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 PDF

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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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compound
formula
crystal form
hours
solution
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PCT/CN2020/088122
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English (en)
French (fr)
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梁从新
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广州高瓴制药有限公司
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Priority to EP24173874.9A priority Critical patent/EP4393492A2/en
Priority to AU2020287139A priority patent/AU2020287139A1/en
Priority to US17/615,437 priority patent/US20220242873A1/en
Priority to CA3142629A priority patent/CA3142629A1/en
Priority to BR112021024530A priority patent/BR112021024530A2/pt
Priority to KR1020227000070A priority patent/KR20220017990A/ko
Priority to JP2021572486A priority patent/JP2022537919A/ja
Priority to EA202192871A priority patent/EA202192871A1/ru
Application filed by 广州高瓴制药有限公司 filed Critical 广州高瓴制药有限公司
Priority to CN202080037087.3A priority patent/CN114007606B/zh
Priority to EP24173596.8A priority patent/EP4385511A2/en
Priority to EP20817954.9A priority patent/EP3981398A4/en
Priority to MX2021014320A priority patent/MX2021014320A/es
Publication of WO2020244349A1 publication Critical patent/WO2020244349A1/zh
Priority to IL288349A priority patent/IL288349A/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • A61K31/4151,2-Diazoles
    • A61K31/41551,2-Diazoles non condensed and containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic 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
    • C07D491/12Heterocyclic 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
    • C07D491/14Ortho-condensed systems
    • C07D491/147Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/4353Heterocyclic 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
    • A61K31/437Heterocyclic 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13Crystalline forms, e.g. polymorphs
    • YGENERAL 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
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design 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

一种作为选择性Jak1/TYK2激酶抑制剂的化合物2-[(2R,5S)-5-[2-甲基呋喃并[3,2-b]咪唑并[4,5-d]吡啶-1-基]四氢吡喃-2-基]乙腈的合成方法,该化合物以7-氯-6-硝基呋喃并[3,2-b]吡啶为起始原料,经亲核取代、钯炭还原、环合反应制备得到。该合成方法反应条件温和、产品收率高、纯度高、适合工业化生产。一种涉及该化合物的晶型、其盐的晶型以及它们的制备方法,该化合物的晶型、其盐的晶型具有良好的理化性质,适合药物开发。

Description

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 技术领域
本发明涉及药物合成领域,具体涉及作为选择性Jak1/TYK2激酶抑制剂的化合物2-[(2R,5S)-5-[2-甲基呋喃并[3,2-b]咪唑并[4,5-d]吡啶-1-基]四氢吡喃-2-基]乙腈(以下可简称为化合物I或式I化合物)的合成方法。本发明还涉及式I化合物的晶型、其盐的晶型以及它们的制备方法。另外,本发明还涉及包含式I化合物的晶型和/或其盐的晶型的药物组合物和药物制剂,以及式I化合物的晶型及其盐的晶型在治疗与Jak1/TYK2相关的疾病和病状的用途。
背景技术
蛋白激酶代表了在调节多种细胞过程和维持细胞功能中发挥重要作用的一大家族的蛋白质。这些激酶至少包括:非受体酪氨酸激酶,如Janus激酶家族(Jak1、Jak2、Jak3和TYK2);受体酪氨酸激酶,如血小板衍生生长因子受体激酶(PDGFR);和丝氨酸/苏氨酸激酶,如b-RAF。
Janus激酶家族包含4个已知的家族成员:Jak1、Jak2、Jak3和酪氨酸激酶2(TYK2)。这些细胞质酪氨酸激酶与膜细胞因子受体(例如常见的γ-链受体和糖蛋白130(gp130)跨膜蛋白)相关(Murray,J.Immunol.178(5):2623-2629,2007)。几乎40种细胞因子受体通过这4种Jak家族成员及其7种下游底物的组合发出信号:转录(STAT)家族成员的信号转导激活剂(Ghoreschi等,Immunol Rev.228(l):273-287,2009)。与其受体结合的细胞因子经由相互和自身磷酸化启动Jak激活。Jak家族激酶反过来使细胞因子受体残基磷酸化,为含有肉瘤同源性2(SH2)的蛋白质(如STAT因子和其他调节剂)产生结合位点,随后由Jak磷酸化激活。活化的STAT进入细胞核,开始促进白细胞细胞运输的存活因子、细胞因子、趋化因子和分子的表达(Schindler等,J.Biol.Chem.282(28):20059-20063,2007)。Jak激活还经由磷酸肌醇3-激酶(PI3K)和蛋白激酶B介导的途径导致细胞增殖。
Jak3和Jak1是常见γ-链细胞因子受体复合物的组分,并且这两者任一种的阻断抑制炎性细胞因子(白细胞介素(IL)-2,4,7,9,15和21)的信号传导(Ghoreschi等,Immunol.Rev.228(l):273-287,2009)。相比之下,其他病理上相关的细胞因子(如IL-6)仅依赖于Jak1。因此,Jak1阻断抑制了许多促炎细胞因子的信号传导(Guschin et al,EMBO J.14(7):1421-1429,1995)。观察到IL-6受体中和抗体—托珠单抗在类风湿性关节炎(RA)中的临床疗效(Maini等,Arthritis Rheum.54(9):2817-2829,2006)。
国际专利申请WO2018067422A1公开了作为选择性Jak1激酶抑制剂的1H-呋喃并[3,2-b]咪唑并[4,5-d]吡啶衍生物及其制备方法,其中公开了式I及其制备方法。合成路线如下:
Figure PCTCN2020088122-appb-000001
生物测试结果表明,式I化合物是有效的选择性Jak1抑制剂,并显示出对IL-6诱导的STAT3磷酸化的选择性抑制,而不显示出对血小板生成素诱导的STAT3磷酸化的选择性抑制。然而,国际专利申请WO2018067422A1没有公开其TYK2的生物活性,而且公开的式I化合物的制备方法中反应温度偏高,杂质偏多,产品收率低,不适合工业化生产。因此,有必要开发一条反应条件温和、产品收率高、纯度高、适合工业化生产的化合物I的制备方法。
目前,现有技术尚无化合物I的晶型及其盐的晶型的报道。药物研发中进行全面系统的多晶型筛选,选择最适合开发的晶型,是不可忽视的重要研究内容之一。基于此,有必要进一步进行化合物I的晶型及其盐的晶型筛选,开发出稳定性好、引湿性低、适合工业化生产的晶型,为药物的后续开发提供更多更好的选择。
发明内容
本发明的目的在于提供一种反应条件温和、产品收率高、纯度高、适合工业化生产的制备式I化合物(即,化合物I)的方法,该方法的合成路线如下:
Figure PCTCN2020088122-appb-000002
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。
在上述步骤1的一些实施方案中:
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。
在上述步骤2的一些实施方案中:
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(g/g)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;
洗涤滤饼是用四氢呋喃洗涤,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,其中洗涤所用的四氢呋喃与式II化合物的体积质量比(mL/g)为2:1至4:1,优选2:1至3:1(步骤2按100%收率折算后得到的式II化合物的质量);优选地,将式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(mL/g)为2:1至5:1,优选2:1至4:1,更优选2:1至3:1(步骤2按100%收率折算后得到的式II化合物的质量)。
在上述步骤3的一些实施方案中,四氢呋喃与式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;或者在上述步骤3的一些实施方案中,四氢呋喃与式II化合物的体积质量比(mL:mg)为1.5:1至5.0:1。
在上述步骤3的一些实施方案中,将式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;在一些实施方案中,所述用于置换的甲苯、四氢呋喃或甲基叔丁基醚与式II化合物浓缩物的体积质量比(mL:mg)为2.0:1至4.0:1;
在上述步骤3的一些实施方案中,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;或者在上述步骤3的一些实施方案中,式II化合物与原乙酸三甲酯的摩尔比为3.0:1至3.5:1;
在上述步骤3的一些实施方案中,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;或者在上述步骤3的一些实施方案中,式II化合物与吡啶盐酸盐的摩尔比为0.2:1至0.3:1;
在上述步骤3的一些实施方案中,向应容器中加入式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;
在上述步骤3的一些实施方案中,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。
在上述步骤3的一些实施方案中,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);
在上述步骤3的一些实施方案中,将得到的式I化合物在50~55℃下真空干燥或鼓风干燥。
本发明的另一目的在于提供一种式I化合物的晶型,在本文中将其称为式I化合物晶型1。
Figure PCTCN2020088122-appb-000003
本发明式I化合物晶型1的X射线粉末衍射图谱在2theta(2θ)值为13.4°±0.2°、17.6°±0.2°、21.9°±0.2°处具有特征峰。
在一些实施方案中,式I化合物晶型1的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。
在一些实施方案中,式I化合物晶型1的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。
非限制性地,本发明式I化合物晶型1的X射线粉末衍射数据如表1所示。
表1
Figure PCTCN2020088122-appb-000004
Figure PCTCN2020088122-appb-000005
非限制性地,本发明式I化合物晶型1的X射线粉末衍射(XRPD)图谱如图1所示。
非限制性地,本发明式I化合物晶型1的差示扫描量热(DSC)图谱如图2所示。DSC图谱显示,本发明式I化合物晶型1的初熔点为173.38℃。
非限制性地,本发明式I化合物晶型1的热失重分析(TGA)图谱如图3所示。TGA图谱显示,本发明式I化合物晶型1从25℃加热到162℃仅有0.42%失重,式1化合物晶型1不含结晶水或溶剂。
非限制性地,本发明式I化合物晶型1的动态水分吸附(DVS)图谱如图4所示。DVS图谱显示,本发明式I化合物晶型1从0%RH-95%RH吸湿增重13.86%,表明该样品有一定的引湿性。脱附过程吸湿曲线出现之后现象,结合DVS测试前后样品XRPD图谱(测试后XRPD图谱如图5所示),表明式I化合物晶型1吸湿后晶型发生转变。
本发明提供了式I化合物晶型1的制备方法,具体如下:
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。
在一些实施方案中,将式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。
在一些实施方案中,所述甲醇与MTBE的体积用量比为3:1-2:1,优选8:3。
在一些实施方案中,将式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。
本发明的另一目的在于提供式I化合物盐的晶型,具体为式I化合物盐酸盐的晶型、硫酸盐的晶型、磷酸盐的晶型、甲磺酸盐的晶型、氢溴酸盐的晶型、富马酸盐的晶型、苯磺酸盐的晶型、柠檬酸盐的晶型、L-(+)-酒石酸(本申请中简称酒石酸)盐的晶型,在本文中分别将其称为式I化合物盐酸盐晶型A、盐酸盐晶型B、盐酸盐晶型C、硫酸盐晶型D、磷酸盐晶型E、磷酸盐晶型F、甲磺酸盐晶型G、氢溴酸盐晶型H、氢溴酸盐晶型J、氢溴酸盐晶型K、富马酸盐晶型L、苯磺酸盐晶型M、柠檬酸盐晶型N、酒石酸盐晶型O。
本发明式I化合物盐酸盐晶型A的X射线粉末衍射图谱在2theta值为7.3°±0.2°、12.1°±0.2°、20.9°±0.2°处具有特征峰。
在一些实施方案中,式I化合物盐酸盐晶型A的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。
在一些实施方案中,式I化合物盐酸盐晶型A的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。
非限制性地,本发明式I化合物盐酸盐晶型A的X射线粉末衍射数据如表2所示。
表2
Figure PCTCN2020088122-appb-000006
非限制性地,本发明式I化合物盐酸盐晶型A的XRPD图谱如图6所示。
非限制性地,本发明式I化合物盐酸盐晶型A的DSC图谱如图7所示。
本发明提供了式I化合物盐酸盐晶型A的制备方法,具体如下:
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。
在一些实施方案中,将式I化合物超声加热溶解于丙酮中。
在一些实施方案中,所述式I化合物的丙酮溶液的浓度为10-50mg/mL,优选20mg/mL。
在一些实施方案中,所述盐酸的丙酮溶液的浓度为15-35mg/mL,优选25mg/mL。
在一些实施方案中,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。
在一些实施方案中,通过离心收集固体,并于30-60℃下真空干燥过夜。
本发明式I化合物盐酸盐晶型B的X射线粉末衍射图谱在2theta值为7.2°±0.2°、20.0°±0.2°、22.6°±0.2°处具有特征峰。
在一些实施方案中,式I化合物盐酸盐晶型B的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。
在一些实施方案中,式I化合物盐酸盐晶型B的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。
非限制性地,本发明式I化合物盐酸盐晶型B的X射线粉末衍射数据如表3所示:
表3
Figure PCTCN2020088122-appb-000007
非限制性地,本发明式I化合物盐酸盐晶型B的XRPD图谱如图8所示。
非限制性地,本发明式I化合物盐酸盐晶型B的DSC图谱如图9所示。
本发明提供了式I化合物盐酸盐晶型B的制备方法,具体如下:
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。
在一些实施方案中,将式I化合物超声加热溶解于乙酸乙酯中。
在一些实施方案中,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。
在一些实施方案中,所述盐酸的乙酸乙酯溶液的浓度为15-35mg/mL,优选25mg/mL。
在一些实施方案中,在加入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。
在一些实施方案中,通过离心收集固体,并于30-60℃下真空干燥过夜。
本发明式I化合物盐酸盐晶型C的X射线粉末衍射图谱在2theta值为10.7°±0.2°、21.5°±0.2°、24.3°±0.2°处具有特征峰。
在一些实施方案中,式I化合物盐酸盐晶型C的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。
非限制性地,本发明式I化合物盐酸盐晶型C的X射线粉末衍射数据如表4所示:
表4
Figure PCTCN2020088122-appb-000008
非限制性地,本发明式I化合物盐酸盐晶型C的XRPD图谱如图10所示。
非限制性地,本发明式I化合物盐酸盐晶型C的DSC图谱如图11所示。
将本发明式I化合物盐酸盐晶型A以溶剂重结晶或转晶,得到本发明式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。
在一些实施方案中,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。
在一些实施方案中,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。
在一些实施方案中,所述搅拌的时长为4-48小时,优选24小时。
在一些实施方案中,通过离心收集固体,并于30-60℃下真空干燥过夜。
本发明式I化合物硫酸盐晶型D的X射线粉末衍射图谱在2theta值为6.0°±0.2°、22.8°±0.2°、25.2°±0.2°处具有特征峰。
在一些实施方案中,式I化合物硫酸盐晶型D的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。
非限制性地,本发明式I化合物硫酸盐晶型D的X射线粉末衍射数据如表5所示:
表5
Figure PCTCN2020088122-appb-000009
非限制性地,本发明式I化合物硫酸盐晶型D的XRPD图谱如图12所示。
非限制性地,本发明式I化合物硫酸盐晶型D的DSC图谱如图13所示。
本发明提供了式I化合物硫酸盐晶型D的制备方法,具体如下:
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。
在一些实施方案中,将式I化合物超声加热溶解于丙酮中。
在一些实施方案中,所述式I化合物的丙酮溶液的浓度为10-30mg/mL,优选20mg/mL。
在一些实施方案中,所述硫酸的丙酮溶液的浓度为15-35mg/mL,优选25mg/mL。
在一些实施方案中,在加入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。
在一些实施方案中,通过离心收集固体,并于30-60℃下真空干燥过夜。
本发明式I化合物磷酸盐晶型E的X射线粉末衍射图谱在2theta值为6.2°±0.2°、15.5°±0.2°、17.4°±0.2°、24.6°±0.2°处具有特征峰。
非限制性地,本发明式I化合物磷酸盐晶型E的X射线粉末衍射数据如表6所示:
表6
Figure PCTCN2020088122-appb-000010
非限制性地,本发明式I化合物磷酸盐晶型E的XRPD图谱如图14所示。
非限制性地,本发明式I化合物磷酸盐晶型E的DSC图谱如图15所示。
本发明提供了式I化合物磷酸盐晶型E的制备方法,具体如下:
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。
在一些实施方案中,将式I化合物超声加热溶解于丙酮中。
在一些实施方案中,所述式I化合物与所述磷酸的摩尔比为1:1.0-1:1.5。
在一些实施方案中,所述式I化合物的丙酮溶液的浓度为10-30mg/mL,优选20mg/mL。
在一些实施方案中,所述磷酸的丙酮溶液的浓度为15-35mg/mL,优选25mg/mL。
在一些实施方案中,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。
在一些实施方案中,通过离心收集固体,并于30-60C下真空干燥过夜。
在一些实施方案中,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。
在一些实施方案中,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。
在一些实施方案中,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。
在一些实施方案中,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。
本发明式I化合物磷酸盐晶型F的X射线粉末衍射图谱在2theta值为16.6°±0.2°、17.2°±0.2°、22.6°±0.2°处具有特征峰。
在一些实施方案中,本发明式I化合物磷酸盐晶型F的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。
在一些实施方案中,本发明式I化合物磷酸盐晶型F的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。
非限制性地,本发明式I化合物磷酸盐晶型F的X射线粉末衍射数据如表7所示。
表7
Figure PCTCN2020088122-appb-000011
非限制性地,本发明式I化合物磷酸盐晶型F的XRPD图谱如图16所示。
非限制性地,本发明式I化合物磷酸盐晶型F的DSC图谱如图17所示。DSC图谱显示,本发明式I化合物磷酸盐晶型F的初始熔点为198.78℃。
非限制性地,本发明式I化合物磷酸盐晶型F的DVS图谱如图18所示。DVS图谱显示,本发明式I化合物磷酸盐晶型F从0%RH-95%RH吸湿增重6.5%。85%RH湿度下,式I化合物磷酸盐晶型F增重0.72%;70%RH湿度下,式I化合物磷酸盐晶型F增重1.95%。吸湿后,式I化合物磷酸盐晶型F晶型未发生改变(吸湿后XRPD图谱如图19所示)。
本发明提供了式I化合物磷酸盐晶型F的制备方法,具体如下:
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;或者
在一些实施方案中,所述第一溶剂为可以有效溶解式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。
在一些实施方案中,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。
在一些实施方案中,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。
在一些实施方案中,将式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。
在一些实施方案中,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。
在一些实施方案中,通过离心收集固体,并于30-60℃,优选50℃下真空干燥。
本发明式I化合物甲磺酸盐晶型G的X射线粉末衍射图谱在2theta值为8.6°±0.2°、19.9°±0.2°、24.9°±0.2°处具有特征峰。
在一些实施方案中,本发明式I化合物甲磺酸盐晶型G的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。
非限制性地,本发明式I化合物甲磺酸盐晶型G的X射线粉末衍射数据如表8所示。
表8
Figure PCTCN2020088122-appb-000012
非限制性地,本发明式I化合物甲磺酸盐晶型G的XRPD图谱如图20所示。
非限制性地,本发明式I化合物甲磺酸盐晶型G的DSC图谱如图21所示。DSC图谱显示,本发明式I化合物甲磺酸盐晶型G的初始熔点为218.78℃。
非限制性地,本发明式I化合物甲磺酸盐晶型G的DVS图谱如图22所示。
本发明提供了式I化合物甲磺酸盐晶型G的制备方法,具体如下:
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。
在一些实施方案中,将式I化合物超声加热溶解于丙酮中。
在一些实施方案中,所述式I化合物的丙酮溶液的浓度为10-30mg/mL,优选20mg/mL。
在一些实施方案中,所述甲磺酸的丙酮溶液的浓度为15-35mg/mL,优选25mg/mL。
在一些实施方案中,在加入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。
在一些实施方案中,通过离心收集固体,并于30-60℃下真空干燥过夜。
本发明式I化合物氢溴酸盐晶型H的X射线粉末衍射图谱在2theta值为7.2°±0.2°、20.7°±0.2°、24.0°±0.2°处具有特征峰。
在一些实施方案中,本发明式I化合物氢溴酸盐晶型H的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。
在一些实施方案中,本发明式I化合物氢溴酸盐晶型H的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。
非限制性地,本发明式I化合物氢溴酸盐晶型H的X射线粉末衍射数据如表9所示。
表9
Figure PCTCN2020088122-appb-000013
非限制性地,本发明式I化合物氢溴酸盐晶型H的XRPD图谱如图23所示。
非限制性地,本发明式I化合物氢溴酸盐晶型H的DSC图谱如图24所示。
本发明提供了式I化合物氢溴酸盐晶型H的制备方法,具体如下:
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。
在一些实施方案中,将式I化合物超声加热溶解于丙酮中。
在一些实施方案中,所述式I化合物的丙酮溶液的浓度为10-30mg/mL,优选20mg/mL。
在一些实施方案中,所述氢溴酸的丙酮溶液的浓度为15-35mg/mL,优选25mg/mL。
在一些实施方案中,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。
在一些实施方案中,通过离心收集固体,并于30-60℃下真空干燥过夜。
在一些实施方案中,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。
在一些实施方案中,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;
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.
本发明式I化合物氢溴酸盐晶型J的X射线粉末射图谱在2theta值为6.2°±0.2°、15.0°±0.2°处具有特征峰。
非限制性地,本发明式I化合物氢溴酸盐晶型J的X射线粉末衍射数据如表10所示。
表10
Figure PCTCN2020088122-appb-000014
非限制性地,本发明式I化合物氢溴酸盐晶型J的XRPD图谱如图25所示。
本发明提供了式I化合物氢溴酸盐晶型J的制备方法,具体如下:
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。
在一些实施方案中,将式I化合物超声加热溶解于乙酸乙酯中。
在一些实施方案中,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。
在一些实施方案中,所述氢溴酸的乙酸乙酯溶液的浓度为15-35mg/mL,优选25mg/mL。
在一些实施方案中,在加入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。
在一些实施方案中,通过离心收集固体,并于30-60℃下真空干燥过夜。
本发明式I化合物氢溴酸盐晶型K的X射线粉末衍射图谱在2theta值为17.1°±0.2°、22.0°±0.2°、24.2°±0.2°处具有特征峰。
本发明式I化合物氢溴酸盐晶型K的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。
本发明式I化合物氢溴酸盐晶型K的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。
非限制性地,本发明式I化合物氢溴酸盐晶型K的X射线粉末衍射数据如表11所示:
表11
Figure PCTCN2020088122-appb-000015
非限制性地,本发明式I化合物氢溴酸盐晶型K的XRPD图谱如图26所示。
非限制性地,本发明式I化合物氢溴酸盐晶型K的DSC图谱如图27所示。
非限制性地,本发明式I化合物氢溴酸盐晶型K的DVS图谱如图28所示。DVS图谱显示,本发明式I化合物氢溴酸盐晶型K从0%RH-95%RH吸湿增重11.84%,表明该样品有一定的引湿性。脱附过程吸湿曲线出现之后现象,结合DVS测试前后样品XRPD图谱(测试后XRPD图谱如图29所示),表明式I化合物氢溴酸盐晶型K吸湿后晶型发生转变。
本发明提供了式I化合物氢溴酸盐晶型K的制备方法,具体如下:
将本发明式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。
在一些实施方案中,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。
在一些实施方案中,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。
在一些实施方案中,搅拌的时长为4-48小时,优选24小时。
在一些实施方案中,通过离心收集固体,并于30-60℃下真空干燥过夜。
本发明式I化合物富马酸盐晶型L的X射线粉末衍射图谱在2theta值为6.1°±0.2°、16.3°±0.2°、26.4°±0.2°处具有特征峰。
本发明式I化合物富马酸盐晶型L的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。
本发明式I化合物富马酸盐晶型L的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。
非限制性地,本发明式I化合物富马酸盐晶型L的X射线粉末衍射数据如表12所示。
表12
Figure PCTCN2020088122-appb-000016
非限制性地,本发明式I化合物富马酸盐晶型L的XRPD图谱如图30所示。
非限制性地,本发明式I化合物富马酸盐晶型L的DSC图谱如图31所示。
本发明提供了式I化合物富马酸盐晶型L的制备方法,具体如下:
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。
在一些实施方案中,将式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。
在一些实施方案中,所述式I化合物的溶液的浓度为10-30mg/mL,优选20mg/mL。
在一些实施方案中,所述富马酸的乙醇溶液的浓度为15-35mg/mL,优选25mg/mL。
在一些实施方案中,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。
在一些实施方案中,通过离心收集固体,并于30-60℃下真空干燥过夜。
本发明式I化合物苯磺酸盐晶型M的X射线粉末衍射图谱在2theta值为7.5°±0.2°、18.5°±0.2°、25.2°±0.2°、29.8°±0.2°处具有特征峰。
本发明式I化合物苯磺酸盐晶型M的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。
本发明式I化合物苯磺酸盐晶型M的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。
非限制性地,本发明式I化合物苯磺酸盐晶型M的X射线粉末衍射数据如表13所示。
表13
Figure PCTCN2020088122-appb-000017
非限制性地,本发明式I化合物苯磺酸盐晶型M的XRPD图谱如图32所示。
非限制性地,本发明式I化合物苯磺酸盐晶型M的DSC图谱如图33所示。DSC图谱显示,本发明式I化合物苯磺酸盐晶型M的初始熔点为198.73℃。
非限制性地,本发明式I化合物苯磺酸盐晶型M的DVS图谱如图34所示。DVS图谱显示,本发明式I化合物苯磺酸盐晶型M从0%RH-95%RH吸湿增重4.6%。85%RH湿度下,式I化合物苯磺酸盐晶型M增重0.54%;70%RH湿度下,式I化合物苯磺酸盐晶型M增重0.97%。吸湿后,式I化合物苯磺酸盐晶型M晶型未发生改变(吸湿后XRPD图谱如图35所示)。
本发明提供了式I化合物苯磺酸盐晶型M的制备方法,具体如下:
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。
在一些实施方案中,将式I化合物超声加热溶解于丙酮中。
在一些实施方案中,所述式I化合物的丙酮溶液的浓度为10-30mg/mL,优选20mg/mL。
在一些实施方案中,所述苯磺酸的丙酮溶液的浓度为15-35mg/mL,优选25mg/mL。
在一些实施方案中,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。
在一些实施方案中,通过离心收集固体,并于30-60℃下真空干燥过夜。
本发明式I化合物柠檬酸盐晶型N的X射线粉末衍射图谱在2theta值为15.8°±0.2°、17.0°±0.2°、21.1°±0.2°处具有特征峰。
非限制性地,本发明式I化合物柠檬酸盐晶型N的X射线粉末衍射数据如表14所示。
表14
Figure PCTCN2020088122-appb-000018
非限制性地,本发明式I化合物柠檬酸盐晶型N的XRPD图谱如图36所示。
非限制性地,本发明式I化合物柠檬酸盐晶型N的DSC图谱如图37所示。
本发明提供了式I化合物柠檬酸盐晶型N的制备方法,具体如下:
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。
在一些实施方案中,将式I化合物超声加热溶解于乙酸乙酯中。
在一些实施方案中,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。
在一些实施方案中,所述柠檬酸的乙酸乙酯溶液的浓度为15-35mg/mL,优选25mg/mL。
在一些实施方案中,在加入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。
在一些实施方案中,通过离心收集固体,并于30-60℃下真空干燥过夜。
本发明式I化合物酒石酸盐晶型O的X射线粉末衍射图谱在2theta值为6.3°±0.2°、26.1°±0.2°、26.9°±0.2°处具有特征峰。
在一些实施方案中,本发明式I化合物酒石酸盐晶型O的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。
在一些实施方案中,本发明式I化合物酒石酸盐晶型O的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。
非限制性地,本发明式I化合物酒石酸盐晶型O的X射线粉末衍射数据如表15所示:
表15
Figure PCTCN2020088122-appb-000019
Figure PCTCN2020088122-appb-000020
非限制性地,本发明式I化合物酒石酸盐晶型O的XRPD图谱如图38所示。
非限制性地,本发明式I化合物酒石酸盐晶型O的DSC图谱如图39所示。DSC图谱显示,本发明式I化合物酒石酸盐晶型O的初始熔点为218.80℃。
非限制性地,本发明式I化合物酒石酸盐晶型O的TGA图谱如图40所示。TGA图谱显示,本发明式I化合物酒石酸盐晶型O从26℃加热到120℃仅有0.05%失重,表明式I化合物酒石酸盐晶型O不含结晶水或溶剂。
非限制性地,本发明式I化合物酒石酸盐晶型O的DVS图谱如图41所示。DVS图谱显示,本发明式I化合物酒石酸盐晶型O从0%RH-95%RH吸湿增重6.85%。80%RH湿度下,式I化合物酒石酸盐晶型O增重1.80%。吸湿后,式I化合物酒石酸盐晶型O晶型未发生改变(吸湿后XRPD图谱如图42所示)。
本发明提供了式I化合物酒石酸盐晶型O的制备方法,具体如下:
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。
在一些实施方案中,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。
在一些实施方案中,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)。
在一些实施方案中,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。
在一些实施方案中,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。
在一些实施方案中,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。
在一些实施方案中,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。
在一些实施方案中,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。
在一些实施方案中,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。
在一些实施方案中,所述程序降温通过以下步骤实现:
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;
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;
继续将体系降温至5-15℃,例如5-10℃,并保温搅拌0.5-3小时,优选1-2小时。
本申请中,所述程序降温指可以使体系分阶段、逐步冷却降低温度,并在某一特定温度区间保持一定时间的步骤。
在一些实施方案中,程序降温过程中,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。
在一些实施方案中,程序降温过程中,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。
在一些实施方案中,所述式I化合物的纯度大于90%,优选大于95%,更优选大于99%。
在一些实施方案中,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。
本发明还提供了包含式I化合物晶型1、式I化合物盐酸盐晶型A、式I化合物盐酸盐晶型B、式I化合物盐酸盐晶型C、式I化合物硫酸盐晶型D、式I化合物磷酸盐晶型E、式I化合物磷酸盐晶型F、式I化合物甲磺酸盐晶型G、式I化合物氢溴酸盐晶型H、式I化合物氢溴酸盐晶型J、式I化合物氢溴酸盐晶型K、式I化合物富马酸盐晶型L、式I化合物苯磺酸盐晶型M、式I化合物柠檬酸盐晶型N和/或式I化合物酒石酸盐晶型O的药物组合物。
本发明还提供了包含式I化合物晶型1、式I化合物盐酸盐晶型A、式I化合物盐酸盐晶型B、式I化合物盐酸盐晶型C、式I化合物硫酸盐晶型D、式I化合物磷酸盐晶型E、式I化合物磷酸盐晶型F、式I化合物甲磺酸盐晶型G、式I化合物氢溴酸盐晶型H、式I化合物氢溴酸盐晶型J、式I化合物氢溴酸盐晶型K、式I化合物富马酸盐晶型L、式I化合物苯磺酸盐晶型M、式I化合物柠檬酸盐晶型N和/或式I化合物酒石酸盐晶型O的药物制剂。
本发明还提供了式I化合物晶型1、式I化合物盐酸盐晶型A、式I化合物盐酸盐晶型B、式I化合物盐酸盐晶型C、式I化合物硫酸盐晶型D、式I化合物磷酸盐晶型E、式I化合物磷酸盐晶型F、式I化合物甲磺酸盐晶型G、式I化合物氢溴酸盐晶型H、式I化合物氢溴酸盐晶型J、式I化合物氢溴酸盐晶型K、式I化合物富马酸盐晶型L、式I化合物苯磺酸盐晶型M、式I化合物柠檬酸盐晶型N和/或式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,其中所述疾病或病状可以是自身免疫性疾病或障碍,例如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。
本发明中,若无特别指明,所涉及温度指反应体系的内温。
针对熔点,本领域技术人员会理解,在DSC测定中,实际测定的初始熔点根据测试仪器、加热速度、结晶形状等参数影响,会出现一定程度的变化;通常,这种变化在±5℃之内。
附图说明
图1为本发明式I化合物晶型1的XRPD图谱。
图2为本发明式I化合物晶型1的DSC图谱。
图3为本发明式I化合物晶型1的TGA图谱。
图4为本发明式I化合物晶型1的DVS图谱。
图5为本发明式I化合物晶型1经DVS测试前后的XRPD叠图。
图6为本发明式I化合物盐酸盐晶型A的XRPD图谱。
图7为本发明式I化合物盐酸盐晶型A的DSC图谱。
图8为本发明式I化合物盐酸盐晶型B的XRPD图谱。
图9为本发明式I化合物盐酸盐晶型B的DSC图谱。
图10为本发明式I化合物盐酸盐晶型C的XRPD图谱。
图11为本发明式I化合物盐酸盐晶型C的DSC图谱。
图12为本发明式I化合物硫酸盐晶型D的XRPD图谱。
图13为本发明式I化合物硫酸盐晶型D的DSC图谱。
图14为本发明式I化合物磷酸盐晶型E的XRPD图谱。
图15为本发明式I化合物磷酸盐晶型E的DSC图谱。
图16为本发明式I化合物磷酸盐晶型F的XRPD图谱。
图17为本发明式I化合物磷酸盐晶型F的DSC图谱。
图18为本发明式I化合物磷酸盐晶型F的DVS图谱。
图19为本发明式I化合物磷酸盐晶型F经DVS测试前后的XRPD叠图。
图20为本发明式I化合物甲磺酸盐晶型G的XRPD图谱。
图21为本发明式I化合物甲磺酸盐晶型G的DSC图谱。
图22为本发明式I化合物甲磺酸盐晶型G的DVS图谱。
图23为本发明式I化合物氢溴酸盐晶型H的XRPD图谱。
图24为本发明式I化合物氢溴酸盐晶型H的DSC图谱。
图25为本发明式I化合物氢溴酸盐晶型J的XRPD图谱。
图26为本发明式I化合物氢溴酸盐晶型K的XRPD图谱。
图27为本发明式I化合物氢溴酸盐晶型K的DSC图谱。
图28为本发明式I化合物氢溴酸盐晶型K的DVS图谱。
图29为本发明式I化合物氢溴酸盐晶型K经DVS测试前后的XRPD叠图。
图30为本发明式I化合物富马酸盐晶型L的XRPD图谱。
图31为本发明式I化合物富马酸盐晶型L的DSC图谱。
图32为本发明式I化合物苯磺酸盐晶型M的XRPD图谱。
图33为本发明式I化合物苯磺酸盐晶型M的DSC图谱。
图34为本发明式I化合物苯磺酸盐晶型M的DVS图谱。
图35为本发明式I化合物苯磺酸盐晶型M经DVS测试前后的XRPD叠图。
图36为本发明式I化合物柠檬酸盐晶型N的XRPD图谱。
图37为本发明式I化合物柠檬酸盐晶型N的DSC图谱。
图38为本发明式I化合物酒石酸盐晶型O的XRPD图谱。
图39为本发明式I化合物酒石酸盐晶型O的DSC图谱。
图40为本发明式I化合物酒石酸盐晶型O的TGA图谱。
图41为本发明式I化合物酒石酸盐晶型O的DVS图谱。
图42为本发明式I化合物酒石酸盐晶型O经DVS测试前后的XRPD叠图。
图43为本发明式I化合物晶型1的 1H NMR图谱。
图44为本发明式I化合物酒石酸盐晶型O的 1H NMR图谱。
图45为本发明式I化合物磷酸盐晶型F在高温和加速条件下放置2周的XRPD叠图。
图46为本发明式I化合物酒石酸盐晶型O在高温和加速条件下放置2周的XRPD叠图。
图47为本发明式I化合物磷酸盐晶型F在高温和加速条件下放置2周的DSC叠图。
图48为本发明式I化合物酒石酸盐晶型O在高温和加速条件下放置2周的DSC叠图。
图49为本发明式I化合物晶型1在高温和加速条件下放置2周的XRPD叠图。
图50为本发明式I化合物晶型1在高温和加速条件下放置2周的DSC叠图。
具体实施方式
下列实施例进一步解释说明本发明,但是,它们并不构成对本发明范围的限制或限定。
Figure PCTCN2020088122-appb-000021
Figure PCTCN2020088122-appb-000022
本发明中使用的原料和试剂的信息如下:
Figure PCTCN2020088122-appb-000023
Figure PCTCN2020088122-appb-000024
实施例
式III化合物的制备
Figure PCTCN2020088122-appb-000025
实施例1 式III化合物的制备
向25ml的三口瓶中加入乙醇(4ml)、式IV化合物(0.20g,1.0eq)、式V化合物(0.18g,1.0eq)和DIPEA(0.39g,3.0eq),开启搅拌;氮气保护下,将体系加热到回流(70-80℃),并在回流温度下搅拌过夜;将体系降温至室温(15-20℃),降温过程中有固体析出;向体系中滴加水(4ml),将体系在室温下(15-20℃)搅拌2小时;过滤,滤饼用乙醇水溶液(2ml,V/V,1:1)淋洗;将滤饼在45-50℃下真空干燥16小时;共得到黄色固体约0.21g,LC-MS纯度96.4%(214nm),收率69%。
MS-ESI:[M+1] +:303.1
1H NMR(400MHz,CDCl 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).
实施例2 式III化合物的制备
向250ml三口瓶中加入乙醇(120ml,20V)、式IV化合物(6.0g,1.0eq)、式V化合物(5.4g,1.01eq)和DIPEA(11.7g,3.0eq),开启搅拌;氮气保护下,将体系加热到70-80℃(内 温)并保温搅拌8小时;将体系降温至室温(15-20℃),降温过程中有固体析出;向体系中滴加水(120ml,20V),将体系在室温下(10-15℃)搅拌2小时;过滤,滤饼用乙醇水溶液(30ml,1:1)淋洗;将滤饼在50℃下真空干燥16小时;共得到黄色固体约7.7g,HPLC纯度95.5%,收率84.3%。
MS-ESI和 1H NMR数据与实施例1一致。
实施例3 式III化合物的制备
向25ml三口瓶中加入乙醇(5ml,10V)、式IV化合物(0.50g,1.0eq)、式V化合物(0.45g,1.01eq)和DIPEA(0.98g,3.0eq),开启搅拌;氮气保护下,将体系加热到70~80℃,回流搅拌5小时;将体系降温至室温(15-20℃),降温过程中有固体析出;向体系中滴加水(5ml,10V),将体系在室温下(10-15℃)搅拌2小时;过滤,滤饼用乙醇水溶液(1:1)(1.5ml,3V)淋洗;将滤饼在50℃下真空干燥16小时;共得到棕色固体约0.54g,HPLC纯度95.4%,收率71%。
MS-ESI和 1H NMR数据与实施例1一致。
实施例4 式III化合物的制备
向25ml三口瓶中加入乙醇(5ml,10V)、式IV化合物(0.50g,1.0eq)、式V化合物(0.45g,1.01eq)和DIPEA(0.72g,2.2eq),开启搅拌;氮气保护下,将体系加热到70-80℃,回流搅拌5小时;将体系降温至室温(15-20℃),降温过程中有固体析出;向体系中滴加水(7.5ml,15V),将体系在室温下(10-15℃)搅拌1小时;将体系冷却至5-10℃,继续搅拌2小时;过滤,滤饼用乙醇水溶液(1:1)(1.5ml,3V)淋洗;将滤饼在50℃下真空干燥16小时;共得到棕色固体约0.57g,HPLC纯度91.4%,收率75%。
MS-ESI和 1H NMR数据与实施例1一致。
实施例5 式III化合物的制备
向250ml三口瓶中加入乙醇(50ml,10V)、式IV化合物(5.0g,1.0eq)、式V化合物(4.5g,1.01eq)和DIPEA(7.2g,2.2eq),开启搅拌;氮气保护下,将体系加热到70-80℃,回流搅拌5小时;将体系降温至室温(15-20℃),降温过程中有固体析出;向体系中滴加水(75ml,15V),将体系在室温下(10-15℃)搅拌1小时;将体系冷却至5-10℃,继续搅拌2小时;过滤,滤饼用乙醇水溶液(1:1,15ml)淋洗;将滤饼在50℃下真空干燥16小时;共得到黄色固体约6.6g,HPLC纯度94.2%,收率86.7%。
MS-ESI和 1H NMR数据与实施例1一致。
实施例6 式III化合物的制备
向500ml的三口烧瓶中加入乙醇(180ml,10V)、式IV化合物(17.8g,1.0eq)、式V化合物(16.0g,1.01eq)和DIPEA(25.7g,2.2eq),开启搅拌;氮气保护下,将体系加热到70-80℃,回流搅拌5小时;将体系降温至室温(15-20℃),降温过程中有固体析出;向体系 中滴加水(270ml,15V),将体系在室温下(10-15℃)搅拌1小时;将体系冷却至5-10℃,继续搅拌2小时;过滤,滤饼用乙醇水溶液(乙醇:水=1:1.5,v/v,40ml)淋洗;将滤饼在50℃下真空干燥16小时;共得到棕色固体约23.0g,HPLC纯度95.3%,收率85.2%。
MS-ESI和 1H NMR数据与实施例1一致。
实施例7 式III化合物的制备
向3000ml的三口烧瓶中加入乙醇(1000ml,10V)、式IV化合物(100g,1.0eq)、式V化合物(89.9g,1.01eq)和DIPEA(143.2g,2.2eq),开启搅拌;氮气保护下,将体系加热到85-90℃(内温:约75℃),回流搅拌10小时;将体系降温至室温(15-20℃),降温过程中有固体析出;向体系中滴加水(1500ml,15V),将体系在室温下(10-15℃)搅拌1小时;将体系冷却至5-10℃,继续搅拌2小时;过滤,滤饼用乙醇水溶液(1:1.5,v/v,200ml)淋洗;将滤饼在50℃下鼓风干燥16小时;共得到红棕色固体130g,HPLC纯度94.2%,收率85.5%。
MS-ESI和 1H NMR数据与实施例1一致。
实施例8 式III化合物的制备
向5000ml的三口烧瓶中加入乙醇(2000ml,10V)、式IV化合物(200g,1.0eq)、式V化合物(179.7g,1.01eq)和DIPEA(286.4g,2.2eq),开启搅拌;氮气保护下,将体系加热到70~80℃(内温:约65-70℃),回流搅拌16小时;将体系降温至室温(15-20℃),降温过程中有固体析出;向体系中滴加水(3000ml,15V),将体系在室温下(10-15℃)搅拌1小时;将体系冷却至5-10℃,继续搅拌2小时;过滤,滤饼用乙醇水溶液(1:1.5,v/v,400ml)淋洗;将滤饼在50℃下鼓风干燥16小时;共得到红棕色固体251g,HPLC纯度93.4%,含量94.7%,含量收率78.1%。
MS-ESI和 1H NMR数据与实施例1一致。
实施例9 式III化合物的制备
向20000ml的三口烧瓶中加入乙醇(5000ml,10V)、式IV化合物(500g,1.0eq)、式V化合物(450g,1.01eq)和DIPEA(723g,2.2eq),开启搅拌;氮气保护下,将体系加热到80-90℃(内温:约70-80℃),回流搅拌16小时;将体系降温至室温(25-30℃),降温过程中有固体析出;向体系中滴加水(7500ml,15V),将体系在室温下(25-30℃)搅拌1小时;将体系冷却至10-15℃,继续搅拌2小时;过滤,滤饼用乙醇水溶液(1:1.5,v/v,1000ml)淋洗;将滤饼用真空烘箱在50-55℃下,真空烘料24h;共得到623g产品,HPLC纯度93.7%,乙醇溶残为0.5%,含量93.1%,含量收率76.2%。
MS-ESI和 1H NMR数据与实施例1一致。
实施例10 式III化合物的制备
向500ml的三口烧瓶中加入乙醇(100ml,10V)、式IV化合物(10.0g,1.0eq)、式V化合物(9.0g,1.01eq)和DIPEA(14.3g,2.2eq),开启搅拌;将体系加热到70~80℃,回流 搅拌16小时;将体系降温至室温(20-30℃),降温过程中有固体析出;向体系中加水(150ml,15V),将体系在室温下(20-30℃)搅拌2小时;将体系冷却至5-10℃,继续搅拌2小时;过滤,滤饼用乙醇水溶液(1:1.5,v/v,25ml)淋洗;将滤饼用真空烘箱在50-55℃下干燥,真空烘料16h;共得到13.7g产品,HPLC纯度93.7%,收率90%。
MS-ESI和 1H NMR数据与实施例1一致。
实施例11 式III化合物的制备
向R0462反应釜中加入乙醇(17Kg,10V)、式IV化合物(2.2Kg,1.0eq)、式V化合物(1.98Kg,1.01eq)和DIPEA(3.19Kg,2.2eq),开启搅拌;氮气保护下,将体系加热到75~80℃(内温:约70-80℃),搅拌16小时;将体系降温至室温(15-25℃),降温过程中有固体析出;向体系中滴加水(33Kg,15V),将体系在室温下(10-15℃)搅拌2小时;将体系冷却至5-10℃,继续搅拌4小时;过滤,滤饼用乙醇水溶液(乙醇:水=1:2,v/v,6.2kg)淋洗;将滤饼在夹套温度45~55℃,真空抽至≤-0.08MPa烘干16小时;共得到棕色固体2.64kg,HPLC纯度94.0%,含量93.4%,含量收率79.04%。
MS-ESI和 1H NMR数据与实施例1一致。
式II化合物的制备
Figure PCTCN2020088122-appb-000026
实施例12 式II化合物的制备
向100ml不锈钢加压釜中依次加入式III化合物(5.0g)、THF(50ml,10V)及钯炭(0.75g,10%Pd/C,50%湿);将体系用氮气置换5次,氢气置换5次;将体系用氢气加压至0.50MPa,加热至25-35℃保温搅拌24小时;将反应溶液用硅藻土过滤,滤饼用四氢呋喃(20ml)淋洗;将滤液浓缩至干,得到4.2g棕色固体,HPLC纯度94.9%,收率93.3%。
MS-ESI:[M+1] +:273.1
1H NMR(400MHz,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).
实施例13 式II化合物的制备
向5000ml不锈钢加压釜中依次加入式III化合物(120.0g)、THF(2400ml,20V)及钯炭(18g,10%Pd/C,50%湿);将体系用氮气置换5次,氢气置换5次;将体系用氢气加压至0.50MPa,加热至25-35℃保温搅拌24小时;将反应液铺硅藻土过滤,滤饼用四氢呋喃(600ml)淋洗(直到TLC显示几乎无荧光);将滤液浓缩得到130g黑色半油状固体,HPLC纯度91.7%,收率120.26%。
MS-ESI和 1H NMR数据与实施例12一致。
实施例14 式II化合物的制备
向5L不锈钢加压釜中依次加入式III化合物(100.0g)、THF(2000ml,20V)及钯炭(15.0g,10%Pd/C,50%湿);将体系用氮气置换5次,氢气置换5次;将体系用氢气加压至0.5-1.0MPa,设定夹套温度30℃,保温搅拌16小时;将反应液铺硅藻土过滤,滤饼用THF(1000ml)洗涤;共得到式II化合物的THF溶液3877g。
后处理一:取上述滤液(1820g,按100%收率折算约含40g式II化合物),用旋转蒸发仪将其浓缩至(2-3V,80-120ml);将体系用乙醇(150ml×2)置换至(2-3V,80-120ml);共得到式II化合物的乙醇溶液78g,含量为47.25%,含量收率92.14%。
后处理二:取上述滤液(450g,按100%收率折算约含10g式II化合物),用旋转蒸发仪将其浓缩至干;共得到10.5g棕红色固体。
后处理三:取上述滤液(450g,折算约10g式II化合物)至烧瓶中;用旋转将其浓缩至约30-40ml(3-4V);用乙醇(50ml×2)将浓缩剩余置换至约30-40ml(3-4V);得到黑色油状浓缩剩余,该浓缩剩余直接投入下一步反应。
MS-ESI和 1H NMR数据与实施例12一致。
实施例15 式II化合物的制备
向500ml三颈烧瓶中依次加入四氢呋喃(240ml,20V)、式III化合物(12.0g)及钯炭(1.8g,5%Pd/C,50%湿);将体系用氮气置换5次,氢气置换5次;将体系在氢气压力(大概0.1MPa)下及室温(25-30℃),保温搅拌48小时;将反应液过滤,滤饼用四氢呋喃(60ml)洗涤;将合并的滤液用旋蒸浓缩至20-30ml;用乙醇(60ml×2)置换至20-30ml;共得到24g式II化合物的乙醇溶液,该溶液直接用于下一步反应。
MS-ESI和 1H NMR数据与实施例12一致。
实施例16 式II化合物的制备
向5000ml三颈烧瓶中依次加入四氢呋喃(1500ml,15V)、式III化合物(100g)及钯炭(15g,5%Pd/C,50%湿);将体系用氮气置换5次,氢气置换5次;将体系在氢气压力(大概0.1MPa)下及室温(20-25℃),保温搅拌48小时;将反应液过滤,滤饼用四氢呋喃(200ml)洗涤;将合并的滤液用旋蒸浓缩至200-300ml;共得到185.6g式II化合物的THF溶液,HPLC纯度94.2%含量43.2%,含量收率94.0%。
MS-ESI和 1H NMR数据与实施例12一致。
实施例17 式II化合物的制备
向20000ml三颈烧瓶中依次加入四氢呋喃(12400ml,20V)、式III化合物(620g)及钯炭(93g,5%Pd/C,50%湿);将体系用氮气置换5次,氢气置换5次;将体系在氢气压力(大概0.1MPa)下及室温(30-35℃),保温搅拌48小时;将反应液铺硅藻土(200g)过滤,滤饼用四氢呋喃(1200ml)洗涤;将合并的滤液用旋蒸浓缩至1200-1800ml;共得到式II化合物的四氢呋喃溶液1664g,HPLC纯度93.8%,含量34.57%,含量收率110.6%。
MS-ESI和 1H NMR数据与实施例12一致。
实施例18 式II化合物的制备
向250ml高压反应釜中加入THF(140ml,70V)、式III化合物(2.0g)和钯炭(0.3g,5%Pd/C,50%湿);盖上釜盖,拧紧螺帽;用氮气置换三次,氢气置换三次;向反应釜内用氢气充入0.50±0.05M Pa左右的压力,关闭进气阀门;开启搅拌装置,转速500r/min;反应釜在25-35℃下保持氢气压力在0.5±0.05M Pa,搅拌反应进行96h;将反应液铺硅藻土(10g)过滤,滤饼用四氢呋喃(60ml)洗涤;将合并的滤液用旋蒸浓缩至干得1.8g半油状固体,HPLC纯度为91.2%。收率99.9%。
MS-ESI和 1H NMR数据与实施例12一致。
实施例19 式II化合物的制备
向500L高压反应釜中加入THF(167Kg,70V),式III化合物(2.64Kg)和钯炭(0.4Kg,5%Pd/C,50%湿);用氮气置换五次,氢气置换五次;向反应釜内用氢气充入0.50±0.05M Pa左右的压力,关闭进气阀门;开启搅拌装置;反应釜在25-35℃下保持氢气压力在0.5±0.05M Pa,搅拌反应进行120h;压滤,滤饼用四氢呋喃(13Kg)洗涤;将合并的滤液减压蒸馏(减压蒸馏到2V~3V)得式II化合物的四氢呋喃溶液:11Kg;HPLC纯度90.7%,含量18.5%;含量收率91.9%。
MS-ESI和 1H NMR数据与实施例12一致。
实施例20 式II化合物的制备
向100ml不锈钢加压釜中依次加入加入四氢呋喃(60ml,12V)、式III化合物(5.0g)及钯炭(0.75g,5%Pd/C,50%湿);将体系用氮气置换5次,氢气置换5次;将体系用氢气加压至0.5-1.0MPa,设定夹套温度为30℃,保温搅拌42小时;反应结束,将反应液铺硅藻土过滤,滤饼用THF(100ml)洗涤;共得到式II化合物的THF溶液197.8g;溶液用旋转蒸发仪将其浓缩至(2-3V,10-15ml);将体系用乙醇(25ml×2)置换至(2-3V,10-15ml);得到的式II化合物乙醇溶液直接用于下一步反应。
MS-ESI和 1H NMR数据与实施例12一致。
式I化合物的制备
Figure PCTCN2020088122-appb-000027
式I化合物的制备
实施例21 式I化合物的制备
向250mL三颈烧瓶中加入式II化合物(5g,1.0eq)、原乙酸三甲酯(6.6g,3.0eq)和THF(125mL);在氮气保护下,将体系加热到回流;向三颈烧瓶中加入吡啶盐酸盐(210mg,0.1eq);在氮气保护下,将体系加热至75±5℃(内温60-63℃)下反应8h,HPLC监测显示式II化合物转化完全,剩余反应液中式I化合物纯度为93.1%。
将体系降温至室温,将体系反应液旋转蒸发浓缩至基本无馏分流出;向体系中加入水(50mL),并用4M氢氧化钠水溶液调节体系pH值至9-10;将体系用乙酸乙酯(50mL)萃取,过滤,滤饼用乙酸乙酯(10mL)淋洗,得到3.5g式I化合物滤饼湿品,LC-MS检测显示式I化合物纯度为99.22%;将过滤及淋洗所得滤液分液,水相用乙酸乙酯(50mL)萃取,合并有机相,并浓缩至干,得2.8g式I化合物粗品,LC-MS检测显示式I化合物纯度为95.08%。
MS-ESI:[M+1] +:297.0
1H NMR(400MHz,DMSO):8.78(s,1H),8.32(d,1H),7.25(d,1H),4.60(m,1H),4.10-4.13(t,2H),3.91(m,1H),2.93-2.98(m,1H),2.80-2.86(m,1H),2.84(s,3H),2.50(m,1H),2.16-2.19(m,1H),1.99-2.02(m,1H),1.69-1.77(m,1H).
实施例22 式I化合物的制备
向3L三颈烧瓶中加入式II化合物(54.0g,1.0eq)、原乙酸三甲酯(71.5g,3.0eq)和THF(1.35L);在氮气保护下,将体系加热到回流;向三颈烧瓶中加入吡啶盐酸盐(2.27g,0.1eq);在氮气保护下,将体系加热至75±5℃(内温60-63℃)并反应8h,HPLC监测显示体系中剩余1.5%式II化合物;将体系冷却至室温,向其中补加原乙酸三甲酯(11.9g,0.5eq)和吡啶盐酸盐(1.14g,0.05eq);在氮气保护下,将体系加热至75±5℃(内温60-63℃)并反应4h,HPLC监测显示体系中剩余0.4%式II化合物,体系反应液中式II化合物纯度为91.6%。
将体系降温至室温,将体系反应液旋转蒸发浓缩至基本无馏分流出;向体系中加入水(540mL,10V),并用4M氢氧化钠水溶液调节体系pH值至9-10;过滤,滤饼依次用水(270mL)和MTBE(270mL)淋洗,所得滤饼于50℃真空干燥16h,得56g式II化合物粗品,HPLC纯度为96.32%;将所得粗品于600mL甲醇中溶清,向其中加入硅基金属消除剂(43g)和活性炭(5.4g),然后将混合液加热至回流并保温1h(内温50℃);将体系冷却至室温,垫硅藻土过滤,并用甲醇(15mL)淋洗至滤液几乎无荧光;浓缩甲醇溶液至干且馏出液滴速明 显变慢,向所得固体中加入MTBE(540mL),将其加热至50℃并回流搅拌1h至全部溶清;将体系冷却至10-15℃并搅拌1h,过滤,滤饼用冷MTBE(100mL)淋洗;所得滤饼于50℃下真空干燥16h得28.0g式I化合物,HPLC纯度为98.8%。
从母液中回收式I化合物:
将前步所得滤液再次浓缩至干,得约23g淡黄色固体;向其中加入MTBE(230mL),升温至50℃,并回流10分钟;向体系中分分批次加入甲醇,至甲醇的总加入量为约30mL,物料基本溶清;将体系降温至10-15℃并搅拌1h;过滤,滤饼用冷MTBE(50mL)淋洗;所得滤饼于50℃下真空干燥16小时,得到8.7g式I化合物的类白色固体,HPLC纯度为97.8%。
进一步精制:
向反应瓶中加入前一步所得纯度为97.8%的式I化合物(共11.7g)及MTBE(60mL),将体系在室温下打浆4h,过滤,滤饼用MTBE(20mL)洗涤,然后将滤饼于50℃真空干燥16h,得到10.8g类白色式I化合物,HPLC纯度为98.1%。
上述式I化合物产品的MS-ESI和 1H NMR数据均与实施例21一致。
实施例23 式I化合物的制备
取实施例14制备得到的未经后处理的式II化合物的THF溶液(45g,其中含式II化合物约1g,1eq)投放至烧瓶中,将该溶液旋转蒸发浓缩至3mL。向烧瓶中加入甲苯(5mL),继续旋转蒸发至3mL,将该步骤进行两次,得到黑色油状浓缩剩余物。
向100mL三颈烧瓶中加入1.0g前步所得黑色油状浓缩剩余物、原乙酸三甲酯(1.32g,3.0eq)及THF(25mL);在氮气保护下,将体系加热到回流;向三颈瓶中加入吡啶盐酸盐(0.08g,0.2eq);在氮气保护下,将体系加热至65-70℃(内温)下反应5h;取样检测,HPLC显示反应液中式II化合物剩余0.48%,式I化合物纯度为90.10%;继续回流反应5h,取样检测,HPLC显示反应液中式II化合物转化完全,式I化合物纯度为91.79%。
实施例24 式I化合物的制备
取实施例14制备得到的未经后处理的式II化合物的THF溶液(450g,其中含式II化合物约10.0g,1eq)投放至烧瓶中,将该溶液旋转蒸发浓缩至20-30mL。向烧瓶中加入甲苯(50mL),继续旋转蒸发至20-30mL,将该步骤进行两次,得到黑色油状浓缩剩余物,将其于THF(20mL,2V)中溶清。
向500mL三颈烧瓶中加入前步所得THF溶液、原乙酸三甲酯(13.2g,3.0eq)及THF(230mL);在氮气保护下,将体系加热到回流;向三颈瓶中加入吡啶盐酸盐(0.8g,0.2eq);在氮气保护下,将体系加热至65-70℃(内温)下反应10h;取样检测,HPLC显示反应液中式II化合物剩余0.7%,式I化合物纯度为90.1%。
将体系降温至室温,加入水(20mL,2V);将体系旋转蒸发浓缩至基本无馏分流出;向体系中补加水(100mL,10V);然后将体系用饱和碳酸钾水溶液调节pH值至9;过滤,滤 饼依次用水(50mL,5V)和MTBE(50mL,5V)淋洗;将淋洗后所得滤饼于50℃下真空干燥16h,得9.2g式I化合物的土黄色粗品,HPLC纯度为89.7%,粗收率84.5%。
式I化合物的精制:
将前步制得的纯度为89.7%的式I化合物粗品(5.0g)与乙醇(50mL)加入至烧瓶中,室温搅拌20分钟,至物料基本溶清;向体系中加入硅胶(5.0g,1X),旋转蒸发浓缩至干待用;将旋干后的固体粗品过硅胶柱(40g,8X),以乙酸乙酯、石油醚混合溶液洗脱(V EA:V PE=2:1);通过TLC检测,收集含有式I化合物的组分并浓缩至干,得到0.5g HPLC纯度为96.5%的式I化合物及3.2g HPLC纯度为99.3%的浅黄色式I化合物。
将HPLC纯度为99.3%的式I化合物及MTBE(30mL)加入至烧瓶中,加热至回流,并回流1h;将体系降温至5-10℃,保温搅拌1h,过滤,滤饼用MTBE(5mL)淋洗后,将滤饼于50℃下真空干燥16h,得到式I化合物的浅黄色至类白色固体2.8g,HPLC纯度为99.8%,无含量>0.1%的杂质,第二步和第三步总收率为47.3%。
实施例25 式I化合物的制备
取实施例14制备得到的未经后处理的式II化合物的THF溶液(130g,其中含式II化合物约56g,1eq)投放至烧瓶中,将该溶液以甲苯(280mL*2)置换浓缩至约120-180mL,继续以THF(280mL)置换浓缩至约120-180mL后,加入THF(500mL)至固体溶清,将所得溶液转移至2L三颈瓶中;继续向体系中加入THF(700mL)和原乙酸三甲酯(74.0g,3.0eq);在氮气保护下,将体系加热至回流;向三颈瓶中加入吡啶盐酸盐(4.5g,0.2eq);在氮气保护下,将体系加热至70~75℃(内温)下反应10h;取样检测,HPLC显示反应液中式II化合物剩余0.1%,式I化合物纯度为93.20%。
将上述反应液冷却至室温,取部分反应液(对应反应前含55g含式II化合物规模)加入水(110mL,2V),然后旋转蒸发浓缩至110-160mL(2-3V);向浓缩剩余中缓慢加入水(400mL,7V);将体系在室温下搅拌30min,然后加入水(440mL,8V),并在室温(25-30℃)下搅拌30min;用50%碳酸钾溶液(1.5g(全溶液质量))调节体系pH至8-9;将体系在室温下(25-30℃)下搅拌30min;降温至10-15℃,并在10-15℃下搅拌2h,抽滤,滤饼用水(100mL)淋洗,将滤饼于50℃干燥24h,得到55g土黄色式I化合物粗品,纯度为96.6%,含量为87.53%,粗品含量收率为80.4%:
式I化合物的精制:
将前步所得HPLC纯度为96.6%的式I化合物粗品(55g)、硅胶(110g,2X)及乙醇(500mL)加入到烧瓶中;将体系加热至50℃,并在50℃搅拌30分钟;将体系旋转蒸发浓缩至基本无馏分流出,然后以正庚烷(200mL)置换至干,向其中混合硅胶,并通过硅胶柱(550g,10X)洗脱,洗脱液为乙酸乙酯正庚烷混合液(V EA:V n-heptane=1:1至纯EA);通过TLC检测,收集式I化合物组分A和交叉组分B。
将组分A旋转蒸发浓缩至约100mL,将浓缩剩余物用约200mL甲醇置换2次,然后用MTBE(约200mL)置换2次,随后向其中加入约300mL MTBE;将体系加热至回流,并 回流1h,而后降温至室温(25-30℃),并在室温下搅拌(1h);将体系降温至5-10℃,并在5-10℃下搅拌2h,过滤,滤饼用MTBE(30mL)淋洗;将淋洗后的滤饼于50℃真空干燥16小时,得到式I化合物的浅黄色固体37.6g,HPLC纯度为99.85%,且无含量>0.1%杂质。
将组分B旋转蒸发浓缩至干,用MTBE(50mL)热打浆1h,然后将体系降温至5-10℃,并在5-10℃下搅拌2h,过滤,滤饼用MTBE(10mL)淋洗;将淋洗后的滤饼于50℃真空干燥16小时,得到式I化合物的浅黄色固体6g,HPLC纯度为99.35%,有2个含量>0.1%的杂质。
将上述纯度为99.35%的式I化合物(4.8g)、MTBE(50mL)及乙醇(5mL)加入至烧瓶中,加热至55-60℃,回流0.5h后将体系降温至室温(25-30℃),并在室温下搅拌1h;将体系降温至5-10℃,并在5-10℃下搅拌2h;过滤,滤饼用MTBE(10mL)淋洗;将淋洗后的滤饼于50-55℃下真空干燥16小时,得到4.0g式I化合物,纯度为99.75%,且无含量>0.1%杂质。
实施例26 式I化合物的制备
取实施例14制备得到的未经后处理的式II化合物的THF溶液(14.5g,其中含式II化合物约5.0g,1eq)投放至烧瓶中,将该溶液以甲苯(25mL*2)置换浓缩至约10-15mL,继续以THF(25mL)置换浓缩至约10-15mL后,加入THF(115mL)至固体溶清,将所得溶液转移至500mL三颈瓶中;继续向体系中加入原乙酸三甲酯(6.6g,3.0eq);在氮气保护下,将体系加热至回流;向三颈瓶中加入吡啶盐酸盐(0.42g,0.2eq);在氮气保护下,将体系加热至70~75℃(内温)下反应15h;取样检测,HPLC显示反应液中式II化合物剩余4.0%;向体系中补加原乙酸三甲酯(0.5g)及吡啶盐酸盐(0.1g),继续将体系在70~75℃(内温)回流5小时;取样检测,HPLC显示反应液中式II化合物剩余0.05%,式I化合物纯度为92.80%。
实施例27 式I化合物的制备
取实施例14制备得到的未经后处理的式II化合物的THF溶液(817g,其中含式II化合物约282.6g,1eq)投放至烧瓶中,将该溶液以甲苯(约1400mL*2)置换浓缩至约550-850mL,继续以THF(约1400mL*2)置换浓缩至约550-850mL后,加入THF(约6500mL)至固体溶清,将所得溶液转移至10L三颈瓶中;继续向体系中加入原乙酸三甲酯(374.0g,3.0eq);在氮气保护下,将体系加热至回流;向三颈瓶中加入吡啶盐酸盐(24.0g,0.2eq);在氮气保护下,将体系加热至70-75℃(内温)下反应12h;取样检测,HPLC显示反应液中式II化合物剩余4.1%,式I化合物纯度为85.5%,向反应体系中补加入原乙酸三甲酯(22g)及盐酸吡啶(1.4g),在氮气保护下,将体系加热至70~75℃(内温)下反应5h;取样检测,HPLC显示反应液中式II化合物剩余0.7%,式I化合物纯度为91.4%。
将前步所得反应液冷却至室温,向其中加入570g水后,旋转蒸发至600-900mL(2-3V),然后将所得浓缩剩余物转移入10L烧瓶中,向其中缓慢加入2000g水(约7V),将体系在室温下搅拌1小时,然后加入2300g水(约8V),将体系在室温(25-30℃)下搅拌1小时,用50%碳酸钾溶液(8.5g)将体系pH调节至8-9;将体系在室温下(25-30℃)下搅拌1小时;将 体系降温至10-15℃,并在10-15℃下搅拌2h,过滤,滤饼用水(500g)淋洗;将淋洗后的滤饼于50℃干燥72小时,取样检测水分,卡尔费休法检测得到水分含量KF为3.2%,得到252g土黄色式I化合物粗品,HPLC纯度为97.5%,含量为89.8%,粗品含量收率为72.3%。
式I化合物精制:
将前步所得252g式I化合物粗品及乙醇(1004g,~1000mL)加入到烧瓶中;将体系加热至50-60℃,并在50-60℃搅拌30分钟,至物料基本溶清;将体系平均分成两份,每份加入硅胶(252g),分别旋转蒸发浓缩至基本无馏分流出;将每份用正庚烷(272g,~400mL)置换至基本无馏分流出,待用;使用硅胶(3000g,200-300目)和正庚烷(5.4kg,~8L)填充压实硅胶柱,并对前步所得粗品固体进行柱层析分离,以正庚烷、乙酸乙酯混合液(1:1V/V,15.5kg,~20L;1:2V/V,28.5kg,~35L;1:5V/V,25.5kg,~25L)及纯乙酸乙酯(62kg,70L洗脱;通过TLC检测,收集式I化合物组分A和交叉组分B。
旋转蒸发浓缩组分A至基本无馏分流出;将浓缩剩余物转移至2000mL烧瓶中,并用MTBE(370g,~500mL)置换至基本无馏分流出;向浓缩剩余物中加入MTBE(1330g,~1800mL);将体系加热至回流,并回流1h;而后将体系降温至室温(25-30℃),并在室温下搅拌(1h);将体系降温至5-10℃,并在5-10℃下搅拌2h;过滤,滤饼用MTBE(75g,~100mL)淋洗,淋洗后的滤饼HPLC纯度为99.9%;将滤饼于50℃真空干燥16小时,得到190g式I化合物,HPLC纯度99.9%,KF检测水分含量0.07%。
旋转蒸发浓缩组分B至干,将所得固体转移至500mL单口瓶中;用MTBE(85g,~120mL)置换至基本无馏分流出;向所得浓缩剩余物中加入MTBE(200g,~300mL)及甲醇(23g,~30mL);将体系加热至回流,并回流1h;将体系降温至室温(25-30℃),并在室温下搅拌(1h);将体系降温至5-10℃,并在5-10℃下搅拌1h;过滤,滤饼用MTBE(22g,~30mL)淋洗;淋洗后的滤饼于50℃真空干燥16小时;得到20g式I化合物的浅黄色固体,HPLC纯度为99.6%。
实施例28 式I化合物的制备
取实施例19制备得到的式II化合物的THF溶液(27.0g,其中含式II化合物约5.0g,1eq)投放至烧瓶中,将该溶液以甲苯(25mL*2)置换浓缩至约10-15mL,继续以THF(25mL)置换浓缩至约10-15mL后,加入THF(115mL)至固体溶清,将所得溶液转移至500mL三颈瓶中;继续向体系中加入原乙酸三甲酯(6.6g,3.0eq);在氮气保护下,将体系加热至回流;向三颈瓶中加入吡啶盐酸盐(0.42g,0.2eq);在氮气保护下,将体系加热至70~75℃(内温)下反应12h;取样检测,HPLC显示反应液中式II化合物剩余0.19%,式I化合物纯度为93.3%。
实施例29 式I化合物的制备
取实施例19制备得到的式II化合物的THF溶液(5.40kg,其中含式II化合物约1.0kg,1eq)投放至烧瓶中,将该溶液以甲苯(4.3kg*2)置换浓缩至约2L,继续以THF(4.3kg)置换 浓缩至约2L,加入THF(19kg)后转移至50L反应釜中;继续向体系中加入原乙酸三甲酯(1.32kg,3.0eq);在氮气保护下,将体系加热至回流;向三颈瓶中加入吡啶盐酸盐(85.0g,0.2eq);在氮气保护下,将体系加热至70-75℃(内温)下反应12h;取样检测,HPLC显示反应液中式II化合物剩余4.22%,式I化合物纯度为80.30%,向反应体系中补加入原乙酸三甲酯(80g)及盐酸吡啶(5g),在氮气保护下,将体系加热至70~75℃(内温)下反应5h;取样检测,HPLC显示反应液中式II化合物剩余0.56%,式I化合物纯度为92.48%。
将前步反应液降温至25℃,加水2.0kg;在45±5℃温度下减压蒸馏至2L体积,向旋蒸瓶中加水2L,并将瓶内料液转至反应釜内,缓慢加水5kg,并在25℃下搅拌1小时;继续向反应釜内加水5kg,在25℃下搅拌1小时;向反应釜内滴加32g 50%碳酸钾溶液,调节体系pH至8~9,并在25℃下搅拌1小时;将反应釜内料液降温至10~15℃,搅拌2小时;过滤,滤饼用2kg水淋洗,后将滤饼于45~55℃真空干燥48小时,得0.91kg式I化合物,KF检测水分含量0.2%,HPLC纯度95.71%;含量为85.39%;含量收率为71.4%。
式I化合物的精制:
将前步所得HPLC纯度为95.71%的式I化合物(0.91kg)及乙醇(3.6kg)加入到20L旋蒸瓶中;将体系加热至50-60℃,并在50-60℃搅拌30分钟,使物料基本溶清;将硅胶(1.82kg)加入到上述旋蒸瓶中,然后在50-60℃下减压浓缩至干成粉末状;将正庚烷(1.82kg)加入到上述旋蒸瓶中,然后在40-50℃下减压浓缩置换至干成粉末状;准备已清洗干净的合适层析柱,然后将硅胶(11kg,200-300目)加入到层析柱中,用氮气压实;将正庚烷(27kg)加入到层析柱中并用氮气压实;将前步浓缩干的式I化合物固体硅胶样加入到层析柱中,用正庚烷(18kg)、正庚烷/乙酸乙酯混合液(1:1V/V,72kg;1:2V/V,158kg;1:5V/V,142kg)、正庚烷/乙酸乙酯混合液(1:5V/V,70kg)、正庚烷/乙酸乙酯混合液(1:5V/V,175kg)、乙酸乙酯(205kg)依次洗脱层析柱,TLC检测,收集式I化合物组分A和交叉组分B。
将组分A置于50L反应釜中,在40-50℃下减压浓缩至最小搅拌体积(~6L);向反应釜中加入MTBE(5.0kg*5),浓缩置换5次;将MTBE(1.2kg)加入到反应釜中,加热体系至回流(50-60℃),并保温回流1h;将体系降温至20-30℃,并在20-30℃保温搅拌(1h);将体系降温至5-10℃,并在5-10℃下搅拌2h;过滤,滤饼用MTBE(0.25kg)淋洗;得0.62kg式I化合物,HPLC纯度100.0%;将滤饼继续于50℃真空干燥16小时,得式I化合物0.55kg,KF检测水分含量0.04%,Pd残留<2ppm。
将组分B加入到反应瓶中,45-50℃水浴减压浓缩至最小搅拌体积(约1L);向反应瓶中加入MTBE(1.5kg*2),45~50℃水浴加热减压蒸馏至最小搅拌体积,置换两次;向反应瓶中加入MTBE(1.5kg)、无水乙醇(0.14kg),加热至50-60℃,搅拌1小时;冷却,反应瓶内料液温度降至20-25℃,保温搅拌1小时;冷却,反应瓶内料液温度降至6-10℃,保温搅拌2小时;过滤,滤饼用MTBE(0.24kg)洗涤;将滤饼、MTBE(1.5kg)\无水乙醇(0.14kg)加入到反应瓶中;搅拌,加热升温至50-60℃,保温搅拌1小时;冷却,反应瓶内料液温度降至20-25℃,保温搅拌1小时;冷却,反应瓶内料液温度降至6-10℃,保温搅拌2小时;过滤,滤饼用MTBE(0.24kg)洗涤;得到湿品115g,HPLC纯度99.8%,最大单杂含量0.09%;将 所得湿品在45-55℃、真空度≤-0.080MPa条件下烘干16小时;得0.10kg式I化合物,KF检测水分含量为0.08%,HPLC纯度99.8%,最大单杂含量0.09%,Pd残留≤2ppm。
以下实施例除另有提及,均以实施例27最终精制得到的式I化合物作为原料。
式I化合物晶型1的制备
实施例30
将实施例21所得式I化合物滤饼湿品与粗品合并,以甲醇(40mL)溶解;向该甲醇溶液中加入硅基金属消除剂(4.0g)和活性炭(1.0g),后加热至50℃搅拌1h;将体系冷却降温至10±5℃并在该温度搅拌0.5h;过滤,滤饼用MTBE(15mL)淋洗;然后将滤饼在50℃下真空干燥16小时,得到2.5g式I化合物的类白色固体,HPLC纯度为98.4%。经检测,该固体为式I化合物晶型1,其XRPD、DSC、TGA和DVS图谱分别如图1-4所示。
式I化合物盐酸盐晶型A的制备
实施例31
称取约50mg式I化合物至小瓶中,加入2.5mL丙酮,超声加热直至完全溶解,配制成20mg/mL的式I化合物的丙酮溶液。将样品瓶置于磁力搅拌板上,在磁力搅拌下,缓慢滴加0.73mL盐酸的丙酮溶液(盐酸的丙酮溶液浓度为25mg/mL),有白色沉淀析出,室温下盖紧瓶盖继续搅拌1天,然后将混悬反应液离心,将收集的固体在40℃下真空干燥过夜,得到式I化合物盐酸盐固体。经检测,该固体为式I化合物盐酸盐晶型A,其XRPD、DSC图谱分别如图6和图7所示。
式I化合物盐酸盐晶型B的制备
实施例32
称取约50mg式I化合物至小瓶中,加入2.5mL乙酸乙酯,超声加热直至完全溶解,配制成20mg/mL的式I化合物的乙酸乙酯溶液。将样品瓶置于磁力搅拌板上,在磁力搅拌下,缓慢滴加0.73mL盐酸的乙酸乙酯溶液(盐酸的乙酸乙酯溶液浓度为25mg/mL),有白色沉淀析出,室温下盖紧瓶盖继续搅拌1天,然后将混悬液离心,将收集的固体在40℃下真空干燥过夜,得到式I化合物盐酸盐固体。经检测,该固体为式I化合物盐酸盐晶型B,其XRPD、DSC图谱分别如图8和图9所示。
式I化合物盐酸盐晶型C的制备
实施例33
称取5mg实施例31所得式I化合物盐酸盐晶型A至小瓶中,加入适量甲醇,将得到样品的混悬液于室温下磁力搅拌过夜后,离心分离固液,收集固体,在40℃下真空干燥过 夜,得到式I化合物盐酸盐固体。经检测,该固体为式I化合物盐酸盐晶型C,其XRPD、DSC图谱分别如图10和图11所示。
实施例34-36
采用与实施例33相同的结晶方法,分别将溶剂替换为乙腈、正庚烷和甲乙酮来制备式I化合物盐酸盐晶型C。经检测,实施例35-实施例37制得的固体化合物的XRPD图谱均与图10一致。
式I化合物硫酸盐晶型D的制备
实施例37
称取约50mg式I化合物至小瓶中,加入2.5mL丙酮,超声加热直至完全溶解,配制成20mg/mL的式I化合物的丙酮溶液。将样品瓶置于磁力搅拌板上,在磁力搅拌下,缓慢滴加0.77mL硫酸的丙酮溶液(硫酸的丙酮溶液浓度为25mg/mL),有白色沉淀析出,室温下盖紧瓶盖继续搅拌1天,然后将混悬液离心,将收集的固体在40℃下真空干燥过夜,得到式I化合物硫酸盐固体。经检测,该固体为式I化合物硫酸盐晶型D,其XRPD、DSC图谱分别如图12和图13所示。
式I化合物磷酸盐晶型E的制备
实施例38
称取约50mg式I化合物至小瓶中,加入2.5mL丙酮,超声加热直至完全溶解,配制成20mg/mL的式I化合物的丙酮溶液。将样品瓶置于磁力搅拌板上,在磁力搅拌下,缓慢滴加0.86mL磷酸的丙酮溶液(磷酸的丙酮溶液浓度为25mg/mL),有白色沉淀析出,室温下盖紧瓶盖继续搅拌1天,然后将混悬液离心,将收集的固体在40℃下真空干燥过夜,得到式I化合物磷酸盐固体。经检测,该固体为式I化合物磷酸盐晶型E,其XRPD、DSC图谱分别如图14和图15所示。
使用离子色谱法对式I化合物磷酸盐晶型E进行成盐比例测试:
称取约0.5g式I化合物磷酸盐晶型E于液相小瓶中,加入1mL水完全溶解,作为样品溶液。将磷酸标准溶液的原液(1000ppm)用水分别稀释10倍和20倍,得到100ppm和50ppm的标准样品溶液。
分别对样品溶液和标准品溶液进行离子色谱测试,测试方法见表16,以标准样品溶液中反离子的浓度对应离子色谱上反离子的峰面积作标准曲线,采用外标法,计算各样品中反离子的浓度,算出式I化合物磷酸盐晶型E中的反离子含量,确定式I化合物磷酸盐晶型E中式I化合物与对应反离子的成盐比例。
表16离子色谱测定方法
Figure PCTCN2020088122-appb-000028
Figure PCTCN2020088122-appb-000029
式I化合物磷酸盐晶型E中反离子含量测定结果见表17,测得0.5g式I化合物磷酸盐晶型E中,式I化合物与磷酸以摩尔比1:1.1投料反应,所得磷酸盐中磷酸根离子实测含量为25.6%,与理论含量24.9%基本相符,成盐摩尔比为1:1.04(式I化合物:磷酸)。
表17式I化合物磷酸盐晶型E中反离子含量测定结果
Figure PCTCN2020088122-appb-000030
实施例39
称取5mg实施例38所得式I化合物磷酸盐晶型E至小瓶中,加入适量甲醇,将得到样品的混悬液于室温下磁力搅拌过夜后,离心分离固液,收集固体,在40℃下真空干燥过夜,得到式I化合物磷酸盐固体。经检测,该固体仍为式I化合物磷酸盐晶型E,其XRPD图谱与图14一致。
实施例40-42
采用与实施例39相同的方法,分别将溶剂替换为乙腈、正庚烷和甲乙酮来制备式I化合物磷酸盐晶型E。经检测,实施例40-实施例42制得的固体化合物的XRPD图谱均与图14一致。
式I化合物磷酸盐晶型F的制备
实施例43
称取约500mg式I化合物至小瓶中,加入20mL丙酮,超声加热直至样品完全溶解,得到25mg/mL的式I化合物的丙酮溶液,将样品瓶置于磁力加热搅拌器上,磁力搅拌并缓慢滴加8.57mL磷酸的丙酮溶液(磷酸的丙酮溶液浓度为25mg/mL),过夜,将混悬液抽滤,固体50℃真空干燥,收集固体并转移到100mL玻璃瓶中,缓慢滴加甲醇,室温下磁力搅拌,直至溶液澄清,再用反溶剂乙酸异丙酯将溶液稀释10倍,搅拌过夜后将混悬液抽滤,固体50℃真空干燥,收集固体,得到式I化合物磷酸盐固体。经检测,该固体为式I化合物磷酸盐晶型F,其XRPD、DSC和DVS图谱,以及经DVS测试后的XRPD图谱分别如图16-图19所示。
式I化合物甲磺酸盐晶型G的制备
实施例44
称取约50mg式I化合物至小瓶中,加入2.5mL丙酮,超声加热直至完全溶解,配制成20mg/mL的式I化合物的丙酮溶液。将样品瓶置于磁力搅拌板上,在磁力搅拌下,缓慢滴加0.73mL甲磺酸的丙酮溶液(甲磺酸的丙酮溶液浓度为25mg/mL),有白色沉淀析出,室温下盖紧瓶盖继续搅拌1天,然后将混悬反应液离心,将收集的固体在40℃下真空干燥过夜,得到式I化合物甲磺酸盐固体。经检测,该固体为式I化合物甲磺酸盐晶型G,其XRPD、DSC和DVS图谱分别如图20、图21和图22所示。
式I化合物氢溴酸盐晶型H的制备
实施例45
称取约50mg式I化合物至小瓶中,加入2.5mL丙酮,超声加热直至完全溶解,配制成20mg/mL的式I化合物的丙酮溶液。将样品瓶置于磁力搅拌板上,在磁力搅拌下,缓慢滴加1.32mL氢溴酸的丙酮溶液(氢溴酸的丙酮溶液浓度为25mg/mL),有白色沉淀析出,室温下盖紧瓶盖继续搅拌1天,然后将混悬反应液离心,将收集的固体在40℃下真空干燥过夜,得到式I化合物氢溴酸盐固体。经检测,该固体为式I化合物氢溴酸盐晶型H,其XRPD和DSC图谱分别如图23和图24所示。
实施例46
称取5mg实施例46所得式I化合物氢溴酸盐晶型H至小瓶中,加入适量乙腈,将得到样品的混悬液于室温下磁力搅拌过夜后,离心分离固液,收集固体,在40℃下真空干燥过夜,得到式I化合物氢溴酸盐固体。经检测,该固体仍为式I化合物氢溴酸盐晶型H,其XRPD图谱与图23一致。
实施例47
采用与实施例46相同的方法,将溶剂替换为甲乙酮制备式I化合物氢溴酸盐晶型H。经检测,实施例48制得的固体化合物的XRPD图谱与图23一致。
式I化合物氢溴酸盐晶型J的制备
实施例48
称取约50mg式I化合物至小瓶中,加入2.5mL乙酸乙酯,超声加热直至完全溶解,配制成20mg/mL的式I化合物的乙酸乙酯溶液。将样品瓶置于磁力搅拌板上,在磁力搅拌下,缓慢滴加1.32mL氢溴酸的乙酸乙酯溶液(氢溴酸的乙酸乙酯溶液浓度为25mg/mL),有白色沉淀析出,室温下盖紧瓶盖继续搅拌1天,然后将混悬反应液离心,将收集的固体在40℃下真空干燥过夜,得到式I化合物氢溴酸盐固体。经检测,该固体为式I化合物氢溴酸盐晶型J,其XRPD如图25所示。
式I化合物氢溴酸盐晶型K的制备
实施例49
称取5mg实施例46所得式I化合物氢溴酸盐晶型H至小瓶中,加入适量正庚烷,将得到样品的混悬液于室温下磁力搅拌过夜后,离心分离固液,收集固体,在40℃下真空干燥过夜,得到式I化合物氢溴酸盐固体。经检测,该固体为式I化合物氢溴酸盐晶型K,其XRPD、DSC和DVS图谱,以及经DVS测试后的XRPD图谱分别如图26-图29所示。
式I化合物富马酸盐晶型L的制备
实施例50
称取约50mg式I化合物至小瓶中,加入2.5mL乙酸乙酯,超声加热直至完全溶解,配制成20mg/mL的式I化合物的乙酸乙酯溶液。将样品瓶置于磁力搅拌板上,在磁力搅拌下,缓慢滴加0.87mL富马酸的乙醇溶液(富马酸的乙醇溶液浓度为25mg/mL),有白色沉淀析出,室温下盖紧瓶盖继续搅拌1天,然后将混悬反应液离心,将收集的固体在40℃下真空干燥过夜,得到式I化合物富马酸盐固体。经检测,该固体为式I化合物富马酸盐晶型L,其XRPD和DSC图谱分别如图30和31所示。
实施例51
采用与实施例50相同的结晶方法,将乙酸乙酯替换为丙酮制备式I化合物富马酸盐晶型L。经检测,实施例51制得的固体化合物的XRPD图谱与图30一致。
式I化合物苯磺酸盐晶型M的制备
实施例52
称取约50mg式I化合物至小瓶中,加入2.5mL丙酮,超声加热直至完全溶解,配制成20mg/mL的式I化合物的丙酮溶液。将样品瓶置于磁力搅拌板上,在磁力搅拌下,缓慢滴加1.34mL苯磺酸的丙酮溶液(苯磺酸的丙酮溶液浓度为25mg/mL),有白色沉淀析出,室温下盖紧瓶盖继续搅拌1天,然后将混悬反应液离心,将收集的固体在40℃下真空干燥过夜,得到式I化合物的苯磺酸盐固体。经检测,该固体为式I化合物苯磺酸盐晶型M,其XRPD、DSC和DVS图谱,以及经DVS测试后的XRPD图谱分别如图32-图35所示。
式I化合物柠檬酸盐晶型N的制备
实施例53
称取约50mg式I化合物至小瓶中,加入2.5mL乙酸乙酯,超声加热直至完全溶解,配制成20mg/mL的式I化合物的乙酸乙酯溶液。将样品瓶置于磁力搅拌板上,在磁力搅拌下,缓慢滴加1.58mL柠檬酸的乙酸乙酯溶液(柠檬酸的乙酸乙酯溶液浓度为25mg/mL),有白色沉淀析出,室温下盖紧瓶盖继续搅拌1天,然后将混悬反应液离心,将收集的固体 在40℃下真空干燥过夜,得到式I化合物的柠檬酸盐固体。经检测,该固体为式I化合物柠檬酸盐晶型N,其XRPD和DSC图谱分别如图36和图37所示。
式I化合物酒石酸盐晶型O的制备
实施例54
称取约50mg式I化合物至小瓶中,加入2.5mL乙酸乙酯,超声加热直至完全溶解,配制成20mg/mL的式I化合物的乙酸乙酯溶液。将样品瓶置于磁力搅拌板上,在磁力搅拌下,缓慢滴加1.12mL L-(+)-酒石酸的乙酸乙酯溶液(L-(+)-酒石酸的乙酸乙酯溶液浓度为25mg/mL),有白色沉淀析出,室温下盖紧瓶盖继续搅拌1天,然后将混悬反应液离心,将收集的固体在40℃下真空干燥过夜,得到式I化合物的L-(+)-酒石酸盐固体。经检测,该固体为式I化合物酒石酸盐晶型O,其XRPD、DSC、TGA和DVS图谱,以及经DVS测试后的XRPD图谱分别如图38-图42所示。
使用 1HNMR法对式I化合物酒石酸盐晶型O进行成盐比例测试:
分别称取约5mg式I化合物和式I化合物酒石酸盐晶型 O至核磁管中,加入0.6mL氘代二甲基亚砜(DMSO d6)溶解样品至澄清溶液,采用Bruker AVANCE 400MHz核磁共振仪按通用方法扫描样品溶液,采集样品的核磁共振一维氢谱数据。
核磁谱图显示式I化合物酒石酸盐晶型 O的 1H NMR谱图相比于式I化合物多了一个氢。由于酒石酸是二元酸,可知游离碱与酒石酸成盐摩尔比为2:1,具体请见图43和图44。
使用化学滴定法对式I化合物酒石酸盐晶型O进行成盐比例测试:
使用非水滴定仪,用甲醇制氢氧化钾滴定液对样品进行滴定,根据滴定液浓度和消耗的滴定液提及,按公式计算样品中酒石酸含量。
表18空白滴定条件
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
表19样品滴定条件
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
ol量取80mL甲醇溶液,置滴定杯中,按空白滴定条件进行滴定,平行滴定三份。精密称定经105℃干燥至恒重的基准邻苯二甲酸氢钾160mg,加入甲醇溶液50mL,超声使溶解后,置滴定杯中,按样品滴定条件进行滴定,平行滴定三份。精密称定式I化合物酒石酸盐晶型O 100mg,加入甲醇溶液80mL,超声使溶解后,置滴定杯中,按样品滴定条件进行滴定,平行滴定三份。
按以下公式计算滴定液的滴定度(T):
Figure PCTCN2020088122-appb-000031
W:基准邻苯二甲酸氢钾称重(g)
V:基准邻苯二甲酸氢钾溶液消耗甲醇制氢氧化钾滴定液体积(mL)
V 0:空白溶液消耗甲醇制氢氧化钾滴定液体积(mL)
M:基准物邻苯二甲酸氢钾的分子量
按以下公式计算样品中酒石酸含量:
Figure PCTCN2020088122-appb-000032
T:经标定的甲醇制氢氧化钾滴定液的滴定度(mol/L)
V:样品溶液消耗甲醇制氢氧化钾滴定液体积(mL)
V 0:空白溶液消耗甲醇制氢氧化钾滴定液体积(mL)
M:酒石酸的分子量
W:样品称重(g)
最终滴定实验结果显示,样品式I化合物酒石酸盐晶型O中含酒石酸19.2w/w%和21.1w/w%,与游离碱:酒石酸摩尔比为2:1的理论值20.2w/w%一致。
实施例55
称取约500mg式I化合物至小瓶中,加入20mL丙酮,超声加热直至完全溶解,配制成25mg/mL的式I化合物的丙酮溶液。将样品瓶置于磁力搅拌板上,在磁力搅拌下,缓慢滴加11.2mL L-(+)-酒石酸的丙酮溶液(L-(+)-酒石酸的丙酮溶液浓度为25mg/mL),搅拌过夜,过滤,将固体在50℃下真空干燥,得到式I化合物的L-(+)-酒石酸盐固体。经检测,该固体为式I化合物酒石酸盐晶型O,其XRPD图谱与图38一致。
实施例56
将2.0g实施例27中由组分A精制得到的HPLC纯度为99.9%的式I化合物与40mL丙酮(20V)加入到烧瓶1#中,搅拌溶清;将0.61g L-(+)-酒石酸与40mL丙酮(20V)加入到烧瓶2#中,搅拌溶清;将2#中的溶液在2-3分钟时间滴加到1#中;将体系升温至50-60℃并搅拌2小时;将体系降温至室温;将体系浓缩至约40mL;将体系在室温25-30℃搅拌1小时;将体系冷却到5-10℃,并在5-10℃下搅拌1小时;过滤,滤饼用鼓风风箱于50-55℃下干燥16小时,得到2.4g产品,HPLC纯度99.6%,收率95.6%。经检测,该固体为式I化合物酒石酸盐晶型O,其XRPD图谱与图38一致。
实施例57
将2.0g实施例27中由组分A精制得到的HPLC纯度为99.9%的式I化合物与40mL丙酮(20V)加入到烧瓶1#中,升温至50-55℃,搅拌溶清;将0.61g L-(+)-酒石酸与40mL丙酮(20V)加入到烧瓶2#中,升温至50-55℃,搅拌溶清;将2#中的溶液在2-3分钟时间滴加到1#中;将体系在45-50℃搅拌2小时;将体系在45-50℃下减压浓缩至40mL;将体系降温至20-25℃,搅拌1小时;将体系降温到5-10℃,并在5-10℃下搅拌1小时;过滤,滤饼用鼓风风箱于50-55℃下干燥16小时,得到2.4g产品,HPLC纯度99.8%,收率95.62%。经检测,该固体为式I化合物酒石酸盐晶型O,其XRPD图谱与图38一致。
实施例58
将36.0g由实施例26组分A精制得到的HPLC纯度为99.85%的式I化合物与720mL丙酮(20V)加入到烧瓶1#中,升温至50-55℃,搅拌溶清;将11.0g L-(+)-酒石酸与720mL丙酮(20V)加入到烧瓶2#中,升温至50-55℃,搅拌溶清;将2#中的溶液在2-3分钟时间滴加到温度处于45-55℃的1#中;将体系在45-50℃下搅拌2小时;将体系减压浓缩至约720mL;将体系冷却到5-10℃,并在5-10℃下搅拌1小时;过滤,滤饼用鼓风风箱于50-55℃下干燥16小时,得到43.6g产品,HPLC纯度99.96%,收率96.6%。经检测,该固体为式I化合物酒石酸盐晶型O,其XRPD图谱与图38一致。
实施例59
将189.6g实施例28中由组分A精制得到的HPLC纯度为99.9%的式I化合物与3792mL丙酮(20V)加入到烧瓶1#中,升温至50-55℃,搅拌溶清;将57.6g L-(+)-酒石酸与3792mL丙酮(20V)加入到烧瓶2#中,升温至50-55℃,搅拌溶清;将2#中的溶液滴加到处于45-55℃的1#中;将体系在45-50℃搅拌2小时;将体系减压浓缩至约3800mL(约20V);将体系降温至17-21℃,搅拌1小时;将体系降温到5-10℃,并在5-10℃下搅拌1小时;过滤,滤饼用鼓风风箱于50-55℃下干燥28小时,得到223.2g产品,HPLC纯度99.98%,收率94.0%。经检测,该固体为式I化合物酒石酸盐晶型O,其XRPD图谱与图38一致。
实施例60
将0.65kg由实施例30中组分A精制方法得到的HPLC纯度为100.0%的式I化合物与7.7kg丙酮加入旋转瓶中,旋转瓶在40~50℃水浴下旋转1小时至溶液澄清;将澄清溶液转入PT1(反应器1)中,经管道过滤器用氮气压入净化区反应釜中;向旋转瓶中加入2.6kg丙酮,洗涤旋转瓶后转入PT1中,经管道过滤器压入反应釜中;将净化室内反应釜内反应液体积标定为13.0L;向旋转瓶中加入7.7kg丙酮和0.198kg L-酒石酸,将旋转瓶在40~50℃水浴下旋转1小时至溶液澄清;将澄清溶液转入PT1中,经管道过滤器用氮气压入PT2(反应器2)中;向旋转瓶中加入2.6kg丙酮,洗涤旋转瓶后转入PT1中,经管道过滤器用氮气压入PT2中;将反应釜内料液温度加热至40~50℃,将PT2中物料于1小时内滴加至反应釜中;将反应釜内物料温度控制在40~50℃,搅拌反应4小时;冷却,将反应釜内温度降至25-35℃;减压蒸馏,真空控制在≤-0.080MPa,反应釜内料液减压蒸馏至标定体积13.0L;冷却,将反应釜内料液温度降至15~25℃,并在该温度搅拌1小时;冷却,将反应釜内温度降至0-10℃;将反应釜内温度控制在0-10℃并搅拌1小时;抽滤,用丙酮(2.5kg)洗涤滤饼;取样分析,滤饼中式I化合物酒石酸盐HPLC纯度为99.98%;最大单杂:0.02%;将滤饼在45-55℃,真空≤-0.080MPa条件下烘干24小时;取样分析,丙酮残留≤5000ppm;冷却,烘箱温度降至15-25℃;烘干后共得到0.74kg产品,取样分析,产品式I化合物酒石酸盐HPLC显示纯度:99.95%;最大单杂:0.03%;溶剂残留合格。经进一步检测,产品为式I化合物酒石酸盐晶型O,其XRPD图谱与图38一致。
实验部分
实验例1溶解度测试
称取适量式I化合物晶型I、式I化合物磷酸盐晶型F和式I化合物酒石酸晶型O各4份,至4mL透明玻璃瓶中,分别加入1mL水、模拟胃液(SGF)、模拟禁食肠液(FaSSIF)和模拟进食肠液(FeSSIF),得到样品的混悬液并将其快速放入摇床(37℃,200rpm)中震荡,5分钟之后观察样品,适量补加样品或者介质来得到轻微的混悬液,再分别于30min、2h、4h和24h时间点取样,并用离心机12000rpm离心10分钟,取上清液,适当稀释之后进高效液相测试,色谱条件见表20。
表20溶解度测试的高效液相色谱条件
Figure PCTCN2020088122-appb-000033
Figure PCTCN2020088122-appb-000034
根据外标法计算样品浓度。测试结果如表21所示。
表21式I化合物晶型1、式I化合物磷酸盐晶型F和式I化合物酒石酸盐晶型O在水、SGF、FaSSIF和FeSSIF介质中不同时间点溶解度结果
Figure PCTCN2020088122-appb-000035
结果表明,式I化合物磷酸盐晶型F和式I化合物酒石酸盐晶型O可显著提高化合物在水、SGF、FaSSIF中的溶解度。式I化合物磷酸盐晶型F在水、SGF、FaSSIF、FeSSIF中24小时时间点的溶解度分别是式I化合物的27、10、60、1倍;式I化合物酒石酸盐晶型O在水、SGF、FaSSIF、FeSSIF中24小时时间点的溶解度分别是式I化合物的9、2、7、1倍。
实验例2稳定性测试1
分别称取约1mg式I化合物晶型1、式I化合物磷酸盐晶型F和式I化合物酒石酸盐晶型O样品,至20mL透明玻璃瓶中,各样品分别放置于加速条件(40℃/75%RH,敞口)和高温(60℃,密封)稳定箱中。敞口的样品,去瓶盖并用扎有针孔的铝箔纸盖住瓶口来避 免交叉污染;闭口的样品,加盖密封。分别于1周、2周时间点取样,用稀释剂(甲醇/水(1/1)(v/v))稀释后,按照表22的色谱条件进液相测试样品纯度。
表22固态稳定性测试的高效液相色谱条件
Figure PCTCN2020088122-appb-000036
根据面积归一化法计算样品纯度。测试结果如表23所示。
表23式I化合物晶型1、式I化合物磷酸盐晶型F和式I化合物酒石酸盐晶型O的短期固态稳定性结果
Figure PCTCN2020088122-appb-000037
结果显示,式I化合物晶型1、式I化合物磷酸盐晶型F和式I化合物酒石酸盐晶型O在2周内外观未发生改变,为类白色粉末,纯度无显著差异,没有明显的杂质增加,表明2周内的化学稳定性良好。XRPD和DSC检测(图45-50)显示式I化合物磷酸盐晶型F和式I化合物酒石酸盐晶型O两个样品的晶型和初熔点与0天对比无显著差异,表明式I化合物磷酸盐和酒石酸盐在高温(60℃)和加速(40℃/75%RH)条件下,2周内的物理稳定性良好。式I化合物晶型1在高温(60℃)和加速(40℃/75%RH)条件下晶型均发生改变,结合游离碱DVS前后表征结果,可知游离碱晶型的稳定性较差。
实验例3稳定性测试2
对式I化合物酒石酸盐晶型O以混悬液平衡法、加热-快速/缓慢冷却结晶法、反溶剂法和溶液挥发结晶法进行试验,考察其在不同溶剂及试验条件下是否会发生转晶,以进一步验证其热力学稳定性。
1.溶液缓慢挥发法(EVA)
称取5份,10mg/份,根据实施例55方法制备的式I化合物酒石酸盐晶型O样品,置于样品瓶中,分别加入适量四氢呋喃、乙醇、甲醇、丙酮和异丙醇(具体用量见表24),超声促使溶解,将所得溶液使用0.45μm尼龙滤膜过滤至新的样品瓶中,将样品瓶敞口放置于通风橱中,室温下(约20~25℃)自然挥发溶剂,收集析出的固体,经检测,5个试验中所得固体均为式I化合物酒石酸盐晶型O,它们的XRPD图谱分别与图38一致。
表24溶液缓慢挥发法实验条件及结果汇总
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
2.混悬液平衡法(Slurry)
称取18份适量的式I化合物酒石酸盐晶型O样品,分别加入一定量的四氢呋喃、乙醇、乙酸乙酯、正庚烷、甲苯、甲基叔丁基醚、异丙醇、甲醇、丙酮(具体用量见表25),以得到每种溶剂体系下的混悬液样品两份,分别将样品放置在室温和高温(50℃)条件下打浆。室温体系的样品瓶(用锡箔纸包裹避光)置于Labquaker旋转器上360°旋转;高温体系的样品放入50℃恒温培养摇床中打浆,分别在3天、7天和14天时取出部分混悬液样品离心处理,收集固体残渣,室温下(约20~25℃)挥发溶剂至干,收集固体,经检测,试验所得固体均为式I化合物酒石酸盐晶型O,它们的XRPD图谱分别与图38一致。
表25混悬液平衡法实验条件及结果汇总
Figure PCTCN2020088122-appb-000038
3.反溶剂法(Anti-solvent)
称取21份适量的式I化合物酒石酸盐晶型O样品,依次加入一定体积的表26中的良溶剂,超声促使溶解,将所得溶液使用0.45μm尼龙滤膜过滤至新的样品瓶中,磁力搅拌下依次向各样品瓶中缓慢滴加不同的反溶剂,将析出固体的溶剂体系离心处理并收集固体,室温下(约20~25℃)挥发溶剂至干;未析出固体的溶剂体系继续搅拌48小时,如果仍未析出固体,则敞口搅拌直至有固体析出。经检测,试验所得固体均为式I化合物酒石酸盐晶型O,它们的XRPD图谱分别与图38一致。
表26反溶剂法实验条件及结果汇总
Figure PCTCN2020088122-appb-000039
5.溶液加热-快速冷却法(HFC)
称取5份,约20mg/份式I化合物酒石酸盐晶型O样品置于样品瓶中,分别加入适量的四氢呋喃、丙酮、乙醇、异丙醇和甲醇(具体用量见表27),将样品瓶置于磁力加热搅拌器上,水浴温度约50℃、转速为200rpm下加热促进样品溶解。保温15min,趁热将各溶液用0.45μm滤膜过滤转移至新样品瓶中,将样品瓶立即放至-20℃冰箱中,过夜后将析出固体的溶剂体系离心收集固体,室温下(约20~25℃)挥发溶剂至干;未析出固体的溶剂体系继续放入-20℃冰箱中,直至有大量固体析出。其中四氢呋喃、丙酮体系中始终未析出固体, 乙醇、异丙醇和甲醇体系所得固体经检测均为式I化合物酒石酸盐晶型O,它们的XRPD图谱分别与图38一致。
表27溶液加热-快速冷却法实验条件及结果汇总
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
6.溶液加热-缓慢冷却法(HSC)
称取5份,约20mg/份式I化合物酒石酸盐晶型O样品置于样品瓶中,分别加入适量的四氢呋喃、丙酮、乙醇、异丙醇和甲醇(具体用量见表28),将样品瓶置于磁力加热搅拌器上,水浴温度约50℃、转速为200rpm下加热促进样品溶解。保温15min,趁热将各溶液用0.45μm滤膜过滤转移至新样品瓶中,并以6℃/h的速率缓慢降温至室温,过夜后将样品瓶放入冰箱冷藏(2-8℃),将析出固体的溶剂体系离心后收集固体,室温下(约20~25℃)挥发溶剂至干;未析出固体的溶剂体系继续放入-20℃冰箱中,直至有大量固体析出。其中四氢呋喃、丙酮、甲醇体系未得到固体,乙醇和异丙醇体系所得固体经检测均为式I化合物酒石酸盐晶型O,它们的XRPD图谱分别与图38一致。
表28溶液加热-快速冷却法实验条件及结果汇总
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
上述实验结果显示,使用包括混悬液平衡法、加热-快速/缓慢冷却结晶法、反溶剂法和溶液挥发结晶法的不同方法对式I化合物酒石酸盐晶型O进行处理,产物仍为单一晶型晶型O。式I化合物酒石酸盐晶型O为热力学稳定的优势晶型。
实验例4 TYK2生物化学测试
称取适量式I化合物进行TYK2生物化学测试。
测定由Reaction Biology Corp,Malvern,PA进行(Anastassiadis et al.Nat Biotechnol.2011;29(11):1039-45)。该步骤简要描述如下。
试剂:
基本反应缓冲液;20mM Hepes(pH 7.5),10mM MgCl 2,1mM EGTA,0.02%Brij35,0.02mg/ml BSA,0.1mM Na 3VO 4,2mM DTT,1%DMSO。分别向每个激酶反应添加所需的辅因子。
反应步骤:
1.在新制备的基本反应缓冲液中制备指定的底物;
2.将所需的辅因子送入上述基质溶液;
3.将指定的激酶送入底物溶液并轻轻混匀;
4.通过Acoustic技术(Echo550;纳升范围)将DMSO中的式I化合物送入激酶反应混合物中,在室温下培养20分钟;
5.向反应混合物中送入 33P-ATP(比活性10μCi/μl)以引发反应;
6.在室温下培养激酶反应2小时;
7.反应被点绘在P81离子交换纸上;
8.通过过滤结合法检测激酶活性。
测试结果表明,式I化合物也是很强的TYK2抑制剂,其IC 50小于10nM。
本领域技术人员可以理解,在本说明书的教导之下,可以对本发明做出一些修改或变化。这些修改和变化也应当在本发明权利要求所限定的范围之内。

Claims (77)

  1. 一种制备式I化合物的方法,该方法的合成路线如下:
    Figure PCTCN2020088122-appb-100001
    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。
  2. 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。
  3. 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。
  4. 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。
  5. 一种式I化合物晶型1
    Figure PCTCN2020088122-appb-100002
    其X射线粉末衍射图谱在2theta值为13.4°±0.2°、17.6°±0.2°、21.9°±0.2°处具有特征峰。
  6. 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。
  7. 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。
  8. 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。
  9. 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。
  10. 一种式I化合物盐酸盐晶型A
    Figure PCTCN2020088122-appb-100003
    其X射线粉末衍射图谱在2theta值为7.3°±0.2°、12.1°±0.2°、20.9°±0.2°处具有特征峰。
  11. 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。
  12. 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。
  13. 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。
  14. 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。
  15. 一种式I化合物盐酸盐晶型B
    Figure PCTCN2020088122-appb-100004
    其X射线粉末衍射图谱在2theta值为7.2°±0.2°、20.0°±0.2°、22.6°±0.2°处具有特征峰。
  16. 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。
  17. 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。
  18. 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。
  19. 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。
  20. 一种式I化合物盐酸盐晶型C
    Figure PCTCN2020088122-appb-100005
    其X射线粉末衍射图谱在2theta值为10.7°±0.2°、21.5°±0.2°、24.3°±0.2°处具有特征峰。
  21. 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。
  22. 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。
  23. 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。
  24. 一种式I化合物硫酸盐晶型D
    Figure PCTCN2020088122-appb-100006
    其X射线粉末衍射图谱在2theta值为6.0°±0.2°、22.8°±0.2°、25.2°±0.2°处具有特征峰。
  25. 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。
  26. 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。
  27. 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。
  28. 一种式I化合物磷酸盐晶型E
    Figure PCTCN2020088122-appb-100007
    其X射线粉末衍射图谱在2theta值为6.2°±0.2°、15.5°±0.2°、17.4°±0.2°、24.6°±0.2°处具有特征峰。
  29. 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。
  30. 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。
  31. 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。
  32. 一种式I化合物磷酸盐晶型F
    Figure PCTCN2020088122-appb-100008
    其X射线粉末衍射图谱在2theta值为16.6°±0.2°、17.2°±0.2°、22.6°±0.2°处具有特征峰。
  33. 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。
  34. 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。
  35. 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。
  36. 一种式I化合物甲磺酸盐晶型G
    Figure PCTCN2020088122-appb-100009
    其X射线粉末衍射图谱在2theta值为8.6°±0.2°、19.9°±0.2°、24.9°±0.2°处具有特征峰。
  37. 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。
  38. 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。
  39. 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。
  40. 一种式I化合物氢溴酸盐晶型H
    Figure PCTCN2020088122-appb-100010
    其X射线粉末衍射图谱在2theta值为7.2°±0.2°、20.7°±0.2°、24.0°±0.2°处具有特征峰。
  41. 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。
  42. 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。
  43. 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。
  44. 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。
  45. 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。
  46. 一种式I化合物氢溴酸盐晶型J
    Figure PCTCN2020088122-appb-100011
    其X射线粉末衍射图谱在2theta值为6.2°±0.2°、15.0°±0.2°处具有特征峰。
  47. 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。
  48. 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。
  49. 一种式I化合物氢溴酸盐晶型K
    Figure PCTCN2020088122-appb-100012
    其X射线粉末衍射图谱在2theta值为17.1°±0.2°、22.0°±0.2°、24.2°±0.2°处具有特征峰。
  50. 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。
  51. 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。
  52. 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。
  53. 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。
  54. 一种式I化合物富马酸盐晶型L
    Figure PCTCN2020088122-appb-100013
    其X射线粉末衍射图谱在2theta值为6.1°±0.2°、16.3°±0.2°、26.4°±0.2°处具有特征峰。
  55. 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。
  56. 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。
  57. 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。
  58. 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。
  59. 一种式I化合物苯磺酸盐晶型M
    Figure PCTCN2020088122-appb-100014
    其X射线粉末衍射图谱在2theta值为7.5°±0.2°、18.5°±0.2°、25.2°±0.2°、29.8°±0.2°处具有特征峰。
  60. 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。
  61. 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。
  62. 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。
  63. 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。
  64. 一种式I化合物柠檬酸盐晶型N
    Figure PCTCN2020088122-appb-100015
    其X射线粉末衍射图谱在2theta值为15.8°±0.2°、17.0°±0.2°、21.1°±0.2°处具有特征峰。
  65. 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。
  66. 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。
  67. 一种式I化合物酒石酸盐晶型O
    Figure PCTCN2020088122-appb-100016
    其X射线粉末衍射图谱在2theta值为6.3°±0.2°、26.1°±0.2°、26.9°±0.2°处具有特征峰。
  68. 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。
  69. 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。
  70. 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。
  71. 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。
  72. 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。
  73. 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。
  74. 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%。
  75. 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。
  76. 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。
  77. 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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