (g).

V: volume of methanol solution of potassium hydroxide consumed for titration of a standard solution of potassium acid phthalate, (ml).

V ₀ : volume of methanol solution of potassium hydroxide consumed for titration of the blank solution, (ml).

M: molecular weight of standard potassium acid phthalate.

The tartaric acid content in the sample was calculated using the following formula:

- 37 044931

T X (V - Ρθ)

Sample ^)=^^^100%

T: titer of calibrated methanol solution of potassium hydroxide, (mol/l).

V: volume of methanolic potassium hydroxide solution used to titrate the sample solution, (ml).

V0: volume of methanolic potassium hydroxide solution used to titrate the blank solution, (ml).

M: molecular weight of tartaric acid W: sample weight, (g).

The final titration results showed that the tartaric acid content of the O tartrate crystalline form of the compound of formula I was 19.2 wt.%, and 21.1 wt.%, respectively, which corresponds to the theoretical value of 20.2 wt.%, that is, when the molar the ratio of free base: tartaric acid is 2:1.

Example 55.

Approximately 500 mg of the compound of formula I was weighed and placed in a small bottle, 20 ml of acetone was added, the system was sonicated and heated until the compound was completely dissolved to obtain a solution of the compound of formula I in acetone at a concentration of 25 mg/ml. The bottle with the sample was placed on a magnetic stirrer plate, stirred on a magnetic stirrer, and 11.2 ml of a solution of L-(+)-tartaric acid in acetone was slowly added dropwise (the concentration of L-(+)tartaric acid in acetone was 25 mg/ml ), the system was stirred overnight, filtered and the solid was dried in vacuo at 50°C to obtain the solid L-(+)-tartrate of the compound of formula I. When tested, the solid was the O tartrate crystalline form of the compound of formula I. The XPRD diffraction pattern corresponds to diffraction pattern in Fig. 38.

Example 56.

To flask No. 1, 2.0 g of the compound of formula I with a purity of 99.9%, determined by HPLC, obtained by purifying component A in example 27, and 40 ml of acetone (20 volumes) were added, the system was stirred until everything was dissolved and the solution did not become transparent; 0.61 g of L-(+)-tartaric acid and 40 ml of acetone (20 volumes) were added to flask No. 2, the system was stirred until everything was dissolved and the solution became clear; the solution from flask No. 2 was added to flask No. 1 over 2-3 minutes; the temperature of the system was increased to 50-60°C, and the system was stirred for 2 hours; the system was cooled to room temperature and concentrated to approximately 40 ml; the system was stirred at room temperature at 25-30°C for 1 hour; the system was cooled to 5-10°C, stirred at 5-10°C for 1 hour; filtered and the filter cake was blown dried at 50-55° C. for 16 hours to obtain 2.4 g of product with an HPLC purity of 99.6% and a yield of 95.6%. When tested, the solid was the O tartrate crystalline form of the compound of formula I. The XPRD diffraction pattern corresponds to the diffraction pattern in FIG. 38.

Example 57.

To flask No. 1, 2.0 g of a compound of formula I with a purity of 99.9%, determined by HPLC, obtained by purifying component A in example 27, and 40 ml of acetone (20 volumes) were added, the temperature was increased to 50-55 ° C, the system was stirred until everything was dissolved and the solution became clear; 0.61 g of L-(+)-tartaric acid and 40 ml of acetone (20 volumes) were added to flask No. 2, the temperature was increased to 50-55°C, the system was stirred until the solution became clear, the solution from flask No. 2 was added into flask No. 1 for 2-3 minutes; the system was stirred at 45-50°C for 2 hours; the system was concentrated in vacuo to approximately 40 ml at 45-50°C; cooled to 20-25°C, stirred for 1 hour; cooled to 5-10°C, stirred at 5-10°C for 1 hour; filtered and the filter cake was blown dried at 50-55° C. for 16 hours to obtain 2.4 g of product with an HPLC purity of 99.8% and a yield of 95.62%. When tested, the solid was the O tartrate crystalline form of the compound of formula I. The XPRD diffraction pattern corresponds to the diffraction pattern in FIG. 38.

Example 58.

To flask No. 1, 36.0 g of a compound of formula I with a purity determined by HPLC of 99.85%, obtained by purifying component A in example 26, and 720 ml of acetone (20 volumes) were added, the temperature was increased to 50-55 ° C , the system was stirred until everything was dissolved and the solution became clear; 11.0 g of L-(+)-tartaric acid and 720 ml of acetone (20 volumes) were added to flask No. 2, the temperature was increased to 50-55°C, the system was stirred until everything was dissolved and the solution became clear ; the solution from flask No. 2 was added to flask No. 1 at a temperature of 45-55°C for 2-3 minutes; the system was stirred at 45-50°C for 2 hours; concentrated in vacuo to approximately 720 ml; cooled to 5-10°C, stirred for 1 hour at 5-10°C; filtered and the filter cake was blown dried at 50-55° C. for 16 hours to obtain 43.6 g of product with an HPLC purity of 99.96% and a yield of 96.6%. When tested, the solid was the O tartrate crystalline form of the compound of formula I. The XPRD diffraction pattern corresponds to the diffraction pattern in FIG. 38.

- 38 044931

Example 59.

To flask No. 1, 189.6 g of the compound of formula I with a purity determined by HPLC of 99.9%, obtained by purifying component A in example 28, and 3792 ml of acetone (20 volumes) were added, the temperature was raised to 50-55 ° C , the system was stirred until everything was dissolved and the solution became clear; 57.6 g of L-(+)-tartaric acid and 3792 ml of acetone (20 volumes) were added to flask No. 2, the temperature was increased to 50-55°C, the system was stirred until everything was dissolved and the solution became clear ; the solution from flask No. 2 was added to flask No. 1 at a temperature of 45-55 ° C; the system was stirred at 45-50°C for 2 hours; concentrated in vacuo to approximately 3800 ml (approximately 20 volumes); cooled to 17-21°C, stirred for 1 hour; cooled to 5-10°C, stirred at 5-10°C for 1 hour; filtered and the filter cake was blown dried at 50-55° C. for 28 hours to obtain 223.2 g of product with an HPLC purity of 99.98% and a yield of 94.0%. When tested, the solid was the O tartrate crystalline form of the compound of formula I. The XPRD diffraction pattern corresponds to the diffraction pattern in FIG. 38.

Example 60.

0.65 kg of the compound of formula I of 100.0% HPLC purity obtained by purifying component A in Example 30 and 7.7 kg of acetone were added to a rotary flask and the flask was spun on a rotary evaporator water bath at 40 -50°C for 1 hour until the solution becomes clear; this clear solution was transferred to RT1 (reactor 1) by nitrogen compression through a pipeline filter to the purification zone; the rotary evaporator flask was washed with 2.6 kg of acetone, and then this washing acetone was transferred to PT1 by compression with nitrogen through a pipeline filter; the volume of the reaction liquid in the reactor in the purification zone was calibrated to 13.0 l; 7.7 kg of acetone and 0.198 kg of L-tartaric acid were added to the rotary evaporator flask, the flask was rotated in a rotary evaporator water bath at 40-50°C for 1 hour until the solution became clear; this clear solution was transferred to RT2 (reactor 2) by compression with nitrogen through a pipeline filter; the rotary evaporator flask was washed with 2.6 kg of acetone, and then this washing acetone was transferred to PT2 by compression with nitrogen through a pipeline filter; the temperature of the liquid material in the reactor was increased to 40-50°C, the material from RT2 was added to reactor RT1 for 1 hour; the temperature of the materials in the reactor was maintained in the range of 40-50°C, the system was stirred and the reaction was carried out for 4 hours; the temperature in the reactor was reduced to 25-35°C; the system was distilled in vacuum at a pressure of <-0.080 MPa to a calibration volume of 13.0 l; the temperature of the liquid material in the reactor was lowered to 15-25°C, and the system was stirred at this temperature for 1 hour, then the temperature in the reactor was lowered to 0-10°C; the temperature in the reactor was maintained in the range of 0-10°C, and the system was stirred for 1 hour; the system was filtered in vacuum, the filter cake was washed with acetone (2.5 kg); samples were collected and analyzed. The purity of the tartrate of the compound of formula I in the filter cake was 99.98% (by HPLC); the maximum content of individual impurities was 0.02%; the filter cake was dried for 24 hours at 45-55°C in vacuum at a pressure of <-0.080 MPa; took samples and analyzed them, the amount of residual acetone was <5000 ppm; the drying cabinet was cooled to 15-25°C; received 0.74 kg of product, took samples and analyzed them. The purity of the tartrate of the compound of formula I according to HPLC was 99.95%; the maximum content of individual impurities was 0.03%; the amounts of residual solvents meet the requirements. Upon further testing, the product was the O tartrate crystalline form of the compound of formula I. The XPRD diffraction pattern corresponds to the diffraction pattern in FIG. 38.

experimental part

Experimental Example 1: Solubility Test.

Weigh out 4 portions of each of the compound of formula I, crystal form 1, phosphate crystal form F of the compound of formula I, and tartrate crystal form O of the compound of formula I, taking an appropriate amount, and each portion is placed in a clear 4 ml glass bottle, add 1 ml of water, artificial gastric fluid (SGF), artificial intestinal fluid in the fasted state (FaSSIF) and artificial intestinal fluid in the fed state (FeSSIF), respectively, to obtain a sample suspension, which was quickly transferred to a shaker (37°C, 200 rpm) and shaken for a certain time. The samples were observed after 5 minutes, some sample or medium was added to form a soft suspension, and samples were taken after 30 minutes, 2 hours, 4 hours and 24 hours, respectively. Samples were centrifuged for 10 min at 12,000 rpm to obtain the supernatant. The supernatant was diluted appropriately and analyzed by high-performance liquid chromatography. Chromatography conditions are shown in table. 20.

- 39 044931

Table 20

Conditions for high performance liquid chromatography when determining solubility

Tool Agilent 1200 DAD HPLC System Chromatographic column Waters XBridge Shield RP184.6x150 mm, 3.5 microns Mobile phase A: 0.1% trifluoroacetic acid solution B: 0.1% solution of trifluoroacetic acid in acetonitrile Column temperature 30°C Detector DMD (DAD) Detection wavelength 230 nm Injection volume 5 µl Column flow rate 1.0 ml/min Duration 15 mn Collection time 15 minutes Elution procedure Time (min) A (%) V (%) 0.0 95 5 7.0 65 35 10.0 5 95 10.1 95 5 15 95 5

The sample concentration was calculated using the external standard method. The test results are presented in table. 21.

Table 21

Solubility results of the compound of formula I crystal form 1, phosphate crystal form F of the compound of formula I and tartrate crystal form O of the compound of formula I in water, SGF, FaSSIF and FeSSIF at different time points

Sample Wednesday Solubility (based on compound of formula I, mg/ml) 30 min 2 hours 4 hours 24 hours Crystal Form 1 of Compound of Formula I Water 1.35 1.73 1.49 1.43 Artificial Gastric Fluid (SGF) 16.40 16.96 15.17 16.41 Artificial fasting intestinal fluid (FaSSIF) 2.59 1.86 1.81 1.56 Artificial intestinal fluid in the fed state (FeSSIF) 2.91 2.20 2.61 3.29 Phosphate crystal form F of the compound of formula I Water 35.73 35.14 36.32 39.53 Artificial Gastric Fluid (SGF) 155.84 176.85 148.76 174.35 Artificial fasting intestinal fluid (FaSSIF) 57.23 79.34 85.21 93.28 Artificial intestinal fluid in the fed state (FeSSIF) 4.22 3.89 3.56 3.64 Crystalline form O tartrate of the compound of formula I Water 12.53 12.11 12.13 12.97 Artificial Gastric Fluid (SGF) 31.18 29.85 33.21 30.22 Artificial fasting intestinal fluid (FaSSIF) 9.95 10.03 10.24 11.36 Artificial intestinal fluid in the fed state (FeSSIF) 4.28 4.31 4.41 3.98

The results showed that the crystalline form F phosphate of the compound of formula I and crystalline

- 40 044931 The O tartrate form of the compound of formula I can significantly exceed the solubility of compound I in water, SGF and FaSSIF. The solubility of the phosphate crystalline form F of the compound of formula I in water, SGF, FaSSIF and FeSSIF at 24 hours was 27.10, 60 and 1 times higher than that of the compound of formula I, respectively; the solubility of the O tartrate crystalline form of the compound of formula I in water, SGF, FaSSIF and FeSSIF at 24 hours was 9, 2, 7 and 1 times higher than that of the compound of formula I, respectively.

Experimental Example 2: Stability Test 1.

Approximately 1 mg of crystalline Form 1 of the compound of Formula I, crystalline Form F of the phosphate of the compound of Formula I, and crystalline Form O of the tartrate of the compound of Formula I were weighed and each sample was placed in a 20 ml transparent glass bottle, respectively, then each sample was placed in a stability test chamber under accelerated degradation conditions (40°C, 75% relative humidity, open) and at high temperature (60°C, closed). For open samples, the bottle cap was removed and the bottle neck was covered with perforated aluminum foil paper to avoid cross-contamination; for unopened samples, bottles were tightly sealed. Samples were taken after 1 and 2 weeks, respectively, the samples were diluted with a diluent (methanol/water 1:1, v/v), and the liquid phase was analyzed in accordance with the chromatographic conditions indicated in Table. 22, and the purity of the samples was determined.

Table 22

Conditions for high-performance liquid chromatography when testing the stability of samples in the solid state

Tool Agilent 1200 DAD HPLC System Chromatographic column WATERS Xbridge C18250x4.6 mm 5 micron Mobile phase A: 20 mM potassium hydrogen phosphate solution; B: methanol Column temperature 40°C Detector DMD (DAD) Detection wavelength 220 nm Injection volume 5.0 µl Column flow rate 1.0 ml/min Duration 35 min Duration after analysis 42 min Sample concentration 0.5 mg/ml Elution procedure Time (min) A (%) V (%) 0 95 5 thirty 25 75 35 25 75

The purity of the samples was calculated using the area normalization method. The test results are presented in table. 23.

Table 23

Stability of the phosphate crystal form 1 of the compound of formula I, the phosphate crystal form F of the compound of formula I, and the tartrate crystal form O of the compound of formula I in the solid state under accelerated degradation conditions

Sample Stability study (purity, area, %) 0 days 60°C 40 °C/75% rel. humid 1 Week 2 weeks Crystal form 1 Week 2 weeks Crystal form Crystal Form 1 of Compound of Formula I 99.80 99.81 99.83 changed 99.82 99.82 changed Phosphate crystal form F of the compound of formula I 99.34 99.32 99.16 without changes 99.33 99.35 without changes Crystalline form O tartrate of the compound of formula I 99.22 99.34 99.36 without changes 99.31 99.36 without changes

- 41 044931

The results showed that the appearance of the compound of Formula I crystal Form 1, phosphate crystal Form F of the compound of Formula I and tartrate crystal Form O of the compound of Formula I did not change over a period of 2 weeks, and they were an almost colorless powder. There were no significant differences in purity and no obvious increase in impurities, indicating good chemical stability over 2 weeks. DPR and DSC tests (FIGS. 45-50) showed that the samples showed no significant differences in the initial crystal forms and initial melting temperatures of the phosphate crystal form F of the compound of formula I and the tartrate crystal form O of the compound of formula I from those after 2 weeks. which indicates good physical stability of the phosphate of the compound of formula I and the tartrate of the compound of formula I at high temperature (60°C) and under accelerated degradation conditions (40°C at 75% relative humidity). The crystalline form 1 of the compound of formula I changed at high temperature (60°C) and under conditions of accelerated degradation (40°C at 75% relative humidity). From the test results of the free base before and after the EAF study, it can be seen that the stability of the crystalline form of the free base was poor.

Experimental Example 3: Stability Test 2.

The O tartrate crystalline form of the compound of formula I was tested using a slurry/solvent equilibrium method, a heat/flash crystallization method, an antisolvent method, and a solvent evaporation and solution crystallization method to determine whether the transformation actually occurred crystals in various solvents and test conditions and to further test their thermodynamic stability.

1. Slow solvent evaporation (EVA) method.

Weighed 5 portions (10 mg/portion) of the O tartrate crystalline form of the compound of formula I obtained in Example 55, and each portion was placed in a sample bottle and added as indicated in the table. 24 quantities of tetrahydrofuran, ethanol, methanol, acetone and isopropanol, the bottles were sonicated to dissolve the samples, the resulting solution was filtered into a new sample bottle with a 0.45 µm nylon membrane, the sample bottle was opened and placed in a fume hood, solvent evaporated naturally at room temperature (about 20-25°C), the precipitated solid was collected. When tested, the resulting solids in these five tests were the O tartrate crystalline form of the compound of Formula I, and their XPRD patterns corresponded to those in FIG. 38.

Table 24

Test conditions and summary of results for the slow solvent evaporation method

Solvent Total solvent volume (ml) Crystal form Tetrahydrofuran 1.8 Crystal form O Ethanol 1.5 Crystal form O Methanol 0.6 Crystal form O Acetone 3.6 Crystal form O Isopropanol 4.8 Crystal form O

2. A method for establishing equilibrium in a suspension/solvent system.

Eighteen portions of crystalline form O tartrate of the compound of formula I were weighed, then to each portion a certain amount of solvent, namely tetrahydrofuran, ethanol, ethyl acetate, n-heptane, toluene, methyl tert-butyl ether, isopropanol, methanol and acetone was added accordingly. specific amounts are listed in Table 25), to obtain two suspension samples for each solvent, the samples were stored in suspension at room temperature and at high temperature (50°C). Sample bottles (wrapped in foil paper to protect from light) at room temperature were placed in a Labquaker rotator for 360° rotation; samples kept at high temperatures were placed in a thermostatic shaker at 50°C and suspended, a portion of the samples was taken on days 3, 7 and 14, respectively, and centrifuged, the solid residue was collected, the solvents were evaporated at room temperature (20-25°C ) to dryness, solids collected. When tested, the resulting solids were the O tartrate crystalline form of the compound of Formula I and their XPRD patterns corresponded to those in FIG. 38.

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34.5 T ethrahydrofuran 1 Crystal form O 28.1 Ethanol 1 Crystal form O 23.1 Ethyl acetate 1 Crystal form O 22.4 n-heptane 1 Crystal form O 20.0 T oluene 1 Crystal form O 20.3 Methyl tert-butyl ether 1 Crystal form O 30.1 Isopropanol 1 Crystal form O 50.6 Methanol 0.5 Crystal form O 28.9 Acetone 1 Crystal form O

3. Method using anti-solvent.

We weighed 21 proportions of the crystalline form O tartrate of the compound of formula I, and successively added a certain volume of the dissolving solvents given in table. 26, the systems were subjected to ultrasonic treatment for dissolution, the resulting solutions were filtered through a nylon membrane with a pore size of 0.45 μm into a new sample bottle, while stirring on a magnetic stirrer, various antisolvents were slowly added dropwise to each sample bottle, a solvent system in which the solid precipitated, centrifuged, the solid was collected, the solvent was evaporated to dryness at room temperature (20-25°C); a solvent system in which no solid precipitated was stirred for 48 hours. If a solid did not precipitate, the system was stirred in an open bottle until the solid precipitated. When tested, the resulting solids were the O tartrate crystalline form of the compound of Formula I and their XPRD patterns corresponded to those in FIG. 38.

Table 26

Test conditions and summary of results for the antisolvent method

Solvent Crystalline form of the product Anti-solvent Solvent Solvent Volume Ratio (ml:ml) (Antisolvent/ Solvent Solvent) Crystal form O n-heptane Tetrahydrofuran 10/2.2 Ethanol 8.5/1.7 Isopropanol 16.8/4.2 Methanol 5/0.5 Acetone 8/4 T oluene Tetrahydrofuran 20/2.2 Crystal form O Ethanol 8.5/1.8 Isopropanol 25.2/4.2 Methanol 5/0.5 Acetone 24/4 Methyl tert-butyl ether Tetrahydrofuran 20/2.2 Crystal form O Ethanol 17/1.8 Isopropanol 25.2/4.2 Methanol 5/0.5 Acetone 24/4 Ethyl acetate Tetrahydrofuran 20/2.3 Crystal form O Ethanol 17/1.7 Isopropanol 25.2/4.2 Methanol 5/0.5 Acetone 24/4

5. Method of heating and rapid cooling of a solution (HFC).

portions (approximately 20 mg/serving) of the O tartrate crystalline form of the compound of formula I were weighed and placed in sample bottles, and the amounts indicated in Table 1 were added. 27 the amount of tetrahydrofuran, acetone, ethanol, isopropanol and methanol, the sample bottles were placed on a magnetic stirrer with heating, heated until dissolved in a water bath at a temperature of approximately 50°C with the stirrer rotating at a speed of 200 rpm. The temperature was maintained for 15 min, the solution was filtered through a 0.45 µm membrane while hot and transferred to new sample bottles, the bottles were immediately transferred to a -20°C refrigerator and kept overnight, solvent systems, in which a solid precipitated, centrifuged and the solid was collected, the solvent was evaporated at room temperature (20-25°C) to dryness; Solvent systems in which no solid precipitated were placed in a refrigerator at -20°C until a large amount of solid precipitated. In systems with tetrahydrofuran and acetone, solid did not precipitate at all times. When tested, the resulting solids from the ethanol, isopropanol and methanol systems were the O tartrate crystalline form of the compound of Formula I and their XPRD patterns corresponded to those in FIG. 38.

Table 27

Test conditions and summary of results for the method of heating and rapidly cooling the solution

Solvent Solvent volume (ml) Crystal form T ethrahydrofuran 1.5 / Acetone 2.0 / Ethanol 0.8 Crystal form O Isopropanol 2.0 Crystal form O Methanol 0.3 Crystal form O

6. Method of heating and slow cooling of a solution (HSC).

portions (approximately 20 mg/serving) of the O tartrate crystalline form of the compound of Formula I were weighed and placed in sample bottles, and the following was added in Table 1. 28 the amount of tetrahydrofuran, acetone, ethanol, isopropanol and methanol, the sample bottles were placed on a magnetic stirrer with heating, heated until dissolved in a water bath at a temperature of approximately 50°C with the stirrer rotating at 200 rpm. The temperature was maintained for 15 min, the solution was filtered through a 0.45 µm membrane while hot and transferred to new sample bottles, slowly cooled to room temperature at a rate of 6°C/h overnight, the sample bottles were placed in refrigerator (2-8°C), solvent systems in which the solid precipitated, centrifuged, the solid was collected, the solvent was evaporated at room temperature (20-25°C) to dryness; Solvent systems in which no solid precipitated were kept in a refrigerator at -20°C until a large amount of solid precipitated. In systems with tetrahydrofuran, acetone and methanol, solids did not settle at all times. When tested, the resulting solids from the ethanol and isopropanol systems were the O tartrate crystalline form of the compound of Formula I and their XPRD patterns corresponded to those in FIG. 38.

Table 28

Test conditions and summary of results for the method of heating and slowly cooling the solution

Solvent Solvent volume (ml) Crystal form T ethrahydrofuran 1.5 / Acetone 0.3 / Ethanol 2.0 / Isopropanol 0.8 Crystal form O Methanol 2.0 Crystal form O

The above test results showed that after treating the O tartrate crystalline form of the compound of formula I with various methods, including a suspension/solvent equilibrium method, a heating and fast/slow cooling crystallization method, an antisolvent method, and a solvent evaporation and crystallization method,

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Claims (8)

solution, it was still a monocrystalline form O. Crystalline form O tartrate of the compound of formula I is the thermally stable predominant crystalline form. Test 4: TYK2 biochemical test. A suitable amount of compound of formula I was weighed out for the TYK2 biochemical test. The test was performed by Reaction Biology Corp, Malvern, PA (Anastassiadis et al. Nat Biotechnol. 2011; 29(11): 1039-45). The stages are briefly described below. Reagents. Main working buffer solution: 20 mM GEPES (pH 7.5), 10 mM MgCl ₂ , 1 mM EGTA, 0.02% bridge, 0.02 mg/ml BSA, 0.1 mM Na ₃ VO ₄ , 2 mM DTT and 1% DMSO. The required cofactors were added to each kinase reaction. Stages of reaction. 1. Prepare the specified substrate in a freshly prepared basic working buffer solution. 2. Transfer of the required cofactor to the above matrix solution. 3. Transfer of the indicated kinase into the substrate solution with gentle stirring. 4. Transfer the compound of formula I in DMSO to the reaction mixture containing the kinase using the Acoustic technique (Echo 550; nanoliter range), culture for 20 minutes at room temperature. 5. Add ³³ P-ATP (specific activity: 10 µCi/µL) to the reaction mixture to start the reaction. 6. Cultivate at room temperature and carry out the kinase reaction for 2 hours. 7. Applying the reaction to P81 ion exchange paper. 8. Testing kinase activity using the filter binding method. The test results showed that the compound of formula I is also a strong inhibitor of TYK2, and its IC ₅₀ is less than 10 nM. One skilled in the art can understand and make certain modifications or changes to the present invention in accordance with the instructions given herein. These modifications and changes fall within the scope of the claims. CLAIM 1. A method for preparing a compound of formula I, the synthesis scheme of which is as follows: I including the following stages: stage 1: adding ethanol, a compound of formula IV, a compound of formula V and DIPEA (diisopropylethylamine) to the reaction vessel, stirring; heating to a temperature of 65-90°C, maintaining this temperature and stirring overnight; cessation of the reaction and reduction of the temperature in the system to 15-30°C; adding water to the system drop by drop, continuing stirring; filtering and washing the filter cake; drying the filter cake to obtain a compound of formula III; stage 2: adding tetrahydrofuran, the compound of formula III obtained in step 1, and palladium on carbon to the reaction vessel; purging the system with nitrogen and then hydrogen; -45 044931 maintaining the temperature in the range of 20-35°C and stirring for 16-120 hours at a hydrogen pressure of 0.1-1.0 MPa; after completion of the reaction, filtering the reaction liquid and washing the filter cake; combining the filtrate and concentrating to obtain a concentrate of the compound of formula II; stage 3: adding the concentrate of the compound of formula II or the compound of formula II obtained in step 2, trimethyl-ortho-acetate and tetrahydrofuran to the reaction vessel; heating the reaction system in the reaction vessel to the boiling point of tetrahydrofuran; adding pyridine hydrochloride to the reaction vessel, reacting the resulting reaction system for 4-20 hours at a temperature of 50 to 90°C, separating and purifying to obtain the compound of formula I. 2. The method according to claim 1, in which at the above stage 1: the volume-mass ratio (ml/g) of ethanol and the compound of formula IV is from 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 1:11.1:2-3, preferably 1:1.01:2.2; after the start of stirring in a nitrogen atmosphere, the reaction mixture is heated to 65-90°C, preferably to 70-90°C, more preferably to 70-80°C, maintaining the specified temperature and stirring for 5-16 hours, preferably 10-16 hours ; after the reaction stops, reduce the system temperature to 15-25°C; the volume-mass ratio (ml/g) of water added to the system and the compound of formula IV is from 10:1 to 20:1, preferably 15:1; after adding water to the system, stirring is carried out for 2-6 hours, preferably for 4 hours, at a temperature of 0-30°C, preferably 5-15°C, more preferably 5-10°C; the filter cake is washed with an aqueous ethanol solution, wherein the volume ratio (ml/ml) of ethanol and water in said aqueous ethanol solution is from 1:1 to 1:2, preferably from 1:1.5 to 1:2; the volume-mass ratio (ml/g) of the aqueous solution of ethanol and the compound of formula IV is from 2:1 to 10:1, preferably from 2:1 to 5:1, more preferably from 2:1 to 3:1; Drying of the filter cake is carried out in a vacuum or using a blower at a temperature of 45-55°C, preferably at 50°C. 3. Method according to claim 1 or 2, in which at the above stage 2: the volume-mass ratio (ml/g) of tetrahydrofuran and the compound of formula III is from 10:1 to 70:1, preferably from 20:1 to 70:1; palladium on carbon is 5% Pd/C with a moisture content of 50%, the weight ratio of palladium on carbon to the compound of formula III is from 0.15:1 to 0.16:1, preferably 0.15:1; the temperature is maintained at 25-35°C and stirred for 24-96 hours at a hydrogen pressure of 0.5-1.0 MPa; the concentrate of the compound of formula II obtained by combining the filtrate and concentrating is a compound of formula II in tetrahydrofuran, where the volume-weight ratio of tetrahydrofuran and compound of formula II is from 2:1 to 4:1, preferably from 2:1 to 3:1; Preferably, the tetrahydrofuran in which the compound of formula II is dissolved is replaced by ethanol to obtain a compound of formula II in ethanol, wherein the volume/weight ratio of ethanol to the compound of formula II is from 2:1 to 5:1, preferably from 2:1 to 4: 1, more preferably 2:1 to 3:1. 4. Method according to any one of claims 1-3, in which, at the above stage 3: the volume-mass ratio (ml:mg) of tetrahydrofuran and the compound of formula II in the concentrate of the compound of formula II is from 1.5:1 to 5.0:1, or the volume-mass ratio (ml:mg) of tetrahydrofuran and the compound of formula II is from 1.5:1 to 5.0:1; preferably the solvent in the concentrate of the compound of formula II is replaced by toluene, tetrahydrofuran or methyl tert-butyl ether for subsequent steps, preferably the volume/weight ratio (ml/mg) of toluene, tetrahydrofuran or methyl tert-butyl ether used to replace the solvent in the concentrate of the compound of formula II, ranges from 2.0:1 to 4.0:1; preferably the molar ratio of the compound of formula II in the concentrate of the compound of formula II and trimethyl ortho-acetate is from 3.0:1 to 3.5:1; or the molar ratio of the compound of formula II and trimethyl ortho-acetate is from 3.0:1 to 3.5:1; preferably the molar ratio of the compound of formula II in the concentrate of the compound of formula II and pyridine hydrochloride is from 0.2:1 to 0.3:1; or the molar ratio of the compound of formula II and pyridine hydrochloride is from 0.2:1 to 0.3:1; preferably, after adding the concentrate of the compound of formula II or the compound of formula II and trimethyl ortho-acetate and the solvent to the reaction vessel, under a protective nitrogen atmosphere, the reaction mixture is heated in the reaction vessel to the boiling point of the solvent; after adding pyridine hydrochloride to the reactor, in a nitrogen atmosphere, the reaction is carried out