WO2020244349A1 - 呋喃并咪唑并吡啶类化合物的合成方法、多晶型物、及盐的多晶型物 - Google Patents
呋喃并咪唑并吡啶类化合物的合成方法、多晶型物、及盐的多晶型物 Download PDFInfo
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- WO2020244349A1 WO2020244349A1 PCT/CN2020/088122 CN2020088122W WO2020244349A1 WO 2020244349 A1 WO2020244349 A1 WO 2020244349A1 CN 2020088122 W CN2020088122 W CN 2020088122W WO 2020244349 A1 WO2020244349 A1 WO 2020244349A1
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Images
Classifications
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to the field of drug synthesis, in particular to the compound 2-[(2R,5S)-5-[2-methylfuro[3,2-b]imidazo[4, as a selective Jak1/TYK2 kinase inhibitor 5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (hereinafter referred to as compound I or compound of formula I) synthesis method.
- compound I or compound of formula I synthesis method.
- the present invention also relates to the crystal form of the compound of formula I, the crystal form of its salt and their preparation method.
- the present invention also relates to pharmaceutical compositions and pharmaceutical preparations containing the crystal form of the compound of formula I and/or the crystal form of the salt thereof, and the crystal form of the compound of formula I and the crystal form of the salt thereof in the treatment of Jak1/TYK2 related Uses for diseases and conditions.
- Protein kinases represent a large family of proteins that play an important role in regulating various cellular processes and maintaining cell functions. These kinases include at least: non-receptor tyrosine kinases, such as the Janus kinase family (Jak1, Jak2, Jak3, and TYK2); receptor tyrosine kinases, such as platelet-derived growth factor receptor kinase (PDGFR); and serine/threon Amino kinase, such as b-RAF.
- non-receptor tyrosine kinases such as the Janus kinase family (Jak1, Jak2, Jak3, and TYK2)
- receptor tyrosine kinases such as platelet-derived growth factor receptor kinase (PDGFR)
- PDGFR platelet-derived growth factor receptor kinase
- serine/threon Amino kinase such as b-RAF.
- the Janus kinase family contains 4 known family members: Jak1, Jak2, Jak3 and Tyrosine Kinase 2 (TYK2). These cytoplasmic tyrosine kinases are associated with membrane cytokine receptors (such as the common gamma-chain receptor and glycoprotein 130 (gp130) transmembrane protein) (Murray, J. Immunol. 178(5): 2623-2629, 2007 ). Almost 40 cytokine receptors signal through the combination of these 4 Jak family members and their 7 downstream substrates: signal transduction activators of transcription (STAT) family members (Ghoreschi et al., Immunol Rev. 228(l): 273-287, 2009).
- STAT signal transduction activators of transcription
- Cytokines that bind to their receptors initiate Jak activation via mutual and autophosphorylation initiate Jak activation via mutual and autophosphorylation.
- the Jak family kinases in turn phosphorylate cytokine receptor residues, creating binding sites for proteins containing sarcoma homology 2 (SH2) (such as STAT factors and other regulators), which are subsequently activated by Jak phosphorylation.
- SH2 proteins containing sarcoma homology 2
- STAT proteins containing sarcoma homology 2
- the activated STAT enters the nucleus and begins to promote the expression of survival factors, cytokines, chemokines and molecules that promote leukocyte cell trafficking (Schindler et al., J. Biol. Chem. 282(28): 20059-20063, 2007).
- Jak activation also leads to cell proliferation via phosphoinositide 3-kinase (PI3K) and protein kinase B-mediated pathways.
- PI3K phospho
- Jak3 and Jak1 are components of common ⁇ -chain cytokine receptor complexes, and blocking of either of these two inhibits inflammatory cytokines (interleukin (IL)-2,4,7,9,15). And 21) signal transduction (Ghoreschi et al., Immunol. Rev. 228(l):273-287, 2009). In contrast, other pathologically related cytokines (such as IL-6) rely only on Jak1. Therefore, Jak1 blockade inhibits the signal transduction of many pro-inflammatory cytokines (Guschin et al, EMBO J.14(7):1421-1429, 1995).
- the object of the present invention is to provide a method for preparing a compound of formula I (ie, compound I) that is suitable for industrial production with mild reaction conditions, high product yield, high purity, and the synthetic route of the method is as follows:
- the method includes the following steps:
- step 1
- step 2 Add the formula II compound concentrate or formula II compound obtained in step 2 to the reaction vessel, as well as trimethyl orthoacetate and tetrahydrofuran (THF); heat the material system in the reaction vessel until the tetrahydrofuran refluxes; to the reaction vessel Pyridine hydrochloride is added to the pyridine, the obtained material system is incubated and reacted at 50-90°C for 4-20 hours, and the compound of formula I is obtained after separation and purification.
- THF trimethyl orthoacetate and tetrahydrofuran
- step 1 In some embodiments of step 1 above:
- volume-to-mass ratio (mL/g) of ethanol to the compound of formula IV is 5:1 to 20:1, preferably 10:1;
- the molar ratio of the compound of formula IV, the compound of formula V and DIPEA is 1:1 ⁇ 1.1:2 ⁇ 3, preferably 1:1.01:2.2;
- the volume-to-mass ratio (mL/g) of the water dropped into the system and the compound of formula IV is 10:1 to 20:1, preferably 15:1;
- the filter cake is washed with an aqueous ethanol solution.
- the volume ratio of ethanol to water (mL/mL) in the ethanol aqueous solution is 1:1 to 1:2, preferably 1:1.5 to 1:2; the volume of the ethanol aqueous solution and the compound of formula IV
- the mass ratio (mL/g) is 2:1 to 10:1, preferably 2:1 to 5:1, more preferably 2:1 to 3:1;
- the filter cake is dried in vacuum or blown air at 45-55°C, preferably 50°C.
- step 2 In some embodiments of step 2 above:
- the volume-to-mass ratio (mL/g) of tetrahydrofuran to the compound of formula III is 10:1 to 70:1, preferably 20:1 to 70:1;
- Palladium on carbon is 5% Pd/C, 50% wet palladium on carbon, and the mass ratio (g/g) of palladium on carbon to the compound of formula III is 0.15:1 to 0.16:1, preferably 0.15:1;
- the filter cake was washed with tetrahydrofuran, and the filtrate was combined and concentrated to obtain the formula II compound concentrate as the tetrahydrofuran solution of the formula II compound, wherein the volume mass ratio (mL/g) of the tetrahydrofuran used for washing to the formula II compound was 2:1 to 4:1, preferably 2:1 to 3:1 (the mass of the compound of formula II obtained in step 2 according to 100% yield); preferably, the tetrahydrofuran solution of the compound of formula II is replaced with ethanol to obtain the ethanol of the compound of formula II A solution in which the volume-to-mass ratio (mL/g) of ethanol to the compound of formula II is 2:1 to 5:1, preferably 2:1 to 4:1, more preferably 2:1 to 3:1 (step 2 is 100% The mass of the compound of formula II obtained after yield conversion).
- the volume mass ratio (mL/g) of the tetrahydrofuran used for washing to the formula II compound was 2:1 to 4:1, preferably 2:1 to 3:1 (the mass of the compound of formula II
- the volume-to-mass ratio (mL:mg) of the compound of formula II in the compound of formula II concentrate is 1.5:1 to 5.0:1; or in some embodiments of step 3 above, tetrahydrofuran
- the volume-to-mass ratio (mL:mg) of the compound of formula II is 1.5:1 to 5.0:1.
- the compound concentrate of formula II is replaced with toluene, tetrahydrofuran or methyl tert-butyl ether and then used in the subsequent steps; in some embodiments, the toluene, tetrahydrofuran or The volume-to-mass ratio (mL:mg) of methyl tert-butyl ether to the concentrate of formula II compound is 2.0:1 to 4.0:1;
- the molar ratio of the compound of formula II to trimethyl orthoacetate in the compound concentrate of formula II is 3.0:1 to 3.5:1; or in some embodiments of the above step 3, the compound of formula II The molar ratio with trimethyl orthoacetate is 3.0:1 to 3.5:1;
- the molar ratio of the compound of formula II to pyridine hydrochloride in the compound concentrate of formula II is 0.2:1 to 0.3:1; or in some embodiments of step 3 above, the compound of formula II and The molar ratio of pyridine hydrochloride is 0.2:1 to 0.3:1;
- the material system in the reactor is heated to the reflux of the solvent ;
- the product is purified using one or more of water, methanol, ethanol and methyl tert-butyl ether.
- the obtained compound of formula I is vacuum dried or air-dried at 50-55°C.
- Another object of the present invention is to provide a crystalline form of the compound of formula I, which is referred to as crystalline form 1 of the compound of formula I herein.
- the X-ray powder diffraction pattern of the crystal form 1 of the formula I compound of the present invention has characteristic peaks at 2theta (2 ⁇ ) values of 13.4° ⁇ 0.2°, 17.6° ⁇ 0.2°, and 21.9° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the crystal form 1 of the compound of formula I has a 2theta value of 9.0° ⁇ 0.2°, 13.4° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.1° ⁇ 0.2°, 21.9° ⁇ 0.2 °, 27.3° ⁇ 0.2° has characteristic peaks.
- the X-ray powder diffraction pattern of the crystalline form 1 of the compound of formula I has a 2theta value 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°, 27.3° ⁇ 0.2° have characteristic peaks.
- XRPD X-ray powder diffraction
- DSC differential scanning calorimetry
- the thermal weight loss analysis (TGA) spectrum of the crystal form 1 of the compound of formula I of the present invention is shown in FIG. 3.
- the TGA chart shows that the crystalline form 1 of the formula I compound of the present invention only has a weight loss of 0.42% when heated from 25°C to 162°C, and the crystalline form 1 of the formula 1 compound does not contain crystal water or solvent.
- the dynamic moisture adsorption (DVS) spectrum of the crystal form 1 of the compound of formula I of the present invention is shown in FIG. 4.
- the DVS spectrum shows that the crystalline form 1 of the compound of formula I of the present invention has a moisture absorption weight increase of 13.86% from 0%RH-95%RH, indicating that the sample has a certain hygroscopicity.
- the present invention provides a method for preparing crystal form 1 of the compound of formula I, which is specifically as follows:
- the crude compound of formula I is dissolved in methanol, stirred at 50°C for 1 hour, cooled to 10°C, and stirred for 0.5h, filtered, the filter cake is rinsed with MTBE, and the filter cake is vacuum dried at 50°C In 16 hours, crystal form 1 of the compound of formula I was obtained.
- the volume ratio of methanol to MTBE is 3:1-2:1, preferably 8:3.
- the silicon-based metal scavenger and activated carbon are added to the system.
- Another object of the present invention is to provide the crystalline form of the compound salt of formula I, specifically the crystalline form of the compound of formula I hydrochloride, the crystalline form of sulfate, the crystalline form of phosphate, the crystalline form of methanesulfonate, the hydrobromide
- the crystal form of acid salt, the crystal form of fumarate, the crystal form of benzenesulfonate, the crystal form of citrate, the crystal form of L-(+)-tartaric acid (referred to as tartaric acid in this application) salt are described herein They are respectively referred to as formula I compound hydrochloride crystal form A, hydrochloride crystal form B, hydrochloride crystal form C, sulfate crystal form D, phosphate crystal form E, phosphate crystal form F, methanesulfonate Salt crystal form G, hydrobromide crystal form H, hydrobromide crystal form J, hydrobromide crystal form K, fumarate crystal form L, benzenesulfon
- the X-ray powder diffraction pattern of the hydrochloride crystal form A of the compound of formula I of the present invention has characteristic peaks at 2theta values of 7.3° ⁇ 0.2°, 12.1° ⁇ 0.2°, and 20.9° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the hydrochloride salt form A of the compound of formula I has a 2theta value of 7.3° ⁇ 0.2°, 12.1° ⁇ 0.2°, 18.7° ⁇ 0.2°, 20.9° ⁇ 0.2°, 23.5 There are characteristic peaks at ° ⁇ 0.2° and 24.0° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the compound of formula I hydrochloride crystalline form A has a 2theta value of 7.3° ⁇ 0.2°, 10.6° ⁇ 0.2°, 12.1° ⁇ 0.2°, 12.8° ⁇ 0.2°, 14.0 There are characteristic peaks at ° ⁇ 0.2°, 18.7° ⁇ 0.2°, 20.9° ⁇ 0.2°, 23.5° ⁇ 0.2°, 24.0° ⁇ 0.2°.
- the present invention provides a method for preparing the hydrochloride crystal form A of the compound of formula I, which is specifically as follows:
- the compound of formula I is dissolved in acetone to obtain the acetone solution of the compound of formula I, the acetone solution of hydrochloric acid is added to the acetone solution of the compound of formula I under stirring, the stirring is continued, the solid is collected, and dried to obtain the compound of formula I hydrochloric acid Salt crystal form A.
- the compound of formula I is dissolved in acetone under ultrasonic heating.
- the concentration of the acetone solution of the compound of formula I is 10-50 mg/mL, preferably 20 mg/mL.
- the concentration of the acetone solution of hydrochloric acid is 15-35 mg/mL, preferably 25 mg/mL.
- stirring is continued at room temperature for 4 to 48 hours, preferably 24 hours.
- the solid is collected by centrifugation and dried under vacuum at 30-60°C overnight.
- the X-ray powder diffraction pattern of the hydrochloride crystal form B of the compound of formula I of the present invention has characteristic peaks at 2theta values of 7.2° ⁇ 0.2°, 20.0° ⁇ 0.2°, and 22.6° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the hydrochloride salt form B of the compound of formula I has a 2theta value of 7.2° ⁇ 0.2°, 10.2° ⁇ 0.2°, 11.5° ⁇ 0.2°, 18.0° ⁇ 0.2°, 20.0 There are characteristic peaks at ° ⁇ 0.2°, 22.6° ⁇ 0.2°, and 25.9° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the hydrochloride salt form B of the compound of formula I has a 2theta value of 7.2° ⁇ 0.2°, 10.2° ⁇ 0.2°, 11.5° ⁇ 0.2°, 14.1° ⁇ 0.2°, 14.5 There are characteristic peaks at ° ⁇ 0.2°, 18.0° ⁇ 0.2°, 20.0° ⁇ 0.2°, 22.6° ⁇ 0.2°, and 25.9° ⁇ 0.2°.
- the present invention provides a method for preparing the hydrochloride crystal form B of the compound of formula I, which is specifically as follows:
- the compound of formula I was dissolved in ethyl acetate to obtain the ethyl acetate solution of the compound of formula I, and the ethyl acetate solution of hydrochloric acid was added to the ethyl acetate solution of the compound of formula I under stirring, the stirring was continued, and the solid was collected. After drying, crystal form B of the hydrochloride salt of the compound of formula I is obtained.
- the compound of formula I is dissolved in ethyl acetate by ultrasonic heating.
- the concentration of the ethyl acetate solution of the compound of formula I is 10-30 mg/mL, preferably 20 mg/mL.
- the concentration of the ethyl acetate solution of hydrochloric acid is 15-35 mg/mL, preferably 25 mg/mL.
- stirring is continued at room temperature for 4-48 hours, preferably 24 hours.
- the solid is collected by centrifugation and dried under vacuum at 30-60°C overnight.
- the X-ray powder diffraction pattern of the hydrochloride salt crystal form C of the formula I compound of the present invention has characteristic peaks at 2theta values of 10.7° ⁇ 0.2°, 21.5° ⁇ 0.2°, and 24.3° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the crystalline form C of the compound of formula I hydrochloride has a 2theta value of 5.3° ⁇ 0.2°, 10.7° ⁇ 0.2°, 21.5° ⁇ 0.2°, 24.3° ⁇ 0.2°, 30.4 There is a characteristic peak at ⁇ 0.2°.
- the hydrochloride crystal form A of the compound of formula I of the present invention is recrystallized or transformed with a solvent to obtain the hydrochloride crystal form C of the compound of formula I of the present invention, wherein the solvent is selected from the group consisting of methanol, acetonitrile, n-heptane and methyl ethyl ketone One or more.
- the solvent is mixed with the hydrochloride crystal form A of the compound of formula I to prepare a suspension, stirred at room temperature, the solid is collected, and dried to obtain the hydrochloride crystal form C of the compound of formula I.
- the solvent is added to the container containing the hydrochloride crystal form A of the compound of formula I, prepared as a suspension, stirred at room temperature, the solid is collected, and dried to obtain the hydrochloric acid of the compound of formula I Salt crystal form C.
- the duration of the stirring is 4 to 48 hours, preferably 24 hours.
- the solid is collected by centrifugation and dried under vacuum at 30-60°C overnight.
- the X-ray powder diffraction pattern of the sulfate crystal form D of the compound of formula I of the present invention has characteristic peaks at 2theta values of 6.0° ⁇ 0.2°, 22.8° ⁇ 0.2°, and 25.2° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the crystalline form D of the compound of formula I sulfate salt has a 2theta value of 6.0° ⁇ 0.2°, 12.3° ⁇ 0.2°, 17.5° ⁇ 0.2°, 22.8° ⁇ 0.2°, 25.2° There is a characteristic peak at ⁇ 0.2°.
- the present invention provides a preparation method of the compound of formula I sulfate salt crystal form D, which is specifically as follows:
- the compound of formula I is dissolved in acetone to obtain the acetone solution of the compound of formula I, the acetone solution of sulfuric acid is added to the acetone solution of the compound of formula I under stirring, the stirring is continued, the solid is collected, and dried to obtain the sulfate of the compound of formula I Form D.
- the compound of formula I is dissolved in acetone under ultrasonic heating.
- the concentration of the acetone solution of the compound of formula I is 10-30 mg/mL, preferably 20 mg/mL.
- the concentration of the acetone solution of sulfuric acid is 15-35 mg/mL, preferably 25 mg/mL.
- stirring is continued at room temperature for 4 to 48 hours, preferably 24 hours.
- the solid is collected by centrifugation and dried under vacuum at 30-60°C overnight.
- the X-ray powder diffraction pattern of the phosphate crystal form E of the compound of formula I of the present invention has characteristic peaks at 2theta values of 6.2° ⁇ 0.2°, 15.5° ⁇ 0.2°, 17.4° ⁇ 0.2°, and 24.6° ⁇ 0.2°.
- the DSC chart of the phosphate crystal form E of the compound of formula I of the present invention is shown in FIG. 15.
- the present invention provides a preparation method of the phosphate crystal form E of the compound of formula I, which is specifically as follows:
- the compound of formula I is dissolved in acetone to obtain the acetone solution of the compound of formula I, the acetone solution of phosphoric acid is added to the acetone solution of the compound of formula I under stirring, the stirring is continued, the solid is collected, and dried to obtain the phosphate of the compound of formula I Crystal Form E.
- the compound of formula I is dissolved in acetone under ultrasonic heating.
- the molar ratio of the compound of formula I to the phosphoric acid is 1:1.0-1:1.5.
- the concentration of the acetone solution of the compound of formula I is 10-30 mg/mL, preferably 20 mg/mL.
- the concentration of the phosphoric acid in acetone solution is 15-35 mg/mL, preferably 25 mg/mL.
- stirring is continued at room temperature for 4-48 hours, preferably 24 hours.
- the solid is collected by centrifugation and dried under vacuum at 30-60C overnight.
- the obtained phosphate crystalline form E of the compound of formula I is recrystallized or transformed with a solvent, and the product is still the phosphate crystalline form E of the compound of formula I, wherein the solvent is selected from methanol, acetonitrile, and n-heptane And one or more of methyl ethyl ketone.
- the solvent is mixed with the phosphate crystal form E of the compound of formula I to prepare a suspension, stirred at room temperature, and the solid is collected and dried.
- the duration of stirring is 4-48 hours, preferably overnight.
- the solid is collected by centrifugation and dried under vacuum at 30-60°C overnight.
- the X-ray powder diffraction pattern of the phosphate crystal form F of the formula I compound of the present invention has characteristic peaks at 2theta values of 16.6° ⁇ 0.2°, 17.2° ⁇ 0.2°, and 22.6° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the phosphate crystal form F of the compound of formula I of the present invention has a 2theta value of 11.6° ⁇ 0.2°, 14.8° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.2° ⁇ 0.2°, There are characteristic peaks at 22.6° ⁇ 0.2° and 26.6° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the phosphate crystal form F of the compound of formula I of the present invention has a 2theta value of 11.1° ⁇ 0.2°, 11.6° ⁇ 0.2°, 14.8° ⁇ 0.2°, 16.6° ⁇ 0.2°, There are characteristic peaks at 17.2° ⁇ 0.2°, 21.2° ⁇ 0.2°, 22.6° ⁇ 0.2°, 26.6° ⁇ 0.2°.
- the DSC spectrum of the phosphate crystal form F of the compound of formula I of the present invention is shown in FIG. 17.
- the DSC chart shows that the initial melting point of the phosphate crystal form F of the compound of formula I of the present invention is 198.78°C.
- the DVS spectrum of the phosphate crystal form F of the compound of formula I of the present invention is shown in FIG. 18.
- the DVS chart shows that the phosphate crystal form F of the compound of formula I of the present invention has a moisture absorption weight increase of 6.5% from 0%RH-95%RH. Under the humidity of 85% RH, the weight of the phosphate crystal form F of the compound of formula I increased by 0.72%; under the humidity of 70% RH, the weight of the phosphate crystal form F of the compound of formula I increased by 1.95%. After moisture absorption, the phosphate crystal form F of the compound of formula I did not change (the XRPD pattern after moisture absorption is shown in Figure 19).
- the present invention provides a preparation method of phosphate crystal form F of the compound of formula I, which is specifically as follows:
- the phosphate crystal form E of the compound of formula I is dissolved in the first solvent to obtain the first solvent solution of the phosphate crystal form E of the compound of formula I, an anti-solvent is added, the solid is collected, and dried to obtain the phosphate crystal form F of the compound of formula I ;or
- the first solvent is a solvent that can effectively dissolve the phosphate crystal form E of the compound of formula I, preferably methanol;
- the antisolvent is a solvent that is difficult to dissolve the phosphate crystal form E of the compound of formula I, preferably acetic acid Propyl ester.
- the amount of the first solvent added is an amount that dissolves all the phosphate crystal form E of the compound of formula I.
- the first solvent solution of the phosphate crystal form E of the compound of formula I is diluted 5-15 times, preferably 10 times, using the anti-solvent.
- a small amount of seed crystals of the phosphate crystal form F of the compound of formula I are added until the system is slightly turbid, and then the anti-solvent is added.
- stirring is continued at room temperature for 4-48 hours, preferably 24 hours.
- the solid is collected by centrifugation and dried under vacuum at 30-60°C, preferably 50°C.
- the X-ray powder diffraction pattern of the mesylate salt crystal form G of the compound of formula I of the present invention has characteristic peaks at 2theta values of 8.6° ⁇ 0.2°, 19.9° ⁇ 0.2°, and 24.9° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the mesylate salt form G of the compound of formula I of the present invention has a 2theta value of 8.6° ⁇ 0.2°, 18.1° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.9° ⁇ 0.2 °, 24.0° ⁇ 0.2°, 24.9° ⁇ 0.2° have characteristic peaks.
- the DSC spectrum of the mesylate salt crystal form G of the compound of formula I of the present invention is shown in FIG. 21.
- the DSC spectrum shows that the initial melting point of the mesylate salt form G of the compound of formula I of the present invention is 218.78°C.
- the present invention provides a method for preparing the mesylate crystal form G of the compound of formula I, which is specifically as follows:
- the compound of formula I is dissolved in acetone to obtain the acetone solution of the compound of formula I, the acetone solution of methanesulfonic acid is added to the acetone solution of the compound of formula I under stirring, the stirring is continued, the solid is collected, and dried to obtain the compound of formula I Form G mesylate salt.
- the compound of formula I is dissolved in acetone under ultrasonic heating.
- the concentration of the acetone solution of the compound of formula I is 10-30 mg/mL, preferably 20 mg/mL.
- the concentration of the methanesulfonic acid solution in acetone is 15-35 mg/mL, preferably 25 mg/mL.
- stirring is continued at room temperature for 4-48 hours, preferably 24 hours.
- the solid is collected by centrifugation and dried under vacuum at 30-60°C overnight.
- the X-ray powder diffraction pattern of the hydrobromide salt crystal form H of the compound of formula I of the present invention has characteristic peaks at 2theta values of 7.2° ⁇ 0.2°, 20.7° ⁇ 0.2°, and 24.0° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the hydrobromide salt crystal form H of the compound of formula I of the present invention has a 2theta value of 7.2° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.8° ⁇ 0.2°, 20.7° ⁇ 0.2 °, 24.0° ⁇ 0.2°, there are characteristic peaks.
- the X-ray powder diffraction pattern of the hydrobromide salt crystal form H of the compound of formula I of the present invention has a 2theta value 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°, 27.5° ⁇ 0.2° have characteristic peaks.
- the present invention provides a preparation method of the hydrobromide salt crystal form H of the compound of formula I, which is specifically as follows:
- the compound of formula I is dissolved in acetone to obtain the acetone solution of the compound of formula I, the acetone solution of hydrobromic acid is added to the acetone solution of the compound of formula I under stirring, the stirring is continued, the solid is collected, and dried to obtain the compound of formula I Hydrobromide salt form H.
- the compound of formula I is dissolved in acetone under ultrasonic heating.
- the concentration of the acetone solution of the compound of formula I is 10-30 mg/mL, preferably 20 mg/mL.
- the concentration of the acetone solution of hydrobromic acid is 15-35 mg/mL, preferably 25 mg/mL.
- stirring is continued at room temperature for 4-48 hours, preferably 24 hours.
- the solid is collected by centrifugation and dried under vacuum at 30-60°C overnight.
- the obtained hydrobromide salt crystal form H of the compound of formula I is recrystallized or transformed with a solvent, and the product is still hydrobromide salt crystal form H, wherein the solvent is selected from one of acetonitrile and methyl ethyl ketone. Kind or two kinds.
- the recrystallization or transformation has the following steps:
- acetonitrile and methyl ethyl ketone are added to the container containing the hydrobromide salt crystal form H of the compound of formula I to prepare a suspension, stirred and centrifuged at room temperature, collected the solid, and dried .
- the X-ray powder emission pattern of the hydrobromide salt crystal form J of the compound of formula I of the present invention has characteristic peaks at 2theta values of 6.2° ⁇ 0.2° and 15.0° ⁇ 0.2°.
- the present invention provides a method for preparing the hydrobromide salt crystal form J of the compound of formula I, which is specifically as follows:
- the compound of formula I was dissolved in ethyl acetate to obtain the ethyl acetate solution of the compound of formula I, and the ethyl acetate solution of hydrobromic acid was added to the ethyl acetate solution of the compound of formula I under stirring, and the stirring was continued to collect The solid was dried to obtain the hydrobromide salt crystal form J of the compound of formula I.
- the compound of formula I is dissolved in ethyl acetate by ultrasonic heating.
- the concentration of the ethyl acetate solution of the compound of formula I is 10-30 mg/mL, preferably 20 mg/mL.
- the concentration of the ethyl acetate solution of hydrobromic acid is 15-35 mg/mL, preferably 25 mg/mL.
- stirring is continued at room temperature for 4 to 48 hours, preferably 24 hours.
- the solid is collected by centrifugation and dried under vacuum at 30-60°C overnight.
- the X-ray powder diffraction pattern of the hydrobromide salt crystal form K of the compound of formula I of the present invention has characteristic peaks at 2theta values of 17.1° ⁇ 0.2°, 22.0° ⁇ 0.2°, and 24.2° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the hydrobromide salt crystal form K of the compound of formula I of the present invention has a 2theta value of 17.1° ⁇ 0.2°, 20.1° ⁇ 0.2°, 22.0° ⁇ 0.2°, 22.6° ⁇ 0.2°, 24.2° ⁇ 0.2 °, 28.8° ⁇ 0.2°, there are characteristic peaks.
- the X-ray powder diffraction pattern of the hydrobromide salt crystal form K of the compound of formula I of the present invention has a 2theta value 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°, 28.8° ⁇ 0.2° have characteristic peaks.
- DSC chart of the hydrobromide salt crystal form K of the compound of formula I of the present invention is shown in FIG. 27.
- the DVS spectrum of the hydrobromide salt crystal form K of the compound of formula I of the present invention is shown in FIG. 28.
- the DVS chart shows that the hydrobromide crystal form K of the compound of formula I of the present invention has a moisture absorption weight increase of 11.84% from 0%RH-95%RH, indicating that the sample has certain hygroscopicity.
- the present invention provides a preparation method of the hydrobromide salt crystal form K of the compound of formula I, which is specifically as follows:
- hydrobromide salt crystal form H of the compound of formula I of the present invention is recrystallized or transformed with n-heptane to obtain the hydrobromide salt crystal form K of the compound of formula I.
- the n-heptane is mixed with the hydrobromide salt crystal form H of the compound of formula I to prepare a suspension, stirred at room temperature, the solid is collected, and dried to obtain the hydrobromide salt crystal of the compound of formula I Type K.
- the n-heptane is added to a container containing the hydrobromide salt crystal form H of the compound of formula I, prepared as a suspension, stirred at room temperature, the solid is collected, and dried to obtain formula I Compound hydrobromide salt crystal form K.
- the duration of stirring is 4 to 48 hours, preferably 24 hours.
- the solid is collected by centrifugation and dried under vacuum at 30-60°C overnight.
- the X-ray powder diffraction pattern of the fumarate crystal form L of the compound of formula I of the present invention has characteristic peaks at 2theta values of 6.1° ⁇ 0.2°, 16.3° ⁇ 0.2°, and 26.4° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the fumarate crystal form L of the compound of formula I of the present invention has a 2theta value of 6.1° ⁇ 0.2°, 13.4° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.3° ⁇ 0.2°, 26.4° ⁇ 0.2 ° has a characteristic peak.
- the X-ray powder diffraction pattern of the fumarate crystal form L of the compound of formula I of the present invention has a 2theta value 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°, 26.4° ⁇ 0.2° have characteristic peaks.
- the XRPD pattern of the fumarate salt crystal form L of the compound of formula I of the present invention is shown in FIG. 30.
- the present invention provides a method for preparing the fumarate crystal form L of the compound of formula I, which is specifically as follows:
- the compound of formula I is dissolved in a solvent to obtain a solution of the compound of formula I, and an ethanol solution of fumaric acid is added to the solution of the compound of formula I under stirring, the stirring is continued, the solid is collected, and dried to obtain the compound of formula I fumar Salt crystal form L.
- the compound of formula I is ultrasonically heated and dissolved in a solvent, wherein the solvent is selected from one or two of ethyl acetate and acetone.
- the concentration of the solution of the compound of formula I is 10-30 mg/mL, preferably 20 mg/mL.
- the concentration of the fumaric acid in ethanol is 15-35 mg/mL, preferably 25 mg/mL.
- stirring is continued at room temperature for 4-48 hours, preferably 24 hours.
- the solid is collected by centrifugation and dried under vacuum at 30-60°C overnight.
- the X-ray powder diffraction pattern of the benzenesulfonate crystal form M of the compound of formula I of the present invention has characteristic peaks at 2theta values 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 benzenesulfonate crystal form M of the compound of formula I of the present invention has a 2theta value 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°, 29.8° ⁇ 0.2° have characteristic peaks.
- the X-ray powder diffraction pattern of the benzenesulfonate crystal form M of the compound of formula I of the present invention has a 2theta value 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°, 29.8° ⁇ 0.2° have characteristic peaks.
- the XRPD pattern of the besylate salt crystal form M of the compound of formula I of the present invention is shown in FIG. 32.
- the DSC spectrum of the besylate salt crystal form M of the compound of formula I of the present invention is shown in FIG. 33.
- the DSC spectrum shows that the initial melting point of the crystalline form M of the besylate salt of the formula I compound of the present invention is 198.73°C.
- the DVS spectrum of the besylate salt crystal form M of the compound of formula I of the present invention is shown in FIG. 34.
- the DVS spectrum shows that the besylate crystal form M of the compound of formula I of the present invention has a moisture absorption weight increase of 4.6% from 0%RH-95%RH.
- the benzene sulfonate crystal form M of the formula I compound increased by 0.54% in weight; under 70% RH humidity, the benzene sulfonate crystal form M of the formula I compound increased by 0.97% in weight.
- the crystalline form M of the compound of formula I besylate remains unchanged (the XRPD pattern after moisture absorption is shown in Figure 35).
- the present invention provides a preparation method of besylate crystal form M of the compound of formula I, which is specifically as follows:
- the compound of formula I is dissolved in acetone to obtain the acetone solution of the compound of formula I, the acetone solution of benzenesulfonic acid is added to the acetone solution of the compound of formula I under stirring, the stirring is continued, the solid is collected and dried to obtain the compound of formula I Benzenesulfonate Form M.
- the compound of formula I is dissolved in acetone under ultrasonic heating.
- the concentration of the acetone solution of the compound of formula I is 10-30 mg/mL, preferably 20 mg/mL.
- the concentration of the acetone solution of benzenesulfonic acid is 15-35 mg/mL, preferably 25 mg/mL.
- stirring is continued at room temperature for 4-48 hours, preferably 24 hours.
- the solid is collected by centrifugation and dried under vacuum at 30-60°C overnight.
- the X-ray powder diffraction pattern of the citrate crystal form N of the compound of formula I of the present invention has characteristic peaks at 2theta values of 15.8° ⁇ 0.2°, 17.0° ⁇ 0.2°, and 21.1° ⁇ 0.2°.
- the present invention provides a method for preparing citrate crystal form N of the compound of formula I, which is specifically as follows:
- the compound of formula I was dissolved in ethyl acetate to obtain the ethyl acetate solution of the compound of formula I, and the ethyl acetate solution of citric acid was added to the ethyl acetate solution of the compound of formula I under stirring, and the stirring was continued to collect the solid , Dried to obtain the citrate crystal form N of the compound of formula I.
- the compound of formula I is dissolved in ethyl acetate by ultrasonic heating.
- the concentration of the ethyl acetate solution of the compound of formula I is 10-30 mg/mL, preferably 20 mg/mL.
- the concentration of the ethyl acetate solution of citric acid is 15-35 mg/mL, preferably 25 mg/mL.
- stirring is continued at room temperature for 4-48 hours, preferably 24 hours.
- the solid is collected by centrifugation and dried under vacuum at 30-60°C overnight.
- the X-ray powder diffraction pattern of the tartrate salt crystal form O of the compound of formula I of the present invention has characteristic peaks at 2theta values of 6.3° ⁇ 0.2°, 26.1° ⁇ 0.2°, and 26.9° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the tartrate salt crystal form O of the compound of formula I of the present invention has a 2theta value of 6.3° ⁇ 0.2°, 12.5° ⁇ 0.2°, 15.1° ⁇ 0.2°, 26.1° ⁇ 0.2°, There are characteristic peaks at 26.9° ⁇ 0.2° and 27.5° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the tartrate salt crystal form O of the compound of formula I of the present invention has a 2theta value of 6.3° ⁇ 0.2°, 11.4° ⁇ 0.2°, 12.5° ⁇ 0.2°, 14.1° ⁇ 0.2°, There are characteristic peaks at 14.4° ⁇ 0.2°, 15.1° ⁇ 0.2°, 26.1° ⁇ 0.2°, 26.9° ⁇ 0.2°, 27.5° ⁇ 0.2°.
- the XRPD pattern of the tartrate salt crystal form O of the compound of formula I of the present invention is shown in FIG. 38.
- the DSC spectrum of the tartrate salt crystal form O of the compound of formula I of the present invention is shown in FIG. 39.
- the DSC spectrum shows that the initial melting point of the tartrate salt crystal form O of the compound of formula I of the present invention is 218.80°C.
- the TGA pattern of the tartrate salt crystal form O of the compound of formula I of the present invention is shown in FIG. 40.
- the TGA chart shows that the tartrate salt crystal form O of the formula I compound of the present invention only has a weight loss of 0.05% when heated from 26°C to 120°C, indicating that the tartrate salt crystal form O of the formula I compound does not contain crystal water or solvent.
- the DVS spectrum of the tartrate salt crystal form O of the compound of formula I of the present invention is shown in FIG. 41.
- the DVS chart shows that the tartrate crystal form O of the compound of formula I of the present invention increases moisture by 6.85% from 0%RH-95%RH. Under 80%RH humidity, the tartrate crystal form O of the compound of formula I gained 1.80% in weight. After moisture absorption, the tartrate salt crystal form O of the compound of formula I did not change (the XRPD pattern after moisture absorption is shown in Figure 42).
- the present invention provides a preparation method of tartrate crystal form O of the compound of formula I, which is specifically as follows:
- the compound of formula I is mixed with the first solvent to obtain a solution of the compound of formula I in the first solvent; tartaric acid is mixed with the second solvent to obtain a solution of the second solvent of tartaric acid;
- the solution of the second solvent is added to the solution of the first solvent of the compound of formula I, the temperature is lowered under stirring, and the solid is collected and dried to obtain the tartrate salt crystal form O of the compound of formula I.
- the first solvent and the second solvent are selected from one or two of acetone and ethyl acetate, respectively.
- 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).
- the molar ratio of the compound of formula I to tartaric acid is 2:1.
- the concentration of the acetone solution of the compound of formula I is 15-70 mg/mL, preferably 40-60 mg/mL, more preferably 50 mg/mL.
- the concentration of the acetone solution of tartaric acid is 5-35 mg/mL, preferably 10-25 mg/mL, more preferably 15 mg/mL.
- 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.
- the tartaric acid is mixed with acetone, and the temperature is increased to 40-60°C, preferably 50-55°C, so that the tartaric acid is dissolved.
- the acetone solution of tartaric acid is added to the acetone solution of the compound of formula I at a temperature of 40-60°C, preferably 45-55°C.
- the program cooling is achieved by the following steps:
- the program cooling refers to a step that can make the system cool down in stages and gradually, and keep it in a certain temperature range for a certain period of time.
- the system is stirred at room temperature 35-60°C, preferably 40-60°C for 0.5-3 hours, preferably 1-2 hours, the system is concentrated to 1/of the original volume. 3-2/3, preferably concentrated to 1/2 of the original volume.
- the purity of the compound of formula I is greater than 90%, preferably greater than 95%, more preferably greater than 99%.
- the collected solids are dried for 5-48 hours, preferably 16-28 hours, in a reduced pressure or blast wind box at 40-60°C.
- the present invention also provides the compound of formula I crystal form 1, the compound of formula I hydrochloride crystal form A, the compound of formula I hydrochloride crystal form B, the compound of formula I hydrochloride crystal form C, the compound of formula I sulfate crystal form D.
- the present invention also provides the compound of formula I crystal form 1, the compound of formula I hydrochloride crystal form A, the compound of formula I hydrochloride crystal form B, the compound of formula I hydrochloride crystal form C, the compound of formula I sulfate crystal form D.
- the present invention also provides the compound of formula I crystal form 1, the compound of formula I hydrochloride crystal form A, the compound of formula I hydrochloride crystal form B, the compound of formula I hydrochloride crystal form C, the compound of formula I sulfate salt crystal form D , Formula I compound phosphate crystal form E, Formula I compound phosphate crystal form F, Formula I compound methanesulfonate crystal form G, Formula I compound hydrobromide salt crystal form H, Formula I compound hydrobromide salt crystal form J.
- the temperature involved refers to the internal temperature of the reaction system.
- the actual measured initial melting point will vary to a certain extent depending on the test instrument, heating speed, crystal shape and other parameters; usually, this change is within ⁇ 5°C. Inside.
- Figure 1 is an XRPD pattern of the crystal form 1 of the compound of formula I of the present invention.
- Figure 2 is a DSC chart of the crystal form 1 of the compound of formula I of the present invention.
- Figure 3 is a TGA chart of the crystal form 1 of the compound of formula I of the present invention.
- Figure 4 is a DVS pattern of the crystal form 1 of the compound of formula I of the present invention.
- Figure 5 is an XRPD overlay of the crystal form 1 of the compound of formula I of the present invention before and after the DVS test.
- Figure 6 is the XRPD pattern of the hydrochloride salt crystal form A of the compound of formula I of the present invention.
- Fig. 7 is a DSC chart of the hydrochloride crystal form A of the compound of formula I of the present invention.
- Figure 8 is the XRPD pattern of the hydrochloride crystal form B of the compound of formula I of the present invention.
- Figure 9 is a DSC chart of the crystalline form B of the hydrochloride salt of the compound of formula I of the present invention.
- Figure 10 is the XRPD pattern of the hydrochloride crystal form C of the compound of formula I of the present invention.
- Figure 11 is a DSC chart of the hydrochloride crystal form C of the compound of formula I of the present invention.
- Figure 12 is the XRPD pattern of the crystalline form D of the sulfate salt of the compound of formula I of the present invention.
- Figure 13 is a DSC chart of the crystalline form D of the sulfate salt of the compound of formula I of the present invention.
- Figure 14 is the XRPD pattern of the phosphate crystal form E of the compound of formula I of the present invention.
- Figure 15 is a DSC chart of the phosphate crystal form E of the compound of formula I of the present invention.
- Figure 16 is the XRPD pattern of the phosphate crystal form F of the compound of formula I of the present invention.
- Figure 17 is a DSC chart of the phosphate crystal form F of the compound of formula I of the present invention.
- Figure 18 is a DVS chart of the phosphate crystal form F of the compound of formula I of the present invention.
- Figure 19 is an XRPD overlay of the phosphate crystal form F of the compound of formula I of the present invention before and after DVS test.
- Figure 20 is the XRPD pattern of the mesylate salt crystal form G of the compound of formula I of the present invention.
- Fig. 21 is a DSC chart of the mesylate salt crystal form G of the compound of formula I of the present invention.
- Figure 22 is a DVS spectrum of the mesylate salt crystal form G of the compound of formula I of the present invention.
- Figure 23 is the XRPD pattern of the hydrobromide salt crystal form H of the compound of formula I of the present invention.
- Figure 24 is a DSC chart of the hydrobromide salt crystal form H of the compound of formula I of the present invention.
- Figure 25 is the XRPD pattern of the hydrobromide salt crystal form J of the compound of formula I of the present invention.
- Figure 26 is the XRPD pattern of the hydrobromide salt crystal form K of the compound of formula I of the present invention.
- Figure 27 is a DSC chart of the hydrobromide salt crystal form K of the compound of formula I of the present invention.
- Figure 28 is the DVS spectrum of the hydrobromide salt crystal form K of the compound of formula I of the present invention.
- Figure 29 is an XRPD overlay of the hydrobromide salt crystal form K of the compound of formula I of the present invention before and after DVS test.
- Figure 30 is the XRPD pattern of the fumarate crystal form L of the compound of formula I of the present invention.
- Figure 31 is a DSC chart of the fumarate crystalline form L of the compound of formula I of the present invention.
- Figure 32 is the XRPD pattern of the benzenesulfonate salt crystal form M of the compound of formula I of the present invention.
- Figure 33 is a DSC chart of the benzenesulfonate salt form M of the compound of formula I of the present invention.
- Figure 34 is a DVS spectrum of the benzenesulfonate salt crystal form M of the compound of formula I of the present invention.
- Figure 35 is an XRPD overlay of the benzenesulfonate salt form M of the formula I of the present invention before and after the DVS test.
- Figure 36 is the XRPD pattern of citrate crystal form N of the compound of formula I of the present invention.
- Figure 37 is a DSC chart of the citrate crystal form N of the compound of formula I of the present invention.
- Figure 38 is an XRPD pattern of the tartrate salt crystal form O of the compound of formula I of the present invention.
- Figure 39 is a DSC chart of the tartrate salt crystal form O of the compound of formula I of the present invention.
- Figure 40 is a TGA chart of the tartrate crystal form O of the compound of formula I of the present invention.
- Figure 41 is the DVS spectrum of the tartrate salt crystal form O of the compound of formula I of the present invention.
- Figure 42 is an XRPD overlay of the tartrate salt crystal form O of the compound of formula I of the present invention before and after DVS test.
- Figure 43 is a 1 H NMR spectrum of the crystal form 1 of the compound of formula I of the present invention.
- Figure 44 is the 1 H NMR spectrum of the tartrate salt crystal form O of the compound of formula I of the present invention.
- Figure 45 is an XRPD overlay image of the phosphate crystal form F of the compound of formula I of the present invention placed under high temperature and accelerated conditions for 2 weeks.
- Figure 46 is an XRPD overlay of the tartrate salt crystal form O of the compound of formula I of the present invention placed under high temperature and accelerated conditions for 2 weeks.
- Figure 47 is a DSC overlay of the phosphate crystal form F of the compound of formula I of the present invention placed under high temperature and accelerated conditions for 2 weeks.
- Figure 48 is a DSC overlay of the tartrate salt crystal form O of the compound of formula I of the present invention placed under high temperature and accelerated conditions for 2 weeks.
- Figure 49 is an XRPD overlay of the crystalline form 1 of the compound of formula I of the present invention placed for 2 weeks under high temperature and accelerated conditions.
- Figure 50 is a DSC overlay of the crystalline form 1 of the compound of formula I of the present invention placed under high temperature and accelerated conditions for 2 weeks.
- Post-treatment 1 Take the above-mentioned filtrate (1820g, converted to 100% yield, containing about 40g compound of formula II), use a rotary evaporator to concentrate it to (2-3V, 80-120ml); use ethanol (150ml ⁇ 2 ) Was replaced to (2-3V, 80-120ml); 78 g of ethanol solution of the compound of formula II was obtained, the content was 47.25%, and the content yield was 92.14%.
- Post-treatment 2 Take the above-mentioned filtrate (450 g, which contains about 10 g of the compound of formula II according to 100% yield), and concentrate it to dryness with a rotary evaporator; a total of 10.5 g of brown-red solid is obtained.
- Post-treatment 3 Take the above-mentioned filtrate (450g, equivalent to about 10g of formula II compound) into the flask; use rotation to concentrate it to about 30-40ml (3-4V); use ethanol (50ml ⁇ 2) to replace the remaining concentrated to about 30-40ml (3-4V); a black oily concentrated residue is obtained, and the concentrated residue is directly put into the next reaction.
- the system was cooled to room temperature, the system reaction solution was concentrated by rotary evaporation until almost no distillate flowed out; water (540mL, 10V) was added to the system, and the pH value of the system was adjusted to 9-10 with 4M sodium hydroxide aqueous solution; filtered, and the filter cake in turn Rinse with water (270mL) and MTBE (270mL), the resulting filter cake was vacuum dried at 50°C for 16h to obtain 56g of the crude compound of formula II with a HPLC purity of 96.32%; the resulting crude product was dissolved in 600mL methanol, and silicon-based was added to it.
- the filtrate obtained in the previous step was concentrated to dryness again to obtain about 23g of light yellow solid; MTBE (230mL) was added to it, heated to 50°C, and refluxed for 10 minutes; methanol was added to the system in batches until the total amount of methanol was added The amount is about 30mL, and the material is basically dissolved; the system is cooled to 10-15°C and stirred for 1h; filtered, the filter cake is rinsed with cold MTBE (50mL); the resulting filter cake is vacuum dried at 50°C for 16 hours to obtain 8.7g The off-white solid of the compound of formula I, the HPLC purity is 97.8%.
- the THF solution of the compound of formula II (45 g, containing about 1 g, 1 eq) of the compound of formula II prepared in Example 14 without post-treatment was put into the flask, and the solution was concentrated to 3 mL by rotary evaporation. Toluene (5 mL) was added to the flask, and rotary evaporation was continued to 3 mL. This step was performed twice to obtain a black oily concentrated residue.
- the THF solution of the compound of formula II (450 g, containing about 10.0 g, 1 eq) of the compound of formula II prepared in Example 14 without post-treatment was put into a flask, and the solution was concentrated by rotary evaporation to 20-30 mL. Toluene (50 mL) was added to the flask, and rotary evaporation was continued to 20-30 mL. This step was performed twice to obtain a black oily concentrated residue, which was dissolved in THF (20 mL, 2V).
- reaction solution was cooled to room temperature, and a part of the reaction solution (corresponding to the scale containing 55g compound containing formula II before the reaction) was added to water (110mL, 2V), and then concentrated by rotary evaporation to 110-160mL (2-3V); Slowly add water (400mL, 7V); stir the system at room temperature for 30min, then add water (440mL, 8V), and stir at room temperature (25-30°C) for 30min; use 50% potassium carbonate solution (1.5g (full Solution quality)) Adjust the pH of the system to 8-9; Stir the system at room temperature (25-30°C) for 30min; Cool down to 10-15°C, and stir at 10-15°C for 2h, filter with suction, filter cake with water (100mL) rinsing, drying the filter cake at 50°C for 24h to obtain 55g of crude product of ocher formula I, purity of 96.6%, content of 87.53%, and yield of crude product is 80.4%:
- Concentrate component A by rotary evaporation to about 100 mL, replace the concentrated residue with about 200 mL of methanol twice, then replace it with MTBE (about 200 mL) twice, then add about 300 mL MTBE to it; heat the system to reflux and reflux 1h, then cooled to room temperature (25-30°C), and stirred at room temperature (1h); cooled the system to 5-10°C, and stirred at 5-10°C for 2h, filtered, filter cake with MTBE (30mL) Leaching: The leached filter cake is vacuum dried at 50° C. for 16 hours to obtain 37.6 g of a light yellow solid of the compound of formula I, with an HPLC purity of 99.85% and no impurities with a content of >0.1%.
- the eluted filter cake was vacuum dried at 50° C. for 16 hours to obtain 6 g of a light yellow solid compound of formula I, with an HPLC purity of 99.35% and two impurities with a content of >0.1%.
- the compound of formula I (4.8g), MTBE (50mL) and ethanol (5mL) with a purity of 99.35% were added to the flask, heated to 55-60°C, refluxed for 0.5h, and then cooled to room temperature (25-30°C) ) And stirring at room temperature for 1h; cooling the system to 5-10°C and stirring at 5-10°C for 2h; filtering, the filter cake is rinsed with MTBE (10mL); the rinsed filter cake is heated at 50- Vacuum drying at 55° C. for 16 hours to obtain 4.0 g of the compound of formula I with a purity of 99.75% and no impurities with a content of >0.1%.
- THF solution of the compound of formula II (14.5g, containing about 5.0g of the compound of formula II, 1eq) prepared in Example 14 without post-treatment was put into the flask, and the solution was replaced with toluene (25mL*2) and concentrated To about 10-15mL, continue to replace and concentrate with THF (25mL) to about 10-15mL, add THF (115mL) until the solid is clear, transfer the resulting solution to a 500mL three-necked flask; continue to add three orthoacetic acid to the system Methyl ester (6.6g, 3.0eq); under the protection of nitrogen, heat the system to reflux; add pyridine hydrochloride (0.42g, 0.2eq) to the three-neck flask; under the protection of nitrogen, heat the system to 70 ⁇ Reaction at 75°C (internal temperature) for 15h; sampling and testing, HPLC showed that the compound of formula II in the reaction solution remained 4.0%; add trimethyl orthoacetate (0.5g) and pyridine hydro
- reaction solution obtained in the previous step was cooled to room temperature, 570g of water was added to it, and then rotary evaporated to 600-900mL (2-3V), and then the concentrated residue was transferred into a 10L flask, and 2000g of water (about 7V) was slowly added to it.
- the system was stirred at room temperature for 1 hour, then 2300g of water (about 8V) was added, the system was stirred at room temperature (25-30°C) for 1 hour, and the pH of the system was adjusted to with 50% potassium carbonate solution (8.5g) 8-9; Stir the system at room temperature (25-30°C) for 1 hour; cool the system to 10-15°C, and stir at 10-15°C for 2 hours, filter, and rinse the filter cake with water (500g); The leached filter cake was dried at 50°C for 72 hours, and the water content was sampled.
- the water content KF was determined by Karl Fischer method to be 3.2%, and 252g of crude oily yellow compound I was obtained.
- the HPLC purity was 97.5% and the content was 89.8%.
- the yield of crude product was 72.3%.
- Concentrate component A by rotary evaporation until almost no distillate flows out; transfer the concentrated residue to a 2000mL flask, and replace it with MTBE (370g, ⁇ 500mL) until almost no distillate flows out; add MTBE (1330g, ⁇ 1800mL) to the concentrated residue ; Heat the system to reflux and reflux for 1h; then cool the system to room temperature (25-30°C) and stir at room temperature (1h); cool the system to 5-10°C and stir at 5-10°C 2h; filter, the filter cake is rinsed with MTBE (75g, ⁇ 100mL), the eluted filter cake has a HPLC purity of 99.9%; the filter cake is vacuum dried at 50°C for 16 hours to obtain 190g of the compound of formula I, with a HPLC purity of 99.9% , KF detects the moisture content of 0.07%.
- Concentrate component B by rotary evaporation to dryness, transfer the obtained solid to a 500mL single-necked flask; replace with MTBE (85g, ⁇ 120mL) until almost no distillate flows out; add MTBE (200g, ⁇ 300mL) and methanol to the concentrated residue obtained (23g, ⁇ 30mL); heat the system to reflux and reflux for 1h; cool the system to room temperature (25-30°C) and stir at room temperature (1h); cool the system to 5-10°C and keep it at 5 Stir at -10°C for 1h; filter, and rinse the filter cake with MTBE (22g, ⁇ 30mL); the rinsed filter cake is vacuum dried at 50°C for 16 hours; 20g of the compound of formula I is obtained as a pale yellow solid with a HPLC purity of 99.6 %.
- Example 35 Using the same crystallization method as in Example 33, the solvent was replaced with acetonitrile, n-heptane and methyl ethyl ketone to prepare the hydrochloride crystal form C of the compound of formula I. After testing, the XRPD patterns of the solid compounds prepared in Example 35 to Example 37 are all consistent with FIG. 10.
- the test method is shown in Table 16.
- the standard curve is calculated based on the concentration of the counter ion in the standard sample solution corresponding to the peak area of the counter ion on the ion chromatography, and the external standard method is used to calculate the The concentration of the counter ion is calculated, the content of the counter ion in the phosphate crystal form E of the compound of formula I is calculated, and the salt formation ratio of the compound of formula I and the corresponding counter ion in the phosphate crystal form E of the compound of formula I is determined.
- Example 39 Using the same method as in Example 39, the solvent was replaced with acetonitrile, n-heptane and methyl ethyl ketone to prepare the phosphate crystal form E of the compound of formula I. After testing, the XRPD patterns of the solid compounds prepared in Example 40 to Example 42 are all consistent with FIG. 14.
- the solid is the phosphate crystal form F of the compound of formula I, and its XRPD, DSC and DVS spectra, and the XRPD spectra after DVS testing are shown in Figs. 16-19, respectively.
- Example 48 Using the same method as in Example 46, the solvent was replaced with methyl ethyl ketone to prepare the hydrobromide salt crystal form H of the compound of formula I. After testing, the XRPD pattern of the solid compound prepared in Example 48 is consistent with that in FIG. 23.
- Example 51 Using the same crystallization method as in Example 50, the crystalline form L of the fumarate of the compound of formula I was prepared by replacing ethyl acetate with acetone. After testing, the XRPD pattern of the solid compound prepared in Example 51 is consistent with that in FIG. 30.
- the NMR spectrum shows that the 1 H NMR spectrum of the tartrate salt crystal form O of the compound of formula I has one more hydrogen than that of the compound of formula I. Since tartaric acid is a dibasic acid, it can be seen that the molar ratio of free alkali to tartaric acid is 2:1, see Figure 43 and Figure 44 for details.
- V 0 Blank solution consumes methanol to prepare potassium hydroxide titrant volume (mL)
- T The titer of the calibrated methanol-made potassium hydroxide titrant (mol/L)
- V 0 Blank solution consumes methanol to prepare potassium hydroxide titrant volume (mL)
- sample formula I compound tartrate salt crystal form O contains tartaric acid 19.2w/w% and 21.1w/w%, which is consistent with the theoretical value of 20.2w/w% with a molar ratio of free base: tartaric acid of 2:1. .
- the product formula I compound tartrate HPLC shows purity: 99.95%; maximum single impurities: 0.03%; solvent The residue is qualified.
- the product is the tartrate salt crystal form O of the compound of formula I, and its XRPD pattern is consistent with FIG. 38.
- the solubility of the phosphate crystal form F of the formula I compound in water, SGF, FaSSIF, FeSSIF at 24 hours is 27, 10, 60, and 1 times that of the compound of the formula I, respectively; the tartrate salt crystal form O of the compound of the formula I in water, SGF
- the solubility of FaSSIF, FeSSIF at 24 hours is 9, 2, 7, and 1 times that of the compound of formula I, respectively.
- the compound of formula I tartrate salt crystal form O was tested by suspension equilibrium method, heating-fast/slow cooling crystallization method, anti-solvent method and solution volatilization crystallization method to investigate whether it will undergo crystal transformation under different solvents and test conditions , To further verify its thermodynamic stability.
- the sample bottle of the room temperature system (wrapped in tin foil to avoid light) is placed on a Labquaker rotator for 360° rotation; the sample of the high temperature system is put into a 50°C constant temperature incubation shaker to be beaten, and the parts are taken out at 3 days, 7 days and 14 days. Centrifuge the suspension sample, collect the solid residue, evaporate the solvent to dryness at room temperature (about 20-25°C), collect the solid, and after testing, the solids obtained in the test are all the compound of formula I tartrate crystal form O, and their XRPD patterns are respectively Consistent with Figure 38.
- the above experimental results show that, using different methods including suspension equilibrium method, heating-fast/slow cooling crystallization method, anti-solvent method and solution volatilization crystallization method to process the compound of formula I tartrate salt crystal form O, the product is still a single crystal Type crystal form O.
- the tartrate crystal form O of the compound of formula I is a thermodynamically stable dominant crystal form.
- Basic reaction buffer 20 mM Hepes (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT, 1% DMSO. Add the required cofactors to each kinase reaction separately.
- test results show that the compound of formula I is also a strong TYK2 inhibitor, with an IC 50 of less than 10 nM.
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Abstract
Description
系统 | Tiamo 2.2 light |
电极 | 装填1M LiCl/EtOH的pH‐电极,Metrohm,编号6.0299.010 |
滴定仪 | Metrohm 809 Titrando |
滴定剂 | 0.1mol/L甲醇制氢氧化钾滴定液 |
滴定体积 | 1mL |
系统 | Tiamo 2.2 light |
电极 | 装填1M LiCl/EtOH的pH‐电极,Metrohm,编号6.0299.010 |
滴定仪 | Metrohm 809 Titrando |
滴定剂 | 0.1mol/L甲醇制氢氧化钾滴定液 |
滴定体积 | 1mL |
样品浓度 | 1.25mg/mL |
溶剂 | 溶剂总体积(mL) | 晶型 |
四氢呋喃 | 1.8 | 晶型O |
乙醇 | 1.5 | 晶型O |
甲醇 | 0.6 | 晶型O |
丙酮 | 3.6 | 晶型O |
异丙醇 | 4.8 | 晶型O |
溶剂 | 溶剂体积(mL) | 晶型 |
四氢呋喃 | 1.5 | / |
丙酮 | 2.0 | / |
乙醇 | 0.8 | 晶型O |
异丙醇 | 2.0 | 晶型O |
甲醇 | 0.3 | 晶型O |
溶剂 | 溶剂体积(ml) | 晶型 |
四氢呋喃 | 1.5 | / |
甲醇 | 0.3 | / |
丙酮 | 2.0 | / |
乙醇 | 0.8 | 晶型O |
异丙醇 | 2.0 | 晶型O |
Claims (77)
- 一种制备式I化合物的方法,该方法的合成路线如下:该方法包括以下步骤:步骤1:向反应容器中加入乙醇、式IV化合物、式V化合物和DIPEA,开启搅拌;加热升温至65~90℃,保温搅拌过夜;停止反应,将体系温度降至15~30℃;向体系中滴加水,继续搅拌;过滤,洗涤滤饼;将滤饼干燥,得到式III化合物;步骤2:向反应容器中加入四氢呋喃、步骤1得到的式III化合物及钯炭;将体系用氮气置换,再用氢气置换;在0.1至1.0MPa的氢气压力下及20-35℃温度下,保温搅拌16-120小时;反应结束后,将反应液过滤,洗涤滤饼;合并滤液并浓缩,得到式II化合物浓缩物;步骤3:向反应容器中加入步骤2所得式II化合物浓缩物或者式II化合物,以及原乙酸三甲酯和四氢呋喃(THF);将所述反应容器中物料体系加热至所述四氢呋喃回流;向所述反应容器中加入吡啶盐酸盐,将所得物料体系在50~90℃下保温反应4-20小时,分离纯化后得式I化合物。
- 根据权利要求1所述的方法,在上述步骤1中:乙醇与式IV化合物的体积质量比(mL/g)为5:1至20:1,优选10:1;式IV化合物、式V化合物和DIPEA的摩尔比为1:1~1.1:2~3,优选1:1.01:2.2;开启搅拌后,氮气保护下,加热升温至65~90℃,优选70~90℃,更优选70~80℃,保温搅拌5-16小时,优选10-16小时;停止反应后将体系温度降至15~25℃;向体系中滴加的水与式IV化合物的体积质量比(mL/g)为10:1至20:1,优选15:1;向体系滴加水后在0-30℃下,优选在5-15℃下,更优选在5-10℃下,搅拌2-6小时,优选搅拌4小时;洗涤滤饼是用乙醇水溶液淋洗,乙醇水溶液中乙醇与水的体积比(mL/mL)为1:1至1:2,优选1:1.5至1:2;乙醇水溶液与式IV化合物的体积质量比(mL/g)为2:1至10:1,优选2:1至5:1,更优选2:1至3:1;滤饼在45-55℃,优选50℃下真空干燥或鼓风干燥。
- 根据权利要求1或2所述的方法,在上述步骤2中:四氢呋喃与式III化合物的体积质量比(mL/g)为10:1至70:1,优选20:1至70:1;钯炭为5%Pd/C,50%湿钯炭,钯炭与式III化合物的质量比为0.15:1至0.16:1,优选0.15:1;在0.5-1.0MPa的氢气压力下在25-35℃下,保温搅拌24-96小时;合并滤液并浓缩得到的式II化合物浓缩物为式II化合物的四氢呋喃溶液,其中四氢呋喃与所述式II化合物的体积质量比为2:1至4:1,优选2:1至3:1;优选地,将所述式II化合物的四氢呋喃溶液用乙醇置换得到式II化合物的乙醇溶液,其中乙醇与式II化合物的体积质量比为2:1至5:1,优选2:1至4:1,更优选2:1至3:1。
- 根据权利要求1-3中任一项所述的方法,在上述步骤3中:四氢呋喃与所述式II化合物浓缩物中式II化合物的体积质量比(mL:mg)为1.5:1至5.0:1;或者四氢呋喃与所述式II化合物的体积质量比(mL:mg)为1.5:1至5.0:1;优选地,将所述式II化合物浓缩物用甲苯、四氢呋喃或甲基叔丁基醚置换后用于后续 步骤;优选地,所述用于置换的甲苯、四氢呋喃或甲基叔丁基醚与所述式II化合物浓缩物的体积质量比(mL:mg)为2.0:1至4.0:1;优选地,所述式II化合物浓缩物中式II化合物与原乙酸三甲酯的摩尔比为3.0:1至3.5:1;或者,所述式II化合物与原乙酸三甲酯的摩尔比为3.0:1至3.5:1;优选地,所述式II化合物浓缩物中式II化合物与吡啶盐酸盐的摩尔比为0.2:1至0.3:1;或者,所述式II化合物与吡啶盐酸盐的摩尔比为0.2:1至0.3:1;优选地,向应容器中加入所述式II化合物浓缩物或者式II化合物,以及原乙酸三甲酯和溶剂后,在氮气保护下,将反应器中物料体系加热至溶剂回流;向反应器中加入吡啶盐酸盐后,在氮气保护下,将所得物料体系在50~90℃,优选65-75℃下保温反应4-20小时,优选5-15小时;优选地,反应结束后,使用水、甲醇、乙醇和甲基叔丁基醚中的一种或多种对产物进行纯化;优选地,对得到的式I化合物进行柱层析分离纯化,其中洗脱剂为乙酸乙酯及正庚烷的混合溶液(V EA:V 正庚烷=1:1至1:0mL/mL);优选地,将得到的式I化合物在50~55℃下真空干燥或鼓风干燥。
- 根据权利要求5所述的式I化合物晶型1,其X射线粉末衍射图谱在2theta值为9.0°±0.2°、13.4°±0.2°、17.6°±0.2°、18.1°±0.2°、21.9°±0.2°、27.3°±0.2°处具有特征峰。
- 根据权利要求5或6所述的式I化合物晶型1,其X射线粉末衍射图谱在2theta值为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°、27.3°±0.2°处具有特征峰。
- 一种如权利要求5-7中任一项所述的式I化合物晶型1的制备方法,包括:将式I化合物粗品用甲醇溶解后,在40-60℃搅拌0.5-2h,降温至5-15℃,并搅拌15min-1h,过滤,滤饼以MTBE淋洗,干燥,得到式I化合物晶型1。
- 根据权利要求8所述的制备方法,包括:将所述式I化合物粗品用甲醇溶解后,在50℃搅拌1h,降温至10℃,并搅拌0.5h,过滤,滤饼以MTBE淋洗,将滤饼在50℃下真空干燥16小时,得到式I化合物晶型1;优选地,所述甲醇与MTBE的体积用量比为3:1-2:1,优选8:3;优选地,将所述式I化合物粗品用甲醇溶解后,向体系中加入硅基金属消除剂和活性炭。
- 根据权利要求10所述的式I化合物盐酸盐晶型A,其X射线粉末衍射图谱在2theta值为7.3°±0.2°、12.1°±0.2°、18.7°±0.2°、20.9°±0.2°、23.5°±0.2°、24.0°±0.2°处具有特征峰。
- 根据权利要求10或11所述的式I化合物盐酸盐晶型A,其X射线粉末衍射图谱在2theta值为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°、24.0°±0.2°处具有特征峰。
- 一种权利要求10-12中任一项所述的式I化合物盐酸盐晶型A的制备方法,包括:将式I化合物溶解于丙酮中,得到式I化合物的丙酮溶液,在搅拌下向所述式I化合物的丙酮溶液中加入盐酸的丙酮溶液,继续搅拌,收集固体,干燥,得到式I化合物盐酸盐晶型A。
- 根据权利要求13所述的制备方法,其中,将式I化合物超声加热溶解于丙酮中;优选地,所述式I化合物的丙酮溶液的浓度为10-50mg/mL,优选20mg/mL;优选地,所述盐酸的丙酮溶液的浓度为15-35mg/mL,优选25mg/mL;优选地,在加入盐酸的丙酮溶液之后,在室温下继续搅拌4-48小时,优选24小时;优选地,通过离心收集固体,并于30-60℃下真空干燥过夜。
- 根据权利要求15所述的式I化合物盐酸盐晶型B,其X射线粉末衍射图谱在2theta值为7.2°±0.2°、10.2°±0.2°、11.5°±0.2°、18.0°±0.2°、20.0°±0.2°、22.6°±0.2°、25.9°±0.2°处具有特征峰。
- 根据权利要求15或16所述的式I化合物盐酸盐晶型B,其X射线粉末衍射图谱在2theta值为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°、25.9°±0.2°处具有特征峰。
- 一种如权利要求15-17中任一项所述的式I化合物盐酸盐晶型B的制备方法,包括:将式I化合物溶解于乙酸乙酯中,得到式I化合物的乙酸乙酯溶液,在搅拌下向所述式I化合物的乙酸乙酯溶液中加入盐酸的乙酸乙酯溶液,继续搅拌,收集固体,干燥,得到式I化合物盐酸盐晶型B。
- 根据权利要求18所述的制备方法,其中,将所述式I化合物超声加热溶解于乙酸乙酯中;优选地,所述式I化合物的乙酸乙酯溶液的浓度为10-30mg/mL,优选20mg/mL;优选地,所述盐酸的乙酸乙酯溶液的浓度为15-35mg/mL,优选25mg/mL;优选地,在加入所述盐酸的乙酸乙酯溶液之后,在室温下继续搅拌4-48小时,优选24小时;优选地,通过离心收集固体,并于30-60℃下真空干燥过夜。
- 根据权利要求20所述的式I化合物盐酸盐晶型C,其X射线粉末衍射图谱在2theta值为5.3°±0.2°、10.7°±0.2°、21.5°±0.2°、24.3°±0.2°、30.4±0.2°处具有特征峰。
- 一种如权利要求20或21所述的式I化合物盐酸盐晶型C的制备方法,包括:将式I化合物盐酸盐晶型A以溶剂重结晶或转晶,得到式I化合物盐酸盐晶型C,其中所述溶剂选自甲醇、乙腈、正庚烷和甲乙酮中的一种或多种。
- 根据权利要求22所述的制备方法,其中,将所述溶剂与所述式I化合物盐酸盐晶型A混合,制备成混悬液,室温搅拌,收集固体,干燥,得到式I化合物盐酸盐晶型C;优选地,将所述溶剂加入至盛放有所述式I化合物盐酸盐晶型A的容器中,制备成混悬液,室温搅拌,收集固体,干燥,得到式I化合物盐酸盐晶型C;优选地,所述搅拌的时长为4-48小时,优选24小时;优选地,过离心收集固体,并于30-60℃下真空干燥过夜。
- 根据权利要求24所述的式I化合物硫酸盐晶型D,其X射线粉末衍射图谱在2theta值为6.0°±0.2°、12.3°±0.2°、17.5°±0.2°、22.8°±0.2°、25.2°±0.2°处具有特征峰。
- 一种如权利要求24或25所述的式I化合物硫酸盐晶型D的制备方法,包括:将式I化合物溶解于丙酮中,得到式I化合物的丙酮溶液,在搅拌下向所述式I化合物的丙酮溶液中加入硫酸的丙酮溶液,继续搅拌,收集固体,干燥,得到式I化合物硫酸盐晶型D。
- 根据权利要求26所述的制备方法,其中,所述式I化合物超声加热溶解于丙酮中;优选地,所述式I化合物的丙酮溶液的浓度为10-30mg/mL,优选20mg/mL;优选地,所述硫酸的丙酮溶液的浓度为15-35mg/mL,优选25mg/mL;优选地,在加入所述硫酸的丙酮溶液之后,在室温下继续搅拌4-48小时,优选24小时;优选地,通过离心收集固体,并于30-60℃下真空干燥过夜。
- 一种如权利要求28所述的式I化合物磷酸盐晶型E的制备方法,包括:将式I化合物溶解于丙酮中,得到式I化合物的丙酮溶液,在搅拌下向所述式I化合物的丙酮溶液中加入磷酸的丙酮溶液,继续搅拌,收集固体,干燥,得到式I化合物磷酸盐晶型E。
- 根据权利要求29所述的制备方法,其中,将所述式I化合物超声加热溶解于丙酮中;优选地,所述式I化合物与所述磷酸的摩尔比为1:1.0-1:1.5;优选地,所述式I化合物的丙酮溶液的浓度为10-30mg/mL,优选20mg/mL;优选地,所述磷酸的丙酮溶液的浓度为15-35mg/mL,优选25mg/mL;优选地,在加入磷酸的丙酮溶液之后,在室温下继续搅拌4-48小时,优选24小时;优选地,通过离心收集固体,并于30-60C下真空干燥过夜。
- 根据权利要求29或30所述的制备方法,其中,对所得式I化合物磷酸盐晶型E以溶剂进行重结晶或转晶,产物仍为式I化合物磷酸盐晶型E,其中所述溶剂选自甲醇、乙腈、正庚烷和甲乙酮中的一种或多种;优选地,重结晶或转晶时,将所述溶剂与所述式I化合物磷酸盐晶型E混合,制备成混悬液,室温搅拌,收集固体,干燥;优选地,重结晶或转晶时,所述搅拌的时长为4-48小时,优选搅拌过夜;优选地,重结晶或转晶时,通过离心收集固体,并于30-60℃下真空干燥过夜。
- 根据权利要求32所述的式I化合物磷酸盐晶型F,其X射线粉末衍射图谱在2theta值为11.6°±0.2°、14.8°±0.2°、16.6°±0.2°、17.2°±0.2°、22.6°±0.2°、26.6°±0.2°处具有特征峰。
- 根据权利要求32或33所述的式I化合物磷酸盐晶型F,其X射线粉末衍射图谱在2theta值为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°、26.6°±0.2°处具有特征峰。
- 一种如权利要求32-34中任一项所述的式I化合物磷酸盐晶型F的制备方法,包括:将式I化合物磷酸盐晶型E以第一溶剂溶解,得到式I化合物磷酸盐晶型E的第一溶剂溶液,加入反溶剂,搅拌,收集固体,干燥,得到式I化合物磷酸盐晶型F;优选地,所述第一溶剂为能溶解式I化合物磷酸盐晶型E的溶剂,优选甲醇;所述反溶剂为难于溶解式I化合物磷酸盐晶型E的溶剂,优选乙酸异丙酯;优选地,所述第一溶剂的加入量为使式I化合物磷酸盐晶型E全部溶解的量;优选地,使用所述反溶剂将所述式I化合物磷酸盐晶型E的第一溶剂溶液稀释5-15倍,优选10倍;优选地,将所述式I化合物磷酸盐晶型E以第一溶剂溶解后,加入少量式I化合物磷酸盐晶型F晶种至体系轻微浑浊,再加入所述反溶剂;优选地,加入所述反溶剂后,在室温下继续搅拌4-48小时,优选24小时;优选地,通过离心收集固体,并于30-60℃,优选50℃下真空干燥。
- 根据权利要求36所述的式I化合物甲磺酸盐晶型G,其X射线粉末衍射图谱在2theta值为8.6°±0.2°、18.1°±0.2°、18.6°±0.2°、19.9°±0.2°、24.0°±0.2°、24.9°±0.2°处具有特征峰。
- 一种如权利要求36或37所述的式I化合物甲磺酸盐晶型G的制备方法,包括:将式I化合物溶解于丙酮中,得到式I化合物的丙酮溶液,在搅拌下向所述式I化合物的丙酮溶液中加入甲磺酸的丙酮溶液,继续搅拌,收集固体,干燥,得到式I化合物甲磺酸盐晶型G。
- 根据权利要求38所述的制备方法,其中,将所述式I化合物超声加热溶解于丙酮中;优选地,所述式I化合物的丙酮溶液的浓度为10-30mg/mL,优选20mg/mL;优选地,所述甲磺酸的丙酮溶液的浓度为15-35mg/mL,优选25mg/mL;优选地,在加入所述甲磺酸的丙酮溶液之后,在室温下继续搅拌4-48小时,优选24小时;优选地,通过离心收集固体,并于30-60℃下真空干燥过夜。
- 根据权利要求40所述的式I化合物氢溴酸盐晶型H,其X射线粉末衍射图谱在2theta值为7.2°±0.2°、17.9°±0.2°、18.8°±0.2°、20.7°±0.2°、24.0°±0.2°处具有特征峰。
- 根据权利要求40或41所述的式I化合物氢溴酸盐晶型H,其X射线粉末衍射图谱在2theta值为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°、27.5°±0.2°处具有特征峰。
- 一种如权利要求40-42中任一项所述的制备方法,包括:将式I化合物溶解于丙酮中,得到式I化合物的丙酮溶液,在搅拌下向所述式I化合物的丙酮溶液中加入氢溴酸的丙酮溶液,继续搅拌,收集固体,干燥,得到式I化合物氢溴酸盐晶型H。
- 根据权利要求43所述的制备方法,其中,将所述式I化合物超声加热溶解于丙酮中;优选地,所述式I化合物的丙酮溶液的浓度为10-30mg/mL,优选20mg/mL;优选地,所述氢溴酸的丙酮溶液的浓度为15-35mg/mL,优选25mg/mL;优选地,在加入氢溴酸的丙酮溶液之后,在室温下继续搅拌4-48小时,优选24小时;优选地,通过离心收集固体,并于30-60℃下真空干燥过夜。
- 根据权利要求43或44所述的制备方法,其中,使用溶剂对所得式I化合物氢溴酸盐晶型H进行重结晶或转晶,产物仍为氢溴酸盐晶型H,其中所述溶剂选自乙腈和甲乙酮中的一种或两种;优选地,所述重结晶或转晶具有以下步骤:将乙腈和甲乙酮中的一种或两种与所述式I化合物氢溴酸盐晶型H混合,制备成混悬液,室温搅拌、离心,收集固体,干燥;更优选地,将乙腈和甲乙酮中的一种或两种加入至盛放有所述式I化合物氢溴酸盐晶型H的容器中,制备成混悬液,室温搅拌、离心,收集固体,干燥。
- 一种如权利要求46所述的制备方法,包括:将式I化合物溶解于乙酸乙酯中,得到式I化合物的乙酸乙酯溶液,在搅拌下向所述式I化合物的乙酸乙酯溶液中加入氢溴酸的乙酸乙酯溶液,继续搅拌,收集固体,干燥,得到式I化合物氢溴酸盐晶型J。
- 根据权利要求47所述的制备方法,其中,将所述式I化合物超声加热溶解于乙酸乙酯中;优选地,所述式I化合物的乙酸乙酯溶液的浓度为10-30mg/mL,优选20mg/mL;优选地,所述氢溴酸的乙酸乙酯溶液的浓度为15-35mg/mL,优选25mg/mL;优选地,在加入所述氢溴酸的乙酸乙酯溶液之后,在室温下继续搅拌4-48小时,优选24小时;优选地,通过离心收集固体,并于30-60℃下真空干燥过夜。
- 根据权利要求49所述的式I化合物氢溴酸盐晶型K,其X射线粉末衍射图谱在2theta值为17.1°±0.2°、20.1°±0.2°、22.0°±0.2°、22.6°±0.2°、24.2°±0.2°、28.8°±0.2°处具有特征峰。
- 根据权利要求49或50所述的式I化合物氢溴酸盐晶型K,其X射线粉末衍射图谱在2theta值为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°、28.8°±0.2°处具有特征峰。
- 一种如权利要求49-51中任一项所述的式I化合物氢溴酸盐晶型K的制备方法,包括:将式I化合物氢溴酸盐晶型H以正庚烷重结晶或转晶,得到式I化合物氢溴酸盐晶型K。
- 根据权利要求52所述的制备方法,其中,将所述正庚烷与所述式I化合物氢溴酸盐晶型H混合,制备成混悬液,室温搅拌,收集固体,干燥,得到式I化合物氢溴酸盐晶型K;优选地,将所述正庚烷加入至盛放有所述式I化合物氢溴酸盐晶型H的容器中,制备成混悬液,室温搅拌,收集固体,干燥,得到式I化合物氢溴酸盐晶型K;优选地,所述搅拌的时长为4-48小时,优选24小时;优选地,通过离心收集固体,并于30-60℃下真空干燥过夜。
- 根据权利要求54所述的式I化合物富马酸盐晶型L,其X射线粉末衍射图谱在2theta值为6.1°±0.2°、13.4°±0.2°、15.7°±0.2°、16.3°±0.2°、26.4°±0.2°处具有特征峰。
- 根据权利要求54或55所述的式I化合物富马酸盐晶型L,其X射线粉末衍射图谱在2theta值为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°、26.4°±0.2°处具有特征峰。
- 一种如权利要求54-56中任一项所述的式I化合物富马酸盐晶型L的制备方法,包括:将式I化合物溶解于溶剂中,得到式I化合物的溶液,在搅拌下向所述式I化合物的溶液中加入富马酸的乙醇溶液,继续搅拌,收集固体,干燥,得到式I化合物富马酸盐晶型L。
- 根据权利要求57所述的制备方法,其中,将所述式I化合物超声加热溶解于溶剂中,其中所述溶剂选自乙酸乙酯和丙酮中的一种或两种;优选地,所述式I化合物的溶液的浓度为10-30mg/mL,优选20mg/mL;优选地,所述富马酸的乙醇溶液的浓度为15-35mg/mL,优选25mg/mL;优选地,在加入富马酸的乙醇溶液之后,在室温下继续搅拌4-48小时,优选24小时;优选地,通过离心收集固体,并于30-60℃下真空干燥过夜。
- 根据权利要求59所述的式I化合物苯磺酸盐晶型M,其X射线粉末衍射图谱在2theta值为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°、29.8°±0.2°处具有特征峰。
- 根据权利要求59或60所述的式I化合物苯磺酸盐晶型M,其X射线粉末衍射图谱在2theta值为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°、29.8°±0.2°处具有特征峰。
- 一种如权利要求59-61中任一项所述的式I化合物苯磺酸盐晶型M的制备方法,包括:式I化合物溶解于丙酮中,得到式I化合物的丙酮溶液,在搅拌下向所述式I化合物的丙酮溶液中加入苯磺酸的丙酮溶液,继续搅拌,收集固体,干燥,得到式I化合物苯磺酸盐晶型M。
- 根据权利要去62所述的制备方法,其中,将所述式I化合物超声加热溶解于丙酮中;优选地,所述式I化合物的丙酮溶液的浓度为10-30mg/mL,优选20mg/mL;优选地,所述苯磺酸的丙酮溶液的浓度为15-35mg/mL,优选25mg/mL;优选地,在加入苯磺酸的丙酮溶液之后,在室温下继续搅拌4-48小时,优选24小时;优选地,通过离心收集固体,并于30-60℃下真空干燥过夜。
- 一种如权利要求64所述的式I化合物柠檬酸盐晶型N的制备方法,包括:将式I化合物溶解于乙酸乙酯中,得到式I化合物的乙酸乙酯溶液,在搅拌下向所述式I化合物的乙酸乙酯溶液中加入柠檬酸的乙酸乙酯溶液,继续搅拌,收集固体,干燥,得到式I化合物柠檬酸盐晶型N。
- 根据权利要求65所述的制备方法,其中,将所述式I化合物超声加热溶解于乙酸乙酯中;优选地,所述式I化合物的乙酸乙酯溶液的浓度为10-30mg/mL,优选20mg/mL;优选地,所述柠檬酸的乙酸乙酯溶液的浓度为15-35mg/mL,优选25mg/mL;优选地,在加入所述柠檬酸的乙酸乙酯溶液之后,在室温下继续搅拌4-48小时,优选24小时;优选地,通过离心收集固体,并于30-60℃下真空干燥过夜。
- 根据权利要求67所述的式I化合物酒石酸盐晶型O,其X射线粉末衍射图谱在 2theta值为6.3°±0.2°、12.5°±0.2°、15.1°±0.2°、26.1°±0.2°、26.9°±0.2°、27.5°±0.2°处具有特征峰。
- 根据权利要求67或68所述的式I化合物酒石酸盐晶型O,其X射线粉末衍射图谱在2theta值为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°、27.5°±0.2°处具有特征峰。
- 根据权利要求67-69中任一项所述的式I化合物酒石酸盐晶型O的制备方法,包括:将式I化合物与第一溶剂混合,溶清后得到式I化合物的第一溶剂的溶液;将酒石酸与第二溶剂混合,溶清后得到酒石酸的第二溶剂的溶液;在搅拌下将酒石酸的第二溶剂的溶液加入至式I化合物的第一溶剂的溶液中,搅拌下程序降温,收集固体,干燥,得到式I化合物酒石酸盐晶型O。
- 根据权利要求70所述的制备方法,其中,所述第一溶剂和第二溶剂分别选自丙酮和乙酸乙酯中的一种或两种;优选地,所述式I化合物与酒石酸的摩尔比为1:(0.5-1.5),优选1:(0.5-0.7),更优选1:(0.55-0.6);优选地,所述式I化合物酒石酸盐晶型O中,式I化合物与酒石酸的摩尔比为2:1;优选地,所述式I化合物的丙酮溶液的浓度为15-70mg/mL,优选40-60mg/mL,更优选50mg/mL;优选地,所述酒石酸的丙酮溶液的浓度为5-35mg/mL,优选10-25mg/mL,更优选15mg/mL;优选地,将所述式I化合物与丙酮混合,升温至40-60℃,优选50-55℃,使式I化合物溶清;优选地,将所述酒石酸与丙酮混合,升温至40-60℃,优选50-55℃,使酒石酸溶清;优选地,在40-60℃,优选45-55℃的温度下将所述酒石酸的丙酮溶液加入至式I化合物的丙酮溶液中;优选地,将收集的固体于40-60℃下,于减压或鼓风风箱中,干燥5-48小时,优选16-28小时。
- 根据权利要求70或71所述的制备方法,其中,所述程序降温通过以下步骤实现:1)将体系在室温35-60℃,优选40-60℃下搅拌0.5-3小时,优选1-2小时;2)继续将体系降温至15-35℃,并保温搅拌0.5-3小时,优选1-2小时;3)继续将体系降温至5-15℃,并保温搅拌0.5-3小时,优选1-2小时。
- 根据权利要求72所述的制备方法,其中,步骤1)中,在将体系在室温35-60℃,优选40-60℃下搅拌0.5-3小时,优选1-2小时后,将体系浓缩至原有体积的1/3-2/3,优选浓缩至原体积的1/2;优选地,步骤2)中,在继续将体系降温至15-35℃,并保温搅拌0.5-3小时,优选1-2小时后,将体系浓缩至原有体积的1/3-2/3,优选浓缩至原体积的1/2。
- 根据权利要求70-73中任一项所述的制备方法,其中,所述式I化合物的纯度大于90%,优选大于95%,更优选大于99%。
- 一种包含根据权利要求5-7中任一项所述的式I化合物晶型1、根据权利要求10-12中任一项所述的式I化合物盐酸盐晶型A、根据权利要求15-17中任一项所述的式I化合物盐酸盐晶型B、根据权利要求20或21所述的式I化合物盐酸盐晶型C、根据权利要求24或25所述的式I化合物硫酸盐晶型D、根据权利要求28所述的式I化合物磷酸盐晶型E、根据权利要求32-34中任一项所述的式I化合物磷酸盐晶型F、根据权利要求36或37所述的式I化合物甲磺酸盐晶型G、根据权利要求40-42中任一项所述的式I化合物氢溴酸盐晶型H、根据权利要求46所述的式I化合物氢溴酸盐晶型J、根据权利要求49-51中任一项所述的式I化合物氢溴酸盐晶型K、根据权利要求54-56中任一项所述的式I化合物富马酸盐晶型L、根据权利要求59-61中任一项所述的式I化合物苯磺酸盐晶型M、根据权利要求64所述的式I化合物柠檬酸盐晶型N和/或根据权利要求67-69中任一项所述的式I化合物酒石酸盐晶型O的药物组合物。
- 一种包含根据权利要求5-7中任一项所述的式I化合物晶型1、根据权利要求10-12中任一项所述的式I化合物盐酸盐晶型A、根据权利要求15-17中任一项所述的式I化合物盐酸盐晶型B、根据权利要求20或21所述的式I化合物盐酸盐晶型C、根据权利要求24或25所述的式I化合物硫酸盐晶型D、根据权利要求28所述的式I化合物磷酸盐晶型E、根据权利要求32-34中任一项所述的式I化合物磷酸盐晶型F、根据权利要求36或37所述的式I化合物甲磺酸盐晶型G、根据权利要求40-42中任一项所述的式I化合物氢溴酸盐晶型H、根据权利要求46所述的式I化合物氢溴酸盐晶型J、根据权利要求49-51中任一项所述的式I化合物氢溴酸盐晶型K、根据权利要求54-56中任一项所述的式I化合物富马酸盐晶型L、根据权利要求59-61中任一项所述的式I化合物苯磺酸盐晶型M、根据权利要求64所述的式I化合物柠檬酸盐晶型N和/或根据权利要求67-69中任一项所述的式I化合物酒石酸盐晶型O的药物制剂。
- 根据权利要求5-7中任一项所述的式I化合物晶型1、根据权利要求10-12中任一项所述的式I化合物盐酸盐晶型A、根据权利要求15-17中任一项所述的式I化合物盐酸盐 晶型B、根据权利要求20或21所述的式I化合物盐酸盐晶型C、根据权利要求24或25所述的式I化合物硫酸盐晶型D、根据权利要求28所述的式I化合物磷酸盐晶型E、根据权利要求32-34中任一项所述的式I化合物磷酸盐晶型F、根据权利要求36或37所述的式I化合物甲磺酸盐晶型G、根据权利要求40-42中任一项所述的式I化合物氢溴酸盐晶型H、根据权利要求46所述的式I化合物氢溴酸盐晶型J、根据权利要求49-51中任一项所述的式I化合物氢溴酸盐晶型K、根据权利要求54-56中任一项所述的式I化合物富马酸盐晶型L、根据权利要求59-61中任一项所述的式I化合物苯磺酸盐晶型M、根据权利要求64所述的式I化合物柠檬酸盐晶型N和/或根据权利要求67-69中任一项所述的式I化合物酒石酸盐晶型O在制备用于治疗与Jak1/TYK2相关的疾病或病状的药物中的用途;优选地,所述疾病或病状是自身免疫性疾病或障碍,更优选类风湿性关节炎或炎症性疾病或障碍,以及癌症或肿瘤增殖性疾病或障碍。
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